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Cellular and/or Tissue Based Products

Cellular and/or Tissue Based Products

Cellular and/or Tissue Based Products

ABSTRACT

Background:  

Also referred to as skin substitutes, cellular and/or tissue products (CTPs) for cutaneous wounds are products originally designed to replace autologous skin grafts in the treatment of burns and chronic wounds.[1] Despite its ability to provide satisfactory coverage of full-thickness wounds, autologous skin grafts are a limited resource, require a painful and invasive procedure, and frequently result in permanent scarring at the donor site.[2] CTPs have the potential to address many of these shortcomings. CTPs attempt to mimic the ECM and its function so as to provide a starting point for the wound healing process.

Indications

  • Burns
  • Chronic wounds, such as diabetic foot ulcers, pressure ulcers, and vascular ulcers (including venous ulcers and arterial ulcers).
  • Epidermolysis bullosa, pyoderma gangrenosum, and surgical wounds
  • Any indication as listed on the package insert

Contraindications:

  • Sensitivity or allergy to CTP components
  • Active, uncontrolled bleeding
  • Active, non-treated infection
  • Malignancy at the wound site
  • Patient’s objection to using products derived from animals (e.g., bovine, porcine, etc)

The main risks surrounding the use of allografts and xenografts for wound healing are graft rejection and transfer of disease from graft to host.

CTP Types:

  • Human Skin Allografts are bioengineered from cadaveric human skin components which have had intact cells removed or treated to avoid immunologic rejection. 
  • Allogeneic Matrices are usually derived from human cells or tissue (fibroblasts, membrane) that may contain metabolically active or regenerative components primarily used for soft tissue support. 
  • Composite Matrices are derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen. 
  • Acellular Matrices are derived from xenogeneic collagen or tissue and include the majority of CTPs

Evidence and Recommendations:

See full-text for evidence of use of CTP on venous leg ulcers, diabetic foot ulcers, pressure ulcers/injuries and acute burns.

Venous ulcers

  • 2CHuman skin allografts: Clinicians might opt to use human skin allografts and compression therapy for patients with non-healing VLU if resources are available (Grade 2C).
  • 2BAllogeneic matrix: For VLUs that failed to reduce at least 30% in 4 weeks of adequate therapy, clinicians might opt for dehydrated human amnion/chorion membrane combined with compression therapy to promote healing  (Grade 2B)
  • 2BComposite matrix: For non-healing VLUs, clinicians might consider bilayered bioengineered living cellular construct and compression over standard therapy (Grade 2B).
  • 2CAcellular matrix: Non-healing VLU can also be treated with acellular collagen matrix derived from porcine intestinal mucosa and compression therapy (Grade 2C).

Diabetic Foot Ulcer

  • 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)
  • 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)
  • 2BAllogeneic 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)
  • 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)
  • Acellular Matrix2BFor non-healing, non-ischemic, 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)

Clinical documentation requirements

To ensure optimal patient care coordination, smooth insurance reimbursement process and audit readiness, clinicians should strive for optimal documentation on medical records. See printable/fillable checklist to facilitate documentation of CTP Medicare coverage eligibility and medical necessity by clinicians at the point-of-care.   

Coding, Coverage, Reimbursement:

  • Medicare covers CTPs and provider/facility fees for patients in both outpatient and inpatient settings, provided criteria are met.
  • Not all CTPs are covered by Medicare. The fact that a CTP is approved by the FDA, has a HCPCS code and a payment rate does not imply coverage. 

  • Coverage requirements may vary across MACs, so make sure to confirm with your MAC or MAC’s LCD

 Interactive Feature Matrices  “Human Skin Allografts”“Allogeneic Matrix”“Composite Matrix” “Acellular Matrix” |  Request for Cellular and/or Tissue Products 

CLINICAL

Overview

This topic provides an overview on cellular and tissue products (CTPs) from the clinical, coverage and reimbursement perspective. For guidance on selection of CPT see "How to Select Cellular and/or Tissue Products". For decision support on different CTP brands, see interactive feature matrices  “Human Skin Allografts”, “Allogeneic Matrix”, “Composite Matrix” and “Acellular Matrix”. 

Cellular and/or tissue products (CTPs), also referred to as "Skin Substitutes" by the Centers for Medicare and Medicaid (Medicare), the Current Procedural Terminology (CPT) and the Healthcare Common Procedure Coding Manuals, have been developed in an attempt to circumvent problems inherent with autografts, allografts and xenografts. CTPs constitute biologic covers for refractory wounds with full thickness skin loss secondary to 3rd degree burns or other disease processes such as diabetic neuropathic ulcers and the skin loss of chronic venous stasis or venous hypertension. The production of these biologic skin substitutes or CTPs varies by company and product, but generally involves the creation of immunologically inert biological products containing protein, hormones or enzymes seeded into a matrix which may provide protein or growth factors proposed to stimulate or facilitate healing or promote epithelization. A variety of biosynthetic and tissue-engineered skin substitution products marketed as human skin equivalents or CTPs are manufactured under an array of trade names and marketed for a variety of indications. All are procured, produced, manufactured, processed and promoted in sufficiently different manners to preclude direct product comparison for equivalency or superiority in randomized controlled trials. Sufficient data is available to establish distinct inferiority to human skin autografts and preclude their designation as skin equivalence.[3]

Background

Definition
  • Cellular and/or tissue products for cutaneous wounds (CTPs) are products originally designed to replace autologous skin grafts in the treatment of burns and chronic wounds.[1] Despite its ability to provide satisfactory coverage of full-thickness wounds, autologous skin grafts are a limited resource, require a painful and invasive procedure, and frequently result in permanent scarring at the donor site.[2] CTPs have the potential to address many of these shortcomings.
  • Bioengineered CTPs were first created in the 1970s, when cultures of keratinocytes successfully resulted in cultured epidermal autografts (CEAs). In the 1980s, Integra Life Sciences Corporation developed Integra, the first dermal substitute. Since then, many developments have been made and many different brands of CTPs have been made available for use in clinical practice. [4]
  • CTPs are also known as “skin substitutes”, although this term is not officially adopted by the U.S. Food and Drug Administration (FDA) for any product or class of products under its regulation. A true “skin substitute” would substitute for skin like an autologous skin graft, and currently no commercially available product fully accomplishes this goal.[5][6]
Relevance
  • The global market for CTPs is expected to reach USD 1.39 billion by 2026, from USD 628.31 million in 2017, at a compounded annual growth rate (CAGR) of 9.3% from 2018 to 2026.[7]
  • Designed to mimic native tissues, CTPs represent above all, an efficient way of meeting the deficiency in donor and skin graft supplies. CTPs are frequently utilized as adjunctive therapy in wound treatment plans.
  • CTPs have gone a long way since its first iteration, but there are still challenges to be addressed, including [1]:
    • More closely mimicking autologous grafts (e.g., skin adnexa, pigmentation, etc)
    • Improvement of angiogenesis through the graft and wound bed
    • Improvement ease of use
    • Safety improvement: risks associated with allografts and xenografts such as graft rejection and transfer of disease from graft to host. These have been minimized with better skin tissue engineering techniques and rigorous donor screening.[8]

