Bioengineered Skin Substitutes

Clinical & Quality Management MEDICAL POLICY
BIOENGINEERED SKIN SUBSTITUTES

Policy Number: 2016M0011B Effective Date: April 1, 2016
Table of Contents: Page: Cross Reference Policy:

POLICY DESCRIPTION 2 Not Available
COVERAGE RATIONALE/CLINICAL CONSIDERATIONS 2
BACKGROUND 8
REGULATORY STATUS 12
CLINICAL EVIDENCE 19
APPLICABLE CODES 21
REFERENCES 26
POLICY HISTORY/REVISION INFORMATION 31
INSTRUCTIONS:
“Medical Policy assists in administering UCare benefits when making coverage determinations for members
under our health benefit plans. When deciding coverage, all reviewers must first identify enrollee eligibility,
federal and state legislation or regulatory guidance regarding benefit mandates, and the member specific
Evidence of Coverage (EOC) document must be referenced prior to using the medical policies. In the event of a
conflict, the enrollee's specific benefit document and federal and state legislation and regulatory guidance
supersede this Medical Policy. In the absence of benefit mandates or regulatory guidance that govern the
service, procedure or treatment, or when the member’s EOC document is silent or not specific, medical policies
help to clarify which healthcare services may or may not be covered. This Medical Policy is provided for
informational purposes and does not constitute medical advice. In addition to medical policies, UCare also uses
tools developed by third parties, such as the InterQual Guidelines®, to assist us in administering health benefits.
The InterQual Guidelines are intended to be used in connection with the independent professional medical
judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.
Other Policies and Coverage Determination Guidelines may also apply. UCare reserves the right, in its sole
discretion, to modify its Policies and Guidelines as necessary and to provide benefits otherwise excluded by
medical policies when necessitated by operational considerations.”
Copyright 2016, Proprietary Information of UCare

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POLICY DESCRIPTION:
This document addresses the use of human skin substitutes (also referred to as artificial skin) for the
treatment of acute and chronic non-healing wounds and soft tissue grafting. The goals are to provide
temporary wound coverage, provide complete wound closure, reduce time to healing, lessen pain,
minimize postoperative contracture, improve aesthetics and functional abilities, obviate the need for more
extensive treatments such as skin grafting or amputation, and improve overall quality of life.
COVERAGE RATIONALE / CLINICAL CONSIDERATIONS:

REASONABLE AND MEDICALLY NECESSARY:
AlloDerm® is considered MEDICALLY NECESSARY in post‐mastectomy breast reconstructive surgery for at
least one of the following indications:
• When there is insufficient tissue expander or implant coverage by the pectoralis major muscle and
additional coverage is required; OR
• When there is viable but compromised or thin post-mastectomy skin flaps that are at risk of dehiscence
or necrosis; OR
• The infra-mammary fold and lateral mammary folds have been undermined during mastectomy and re-
establishment of these landmarks is needed.
Apligraf® is considered MEDICALLY NECESSARY for at least one of the following indications:
• Venous insufficiency skin ulcers with all the following characteristics:
o Chronic, non-infected, partial or full-thickness ulcers due to venous insufficiency,
o Standard therapeutic compression also in use,
o At least one month of conventional ulcer therapy (such as standard dressing changes, and standard
therapeutic compression) has been ineffective.
• Diabetic foot ulcers with all the following characteristics:
o Full-thickness neuropathic diabetic foot ulcers,
o Extends through the dermis but without tendon, muscle, joint capsule, or bone exposure,
o At least four weeks of conventional ulcer therapy (such as surgical debridement, complete off-
loading and standard dressing changes) has been ineffective.
Artiss® fibrin sealant is considered MEDICALLY NECESSARY for the treatment of individuals with severe
burns when all of the following criteria are met:
• The treatment is specific to noninfected partial-thickness burn wounds and donor site wounds,
• Excision of the burn wound is complete (e.g., nonviable tissue are removed) and homeostasis achieved,
• Sufficient autograft tissue is not available at the time of excision, OR
• Autograft is not desirable due to the individual's physiologic condition (e.g., individual has multisystem
injuries such that creating new wounds may cause undue stress).
Biobrane® is considered MEDICALLY NECESSARY for the treatment of burn wounds when all of the
following criteria are met:
• The treatment is specific to noninfected partial-thickness burn wounds and donor site wounds,
• Excision of the burn wound is complete (e.g., nonviable tissue are removed) and homeostasis achieved,

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• Sufficient autograft tissue is not available at the time of excision, OR

• Autograft is not desirable due to the individual's physiologic condition (e.g., individual has multisystem
injuries such that creating new wounds may cause undue stress).
Dermagraft® is considered MEDICALLY NECESSARY when used for at least one of the following indications:
• The treatment of full-thickness diabetic foot ulcers of greater than six weeks duration that has not
adequately responded to standard therapy, that extend through the dermis, but without tendon,
muscle, joint capsule, or bone exposure; OR
• When used on wounds with dystrophic epidermolysis bullosa.
Epicel™ is considered MEDICALLY NECESSARY for the treatment of deep dermal or full-thickness burns
when all of the following medical necessity criteria are met:
• The burns comprise 30 percent or greater of total body surface area,
• When used in conjunction with split-thickness autografts or alone in individuals for whom split-
thickness autografts may not be an option due to the severity and extent of their burns,
• Approval has been obtained for the use of Epicel™ in accordance with the above US Food and Drug
Administration (FDA)-labeled indications under the Humanitarian Device Exemption (HDE).
Epifix® is considered MEDICALLY NECESSARY for the treatment of:

