Diabetic Foot Ulcer - Treatment

Last updated on 6/5/24 | First published on 9/14/18 | Literature review current through Oct. 2024 [cite]

Authors: Elaine Horibe Song MD, PhD, MBA, Samantha Kuplicki MSN, APRN-CNS, AGCNS-BC, CWS, CWCN-AP, CRNFA, Scott A. Robinson MD, Alex K. Wong MD, FACS, Topic editors: Laura Shin DPM, PhD, more...

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ABSTRACT

Diabetic foot ulcer (DFU) is the leading cause of lower-extremity amputation and hospitalization.[1] Once lower extremity amputation due to diabetes has occurred, access to care and treatment seem ineffective in preventing death.[2] Mortality rate at 5 years post diabetes-related amputation has been described as high as 74%, worse than most cancers.[2][3]

For Introduction and Assessment of DFU: See "Diabetic Foot Ulcer - Introduction and Assessment"

Treatment summary

DFUs are best managed by a multidisciplinary team, and most can be treated with protocols tailored to non-ischemic/non-infected, infected, ischemic or infected/ ischemic DFUs, customized to each patient's needs. See summary of protocols in 'Initial management of diabetic foot ulcer based on classification' in this topic

Hospital admission: is indicated for diabetic foot ulcers (DFUs) involving deeper structures (e.g, tendon, ligaments, bone), with severe infection (or some cases of moderate infection) and/or with severe ischemia

Whether the patient is treated in the outpatient or inpatient setting, an adequate treatment plan for DFUs should aim to:

Treat the cause:
- For patients with an infected DFU: treat infection with debridement, topical antimicrobial agents and systemic antibiotics. Collect wound culture after debridement to guide definitive antibiotic therapy. Surgical interventions are needed for abscess, compartment syndrome or necrotizing fasciitis
- For patients with an ischemic DFU: aggressive cardiovascular risk management is recommended. Order vascular imaging studies if n oninvasive tests suggest ischemia (toe pressure < 30 mmHg or TcPO2 < 25 mmHg, if non-healing DFU with either an ankle pressure < 50 mmHg or ABI < 0.5). To see which patients benefit from non-urgent vascular imaging and revascularization, see topic "Diabetic Foot Ulcer Associated with Ischemia - Management".
- For all patients with DFU: mitigate/ eliminate any factors impeding healing, tight glycemic control, address nutritional deficiencies; eliminate pressure/ friction/ shear forces that trigger DFU (offloading, correction of foot deformities). Severe infection and/or ischemia should be addressed in conjunction with offloading devices.
Address patient's and caregiver's concerns
- Ensure patient has adequate supplies and help for dressing changes.
- Refer to behavioral medicine for depression and anxiety
- Discuss pain management for chronic issues
Provide effective local wound care: interventions for healable and non-healable/ maintenance DFUs are provided in this topic
- 1BInitial sharp debridement with callus removal (Grade 1B) and subsequent culture with validated method if infection is suspected. Serial debridements can be accomplished with a combination of debridement methods. Do not debride if circulation is severely impaired (dry gangrene). Obtain vascular imaging and consider revascularization prior to debridement

2CFor infected DFUs and non-healing ulcers, antimicrobial dressings are indicated (Grade 2C).
1CApply dressings that will manage excess exudate, protect periwound skin and maintain a moist wound bed, with the least amount of dressing changes possible (Grade 1C)

Plan reassessment: If a DFU with potential to heal does not decrease in area by 50% in 4 weeks despite adequate care, treatment plan should be reassessed, with re-evaluation of differential diagnoses and/or consideration for adjunctive and surgical therapies [4]

Adjunctive therapy:

1BHyperbaric oxygen therapy (HBO) is recommended for refractory DFUs classified as Wagner 3 or higher (Grade 1B). For HBO treatment protocol and transcutaneous oximetry algorithm see topics "Diabetic Foot Ulcer - Hyperbaric Oxygen Therapy" and "Transcutaneous Oximetry"
2CNegative pressure wound therapy may be used to promote healing of refractory DFUs or postoperative wounds, such as post-amputation wounds (Grade 2C). See topic "Negative Pressure Wound Therapy"
2CPhototherapy (low level light therapy) may be used as an adjunctive therapy for DFUs Wagner 1 or 2 (Grade 2C).
As for wound coverage, clinicians may opt for cellular and/or tissue products, skin grafts, flaps, free flaps to promote healing of refractory DFUs. Other interventions such as platelet-derived growth factor (becaplermin), and platelet-rich-plasma (PRP) may also be viable options. See topic "Cellular and/or Tissue Products".

Prevention: See topic "Diabetic Foot Ulcer - Prevention"

When to refer to specialists

Surgeon with experience in foot surgery: tissue loss, infection and palpable pulses, urgent surgical intervention for deep abscesses, compartment syndromes, and all necrotizing soft tissue infections.[5]
Vascular specialist: if PAD is suspected. Urgent referral if acute limb ischemia, manifested by six ‘Ps’ (onset<2 weeks): pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis. Critical limb ischemia (onset >2 weeks): ischemic rest pain, non healing wound/ulcers, or gangrene attributable to objectively proven arterial occlusive disease.[6]
Nutritionist at initial evaluation, orthotist for offloading, podiatrist for foot deformities, hyperbaric oxygen therapy specialist for Wagner 3 and above. Respective specialists if associated metabolic, hematologic, autoimmune, oncologic diseases are suspected.

ICD-10 Coding: See section on 'Coding' in "Diabetic Foot Ulcer - Introduction and Assessment"

Clinical guidelines and Quality Measures: see "Diabetic Foot Ulcer - Overview"

 Algorithm for Management of Diabetic Foot Ulcers

TREATMENT

Overview

This topic covers management of diabetic foot ulcers (DFUs). For more details on antibiotic therapy and management of diabetic foot ulcer (DFU) associated with infection, see topic "Diabetic Foot Ulcer Associated with infection - Management". For indications of surgical revascularization for patients with DFU associated with ischemia, see topic "Diabetic Foot Ulcer Associated with Ischemia - Revascularization" For clinical guidelines and quality measures specific to DFU, see "Diabetic Foot Ulcers - Overview". For an introduction and assessment of DFU including epidemiology, risk factors, etiology, pathophysiology, history, physical examination, diagnosis, differential diagnoses, documentation and ICD-10 coding, see "Diabetic Foot Ulcers - Introduction and Assessment". For prevention and a section for clinicians on patient education, see "Diabetic Foot Ulcers - Prevention".

DFUs are best managed by a multidisciplinary team, and most can be treated with protocols tailored to non-ischemic/non-infected, infected, ischemic or infected/ ischemic DFUs, customized to each patient's needs. A customized treatment plan is created with patient's input, based on a comprehensive assessment that:

Identifies risk factors for development of DFU, and complications such as lower extremity amputation, delayed healing, and infections
Differentiates from other types of lower extremity ulcers, which require different treatments
Categorizes DFUs as "neuropathic", "ischemic" or "neuroischemic".[7][8][9][10][11][12] Categorization helps determine most adequate treatment plan. For details, see 'Typical characteristics of DFUs according to etiology' in "Diabetic Foot Ulcers - Introduction and Assessment".
- Neuropathic: no signs of macrovascular ischemia (~35% of DFUs)
- Ischemic: signs of macrovascular ischemia but no signs of neuropathy (~15% of DFUs)
- Neuroischemic: with signs of ischemia and neuropathy (~ 50% of DFUs)
Assesses presence of infection (e.g., soft tissue, osteomyelitis)
Determines ulcer prognosis or "healability", that is, the potential of the ulcer to heal with conservative treatment only.[13][14] For details, see 'Ulcer healability' in "Diabetic Foot Ulcers - Introduction and Assessment":
- Healable: underlying cause of the ulcer can be treated, patient adheres to treatment and there are no factors that impede ability to heal
- Maintenance: ulcer has healing potential but patient or health system barriers compromise healing
- Non-healable: underlying cause cannot be treated conservatively, or blood supply to the wound is inadequate (e.g., critical limb ischemia), or co-factors that impede ulcer healing (e.g., terminal organ failure, ulcer is a malignant tumor). If cause or comorbidities impeding healing cannot be treated with a conservative approach but can be surgically treated, surgical consult/ referral is recommended. If patient is a poor surgical candidate, ulcer is treated as non-healable.
Determines if patient needs to be admitted to the hospital or can be treated in an outpatient setting.

An adequate treatment plan for DFUs aims to[13][14]:

Treat the cause and other factors impeding healing
Assess patient's and caregiver's concerns
Provide effective local wound care

If a healable DFU does not decrease in size by 50% in 4 weeks despite adequate treatment, treatment plan should be reassessed, differential diagnoses re-evaluated and adjunctive therapies considered.[15][16][17]

See Algorithm for Management of Diabetic Foot Ulcers (Algorithm 1)

Algorithm 1. Algorithm for Management of Diabetic Foot Ulcers (click link to enlarge)

Treatment goals

Healable DFU

In general, the goals for healable DFUs are to promote ulcer healing and prevent new or recurrent ulcers. Patient's concerns that may not be initially obvious need to be taken into account when creating a treatment or care plan.
Typically, for healable DFUs, at least 50% decrease in size in the first 4 weeks of treatment with standard care is expected, which is associated with complete ulcer healing by 12 weeks.[15][16]
If a DFU fails to show 50% decrease in size after 4 weeks of standard wound care, plan reassessment is recommended, with consideration for adjunctive treatment options.[17] Many adjunctive therapies are only covered by Medicare and other private insurers if DFUs fail to show evidence of healing with standard therapy for 4 weeks.[18] (See sections 'Plan Reassessment', 'Adjunctive Treatment' below)

Non-healable or maintenance DFU

For maintenance or non-healable DFUs, palliative wound care goals include prevention of ulcer progression, management of pain, bioburden, exudate. Patient's concerns and comfort should be prioritized when creating a treatment or care plan.

Management by ulcer classification

Classification of DFUs using one of the validated systems may help determine treatment. See 'Diabetic Foot Ulcer Infection and Classification Systems' in "Diabetic Foot Ulcer - Introduction and Assessment" Despite differences, classification systems allow clinicians to identify DFUs as "non-infected and non-ischemic", "infected", "ischemic" and "infected and ischemic", and help determine management approach. See Table 1 below. maybe add this in Intro topic under classification?

Table 1. DFU classification stages and suggested management approach

DFU Classification

Main DFU types by etiology

Manage DFU as...

Wagner: 1 and 2
UT: 1A, 2A, to 3A
WIfi: W1 to 3, I0, fi0

Neuropathic

Non-infected, nonischemic

Wagner: 3
UT: 1B, 2B, 3B
WIfi: W1 to 3, I0, fi 1 to 3

Neuropathic

Complicated with infection

Infected

Wagner: 4,5 (gangrene only)
UT: 1C, 2C, 3C
WIfi: W1 to 3, I1 to 3, fi0

Neuroischemic

Ischemic

Ischemic

Wagner: no adequate grade
UT: 1D, 2D, 3D
WIfi: W1 to 3, I1 to 3, fi1 to 3

Neuroischemic OR Ischemic

Complicated with infection

Combined infected and ischemic

Table 2 summarizes initial DFU management approaches, based on the latest clinical guidelines by the Society for Vascular Surgery (SVS), American Podiatric Medical Association, International Working Group on the Diabetic Foot (IWGDF), and Infectious Diseases Society of America (IDSA).[19][20]:

Table 2. Initial management of diabetic foot ulcer based on classification

DFU Classification

Treat the cause

Local Wound Care

Hospital Admission

Consults/ referrals

Non-infected, non-ischemic DFU

Wagner: 1 and 2
UT: 1A, 2A, to 3A
WIfi: W1 to 3, I0, fi0

Management of underlying conditions
Offloading: total contact casts (TCCs) and irremovable cast walkers have the highest offloading capacity, followed by removable walkers.

Comprehensive local wound care including wound debridement, control of edema and bioburden, wound moisture balance with appropriate dressings and periwound skin protection

DFU that involves ligaments, tendons, muscles or deeper structures may require debridement in the operating room

Nutritionist for glycemic and nutritional assessments,
Orthotist for offloading
Podiatrist for foot deformities

Infected DFU

Wagner: 3
UT: 1B, 2B, 3B
WIfi: W1 to 3, I0, fi 1 to 3

Treat the cause

Management of underlying conditions, control infection:
Osteomyelitis: confirm with probe-to-bone test and imaging exams
Infection: collect culture before antibiotics if possible. Type and duration of antibiotics depend on severity of infection and depth of the ulcer
Abscess, compartment syndrome and necrotizing fasciitis require urgent surgical intervention, which may include revascularization or amputation
Offloading: removable off-loading devices may be needed to better visualize the ulcer; total contact cast should be used with caution. Severe infection should be treated before use of offloading devices

(See sections 'Assessment: Diabetic Foot Infection' in "Diabetic Foot Ulcer - Introduction and Assessment" and 'For infected DFUs - Infection control' in this topic)

Local wound care

Comprehensive local wound care including wound debridement, control of edema and bioburden, wound moisture balance with appropriate dressings and periwound skin protection
IDSA/IWGDF recommend initial sharp debridement for all infected DFU

Hospital admission

The IDSA/IWGDF recommend initial hospital admission for all DFU patients with severe infection and for selected patients with moderate infection and complicating factors (e.g. PAD, lack of home support or lack of ability to comply with required outpatient treatment regimen)

Consults/referrals

Same as for non-infected, non-ischemic DFU
Infectious disease or clinical microbiology specialist
Surgeon who is familiar with foot anatomy.
Hyperbaric oxygen therapy specialist.
If lack of local resources, providers might consider telemedicine to ensure expert input on infected DFU management.

(See topic "Diabetic Foot Ulcer - Hyperbaric Oxygen Therapy)

Ischemic DFU

Wagner: 4,5 (gangrene only)
UT: 1C, 2C, 3C
WIfi: W1 to 3, I1 to 3, fi0

Treat the cause

Management of underlying conditions, ensure adequate vascular supply:
PAD severity should be assessed with vascular imaging studies if non-invasive tests suggest ischemia. For moderate or severe PAD,revascularization should be considered
Offloading: removable off-loading devices may be needed to better visualize the ulcer, total contact cast should be used with caution. Severe ischemia should be treated before use of offloading devices

(See section 'Diagnosis: Peripheral Artery Disease (PAD)' in "Diabetic Foot Ulcer - Introduction and Assessment" and section' “For Ischemic DFUs - Adequate Vascular Supply' in this topic)

Local wound care

Comprehensive local wound care including control of edema and bioburden, wound moisture balance with appropriate dressings and periwound skin protection
Debridement is relatively contraindicated in patients with PAD

Hospital admission

The IWGDF recommends urgent vascular imaging and revascularization for DFU patients with a toe pressure < 30 mmHg or the TcPO2 < 25 mmHg, and for patients with a non-healing DFU with either an ankle pressure < 50 mmHg or ABI < 0.5

Consults/referrals

Same as for non-infected, non-ischemic DFU
Vascular specialist, with urgency depending on severity of ischemia
Hyperbaric oxygen therapy specialist

(See topic "Diabetic Foot Ulcer - Hyperbaric Oxygen Therapy)

Combined infected and ischemic DFU

Wagner: no adequate grade
UT: 1D, 2D, 3D
WIfi: W1 to 3, I1 to 3, fi1 to 3

Treat the cause

Management of underlying conditions
At higher risk for non-healing and amputation. Emergency treatment required.[19][21] A well coordinated multidisciplinary team and all items listed separately for Infected DFU and Ischemic DFU above are needed.
Aggressive control of infection, timely and thorough debridement and/or other surgical procedure to treat infection (e.g, incision and drainage), with revascularization immediately after infection is controlled
If DFU does not respond promptly after interventions to treat infection (e.g. abscess drainage), revascularization should be strongly considered
In case of severe infection in the ischemic foot, especially in patients with systemic signs of sepsis (e.g. hemodynamic instability), immediate amputation may be the only option.[21]

Local wound care

Aggressive control of infection
If life-threatening infection (e.g. gas gangrene or necrotizing fasciitis) may need amputation. Severely ischemic limbs will require revascularization

Hospital admission

Indicated for patients with moderate/severe infection and PAD, or for patients unable to comply with requirements of outpatient treatment regimen

Consults/referrals

Same as for infected and ischemic DFU
Vascular surgeon should be involved early on to consider revascularization
Hyperbaric oxygen therapy specialist: if amputation is needed, level of amputation can be determined with transcutaneous oximetry. Hyperbaric oxygen therapy may be used to promote wound healing post amputation

(See topics "Transcutaneous Oximetry" and "Diabetic Foot Ulcer - Hyperbaric Oxygen Therapy)

Treat the cause and co-factors impeding healing

For all DFU patients (with healable, non-healable or maintenance DFU, DFUs associated with infection and/or ischemia):

Address factors that can affect wound healing, to promote healing of existing DFUs and to prevent new or recurring ulcers.
Control diabetes: optimal diabetic control should be achieved, aiming at HbA1c<7% with strategies to minimize hypoglycemia.[17] Other risk factors such as hypertension, smoking and hyperlipidemia should also be managed.
Correct nutritional deficiencies: besides impairing tissue regeneration, nutritional deficiencies can result in foot edema, which delays DFU healing [9][22]
Eliminate pressure/friction/shear forces that trigger DFUs: alleviate with offloading devices or surgical procedures, protect from physical trauma, correct foot deformities. For non-healable or maintenance DFU, clinicians may opt for implementing these interventions to the extent acceptable by patient and family

For patients with infected DFU:

Treat infection, control bioburden. See summary in section 'For infected DFUs - Infection control' below, or for more details on antibiotic therapy and management of infected DFUs, see topic "Diabetic Foot Ulcer Associated with Infection - Management".

For patients with ischemic DFU:

Address PAD to ensure adequate blood supply: for DFU considered non-healable with conservative approach due to severe ischemia, surgical treatment is critical to proper wound healing, regardless of other interventions.[23] See summary in section 'For Ischemic DFUs - Adequate Vascular Supply' below.
Provide aggressive cardiovascular risk management that includes smoking cessation, treatment of hypertension and hyperlipidemia with statin, low-dose aspirin or clopidogrel.[21]

Details and evidence on interventions to treat the causes are listed below:

Intensive glucose control

1BFor patients with DFU or at risk of DFU, we recommend intensive glucose control (HbA1c, 6%-7.5%) over less intensive glycemic control to reduce risk of lower extremity amputation, if this can be achieved without significant hypoglycemia (Grade 1B)
- Rationale: DFUs is caused by several factors, most notably peripheral neuropathy, PAD and changes in foot structures (See section 'Pathophysiology' in "Diabetic Foot Ulcer - Introduction and Assessment"). These factors have been associated with hyperglycemia and with the altered metabolic state of diabetes, hence the importance of glycemic control.[24] Interventions to control hyperglycemia include exercise (e.g. combined aerobic and resistance exercise) [25], behavioral modifications (e.g, frequent checking of glucose levels, interventions to increase adherence to medication) and diet (e.g, healthy eating programs, nutritional supplements).[24] Clinical guidelines [17][26][27] suggest intensive glucose control (HbA1c, 6%-7.5%) to promote DFU healing, despite the fact that to date, there has been no controlled randomized clinical trial that compared the effect of intensive glucose control with conventional glucose control on DFU healing.[24] However, there is moderate certainty evidence that compared with conventional glucose control, intensive glucose control is significantly more effective in decreasing risk of amputation in patients with DFU (evidence level B). [28] Lower extremity amputation is preceded by a DFU in 85% of the cases.[24] It is important to note however, that in a meta-analysis tight glycemic control was associated with a clear risk of serious hypoglycemia, which seemed to be greater when the HbA1c target was 6.0% (42 mmol/mol) rather than 6.5% (48 mmol/mol).[29][30] From a patient's perspective, given a choice, most patients with DFU would resist the behavioral change needed for intensive glucose control. Therefore, clinicians should strive to educate patients of the importance of intensive glucose control and ensure patients understand where and how to achieve it. In the U.S., Medicare covers many resources for intensive glucose control, for instance: nutritional counseling, HbA1 tests, home glucose monitoring devices and supplies, diabetes self-management program (10 hours of training). [31]

Nutrition

For all patients with DFU, clinical guidelines recommend nutritional assessment and nutritional support only if an individual is undernourished.[26][27]
- Rationale: To date, there is lack of evidence to recommend nutritional support for all patients with DFU regardless of nutritional status. Three randomized controlled trials evaluated nutritional supplementation in patients with DFU and analyzed different interventions applied on heterogeneous patient populations. Even obese individuals with adequate kilocalories intake can have inadequate intake of macronutrients and micronutrients.[32] The patient’s weight, prealbumin level (reflecting recent protein consumption), and serum albumin (reflecting long-term protein consumption) are useful in identifying patients who are outside the norms.[27] Clinicians should ensure patients have sufficient calories from a balanced diet of carbohydrates, fats, and protein, and supplementing protein, fluid, and vitamins A and C as needed. Deficiencies in arginine, glutamine, and zinc should also be considered, and supplemented if deficient.[33]
2BFor patients with uninfected DFUs, at risk of malnutrition and/or at risk of developing poor limb perfusion, clinicians might opt to administer an oral supplement enriched with arginine, glutamine, and ß-hydroxy-ß-methylbutyrate to promote healing of DFU (Grade 2B)
- Rationale: There is moderate certainty evidence that oral supplementation with arginine, glutamine, and ß-hydroxy-ß-methylbutyrate can aid in DFU healing in patients with uninfected DFUs (UT 1A), at risk of malnutrition (albumin level = 40 g/l) and/or at risk of developing poor limb perfusion (ankle–brachial index < 1.00).[34] Oral supplements are usually not covered by Medicare.

Offloading

Offloading is one of the cornerstones of DFU treatment and prevention.[35] Most treatments do not eliminate the underlying mechanism resulting in a DFU - abnormal pressure and shear stress are still present and long-term offloading is necessary.[27] For details on offloading devices, see topic "Offloading Devices".

Offloading may be achieved with devices or surgical procedures.
Several offloading devices exist. They can be roughly classified as:
- Non-removable (e.g., total contact cast, knee-high cast walker rendered non-removable, also known as instant total contact cast)
- Removable (e.g. removable walker, half-shoes)
- Other (e.g., crutches, wheelchair)
Offloading devices have different levels of offloading capacity, which directly correlates with their efficacy in healing or preventing DFUs.[35] Total contact casts (TCCs) (Figure 1) and irremovable cast walkers (also known as instant total contact or iTCC; Figure 2) have the highest offloading capacity, followed by removable walkers (Figure 2). [35][36] The application of TCCs require some training and may be time consuming in a busy clinic, however, they are the gold standard in offloading.

Figure 1. Total contact casts (TCCs). Left: one-piece, roll-on TCC; right: traditional TCC

Figure 2. Left: irremovable cast walker. Right: removable walker.