How the intervention works

  • The skin is comprised of epidermis, dermis and hypodermis, and contain extracellular matrix (ECM, also known as “scaffold”), cells and growth factors. When the skin is injured, cells migrate to the wound and growth factors orchestrate the wound healing process. However, in chronic or large wounds the natural wound healing process is impaired or insufficient. CTPs may be of benefit in these cases.[9]
  • Unlike autologous skin grafts, CTPs usually do not stay in the wound for more than a few weeks (as demonstrated by biochemical markers and DNA evidence), and there is generally no true “take” of the CTP into the wound bed.[10]
  • While the mechanisms of action are still being elucidated, application of CTPs on chronic wounds leads to significant improvement in various clinical scenarios.[11] CTPs act as a temporary cover that protects the wound bed from fluid loss and contamination, accelerate wound healing processes by stimulating release of cytokines and growth factors, and possibly attract differentiated cells (e.g., fibroblasts, endothelial cells) or stem cells to the wound.[10][11][12][13]
  • General principles that guide the design of modern functional CTPs include [4][14]:
    • Protection of the integument from loss of fluid and infection
    • Provision of a stable, biodegradable scaffold to promote the synthesis of new dermal tissue
    • Allowing cells (from host or other origin) to proliferate within the scaffold, which will act as functional dermal cells, rather than scar tissue
    • Resistance to tearing forces while being easy to handle and apply under routine conditions
    • Reduction of pain and discomfort for the patient

Composition of cellular and/or tissue products

CTPs attempt to mimic the ECM and its function so as to provide a starting point for the wound healing process. As such, CTPs may be composed of ECM, cells and/or growth factors.[9]

Extracellular matrix
  • The ECM has been traditionally viewed as a spatially defined structure in which cells and growth factors are embedded. It is now known that ECM is an active and heterogeneous tissue component capable of influencing cell survival, proliferation and function, and thus a pivotal element in wound healing. [15] In addition, ECM also controls soluble factors, nutrients and waste products within tissues. [16]
  • ECM components, mostly produced by fibroblasts, can be classified in three types [15]:
    • Fiber-forming structural molecules (e.g., collagen, fibrin): provide structure to ECM
    • Non-fiber forming structural molecules (i.e., proteoglycans and glycosaminoglycans): fill the majority of the interstitial space. Proteoglycans provide protein anchoring and regulate collagen and fibrin formation Glycosaminoglycans provide bulk and maintain hydration in ECM
    • Matricellular proteins (e.g., osteopontin): expressed temporarily in wounded skin, important for cell signalling.
Cells
  • Human skin contain different types of cells (e.g. keratinocytes, melanocytes, fibroblasts, endothelial cells, Langerhans cells (LCs), etc). All of them are pivotal elements for the skin normal function, but not critical for making CTPs. Some CTPs have cells and depending on which cells are added, CTPs will have specific features and have their functionality/complexity enhanced.[9]
Growth factors
  • Secreted by many types of cells, proteins that act as growth factors (e.g. TGF-α/ TGFβ, interleukin-1, interleukin-6, and interleukin-8) play a major role in wound healing.[17][18][19][20]
  • In chronic wounds, cells senesce and do not produce enough growth factors. Also, growth factors are degraded by proteases, perpetuating the wound healing stalled state.
  • CTPs with added growth factors may trigger cell migration, promote neovascularization, decrease fibrosis, and thus support a more efficient wound regeneration process. [9]

General Indications and Contraindications

Indications

From a practical standpoint
  • CTPs are generally indicated in the treatment of [21]:
    • Burns
    • Chronic wounds, such as diabetic foot ulcers, pressure ulcers, and vascular ulcers (including venous ulcers and arterial ulcers).
    • Epidermolysis bullosa, pyoderma gangrenosum, and surgical wounds
  • The package insert of each product should clearly state indications approved for the CTP by the responsible regulatory body in each country
  • Indications covered by Medicare and commercial insurers may vary according to their coverage criteria (see section on ‘Coding, Coverage and Reimbursement’ below)
From the US FDA perspective

Indications of each CTP depend on how the CTP is classified and regulated. Typically CTPs are regulated under one of the four categories described below, depending on the origin and composition of the product [1][22]:

  • Section 361 of the PHS Act [21 CFR 1270 & 1271]: of human origin, these CTPs are referred to as Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). HCT/Ps are minimally manipulated and are intended for homologous use only. Homologous use means “the repair, reconstruction, replacement, or supplementation of a recipient's cells or tissues with an HCT/Ps that performs the same basic function or functions in the recipient as in the donor.”[1][23][24] Establishments that manufacture HCT/Ps are required to register with the FDA before commercializing their products.
    • Human skin allografts fall under this category; indications usually include: “supplemental support, protection, reinforcement, or covering for wounds, tendon, muscle, bones”
    • Amniotic membranes also fall under this category; indications usually include “serving as a selective barrier, protection and covering of a wound”[24]
  • Class III medical device: these CTPs obtain approval through a premarket approval process (PMA).[1] There are 3 CTPs in the US that underwent the PMA process (Integra Omnigraft Dermal Regeneration Matrix - now called the Integra Dermal Regeneration Template, Dermagraft,  and Apligraf). Indications are specific to each product. For instance:
    • Apligraf is approved for the indications below:
      • “Use with standard therapeutic compression for the treatment of noninfected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1 month duration and which have not adequately responded to conventional ulcer therapy”
      • “Use with conventional diabetic foot ulcer care for the treatment of full-thickness neuropathic diabetic foot ulcers of greater than three weeks duration which extend through the dermis but without tendon, muscle, capsule or bone exposure”
  • Class I or II medical device: these CTPs obtain approval through 510 (K) submissions. In 510(K) submissions, manufacturers need to prove that the CTP is substantially equivalent to another legally marketed CTP that is not subject to a PMA. As a result, specific indications also vary for each product. For instance:
    • EndoForm Dermal Template (extracellular matrix derived from ovine forestomach) is approved “For single use in the treatment of the following wounds: partial and full-thickness wounds; pressure ulcers; venous ulcers; diabetic ulcers; chronic vascular ulcers; tunneled/undermined wounds; surgical wounds (donor sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence); trauma wounds (abrasions, lacerations, second-degree burns, and skin tears); draining wounds.”
  • Humanitarian Device Exemption: CTPs regulated under this provision are indicated in the management of conditions that affect or is manifested in fewer than 4,000 individuals in the United States per year.[1][22]

Currently there are 74 skin substitute products regulated by FDA and sold in the United States. Three products have gone through the PMA process, 26 products have gone through the 510(k) premarket submission process, and 45 products are regulated as HCT/Ps, and are derived from human cadaver skin and human placental membranes.[25]

Contraindications

Contraindications may also vary for each CTP, so it is strongly recommended that clinicians read the package insert before use. In general, contraindications include:

  • Sensitivity or allergy to CTP components
  • Active, uncontrolled bleeding
  • Active, non-treated infection
  • Malignancy at the wound site
  • Patient’s objection to using products derived from animals (e.g., bovine, porcine, etc) or tissue types (e.g., placental derived)

    Types of Cellular and/or Tissue Products

    There are many different CTP classifications, each with pros and cons. Recently, a classification system that takes elements from previous systems was described by Davison-Kolter et al., with the goal to create a system that is both intuitive for clinicians and relevant to biomaterial scientists.[2] In this system, cellularity is considered the most important discriminator among CTPs since the presence of cells increases the rejection risk and increases manufacturing complexity.[2][25] According to the Davison-Kolter system, CTPs can be characterized according to:

    • Cellularity:
      • Cellular: indicates presence of viable cells in the CTP. Presence of live cells has impact on storage, availability, cost, clinical application, and pose higher risk of host rejection if cells are not autologous.
      • Acellular: means that there are no viable cells in the CTP. Cellular materials are removed from the CTP through a decellularization process, in order to reduce risk of infection and rejection of the CTP by the recipient. Efficient decellularization methods remove cells with minimal disruption to the ECM (e.g., gamma-irradiation, freeze-thaw cycling method).[26] Some decellularization methods may also lead to more local tissue scarring due to enhanced ECM degradation.
    • Layering:
      • Single layer: generally replace either the epidermis or the dermis
      • Bilayer: generally replace both the epidermal and dermal components of the skin
    • Replaced structure:
      • Epidermis: Simple epidermal substitutes include materials such as cultured epithelial autografts. When used alone, these often result in worse clinical outcomes.
      • Dermis: Dermal substitutes or full-thickness substitutes provide greater stability, resulting in much more effective wound healing, and decreased scar tissue formation
      • Both
    • Materials used
      • Synthetic: include polyesters (e.g., polycaprolactone, poly-glycolic acid, poly-lactic acid), nylon or polyglactin meshes, and silastic or silicone membranes
      • Natural: natural polymers, such as proteins (e.g., collagen, elastin, fibrin, gelatin, silk fibroin), polysaccharides (e.g., hyaluronic acid, chondroitin sulfate, alginate), or decellularized matrices, which are (typically) composites of extracellular matrix proteins such as collagen and glycosaminoglycans
      • Both
    • Permanence:
      • Temporary (biodegradable): made of natural materials such as collagen, elastin, and other biological proteins
      • Permanent (nonbiodegradable): includes silicones, nylons