 Neuropathic diabetic foot ulcers (DFUs) when all of the following criteria are met:
o The patient has the current medical diagnosis of either Type I or Type II diabetes mellitus
o The patient does not have a current HbA1c reading above 12%
o Only for partial or full thickness ulcers of greater than four weeks in duration, with documented
failure of prior treatment to heal the wound
o Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure
o Ulcer must exhibit no signs of infection
o Patient must have adequate circulation to the affected extremity
o Conservative measures must be in place (e.g., debridement, non-weight bearing, use of pressure-
reducing footwear)
 Non-infected partial or full-thickness skin ulcers due to venous insufficiency (e.g., venous stasis ulcers):
o Only for ulcers that have failed to respond to documented conservative measures of greater than
four (4) weeks in duration (e.g., wound tissue hydration with saline, regular dressing changes,
debridement, and standard therapeutic compression).
Grafix®Core is considered MEDICALLY NECESSARY for treatment of Standard diabetic foot ulcers (DFUs)
when all of the following criteria are met:
• The patient has the current medical diagnosis of either Type I or Type II diabetes mellitus,
• The patient does not have a current HbA1c reading above 12%,
• Only for partial or full thickness ulcers of greater than four weeks in duration, with documented failure
of prior treatment to heal the wound,
• Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure,
• Ulcer must exhibit no signs of infection,
• Patient must have adequate circulation to the affected extremity,
• Conservative measures must be in place:
o Debridement of necrotic tissue

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o Non-weight bearing regimen

o Use of pressure-reducing footwear
GRAFTJACKET® Regenerative Tissue Matrix is considered MEDICALLY NECESSARY for treatment of full-
thickness diabetic foot ulcers greater than four-week duration that extend through the dermis, but without
tendon, muscle, joint capsule or bone exposure.
Hyalomatrix® is considered MEDICALLY NECESSARY for the treatment of deep burns and full‐thickness
wounds; also provides a wound preparation support for the implantation of autologous skin grafts.
Integra™ Bilayer Matrix Wound Dressing, Dermal Regeneration Template, and Meshed Bilayer Wound
Matrix, artificial skin substitutes products, are considered MEDICALLY NECESSARY in the post-excisional
treatment of severe burns (full-thickness, 3rd degree), or (deep partial-thickness, 2nd degree) when
autografting is not feasible due to the individual's weakened physiological condition where there is a
limited amount of their own skin to use or they are too ill to have more wound sites created.
Oasis® Wound Matrix and Oasis® Ultra Tri-Layer Matrix are considered MEDICALLY NECESSARY for
treatment of chronic, noninfected, partial- or full-thickness lower-extremity vascular ulcers, which have not
adequately responded following a one-month period of conventional ulcer therapy.
OrCel™, a composite skin substitute, is considered MEDICALLY NECESSARY for the following indications:
• Dystrophic epidermolysis bullosa in children who are undergoing reconstructive hand surgery.
• Full-thickness (3rd degree) and partial-thickness (2nd degree) thermal burns.
• Healing donor site wounds in burn victims.
Primatrix™, Dermal Repair Scaffold is an acellular dermal tissue matrix considered MEDICALLY NECESSARY
for wound management for the following conditions:
• Partial thickness wounds
• Full thickness wounds with or without exposed bone and/or exposed tendon
• Pressure ulcers
• Diabetic ulcers
• Venous ulcers
• Surgical wounds
• Trauma wounds
• Tunneled/undermined wounds
• Draining wounds
Treatment courses typically involve a maximum of five applications.
TransCyte™, a allogeneic human dermal fibroblasts dressing, is considered MEDICALLY NECESSARY for the
following uses:
• Temporary wound covering to treat surgically excised full-thickness (3rd degree) and deep partial-
thickness (2nd degree) thermal burn wounds in persons who require such a covering before autograft
placement.
• The treatment of middermal to indeterminate depth burn wounds that typically require debridement
and that may be expected to heal without autografting.
Theraskin®, a biologically active cryopreserved human skin allograft, is considered MEDICALLY NECESSARY

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for the treatment of venous stasis ulcers (VSUs) and standard diabetic foot ulcers (DFUs) when all of the
following criteria are met:
• The patient has the current medical diagnosis of either Type I or Type II diabetes mellitus,
• The patient does not have a current HbA1c reading above 12%,
• Only for partial or full thickness ulcers of greater than four weeks in duration, with documented failure
of prior treatment to heal the wound,
• Ulcer extends through the dermis, with or without tendon, muscle, capsule or bone exposure,
• Ulcer must exhibit no signs of infection,
• Patient must have adequate circulation to the affected extremity,
• Conservative measures must be in place:
o Debridement of necrotic tissue
o Non-weight bearing regimen
o Use of pressure-reducing footwear
o Acceptable methods of wound care, such as saline moistened dressings
INVESTIGATIONAL AND NOT MEDICALLY NECESSARY:

• When criteria above are not met, or for any other application not listed, the use of AlloDerm®,
Apligraf®, Artiss®, Biobrane®, Dermagraft®, Epicel®, Epifix®, Grafix®Core, Hyalomatrix®, GRAFTJACKET®
Regenerative Tissue Matrix, Integra Bilayer Matrix Wound Dressing®, Oasis®, OrCel®, Primatrix™,
TransCyte®, and Theraskin® are considered EXPERIMENTAL/INVESTIGATIONAL AND NOT MEDICALLY
NECESSARY.
• The use of all other allogeneic, xenographic, synthetic and composite skin substitutes products for
wound healing or soft tissue grafting, not addressed in the Coverage Determination section, including
but not limited to the following products, is considered INVESTIGATIONAL AND NOT MEDICALLY
NECESSARY:
• AlloMax™
• Allopatch HD™
• Alloskin™
• Alloskin RT™
• AmnioFix™
• Arthroflex™
• Avaulta Plus™
• C-QUR™
• CellerateRX®
• CollaFix™
• Collamend™
• Conexa™
• CorMatrix®
• CRXa™
• Cuffpatch™
• Cymetra®
• Dermacell™
• Dermamatrix®
• Endoform™

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• ENDURAgen™
• Epidex®
• E-Z Derm™
• Flex HD®
• Gammagraft™
• GORE BIO-A® Fistula Plug
• Graftjacket™ Xpress injectable
• Hyalomatrix®
• Inforce®
• Integra™ Neural Wrap
• Matriderm®
• Matristem®
• MediHoney®
• Medeor™
• Mediskin®
• Memoderm™
• Menaflex™ Collagen Meniscus Implant
• Meso BioMatrix™
• Neoform Dermis™
• Neuragen®
• NeuraWrap™
• Neuroflex™
• NeuroMatrix™
• OrthADAPT™
• Pelvicol®
• Pelvisoft®
• Permacol™
• PTFE felt™
• Promogran™
• Puracol®
• SportMesh™
• Strattice™
• SurgiMend®
• Surgisis® Biodesign™AFP™ Anal Fistula Plug,
• Surgisis® Biodesign™ Gold™ Inguinal Hernia Matrix
• Surgisis® Biodesign™ Recto-Vaginal Fistula Plug
• Talymed™
• TenoGlide™
• TissueMend®
• Unite™
• Veritas® Collagen Matrix
• Xelma™
• X-Repair™
• XenMatrix™

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Clinical Considerations:
General Utilization Guidelines:
• Treatment with skin substitute occurs weekly, and is expected to last up to twelve (12) weeks.
• Reapplication of skin substitute within one week for the same ulcer is considered not reasonable
and necessary.
• Re-treatment within one year following the last successful application with is considered not
reasonable and necessary.
• Re-treatment of an ulcer following the unsuccessful treatment where it consisted of two (2) failed
applications is considered not reasonable and necessary.
Contraindications include:
 Evidence of arterial occlusive disease, i.e., ankle-brachial index (ABI) < 0.65.
 Evidence of infection in ulcer(s) targeted for treatment.
 Exudate consistent with heavy bacterial contamination, or necrotic tissue that would interfere with
graft take and healing.
 Active Charcot disease.
 Hypersensitivity or allergy to any components of the skin substitutes
The efficacy and safety of these skin substitutes in patients who are pregnant or lactating, have
uncontrolled diabetes, or are currently being treated with corticosteroids, immunosuppressants, or
chemotherapy have not been established (Sabolinski et al., 1996; Falanga et al., 1998; Falanga and
Sabolinski, 1999).
Evaluation/Risk Assessment/Screening
• Initial and continuous pressure ulcer risk assessment using reliable scales
• Nutritional assessment with a validated measure
• Document medical and surgical history
• Assessment of psychosocial conditions and quality of life
• Environmental assessment
• Physical examination, including wound assessment
• Diagnostic tests
Prevention/Rehabilitation
• Skin inspection and maintenance
• Hydration and nutrition plan of care
• Rehabilitative and restorative programs
• Positioning standards of care to manage pressure ulcers
• Off-loading equipment including chairs, intensive care, and operating rooms
• Interdisciplinary team approach
• Education
Management/Treatment
o Remove/alleviate all causes of pressure ulcer damage
o Debride, cleanse, and dress the wound
o Advanced or adjuvant interventions
o Surgical interventions