OFFLOADING DEVICES TO PROMOTE DFU HEALING

1B For patients with DFU, we recommend offloading to promote faster DFU healing (Grade 1B)
- Rationale: Offloading is one of the cornerstones in the management of DFU.[35] Guidelines are in agreement that offloading should be used to promote healing of DFUs. This strong recommendation is based on several RCTs of moderate certainty evidence (evidence level B).[37][17][26][27][38][39]
- Indications: Offloading should be part of the treatment plan of all DFUs - ischemic or nonischemic, infected or non-infected, plantar or non plantar - but for each case, a specific offloading modality may be more appropriate. For instance, management of ischemic or infected DFUs requires attention to many other factors. However, offloading in these complex cases may be even more important than in cases with no infection or ischemia, due to the increased risk of limb loss in these patients.[37] Non-removable offloading devices that impair frequent ulcer inspections should not be employed in complex cases as they impair visualization of the DFU on a daily basis.[15] Of note, it is recommended that for severely infected or ischemic DFU, infection or ischemia be resolved first before offloading is employed.[37]
- Adverse effects: Offloading may be accompanied by adverse effects, such as infection and maceration.[40] These side effects can be avoided by utilizing dressings that manage exudate and by increasing follow-up frequency for patients at higher risk of infection. If adverse effects develop, clinicians do not need to discontinue offloading, but may switch to a different offloading modality or adjust the offloading device in use.[40]
- Patient adherence: adherence to offloading has been reported to be low, as devices frequently limit mobility and require patients to change their routine.[37][40] It is important to understand if patients have the environmental and psychological support needed to deal with difficulties related to offloading, and involve patients in the decision process of the offloading strategy to increase their adherence to treatment.[40] Any offloading is better than no offloading.[15]
- As for costs: DFU treatment costs are directly related to length of treatment. Risk of infection increases when ulcers take longer to heal so efforts should be made to accelerate healing. Studies on offloading cost-effectiveness are scarce, but one study showed that patients treated with offloading devices incurred only half the costs compared with patients who did not use offloading devices.[35][41] Not all types of offloading devices for patients with DFU are a covered benefit by Medicare and major insurers.
- Checkpoint: The hallmark of an appropriately offloaded DFU is a noticeable lack of undermining at the edges of the ulcer at follow up.[23][42] Absence of calluses and/or bruising of the wound bed also indicate appropriate offloading.
1B To promote healing of non-infected, nonischemic plantar forefoot or midfoot DFUs, we recommend offloading with a non-removable knee-high offloading device such as total contact cast (TCC) or fixed ankle knee-high walking boot rendered non-removable (instant TCC or iTCC) (Grade 1B)
- Rationale: According to recent systematic reviews [43][40][44][45][46], non-removable offloading knee-high devices - both TCCs or iTCCs - are superior in promoting healing of non-complex DFU cases compared to other offloading modalities (Evidence level B), a finding that supports several clinical guidelines.[17][37][38] It has been shown that non-removable knee-high offloading devices can heal more DFUs in a shorter period of time (4 weeks) compared to a removable cast walker (6 weeks).[47][48] As devices are non-removable, patient adherence to treatment greatly increases. On the other hand, non-removable knee-high offloading devices make it difficult to inspect ulcers on a daily basis, reduce mobility, make iatrogenic lesions more difficult to detect, and can lead to muscle wasting due to prolonged immobilization. [40]
- Contraindications: Because the ulcer cannot be checked regularly, non-removable offloading devices are contraindicated in patients with mild infection associated with mild PAD, in patients with severely infected and/or severely ischemic DFUs or in patients with heavily exudative ulcers.[37] However, if a patient has either a mild PAD or a mild infection under control with antibiotics, this patient may still be a candidate for non-removable knee-high devices.[37]
- Patient adherence: Patients with DFUs seem to prefer TCCs over removable cast walkers (RCWs), largely because wound healing appears to be improved with total contact casting. However, cost, comfort, and convenience are concerns for patients.[36] Non-removable knee-high devices can also limit daily life activities, such as sleeping, bathing, driving, thus many patients may prefer not to use it. Because benefits clearly outweigh harms, clinicians need to educate patients and obtain their buy-in by having them be part of the decision process.
- Use of resources: Despite the fact that non-removable knee-high devices are considered the gold standard for offloading non-complex DFU, they are still vastly underutilized.[37] A study showed that in a large sample of patients in the U.S., only 6% of patients received it, and among those who received it, average cost of treatment was half the cost of those who did not.[41] Barriers to a more widespread use of non-removable knee-high devices include the need for specialized cast technicians who can apply TCCs, the relatively longer duration of the procedure to apply a TCC, and issues with Medicare reimbursement. Technically, Medicare covers TCCs and their application. Appropriate employment of debridement codes can help reduce TCC reimbursement issues.
- In order to overcome the potential lack of infrastructure, expertise, and/or personnel to apply TCC, the iTCC was created. iTCC (i.e. RWCs rendered non-removable) is as effective as TCC and does not require a specialized technician. However, the walker used for iTCCs are not covered by Medicare for this indication.[49]
2BFor patients with a plantar forefoot or midfoot DFU that requires frequent dressing changes (e.g., heavy exudate, uncontrolled mild infection, mild PAD) or for whom a non-removable knee-high device is contraindicated or non-tolerated, consider offloading with a removable knee-high cast walker (RCW) or an ankle-high offloading device as the second choice instead of a removable half-shoe to promote faster DFU healing (Grade 2B).
- Rationale: Although not as effective in healing DFUs, removable devices like a RCW have also become popular for offloading DFUs. [37] For patients who cannot use non-removable knee-high devices, evidence of moderate uncertainty (evidence level B) support use of RCW over half shoes.[44][47][38] RCW allows for easy foot inspection, functions as immediate offloading device and can be reused. These properties are useful in plantar DFU cases that require frequent ulcer inspections and local care, such as high level of exudate, mild infection that is not under control yet, mild PAD with some doubt regarding potential for wound healing, plantar DFU in which both a mild infection that is under control and a mild PAD with potential for healing are present. [37] The downside of the fact that RCWs are easily removable is the potential for patients not to use them constantly (decrease in patient adherence).[37][40] Clinicians may also prefer to use RCWs over non-removable devices, as application of RCWs does not require technical expertise. However, unlike TCCs, RWCs are not covered by Medicare [49] and the patient’s ability to afford a RWC needs to be taken into account.
2CFor patients with non-infected, nonischemic plantar forefoot or midfoot DFU who cannot tolerate TCC or RWC, or for patients with plantar DFU that requires frequent dressing changes (e.g., heavy exudate, uncontrolled mild infection, mild PAD) who cannot tolerate knee-high removable devices (RWC), consider offloading with removable offloading shoes (Cast shoe, half shoe or custom made footwear) to promote DFU healing (Grade 2C)
- Rationale: when a knee-high device is contraindicated or cannot be tolerated by the patient, removable offloading shoes may be an option. Although not as effective in promoting DFU healing compared to TCC or RWC, use of removable offloading shoes such as cast shoe (e.g., Scotch Cast boot, Ransart boot), half shoe or custom made footwear when the prior two are not an option are better than no offloading.[47] Effectiveness of removable shoes in DFU healing has been shown by many retrospective observational studies (Evidence level C) [50][51] and more controlled trials are needed to improve level of evidence. One advantage of removable offloading shoes is that they are removable, thus allowing regular inspection and redressing of the wound; at the same time, this is one of the disadvantages (i.e., enabling the patient's noncompliance). An alternative cast for the noncompliant patient would be a non-removable Scotch Cast boot. [42]
- Patients may prefer to use ankle-high offloading modalities over a knee-high device as they are more comfortable and do not limit activity as much. However, knee-high modalities have superior outcomes and should be preferred when no contraindications.[47] Among offloading shoes, patients might prefer comfortable cast shoe or custom-made temporary shoe over a half-shoe or forefoot offloading shoe, because the latter has a significant negative rocker outsole that may cause balance problems during gait.[37]
- The cost of treatment is relatively low for forefoot offloading shoes and cast shoes, both requiring no replacement during treatment. Medicare covers specific types of half shoes. Costs for custom-made temporary shoes are higher; cost-effectiveness has not been reported [37]

1C For plantar DFUs, we recommend against using using postoperative shoes, conventional or standard therapeutic shoes or customary footwear for offloading (Grade 1C)

- Rationale: Although shoes are among the most used offloading devices to treat DFUs in clinical practice [35], there are no studies that support their superior effectiveness in healing DFUs. In fact, a randomized controlled trial concluded that accommodative footwear proved inferior to TCC.[52] Thus, recent clinical guidelines are against use of conventional shoes to treat plantar DFU.[17][37][38] Physicians and patients’ preference may be skewed towards conventional footwear due to the fact that they are removable, easy to don and allow patient to walk more easily. However, harms (e.g. longer time to heal and consequent increased risk of infection) outweigh benefits and clinicians need to work with their patients to increase this understanding. Despite lower cost and Medicare coverage, these types of offloading devices are not expected to be cost-effective and should be avoided when treating plantar DFUs.[37]
2CFor non-plantar DFU without ischemia or un controlled infection, the IWGDF and the Society for Vascular Surgery (SVS) suggest clinicians use shoe modifications, temporary therapeutic footwear, toe spacers or orthoses as offloading devices to promote DFU healing (Grade 2C).[17][37]
- Rationale: Based on expert opinion, the IWGDF and the SVS are in favor of using these modalities to offload non-plantar DFUs.[38] The specific modality will vary according to location and patient’s and physician’s preference. Costs for these modalities are relatively low [37] and are mostly covered by Medicare.[53]
For severely infected or ischemic DFU, infection or ischemia should be resolved first before offloading is employed.[37]

OFFLOADING SURGICAL PROCEDURES TO PROMOTE DFU HEALING

2CFor patients with plantar forefoot DFU without ischemia or uncontrolled infection, that failed to heal despite adequate conservative standard therapy the IWGDF suggests the following surgical procedures to promote DFU healing (Grade 2C):
- Posterior tendon (Achilles) lengthening: for patients with equinus [54][55]
- Single or pan metatarsal head resection: for patients without digital gangrene and single forefoot ulcer (single metatarsal head resection) or with multiple plantar forefoot ulcers (pan metatarsal head resection). [56]
- Metatarsal-phalangeal joint arthroplasty in addition to TCC to heal sub-interphalangeal joint ulcers [37][57][58]
  Rationale: This suggestion is based on low certainty evidence (evidence level C).[37][54][55][56][57][58] While these procedures have been shown to decrease time to healing, and not significantly increase the number of ulcers healed, they can result in post-operative infection, problems with gait, and development of transfer ulcers at other sites. Thus, it is unclear if benefits outweigh potential harms. In cases in which patients have been treated with standard therapy (e.g, knee-high offloading devices) and the DFU has failed to heal, a surgical offloading approach might be beneficial. Costs of surgical offloading are generally higher than for other conservative offloading modalities. [37]
2CFor patients with distal toe DFU without ischemia or uncontrolled infection, that failed to heal despite adequate conservative standard therapy, the IWGDF suggests digital flexor tenotomy to promote DFU healing (Grade 2C).
- Rationale: This procedure can be performed in an outpatient setting, without need for subsequent immobilization, and is not likely to negatively affect foot function.[37]

Protection from physical trauma:

Most DFU are triggered by some degree of pressure and shear forces. Footwear should be examined for proper fit, wear and tear and presence of foreign bodies (sock, small stones, pet hair, pins, etc) that may traumatize the foot. Footwear worn at home and work also need to be inspected if possible.[23]

Correction of foot deformities:

Foot deformities and biomechanical impairments need to be addressed to avoid re-ulceration, prevent DFUs and subsequent amputations. Foot deformities include hammertoe, bunion, rocker bottom deformity, and Charcot arthropathy. Procedures to improve biomechanics include tendon release, transfer, tenotomy, bumpectomy, and others.[9]

For infected DFUs - Infection control

This section summarizes latest recommendations on management of infected DFU by the Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF). [20][19]For more details on management of infected DFUs, see topic "Diabetic Foot Ulcer Associated with Infection - Management".
Besides standard DFU care as described on this topic, management of healable infected DFUs includes debridement, topical antimicrobial agents, systemic antibiotics and surgical interventions. Debridement and removal of devitalized tissue reduce bacterial bioburden.[27] Wound culture, obtained right after debridement and before initiation of empiric antibiotic therapy, guides definitive antibiotic therapy. (See sections 'Diagnosis: Wound Cultures' and 'Diagnosis: Bone biopsy' in "Diabetic Foot Ulcer - Introduction and Assessment"). Surgical procedures are needed for deep abscess, compartment syndrome and virtually all necrotizing soft tissue infections. Osteomyelitis can be treated either primarily medically with antibiotics, or surgically.
Patients with infected DFUs with life-threatening infection (e.g. gas gangrene or necrotizing fasciitis) may need amputation.[21]
Patients with infected and ischemic DFUs are at particularly high risk for major limb amputation.[21]

ANTIMICROBIAL TOPICAL AGENTS

2C We suggest use of antimicrobial dressings (e.g., impregnated with medical-grade honey, silver, iodine, polyhexamethylene biguanide or PHMB) for clinically infected DFUs and for DFUs that fail to show progress in healing despite standard care (Grade 2C)
- Rationale: Clinical guidelines recommend against use of antimicrobial dressings to promote healing in the majority of cases with uninfected DFU.[27][17][20] Instead, topical antimicrobial agents are recommended for DFUs with high level of bacteria ( >10^5 CFU/g of tissue) post debridement [27] and for non-healing wounds.[23][59] Despite these recommendations, a recent meta-analysis [60] concluded that there is low-certainty evidence (evidence level C) that more DFUs - infected or not infected - may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing (relative risk 1.28; 95% confidence interval 1.12 to 1.45). It is not clear if a specific type of antimicrobial dressing is superior to another. However, clinicians should note that evidence is still of low certainty, and use of antimicrobials may result in local adverse effects (e.g., allergy, unknown effect on wound healing) and increased risk of bacterial resistance.[20][61] Furthermore, as it relates to coverage, topical antiseptics and topical antibiotics do not have a special coverage arrangement under the Medicare part B surgical dressing benefit.[62] Also, many antimicrobial impregnated dressings have similar HCPCS codes as their non-antimicrobial impregnated counterparts, even though they are more costly to manufacture. As a result, if an antimicrobial impregnated dressing is ordered for a Medicare part B covered patient, the DME supplier might substitute it for another lower cost product with similar HCPCS.[63] When paid out-of-pocket, antimicrobial impregnated dressings are typically more expensive than their non-antimicrobial impregnated counterparts.
- For patients with signs of DFU infection, topic and systemic antibiotic therapy should be initiated promptly.

SYSTEMIC ANTIBIOTICS

1CThe IDSA/IWGDF recommend against treating clinically uninfected wounds with antibiotics (Grade 1C)
- Rationale: In the absence of infection, no evidence has been found in the literature supporting use of antibiotics to promote DFU healing or prevent infection.[19][20][27][64][65]

1C For infected DFUs, we recommend clinicians obtain culture and start empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agents, and then implement definitive therapy based on the culture and sensitivity results, and the patient’s clinical response to the empiric regimen (Grade 1C)
- Rationale: Infected DFUs can turn into a limb and life-threatening condition, and must be treated promptly. The IDSA/IWGDF [19][20] and other clinical guidelines [17][27] recommend starting empiric antibiotic regimen after a specimen for culture is properly collected, and adjusting the regimen based on culture and sensitivity results and response to the initial course of antibiotics. Of note, antibiotic therapy alone is insufficient, unless combined with standard wound care (debridement, offloading, moisture balance). [20]
As for choice of specific antibiotic agents for empiric therapy, low certainty evidence shows that no one antibiotic treatment is superior to others in promoting infection resolution or in having fewer side effects (evidence level C). For guidance on antibiotic selection for infected DFU, see topic "Diabetic foot ulcer Associated with Infection - Management"

SURGICAL PROCEDURES FOR SOFT TISSUE INFECTIONS

1CFor most cases of deep abscess, compartment syndrome and virtually all necrotizing soft tissue infections, the IWGDF recommends urgent surgical intervention (Grade 1C).
- Surgical consult/referral is recommended. Interventions can range from minor debridement or drainage to extensive resections, revascularization or major amputation, and should be performed by a surgeon with thorough knowledge of anatomy of the foot and its compartments.[19]

MANAGEMENT OF OSTEOMYELITIS

2BFor patients with DFU and forefront osteomyelitis but no ischemia or necrotizing soft tissue infections, clinicians may opt to use either primarily surgical or primarily medical strategies to treat osteomyelitis (Grade 2B).
2CFor patients with DFUs and osteomyelitis in any foot location, with or without comorbidities, clinicians may also opt to use either primarily surgical or primarily medical strategies (Grade 2C).
- Both medical (i.e., antibiotics) and surgical approaches have advantages and disadvantages, and can be effective in treating osteomyelitis.[20][19][66][67] Selection between medical or surgical approach should be based on several factors such as patient condition and preference, mobility, comorbidities and others. For further guidance on selection of osteomyelitis management approach, see topic "Diabetic foot ulcer Associated with Infection - Management"

For Ischemic DFUs - Promote Adequate Vascular Supply

People with diabetes with a DFU, signs or symptoms of vascular disease, absent pulses on screening foot examination or older than 50 years old need a more objective vascular evaluation and consideration for a possible referral to a vascular specialist.[68] See section 'Peripheral Artery Disease (PAD) in patients with DFU' in "Diabetic Foot Ulcer - Introduction and Assessment"
For patients with ischemic DFUs (DFUs associated with PAD), to promote DFU healing and prevent amputation, clinical guidelines recommend revascularization with either surgical bypass or endovascular therapy.[17][21][27]

ischemic DFU

Which patients need urgent vascular imaging and surgical revascularization?

The vascular exam findings below indicate high risk for limb ischemia in patients with DFU, and thus DFU is considered non-healable with conservative therapy only. If one or more findings are present, patients should be considered for urgent vascular imaging and revascularization [69][21][70][71]:

ABI <0.5*
Continuous doppler wave ultrasound with monophasic flow
Toe pressure < 30 mmHg
TcPO2 < 25 mmHg

* Medial arterial calcification and non-compressive vessels may result in falsely elevated ABI in patients with diabetic neuropathy [69][68][72]. Thus, regardless of ABI values, to rule out PAD these patients should undergo TcPO2, continuous wave Doppler examination or TP/TBI.[69][21][73]

For patients with DFU and PAD with exam findings different from the ones above, prediction of patients most likely to require and to benefit from revascularization can be based on the Society for Vascular Surgery (SVS) Wound, Ischemia, and foot Infection (WIfI) lower extremity threatened limb classification. See topic "Diabetic Foot Ulcer Associated with Ischemia - Revascularization"
For all patients with DFU and PAD, irrespective of the results of bedside tests: if the ulcer does not improve within 6 weeks despite optimal management and have no other likely cause of poor wound healing, the IWGDF recommends vascular imaging and revascularization. PAD is not the only cause of reduced perfusion in a lower extremity; edema and infection should be ruled out and treated accordingly.[21][70][71]
For patients with DFU and PAD for whom, from the patient perspective, the risk-benefit ratio for the probability of success is unfavorable, the IWGDF recommends clinicians avoid revascularization.[21] Some examples are patients who:
- Are severely frail
- Have a short life expectancy
- Have poor functional status or are bed bound
- Have a large volume of tissue necrosis that renders the foot functionally unsalvageable
For patients with DFU and PAD for whom, from the patient perspective, the risk-benefit ratio for the probability of success is unclear, revascularization may be inappropriate. In clinical decision-making, it should be taken into account that even severely ischemic ulcers can heal without a revascularization; as noted, two observational studies reported healing rates of about 50% (with or without minor amputations).[21][74][75]

ischemic and infected DFU

Patients with ischemic and infected DFUs are at particularly high risk for major limb amputation.
- If infection is severe, patient should be treated as a medical emergency with immediate drainage, debridement, culture, antibiotics and consideration for revascularization.[21]
- If infection is non-limb-threatening, the blood supply to the foot should be optimized before surgical debridement to ensure that potentially viable tissue is not unnecessarily removed.[21]

Address Patient's Concerns

For all patients (with healable, non-healable or maintenance DFU), concerns should be addressed and plan of care adjusted accordingly, aiming to increase patient adherence.[59] Addressing patient's concerns is important, as successful treatment of DFUs largely depends on patient adherence to plan of care (e.g., adequate use of offloading devices). If patients have concerns, adherence to plan of care may be compromised, which will affect outcomes.

Chronic diseases such as diabetes are best managed when centered around self-management and patient engagement. Self-management is ‘‘the systematic provision of education and supportive interventions to patients by healthcare staff, to increase patients’ skills and confidence in managing their health problems, including regular assessment of progress and problems, goal setting, and problem-solving support.’’[59] Thus, patient and caregiver/family education takes a central role in DFU management and prevention. add link to pat ed
Depression and anxiety are very common among patients with DFUs, affecting up to 40% of patients.[76] Depression adversely affects potential for wound healing [77] thus, referral/consult for psychological support and therapies is recommended. Individuals with diabetes who received psychological therapies demonstrated significant improvement in A1c and reduction of psychological distress including depression and anxiety.[59]
Pain is usually underestimated when treating patients with DFU.[78] However, patients with painful DFUs have poorer health-related quality of life when compared to those who do not report pain.[79]

Pain control

1CIt is recommended that clinicians manage pain by administering analgesics and addressing the underlying causes of pain (Grade 1C)
- Rationale: Despite having loss of protective sensation (LOPS), DFU patients can feel pain of neuropathic or nociceptive characteristics. Pain is also associated with ischemia or infection.[9][80] Manifestations of pain also include depression, anxiety and sleep disturbance.[26] As such, the Wound, Ostomy and Continence Nurses Society recommends that pain management strategies include utilization of a multidisciplinary team for pain management, and pharmacological interventions which may improve quality of life.[26] Trauma and wound-related pain during dressing changes can be minimized with use of low, non-adherent or soft silicone dressings and avoidance of unnecessary manipulation of the wound.[23]
- Analgesics: Clinicians might opt to follow the World Health Organization (WHO) Pain Ladder for cancer patients, with modifications for wound care. Benefits and harms of each step should be considered. In summary[81]:
- - Step 1: A non-opioid analgesic (e.g., NSAID) with or without an analgesic adjuvant. Adjuvants include tricyclic antidepressants, anticonvulsants, antihistamines, benzodiazepines, steroids, and phenothiazines.
  - Step 2: If pain is not controlled: Continue the initial medication and add an opioid, such as codeine or tramadol, and an adjuvant
  - Step 3: If pain is not controlled: discontinue second step medications and initiate a more potent oral narcotic

Lifestyle modifications

Family and caregivers may underestimate potential complications of a non-treated DFU (e.g. amputation, infection) and might expect the patient to carry on with work and daily activities normally. Offloading, glycemic control, and other interventions needed to treat the DFU need to be included into the patient's and family's routine.

Local wound care

For all patients (healable, non-healable, maintenance), appropriate local wound care should be implemented. Table 3 summarizes local wound care interventions for healable and non-healable/maintenance DFU.[13][14] Evidence and recommendation for each intervention are listed after the table. For customized, wound-specific recommendations, use Wound Prep and Dress Tool.