      Other criteria that are relevant for CTP classification are:

      • Origin of the CTP:
        • Autologous: from the patient
        • Allogeneic: from another not genetically identical human
        • Xenogeneic: from another species other than human
      • Cross-linking:
        • Cross-linked collagen: cross-linking collagen improves the mechanical properties and decreases degradation rates of collagen scaffolds, however it may increase inflammation and cause foreign body reactions. Cross-linking can be done with chemical (aldehydes), heat or radiation.[27]
        • Non-cross-linked collagen: collagen scaffolds may degrade more quickly, however a more natural structure is maintained.

      Classification adopted by Medicare

      In the U.S., Medicare has been utilizing the following CTP classification on several Local Coverage Determinations: human skin allografts (HSA), allogeneic matrices (AM), composite matrices (CM), and acellular matrices (ACM) [22][28]

      • Human Skin Allografts are bioengineered from human skin components and human tissue which have had intact cells removed or treated to avoid immunologic rejection. They are available in different forms promoted to allow scaffolding, soft tissue filling, growth factors and other bioavailable hormonal or enzymatic activity. See interactive feature matrix for Human Skin Allografts
      • Allogeneic Matrices are usually derived from human neonatal fibroblasts of the foreskin that 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. See interactive feature matrix for Allogeneic Matrices
      • Composite Matrices are derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen. These are also referred to as human skin equivalent but are unable to be used as autografts due to immunologic rejection or degradation of the living components by the host. Active cellular components continue to generate bioactive compounds and protein that may accelerate wound healing and epithelial regrowth. See interactive feature matrix for Composite Matrices
      • Acellular Matrices are derived from other than human skin and include the majority of CTPs (of note, there are acellular matrices derived from human skin as well, however in this classification adopted by Medicare, an acellular matrix derived from human skin would be considered as a “human skin allograft”). All CTPs in this class 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. See interactive feature matrix for Acellular Matrices

      Medicare has a separate category for blood-derived products for chronic non-healing wounds, such as autologous platelet-rich plasma (PRP)

      • Blood-derived products: Autologous blood derived products for chronic, non-healing wounds includes both: (1) platelet derived growth factor (PDGF) products (such as Procuren), and (2) PRP (such as AutoloGel). PRP is produced in an autologous or homologous manner. Autologous PRP is comprised of blood from the patient who will ultimately receive the PRP. Alternatively, homologous PRP is derived from blood from multiple donors.[29]  

      A multitude of brands exist within each CTP type, most have not been tested in randomized controlled trials (RCTs). Table 1 below shows examples of CTPs within each of the categories above, selected based on the quantity/availability/accessibility of RCTs in wound care associated with each of them.

      Table 1. Classification of cellular and tissue products utilized by Medicare, and examples. CTP: cellular and tissue product, RCT=randomized controlled trial. To compare brands within each type of CTP see CTPs Interactive Feature Matrices    

      Description Examples of brand names and associated RCTs 
      Features/comments
      Human skin allograft
      Cadaveric human skin GraftJacket [30][31][32][33][34]
      • Acellular, single layer, dermal substitute, natural (acellular dermis), temporary

      Theraskin [35][36] 
      • Cryopreserved human skin with fibroblasts and keratinocytes 
      • Cellular, bilayer, natural, temporary

       AlloPatch [37]
      • Acellular, reticular, allogenic human dermis

      DermACELL [34][38]

      • Acellular, dermal replacement
      Allogeneic matrix
      Neonatal foreskin fibroblasts on a scaffold  
      Dermagraft [36][39][40][41][42][43][44][45][46][47]
      • Polyglactin mesh with neonatal foreskin fibroblasts 
      • Cellular— allogeneic neonatal fibroblasts, single layer, dermal substitute, synthetic and natural, temporary 

      TransCyte [48][49][50]
      • Human fibroblast-derived temporary wound cover consisting of polymer membrane and donated neonatal human fibroblast cells cultured in vitro on a nylon mesh, typically used for acute burns
      Human amnion and/or chorion membrane 
      EpiFix ® ) allograft for the treatment of venous leg ulcers. | Bianchi C, Cazzell S, Vayser D, Reyzelman AM, Dosluoglu H, Tovmassian G, EpiFix VLU Study Group. et al. | 2018">[51][52][53][54][55][56][56][57]  
      • Dehydrated amnion/chorion membrane
      • Acellular, composed of multiple layers including a single layer of dehydrated epithelial cells, a basement membrane and an avascular connective tissue matrix, dermal replacement

      Amnioexcel [58] 
      • Dehydrated amniotic membrane
      • Acellular, dermal replacement

      Grafix [59][46] 
      • Cryopreserved placental membrane

      Amnioband [60]
      • Dehydrated amnion/chorion membrane
      • Acellular, dermal replacement

      No brand, made by researchers  [61]
      • Cryopreserved amniotic membrane
      Composite matrix
      Human keratinocytes and fibroblasts supported by a scaffold  
      Apligraf [35][56][55][62][63][64][65][66][67]
      • Bovine type 1 collagen with human fibroblasts and keratinocytes 
      • Cellular—allogeneic neonatal keratinocytes and fibroblasts, bilayer, epidermis and dermis (full-thickness substitute, natural—bovine collagen type I in the dermis layer, temporary
      Acellular matrix
      Allogeneic or xenogeneic derived collagen, membrane, or cellular remnants 
      Acell Cytal™ Wound Matrix (Matristem) [68][47]
      • Porcine urinary bladder matrix
      • Acellular, single layer, urinary bladder matrix, natural-porcine, temporary 

      Oasis Wound Matrix  [69][70][71][72][73][74][75] 
      • Porcine small intestine collagen
      • Acellular, single layer, natural - porcine, temporary

      Ialuset cream and gauze pad [76][77]
      • Hyaluronic acid on gauze pad

      Hyalomatrix [78]

      • Biodegradable wound contact layer made of a derivative of hyaluronic acid in fibrous form with an outer layer comprised of a semipermeable silicone membrane
      • Acellular, double layer, dermal replacement

      Promogran [79][80][81]
      • Oxidized regenerated cellulose/collagen matrix (ORC/collagen matrix)
      • Protease-modulating dressing 

      Biobrane  [82][83][84][85][48]
      • Silicone membrane bonded to a nylon mesh to which peptides from a porcine dermal collagen source have been bonded to the nylon membrane 

      Integra (dressing sheet or flowable) [86][87][88][88][88][89]
      • Dressing: Porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan and a semi-permeable polysiloxane (silicone layer)
      • Flowable: granulated cross-linked bovine tendon collagen and glycosaminoglycan

      Evidence and Recommendations

      It is important to note that clinical evidence obtained from randomized controlled trials (RCTs) is not available for the majority of CTPs, and many of the existing RCTs are sponsored by manufacturers, which raises concern about publication bias or selective outcome reporting in that poor results may not be published.[25] Many CTPs are mentioned on case reports and retrospective studies, however the design of these types of studies results in evidence with lower level of certainty as compared to that generated by RCTs. Types of wounds/ ulcers for which RCTs have been published include diabetic foot ulcers, venous leg ulcers, pressure ulcers/injuries, and burns.