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o Documentation of response
o Palliative care
Follow-Up Care
The individual should be self-sufficient with follow-up care or have the required support system to
participate in the follow-up care associated with skin substitutes.
BACKGROUND:
Skin wounds can be caused by a variety of different events, including thermal burns, venous stasis,
ischemia, pressure, trauma, or surgery, and as a result of an underlying skin disorder such as epidermolysis
bullosa (EB). According to the American Burn Association (ABA), an estimated 1 million burn injuries occur
annually in the United States. Burn injuries result in approximately 4500 deaths, 45,000 hospitalizations,
and 700,000 emergency room visits per year. The average size of a burn injury among patients admitted to
burn centers is approximately 14% of the total body surface area (TBSA). Partial-thickness, or second-
degree, burns are those in which there is damage to the epidermis and the upper portion of the dermis.
Serious burns are treated by split-thickness autographs (STGs), which include part of the dermis, and are
obtained from such areas as the inner thigh or buttocks, and placed on the wound.
Chronic wounds, including venous ulcers, diabetic foot ulcers, and pressure sores, are a major public health
problem in the United States; the total prevalence of these wounds has been estimated to range from 3 to
6 million. Difficult-to-heal wounds lead to high rates of morbidity and mortality, negative effects on quality
of life, and high healthcare costs. Lower extremity ulcers affect approximately 1% of the adult population
and approximately 3.6% of persons older than 65 years. While lower extremity ulcers have numerous
causes, such as venous disease, arterial disease, mixed venous-arterial disease, diabetic neuropathy,
trauma, immobility, and vasculitis, over 90% of the lesions are related to venous or arterial disease and
neuropathy.
SKIN GRAFTING.
There are currently a wide variety of products available for soft tissue grafting and wound treatment. These
products may be derived from allogeneic, xenographic, synthetic, or a combination of any or all of these
types of materials.
Autologous skin grafts also referred to as autografts, are permanent covers that use skin from different
parts of the individual's body. These grafts consist of the epidermis and a dermal component of variable
thickness. A split-thickness skin graft (STSG) includes the entire epidermis and a portion of the dermis. A
full-thickness skin graft (FTSG) removes all the layers of the skin. Although autologous skin grafts are the
optimum choice for wound coverage, areas of skin for harvesting may be limited, particularly in cases of
large burns; in addition, the procedures are invasive and painful. Allografts (which use skin from another
human [e.g., cadaver]) and xenografts (which use skin from another species [e.g., porcine or bovine]) may
also be employed as temporary skin replacements, but they must later be covered by an autograft.
BIOENGINEERED SKIN SUBSTITUTES.
Because of problems inherent with autografts, allografts, and xenografts, bioengineered skin substitutes
have been developed. These are products used for non-healing wound treatment and soft tissue grafting
on patients with life threatening full-thickness (3rd degree) or deep partial‐thickness (2nd degree) burns,
surgical wounds, diabetic ulcers, venous ulcers, and epidermolysis bullosa. These products are

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manufactured by starting with a few human cells in which tissue engineers simulate the environments that
allow cells to develop into viable tissue. The specific procedure varies by company, but it generally involves
seeding the selected cells onto some type of matrix, where they are then provided with the proteins and
growth factors necessary for them to grow and multiply into the desired tissue.
A variety of biosynthetic and tissue-engineered human skin equivalents (HSE) are manufactured under an
array of trade names and marketed for various purposes. All of these products are procured, produced,
manufactured or processed in sufficiently different manners that they cannot be addressed and evaluated
as equivalent products.
Bioengineered skin substitutes are classified into the following types:
 Cultured epithelial autografts
 Human skin allografts derived from donated human cadaver tissue
 Allogenic matrices derived from human neonatal fibroblasts
 Composite matrices derived from human keratinocytes, fibroblasts, and bovine or porcine collagen
 Acellular matrices derived from porcine or bovine collagen
CULTURED EPITHELIAL AUTOGRAFTS (CEAs): Examples include, but may not be limited to:
 Epicel™ (cultured epidermal autograft [CEA]) (Genzyme Tissue Repair; Cambridge, MA). Sheets of skin
cells intended to replace the epidermis on severely burned patients. The patient’s own skin cells are
grown or cultured from a postage‐stamp sized sample of the patient’s own healthy skin. The skin cells
are grown on a layer of irradiated mouse cells, making Epicel® a xenotransplantation product.
(Genzyme Corp., 2007).
 EpiDex™ (DFH Pharmaceuticals, Inc.; Fort Worth, TX) is a fully differentiated autologous epidermal
equivalent derived from outer root sheath keratinocytes that is grown directly from plucked hair
follicles. Cell cultures expand for five to six weeks, after which time the product is applied non-
surgically. One study was insufficiently powered to allow assumptions about its effect on the
population. In a second study, there was no significant difference between the groups in the frequency
of complete ulcer closure or time to complete closure. At this time, EpiDex™ has no FDA designation.
 Epifix®. A natural, amniotic membrane allograft used in the treatment of chronic and acute wounds
and is considered reasonable and necessary in the wound management for patients with neuropathic
diabetic foot ulcers (DFUs) and non-infected partial and full-thickness skin ulcers due to venous
insufficiency.
 Grafix Core® (cellular repair matrix) HCT/P is a cryopreserved chorion matrix and GRAFIX PRIME is a
cryopreserved amnion matrix retaining the neonatal mesenchymal stem cells, fibroblasts and epithelial
cells that are known to produce biologically active growth factors in the native tissue. These growth
factors provide the product with multipotent characteristics, meaning that it can support migration,
proliferation and differentiation of several types of host cells (epithelial, endothelial, fibroblasts) known
to support tissue regeneration.
 Hyalomatrix® (Laserskin®) (Fidia Advanced Biopolymers; Abano Terme, Italy). A bioresorbable dermal
substitute made of HYAFF®, a long-acting derivative of hyaluronic acid providing a microenvironment
purportedly suitable for optimal tissue repair and accelerated wound healing. Specifically intended for
the treatment of deep burns and full‐thickness wounds; also provides a wound preparation support for
the implantation of autologous skin grafts.