Table 3. Local wound care for diabetic foot ulcers

	Healable	Non-healable/ maintenance
Cleansing	Gently cleanse with normal saline, sterile water or commercial wound cleanser. Irrigate wound with > 100 mL of room/body temperature solution at low pressure (4-15 psi)	Keep wound bed dry
Debridement	Topical anesthetics such as lidocaine-prilocaine cream if needed to reduce debridement pain. Initial sharp debridement of all devitalized tissue and callus. Subsequent debridement may be mechanical, autolytic, enzymatic, surgical or combination of methods Urgent surgical intervention for foot infections involving abscess, gas, or necrotizing fasciitis	Conservative debridement of nonviable tissue only. Do not debride if circulation is severely impaired (dry gangrene). Obtain vascular imaging and consider revascularization prior to debridement
Infection and bioburden control	Use antimicrobial dressings only in cases of clinical infection or if no healing is seen despite appropriate care Antimicrobial dressings. (with cadexomer iodine, silver, etc): For light exudate: hydrogel or hydrogel colloidal sheet-based For moderate, heavy exudate: alginate, hydrofiber, super absorbent If clinical infection, collect wound culture, initiate empiric antibiotic therapy and adjust based on culture results Surgical referral needed for abscess, compartment syndrome, necrotizing fasciitis	If minimal or light exudate, consider antiseptic solution (e.g. povidone iodine, chlorhexidine) If signs of clinical infection, and moderate or heavy exudate, consider non-adherent antimicrobial dressings (with cadexomer iodine, silver, etc): If signs of clinical infection, collect culture prescribe empiric antibiotics, then adjust according to culture results If life-threatening infection (e.g. gas gangrene or necrotizing fasciitis) may need amputation. Severely ischemic limbs will require revascularization
Peri-wound skin care	If excessive exudate: use zinc-based barrier to protect periwound If xerosis (dry skin) use emollient on the feet for skin hydration
Moisture balance	Fill deep wounds to avoid dead space. Maintain wound moisture with: Hydrocolloid, hydrogel, foam dressings Manage exudate with: alginate, fiber gelling dressing (hydrofiber), foam dressings, composite, specialty absorptive	Apply appropriate non-adherent dressing OR If minimal or light exudate: paint wound with antiseptics (e.g. povidone iodine) If dry or wet gangrene: moisture retentive dressing may cause limb threatening infection Avoid conventional dressing products that require daily dressing changes

Cleansing

2CWe suggest that healable non-infected DFU be cleansed with a neutral, non-irritating, non-toxic, non-antimicrobial solution such as sterile saline or water initially and at each dressing change, and that routine wound cleansing be accomplished with a minimum of chemical and/or mechanical trauma (4-15psi or pressure) (Grade 2C).
- Rationale: Although there is minimal evidence that routine cleansers can result in improvement of DFU and Medicare part B does not cover wound cleansers, DFU frequently have debris in and around the wound area, which must be cleansed before debridement or dressing application.[19][27][82]

Debridement

1BTo promote DFU healing, we recommend debridement over no debridement of devitalized tissue and surrounding callus for healable DFUs at initial assessment and for maintenance, at intervals dependent on the production rate of exudate and devitalized tissue (usually 1-4 weeks) (Grade 1B)
- Rationale: Professional opinion is united in support of the use of debridement aids in wound healing, despite moderate certainty evidence that it encourages healing.[17] Debridement of DFU has many benefits: it enables visualization of the true dimensions of the ulcer, allows drainage of exudate and removal of dead tissue (which renders infection less likely), and enables collection of adequate culture samples. Removal of surrounding callus reduces pressure load on the wound.[17][83][84] Furthermore, Medicare part B will only cover surgical dressings for ulcers that have been debrided or surgically created.[62] Adequate debridement requires debridement of callus, wound bed necrotic tissue and ulcer's edge undermining. [85]
For non-healable or maintenance wounds, expert opinion suggests against active aggressive debridement. [59] Aggressive debridement without adequate blood supply and immune defense may increase risk of infection (especially if the wound bed is excessively moist) and increase size of a wound that is already difficult to heal. Instead, these wounds should be kept dry, and necrotic tissue may be carefully removed.
2CAs for debridement techniques for healable DFUs, given the lack of sufficient evidence for superiority of any specific method, we suggest initial sharp debridement, followed by debridement method(s) that encourage patient adherence to the care plan (Grade 2C)
- Rationale: When choosing debridement methods, it is important that clinicians take into account relative contraindications such as severe ischemia, clinical context, availability of expertise and supplies, patient tolerance and preference, cost-effectiveness, professional licensing restrictions and insurance coverage. Systematic reviews and meta-analyses [83][84][86] found that studies comparing different methods of debridement provide only low quality evidence due to methodological limitations. Therefore, choice of debridement method should be at the clinician’s and patient’s discretion. The chosen method should encourage patient compliance with the overall care plan. [17]
- Debridement methods are described below:
- Conservative sharp debridement with curette,scissors, scalpel, and forceps: considered “gold standard”[23] for DFU patients with superficial ulcers, without severe PAD (relative contraindication), who are not on active anticoagulant therapy, and are not surgical candidates. Despite there being only one article that provides low quality evidence on sharp debridement to promote DFU healing [85][87], it is the preferred method by several guidelines, as it is selective and fast.[17][20][27][87] It must be performed by trained, licensed healthcare practitioners (not necessarily a physician or qualified non-physician practitioner), and it is often performed at bedside or in a procedure room. The patient should be forewarned that bleeding is likely and that the wound will appear larger after the procedure, when its full extent is exposed.[20] This method does not have the extra risks associated with general/regional anesthesia and costs of surgical facilities. It is less aggressive than surgical debridement and is fast, but may also be imprecise and may carry the greatest risk of tissue damage of any of the debridement methods.[88]
- Surgical debridement: urgent surgical debridement is indicated for patients with infected DFU with gas, abscess or necrotizing fasciitis. [20] It is also indicated for patients with deeper DFUs, with large necrotic areas or associated cellulitis/ osteomyelitis, but without severe PAD, significant clotting disorders, active anticoagulant therapy, or other contraindications for general/regional anesthesia. Surgical debridement is rapid and highly selective, but is resource intensive (needs operating room and personnel; in the U.S., must be performed by a physician or qualified non-physician practitioner), may cause excessive bleeding, transient bacteremia, damage to tendons and nerves, and add risks associated with general/regional anesthesia if anesthesia is needed. Of note, in patients with a non-limb-threatening infection and signs of PAD, the blood supply to the foot should be optimized before surgical debridement to ensure that potentially viable tissue is not unnecessarily removed.[21]
- Enzymatic debridement: for patients who cannot tolerate sharp or surgical debridement or if resources are not available. Collagenase may be applied on non-infected DFUs at a thickness of ~2mm daily and covered with a non-adherent dressing. [89] An industry-sponsored study compared DFU healing progress over 6 weeks between collagenase and silver containing products and found that both were equivalent in both DFU size reduction and infection rates.[90] Collagenase should not be used with products that inhibit its activity, including certain silver products. See interactive topic "Products that inhibit collagenase enzymatic activity"
- Autolytic debridement (e.g., hydrogels, hydrocolloid): indicated for patients with no signs or no potential for infection (e.g, ischemia of the limb or digit), and when sharp or surgical debridement is not available or not an option.[23] Low quality evidence supports use of hydrogels compared with gauze to promote wound healing. [84] Autolytic debridement is done by occluding the wound with a dressing that traps exudate in the wound, allowing endogenous proteolytic enzymes produced by macrophages present in exudate to selectively liquefy necrotic tissue.[91] This method is slow and needs exudate but it is highly selective, painless and requires only minimal clinical training.[61] Moisture-donating dressing can predispose to maceration. Moisture-retentive dressings are not recommended for patients with ischemia and/or dry gangrene.[23]
- Biological debridement (e.g, maggots): indicated for DFU patients with no personal bias against maggots, when sharp or surgical debridement is not available or not an option.[19] The exact mechanism of maggot biotherapy is not yet known, but it appears to be useful for carefully selected necrotic and infected wounds.[20] Larval therapy is not recommended as the sole method of debridement for neuropathic DFUs as the larvae cannot remove callus.[23][92] Low quality evidence showed that larval debridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not result in higher complete healing (RR, 1.27; 95% CI, 0.84-1.91). No significant difference in wound healing was found between autolytic debridement and larval debridement. [84]
- High pressure jet debridement: for DFU patients with same indication and contraindications as sharp debridement, when sharp/surgical debridement or other forms of debridement are not available. This method forces water or saline into a nozzle to create a high-energy cutting beam, which enables precise visualization and removal of devitalized tissue in the wound bed. [23][93] Low-quality evidence showed that hydrosurgical debridement had similar wound healing outcomes to standard surgical debridement. [84] Cost of the device may be a constraint.
- Low-frequency ultrasonic debridement (LFUD): for DFU patients with same indication and contraindications as sharp debridement. LFUD generates sound waves ranging from 20 to 40 kHz (undetectable to human hearing), delivered to the ulcer through a liquid medium such as normal saline. LFUD is thought to increase in cellular activity and promote ulcer healing. A systematic review with 2 RCTs found no difference in healing outcomes between non surgical sharp debridement and low frequency ultrasonic debridement of DFUs (RR = 0.92; 95% CI = 0.76-1.11).[86] Cost of device may limit its utilization.

Infection and bioburden control

For a summary of latest recommendations on management of infected DFU by the Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF), see section 'For infected DFUs - Infection control' in this topic.[19][20] For more details on management of infected DFUs, see topic "Diabetic Foot Ulcer Associated with Infection - Management".
For healable DFUs, interventions to manage infection include debridement, topical antimicrobial agents, systemic antibiotics and surgical procedures:
- If no signs of infection, clinical guidelines suggest against use of antimicrobial dressings.[27] Instead, topical antimicrobial agents are recommended for DFUs with high level of bacteria ( >10^5 CFU/g of tissue) post debridement [27] and for non-healing wounds.[23][59]
- If no signs of infection but no signs of epithelialization within 2 weeks from debridement, culture of material collected after debridement, with tissue biopsy or validated swab technique culture is recommended.[27]
- If mildly infected, or non-healing DFU, expert consensus [23][94][94] recommends an initial two-week period of antimicrobial dressings with regular inspections (e.g., daily). After 2 weeks:
- - If there is improvement in the wound, but signs of infection are still present: clinicians may opt to continue with the initial antimicrobial dressing, with further regular reviews
  - If both the wound and infection have improved: antimicrobial should be discontinued and a non-antimicrobial dressing applied
  - If there is no improvement: clinicians can opt to discontinue antimicrobial treatment and re-culture the wound, and review need for surgical therapy (e.g, revascularization).
For non-healable/maintenance DFU, keeping the ulcer dry, using topical antiseptic agents (e.g., povidone iodine or chlorhexidine), and systemic antibiotics if systemic signs of infection are usually appropriate.[59] A nonviable limb with a potentially life-threatening infection (e.g. gas gangrene or necrotizing fasciitis) may need amputation. Severely ischemic limbs will require revascularization.[21]

Peri-wound Care

xerosis (dry skin)

2BFor diabetic patients with xerosis (dry skin), we suggest application of an emollient on the feet to improve skin hydration (Grade 2B)
- Rationale: Xerosis, hyperkeratosis, and fissures are mild complications resulting from peripheral neuronal impairment in patients with diabetic foot, xerosis being the most common complication related to diabetes mellitus. These complications are risk factors for infections and ulcers 3 Randomized controlled trials (RCTs) comparing moisturizers with a “sham” base cream [95][96][97] have shown that topical emollients are of benefit in managing xerosis and improving skin condition (moderate certainty evidence, level B due to risk of bias). Many active ingredients can be used, and the most common are urea and ammonium lactate. A systematic review of studies comparing different kinds of ingredients could not conclude if a specific type is superior.[98] Skin protectants are however, not covered by Medicare and most insurance plans, so cost is an important factor to be considered.

Moisture management and dressing selection

Selection of primary and secondary dressings should follow established wound bed preparation principles. [14][13][99] For customized, wound-specific recommendations, use Wound Prep and Dress Tool. For practical information on dressing indications, contraindications, application, Medicare coverage and brands see "Dressing Essentials" and "Dressing Brands Quick Reference". General recommendations and evidence regarding dressings for DFUs are listed below.

1BFor non-infected healable DFUs, we recommend clinicians apply a topical dressing that will manage excess exudate, protect periwound skin and maintain a moist wound bed, with the least amount of dressing changes possible (Grade 1C)
- Rationale: Excess exudate should be contained by absorptive dressings, as it can result in periwound maceration, enlarge the wound and impede healing.[17] It has been shown that chronic wound exudate has high concentrations of proteases and inflammatory cytokines that prohibit wound healing and may damage the fragile periwound skin.[100][101][102] It is important to achieve moisture balance for adequate wound healing.[17][20][27] Several experimental studies support the hypothesis that a moist wound bed increases wound healing when compared to a dry wound bed, by facilitating cell migration and matrix formation.[103][104] Of note, wet-to-dry dressings are not considered continuously moist [17] and require frequent dressing changes, which increases cost of care. Caution is required with the use of occlusive moisture retaining dressings (i.e., films, hydrocolloids, acrylates), especially if infection is suspected. DFU patients may be immunosuppressed and clinically unsuspected infection can exacerbate if occlusive dressings are applied.[9] To make a cost-effective choice, clinicians should consider dressings that have good absorptive capacity and at the same time can keep the wound bed moist.
For infected DFUs, regular inspection and assessment are needed due to the potential quick changes of the DFU status. In such cases, it is not appropriate to use dressings designed to be left in situ for more than five days and frequent daily inspections are preferred until infection is controlled.[23]
For non-healable/maintenance DFUs, if minimal or no exudate, a topical antiseptic may be used. If exudate management is needed, non-adherent dressings may be applied.
2C For healable DFUs, taking into consideration Medicare coverage, costs and wound characteristics, we suggest clinicians initiate treatment with one of the primary dressings below, along with debridement and offloading (Grade 2C)
- - For full-thickness wounds with high or heavy exudate: composite, specialty absorptive, alginate, fiber gelling dressing (hydrofiber)
  - For full-thickness wounds with moderate levels of exudate: composite dressings, specialty absorptive, foam dressings
  - For wounds with light levels of exudate: non-adherent dressing, hydrocolloid
  - For wounds with minimal levels of exudate: non-adherent dressings, film or hydrogel
  - For infected wounds: antimicrobial dressings.
  - For DFU patients with pain at dressing changes or with LOPS, who are at higher risk of trauma at dressing change: low or non-adherent dressings. [23]
- Rationale: Current evidence, highlighted by several systematic reviews and meta-analyses, suggests that no dressing type is superior to another in promoting DFU healing.[105][106][107][108][109][110][60][111][111] However, evidence is of low certainty (evidence level C) due to unclear or high risk of bias of the studies included in the meta-analyses. A few studies have reported some degree of difference in effectiveness when two different types of dressings were compared with each other. Low quality evidence (evidence level C) suggests that hydrogel dressing is more effective than basic wound contact dressing [106][107][111], and that antimicrobial dressings are more effective than non-antimicrobial in healing DFU.[60] However, authors of these reviews and of main clinical guidelines concluded that due to the uncertainty of the quality of these studies, these findings alone do not justify a change in practice. Any potential change would need to be supported by clinical experience and other factors, such as costs, wound characteristics, ease of use, patient’s and provider’s preference.[17][20][26][27]
- Use of resources: With respect to cost, it is important that clinicians consider not only the cost of dressings when selecting dressings, but also cost of other resources needed to utilize each type of dressing. A cheaper dressing that requires multiple dressing changes by clinicians will result in higher total costs compared to a more expensive dressing that requires less frequent dressing changes or does not require trained personnel for application.[17][9][27] As for cost-effectiveness, a few small or manufacturer-sponsored studies [112][113][91] suggest that specific dressings are more cost-effective than others, however these studies are of low certainty evidence and thus not sufficient to justify a change in practice.
- Wound characteristics: characteristics such as wound bed, depth, exudate should be considered when choosing dressings for DFUs. Consideration should be made to change a product if a DFU does not show signs of improvement after a couple of weeks. Adverse effects such as maceration, infection, or further loss of tissue should prompt a change in wound dressing as well.[17] When selecting dressings for DFUs, increased susceptibility to infection due to decreased immune response should be taken into account.[9] Hydrogels and occlusive dressings such as hydrocolloids can exacerbate clinically unsuspected (occult) infection. Poor hygiene also contributes to increasing infection rates.[114]. For customized, wound-specific recommendations, use Wound Prep and Dress Tool. For practical information on dressing indications, contraindications, application, Medicare coverage and brands see "Dressing Essentials" and "Dressing Brands Quick Reference"

Practice Tips - Dressing Changes and Application [23]

Do's

For infected or highly exudative DFUs: consider inspecting ulcer and changing dressings daily, and then every two or three days once the infection is stable. A different type of dressing may be needed as the status of the wound changes.
Patients with non-infected DFUs who prefer to change the dressing themselves need to be instructed on the use of aseptic technique, and on recognition of signs of deterioration, such as increased pain, swelling, odor, purulence or septic symptoms. Their DFUs should be reviewed at regular intervals by a healthcare professional.
Use appropriate techniques (e.g., avoid creasing the dressing or making it too bulky) and take care when dressing weight-bearing areas
Ensure wound dead space is eliminated (e.g. use a dressing that conforms to the contours of the wound bed)
Remember that footwear needs to accommodate any dressing.

Dont's

Avoid bandaging over toes as this may cause a tourniquet effect (instead, layer gauze over the toes and secure with a bandage from the metatarsal heads to a suitable point on foot)
Avoid strong adhesive tapes on fragile skin
Avoid tight bandaging at the fifth toe and the fifth metatarsal head (trim the bandage back)

Plan Reassessment

Healable DFUs that fail to reach a 50% decrease in size after 4 weeks of treatment with standard therapy should be reassessed.[17][27] (For details on standard therapy, see sections 'Treat the Cause', 'Address Patient's Concerns' and 'Local Wound Care' above). Re-evaluation of the patient and ulcer should be performed before use of adjuvant therapies.[17][27] Re-evaluation should include assessment of adequate offloading, any ongoing soft tissue infection or osteomyelitis, need for debridement, excessive exudate, impaired extremity vascular flow, uncontrolled glycemia and malnourishment. Differential diagnosis should be considered as well. A checklist such as the one shown in Table 4 can be useful in reassessing plan of care:

Table 4. Checklist for reassessment of DFU treatment plan

Check differential diagnoses

Wound biopsy: consider obtaining a biopsy of a recalcitrant or atypical wound, as a lesion that appears to be a DFU may on occasion be a malignant lesion (eg, melanoma or Kaposi sarcoma) [20] See section 'Differential Diagnosis' in "Diabetic Foot Ulcer - Introduction and Assessment"

For all healable DFUs: is the cause being adequately addressed?

Check for adequate glycemic control and nutritional intake
Check for any co-factors that may be impeding healing (e.g., medications, smoking, immunosuppression, etc). See 'Ulcer healability' in "Diabetic Foot Ulcer - Introduction and Assessment".
Check for adequate pressure redistribution and offloading
- The hallmark of an appropriately offloaded DFU is a noticeable lack of undermining at the edges of the ulcer at follow up. [23][42]
- Is the patient adherent to the chosen offloading modality? Has there been any physical trauma to the foot? Are foot deformities present?
Check for soft tissue infection and/or osteomyelitis
- For assessment and diagnosis of infected DFU, see section 'Assessment: Diabetic Foot Infection' in "Diabetic Foot Ulcer - Introduction and Assessment"
Check for adequate vascular supply to the ulcer
- For assessment and diagnosis of PAD, see section 'Diagnosis: Peripheral Artery Disease (PAD)' in "Diabetic Foot Ulcer - Introduction and Assessment"

For all healable DFUs: is local wound care adequate?

Debridement: Ensure adequate removal of devitalized tissue and surrounding callus (See section 'Debridement' above)
Dressings: Aim is to manage excess exudate, protect periwound skin and maintain a moist wound bed, with the least amount of dressing changes possible (See section 'Moisture management and dressing selection' above)

For all healable DFUs: are patient's concerns addressed?

If patient is not adherent to treatment plan, what are the factors that prevent patient from adherence?

For healable infected DFUs: assess the following factors[20]

Is there unidentified or untreated limb ischemia?
Is there unidentified necrotic soft tissue or bone?
Is there an undrained abscess?
Has the wound been adequately debrided?
Is there osteomyelitis that has not yet responded?
Is there an untreated or an unidentified pathogen?
Is there an antibiotic delivery problem?
Is there an antibiotic non adherence issue?
Have all metabolic aberrations been corrected?

Adjunctive Therapy

Adjunctive therapies to promote DFU healing should only be considered if the DFU does not decrease by 50% after 4 weeks of comprehensive care including offloading, debridement, control of bioburden, control of edema, and wound moisture balance with appropriate dressings.[17][20][27] Evidence supporting these potentially costly adjunctive therapy interventions are not sufficiently strong to justify them as primary therapy.[20] Choice of adjuvant therapy is based on clinical findings, availability of resources, and cost-effectiveness.[17] Patient and ulcer should be re-evaluated prior to initiating adjunctive therapy. (See 'Plan Reassessment' above)

Biophysical Interventions

Hyperbaric Oxygen Therapy (HBO)

1BFor patients with DFU classified as Wagner 3 or higher, which failed to respond to standard therapy administered for at least 30 days, we recommend HBO therapy as an adjunctive therapy to promote DFU healing and decrease chances of amputation (Grade 1B).
2BFor other patients with DFUs that failed to respond to at least 30 days of standard therapy and have demonstrated good transcutaneous oxygen values response to 100% oxygen, clinicians might consider HBO therapy to promote DFU healing and decrease chances of amputation (Grade 2B).
- Rationale: Several clinical guidelines [17][27][115][116], backed by evidence of moderate certainty (evidence level B), support the use of HBO as an adjunctive therapy to promote DFU healing and decrease amputation rates if the DFU fails to heal after 4-6 weeks of standard therapy. Nevertheless, a 2017 RCT concluded that HBOT does not offer an additional advantage to comprehensive wound care in reducing the indication for amputation or facilitating wound healing in patients with chronic DFUs. This RCT was heavily criticized by experts in the field for potential methodological flaws, some of which were also recognized later by the authors of this RCT (e.g, outcome "amputation" was evaluated by a single surgeon, not based on actual amputation, but on indication for amputation as assessed from patient pictures and clinical data). [117][118][119][120][121]
- Standard therapy for DFUs should include assessment, correction of vascular abnormalities, optimization of nutritional status and glucose control, debridement, moist wound dressing, offloading and treatment of infection. HBO therapy in this context has been shown to be cost-effective particularly based on a long-term perspective.[122][123] Medicare covers HBO as an adjunctive therapy for patients with DFU classified as Wagner 3 or higher, which failed to respond to at least 30 days of standard care [124], in line with a study that found that HBO treatment has higher levels of efficacy in the healing of ulcers in grade 3 and 4 patients (as compared to other Wagner levels). [125] All other patients should be selected for this adjunctive therapy carefully due to the cost and burden of prolonged daily treatment. Transcutaneous oximetry values can help stratify patients and predict those who are most likely to benefit from HBO. Ideal candidates should have transcutaneous oxygen values above 30 and below 40, and these levels should double with breathing 100% oxygen with a mask.[9] For detailed treatment protocol, see topic "Diabetic Foot Ulcer - Hyperbaric Oxygen Therapy". For a practical algorithm on use of transcutaneous oxygen in HBO, see topic "Transcutaneous Oximetry".