      Venous Ulcers

      Please see “Venous ulcers”, section on ‘Cellular and/or Tissue Products’ for rationales and summary of evidence supporting the recommendations below.

      • 2CHuman skin allografts: Clinicians might opt to use human skin allografts and compression therapy for patients with non-healing VLU if resources are available (Grade 2C).
      • 2BAllogeneic matrix: For VLUs that failed to reduce at least 30% in 4 weeks of adequate therapy, clinicians might opt for dehydrated human amnion/chorion membrane combined with compression therapy to promote healing  (Grade 2B)
      • 2BComposite matrixFor non-healing VLUs, clinicians might consider bilayered bioengineered living cellular construct and compression over standard therapy (Grade 2B).
      • 2CAcellular matrixNon-healing VLU can also be treated with acellular collagen matrix derived from porcine intestinal mucosa and compression therapy (Grade 2C).

      Diabetic Foot Ulcers

      Please see “Diabetic Foot Ulcers”, section on ‘Cellular and/or Tissue Products’ for rationales and summary of evidence supporting the recommendations below.

      • 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)
      • 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)
      • 2BAllogeneic 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)
      • 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)
      • Acellular Matrix: 2BFor non-healing, non-ischemic, 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)

      Pressure ulcers/injuries

      Evidence of use of CTPs for pressure ulcers/injuries as reported by RCTs is relatively scarce. Many case reports and retrospective studies are available, however the design of these types of studies results in evidence with lower level of certainty as compared to that generated by RCTs.

      • Allogeneic matrix: A small RCT (evidence level C due to small size and no assessors’ blinding) reported that complete pressure ulcer healing occurred only in the interventional group (pressure ulcers treated with amniotic membranes) (p<0.001). Partial healing was significantly higher in the amnion group (p<0.03) compared with the control group (pressure ulcers treated with local Dilantin powder).[61]
      • Acellular matrix:
        • A small RCT (evidence level C due to small size, surrogate endpoint, unclear assessors’ blinding) concluded that compared with foam-treated pressure ulcers, ORC/collagen matrix–treated pressure ulcers wounds showed a statistically significant faster healing rate at 12 weeks. Healing rates positively correlated with a decreased activity of elastase and plasmin in wound exudates.[79]
        • An RCT (130 participants) compared the effect of an extracellular wound matrix made from porcine small intestinal submucosa (SIS, Oasis® Wound Matrix) with standard care on healing of Stage 3 and 4 PU/PI with 0 to >12 months duration. Overall, the proportion of complete healing and the percentage of patients with a 90% reduction in ulcer surface in the SIS group at 12 weeks of treatment were higher than in the standard of care group (40% compared to 29%, p = 0.111 and 55% compared to 38%, p = 0.037). Results suggest that SIS may promote healing of more PUs/PIs, however data were not statistically significant and participating healthcare professionals, patients and assessors were not blinded. ® wound matrix) for treating full-thickness pressure ulcers: A randomized clinical trial. | Brown-Etris M, Milne CT, Hodde JP et al. | 2018" target="_blank">[90]

      Burns

      For the management of partial thickness burns, evidence derived from RCTs suggests that:

      • Bioengineered skin substitutes, namely Biobrane, TransCyte, Dermagraft, and allogeneic cultured skin, are at least as efficacious as topical agents/wound dressings or allograft. [67]
      • Apligraf combined with autograft is at least as efficacious as autograft alone. [67]
      • Suprathel, a polylactide-based copolymer, was shown to result in satisfactory skin quality and scar formation outcomes for deep dermal burns as compared with autologous skin.[91] Another study compared Suprathel with Omiderm and concluded that although less cost-effective than Omiderm, Suprathel provided more patient comfort. [92]

      For the management of full thickness burns, evidence derived from RCTs suggests that:

      • In a 3-arm comparison among Integra(®), viscose cellulose sponge Cellonex™ or partial thickness skin autograft, all treatments after 12 months demonstrated equal clinical appearance, as well as histological and immunohistochemical findings.[88]
      • When compared with cadaveric skin allograft, Integra for treatment of full-thickness burns in pediatric patients was associated with statistically significant better outcomes upon long term follow up (2 years). Outcomes included improved scarring in terms of height, thickness, vascularity, and pigmentation. [89]

      Risks

      The main risks surrounding the use of allografts and xenografts for wound healing are graft rejection and transfer of disease from graft to host.

      • Rejection: Rejection of modern tissue substitutes is very rare for a number of reasons. Cultured epidermal cells do not express major histocompatibility class II HLA-DR antigens and are not contaminated with Langerhans cells which function as the antigen presenting cells of the skin. Second, a number of CTPs are processed to render them acellular, leaving only a protein scaffold. Other cellular substitutes often populate the graft with fetal cells that are less likely to trigger an immune response.
      • Transfer of disease from graft to host: like blood and other donated tissues, allografts are rigorously tested for a range of pathogens (including HIV, syphilis, hepatitis B and C) to reduce the risk of disease transmission to the host. They must all obtain US Food and Drug Administration (FDA) approval before clinical application, and/or facilities manufacturing them must be approved by the FDA. In the U.S, many states have regulations that also must be met. A manufacturer may also opt to be accredited by a tissue banking organization (e.g, American Association of Tissue Banks), which often have strict regulations.

      Current limitations of CTPs

      • Functional limitations: existing CTPs can only restore a few functions of autologous skin. Areas treated with CTPs do no not regain skin adnexal structures, including hair follicles and sweat glands. [4] Challenges remain restoration of functions such as sensation, thermoregulation, and perspiration [17]
        • Commercially available skin substitutes mostly replace a single layer of the skin:
          • Epidermal skin substitutes are effective in providing rapid and temporary external coverage of wounds but lack the underlying connective tissue (dermal and subcutaneous) that provides the elasticity and mechanical stability of regenerated skin.
          • Dermal skin substitutes restore the mechanical strength of skin and also provide the blood supply that nourishes epidermal layers. However, dermal layers require gradual revascularization after in-vivo implantation before application of an autologous partial thickness skin graft. Revascularization of dermal layers occurs by ingrowth of bed vessels (angiogenesis) into the graft. This process can take up to 3 weeks and significantly limits the capacity to obtain wound closure in a short period of time. Some CTPs currently allow angiogenesis. [93]
            • Dermis can be divided in papillary (superficial) and reticular. A novel CTP made of reticular dermis (AlloPatch Pliable, Musculoskeletal Transplant Foundation, Edison, N.J) has been shown to retain biological components known to facilitate wound healing and potentially minimize scarring. [94]
      • Cosmetic limitations:
        • Hypopigmentation: Hypopigmentation is commonly seen, as a result of the lack of commercially available skin substitute that incorporates melanocytes [4] [17]
        • Scarring: Different CTPs result in wound healing with different amounts of scarring.[4][95] Thick scars and fibrosis may be observed in wounds treated with CTPs with stiffer ECM (higher collagen levels).[4][96] ECM stiffness has an effect on mechanotransduction, the process of how mechanical stimuli affect cells.[96] Stiffer ECM may promote wound healing through fibrosis, resulting in thick scars, a suboptimal but common outcome in chronic wound healing.[4][96]
      • Ease of use/ logistics: most CTPs are decellularized or xenogeneic. Better outcomes could potentially be obtained with cellular CTPs with added growth factors, however off-the-shelf unavailability of cellular CTPs is a major limitation. The use of laboratory-cultured cells seeded into scaffolds has been shown to be time/resource intensive because extensive cell culture procedures are involved for the different cell types used. Cells usually require 2 to 3 weeks of cell culture before they are ready for grafting. This time lag constraints regular use of cell-seeded skin substitutes in clinical scenarios, in particular in traumatic causes.[93] In addition, if cells are frozen, CTP needs to be maintained in a temperature controlled environment and thawed prior to using.