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HUMAN SKIN ALLOGRAFTS DERIVED FROM DONATED HUMAN CADAVER TISSUE: Examples include, but
may not be limited to:
 AlloDerm® (Life Cell Corp.; The Woodlands, TX). AlloDerm is an acellular dermal matrix designed to
serve as a biologic scaffold for normal tissue remodeling. Processed from human cadaver skin with the
cells responsible for immune response and graft rejection removed. The remainder is a matrix or
framework of natural biological components, ready to enable the body to mount its own tissue
regeneration process. (Jones et al., 2002).
 Alloskin™ (AlloSource Inc.; Centennial, CO). An allograft derived from epidermal and dermal cadaveric
tissue and suggested for wound care.
 Cymetra® (Life Cell Corp.; The Woodlands, TX). An injectable form of AlloDerm® that has been
processed into micronized particles; suggested for the correction of soft‐tissue defects, such as
injection laryngoplasty.
 GammaGraft™ (Promethean LifeSciences, Inc.; Pittsburgh, PA). GammaGraft™ is an irradiated
composite allograft that can be stored at room temperature. According to the manufacturer,
GammaGraft™ is indicated in various types of wounds and is used primarily as a temporary dressing
that may require multiple applications.
 GRAFTJACKET® Regenerative Tissue Matrix (Wright Medical Technology; Arlington, TN). This is a
product derived from cadaver skin from which the epidermis and all cellular components are removed
while preserving the matrix and biochemical factors. Graftjacket is to be used for the repair or
replacement of damaged or inadequate integumental tissue or for other homologous uses of human
integument (Wright Medical Technology Inc., 2008). It is suggested for diabetic foot ulcers.
 GRAFTJACKET® EXPRESS Scaffold (Wright Medical Technology; Arlington, TN). This allograft is a
micronized (finely ground) decellularized soft tissue scaffold indicated for the repair or replacement of
damaged or inadequate integumental tissue, specifically deep, dermal wounds that exhibit tunneling
and extension from the wound base that may move into the tendon and bone.
 TheraSkin® (Soluble Solutions, Newport News, Va.). A biologically active cryopreserved human skin
allograft with both epidermis and dermis layers; the cellular and extracellular composition provides a
supply of growth factors, cytokines and collagen to supposedly promote wound healing.
ALLOGENIC MATRICES DERIVED FROM HUMAN NEONATAL FIBROBLASTS: Examples include, but may not
be limited to:
 AlloMaxTM (Bard Davol, Inc.). A sterile regenerative human collagen matrix suggested for soft tissue
repair, including hernia and abdominal wall reconstruction, and post‐mastectomy breast
reconstruction.
 Celaderm® (Advanced BioHealing; Westport, CT) is a cultured epithelial allograft that contains
metabolically active human foreskin-derived allogeneic keratinocytes. At this time, this product has no
FDA designation.
 Dermagraft® (Advanced BioHealing; Westport, CT / Smith & Nephew, Inc.; La Jolla, CA). This product is
a living dermal replacement that employs human neonatal foreskin fibroblasts. The mesh is a
biodegradable material that disappears after being in place for three to four weeks. It is used in the
treatment of full-thickness diabetic foot ulcers of greater than six weeks duration that extends through
the dermis, but without tendon, muscle, joint capsule, or bone exposure. It is also used for treatment
of wounds in individuals with dystrophic epidermolysis bullosa (DEB).

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COMPOSITE MATRICES DERIVED FROM HUMAN KERATINOCYTES, FIBROBLASTS AND BOVINE OR

PORCINE COLLAGEN: Examples include, but may not be limited to:
 Apligraf® (Organogenesis, Inc.; Canton, MA). Formerly marketed as Graftskin. Much like human skin as
it has two primary layers: the epidermal (outer) layer consists of live keratinocytes, while the dermal
(inner) layer contains living fibroblasts. Also referred to as human skin equivalent.
 OrCel™ (formally Composite Cultured Skin) (Ortec International, Inc.; New York, NY). A bi-layered skin
substitute that uses human epidermal keratinocytes and dermal fibroblasts that are cultured into two
separate layers on a bovine collagen sponge. As healing occurs at the site of the wound, the OrCel®
dissolves and the patient’s own skin cells then replace the OrCel® cells to create a new skin surface.
 TransCyte™ (formally Dermagraft TC™ [Dermagraft Transitional Covering]) (Advanced BioHealing;
Westport, CT). A human fibroblast‐derived temporary skin substitute consisting of a polymer
membrane and neonatal human fibroblast cells cultured under aseptic conditions in vitro on a nylon
mesh. Purportedly, as fibroblasts proliferate within the nylon mesh, they secrete human dermal
collagen, matrix proteins and growth factors.
ACELLULAR MATRICES DERIVED FROM PORCINE, OVINE, OR BOVINE COLLAGEN: Examples include, but
may not be limited to:
 Biobrane® (UDL Laboratories Inc.; Rockford, IL) (formerly a product of Mylan/Bertek Laboratories). This
product is an acellular dermal matrix constructed using collagen (porcine type 1) that is incorporated
with both silicone and nylon, and mechanically bonded to a flexible knitted nylon fabric. The
semipermeable membrane is comparable to human skin as it controls the loss of water vapor, allows
for drainage of exudates, and provides permeability to topical antibiotics. The nylon/silicone
membrane provides a flexible adherent covering for the wound surface.
 Endoform™ Dermal Template (Mesynthes Ltd, Wellington, New Zealand). This product is an
extracellular matrix derived from sheep collagen (forestomach) and intended for single use in the
treatment of wounds.
 EZ Derm™ (Brennen Medical, Inc.; St. Paul, MN). A porcine derived xenograft in which the collagen has
been chemically cross‐linked with aldehyde (a chemical compound) purportedly to provide strength
and durability.
 Integra® Dermal Regeneration Template (Integra LifeSciences Corp.; Plainsboro, NJ) is a bi-layered
extracellular matrix of fibers of cross-linked bovine collagen and chondroitin-6-sulfate (a component of
cartilage) with silicone backing. Once an organized regeneration of dermal tissue is formed
(neodermis), the disposable silicone sheet is removed and an ultrathin autograft is placed over the
neodermis.
 Integra™ Bilayer Matrix Wound Dressing and Integra™ Meshed Bilayer Wound Matrix (Integra
LifeSciences Corp.; Plainsboro, NJ). A biodegradable porous matrix of cross-linked bovine tendon
collagen and glycosaminoglycan intended to provide a scaffold for cellular invasion and capillary
growth. Wound closure is typically complete within 30 days.
 Integra™ Flowable Wound Matrix (Integra LifeSciences Corp.; Plainsboro, NJ) is comprised of
granulated cross-linked bovine tendon collagen and glycosaminoglycan, which is hydrated with saline
for injection into difficult to access wound sites and tunneled wounds.