Negative Pressure Wound Therapy (NPWT)

2CFor patients with non-infected, nonischemic DFUs that have failed to respond to 4 weeks of adequate standard care or for patients with wounds from a diabetic foot amputation (postoperative wound) clinicians might opt to use adjunctive NPWT instead of standard dressings to promote wound healing (Grade 2C)
- Rationale: Negative Pressure Wound Therapy (NPWT) is a technique for applying continuous or intermittent negative pressure to wounds via a material that fills the wound.[87] NPWT may improve wound healing by reducing edema, removing bacterial products, and approximating edges of the wound.[27] Clinical guidelines suggest use of NPWT as an adjunctive therapy to promote healing of post-surgical wounds in patients with DFU (post amputation and/or skin grafting), or after debridement of non-surgical DFUs.[17][26][27][87] Evidence of NPWT used in these contexts is considered of low certainty (evidence level C), as outlined by recent systematic reviews and meta-analyses.[126][127][128] Despite its benefits, potential adverse effects of NPWT have been described, including wound maceration, retention of dressings and wound infection.[87] As for cost-effectiveness, a retrospective analysis of reimbursement claims demonstrated reduced numbers of amputations in NPWT groups compared to traditional therapies, regardless of wound depth,[129] faster DFU healing, and decreased resource utilization due to reduction in nursing visits.[17][130] High cost of NPWT products and access to trained personnel for application of NPWT dressings should be factored in when considering this treatment modality.[17] NPWT is a Medicare-covered benefit for patients with DFU treated in the home and inpatient settings, provided requirements are met.[131] See topic "Negative Pressure Wound Therapy"

Phototherapy

2CFor non-infected, nonischemic refractory D FUs Wagner stage I or II, clinicians might opt for phototherapy (also known as low-level light therapy) as an adjunctive therapy compared to standard care alone, when resources are available (Grade 2C). Note: this intervention is not covered by Medicare
- Rationale: Phototherapy is a relatively new, non-invasive, pain-free treatment method that has received clearance from the US Food and Drug Administration for its beneficial effects on tissue healing and pain relief. For wound healing, the commonly used form of phototherapy is low-level light therapy (LLLT).[132] In addition to LLLT, a relatively new type of phototherapy, light-emitting diode (LED), is also used for wound healing. [133] Both in vitro and in vivo studies suggest that LLLT stimulates specific metabolic processes in wound healing.[134] There is some evidence that phototherapy as an adjunctive treatment of refractory DFUs is more effective than standard of care alone (evidence level C). However, Medicare currently does not cover phototherapy (i.e, infrared and/or near-infrared light and/or heat, including monochromatic infrared energy to treat diabetic and/or non-diabetic peripheral sensory neuropathy, wounds and/or ulcers of the skin and/or subcutaneous tissues [135] Thus, clinicians need to consider costs of treatment and availability of resources before opting for this modality.

Wound Coverage

Prior to initiating any wound coverage procedure (i.e. skin autografts, flaps, or skin equivalents), it is recommended that:

The ulcer bed be prepared adequately, by removing slough, debris, necrotic tissue and management of bioburden levels, preferably to 10^5 CFU/g of tissue, with no beta hemolytic streptococci in the ulcer. A wound containing contaminated foci with greater than 10^5 CFU/g of tissue cannot be readily closed, as the incidence of wound infection that follows is 50–100%. [27]
A reliable vascular status is obtained: if well granulating after wound preparation, skin graft or a small local flap can be performed. [136] Well-granulating wound itself is an indication for good vascularity. However, if healing is stalling, then further evaluation using transcutaneous oxygen pressure measurement (TCOM) or angiograms may be warranted to evaluate the arterial flow and prepare for vascular intervention. The same evaluation and approach to ensure vascularity are needed for complex wounds waiting for reconstructive procedure. [137]

Autografts

2CFor patients with non-infected, non-ischemic, superficial DFU with no bone/tendon/vessels exposure, and that failed to heal by 50% despite 4 weeks of standard care, clinicians might opt for surgical wound coverage with autologous skin grafts, followed by continued offloading (Grade 2C).
- Rationale: Autologous skin grafting may be the treatment of choice in many areas where other adjunctive therapies are not available.[9] Skin grafts should be avoided on deeper and severe DFU, especially when they are located in weight-bearing areas of the foot, with little subcutaneous tissue between the graft and the underlying bone. In these cases, a flap is preferred.[138] Low certainty evidence provided mainly by a observational study [139] supports use of autologous skin grafts as wound coverage over standard conservative dressings to treat DFUs (evidence level C). There appears to be no difference in outcome between meshed skin graft or ordinary split thickness skin graft in DFU coverage (evidence level C). [140] Autografts take well on DFU, reduce healing time and is safe in this patient population. [139] Postoperative offloading is essential to promote faster healing and prevent recurrence. Autografts are a covered procedure by Medicare and billing is done with CPT codes. There is no Medicare-imposed need for clinicians to observe failure of conservative therapies before choosing skin autografts. check
Types of autografts include:
- Meshed skin grafts, ordinary split thickness skin graft: Despite benefits of autologous skin grafts, patients may still prefer standard care with dressings due to the need for creation of a new wound (donor site).[139] As for resources, clinicians should factor in the need for anesthesia, surgeons and a surgical facility when considering this option.
- Epidermal skin grafts: harvested with an automated epidermal harvesting tool (Cellutome), epidermal skin grafts may be a viable option for wound coverage in patients with DFU. Harvesting can be done without anesthesia, at the bedside or at the office. Low certainty evidence is supported by observational studies that involved patients with other types of chronic ulcers besides DFU (evidence level C). [141]

LOCAL Flaps

2C For patients with non-infected, nonischemic, small to moderate size DFUs with exposure of bone/tendon/vessels, with enough local tissue available for coverage, and that failed to heal by 50% despite 4 weeks of standard care, clinicians might opt for surgical wound coverage with local flaps followed by continued offloading (Grade 2C)
- Rationale: Local flaps may provide coverage for exposed bone, tendon or vessels provided the DFU is small or moderate and local tissue is available. Flaps are preferred over skin grafts on weight-bearing areas of the foot with little subcutaneous tissue between ulcer and underlying bone. Evidence is derived mainly from observational studies (evidence level C).[138] Local flaps can be random (advancement, transpositional, or rotating) or vascularized (pedicled, fasciocutaneous or muscle). Local intrinsic muscle flaps (e.g., abductor digiti minimi demonstrated a relatively high success rate when used for the definitive closure of DFUs with exposed bone, joint or tendon, where skin grafting or local random flaps would not adequately address the defect or have failed.[142] When planning a flap cover, several factors must be taken into account; these include consideration of the extent, location, size, appearance, depth of the wound, exposed structures, the normal tissues available; vascularity of the limb; surgeon’s skills and patient factors. [138]

FREE FLAPS

2CFor patients with non-infected, nonischemic, complex DFU with exposure of bone/tendon/vessels, with no local tissue available for coverage, and that failed to heal by 50% despite 4 weeks of standard care, clinicians might opt for surgical wound coverage with free flaps followed by continued offloading (Grade 2C)
- Rationale: Traditionally, diabetes has been considered as a relative contraindication for free flap to the lower extremity, due to the misconception that patients with diabetes have a higher incidence of small vessel disease leading to foot ulcers.[143] However, other researchers were unable to demonstrate an increased incidence of arterial occlusive disease or endothelial proliferation in the diabetic population.[138][144][145] Low-certainty evidence is derived mainly from observational studies and case series [138][143][146] that support use of free flaps as an adjunctive treatment for DFUs (evidence level C). A pooled flap survival rate of 91.9% has been demonstrated in highly specialized units using free flaps in selected patients with diabetes and non-traumatic lower limb wound. [146] However free flaps are still underutilized, due to a possible reluctance to routinely perform this type of surgery, limited availability of specialists or the unfamiliarity of the treating doctor with free tissue transfer reconstructive options.[146]
Criteria to increase likelihood of successful outcomes when using free flaps to treat refractory DFUs include [146]:
- No significant renal function impairment
- No significant systemic illness likely to be exacerbated by multiple operations and prolonged rehabilitation
- Patient previously ambulatory, with the aim to restore a functional limb
- Patient likely to engage with the significant physiotherapy required for a return to normal living.
- Peak blood flow velocity of >40 cm/s in recipient artery
Preoperative workup includes [137][146]:
- Noninvasive computerized tomography (CT) angiogram or an invasive angiogram to evaluate the vascular status.
- Ultrasound duplex scan to guide selection of recipient vessels for the free flap or to refer for vascular intervention when no recipient vessels can be identified. Having an adequate flow to the region of reconstruction is essential prior to microsurgery reconstruction. If vascular intervention fails and wound progresses, amputation is warranted.
Free flap options include [137][138][147]: anterolateral thigh fasciocutaneous flaps, radial forearm fasciocutaneous flaps, lateral arm fasciocutaneous flaps, gracilis musculocutaneous flaps, tensor fascia latae flap, deep inferior epigastric perforator flap , and parascapular flap.

Cellular and/or Tissue Products (CTP)

In the U.S., Medicare covers application of CTPs on DFUs that despite 4 weeks of standard care, have increased or not changed in size or depth, and have shown no indication that improvement is likely (such as granulation, epithelialization or progress towards closing).[18] Standard care should include debridement, offloading, moist/exudate control, adequate management of underlying diseases and documented attempt to engage patient in smoking cessation if applicable.[18][148] Most CTPs may be applied in an outpatient setting. The choice of CTP relies heavily on evidence, physician/patient preference, costs, availability of resources and accessibility to CTPs.[18][149] CTPs that are not considered drugs and/or biological products can be categorized in one of the categories below [18] and may be covered by Medicare and private insurers if all requirements are met. For more details on CTP, see topic "Cellular and/or Tissue Products". For guidance on how to select CTPs, see "How to Select Cellular and/or Tissue Products". For decision support on different features of CTP brands, see CTP Interactive Feature Matrix.

2CFor non-infected, nonischemic DFUs that fail to decrease in size by at least 50% after 4 weeks of documented standard wound care, we suggest application of cellular and/or tissue products to promote DFU healing and decrease risk of amputation (Grade 2C)
- Rationale: Cellular and/or Tissue Products (CTPs) allow patients with refractory DFUs the chance to receive wound coverage in an outpatient setting, without problems inherent with autografts (e.g., autograft harvesting, hospital stay, anesthesia risks, donor area). Use of CTPs as a general modality to promote healing of refractory DFUs or prevent amputation is supported by low-certainty evidence (evidence level C). [149] Specific modalities of CTPs have different levels of evidence (see below). CTPs promote closure of the ulcer through the addition of extracellular matrices that induce growth factors and cytokine expression, although the exact mechanism underlying the process remains unclear. [149] Several randomized controlled trials reported no increased risk of adverse events in groups that used CTPs, compared to groups that used only standard care.[149] Certain CTPs may not be available in some countries, and only medical professionals who are licensed in their respective states for application of CTPs may apply them.[18] Cost-effectiveness of CTPs in promoting DFU healing compared to standard of care is still uncertain.[149]
- As for outcomes, a systematic review concluded that placenta-based CTPs (i.e. placenta-derived allogeneic matrices) exhibited the best wound healing probability for DFUs, followed by CTPs with living cells (e.g. Apligraf), and acellular matrices, compared with standard of care.[150]

2CHuman skin allografts: For non-infected, nonischemic refractory DFUs, clinicians might opt to apply human skin allografts as an adjunctive therapy to promote wound healing (Grade 2C)
- Rationale: Human skin allografts (HSA) are engineered from human skin components and human tissue which have had intact cells removed or treated to avoid immunologic rejection. There is some evidence that HSA is more effective in promoting DFU healing compared to standard of care alone (evidence level C) - more specifically Graftjacket (an acellular human dermis product), AlloPatch (acellular, reticular, allogenic human dermis), DermACELL [151][152][149][153][154] and TheraSkin [155]. It has also been shown that HSA (TheraSkin) is as effective as Composite Matrix (Apligraf) [156] or as Allogeneic Matrix (Dermagraft) [157] in promoting DFU healing (evidence level C).[149] HSA are available in different forms to allow scaffolding, soft tissue filling, growth factors and other bioavailable hormonal or enzymatic activity. Most HSA are indicated for use on DFUs with no exposed tendon/bone/vessels, however TheraSkin seems to be an exception in the sense it may be applied over these structures.[148] Studies have shown no increased rates of infection or graft-related complications when using HSAs. [153]
- When choosing CTPs, clinicians need to consider factors such as the need for storage in freezers (some HSA are shelf-stable at ambient temperature, others are cryopreserved), frequency of reapplication suggested by manufacturer, cost (some are classified by Medicare as “high cost” and others as “low cost”), and clinicians’ experience. Medicare covers HSAs applied in various care settings.

2B Allogeneic matrix: For patients with non-infected, nonischemic, DFUs refractory to 4 weeks of standard of care, we suggest consideration of human fibroblast-derived dermal substitute or allogeneic matrices derived from amniotic/chorion tissues to promote DFU healing and prevent amputation (Grade 2B)
- Rationale: Allogeneic matrices include products derived from human neonatal fibroblasts of the foreskin (HNFF) and derived from amniotic/chorion/placental tissues. These matrices may contain metabolically active or regenerative components primarily used for soft tissue support, though some have been approved for the treatment of full-thickness skin and soft tissue loss. Most are biodegradable and disappear after 3-4 weeks implantation.[18]
- Dermagraft is a type of HNFF, indicated for full-thickness DFUs that do not involve muscle/tendon/cartilage/bone. [148] The recommendation by the Society of Vascular Surgery [17] to use HNFF instead of standard care alone to promote healing of recalcitrant DFUs is supported by moderate-certainty evidence (evidence level B). [149] Use of HNFF results in no additional adverse effects.[148] Fibroblasts from the dermis are relatively non-antigenic and do not express HLA-DR markers, therefore Dermagraft is not expected by the manufacturer to cause an immune reaction.[148] Choice for HNFF may be affected by the need to store it in freezers and by a relatively shorter shelf-life (6 months from the time of cryopreservation) compared to other shelf-stable CTPs. Cost-effectiveness should also be taken into consideration: according to Gilligan et al [158], acellular matrix (OASIS Wound Matrix) may be more cost-effective in treating DFUs compared to HNFF. However, this study has limitations that increase its risk of bias (small sample size and sponsored by manufacturer).
- Many allogeneic matrices for chronic wounds are derived from amniotic/chorion/placental tissues. There is evidence that these products (more specifically, dehydrated human amnion/chorion membrane or dHACM) are more effective in healing refractory DFUs compared with standard care alone (evidence level B).[149][159][160][161][162][163][164][165] These allogeneic matrices may be shelf-stable at ambient conditions for 5 years. dHACM seems to be more cost-effective than bilayered bioengineered skin (Apligraf) in treating refractory DFUs, due to faster healing and fewer number of dressings needed until complete healing.[160] Dehydrated human umbilical cord allograft (EpiCord) has also been shown to promote faster healing of refractory DFUs compared to alginate dressings.[166] When viable, cryopreserved human placental membrane was compared with bilayered bioengineered skin (Apligraf), the proportion of patients achieving complete wound closure at 9 weeks was similar, but cost of treatment of DFUs < 5cm2 with cryopreserved human placental membrane was lower.[167]

2BComposite Matrix: For non-infected, nonischemic, full-thickness DFU with no tendon/muscle/cartilage/bone exposure that failed 4 weeks of standard therapy, we suggest use of bilayered bioengineered skin to promote DFU healing (Grade 2B)

- Rationale: Composite matrices are derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen. Active cellular components continue to generate bioactive compounds and protein that may accelerate wound healing and epithelial regrowth.[18] Apligraf, a bilayered engineered skin, is an example of composite matrix. The recommendation by the Society of Vascular Surgery [17] to use bilayered engineered skin to promote healing of recalcitrant DFUs is backed by moderate-certainty evidence (evidence level B) that bilayered engineered skin is more effective than standard care alone and results in no additional adverse effects. [149] Clinicians should take in consideration factors such as shelf life, clinical experience and costs when choosing CTPs. Apligraf is shipped ready to use and should be used within 15 days as there are living cells in media. Industry-sponsored studies conducted in the U.S. with Medicare data have shown that use of Apligraf to promote healing of recalcitrant DFUs was more costly than other CPTs (i.e., EpiFix -a type of allogeneic matrix, Matristem, and Oasis - both considered acellular matrices).[160][168]
Acellular matrix: 2BFor non-healing, nonischemic, non-infected full-thickness DFU with no tendon/muscle/cartilage/bone exposure, clinicians might opt for acellular bilayer matrix to promote healing. (Grade 2B). 2CAlternatively, we suggest consideration of the use of extracellular matrix products employing porcine small intestinal submucosal tissue or porcine urinary bladder as an adjunctive therapy (Grade 2C)

- Rationale: Acellular matrices (ACM) are derived from other than human skin and include the majority of CTPs. All are composed of allogeneic or xenogeneic derived collagen, membrane, or cellular remnants proposed to simulate or exaggerate the characteristics of human skin. All propose to promote healing by the creation of localized intensification of an array of hormonal and enzymatic activity to accelerate closure by migration of native dermal and epithelial components, rather than function as distinctly incorporated tissue closing the skin defect.[18] Compared to standard of care, acellular matrices coupled with standard of care seem to promote faster healing and a higher healing rate [169] - more specifically, acellular bilayer matrix (Integra Dermal Regeneration Template) [170], one application (on average) of fetal bovine acellular dermal matrix (PriMatrix) [171] and fish skin graft (Omega3 Wound; Kerecis) [172].
- Xenografts of any animal source may induce inflammatory reactions thus should not be used in individuals with known sensitivity or allergy. ACMs are usually shelf stable at ambient temperatures.
2CSynthetic matrix: For non-healing, nonischemic, non-infected full-thickness DFU with no tendon/muscle/cartilage/bone exposure, clinicians might opt for synthetic matrix to promote healing. (Grade 2C)

Rationale: Synthetic matrices are CTPs made from synthetic materials that mimics skin properties. A 2022 industry-sponsored RCT found that the use resorbable glass microfiber matrix (Mirragen; Advanced Wound Matrix [BBGFM]) showed that BBGFM promoted statistically significant higher proportion of DFU healed at 12 weeks compared to standard of care. The mean number of BBGFM applications was 6.0 (low certainty evidence).[175]

Other biologics

2CBlood-derived products: For more superficial, non-infected, nonischemic DFUs (Texas 1A or 2A) that failed 4 weeks of standard therapy, clinicians might consider autologous blood clot product in addition to standard care, if other CTPs are not available (Grade 2C).

Rationale: Autologous blood clot product (e.g. ActiGraft, which received 510(k) clearance from the U.S. Food and Drug Administration, FDA) is a biodegradable scaffold that attempts to mimic the body’s healing mechanisms by replacing the extra-cellular matrix (ECM) missing in chronic DFUs with a fibrin-based matrix. The blood clot product is created at the point-of-care, applied to the wound and covered with primary and secondary dressing to serve as an ECM for the wound healing process. There are currently no RCTs comparing this CTP with standard of care or any other CTP, however there is low certainty evidence that the CTP might be safe and efficacious when treating superficial DFUs, as shown by an industry-sponsored, small non-randomized clinical trial with 20 patients.[176] Autologous blood clot product is currently classified by Medicare as a low cost skin substitute.

2CPlatelet-derived growth factor (PDGF) and other growth factors: For patients with non-infected, nonischemic refractory DFUs, with no neoplasms, clinicians might opt for recombinant human platelet-derived growth factor (becaplermin) to promote DFU healing (Grade 2C)
- Rationale: Growth factors are considered to be a potentially important technological advance in the area of wound healing [177][178] . Chronic wound healing may be limited by a lack of the necessary growth factors, healing may expedited by replacing or stimulating these growth factors.[178] Growth factors include recombinant human platelet-derived growth factor (becaplermin), platelet-derived wound healing formula, allogeneic platelet-derived growth factor, autologous growth factor, transforming growth factor beta 2, arginine-glycine-aspartic acid peptide matrix, recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. There is some evidence suggesting that growth factors may increase the likelihood of complete DFU healing compared to standard of care only (Evidence level C). However, this evidence is drawn mainly from studies that used recombinant human platelet-derived growth factor (REGRANEX* (becaplermin) Gel 0.01%) and platelet-derived wound healing formula (studies on autologous platelet-rich plasma not included). An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of becaplermin gel, 0.01% in a postmarketing retrospective cohort study. Becaplermin should only be used when the benefits can be expected to outweigh the risks and should be avoided in patients with malignancies. Becaplermin is covered by Medicare Part D and Medicare Advantage Plans if requirements are met

2B Autologous Platelet-Rich-Plasma (PRP): For non-infected, nonischemic refractory DFUs, clinicians might opt for use of autologous platelet-rich plasma (PRP) to promote DFU healing compared with standard of care alone, when resources are available (Grade 2B).

- Rationale: Autologous platelet-rich plasma (PRP) can also be considered a growth factor-based therapy and has been increasingly used clinically to treat cutaneous chronic wounds.[179] There are several techniques used to obtain autologous PRP, although some are not standardized or approved. Although lacking enough evidence as a treatment for other types of chronic wounds, use of autologous platelet-rich plasma as an adjunctive therapy to promote healing of refractory DFUs is supported by moderate certainty evidence (evidence level B).[180][181] When considering use of PRP as an adjunctive therapy, it is important to bear in mind that use of these interventions require trained personnel, and can be costly.
- Coverage: Effective for claims with dates of service on or after April 13, 2021, Medicare started to accept and pay for autologous PRP for the treatment of chronic non-healing diabetic wounds for a duration of 20 weeks, when prepared by devices whose Food and Drug Administration-cleared indications include the management of exuding cutaneous wounds, such as diabetic ulcers.[182]

2CGranulocyte-colony stimulating factor (G-CSF): For patients with infected DFUs, clinical guidelines do not support use of G-CSF as routine [20] or adjunctive treatment [19][127], unless part of a clinical trial. (Grade 2C, against)
- Although there is some evidence that it can reduce need for surgical interventions, especially amputations, there is no evidence it can help cure infections or heal ulcers. [183]
2CAutologous stem cell therapy: For patients with refractory DFU, we currently do not suggest use of autologous stem cell therapy to promote healing of refractory DFUs (Grade 2C, against)

Rationale: Although there is some evidence that autologous stem cell therapy may help heal DFUs,[184][185][186] trials so far have been small, with unclear or heterogenous treatment protocol (i.e., variable number of cells injected, use of different types of autologous stem cells), and many did not distinguish ulcer etiology between neuropathic DFU and critical limb ischemia (evidence level C). Furthermore, this intervention requires skilled personnel and a laboratory, is considered experimental and is only covered by Medicare when treatment occurs as part of an approved clinical trial.

Transitioning to preventative interventions

Once the DFU has healed, the ulcer is considered in remission. Recurrence rates range from 8–59%[27] however, up to 75% of DFUs may be preventable.[187] Therefore, long-term maintenance with preventative interventions must be addressed even for healed ulcers to prevent recurrence. Follow up every 1-3 months is recommended. See topic "Diabetic Foot Ulcer - Prevention".