      Experimental CTPs

      Smart scaffolds
      • Smart scaffolds, also known as cellular and bioactive constructs, represent advances of tissue engineering that aim to mimic the multifunctionality of natural ECM. They may deliver cells and/or biomolecules such as growth factors and proteins to the wound in a programmable manner. Although significant progress has been made in development of these scaffolds, few have met demands for pre-clinical or clinical applications so far. [16]
        • Growth factors are proteins secreted by many types of cells and play a major role in wound healing.[17] An experimental study suggested that smart keratinocyte scaffolds with growth factors are more efficacious for epidermal regeneration compared to keratinocytes only. [17] [97]
      • Development efforts have been focusing on smart scaffolds that can be programmed to deliver different growth factors at different stages of wound healing [17], achieve long-term stability, integrate with native tissues and have decreased potential for side effects. [16]

      How to choose CTPs

      For guidance on selection of CPT see "How to Select Cellular and/or Tissue Products". For decision support on different CTP brands, see interactive feature matrices  “Human Skin Allografts”, “Allogeneic Matrix”, “Composite Matrix” and “Acellular Matrix”. 

        Prescribing/ordering

        Prescription from a qualified healthcare professional (QHP) is required. Orders may be placed with manufacturers and/or distributors. Information needed for ordering include:

        • Patient’s demographics
        • Insurance information and policy: Medicare, Medicaid, commercial payers
          • Some commercial payers may also require prior authorization/pre-certification or predetermination for specific CTPs
        • Diagnosis, ICD-10
        • Tentative procedure date, delivery date
        • Quantity of packaged CTP: How supplied; CTPs come in different sizes
        • Number of units of CTP: Typically units are measured in square centimeters
        • Prescriber information and signature

        Documentation requirements

        To ensure optimal patient care coordination, smooth insurance reimbursement process and audit readiness, clinicians should strive for optimal documentation on medical records. For Medicare beneficiaries, clinicians should follow Local Coverage Determinations (LCD) provided by their state’s Medicare Administrative Contractor (MAC) and/or National Coverage Determinations. See section ‘Coding, Coverage, Reimbursement’. Table 2 in the section herein offers a checklist to assess Medicare CTP coverage eligibility (outpatient). Table 3 offers a checklist on Medicare documentation requirements to justify use of CTPs. We also provide a printable/fillable checklist to facilitate documentation of CTP Medicare coverage eligibility and medical necessity by clinicians at the point-of-care.   

        •    Request for Cellular and/or Tissue Products 

        Medical records documentation requirements may vary across MACs, so make sure to confirm with your MAC or MAC’s LCD. Listed below are documentation requirements compiled from existing LCDs. [22][28][98][99] All documentation must be maintained in the patient’s medical record and made available to the contractor upon request:

        1. Every page of the record must be legible and include appropriate patient identification information (e.g., complete name, dates of service[s]). The documentation must include the legible signature of the physician or non-physician practitioner responsible for and providing the care to the patient.
        2. The submitted medical record must support the use of the selected ICD-10-CM code(s). The submitted CPT/HCPCS code must describe the service performed.
        3. Medical record documentation must support the medical necessity of the services as directed by MAC’s LCDs.
        4. The documentation must support that the service was performed and must be included in the patient’s medical record. This information is normally found in the history and physical, office/progress notes, hospital notes, and/or procedure report.
          1. An operative note must support the procedure (e.g. application of skin substitute graft to legs) for the relevant date of service (first application starts the 12 week episode of care). At a minimum the operative note(s) should include pre and post op diagnosis, name of surgeon, anesthesia, reason for the procedure, complete description of the procedure including product used (with identifying package label in the chart), and relevant findings
        5. The medical record must clearly show that the criteria listed under the Covered Indications and Limitations sections of the MAC’s LCD have been met, as well as, the appropriate diagnosis and response to treatment.
          1. Documentation of response requires measurements of the initial ulcer, measurements at the completion of at least four weeks of appropriate wound care and measurements immediately prior to placement and with each subsequent placement of the bioengineered skin substitute or CTP.
        6. The documentation must support the need for skin substitute application and the product used.
          1. Documentation should include an assessment (generally in an E/M service) outlining the plan for skin replacement surgery and the choice of skin substitute product for the 12 week period as well as any anticipated repeat applications in the 12 week period.
          2. Some products highlight one application needed in an episode of care, so no anticipated repeat applications and some products note the need for repeat applications at varying intervals in the 12 week episode of care.
          3. The risk versus benefit of the procedure and alternative options for care should be documented as discussed with the patient.
        7. A description of the wound(s) must be documented at baseline (prior to beginning conservative treatment) relative to size, location, stage, duration, and presence of infection, in addition to type of treatment given and response.
          1. This information must be updated in the medical record throughout treatment.
          2. Wound description must also be documented pre and post treatment with the skin substitute graft being used.
          3. If obvious signs of worsening or lack of treatment response is noted, continuing treatment with the skin substitute would not be considered medically reasonable and necessary without documentation of a reasonable rationale for doing so.
        8. Documentation of smoking history, and that the patient has received counseling on the effects of smoking on surgical outcomes and treatment for smoking cessation (if applicable) as well as outcome of counselling must be in the medical record.
        9. The amount of utilized and wasted skin substitute must be clearly documented in the procedure note with the following minimum information:
          1. Date, time and location of ulcer treated;
          2. Name of skin substitute and how product supplied;
          3. Amount of product unit used;
          4. Amount of product unit discarded;
          5. Reason for the wastage;
          6. Manufacturer’s serial/lot/batch or other unit identification number of graft material. When manufacturer does not supply unit identification, record must document such.
          7. It is expected that where multiple sizes of a specific product are available, the size that best fits the wound with the least amount of wastage will be utilized.

        Table 2: Checklist - Cellular and/or tissue products Medicare coverage eligibility (outpatient)

        CTPs Medicare coverage eligibility
        • Medicare covers application of skin substitutes to Ulcers or Wounds with Failed Response that are:
          • Partial- or full-thickness ulcers, not involving tendon, muscle, joint capsule or exhibiting exposed bone or sinus tracts, with a clean granular base;
          • Skin deficit at least 1.0 cm² in size;
          • Clean and free of necrotic debris or exudate;
          • Free of soft tissue infection and/or osteomyelitis
          • Have adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by physical examination (e.g., Ankle-Brachial Index [ABI] of no less than 0.60, toe pressure greater than 30mm Hg);
          • For diabetic foot ulcers, the patient’s medical record reflects a diagnosis of Type 1 or Type 2 Diabetes and also reflects medical management for this condition.
        • Failed Response is defined as an ulcer or skin deficit that has failed to respond to documented appropriate wound-care measures implemented for at least 4 weeks. Ulcer has increased in size or depth, or has not changed in baseline size or depth and has no indication that improvement is likely (such as granulation, epithelialization or progress towards closing)
        • Appropriate wound care therapy must have been effectively implemented and documented for at least 4 weeks. Interventions include:
          • Control of edema, venous hypertension or lymphedema
          • Control of any nidus of infection or colonization with bacterial or fungal elements
          • Elimination of underlying cellulitis, osteomyelitis, foreign body, or malignant process
          • Appropriate debridement of necrotic tissue or foreign body (exposed bone or tendon)
          • For diabetic foot ulcers, appropriate non-weight bearing or off-loading pressure
          • For venous stasis ulcers, compression therapy provided with documented diligent use of multilayer dressings, compression stockings of greater than 20mmHg pressure, or pneumatic compression
          • Provision of wound environment to promote healing (protection from trauma and contaminants, elimination of inciting or aggravating processes)
          • Patients who have smoked will have ceased smoking or have refrained from systemic tobacco intake for at least 4 weeks during conservative wound care and prior to planned bioengineered skin replacement therapy.
        • For chronic lower extremity ulcers, conditions below also need to be met:
          • For diabetic foot ulcer: Presence of neuropathic diabetic foot ulcer(s) having failed to respond to documented conservative wound-care measures of greater than 4 weeks, during which the patient is compliant with recommendations, and without evidence of underlying osteomyelitis or nidus of infection.
          • For venous leg ulcer: Presence of a venous stasis ulcer for at least 3 months but unresponsive to appropriate wound care for at least 30 days with documented compliance.
          • For full thickness skin loss ulcer that is the result of abscess, injury or trauma: failure to respond to appropriate control of infection, foreign body, tumor resection, or other disease process for a period of 4 weeks or longer.
        • Ulcer does not fall under any items listed as “limitations” 
        Table 3 - Checklist - Medicare documentation requirements to justify use of CTPs
        Medicare documentation requirements for use of CTPs