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 Matristem® Wound Matrix (ACell Inc. Jessup, MD) is a porcine-derived, single or multi-layer,
extracellular matrix sheet. This product is used for the management of partial and full-thickness
wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined
wounds, surgical wounds (e.g., donor sites/grafts, post-Moh's surgery, podiatric, wound dehiscence),
trauma wounds (e.g., abrasions, lacerations, second degree burns, skin tears), and draining wounds.
 Matristem Micromatrix® (ACell Powder Wound Dressing) (ACell Inc. Jessup, MD) is composed of
porcine collagen from urinary bladder matrix that is lyophilized to be used as a topical application. This
product is marketed as a wound healing powder that helps regenerate hair in the donor and recipient
regions of hair transplant individuals.
 Matristem® Burn Matrix (ACell Inc. Jessup, MD) is a porcine-derived, single or multi-layer, extracellular
matrix sheet.
 Oasis Wound Matrix™ (Cook Biotech, Inc; West Lafayette, IN). A naturally derived ECM, created from
the submucosal layer of porcine small intestine; proposed to support the body's healing process by
providing an acellular scaffold that accommodates remodeling of host tissue. This product also contains
other biologically active components that may stimulate healing such as glycosaminoglycans,
proteoglycans, fibronectin, and growth factors (Mostow et al., 2005).
 Oasis Burn Matrix™ (Cook Biotech, Inc; West Lafayette, IN) is a product derived from porcine small
intestinal submucosa (SIS). This product is intended for the management of second degree burns and
donor sites.
 PriMatrix™ Dermal Repair Scaffold (TEI Biosciences Inc.; Boston, MA) (formerly DressSkin). A naturally
derived, ECM created from the submucosal layer of porcine small intestine; proposed to support the
body's healing process by providing an acellular scaffold that accommodates remodeling of host tissue.
Primatrix is designed to incorporate collagen into the wound bed and stimulate rapid tissue granulation
and native collagen production. A viral inactivation process is included in its manufacture to protect
against potentially contaminating viruses. This biological matrix is appropriate for treatment of a
variety of different types of wounds, including skin ulcers, second-degree burns, surgical wounds,
trauma wounds, post-Mohs surgical wounds, and tunneled wounds (TEI Biosciences, 2008).
REGULATORY STATUS:
1. U.S. FOOD AND DRUG ADMINISTRATION (FDA):
Depending on the purpose of the product and how it functions, skin substitutes are regulated by the
FDA premarket approval (PMA) process, 510(k) premarket notification process, or the FDA regulations
for banked human tissue.
Products that are classified by the FDA as an interactive wound and burn dressing are approved under
the PMA process as a class III, high-risk device and require clinical data to support their claims for use.
These devices may be used as a long-term skin substitute or a temporary synthetic skin substitute. They
actively promote healing by interacting directly or indirectly with the body tissues. Examples of these
devices include Apligraf® (Organogenesis Inc., Canton, MA) and Dermagraft® (Advanced BioHealing,
Inc., LaJolla, CA).
Other wound care devices (Class II) are approved by the 510(k) process, and their primary purpose is to