APPENDIX

Summary of Evidence

SOE – Cleansers

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The 2016 IWGDF Guidelines for DFU recommends that ulcers be cleaned regularly with water or saline (Strong C) [19]
The 2016 Wound Healing Society guideline for DFU recommends that wounds be cleansed initially and at each dressing change using a neutral, non-irritating, non-toxic solution, such as sterile saline or water. Tap water should be used if water is potable. Routine wound cleansing should be accomplished with a minimum of chemical and/or mechanical trauma (evidence level C) Authors also mention that experimental data suggest that a nontoxic surfactant may be useful as may fluid delivered by increased intermittent pressure. [27]
A Cochrane 2012 systematic review included 1 RCT that analyzed risk of infection in chronic wounds cleansed with water or saline and concluded that for chronic wounds, there is no difference in the risk of developing an infection when cleansed with tap water or normal saline. The body of evidence can be considered of low quality of evidence due to small sample size of the RCT and absence of other trials (evidence level C). Authors also stated that in the absence of potable tap water, boiled and cooled water as well as distilled water can be used as wound cleansing agents [82]

SOE - Debridement

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The 2016 Society for Vascular Surgery (SVS) systematic review and meta-analysis on debridement for DFU included 13 studies (788 patients). The risk of bias in the included studies was moderate. Meta-analysis of three RCTs showed that autolytic débridement significantly increased healing rate compared with standard wound débridement (RR, 1.89; 95% CI, 1.35-2.64). Meta-analysis of 4 comparative studies (one RCT) showed that larval débridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not aid complete healing (RR, 1.27; 95% CI, 0.84-1.91). No significant difference in wound healing was found between autolytic débridement and larval débridement (one RCT). Surgical débridement had shorter healing time compared with conventional wound care (one RCT). Ultrasound débridement was associated with reduction in wound size compared with surgical débridement. Hydrosurgical débridement had similar wound healing outcomes to standard surgical débridement.In general, comparative effectiveness evidence was of low quality, and the débridement method is recommended to be at the clinician’s discretion, with the goal of wound size reduction to full healing. The chosen débridement method should encourage patient compliance with the overall care plan.[17][84]
The latest Cochrane systematic review that evaluated whether debridement for DFU promotes wound healing was published in 2010 and included 6 RCTs. Authors acknowledged that debridement is recommended by most guidelines, however quality of evidence to support debridement to promote wound healing is low. All RCTs are at high risk of bias. The evidence suggests that hydrogels are significantly more effective in healing diabetic foot ulcers compared to gauze (Relative Risk 1.84, 95% Confidence Interval (CI)1.3 to 2.61). Surgical debridement showed no significant benefit over standard treatment. One small trial, available in abstract form only, suggested that larvae resulted in a greater reduction in wound area compared with hydrogel, but this evidence has not been confirmed by publication of full trial results [83]
The 2016 International Wound Group for Diabetic Foot (IWGDF), the 2016 Wound Healing Society (WHS), the 2012 Infectious Disease Society of America (IDSA) and the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) guidelines support debridement of VLU to promote wound healing, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn (see table below) [17] [20] [27] [87] :

Intervention for DFU	IWGDF	IDSA	SVS	WHS
DFU debridement at initial evaluation vs. no debridement	Strong C	Strong B	Strong B	Level I
Additional maintenance debridement of DFU	Strong C	Debridement should be repeated as often as needed if nonviable tissue continues to form	Strong B (1-4 week intervals)	Level I
Sharp debridement	Strong C	Strong C	Strong B	Level I
Autolytic	Hydrogels may have some benefit in terms of wound healing when compared with saline moistened gauze, but the risk of bias in the published studies was high	Weak C	2CSVS suggests initial sharp débridement with subsequent choice of débridement method based on clinical context, availability of expertise and supplies, patient tolerance and preference, and cost-effectiveness (Grade Weak C).	The method of debridement chosen may depend on the status of the wound, the capability of the health provider, the overall condition of the patient, and professional licensing restrictions.
Hydrosurgical debridement	Low evidence	n/a
Ultrasonic debridement	n/a	n/a
Enzymatic Debridement	Low evidence	n/a
Biological debridement	Low evidence	Weak C
Mechanical debridement	n/a	Weak C

We reviewed the Cochrane and SVS systematic reviews and the studies that the guidelines above used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above. Applying the GRADE framework to the combined body of evidence, we found that:
- Evidence that support the recommendation to perform debridement at initial evaluation and for maintenance to promote DFU healing compared to no debridement was of low quality (evidence level C), provided mainly by observational studies or RCTs at high risk of bias.
- Current studies do not provide sufficient evidence to conclude with confidence which method of debridement confers most benefit in the healing of DFU. Studies that concluded that one method was superior than other had important methodological limitations (level C).

SOE - Exudate and moisture management

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The 2016 Wound Healing Society (WHS), the 2012 Infectious Disease Society of America (IDSA) and the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) guidelines support managing DFU exudate, protecting periwound skin and maintaining a moist wound bed, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn

Intervention for VLU	SVS	WHS	IDSA
Manage DFU exudate and protect periwound skin	Strong B	Level I	Strong C
Maintain a moist wound bed	Strong B	Level III	Strong C

We reviewed the studies that the three guidelines used to grade quality of evidence and strength of recommendation for each of intervention above and found that:

The recommendation to manage DFU exudate and protect periwound skin is supported by low quality evidence (evidence level C), provided mainly by laboratory experimental studies that demonstrated that exudate may impede the healing of chronic wounds [100] or detected higher quantities of MMP in exudate of chronic wounds, compared to that of acute wounds. [101] [102] Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention, as they primarily compared effectiveness of different dressings in DFU healing, and did not necessarily evaluate effect of DFU exudate and MMP in wound healing and peri-wound skin integrity.
The recommendation to maintain a moist wound bed is supported by low quality evidence (evidence level C), provided mainly by laboratory experimental studies that demonstrated that moist environments promote faster wound healing. [103] [104] Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention, as they did not necessarily evaluate effect of moist vs. non-moist environment in wound healing.

SOE - Wound dressings - type of wound dressings

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A 2015 Cochrane overview of systematic reviews [111] included 13 reviews that evaluated dressings to promote healing of DFUs and concluded that there is currently no robust evidence of differences between wound dressings for any outcome in foot ulcers in people with diabetes (treated in any setting). Main comparisons described by the reviews and the level of evidence of each of them are depicted below:

Intervention	Comparator	Evidence level
No clear evidence of difference between the following dressings in DFU healing
Basic wound contact	alginate	Moderate (B)
Basic wound contact	hydrofiber	Moderate (B)
Basic wound contact	iodine-impregnated	Moderate (B)
Basic wound contact	Protease-modulating matrix	Moderate (B)
Foam	Matrix-hydrocolloid	Low (C)
Iodine-impregnated	Hydrofiber	Moderate (B)
Alginate	Silver-hydrofiber	Moderate (B)
Evidence of a difference in wound healing between dressings was reported for the following (favored intervention in bold):
Basic wound contact	Hydrogel	Low (C)
Basic wound contact	Foam	Very Low
Foam	Alginate	Very Low

Alginate: Low-quality evidence (Evidence level C due to high risk of bias) suggests that alginate wound dressings are equally effective in healing DFU than other types of dressing, however many trials in this field are very small and underpowered to detect any statistically significant difference
- A 2013 Cochrane systematic review evaluated 6 RCTs (375 participants) found no evidence that alginate is more effective in promoting DFU healing compared to other dressings. These RCTs compared alginate dressings with basic wound contact dressings, foam dressings and a silver-containing, fibrous-hydrocolloid dressing. Meta analysis of two studies found no statistically significant difference between alginate dressings and basic wound contact dressings: risk ratio (RR) 1.09 (95% CI 0.66 to 1.80). Pooled data from two studies comparing alginate dressings with foam dressings found no statistically significant difference in ulcer healing (RR 0.67, 95% CI 0.41 to 1.08). There was no statistically significant difference in the number of diabetic foot ulcers healed when an antimicrobial (silver) hydrocolloid dressing was compared with a standard alginate dressing (RR 1.40, 95% CI 0.79 to 2.47). All studies had short follow-up time (six to 12 weeks), and small sample sizes (Evidence level C). [105]

A 2017 RCT (31 participants) concluded that DFUs treated with Acticoat (nAg alginate) healed faster than DFU treated with manuka honey or with conventional dressing (tulle) in 12 weeks. [188] The study was small and underpowered to detect statistically significant difference and had a surrogate endpoint at 12 weeks (evidence level C). Acticoat (HCPCS A9270) is considered a non-covered item by Medicare

Hydrogel: Low-quality evidence (Evidence level C due to impreciseness, different baselines at the start of study and unclear risk of bias) suggests that hydrogel dressings are more effective in healing DFU when compared with basic wound contact dressings. We reviewed the systematic reviews below and agree with the classification given by the 2013 and 2015 Cochrane reviews (evidence level C).
- The latest 2013 Cochrane systematic review and meta-analysis on hydrogel dressings and DFU included 5 RCTs (446 participants) comparing effectiveness of hydrogel dressings and other interventions in DFU healing. [106] Meta analysis of 3 of the 5 RCTs (198 participants) comparing hydrogel dressings with basic wound contract dressings found significantly greater healing with hydrogel (RR 1.80, 95% confidence interval, 1.27 to 2.56). Authors concluded that there is some evidence to suggest that hydrogel dressings are more effective in healing lower grade diabetic foot ulcers than basic wound contact dressings however this finding is uncertain due to risk of bias in the original studies (note of editor: the review did not specify level of evidence, but editors assume a level C, based on small size, unclear risk of bias and different baselines at the start of the studies). Authors also highlighted that at the time of publication was no research evidence to suggest that hydrogel is more effective than larval therapy or platelet-derived growth factors in healing diabetic foot ulcers, nor that one brand of hydrogel is more effective than another in ulcer healing.
- The 2015 Cochrane review [111] of systematic reviews analyzed 3 systematic reviews that compared hydrofiber and basic wound dressings [83] [106] [108]. These 3 reviews performed meta-analyses of the same studies. All reviews found evidence of an increase in the number of wounds healed in the hydrogel-treated group, however the direct estimate was classed as being of low quality (evidence level C) by Dumville et al [108]
- A 2016 meta-analysis [107] of the same 3 RCTs (198 participants) analyzed by the 2013 Cochrane meta-analysis [106] comparing hydrogel dressing and basic wound contact dressing found moderate level evidence that hydrogel dressings are more effective in promoting DFU healing compared to basic wound contact dressings (RR 1.80, 95% confidence interval, 1.27 - 2.56]). Authors gave a 2A recommendation in favor of using hydrofiber over basic wound contact dressings to promote DFU healing

Foam: Low-quality evidence (Evidence level C, due to high risk of bias - studies are small, have limited follow up times, and/ or are sponsored by manufacturers) suggests that foam dressings when compared to basic wound contact dressings, alginate or hydrocolloid (matrix) dressings are equally effective and present no difference in adverse effects in healing DFUs.

A 2013 Cochrane systematic review and meta-analysis on foam dressings and DFU included 6 RCTs (157 participants) comparing effectiveness of foam dressings with other interventions in DFU healing. [109] Meta analysis of 2 RCTs (49 participants) indicated that foam dressings do not promote the healing of DFUs compared with basic wound contact dressings (RR 2.03, 95%CI 0.91 to 4.55). Pooled data from 2 RCTs (50 participants) comparing foam and alginate dressing found no statistically significant difference in ulcer healing (RR 1.50, 95% CI 0.92 to 2.44). There was no statistically significant difference in the number of DFUs healed when foam dressings were compared with hydrocolloid (matrix) dressings in 1 RCT (40 participants). All included studies were small and/or had limited follow-up times. Authors concluded that currently there is no research evidence to suggest that foam wound dressings are more effective in healing DFUs than other types of dressing however all trials in this field are very small (evidence level C)
The 2015 Cochrane review [111] of systematic reviews analyzed 5 systematic reviews that compared foam and alginate dressings [105] [108] [109] [189] [190]. Four of these 5 reviews analyzed the same 2 RCTs. Overall data across these 4 systematic reviews reported no clear evidence of a difference between these dressings, although an estimate based on indirect as well as direct evidence found that more wounds healed with foam dressings than with alginate dressings. [108] Estimates were very uncertain and imprecise (evidence level C)
A 2016 meta-analysis [107] evaluated 2 RCTs (50 participants) comparing the effectiveness of alginate and foam dressings in DFUs healing and concluded that there was no difference between the treatment groups (RR 0.67, 95% confidence interval, 0.41-1.08). The same meta-analysis evaluated 3RCTs (99 participants) that compared foam and basic wound contact dressings and also found no difference in DFUs healing between the two interventions (RR 1.45, 95% confidence interval, 1.00-2.09). Authors graded the evidence as level B (evidence level B).
A 2016 observational study [191] included 208 participants and compared effectiveness of highly hydrophilic polyurethane foam dressing with basic wound contact dressing in promoting DFU healing. Complete wound healing occurred in 87 patients (63.5%) in the polyurethane foam dressing group and in 28 patients (39.4%) in the control group within 12 weeks ( P G .05, X 2 test). The mean percentage of wound area reduction in both groups was statistically significant ( P G .05, Mann-Whitney U test). The mean time required for complete closure in patients who achieved complete healing within 12 weeks was 6.2 (SD, 3.4) weeks and 7.3 (SD, 2.6) weeks in the polyurethane foam dressing and control groups, respectively ( P G .05, Mann-Whitney U test). Authors concluded that highly hydrophilic polyurethane foam dressings may be an effective intervention in the treatment of DFU.
A 2017 case series [192] included 53 patients with DFU, VLU and PI treated with regular debridement with the use of ovine-based collagen extracellular matrix dressings and gentian violet/methylene blue polyurethane antibacterial foam dressings. Average time to closure for all wounds was 10.6 weeks (range, 5-24 weeks). All wounds were 100% reepithelialized by week 20 except 1 DFU that reepithelialized at week 24. The average cost of care for a single wound episode (from presentation to closure) was $2749.49. The effects of a foam dressing was not studied separately and sample size for DFU was small. (Evidence level C)

Hydrocolloid: Evidence suggests that hydrocolloid dressings have no statistically significant difference in DFUs healing when compared with basic wound contact dressings (evidence level B), foam dressings, alginate dressings and a topical treatment

A 2013 Cochrane systematic review [110] evaluated 5 RCTs (535 participants) that compared hydrocolloids with basic wound contact dressings, foam dressings, alginate dressings and a topical treatment. Meta-analysis of 2 studies [91] [193] indicated no statistically significant difference in ulcer healing between fibrous-hydrocolloids and basic wound contact dressings [Risk ratio 1.01 (95% CI 0.74 to 1.38)] (Evidence level B). One of these 2 studies [91] found that a basic wound contact dressing (a non-adherent, knitted, viscose filament gauze) was more cost-effective than a fibrous-hydrocolloid dressing (Aquacel) in promoting DFU healing in the UK, as in that study, higher cost of Aquacel was not offset by the fewer dressings required. One study compared a hydrocolloid-matrix dressing (Cutinova Hydro, S&N Hlth) with a foam dressing (Allevyn, S&N Hlth) and found no statistically significant difference in the number of ulcers healed. There was no statistically significant difference in healing between an antimicrobial (silver) fibrous-hydrocolloid dressing (Aquacel Ag, ConvaTec) and standard alginate dressing [194]; an antimicrobial dressing (iodine-impregnated) and a standard fibrous hydrocolloid dressing or a standard fibrous hydrocolloid dressing and a topical cream containing plant extracts [195]. Authors concluded that currently there is no research evidence to suggest that any type of hydrocolloid wound dressing is more effective in healing DFUs than other types of dressing or a topical cream containing plant extracts.
A 2016 systematic review and meta-analysis [107] analyzed the same studies the 2013 Cochrane review evaluated and concluded that there was no difference in effectiveness of hydrocolloids compared with basic wound contact dressings in promoting DFU healing [RR 1.1, confidence interval of 95%, (0.85, 1.44)]

Collagen:
- A 2012 manufacturer sponsored study that utilized disease modeling data (as opposed to real RCT data) concluded that Promogran may be more cost-effective than good wound care with non-adherent gauze in healing DFUs in four European countries (France, Germany, Switzerland and UK). [113] Assumptions used in disease modeling are frequently derived from expert opinion (Evidence level C)

Antimicrobial dressings: Low-certainty evidence (evidence level C) suggests that more DFUs - infected or not infected - may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing.
- A 2017 Cochrane systematic review and meta-analysis [60] included 5 RCTs (945 participants) that compared effectiveness of antimicrobial dressings and non-antimicrobial dressings in DFUs healing, and found that more wounds may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing [RR: 1.28, 95% confidence interval (1.12 to 1.45)]. Authors considered this finding as low-certainty evidence (evidence level C) due to risk of bias. It was uncertain whether antimicrobial dressings can aid in infection healing or prevent infection in DFUs (low-certainty evidence, level C). Where reported, the grade of ulcer in the studies ranged from I to III. Some studies enrolled patients with ulcers with duration longer than 30 days, others did not specify duration of the ulcer at enrollment. Three studies evaluated silver-containing dressings ( Gottrup 2013 ; He 2016 ; Jude 2007 ), one a honey-containing dressing ( Imran 2015 ), and one an iodine-containing dressing ( Jeffcoate 2009 ). Wounds were not infected at baseline in one study ( Gottrup 2013 ); mixed infected and not infected in one study ( Jude 2007 ); and not reported in the remaining three studies. Authors concluded that antimicrobial dressings probably increase the number of healing events in the medium term compared with non-antimicrobial dressings (evidence level C). However, the effect antimicrobial dressings on the incidence of infection, other outcomes, and adverse events is unclear (evidence level C)
- As for cost-effectiveness, one small, manufacturer sponsored RCT (41 participants) [112] compared treatment with a cadexomer iodine ointment to “standard treatment”, which included a gentamicin solution, in people with a grade I or II ulcer and followed them for 12 weeks. Cadexomer iodine was shown to be dominant compared to standard treatment. [196] However, according to the 2017 Cochrane review, it is uncertain whether there was a difference in the risk ratio of healing between these treatments: RR 2.16, 95% CI 0.47 to 9.88 (very low-certainty evidence - downgraded twice for imprecision and once for risk of bias)

SOE - Antimicrobial Topical Agents

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Antimicrobial dressings: Low-certainty evidence (evidence level C) suggests that more DFUs - infected or not infected - may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing.

The 2016 Wound Healing Society (WHS) [27], the 2012 Infectious Disease Society of America (IDSA) [20] and the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17] guidelines do not advocate for use of antimicrobial dressings for most uninfected DFU. The 2012 Wound and Ostomy and Continence Nurses Society (WOCN) [26] recommends instituting a short course of antimicrobial agent along with careful daily monitoring of the DFU for signs of infection

Intervention	SVS	WHS	IDSA	WOCN
Use antimicrobial dressings to treat DFU	“There is minimal evidence for increased rate of healing with other popular wound dressings, including honey and topical silver”	“Selectively use adjuvant agents (topical, device, and/or systemic) after evaluating a patient and their ulcer characteristics and when there is a lack of healing progress in response to more traditional therapies”	“We do not advocate using topical antimicrobials for most clinically uninfected wounds”	“Institute a short course of a topical antimicrobial agent along with careful daily monitoring of the neuropathic ulcer for signs of infection. Level of Evidence = B”

A 2006 Cochrane review of treatment with silver-based wound dressings or topical agents for DFU [197] found no RCTs reporting outcomes on healing rates or infection resolution, and thus could not draw any conclusion related to their effectiveness on healing DFU
A 2015 Cochrane systematic review on topical honey for treating wounds [198] concluded that it may reduce healing time for mild-to-moderate superficial and partial-thickness burns and infected postoperative wounds, but did not significantly hasten leg ulcer healing
A 2016 systematic review of the effectiveness of interventions in the management of diabetic foot infections [199] found six studies that investigated the use of topical agents, but the methods and results did not allow the authors to draw any definitive conclusions. [60]
A 2017 Cochrane systematic review and meta-analysis [60] included 5 RCTs (945 participants) that compared effectiveness of antimicrobial dressings and non-antimicrobial dressings in DFUs healing, and found that more wounds may heal when treated with an antimicrobial dressing than with a non-antimicrobial dressing [RR: 1.28, 95% confidence interval (1.12 to 1.45)]. Authors considered this finding as low-certainty evidence (evidence level C) due to risk of bias. It was uncertain whether antimicrobial dressings can aid in infection healing or prevent infection in DFUs (low-certainty evidence, level C). Where reported, the grade of ulcer in the studies ranged from I to III. Some studies enrolled patients with ulcers with duration longer than 30 days, others did not specify duration of the ulcer at enrollment. Three studies evaluated silver-containing dressings ( Gottrup 2013 ; He 2016 ; Jude 2007 ), one a honey-containing dressing ( Imran 2015 ), and one an iodine-containing dressing ( Jeffcoate 2009 ). Wounds were not infected at baseline in one study ( Gottrup 2013 ); mixed infected and not infected in one study ( Jude 2007 ); and not reported in the remaining three studies. Authors concluded that antimicrobial dressings probably increase the number of healing events in the medium term compared with non-antimicrobial dressings (evidence level C). However, the effect antimicrobial dressings on the incidence of infection, other outcomes, and adverse events is unclear (evidence level C). Given the weak available evidence, authors could not draw a firm conclusion on the role of any topical antimicrobial in the treatment or prevention of wound infection in people with foot ulcers and diabetes.
As for cost-effectiveness, one small, manufacturer sponsored RCT (41 participants) published in 1996 [112] compared treatment with a cadexomer iodine ointment to “standard treatment”, which included a gentamicin solution, in people with a grade I or II ulcer and followed them for 12 weeks. Cadexomer iodine was shown to be dominant compared to standard treatment. [196] However, according to the 2017 Cochrane review, it is uncertain whether there was a difference in the risk ratio of healing between these treatments: RR 2.16, 95% CI 0.47 to 9.88 (very low-certainty evidence - downgraded twice for imprecision and once for risk of bias)

SOE - Xerosis

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A 2002 RCT (40 participants) compared the efficacy of a test moisturizer containing 10% urea and 4% lactic acid with its emulsion base vehicle in the treatment of xerosis of the feet in patients with diabetes. Feet treated with the vehicle cream (control) had an initial mean xerosis grading of 6.17 (+/- 0.79) and a final xerosis grading of 4.38 (+/- 2.20). In the treatment group, mean xerosis grading diminished from 6.13 (+/- 0.73) to 3.19 (+/- 2.23) after 4 weeks (P < 0.01). Authors concluded that regular use of a moisturizer was found to be beneficial in the treatment of moderate-to-severe xerosis of the feet in patients with diabetes (evidence level C, due to small size and surrogate endpoint). [96]
A 2011 RCT (54 participants) [95] compared the efficacy of Pédimed(®) cream and its placebo in the treatment of foot xerosis in diabetic patients. A decrease in XAS score that was more marked with Pédimed(®) than with placebo was observed from D14 (38.1% vs 20.9%, P<0.0001), reaching 61.9% vs 34.9% at D28 (P<0.0001). However, study is industry sponsored and at moderate level of bias due to surrogate endpoint (evidence level B)
A 2017 RCT (57 participants) [97] compared an emollient (Dexeryl®) to its placebo in treating xerosis of DFU. Compared with the vehicle, the emollient also significantly improved the overall skin score, hydration index, D-Squame® (CuDerm Corporation, Dallas, TX, USA) test, skin roughness and patients' opinions.Treatment with an emollient is effective for improving foot xerosis in patients with diabetes. Study had surrogate endpoint of 28 days, and was industry-sponsored (evidence level B)
A 2017 systematic review included 22 studies that evaluated use of emollients to treat xerosis in patients with DFU. Studies analyzed 12 different active ingredients, and urea was the most researched active ingredient (14 studies), with ammonium lactate being next (7 studies). Authors could not reach a conclusion related to which active ingredient was best, due to high risk of bias (evidence level C). [98]

SOE - Systemic Antibiotics

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based on results of appropriately collected culture and sensitivity testing as well as the patient’s clinical response to the empiric regimen.