        Baseline: prior to beginning conservative treatment

        • A description of the wound(s) with size, location, stage, duration, and presence of infection, in addition to type of treatment given and response (signs of improvement include contraction and advancement of epithelial margins and/or granulation, etc).
        • Comprehensive history & physical
        • Legible signature of the QHP responsible for and providing the care to the patient.
        • ICD-10-CM Codes

        Pre-CTP service documentation: At each visit during conservative treatment (documentation of failed response to 4 weeks of adequate conservative treatment is required for Medicare coverage)

        • A description of the wound(s) with size, location, stage, duration, and presence of infection, blood supply to the wound, in addition to type of treatment given and response.
        • Updated medication history, review of pertinent medical problems that may have occurred since the previous wound evaluation
        • Documentation of smoking cessation counseling and cessation measures prescribed. Patients who have smoked will have ceased smoking or have refrained from systemic tobacco intake for at least 4 weeks during conservative wound care and prior to planned bioengineered skin replacement therapy.
        • Adequate treatment of the underlying disease contributing to the wound. Documentation of appropriate therapy for treatment of chronic lower extremity wounds include:
          • Patient adherence to plan of care
          • Control of edema, venous hypertension or lymphedema
          • Control of any nidus of infection or colonization with bacterial or fungal elements
          • Elimination of underlying cellulitis, osteomyelitis, foreign body, or malignant process
          • Appropriate debridement of necrotic tissue or foreign body (exposed bone or tendon)
          • For diabetic foot ulcers, appropriate non-weight bearing or off-loading pressure
          • For venous stasis ulcers, compression therapy provided with documented diligent use of multilayer dressings, compression stockings of greater than 20 mmHg pressure, or pneumatic compression
          • Provision of wound environment to promote healing (protection from trauma and contaminants, elimination of inciting or aggravating processes)
        • Documentation of specific interventions that have failed and reason why
        • Appropriate diagnoses ICD-10-CM Codes
        • Treatment plan:
          • Plan for skin replacement surgery and the choice of skin substitute product for the 12 week period as well as any anticipated repeat applications in the 12 week period.
          • Risk versus benefit of the procedure and alternative options for care should be documented as discussed with the patient.
        • Legible signature of the QHP responsible for and providing the care to the patient.

        At each CTP application:

        • Application number and improvement since last treatment
          • A description of the wound(s) with size, location, stage, duration, and presence of infection and osteomyelitis, adequate blood flow, in addition to type of treatment given and response.
            • Baseline measurements taken immediately prior to initiation of treatment and with each subsequent placement of the CTP
            • If obvious signs of worsening or lack of treatment response is noted, continuing treatment with the skin substitute would not be considered medically reasonable and necessary without documentation of a reasonable rationale for doing so
        • Appropriate wound dressing changes, patient compliance, and off-loading (if applicable)
        • Procedure/operative note
          • Procedure (e.g. application of skin substitute graft to legs)
          • Pre and post op diagnosis
          • Name of QHP applying CTP
          • Anesthesia
          • Reason for the procedure
          • Complete description of the procedure including product used (with identifying package label in the chart), and relevant findings
          • Amount of CTP used and amount discarded (wastage)
            • Date, time and location of ulcer treated;
            • Name of skin substitute and how product supplied;
            • Amount of product unit used;
            • Amount of product unit discarded;
            • Reason for the wastage;
            • Manufacturer’s serial/lot/batch or other unit identification number of graft material. Expiration date. When manufacturer does not supply unit identification, record must document such.
              • It is expected that where multiple sizes of a specific product are available, the size that best fits the wound with the least amount of wastage will be utilized.
        • QHP’s choice of fixation
        • Legible signature of the QHP responsible for and providing the care to the patient.
        • ICD-10-CM Codes

        add section on patient education

        CODING, COVERAGE AND REIMBURSEMENT

        There are two sets of codes used for coding and billing of application of CTP:

        • Current Procedural Terminology (CPT) codes, used for provider and facility fees, and
        • Healthcare Common Procedure Coding System (HCPCS) Level II, used to claim reimbursement of CTP (these will be used by providers/facilities billing the payor directly)

        Typical Medicare reimbursement for CTP is as follows:

        • Medicare covers CTPs and provider/facility fees for patients in both outpatient and inpatient settings, provided criteria are met.
          • It is important to note that certain CTPs are only covered for use the outpatient setting (hospital based outpatient departments, ambulatory surgery center and/or physician’s office) and others only for use in inpatient settings. Check with your Medicare Administrative Contractor (MAC).
          • Not all CTPs are covered by Medicare. The fact that a CTP is approved by the FDA, has a HCPCS code and a payment rate does not imply coverage. MACs determine what is reasonable and necessary and whether it is covered/excluded from payment. [100]
          • There is also coverage variability across Medicare jurisdictions (Medicare beneficiaries who live in different states do not have access to the same CTPs), so make sure to check your MAC’s LCD or directly with your MAC
        • In outpatient settings:
          • Hospital-based outpatient departments (HOPD):
            • Product and facility: Reimbursement follows the Medicare outpatient prospective payment system (OPPS). Reimbursement for most CTPs are bundled with the amount Medicare pays the facility ("facility payment rate"). A few CTPs are granted a temporary OPPS pass-through status and may be reimbursed separately from the facility payment rate, but the vast majority is packaged into the OPPS payment for the associated CTP application procedure.
            • For OPPS bundling purposes, Medicare classifies CTPs in “high cost” or “low cost”:
              • High cost CTP: should be reported in combination with one of the CPT application codes 15271 to 15278. 
              • Low cost CTP: should be reported in combination with one of the CPT application procedures C5271 to C5278
              • HOPDs should report both the CPT application code and the applicable products’ HCPCS codes when submitting claims.
              • The OPPS packaged payment rate for the CPT application codes above includes reimbursement for facility overhead/supplies and reimbursement for high cost CTPs (when reported with CPT application codes 15271 to 15278) or low cost CTPs (when reported with CPT application procedures C5271 to C5278).
            • CTP with pass-through status:
              • Currently, CTPs with pass-through status are PuraPly™and  PuraPly Antimicrobial. 
              • All OPPS pass-through skin substitute products should be billed in combination with one of the skin application procedures described by CPT codes 15271-15278.
              • HOPDs will receive additional payment for a OPPS pass-through CTP only if the product cost exceeds the dollar value that CMS allocated for the device offset in the procedure allowable rate. [100]
            • Services: For claims related to application of CTPs by a qualified healthcare professional (QHP) use the CMS-1500 claim form. Utilize CPTapplication codes 15271 to 15278 regardless of whether the CTP is considered "low" or "high cost". QHP's services are reimbursed according to the Medicare Physician Fee Schedule Payment Rates. For applications performed at an HOPD, refer to the "Facility Payment Rate" (or "Physician Reimbursement - Facility"), which is typically lower than the "Non-facility Payment Rate" reserved for services performed at a QHP's office.
          • Qualified healthcare professional (QHP)’s office:
            • The CMS-1500 claim form should include billing for both the product and procedure on date when services were rendered.
              • Product: CTPs with HCPCS codes that begin with ‘‘C’’ cannot be used at the QHP’s office.[101] HCPCS codes that start with “Q” are reported per square centimeter of product purchased, like at HOPDs. [101] 
                • Reimbursement amounts for certain CTPs are listed on the Medicare Part B Average Sales Price (ASP) list published quarterly by CMS. CTPs that are not listed may be reimbursed by Medicare based on submitted invoice cost when administered in the QHP’s office. However, some Medicare Administrative Contractors (MAC) also list their own ASP amounts [102]
                • When data on CTPs that are separately reimbursed are available, WoundReference displays the CTP payment rate on the CTP product page, in the Essentials table, "Product Reimbursement" tab.
              • Services and office: CPT codes 15271 to 15278 are used to bill for QHP’s services (“low cost CTP” CPT application procedures C5271 to C5278 do not apply at the QHP office. [101] QHP's services are reimbursed according to the Medicare Physician Fee Schedule Payment Rates. For applications performed at an Office, refer to the "Non-facility Payment Rate" (or "Physician Reimbursement - Office"), reserved for services performed at a QHP's office. This payment rate includes reimbursement for the QHP's service and office overhead/supplies as well. 
          • Home Health: currently Medicare does not reimburse application of CTPs by home health agencies.
          • Tips for HOPD and QHP’s office:
            • Correctly calculate and report number of units of product and service: CPT® application codes are described in either ‘‘25- or 100-sq-cm increments’, whereas HCPCS for product codes are described as‘‘per square centimeter.’’ For instance, if a QHP purchases a 22 square centimeter product and applies on a 15 square centimeter wound, service should be reported as 1 unit of application code 15275 (reportable for the first 25 sq. cm of a wound), and product should be reported as 22 units of the appropriate HCPCS code for the product. [101]
            • Modifiers: LCDs of each MAC may have specific instructions on the need to append the product codes with the JC modifier (skin substitute used as a graft)
            • Unused/discarded portion: All clinicians are required by Medicare to document the discarded portion of the CTP in the patient’s medical record. For QHPs’ offices, the discarded amount shall be billed on a separate claim line using the JW modifier. HOPDs must report the discarded portions only if the CTPs has a pass-through status.[101]
        • In inpatient settings:
          • Hospitals: CTPs are not separately reimbursed and are included in DRG payment.
          • Skilled nursing facility: absorbs cost in first 100 days, then patient absorbs cost under Medicare Part B (if available)

        Medicare Administrative Contractors and Local Coverage Determinations

        Medicare coverage of provider and facility fees related to application of CTPs is managed by Medicare Administrative Contractors (MAC), under Medicare Part A or Part B. Each jurisdiction may have its own specific local coverage determination and policies, as follows:

        • Novitas Solutions, Inc.
          • Application of Bioengineered SKIN Substitutes to Lower Extremity Chronic Non-Healing Wounds (L35041) [3]
          • Application of Bioengineered Skin Substitutes to Lower Extremity Chronic Non-Healing Wounds Policy (A54117) [103]
        • CGS Administrators, LLC:
          • Wound Application of Cellular and/or Tissue Based Products (CTPs), Lower Extremities (L36690) [28]
        • Palmetto: no active LCD. LCD and article below retired on 1/3/2019 due to the rapidly changing nature of this category of treatments- skin substitutes vs. wound dressings.
          • Application of SKIN SUBSTITUTES (L36466) - Retired [99]
          • Billing Requirements for Application of SKIN SUBSTITUTES (Part B Services Only) (A55035) - Retired [104]
        • First Coast Service Options, Inc. (FCSO):
          • Application of SKIN SUBSTITUTE Grafts for Treatment of DFU and VLU of Lower Extremities (L36377) [98]
          • Response to Comments: Application of SKIN SUBSTITUTE Grafts for Treatment of DFU and VLU of Lower Extremities (A55813) [105]
        • National Government Services, Inc. (NGS): no active LCD
        • Noridian:
          • Local Coverage Article: Use of Amniotic Membrane Derived Skin Substitutes (A56155) [106]
          • Local Coverage Article: Use of Amniotic Membrane Derived Skin Substitutes (A56156) [107]
        • Wisconsin Physicians Service Insurance Corporation (WPS): no active LCD

        CPT® Codes

        High cost

        Table 4 illustrates CPT ® codes for application of “high cost” CTP (applicable to hospital-based outpatient departments, ambulatory surgical center and qualified healthcare professional’s office (QHP). Of note, ‘High-cost’’ and ‘‘low-cost’ designation of products does not apply to QHPs’ offices. To see current average rates: on WoundReference, go to the webpage of the CTP of interest, find the “Essentials” table, click on “Procedures Reimbursement” tab.

        Table 4. CPT ® codes for application of “high cost” CTP

        CPT ® Codes

        Description

        15271

        Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq. cm or less of wound surface area

        15272

        each additional 25 sq. cm wound surface area, or part thereof (List separately in addition to code

        for primary procedure)

        15273

        Application of skin substitute graft to trunk, arms, legs, total wound surface greater than or equal to 100 sq. cm; first 100 sq. cm wound surface area, or 1% of body area of infants and children

        15274

        each additional 100 sq. cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof (List separately in addition to code for primary procedure)

        15275

        Application of skin substitute graft to face, scalp, feet, etc., total wound surface area up to 100 sq. cm; first 25 sq. cm or less

        15276

        each additional 25 sq. cm wound surface area, or part thereof (List separately in addition to code for primary procedure)

        15277

        Application of skin substitute graft to face, scalp, feet, etc., total wound surface area greater than or equal to 100 sq. cm; first 100 sq. cm wound surface area, or 1% of body area of infants and children

        15278

        each additional 100 sq. cm wound surface area, or part thereof, or each additional 1% of body area of infants and children) (List separately in addition to code for primary procedure)

        Low cost

        Table 5 illustrates CPT ® codes for application of “low cost” CTP (applicable to hospital-based outpatient departments, ambulatory surgical center). Of note, ‘‘High-cost’’ and ‘‘low-cost’ designation of products does not apply to QHPs’ offices. To see current average rates: on WoundReference, go to the webpage of the CTP of interest, find the “Essentials” table, click on “Procedures Reimbursement” tab.

        Table 5 CPT ® codes for application of “low cost” CTP

        CPT ® Codes

        Description

        C5271

        Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area

        C5272

        Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof (list separately in addition to code for primary procedure)

        C5273

        Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children

        C5274

        Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof (list separately in addition to code for primary procedure)

        C5275

        Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area

        C5276

        Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof (list separately in addition to code for primary procedure)

        C5277

        Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children

        C5278

        Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof (list separately with primary procedure)

        HCPCS Level II Codes

        Each CTP is assigned a different HCPCS Level II code. To find each CTP’s HCPCS: on WoundReference, go to the webpage of the CTP of interest, find the “Essentials” table, click on “HCPCS II” tab.