Page. 12 of 31
protect the wound and provide a scaffold for healing. They may or may not be integrated into the body
tissue. Some devices are rejected by the body after approximately ten days to several weeks and
removed prior to definitive wound therapy or skin grafting. Integra™ Bilayer Matrix Wound Dressing
(BMWD) (Integra LifeSciences Corp., Plainsboro, NJ) and Oasis® Wound Matrix (Cook Biotech, Inc.,
West Lafayette, IN) are examples of these devices.
Human tissue products (acellular) require no FDA clearance or approval and are intended for
homologous use only. [Title 21 Code of Federal Regulations (CFR), Section 1271.10(a) 2005].
National Government Services does not cover Class II or Human Tissue products unless otherwise
specified in an attached article or a separate LCD.
National Government Services will consider the use of Class III products eligible for coverage when used
in keeping with the FDA's approved indications for those products.
Donated skin that requires minimal processing and is not significantly changed in structure from its
natural form is classified by the FDA as banked human tissue. It is not considered a medical device, and
does not require PMA or 510(k) approval. Donated skin is regulated by the American Association of
Tissue Banks (AATB) and the FDA guidelines for banked human tissue. AATB oversees a voluntary
accreditation program and the FDA focuses on preventing the transmission of communicable diseases
by requiring donor screening and testing. Tissue establishments must register with the FDA and list
each cell or tissue produced. An example of a banked human tissue product is AlloDerm, an acellular
dermal matrix (FDA, 2004; Department of Health and Human Services, 2001).
 AlloDerm® (Life Cell Corp.; The Woodlands, TX). AlloDerm® is regulated as human tissue and
subject to the rules and regulations of banked human tissue, regulated by the American Association
of Tissue Banks (AATB); hence, it is not subject to FDA pre-notification approval (LifeCELL
Corporation, 2008).
 Alloskin™ (AlloSource Inc.; Centennial, CO). FDA regulation of human tissue does not include
review and approval for safety and effectiveness.
 Apligraf® (Organogenesis, Inc.; Canton, MA). Apligraf gained FDA PMA based on its efficacy with
venous ulcers. Apligraf® also has FDA PMA for use in the treatment of diabetic foot ulcers.
 Biobrane® (UDL Laboratories Inc.; Rockford, IL). This product holds an FDA 510(k) approval for the
treatment of clean partial-thickness burn wounds and donor site wounds.
 Celaderm® (Advanced BioHealing; Westport, CT). At this time, this product has no FDA designation,
and no published study outcomes were found in the literature. Individuals are currently being
enrolled in an FDA-approved study to evaluate the safety of Celaderm® in humans and to assess its
potential for acceleration of healing of venous leg ulcers.
 Cymetra® (Life Cell Corp.; The Woodlands, TX). The FDA considers Cymetra® banked human tissue
because it is minimally processed and not significantly changed in its structure from the natural
material.
 Dermagraft® (Advanced BioHealing; Westport, CT / Smith & Nephew, Inc.; La Jolla, CA).
Dermagraft® has received FDA premarket approval (PMA) for use in the treatment of full-thickness
diabetic foot ulcers of greater than six weeks duration that extend through the dermis, but without
tendon, muscle, joint capsule, or bone exposure.
 Endoform™ Dermal Template (Mesynthes Ltd, Wellington, New Zealand). Endoform™ received an

Page. 13 of 31
FDA 510(k) Premarket Notification from the FDA. The product is similar to Integra™ and Oasis,™
which were cited as predicate devices. Indications are similar to other acellular matrix products and
include the following: treatment of partial and full-thickness wounds, pressure ulcers, venous
ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds
(e.g., donor sites/grafts, post-Moh’s surgery, post-laser surgery, podiatric, wound dehiscence,
trauma wounds (e.g., abrasions, lacerations, second-degree burns, and skin tears), and draining
wounds.
 Epicel™ (Genzyme Tissue Repair; Cambridge, MA). The FDA considers Epicel™ to be a cultured
epidermal autograft, dressing, wound, and burn interactive that does not require an FDA
designation. For burns, Epicel™ has been approved by the FDA under the humanitarian device
(HDE) designation for use in individuals who have deep dermal or full-thickness burns comprising a
total body surface area of greater than or equal to 30 percent.
 EpiDex™ (DFH Pharmaceuticals, Inc.; Fort Worth, TX). At this time, EpiDex™ has no FDA
designation.
 EpiFix® (MiMedx Group, Inc). Epifix® is regulated by the FDA as Human Cells, Tissues, and Cellular
and Tissue Based Products. Indications include wound management for patients with neuropathic
diabetic foot ulcers (DFUs) and non-infected partial and full-thickness skin ulcers due to venous
insufficiency (e.g., venous stasis ulcers).
 EZ Derm™ (Brennen Medical, Inc.; St. Paul, MN). EZ Derm™ has FDA 510(k) approval for the
treatment of partial-thickness burns and venous, diabetic, and pressure ulcers.
 GammaGraft™ (Promethean LifeSciences, Inc.; Pittsburgh, PA). At this time, it has No FDA
designation.
 Grafix Core (Osiris Therapeutics, Inc.).
 Graftjacket®: Graftjacket Matrix, Graftjacket Xpress Scaffold, and Graftjacket Ulcer Repair Matrix
(Wright Medical Technology; Arlington, TN): These products are made from human donor skin,
which undergoes a process that removes the epidermis and dermal cells, thereby creating an
acellular dermis. Similar to AlloDerm, human cells or tissues intended for implantation,
transplantation, infusion, or transfer into a human recipient are regulated as human cell, tissue,
and cellular- and tissue-based products; hence, it is not subjected to FDA pre-notification approval
(FDA, 2009).
 Hyalomatrix® (Laserskin®) (Fidia Advanced Biopolymers; Abano Terme, Italy). This product has
received FDA 510(k) approval and is indicated for the management of wounds in the granulation
phase (e.g., pressure ulcers, venous and arterial leg ulcers, diabetic ulcers, surgical incisions,
second-degree burns, skin abrasions, lacerations, partial-thickness grafts and skin tears, and
wounds and burns treated with meshed grafts).
 Integra® Dermal Regeneration Template (Integra LifeSciences Corp.; Plainsboro, NJ). Integra® has
an FDA PMA for treatment of life-threatening, full-thickness or deep partial-thickness thermal
injuries where sufficient autograft is not available at the time of excision or not desirable due to the
physiologic condition of the individual. This product also has an FDA PMA for repair of scar
contractures.
 Integra™ Bilayer Matrix Wound Dressing and Integra™ Meshed Bilayer Wound Matrix (Integra
LifeSciences Corp.; Plainsboro, NJ). FDA has approved these products for indications that include
management of partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers,