Intervention	SVS	WHS	IDSA
Use empiric antibiotic regimen on the basis of the severity of the infection and the likely etiologic agents	Supports IDSA	n/a	Strong, low
Definitive therapy be based on the results of an appropriately obtained culture and sensitivity testing of a wound specimen as well as the patient’s clinical response to the empiric regimen	Supports IDSA	Level II	Strong, low

A 2015 Cochrane systematic review that included 20 RCTs (3791 participants) concluded that evidence for the relative effects of different empiric systemic antibiotics for the treatment of foot infections in diabetes is very heterogeneous and generally at unclear or high risk of bias (evidence level C) due to limitations in the design of the RCTs. Therefore, it is not clear if any specific empiric systemic antibiotic treatment is better than others in resolving infection or in terms of safety. One RCT suggested that ertapenem with or without vancomycin is more effective in achieving clinical resolution of infection than tigecycline. [64]
Low-certainty evidence (evidence level C) suggests that there is no specific systemic antibiotic treatment that is better than others in resolving infection or in terms of safety.[200]

SOE - Offloading

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Moderate to high certainty evidence (evidence level B) supported by several RCTs suggest that offloading promotes faster DFU healing compared with no offloading.

A 2013 Cochrane systematic review [44] analyzed 2 RCTs (98 participants) that compared non-removable pressure relieving device with no pressure relief in DFU healing. Both trials reported that significantly more ulcers healed in the TCC (non-removable) group. Overall, studies were at moderate risk of bias.
The 2023 and 2016 International Working Group on the Diabetic Foot (IWGDF) [37][38], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines recommend offloading to promote DFU healing, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn.

Intervention	IWGDF	SVS	WHS	WOCN
Offloading of high pressure areas to heal DFUs	Yes - but does not specify recommendation strength or evidence level	Yes - but does not specify recommendation strength or evidence level	Level I	Yes - but does not specify recommendation strength or evidence level

SOE - Non-removable knee-high offloading device

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Moderate level evidence support the use of non-removable knee-high offloading devices instead of other modalities to promote healing of nonischemic, non-infected forefoot DFUs (Evidence level B)

A 2017 Canadian health technology assessment with systematic review [36] included 13 RCTs and found that the evidence suggests that total contact casting, removable cast walkers, and irremovable cast walkers are beneficial in the treatment of neuropathic, non infected foot ulcers in patients with diabetes but without severe peripheral arterial disease.
- Compared to removable cast walkers, ulcer healing was improved with total contact casting (moderate quality evidence; risk difference 0.17 [95% confidence interval 0.00-0.33]) and irremovable cast walkers (low quality evidence; risk difference 0.21 [95% confidence interval 0.01-0.40]).
- There was no difference in ulcer healing between total contact casting and irremovable cast walkers (low quality evidence; risk difference 0.02 [95% confidence interval -0.11-0.14]).
- The economic analysis showed that total contact casting and irremovable cast walkers were less expensive and led to more health outcome gains (e.g., ulcers healed and quality-adjusted life-years) than removable cast walkers. Irremovable cast walkers were as effective as total contact casting and were associated with lower costs.
A 2016 IWGDF systematic review [43] included 2 systematic reviews and meta-analyses, 32 RCTs, 15 other controlled studies, and another 127 non controlled studies. Authors found that:
1. For healing of forefoot DFU, 2 meta-analyses [40] [44] showed that non-removable offloading are more effective than removable offloading. (considered by IWGDF high quality evidence, but studies used by the meta-analyses were of moderate quality evidence)
2. On the basis of one RCT and mostly non-controlled studies, cast shoes, forefoot offloading shoes, and custom-made temporary shoes appear to promote healing of neuropathic plantar ulcers.
3. Due to the limited number of controlled studies, clear evidence on the efficacy of surgical offloading and felted foam is not yet available. Interestingly, surgical offloading seems more effective in preventing than in healing ulcers. A number of controlled and uncontrolled studies show that plantar pressure can be reduced by several conservative and surgical approaches.
4. The evidence base to support the use of other offloading interventions in DFU healing is still limited and of variable quality.
A 2016 SVS-commissioned systematic review [46] analyzed 19 studies, (1605 patients), of which 13 were RCTS that compared TCC with other offloading modalities to promote DFU healing.The risk of bias in the included studies was moderate. This analysis demonstrated faster wound healing with total contact casting over removable cast walker (weighted mean difference,12.36 days; 95% CI, 22.63-2.09;p=0.18), therapeutic shoes (RR, 0.34; 95% CI, [0.15-0.79]), and conventional therapy (RR, 1.76; 95% CI, [0.77-4.02]). There was no advantage of irremovable cast walkers over total contact casting. There was improved healing with half-shoe compared with conventional wound care. Therapeutic shoes and insoles reduced relapse rate in comparison with regular footwear. Data were sparse regarding other off-loading methods. This review included only a fraction of what other meta-analyses included.
A 2015 systematic review and meta-analysis [40] analyzed 8 RCTs that compared non-removable pressure relieving device with removable cast walkers and concluded that non-removable devices are more effective in promoting DFU healing (RR 0.31 95% CI [0.19, 0.52] p<0.01). All studies analyzed by the 2013 Cochrane systematic review [44] were also included in this review. Studies were at moderate risk for bias (evidence level B).
A 2013 Cochrane systematic review [44] analyzed 5 RCTs (230 participants) that compared non-removable total contact device with a removable device. Significantly more ulcers healed in the non-removable device group (RR 1.17 95% CI 1.01 to 1.36). Authors concluded that non-removable, pressure-relieving casts are more effective in healing DFUs than removable casts, or dressings alone. All five studies were overall at moderate risk of bias. The same review cited one RCT (50 participants) [47] which compared a removable cast walker (Aircast Diabetic Walker) with a temporary therapeutic half shoe. The trial had a moderate risk of bias as allocation concealment was unclear. Although there was no difference in the number of ulcers healed between the groups, time to healing in the removable cast walker group was six weeks compared with nine weeks in the temporary therapeutic shoe group. Significant difference in cumulative wound survival was noted by the study authors at 12 weeks between patients treated with a half shoe and RCW (P value 0.033).
A 2013 systematic review [45] analyzed 11 RCT and 2 non-RCTs (661 participants) that compared non-removable off-loading devices (Total Contact Cast) and therapeutic shoes showed that the former were statistically significantly more effective at achieving complete healing of diabetic foot ulcers than therapeutic shoes, although there was substantial between-study heterogeneity (RR 1.68, 95% CI 1.09 to 2.58; six studies).Authors concluded that non-removable off-loading devices (regardless of type) were more likely to result in ulcer healing than removable off-loading devices.

The 2016 International Working Group on the Diabetic Foot (IWGDF) [37], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines support offloading DFUs to promote ulcer healing. As for different modalities, while IWGDF and SVS strongly recommend non-removable devices (total contact cast-TCC, or irremovable fixed ankle knee high walking boot) as first line offloading modality for nonischemic, non-infected forefoot DFUs, WHS and WOCN do not specify a preferred modality. WHS recognizes crutches, walkers, wheelchairs, custom shoes, depth shoes, shoe modifications, custom inserts, custom relief orthotic walkers, diabetic boots, forefoot and heel relief shoes, and total contact casts as acceptable offloading methods for DFUs. As for levels of evidence for offloading non complex DFUs with a non-removable device, the IWGDF assigned level A (high quality) whereas SVS assigned level B (moderate quality). In reviewing the body of evidence on which IWGDF classed the quality of evidence, we noticed that it referred to 2 systematic reviews - a 2013 Cochrane review [44] and a 2015 review [45] - whose authors considered quality of evidence collected as moderate. Thus, we also concur with the authors of these systematic reviews and currently consider quality of the evidence body as moderate

Intervention	IWGDF	SVS	WHS	WOCN
Offloading with a total contact cast (TCC) or irremovable fixed ankle walking boot	1AGrade 1A	1BGrade 1B	n/a	n/a

SOE - Offloading removable walker

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Based on two relatively small RCTs [48] [201], there is moderate level evidence to suggest that a removable walker rendered irremovable is as effective as a TCC in healing neuropathic plantar forefoot ulcers (Relative risk ratio=1.06; 95% CI 0.88 – 1.27, p =0.31). Studies were industry sponsored, and were at unclear or high risk of bias for allocation concealment, blinding and incomplete outcome reporting

The 2016 International Working Group on the Diabetic Foot (IWGDF) [37], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines support offloading DFUs to promote ulcer healing. The table below focuses on removable cast walkers

Intervention	IWGDF	SVS	WHS	WOCN
In patients with DFU requiring frequent dressing changes, off-loading with a removable cast walker as an alternative to TCC and irremovable fixed ankle walking boot	2BGrade 2B	2CGrade 2C	n/a	n/a

SOE - Offloading - conventional shoes to heal DFU

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The 2016 International Working Group on the Diabetic Foot (IWGDF) [37], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines support offloading DFUs to promote ulcer healing. However therapeutic shoes should not be used to promote DFU healing

Intervention	IWGDF	SVS	WHS	WOCN
Do not use conventional or standard therapeutic shoes to heal a DFU	1CGrade 1C	2CGrade 2C	n/a	n/a

SOE - Offloading non-plantar DFU

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The 2016 International Working Group on the Diabetic Foot (IWGDF) [37], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines support offloading DFUs to promote ulcer healing. The table below focuses on non-plantar DFUS

Intervention	IWGDF	SVS	WHS	WOCN
In patients with non-plantar wounds, use any modality that relieves pressure at the site of the ulcer	2CGrade 2C	1CGrade 1C	n/a	n/a

SOE- offloading surgical procedures to heal DFU

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The 2016 International Working Group on the Diabetic Foot (IWGDF) [37], the 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines support offloading DFUs to promote ulcer healing. The table below focuses on offloading surgical procedures

Intervention

IWGDF

SVS

WHS

WOCN

Surgical Achilles tendon lengthening, single or pan metatarsal head resection, or joint arthroplasty when conservative treatment fails to heal non-complicated DFUs

2CGrade 2C

n/a

Digital flexor tenotomy when conservative treatment fails,

to heal a distal toe ulcer in patients with non-complicated DFUs and hammertoes

2CGrade 2C

n/a

SOE - Intensive Glucose Control

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A 2018 systematic review and meta-analysis [25] included 20 RCTs (1357 participants) and concluded that exercise has a significant effect on reducing HbA1c [ -0.45% (P< 0.00001)], while combined exercise is more effective compared to aerobic or resistance exercise alone [ -0.19% (P=0.1), -0.25% (P=0.0006), and -0.64% (P=0.006) for aerobic vs. resistance, combined vs. aerobic, and combined vs. resistance exercise, respectively]. Exercise also improves ABI [0.03 (P=0.002)]. However, evidence regarding the association between exercise and peripheral neuropathy and risks of diabetic foot ulcers in people with type 2 diabetes remains insufficient.
A 2016 Cochrane review [24] could not qualify any RCT to analyze effects of intensive glucose control compared with conventional glucose control. Authors identified only 1 RCT that met the inclusion criteria but the trial was terminated due to recruiting difficulties. There are 2 ongoing trials but there are no results yet.Therefore authors were unable to conclude whether intensive glycemic control when compared to conventional glycemic control has a positive or detrimental effect on the treatment of DFU. Previous evidence has however highlighted a reduction in risk of limb amputation (due to various causes) in people with type 2 diabetes with intensive glycaemic control. [202] Whether this applies to people with foot ulcers in particular is unknown. Authors conclude that the exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation. The lack of evidence however should not deter efforts to achieve optimal glycemic control in people with diabetic foot ulcers to encourage healing as is current practice.
A 2016 systematic review and meta-analysis [28] included 9 RCT (10,897 patients) that compared the effect of intensive glycemic control (HbA1c, 6%-7.5%) with less intensive glycemic control on lower extremity amputation in patients with type 2 diabetes. Studies were deemed to be at moderate risk of bias. Compared with less intensive glycemic control, intensive control was associated with a significant decrease in risk of amputation (RR= 0.65; 95% CI= 0.45-0.94). Authors concluded that compared with less intensive glycemic control therapy, intensive control may decrease the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.

The 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26] guidelines recommend adequate glycemic control to promote DFU healing

Intervention	WOCN	SVS	WHS
Adequate glycemic control to promote DFU healing	Level B	2BGrade 2B	Level II

SOE- Nutrition

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Systematic review and meta-analyses:

A 2016 systematic review and meta-analysis [203] included 3 RCTs (390 participants) that compared nutritional support with no nutritional support to promote DFU healing or preserve a limb [34] [204] [205] Authors concluded that nutritional support was of value to promote DFU healing (RR = 1.17, 95% CI = 0.93-1.47). However, nutritional interventions across the 3 studies varied significantly (herbal concoction [204], extra calories [205] or arginine, glutamine and ß-hydroxy-ß-methylbutyrate [34] and the pooled result of the meta-analysis is not statistically significant.
A 2013 systematic review [206] identified 4 human studies and 9 animal studies related to diabetes and wound healing. Authors concluded that while supplement studies in animal models with arginine and vitamin E were positive, there were no significant differences in the human studies reviewed. More human studies need to be conducted to determine the efficacy of these nutritional supplements in promoting wound healing.

Randomized Clinical Trials:

In 2014, Armstrong et al. [34] conducted a RCT (270 participants) that compared the effect of an oral supplement enriched with arginine, glutamine, and ß-hydroxy-ß-methylbutyrate with a standard supplement on DFU healing at 16 weeks in patients with UT 1A DFUs. However, this study found no difference in patients where the albumin was normal. There was positive effect in patients with poor limb perfusion and/or low albumin. This would indicate that appropriate nutritional interventions could potentially help individuals who have either nutritional deficiencies or unreconstructable peripheral vascular disease. [32] This study was industry sponsored and had a surrogate endpoint (evidence level B)
In 2008, Leung et al [204], conducted a RCT (80 participants) comparing nutritional supplementation with a herbal concoction and placebo in limb salvage in patients with DFU. Limb salvage was achieved in 85% of the patients. Among the early failures, three each came from the treatment and placebo groups. After shifting to herbal treatment (without unblinding of the original treatment), all were rescued in those initially assigned to herbal concoction (6 out of 6) while only 50% (6 out of 12) were rescued from among those initially assigned to placebo. Study is at high level of bias due to selective reporting and different baseline demographics between groups (evidence level C)
In 2004, Eneroth et al. [205] conducted a RCT (53 participants) comparing the effects of extra calories (400 kcal) with placebo in DFU healing of patients aged over 60 with diabetes mellitus and a Wagner grade I-II foot ulcer of over four weeks' duration. A third of the patients were malnourished. There was no statistically significant difference between the outcomes of the two groups. Authors concluded that they encountered several methodological problems and were unable to demonstrate an improved wound healing rate in these patients. Study is at high level of bias due to selective reporting (evidence level B)

Observational studies

In 2013, Zhang et al. [207] conducted an observational study to investigate the relationship between indicators correlated to nutritional status and outcome. A total of 192 hospitalized patients with Wagner grade 1-5 ulcers and 60 patients with Wagner grade 0 ulcers (all had type 2 diabetes) were assessed by the following: subjective global assessment (SGA), anthropometric measurements, biochemical indicators and physical examinations to evaluate nutritional status, severity of infection and complications. Patient outcome was recorded as healing of the ulcer and the patients were followed up for 6 months or until the wound was healed. The percentage of malnutrition was 62.0% in the DFU patients. The risk of poor outcome increased with malnutrition [odds ratio (OR), 10.6, P< 0.001]. The nutritional status of the DFU patients was independently correlated with the severity of infection and outcome (both P< 0.001) and Wagner grades and nutritional status (SGA) were independent risk factors for patient outcome (both P< 0.001). Nutritional status deteriorated as the severity of the DFU increased, and malnutrition was a predictor of poor prognosis.

SOE - Adjunctive Therapy: Hyperbaric Oxygen Therapy

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We reviewed the clinical guidelines, systematic reviews, meta-analyses and clinical trials summarized below. Applying the GRADE framework to the combined body of evidence, we found that:

Moderate certainty evidence supports the use of HBO as an adjunctive therapy to promote DFU healing and prevent amputation (evidence level B). The systematic reviews and meta-analyses [208][209] included the same RCTs. Both agreed that HBO as an adjunctive therapy significantly improved DFU healing, however they differed in regards to amputation prevention. The 2015 Cochrane meta-analysis [208] calculated the relative risk between intervention and control, and the 2016 SVS-commissioned meta-analysis [209] calculated the Peto odds ratio, which was considered by authors of the 2016 meta-analysis as more precise. Clinical guidelines also relied on the same RCTs to grade evidence, however their classification system differed. In analyzing the RCTs, most were small and were at high or moderate risk of bias, however one larger RCT (94 participants) [210] was better designed and can be considered of moderate evidence level (evidence level B)

Systematic reviews and meta-analyses

A 2017 systematic review and meta-analysis [211] included 9 RCTs (n=526 participants). No difference was found in the incidence of healed ulcers (risk ratio [RR] = 2.22; 95% CI, 0.87–5.62;P=0.32), minor amputations (RR=0.95; 95% CI, 0.39–2.29;p=0.91), major amputations (RR=0.47; 95% CI, 0.17–1.28;p=0.14, and adverse events (RR=1.00; 95% CI, 0.64– 1.56;P=0.99) between the HBOT and standard therapy (ST) groups. HBOT was associated with a greater reduction in the ulcer wound area versus ST (standard mean difference=1.12; 95% CI,0.20–2.04;P=0.04). Evidence can be considered of low certainty, due to small size of each RCT, heterogeneity of treatment protocols among RCTs. One large RCT that likely skewed the overall results of the meta-analysis was largely criticized by experts due to methodological flaws (e.g., surrogate endpoint/outcome: analysis of outcome "amputation" was not the actual amputation per se, but impression of a single vascular surgeon based on patients' photos and clinical information on whether amputation was indicated or not).
A 2016 systematic review and meta-analysis [209] included 18 studies, of which 9 were RCTs, enrolling 1526 participants in total. Based on six RCTs, HBOT was associated with increased healing rate (OR, 14.25; 95% CI, 7.08-28.68, I2 = 0%) and reduced major amputation rate (OR, 0.30; 95% CI, 0.10-0.89, I2 = 59%) compared with conventional therapy. The quality of this evidence is considered low to moderate, potentially downgraded due to methodologic limitations of the included studies. In the experimental groups, HBO was given in addition to conventional therapy (wound care and offloading). In most studies, HBO was given at 2.0 to 3.0 atmospheric pressure in daily 90-minute sessions in a monoplace or multiplace chamber. On average, patients received 30 sessions, although a few patients in one study received 60 sessions [212] [213]. Authors concluded that there is low- to moderate-quality evidence supporting the use of HBO as an adjunctive therapy to enhance DFU healing and potentially prevent amputation.
A 2015 Cochrane systematic review and meta-analysis [208] pooled data of 5 RCTs (205 participants) (149,151) [214] [215], showed an increase in the rate of ulcer healing (RR: 2.35, 95% confidence interval (CI) 1.19 - 4.62; P = 0.01) with HBO at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of 5 RCTs with 312 participants, RR 0.36, 95% CI 0.11 - 1.18). Authors concluded that In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results.

Randomized controlled trials (not included in earlier systematic reviews)

A 2017 RCT (157 participants) [216]compared outcomes of patients with DFU (Wagner 2-4) who received HBO and standard of care with those who received sham and standard of care only. In addition to comprehensive wound care, participants were randomly assigned to receive 30 daily sessions of 90 min of HBOT (breathing oxygen at 244 kPa) or sham (breathing air at 125 kPa). Patients, physicians, and researchers were blinded to group assignment. At 12 weeks post randomization, the primary outcome was freedom from meeting the criteria for amputation as assessed by a vascular surgeon. Secondary outcomes were measures of wound healing. Criteria for major amputation were met in 13 of 54 patients in the sham group and 11 of 49 in the HBOT group (odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846). Twelve (22%) patients in the sham group and 10 (20%) in the HBOT group were healed (0.90 [0.35, 2.31], P = 0.823). Authors concluded that HBOT does not offer an additional advantage to comprehensive wound care in reducing the indication for amputation or facilitating wound healing in patients with chronic DFUs. This RCT was heavily criticized by experts in the field for potential methodological flaws.[117][118][119][119] Authors of this RCT concurred that actual amputation rates could not be measured and instead a surrogate endpoint/outcome was used [121] - a single vascular surgeon evaluated patients' photos and clinical data (but not the actual patient in most cases) and deemed whether amputation was indicated or not. Also, authors did not select candidates most likely to benefit from HBO as measured by established transcutaneous oximetry assessment protocols.

Clinical guidelines

The 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26], the 2014 Undersea and Hyperbaric Medicine Society (UHMS) [115] and the 2017 European Committee for Hyperbaric Medicine (ECHM) [116] guidelines support the use of HBO as an adjunctive therapy to promote DFU healing and prevent amputation

Intervention	SVS	WHS	WOCN	UHMS	ECHM
Hyperbaric oxygen therapy as adjunctive therapy to promote DFU healing and reduce amputation rates	2BGrade 2B	Level I	Level B	AHA Class I	2BGrade 2B

Observational studies:

A recent longitudinal observational cohort study by Margolis et al [217] on 6259 individuals with diabetes, adequate lower limb arterial perfusion, and foot ulcer found that the use of HBO neither improved the likelihood of healing nor prevented amputation in a cohort of patients defined by Centers for Medicare and Medicaid Services eligibility criteria.The authors concluded that the usefulness of HBO in patients with DFUs needs to be reevaluated.

SOE - Adjunctive Therapy: Negative Pressure Wound Therapy

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We reviewed the clinical guidelines, systematic reviews, meta-analyses and clinical trials summarized below. Applying the GRADE framework to the combined body of evidence, we found that:

Low certainty evidence supports the use of negative pressure wound therapy (NPWT) as an adjunctive therapy to promote DFU healing for both postoperative wounds (i.e. wound from a diabetic foot amputation) and non-surgical DFUs (evidence level C).