        Modifiers

        • JC skin substitute used as a graft
        • JD skin substitute not used as a graft
        • JW drug or biological amount discarded/not administered to any patient

        Medicare Coverage and Utilization

        See Coverage eligibility and documentation checklist 'Request for Cellular and/or Tissue Products'

        Medicare eligibility

        Coverage requirements may vary across MACs, so make sure to confirm with your MAC or MAC’s LCD. Listed below are coverage eligibility requirements compiled from existing LCDs.[22][28][98][99]

        • Medicare covers application of skin substitutes to Ulcers or Wounds with Failed Response that are
          • Partial- or full-thickness ulcers, not involving tendon, muscle, joint capsule or exhibiting exposed bone or sinus tracts, with a clean granular base;
          • Skin deficit at least 1.0 cm² in size;
          • Clean and free of necrotic debris or exudate;
          • Free of soft tissue infection and/or osteomyelitis
          • Have adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by physical examination (e.g., Ankle-Brachial Index [ABI] of no less than 0.60, toe pressure greater than 30 mm Hg);
          • For diabetic foot ulcers, the patient’s medical record reflects a diagnosis of Type 1 or Type 2 Diabetes and also reflects medical management for this condition.
        • Failed Response is defined as an ulcer or skin deficit that has failed to respond to documented appropriate wound-care measures implemented for at least 4 weeks. Ulcer has increased in size or depth, or has not changed in baseline size or depth and has no indication that improvement is likely (such as granulation, epithelialization or progress towards closing)
        • Appropriate wound care therapy must have been effectively implemented and documented for at least 4 weeks. Interventions include:
          • Control of edema, venous hypertension or lymphedema
          • Control of any nidus of infection or colonization with bacterial or fungal elements
          • Elimination of underlying cellulitis, osteomyelitis, foreign body, or malignant process
          • Appropriate debridement of necrotic tissue or foreign body (exposed bone or tendon)
          • For diabetic foot ulcers, appropriate non-weight bearing or off-loading pressure
          • For venous stasis ulcers, compression therapy provided with documented diligent use of multilayer dressings, compression stockings of greater than 20 mmHg pressure, or pneumatic compression
          • Provision of wound environment to promote healing (protection from trauma and contaminants, elimination of inciting or aggravating processes)
          • Patients who have smoked will have ceased smoking or have refrained from systemic tobacco intake for at least 4 weeks during conservative wound care and prior to planned bioengineered skin replacement therapy.
        • For chronic lower extremity ulcers, conditions below also need to be met:
          • For diabetic foot ulcer: Presence of neuropathic diabetic foot ulcer(s) having failed to respond to documented conservative wound-care measures of greater than 4 weeks, during which the patient is compliant with recommendations, and without evidence of underlying osteomyelitis or nidus of infection.
          • For venous leg ulcer: Presence of a venous stasis ulcer for at least 3 months but unresponsive to appropriate wound care for at least 30 days with documented compliance.
          • For full thickness skin loss ulcer that is the result of abscess, injury or trauma: failure to respond to appropriate control of infection, foreign body, tumor resection, or other disease process for a period of 4 weeks or longer.

        Coverage limitations and utilization guidance

        Policies may vary across MACs, so make sure to confirm with your MAC or MAC’s LCD. Listed below are coverage limitations and utilization guidance compiled from existing LCDs. [22][28][98][99]

        • CTPs are not covered for partial thickness loss with the retention of epithelial appendages
        • Skin substitute grafts will be allowed for the episode of wound care in compliance with FDA guidelines for the specific product (see utilization guidelines) not to exceed 10 applications or treatments. In situations where more than one specific product is used, it is expected that the number of applications or treatments will still not exceed 10.
        • Simultaneous use of more than one product for the episode of wound is not covered. Product change within the episode of wound is allowed, not to exceed the 10 application limit per wound per 12 week period of care.
        • Treatment of any chronic skin wound will typically last no more than twelve [14] weeks.
        • Repeat or alternative applications of skin substitute grafts are not considered medically reasonable and necessary when a previous full course of applications was unsuccessful.
        • Retreatment of healed ulcers, those showing greater than 75% size reduction and smaller than 0.5 sq.cm, is not considered medically reasonable and necessary.
        • Skin substitute grafts are contraindicated and are not considered reasonable and necessary in patients with inadequate control of underlying conditions or exacerbating factors (e.g., uncontrolled diabetes, active infection, etc).
        • Skin substitute grafts are contraindicated in patients with known hypersensitivity to any component of the specific skin substitute graft (e.g., allergy to avian, bovine, porcine, equine products).
        • Repeat use of surgical preparation services (CPT codes 15002, 15003, 15004, and 15005) in conjunction with skin substitute application codes will be considered not reasonable and necessary
        • Re-treatment within one [1] year of any given course of skin substitute treatment for a venous stasis ulcer or (diabetic) neuropathic foot ulcer is considered treatment failure and does not meet reasonable and necessary criteria for re-treatment of that ulcer with a skin substitute procedure.
        • MAC Noridian Healthcare Solutions only covers CTPs derived from amniotic membranes for VLUs and DFUs [106][107]

        Medicare Coverage with Evidence Development (CED) 

        • Medicare covers certain interventions being evaluated in clinical trials in the U.S, that meet criteria listed on NCDs created specifically for this purpose.[108]

        Commercial Health Plans

        • UnitedHealthcare Oxford Clinical Policy: Skin and Soft Tissue Substitutes [109]
        • Boston Medical Center Health Plan, Inc Policy: Skin Substitutes in the Outpatient Setting [110]

        CMS QUALITY MEASURES

        Below are measures that are directly related to CTPs.[111] Medicare Quality Payment Program currently does not have CTP-specific measures. Listed below are CTP measures issued by the US Wound Registry.

        Setting CMS Program Developed by Measure ID Title Description
        Outpatient Quality Payment Program - Merit-based incentive payment system (MIPS) (*)
        US Wound Registry CDR-9 Appropriate use of Cellular and/or Tissue Based Product (CTP) in diabetic foot ulcers (DFUs) or venous leg ulcer (VLUs) 
        Percent of patients 18 or older with venous or diabetic foot ulcer who receive cellular and/or tissue based products (CTPs) appropriately. Appropriate Use of CTPs for a DFU or VLU is defined as use that adheres to Medicare coverage policy regarding the total number of applications over a specific timeframe. Regional Medicare Administrative  Carrier (MAC) policies differ but using the most restrictive Local Coverage Determination (LCD),  appropriate use is defined as:  No more than 10 applications per wound, CTP applications do not continue if the wound is unchanged in size or larger in size after 4 weeks have elapsed from the first application, CTP applications do not continue once the wound is 0.5 cm2 or smaller. Prior to application of a CTP, patient should undergo vascular assessment to exclude ischemia, control bioburden, and debride necrotic material, as well as provide other appropriate basic interventions such as compression of a venous ulcer or offloading of a diabetic foot ulcer. Currently the benchmark rate is only 23%. 
        * The Quality Payment Program was implemented in the U.S. by Medicare in 2017. Merit-based incentive payment system (MIPS) is designed for eligible clinicians who bill under Medicare Part B.

        REVISION UPDATES


        DateDescription
        4/1/2019Added new section 'Commercial Health Plans', Oxford Health Plans Policy and Boston Medical Center Health Plan, Inc Policy

        Official reprint from WoundReference® woundreference.com ©2018 Wound Reference, Inc. All Rights Reserved
        Use of WoundReference is subject to the Subscription and License Agreement. ​
        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.

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        Topic 16 Version 1.1

        Subtopics

        Skin Substitute:Duration of ulcer - approximately 89 weeksWound free of infection, osteomyelitis, surrounding cellulitis, tunnels/tracts, necrotic tissue - yesInitial Application/Reapplication - 3rd applicationSkin substitute used - Grafix PrimeMethod of fixation - Mepitel, steristripsLot # - A160300Unit # - 16003Part # - PS60013Expiration date - 6/14/18

        Allogeneic Matrices are cellular and/or tissue products usually derived from human neonatal fibroblasts of the foreskin, and may contain metabolically active or regenerative components

        Composite Matrices are a type of cellular and/or tissue products derived from human keratinocytes and fibroblasts supported by a scaffold of synthetic mesh or xenogeneic collagen.

        Human Skin Allografts are bioengineered from human skin components and human tissue which have had intact cells removed or treated to avoid immunologic rejection.