Systematic reviews and meta-analyses:

A 2018 Cochrane systematic review and meta-analysis [128] included 11 RCTs (972 participants). This is an update of the 2013 systematic review described here.[126] Authors concluded that there is low-certainty evidence to suggest that NPWT, when compared with wound dressings, may increase the proportion of wounds healed and reduce the time to healing for postoperative foot wounds and ulcers of the foot in people with DM. For the comparisons of different pressures of NPWT for treating foot ulcers in people with DM, it is uncertain whether there is a difference in the number of wounds closed or covered with surgery, and adverse events. Specifically, for NPWT compared with dressings for postoperative wounds: data from the two studies suggest that it is uncertain whether there is a difference between groups in amputation risk (RR 0.38, 95% CI 0.14 to 1.02; 292 participants; very low-certainty evidence, downgraded once for risk of bias and twice for imprecision. For NPWT compared with dressings for foot ulcers: Data from three studies (441 participants) suggest that people allocated to NPWT may be at reduced risk of amputation compared with people allocated to dressings (RR 0.33, 95% CI 0.15 to 0.70; I² = 0%; low-certainty evidence; downgraded once for risk of bias and once for imprecision). For low-pressure compared with high-pressure NPWT for foot ulcers: There was no clear difference in the number of wounds closed or covered with surgery between groups (RR 0.83, 95% CI 0.47 to 1.47; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision) and adverse events (RR 1.50, 95% CI 0.28 to 8.04; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision).
A 2014 AHRQ systematic review included 7 studies that evaluated NPWT in the home setting. Authors were unable to draw conclusions about the efficacy or safety of NPWT for the treatment of chronic wounds in the home setting due to insufficient evidence. Though NPWT has been used across the wound care spectrum, significant research gaps remain.[218]
A 2014 systematic review and meta-analysis [219] included 8 RCTs (669 participants). Overall, compared with the non–negative-pressure wound therapy–treated diabetic foot ulcers, negative pressure resulted in a significantly higher proportion of healed ulcers (relative risk, 1.52; 95 percent CI, 1.23 to 1.89; p < 0.001), more reduction of ulcer area (standardized mean difference, 0.89; 95 percent CI, 0.41 to 1.37; p = 0.003), and shorter time to wound healing (standardized mean difference, -1.10; 95 percent CI, -1.83 to -0.37; p = 0.003). Negative-pressure wound therapy patients also experienced significantly fewer major amputations (relative risk, 0.14; 95 percent CI, 0.04 to 0.51; p = 0.003), but the rate of minor amputations was not affected (p = 0.837). No significant difference was observed between negative-pressure wound therapy and non–negative-pressure wound therapy (p = 0.683). No heterogeneity among studies was detected. Authors concluded that negative-pressure wound therapy appears to be more effective for diabetic foot ulcers compared with non–negative-pressure wound therapy, and has a similar safety profile. However, authors recognized that results could have been affected by some limitations of the design of the meta-analysis, such as the fact that baseline ulcer characterization was not standardized. The meta-analysis pooled data from RCTs with different patient conditions; for instance, in one RCT patients had post-amputation wounds and in another, patients had debrided DFU but no previous amputation. [220][221] Many of the RCTs in this review were excluded from the 2013 Cochrane review due to lack of relevant outcome, or not being a RCT due to lack of randomized allocation (using alternation instead). Furthermore, this 2014 meta-analysis pooled studies that have different patient populations, who either used NPWT post lower extremity amputation or after a debrided DFU with no previous amputation. These types of patients represent different indications of NPWT and are too different to be pooled.
A 2013 Cochrane systematic review included 5 RCT (605 participants).[126]Two studies (total of 502 participants) [220][221] compared negative pressure wound therapy with standard moist wound dressings. The first of these [220] was conducted in people with DM and post-amputation wounds and reported that significantly more people healed in the negative pressure wound therapy group compared with the moist dressing group: (risk ratio 1.44; 95% CI 1.03 to 2.01). The second study [221], conducted in people with debrided foot ulcers, also reported a statistically significant increase in the proportion of ulcers healed in the negative pressure wound therapy group compared with the moist dressing group: (risk ratio 1.49; 95% CI 1.11 to 2.01). However, authors noted that these studies were at risk of performance bias, so caution is required in their interpretation. Findings from the remaining three studies provided limited data, as they were small, with limited reporting, as well as being at unclear risk of bias. Authors concluded that there is some evidence to suggest that negative pressure wound therapy is more effective in healing post-operative foot wounds and ulcers of the foot in people with DM compared with moist wound dressings. However, these findings are uncertain due to the possible risk of bias in the original studies. (Evidence level C). The larger trials included in the 2013 Cochrane review [126] were considered by authors as low quality evidence due to lack of assessor and patient blinding and attrition bias (evidence level C).

Clinical guidelines

The 2016 International Working Group on the Diabetic Foot (IWGDF) [87], 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27], the 2012 Wound, Ostomy, and Continence Nurses Society (WOCN) [26], guidelines support the use of NPWT as an adjunctive therapy to promote DFU healing.
The IWGDF analyzed 2 groups of patients: patients with non-surgical DFUs and patients with post-surgical wounds. Evidence of use of NPWT for patients with non-surgical DFUs was considered of low certainty, while use of NPWT for post-surgical wounds was considered of moderate certainty. However, upon analyzing the studies on which recommendations were made, it was noted that the evidence grading for post-surgical wounds was based on 2 large RCTs and 1 small RCT, and 1 of the large RCTs [221] was not related to post-surgical wounds, but to non-surgical wounds.

Intervention	IWGDF	WHS	SVS	WOCN
Negative pressure wound therapy to promote DFU healing	Weak, moderate	Level I	2BGrade 2B	Level C

SOE - Adjunctive Therapy: Skin autografts

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Low certainty evidence provided mainly by a observational study [139] support use of autologous skin grafts as wound coverage to treat DFUs (evidence level C). There appears to be no difference in outcome between meshed skin graft or split thickness skin graft in DFU coverage (evidence level C). [140]

Randomized clinical trials:

In 2004, Puttirutvong et al [140] conducted the only RCT studying autografts for treatment of DFUs. The study involved 80 participants and compared meshed skin graft with split thickness skin graft in DFU coverage. There was no difference in outcome between the 2 groups of patients. This study is considered by a Cochrane systematic review as being at unclear risk of bias [149]

Observational study:

A 2008 non-randomized case-controlled prospective comparative study [139] (100 participants) compared autologous skin grafting (graft group) with conservative dressings (control group) in promoting DFU healing. Wound management in both groups was standardised with regard to the dressing materials (which comprised a multilayer dressing including paraffin gauze and diluted povidone-iodine soaked gauze), wound care and surgeon involvement. The mean healing time and mean length of hospital stay were significantly shorter in the graft group compared with the control group (p<0.001). Authors concluded that split-skin grafting is an effective method of managing diabetic foot ulcers as, compared with the conservative dressings used in this study, it reduced healing times and the length of hospital stay, while donor-site morbidity was minimal.

SOE - Cellular and/or Tissue Products

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Systematic reviews

A 2016 Cochrane systematic review and meta-analysis [149] included 17 RCTs (1655 participants) that compared skin grafts or skin substitutes in conjunction with standard of care (SC) with standard care alone or with another skin graft or skin equivalent to promote healing of DFU and reduce amputation rates. Based on the studies included in this review, the overall therapeutic effect of skin grafts and tissue replacements used in conjunction with standard care shows an increase in the healing rate of foot ulcers [13 RCTs, risk ratio (RR) 1.55, 95% confidence interval (CI) 1.30 to 1.85, low quality of evidence) and slightly fewer amputations in people with diabetes compared with standard care alone (RR 0.43, 95% CI 0.23 to 0.81; risk difference (RD) -0.06, 95% CI -0.10 to -0.01, very low quality of evidence). No specific type of skin graft or tissue replacement showed a superior effect on ulcer healing over another type of skin graft or tissue replacement. In addition, evidence of long term effectiveness is lacking and cost-effectiveness is uncertain.

Guidelines

The 2016 International Working Group on the Diabetic Foot (IWGDF) [87], 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27] guidelines support the use of CPT as an adjunctive therapy to promote DFU healing

Intervention	IWGDF	WHS	SVS
Do not select bioengineered skin products in preference to accepted standards of good quality care	Strong, low	n/a	n/a
Cellular and acellular skin equivalents to improve healing of DFUs that fail to demonstrate improvement(>50% wound area reduction) after a minimum of 4 weeks of standard wound therapy	n/a	Level I	Grade 1B

SOE - Cellular and/or Tissue Products: Human Skin Allografts

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-Systematic reviews

A 2023 systematic review and meta-analysis evaluated 38 RCTs (3862 patients) and concluded that placenta-based tissue products exhibited the best wound healing probability (p-score = 0.90), followed by skin substitutes with living cells (p-score = 0.70), acellular skin substitutes (p-score = 0.56), and advanced topical dressings (p-score = 0.34) compared with standard of care. [150]
A 2016 Cochrane systematic review and meta-analysis evaluated 2 RCT (114 participants) that compared the effectiveness of GraftJacket (a human skin allograft derived from acellular human dermis) with standard care only in promoting DFU healing. GraftJacket was more effective than standard of care in healing DFU [RR 1.9, 95% CI, (0.97, 3.71)]. The 2 RCTs are at unclear or high risk of bias due to detection bias (evidence level C) [149]

- Randomized controlled trials

A 2022 industry-sponsored RCT (n=100 patients) by Armstrong et al [155] compared the response of 100 subjects with non-healing Wagner 1 DFUs of which 50 were treated with weekly cryopreserved bioactive split thickness skin allograft (BSA) (TheraSkin; Misonix,Inc., Farmingdale, NY) and standard of care with 50 subjects treated with standard of care (SOC, collagen alginate dressing) for 12 weeks or until healed. Both groups received standardized care that included glucose monitoring, weekly debridement's as appropriate, and an offloading device. The result illustrated in the intent-to-treat analysis at 12 weeks showed that 76% (38/50) of the BSA-treated DFUs healed compared with 36% (18/50) treated with SOC alone (adjusted P = .00056). Mean PAR at 12 weeks was 77.8% in the BSA group compared with 49.6% in the SOC group (adjusted P = .0019). The average time for closure within the 12‐week period for BSA was 46.9 days, with an average of 6.7 applications (95% CI: 38.7‐55.1) vs closure with SOC was 65.3 days (95% CI: 57.7‐72.9). This difference was statistically significant (P = .0019). Authors concluded that adding BSA to SOC appeared to significantly improve wound healing with a lower incidence of adverse events related to treatment compared with SOC alone. Evidence can be considered of moderate certainty due to lack of blinding of healthcare personnel and patients (evidence level B).
A 2017 industry-sponsored RCT (168 participants) by Cazzell et al.[151] compared the efficacy and safety of a human acellular dermal matrix (ADM) - DermACELL, D-ADM, with a conventional care arm and an active comparator human ADM arm, GJ-ADM - GraftJacket, for the treatment of chronic diabetic foot ulcers. Single application D-ADM subjects showed significantly greater wound closure rates than conventional care at all three endpoints while all applications D-ADM displayed a significantly higher healing rate than conventional care at Week 16 and Week 24. GJ-ADM did not show a significantly greater healing rate over conventional care at any of these time points. Authors concluded that D-ADM demonstrated significantly greater wound healing, larger wound area reduction, and a better capability of keeping healed wounds closed than conventional care in the treatment of chronic DFUs. Evidence can be considered of low certainty due to lack of blinding of healthcare personnel and patients, and lack of standardization in criteria for a second application of ADM)
A 2011 RCT (28 participants) by DiDomenico et al. [156] compared the efficacy of Theraskin (a human skin allograft derived from cadaveric split thickness skin graft) and Apligraf (a composite matrix that is a bioengineered skin substitute), in treating DFUs and found no statistically significant difference between the patient groups. Authors assessed 29 wounds from 28 patients—17 wounds received Apligraf and 12 wounds received Theraskin. At 12 weeks, Theraskin closed 66.7% of wounds and Apligraf closed 41.3% of wounds. At 20 weeks, the Theraskin closure rate remained at 66.7% and the Apligraf closure rate increased to 47.1% (RR 0.71 95% CI (0.37-1.34). [149]. Most patients received only a single application of either Theraskin or Apligraf, and the average wound closure time was 5 weeks for the Theraskin group and 6.86 weeks for the Apligraf group. No unexpected adverse effects were reported in this study [148]

SOE - Cellular and/or Tissue Products: Allogeneic Matrices

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AM derived from human neonatal fibroblasts of the foreskin

- Systematic reviews

A 2016 Cochrane systematic review and meta-analysis included 3 RCTs (620 participants) [222][223][224] that compared the effectiveness of Dermagraft (Smith and Nephew, Largo, FL, USA) a cryopreserved human fibroblast-derived dermal substitute to standard wound care in promoting DFU healing. The meta-analysis showed that significantly more DFUs treated with Dermagraft healed than DFUs treated with standard care only [RR 1.5, CI 95%, (0.85, 2.65)][149] 1 RCT (314 participants) [223] evaluated the effectiveness of Dermagraft in preventing amputations and found that among patients with DFUs treated with Dermagraft compared to standard of care only there was a lower incidence of amputation [RR-0.04, CI 95%, (-0.09, 0.01)]. The body of evidence can be considered of moderate certainty (Evidence level B), downgraded as a result of risk of bias due to lack of blinding of outcome assessment.

AM derived from amniotic/chorion/placental tissues

- Systematic reviews

A 2020 systematic review and meta-analysis [164] included 6 RCTs (312 DFUs) comparing human-derived acellular dermal matrices (H-ADMs) with standard of care (SOC) to evaluate the number of healed ulcers at 12 and 16 weeks and number of days to complete healing. As a secondary outcome, the efficacy of 3 H-ADM subtypes are studied. The results show H-ADMs are more effective in healing patients within a 12-week (3.14; range, 2.04-4.83) and 16-week period (2.35; range, 1.25-4.43) in comparison with SOC. Further, the mean time to complete healing was shorter in the H-ADM group (-2.31 days; range, -2.67 to -1.95 days) in comparison with SOC. Within the subgroups, 2 H-ADMs were associated with a higher likelihood of complete healing within 12 weeks when compared with SOC. The third H-ADM had a point estimate, which suggested superiority over SOC. Authors concluded that H-ADMs are associated with a higher likelihood of complete healing and fewer days to complete healing within a 12-week and 16-week periods when compared with SOC. Also, the commercial products performed similarly.
A 2018 systematic review and meta-analysis [225] included 6 RCTs (331 participants) and compared effectiveness of amniotic membrane with standard of care. Meta-analysis showed that DFUs treated with amniotic membranes healed on average 32 days faster compared to those treated with standard of care 32.38 [CI:-41.05;-23.71] but this result was not statistically significant (p=0.83) with a 95 %CI. Also, wound healing in the group treated with amniotic membrane occurs 2.32 times more often than in the control group, but this result is not statistically significant either. Among the RCTs included, the largest RCT (n=100) [160] showed that amniotic membrane (EpiFix) promoted complete and faster healing of more DFUs compared to Apligraf or standard care, and was more cost-effective than Apligraf (adjusted P = 0.00019).
A 2017 systematic review and meta-analysis [226] included 7 RCTs showed that patients receiving amniotic membrane + standard therapy had far fewer incomplete healing wounds than those receiving standard of care alone. Assessment of the wound healing state at 4 and 6 weeks revealed that the wound healing state was almost the same, but there was a net difference of wound healing state at 12 weeks (Z = 4.96; P<0.00001; OR 0.10; 95% CI 0.04–0.24). Authors concluded that human amnion/chorion membrane + standard of care treatment heals DFUs significantly faster than standard of care alone. When using the amnion in patients with DFUs, the optimal times to assess progress in wound healing should be 4 and 12 weeks.
A 2016 Cochrane systematic review included 1 RCTs (25 participants) that compared the effectiveness of EpiFix [159] to standard wound care in promoting DFU healing. The meta-analysis showed that significantly more DFUs treated with EpiFix healed than DFUs treated with standard care only [RR 11.08, CI 95% (1.69, 72.82)].[149] The group using EpiFix also had a statistically significant lower incidence of amputations [RR 0.19, CI 95%, (0.01, 3.52)]. Evidence can be considered of low certainty (evidence level C) downgraded as a result of risk of bias due to lack of blinding of outcome assessment and lack of blinding of participants and personnel [149]

- Randomized controlled trials (recent)

A 2020 industry-sponsored RCT (n=76 DFUs) [165] aimed to determine the effectiveness of hypothermically stored amniotic membrane (HSAM) versus standard of care (SOC) in diabetic foot ulcers (DFUs). HSAM was applied directly with the stromal side in contact with the wound per manufacturer specifications on the open ulcer bed at weekly intervals or until healed. Authors found that the Cox wound closure for HSAM (38 wounds) was significantly greater (p = 0.04) at weeks 12 (60 vs 38%), and 16 (63 vs 38%). The probability of wound closure increased by 75% (Hazard Ratio = 1.75; 95% CI: 1.16-2.70). HSAM showed >60% reductions in area (82 vs 58%; p = 0.02) and depth (65 vs 39%; p = 0.04) versus SOC. Authors concluded that HSAM increased frequency and probability of wound closure in DFUs versus SOC. Limitations of this trial included the lack of blinding in using a skin substitute compared with standard bandages as the primary wound contact material.
A 2018 industry-sponsored non-inferiority RCT (62 participants) [167] compared viable, cryopreserved human placental membrane with bilayered bioengineered skin (Apligraf) in the treatment of chronic DFU. The proportion of patients achieving complete wound closure at 9 weeks was similar (9.68, 90% CI: [10.67, 28.94]), but cost of treatment of DFUs < 5cm2 with cryopreserved human placental membrane was lower (level of evidence can be considered of moderate certainty B, due to lack of blinding of healthcare personnel and patients)
A 2018 RCT (155 participants)[166] analyzed safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non-healing DFU. The primary study endpoint was the percentage of complete closure of the study ulcer within 12 weeks. ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord-treated and 26 of 48 (54%) for alginate-treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate-treated ulcers, P < 0.0001. Seventy-five subjects experienced at least one adverse event, with a total of 160 adverse events recorded. There were no adverse events related to either EpiCord or alginate dressings. Evidence can be considered of moderate certainty (level B) due to lack of assessor, provider and patient blinding. Study was industry-sponsored.
A 2018 RCT (110 participants) [162] compared efficacy of dehydrated human amnion/ chorion membrane allograft (dHACM) with alginate in treating non-healing DFU. Patients were randomly assigned to receive weekly dHACM application in addition to offloading or standard of care with alginate wound dressings, for 12 weeks. The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per-protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT — 70% versus 50%, P = 0.0338, per-protocol — 81% versus 55%, P = 0.0093). Evidence can be considered of moderate certainty (level B) due to lack of provider and patient blinding. Study was industry-sponsored.
A 2016 RCT (40 participants) [227] compared aseptically processed dehydrated human amnion and chorion allograft (dHACA, Amnioband) versus standard of care (SOC) in facilitating wound closure in nonhealing DFUs. At 6 weeks, 70% (14/20) of the dHACA-treated DFUs healed compared with 15% (3/20) treated with SOC alone. Furthermore, at 12 weeks, 85% (17/20) of the DFUs in the dHACA group healed compared with 25% (5/20) in the SOC group, with a corresponding mean time to heal of 36 and 70 days, respectively. At 12 weeks, the mean number of grafts used per healed wound for the dHACA group was 3.8 (median 3.0), and mean cost of the tissue to heal a DFU was $1400. Authors concluded that aseptically processed dHACA heals diabetic foot wounds significantly faster than SOC at 6 and 12 weeks with minimal graft wastage. Evidence can be considered of low certainty (level C) due to small size, lack of allocation concealment. Study was industry-sponsored.
A 2016 RCT (29 participants) evaluated dehydrated amniotic membrane allograft (AmnioExcel, Derma Sciences Inc, Princeton, NJ) plus standard of care (SOC) compared to SOC alone for the closure of chronic diabetic foot ulcers (DFUs). [161] Thirty-three percent of subjects in the DAMA+SOC cohort achieved complete wound closure at or before week 6, compared with 0% of the SOC alone cohort (intent-to-treat population, P = 0.017). Evidence can be considered of low certainty (evidence level C) due to high risk of bias (surrogate endpoint and small trial size)
A 2016 RCT (100 participants) [160] compared effectiveness of EpiFix (dehydrated amniotic membrane), Apligraf and standard care in promoting DFU healing after 12 weeks of care. Authors found that EpiFix promoted complete and faster healing of more DFUs compared to Apligraf or standard care, and was more cost-effective than Apligraf (adjusted P = 0.00019). No difference in probability of healing was observed for the Apligraf and SWC groups. Median number of grafts used per healed wound were 6 (range 1–13) and 2.5 (range 1–12) for the Apligraf and EpiFix groups, respectively. Median graft cost was $8918 (range $1,486–19,323) per healed wound for the Apligraf group and $1,517 (range $434–25,710) per healed wound in the EpiFix group ( P < 0·0001). Evidence can be considered of moderate uncertainty (evidence level B) due to lack of blinding of personnel and participants.

Prospective studies

A 2019 industry-sponsored non-randomized, non-controlled, prospective, multicenter study (n=60) [228] evaluated the efficacy and safety of an acellular dermal matrix allograft, DermACELL (D-ADM; LifeNet Health, Virginia Beach, Virginia), in the treatment of large, complex diabetic foot ulcers (DFUs) that probed to tendon or bone (Wagner grade 3 or 4 DFUs between 4 weeks and 1 year in duration). All participants received one application of D-ADM at baseline and could receive one additional application if wound healing arrested. Ulcers were assessed weekly for 16 weeks using a laser measuring device. Sixty-one participants were enrolled, with an average wound area of 29.0 cm; 59 of these ulcers showed exposed bone. The entire per-protocol population (n = 47) achieved 100% granulation. The mean time to 100% granulation was 4.0 weeks with an average of 1.2 applications of D-ADM. Mean percent wound area reduction was 80.3% at 16 weeks. Those DFUs 15 cm or smaller were substantially more likely to close than DFUs larger than 29 cm (P = .0008) over a 16-week duration. No complications were associated with the use of the studied matrix. Authors concluded that D-ADM demonstrated the ability to rapidly reduce the size of large, complex DFUs with exposed bone. Some wounds did not completely heal by 16 weeks; however, the significant reduction in size suggests that these large, complex wounds may heal if given more time. This study lacks control arm and is industry-sponsored.

SOE - Cellular and/or Tissue Products: Composite Matrices

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Systematic reviews

A 2016 Cochrane systematic review included 2 RCTs (290 participants) [229][230] that compared the effectiveness of Apligraf to standard wound care in promoting DFU healing. The meta-analysis showed that significantly more DFUs healed when treated with Apligraf than when treated with standard care only [RR 1.55, CI 95% (1.17, 2.04)].[149] Evidence by the combined studies can be considered of moderate certainty (evidence level B) downgraded as a result of risk of bias due to lack of blinding of participants and personnel [149]

Randomized controlled trials

A 2016 RCT (100 participants) [160] compared effectiveness of EpiFix (dehydrated amniotic membrane), Apligraf and standard care in promoting DFU healing after 12 weeks of care. Authors found that EpiFix promoted complete and faster healing of more DFUs compared to Apligraf or standard care (adjusted P = 0.00019), and was more cost-effective than Apligraf. No difference in probability of healing was observed for the Apligraf and standard care groups. Median number of grafts used per healed wound were 6 (range 1–13) and 2.5 (range 1–12) for the Apligraf and EpiFix groups, respectively. Median graft cost was $8918 (range $1,486–19,323) per healed wound for the Apligraf group and $1,517 (range $434–25,710) per healed wound in the EpiFix group ( P < 0.0001). Evidence can be considered of moderate uncertainty (evidence level B) due to lack of blinding of personnel and participants.
A 2011 RCT (28 participants) by DiDomenico et al. [156] compared the efficacy of Theraskin and Apligraf (Organogenesis, Canton, MA, USA), a bioengineered skin substitute, in treating DFUs and found no statistically significant difference between the patient groups. The authors hypothesized that Theraskin and Apligraf would yield the same results for wound closure rate and number of grafts required when treating DFU. DiDomenico et al. assessed 29 wounds from 28 patients—17 wounds received Apligraf and 12 wounds received Theraskin. At 12 weeks, Theraskin closed 66.7% of wounds and Apligraf closed 41.3% of wounds. At 20 weeks, the Theraskin closure rate remained at 66.7% and the Apligraf closure rate increased to 47.1% (RR 0.71 95% CI (0.37-1.34). [149]. Most patients received only a single application of either Theraskin or Apligraf, and the average wound closure time was 5 weeks for the Theraskin group and 6.86 weeks for the Apligraf group. No unexpected adverse effects were reported in this study [148]

Cost-effectiveness studies

A 2016 industry-sponsored, retrospective cost and effectiveness study (13,193 skin substitute treatment episodes) [168] compared the relative product cost and clinical outcomes of four skin substitutes used as adjunctive treatments for DFUs (Apligraf-HML, Dermagraft-HSL, OASIS-SIS, and MatriStem-UBM), as per 2011-2014 Medicare claims data. The percentage of DFUs that healed at 90 days were: UBM 62%; SIS 63%; HML 58%; and HSL 58%. Medicare reimbursements for skin substitutes per DFU episode for UBM ($1435 in skin substitutes per episode) and SIS ($1901) appeared to be equivalent to each other. Both were less than HML ($5364) or HSL ($14,424) (p<0.0005 in all four tests). HML was less costly than HSL (p<0.0005). Analysis of the four skin-substitute types resulted in a demonstration that UBM and SIS were associated with both shorter DFU episode lengths and lower payer reimbursements than HML and HSL, while HML was less costly than HSL but equivalent in healing.

SOE - Cellular and/or Tissue Products: Acellular Matrices

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Systematic reviews

A 2022 systematic review and meta-analysis included 9 RCTs (n=897 patients) [169] examined the efficacy and safety of acellular matrix (AM) therapy for patients with DFUs. Authors found that compared with the standard therapy (ST) group, patients allocated to AM group had a higher complete healing rate both at 12 weeks (risk ratio (RR) = 1.73, 95% confidence interval (CI): 1.31 to 2.30) and 16 weeks (RR = 1.56, 95% CI: 1.28 to 1.91), a shorter time to complete healing (mean difference (MD) = −2.41; 95% CI: -3.49 to -1.32), and fewer adverse events (RR = 0.64, 95% CI: 0.44 to 0.93). Authors concluded that AM therapy as an adjuvant treatment could further promote the healing of full-thickness, noninfected, and nonischemia DFUs. Evidence can be considered of low certainty (level c) due to sponsorship bias, differences in AM products and standard therapies in each study, relatively small sample size of each study.
A 2016 Cochrane systematic review included 1 RCTs (26 participants) [173] that compared the effectiveness of Oasis to that of Dermagraft (allogeneic matrix) in promoting DFU healing. There was no statistically significant difference between the groups [RR 1.1, CI 95% (0.75 - 1.6)].[149] Authors also evaluated cost of dressings. Average number of Dermagraft dressings applied was 2.54 ± 0.78, while the average number of Oasis applied was 6.46 ± 1.39. This translates to an estimated cost of $3505 for Dermagraft dressings ($1380 each) and an estimated cost of $807 for Oasis dressings ($125 each) - these amounts did not include nursing time, which can add significant costs to the treatment. This issue was addressed by Gilligan et al [158] Evidence can be considered of low certainty (evidence level C) due to high risk of bias from lack of blinding of assessors, participants and personnel and small sample size [149]

Randomized controlled trials

A 2021 industry-sponsored RCT (n=207 patients) by Lantis et al [171] evaluated the safety and efficacy of a fetal bovine acellular dermal matrix (FBADM, PriMatrix) plus standard of care (SOC) for treating hard-to-heal diabetic foot ulcers (DFUs). The study included a 2-week run-in period, a 12-week treatment phase and a 4-week follow-up phase. The primary endpoint was complete wound closure at 12 weeks. Authors found that at the first analysis point, patients treated with FBADM were found to be significantly more likely to achieve complete wound closure compared with SOC alone (mITT: 45.6% versus 27.9% p=0.008; mPP: 59.5% versus 35.6% p=0.002). The difference in outcome yielded an odds ratio of 2.2 (95% confidence interval (CI): 1.2, 3.9; p=0.008). Median time to closure within 12 weeks was 43 days for the FBADM group compared to 57 days for the SOC group (p=0.36). The median number of applications of FBADM to achieve closure was one. Authors concluded that in many cases a single application of FBADM in conjunction with SOC offers a safe, faster and more effective treatment of DFUs than SOC alone. Evidence can be considered of moderate certainty (level B) due to high risk of bias from lack of blinding of assessors, participants. Authors note that there is a patient selection bias, as the study population was likely to be healthier than the real-world patients with DFUs.
A 2021 industry sponsored RCT (n=49 patients) [172] compared use of fish skin graft with standard of care (SOC) using collagen alginate dressing in the management of treatment-resistant diabetic foot ulcers (DFUs), defined as superficial ulcers not involving tendon capsule or bone. Patients with DFUs who were first treated with SOC (offloading, appropriate debridement, and moist wound care) for a 2-week screening period were then randomized to either receiving SOC alone or SOC plus fish skin graft applied weekly for up to 12 weeks. Both study arms received a once-weekly visit that included debridement, reapplication, and dressing change in the clinic; patients in the SOC arm were additionally allowed dressing changes at home, whether by themselves or a caregiver. The primary endpoint was the percentage of wounds closed at 12 weeks. At 12 weeks, 16 of 24 patients' DFUs (67%) in the fish skin arm were completely closed, compared with 8 of 25 patients' DFUs (32%) in the SOC arm (P value = .0152 [N = 49]; significant at P < .047). Authors concluded that the application of fish skin graft to previously nonresponsive DFUs resulted in significantly more fully healed wounds at 12 weeks than SOC alone. Evidence level for this RCT can be considered of low certainty due to small sample size (imprecision), lack of patient/ healthcare personnel binding, and sponsorship bias.
A 2017 non industry sponsored RCT by Campitiello et al [231] (n=48 participants) evaluated use of flowable acellular matrix (Integra Flowable Matrix) on healing of Wagner 3 DFUs, compared with wet dressing. Complete DFU healing in the whole study population at 6 weeks was 69.56% (Integra Flowable Wound Matrix group, 86.95%, control group, 52.17%; p = 0.001). Amputation and rehospitalization rates were higher in the control group compared to the first group, therefore, the difference was statistically significant (p = 0.0019; p = 0.028, respectively). Evidence level for this RCT can be considered of low certainty due to small sample size (imprecision), lack of patient/ healthcare personnel/ assessor blinding, unclear randomization method, surrogate endpoint (short follow up of 6 weeks) (Evidence level C).
A 2016 industry-sponsored RCT by Frykberg et al [174] (56 participants, partial report) analyzed the effectiveness of Matristem (acellular matrix derived from porcine urinary bladder) and Dermagraft (allogeneic matrix) in refractory DFU healing. Results show no difference in effectiveness so far. Evidence can be considered of low certainty so far due to small sample size and lack of participant/personnel blinding (evidence level C)
A 2015 industry-sponsored large multi-centric RCT (307 participants) [170] compared use of Integra Dermal Regeneration Template (IDRT) with standard of care for the healing of refractory DFUs. Complete DFU closure during the treatment phase was significantly greater with IDRT treatment (51%) than control treatment (32%; p <0.001) at sixteen weeks. The median time to complete DFU closure was 43 days for IDRT subjects and 78 days for control subjects in wounds that healed. The rate of wound size reduction was 7.2% per week for IDRT subjects vs. 4.8% per week for control subjects (p < 0.012). Authors concluded that for the treatment of chronic DFUs, IDRT treatment decreased the time to complete wound closure, increased the rate of wound closure, improved components of quality of life and had less adverse events compared with the standard of care treatment. This RCT was published after authors of the 2016 Cochrane systematic review finalized literature review and thus was not included in the systematic review. Evidence level of this industry sponsored RCT can be considered of moderate certainty (level B), due to lack of blinding of patients and healthcare personnel.

Cost-effectiveness studies

A 2017 industry-sponsored cost-effectiveness study by Guest et al [232] utilized a Markov model to estimate cost-effectiveness of DFUs treated with adjunctive Oasis or standard care alone in a 12 month period using Medicare data. Authors found that the use of adjunctive Oasis instead of standard care alone is expected to lead to a 42% increase in the number of ulcer-free months, 32% increase in the probability of healing, and concluded that Oasis is more cost-effective than standard of care in treating refractory DFUs
A 2016 industry-sponsored, retrospective cost and effectiveness study (13,193 skin substitute treatment episodes) [168] compared the relative product cost and clinical outcomes of four skin substitutes used as adjunctive treatments for DFUs (Apligraf-HML, Dermagraft-HSL, OASIS-SIS, and MatriStem-UBM), as per 2011-2014 Medicare claims data. Both Matristem and Oasis are Acellular Matrices. The percentage of DFUs that healed at 90 days were: UBM 62%; SIS 63%; HML 58%; and HSL 58%. Medicare reimbursements for skin substitutes per DFU episode for UBM ($1435 in skin substitutes per episode) and SIS ($1901) appeared to be equivalent to each other. Both were less than HML ($5364) or HSL ($14,424) (p<0.0005 in all four tests). HML was less costly than HSL (p<0.0005). Analysis of the four skin-substitute types resulted in a demonstration that UBM and SIS were associated with both shorter DFU episode lengths and lower payer reimbursements than HML and HSL, while HML was less costly than HSL but equivalent in healing.
In a 2015 cost-effectiveness study, Gilligan et at [158] utilized data from Landsman’s trial [173] and estimated the total costs for the treatment including the cost and average number of dressings, cost of office visits and medical assessment necessary for complete healing. On average, in the cost-effectiveness analysis, the predicted 12-week cost per diabetic foot ulcer was USD 2522 for OASIS® (less costly) and USD 3889 for treatment with Dermagraft®. Dressings were equally effective.

SOE - Cellular and/or Tissue Based Products: Synthetic Matrix

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Randomized controlled trials

A 2022 industry-sponsored RCT (n=40 patients) by Armstrong et al. [175] compared resorbable glass microfiber matrix (Mirragen; Advanced Wound Matrix [BBGFM]; ETS Wound Care, Rolla, Missouri) with a standard of care group (SOC, collagen alginate dressing) at 12 weeks to help promote healing of DFU Wagner 1. The result illustrated in the intent-to-treat analysis at 12 weeks showed that 70% (14/20) of the BBGFM-treated DFUs healed compared with 25% (5/20) treated with SOC alone (adjusted P = .006). Mean PAR at 12 weeks was 79% in the BBGFM group compared with 37% in the SOC group (adjusted P = .027). Mean change in neuropathic score between baseline and up to 12 weeks of treatment was 2.0 in the BBGFM group compared with -0.6 in the SOC group where positive improvement in scores are better (adjusted P = .008). The mean number of BBGFM applications was 6.0. Authors concluded that adding BBGFM to SOC significantly improved wound healing with no adverse events related to treatment compared with SOC alone. Subjects were withdrawn from study at 6 weeks if they were not responding to the intervention BBGFM and this resulted in censoring of outcomes. Evidence level of this industry sponsored RCT can be considered of low certainty (level C), due to lack of blinding of patients and healthcare personnel, small size, outcome selection bias and industry sponsorship.

SOE - Phototherapy (LLLT)

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Systematic Review

A 2018 systematic review and meta-analysis [134] included 7 RCTs involving 194 participants. The results of meta-analysis showed that LLLT has emerged as a potential noninvasive treatment for DFUs, as LLLT was found to effectively reduce the ulcer area [weighted mean difference (WMD) 34.18, 95% confidence intervals (CI) 19.38–48.99, P < 0.00001], improve the complete healing rate [odds ratio (OR) 6.72, 95% CI 1.99–22.64, P = 0.002]. Qualitative analysis of the included RCTs found that LLLT also played a role in the treatment of DFUs through promoting rapid granulation formation and shortening ulcer closure time, as well as alleviating foot ulcer pain. None of the treatment-related adverse event was reported. Due to small sample size of the included RCTs and lack of blinding in the majority of RCTs, evidence can be considered of low certainty (evidence level C)
A 2017 Cochrane systematic review and meta-analysis [233] that included 8 RCTs (316 participants) evaluated the effectiveness of phototherapy as an adjunctive treatment to promote DFU healing. Meta-analysis of 4 RCTs (116 participants) [134] [234] [235] [236] indicated that participants receiving phototherapy may experience a greater proportion of wounds completely healed during follow-up compared with those receiving no phototherapy/placebo (64.5% for the phototherapy group versus 37.0% for the no phototherapy/placebo group; RR 1.57, 95% confidence interval 1.08 to 2.28; low-quality evidence, downgraded for study limitations and imprecision). 2 RCTs found no difference in adverse events between groups treated with phototherapy and placebo. Authors concluded that phototherapy, when compared to no phototherapy/placebo, may increase the proportion of wounds completely healed during follow-up and may reduce wound size in people with diabetes, but there was no evidence that phototherapy improves quality of life. Due to the small sample size and methodological flaws in the original trials, the quality of the evidence was low (evidence level C)
A 2016 systematic review [237] included 4 of the studies included in the 2017 Cochrane Review and found that all reviewed RCTs demonstrated therapeutic outcomes with no adverse events using LLLT for treatment of DFU compared to placebo or control.

Randomized Controlled Trial

A 2017 RCT by Mathur et al [238] (30 participants) compared DFUs treated with phototherapy (low-level laser therapy, or LLLT) with standard of care for the treatment of refractory non-infected DFUs (Meggitt-Wagner grade I). Authors found that after 2 weeks, the percentage ulcer area reduction was 37 ± 9% in the LLLT group and 15 ± 5.4% in the control group (p < 0.001). For ~75% of wounds of the treatment group, wound area reduction of 30-50% was observed. In contrast, for the control group, ~80% of wounds showed a wound area reduction of <20% on day 15. Authors concluded that LLLT is beneficial as an adjunct to conventional therapy in the treatment of diabetic foot ulcers. (evidence level C due to small sample size and surrogate end point)

SOE - Growth Factors

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Systematic Review:

A 2015 Cochrane systematic review and meta-analysis [178] assessed outcomes of 28 trials using 11 different growth factors predominantly used as topical agents including: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor beta 2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Overall, the quality of the trials was low with a high risk of bias. In a meta-analysis of 12 trials, the use of any growth factor compared with placebo or no growth factor significantly increased the number of participants with complete wound healing (53 versus 35 percent). The results were mainly based on platelet-derived wound healing formula (64 versus 26 percent, two trials, RR 2.45, 95% 1.27 to 4.74), and recombinant human platelet-derived growth factor (becaplermin) (48 versus 33 percent, five trials RR 1.47, 95% CI 1.23 to 1.76). No clear differences were apparent with respect to amputation rates, but only two trials were included in this analysis. Authors found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). There is insufficient evidence from RCTs to recommend or refute the use of growth factors in treating diabetic foot ulcers.

Guidelines

The 2016 International Working Group on the Diabetic Foot (IWGDF) [87], 2016 Society for Vascular Surgery in association with American Podiatric Medical Association (SVS) [17], the 2016 Wound Healing Society (WHS) [27] guidelines have different opinions regarding use of growth factors as adjunctive therapy to treat refractory DFUs. WHS does not recommend while SVS does.

Intervention	IWGDF	WHS	SVS
For refractory DFUs, use of growth factors to promote DFU healing, including platelet-derived growth factors (PDGF), recombinant PDGF, epidermal growth factor, etc)	1CDo not use PDGF as first line therapy (Grade 1C)	Level I, against use of intervention	1BGrade 1B, in favor of using PDGF as an adjunctive therapy if DFU does not decrease in size by at least 50% after 4 weeks of standard of care

SOE - Growth Factors: Platelet-rich Plasma (PRP)

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Systematic reviews and meta-analyses

A 2018 meta-analysis [239] included 15 RCTs with 829 patients were eligible for the present analysis. Compared with standard care/conventional treatment, PRP significantly improved the healing rate of DFUs (RR=1.39, 95% CI 1.29 to 1.50, P < 0.00001), shortened the healing time (MD= -9.18, 95% CI -11.32 to -7.05, P < 0.00001), reduced the incidence of infection (OR= 0.34, 95% CI 0.15 to 0.77, P = 0.009). Authors considered evidence of low to moderate certainty (C to B)
A 2018 systematic review [240] included eleven articles (322 PRP subjects, 126 controls) that showed that healing rate was significantly faster with PRP application compared to controls (0.68 ± 0.56 cm 2 /wk vs 0.39±0.09cm 2/wk; P <0.001). There were significantly lower adverse effects reported with PRP application compared to controls. The authors conclude that the topical application of PRP for DFUs results in statistically superior healing rates compared to controls with lower complication rates. Authors of this review classified evidence level as C. The review was conducted prior to the publication of a large RCT in 2018 ([181]), and thus did not factor it in when classifying level of evidence.
A 2016 Cochrane systematic review and meta-analysis [180] included 2 RCTs [241][242] that analyzed the effectiveness of autologous platelet rich plasma (PRP) may increase the healing of foot ulcers in people with diabetes compared with standard care (with or without placebo) (RR 1.22, 95% CI 1.01 to 1.49; I2 = 0%, low quality evidence, 2 RCTs, 189 participants). PRP may improve the healing of foot ulcers associated with diabetes, but this conclusion is based on low quality evidence from two small RCTs. It is unclear whether PRP influences the healing of other chronic wounds.

Randomized controlled trials

A 2018 RCT [181] (269 participants) compared DFU healing outcomes in patients with refractory DFUs treated with PRP (Leucopatch) and standard of care. In the LeucoPatch group, 45 (34%) of 132 ulcers healed within 20 weeks versus 29 (22%) of 134 ulcers in the standard care group (odds ratio 1·58, 96% CI 1·04-2·40; p=0·0235) by intention-to-treat analysis. Time to healing was shorter in the LeucoPatch group (p=0·0246) than in the standard care group. No difference in adverse events was seen between the groups. Authors concluded that the use of LeucoPatch is associated with significant enhancement of healing of hard-to-heal foot ulcers in people with diabetes. Evidence level B due to lack of participant and clinician blinding. Industry funded RCT.
A 2017 RCT [243] included 56 patients of both sex from 18 to 80 years, with clean chronic diabetic foot ulcers divided into 2 equal groups. The first group was treated by antiseptic ointment dressing, and the second group was treated by autologous platelet gel. Statically significant increase in healing rate was found in the PRP-treated group, and complete healing was achieved in 86% of them in comparison to 68% of the control group at the end of 12 weeks. In the study group, rate of healing per week was greater during the first 8 weeks and starts to decline afterward. The use of platelet gel showed a lower rate of wound infection. Evidence level C due to small sample size, high/unclear risk of bias from lack of blinding of personnel/patient, no mentioning of how participants randomization and allocation were done

Guidelines

The 2016 International Working Group on the Diabetic Foot (IWGDF) [87], and the 2016 Wound Healing Society (WHS) [27] guidelines do not support the use of autologous platelet rich plasma as a first line therapy. WHS does not recommend use of platelet-rich plasma as an adjunctive therapy to promote DFU healing. WHS cites the 2016 Cochrane systematic review [180] to support its view against use of platelet-rich plasma, however the systematic review concludes that there is some evidence supporting its use to promote DFU healing (evidence level C).

Intervention	IWGDF	WHS
For refractory DFUs, use of autologous platelet-rich plasma	Do not use autologous platelet rich plasma as first line therapy (Grade 1C)	Level I, against use of intervention

SOE - Autologous stem cell therapy

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Systematic reviews and meta-analyses

A 2022 meta-analysis included a total of 14 studies using mostly autologous stem cells, with 683 participants.[186] Among those, 10 were RCTs, 3 were controlled clinical studies, and 1 was a retrospective study. The meta-analysis showed that stem cell therapy was more effective than conventional therapy in terms of ulcer or wound healing rate [OR = 8.20 (5.33, 12.62)], improvement in lower extremity ischemia(new vessels) [OR = 16.48 (2.88, 94.18)], ABI [MD = 0.13 (0.04, 0.08)], TcO2[MD = 4.23 (1.82, 6.65)], pain-free walking distance [MD = 220.79 (82.10, 359.48)], and rest pain score [MD = − 1.94 (− 2.50, − 1.39)], while the amputation rate was significantly decreased [OR = 0.19 (0.10, 0.36)]. Authors concluded that this meta-analysis of the current studies has shown that stem cells are significantly more effective than traditional methods in the treatment of diabetic foot and can improve the quality of life of patients after treatment. However, there were several limitations of this meta-analysis, such as:

The included studies did not distinguish stem cells from other types of somatic cells and included several types of autologous stem cells and somatic cells (2 used peripheral blood mononuclear cells (PBMNCs), 2 used bone marrow-derived mesenchymal stem cells (BMMSCs), 3 used bone marrow-derived mononuclear cells (BMMNCs), 1 used bone marrow-enriched tissue repair cells (BMTRCs), 1 used CD133+ cells, 1 used micro-fragmented adipose tissue, 1 used human processed lipoaspirate cells, 1 used bone marrow-derived cells (BMDC), 1 used peripheral blood progenitor cells (PBPCs), 1 used BMMNCs + PBPCs, and 2 used human umbilical cord mesenchymal stem cells (HUCMSCs).
Some of the included studies were of low quality, 4 were non-randomized controlled studies, and 3 RCTs did not describe specific methods for using blind methods for participants and implementers in detail, leading to combined conclusions

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NOTE: This is a controlled document. This document is not a substitute for proper training, experience, and exercising of professional judgment. While every effort has been made to ensure the accuracy of the contents, neither the authors nor the Wound Reference, Inc. give any guarantee as to the accuracy of the information contained in them nor accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omissions in the contents of the work.

REFERENCES

Topic 1053 Version 1.0

SUBTOPICS

Diabetic Foot Ulcer Associated with Infection - Management P

Topical agents, systemic antibiotics surgical interventions for diabetic foot ulcers soft tissue infection

Diabetic Foot Ulcer Associated with Ischemia - Management P

ABSTRACTVenous Leg Ulcers (VLU) are relatively common, affecting 1% of the population in the U.S.[1] VLU can be defined as an open skin lesion of the leg or foot t

Case: Surgical offloading of a lesser toe DFU with flexor tenotomy P

This case demonstrates a classic presentation of a lesser toe diabetic foot ulcer which resolved quickly with percutaneous surgical release of the hammertoe deformity. Includes video depicting the procedure.