Page. 14 of 31
chronic vascular ulcers, surgical wound (donor sites/grafts, post-Moh's surgery, post-laser surgery,
podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second degree burns, and
skin tears), and draining wounds.
 Integra™ Flowable Wound Matrix (Integra LifeSciences Corp.; Plainsboro, NJ). According to the
FDA 510(k) summary, this product is equivalent in function and intended use to the Integra™
Matrix Wound Dressing.
 Matristem Micromatrix® (ACell Inc. Jessup, MD). Matristem Micromatrix® has also received 510k
Premarket Notification for the same indications as Matristem® Wound Matrix. This product is
marketed as a wound healing powder that helps regenerate hair in the donor and recipient regions
of hair transplant individuals.
 Matristem® Wound Matrix (ACell Inc. Jessup, MD). Matristem® Wound Matrix has received FDA
Premarket Notification for the management of partial and full-thickness wounds, pressure ulcers,
venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical
wounds (e.g., donor sites/grafts, post-Moh's surgery, podiatric, wound dehiscence), trauma
wounds (e.g., abrasions, lacerations, second degree burns, skin tears), and draining wounds.
 Oasis® Wound Matrix: Oasis Wound Matrix is regulated by the FDA as a Class II (moderate risk)
device. This product received FDA 510(k) approval (K061711), granted to Cook Biotech Inc. on July
19, 2006. It is an animal-derived extracellular matrix that is supplied sterile and is intended for
single use in the management of various wounds such as partial and full-thickness wounds,
pressure, venous, diabetic, and chronic vascular ulcers, tunneled/undermined wounds, surgical
wounds, trauma wounds, and draining wounds (FDA 2006b). The product is identical to an earlier
product developed by Cook Biotech Inc. (SIS wound dressing II, K993948, issued January 6, 2000)
(FDA, 2000). The FDA approved a name change to Oasis Wound Matrix to acknowledge that it
contains glycosaminoglycans and other matrix components not found in other purified collagen-
alone materials that can stimulate cell differentiation in cell culture assay, an indicator of
bioactivity (Schaum and Farley, 2006).
 OrCel™ (Ortec International, Inc.; New York, NY). OrCel™ has received FDA PMA for the treatment
of fresh, clean split-thickness donor site wounds. OrCel™ has received an HDE for the treatment of
surgical wounds and donor sites associated with mitten-hand deformities in individuals who have
recessive dystrophic epidermolysis bullosa (RDEB).
 PriMatrix™ Dermal Repair Scaffold (TEI Biosciences Inc.; Boston, MA) (formerly DressSkin). This
product received initial FDA 510(k) approval (K061407), granted to TEI Biosciences Inc. on June 29,
2006. This product is indicated for the management of wounds, including partial- and full-thickness
wounds, pressure, diabetic, and venous ulcers, second-degree burns, surgical wounds, trauma
wounds, tunneled/undermined wounds, and draining wounds (FDA, 2006a).
 Promogran®: Promogran Matrix Wound Dressing received FDA 510(k) approval (K014129), granted
to Johnson & Johnson Medical Ltd. on February 14, 2002. Promogran is indicated for use in patients
with diabetic ulcers, venous ulcers, ulcers caused by mixed vascular etiologies, full- and partial-
thickness wounds, donor sites and other bleeding surfaces, abrasions, traumatic wounds, and
dehisced surgical wounds (FDA, 2002).
 TheraSkin® (Soluble Solutions, Newport News, Va.) is a biologically active cryopreserved human skin
allograft and has both epidermis and dermis layers. The FDA has classified TheraSkin™ as banked
human tissue and, therefore, is subject to the rules and regulations of banked human tissue.

Page. 15 of 31
 TransCyte™ (Advanced BioHealing; Westport, CT). TransCyte™ received FDA PMA as a temporary
wound covering for surgically excised full-thickness and deep partial-thickness burn wounds in
individuals who require such a covering prior to autograft placement.
 Xelma®: Xelma has not yet received premarket approval from the FDA.
2. CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS):
Local Coverage Determination (LCD):
 (L26003) Biologic Products for Wound Treatment and Surgical Interventions
 A50627 - AlloDerm® Regenerative Tissue Matrix – Related to LCD L26003 opens in new window
 A46092 - Apligraf® – Related to LCD L26003 opens in new window
 A45056 - Biologic Products for Wound Treatment and Surgical Interventions - Supplemental
Instructions Article opens in new window
 A46090 - Dermagraft® – Related to LCD L26003 opens in new window
 A52159 - EpiFix® - Related to LCD L26003 opens in new window
 A53933 - Grafix® - Related to LCD L26003 opens in new window
 A49404 - GRAFTJACKET® Regenerative Tissue Matrix-Ulcer Repair and GRAFTJACKET® XPRESS
Flowable Soft Tissue Scaffold – Related to LCD L26003 opens in new window
 A46085 - Integra® Dermal Regeneration Template and Integra® Bilayer Matrix Wound Dressing –
Related to LCD L26003 opens in new window
 A46082 - OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix – Related to LCD L26003 opens
in new window
 A52087 - Primatrix™ Dermal Repair Scaffold - Related to LCD L26003 opens in new window
 A50504 - TheraSkin® – Related to LCD L26003
 A40531 - Skin substitutes
CMS covers the use of skin substitutes and related products in the treatment of lower extremity ulcer
disease. The LCD does not pertain or otherwise apply to the use of any skin substitutes or related
products in the treatment of burns, skin cancer, or for true reconstructive surgery.
The Food and Drug Administration (FDA) distinguishes between products according to function (wound
management, e.g., wound dressings and wound treatment, e.g., bioactive skin substitutes.) The former
(Class II) requires 510(k) pre-market notification for FDA clearance while the latter (Class III) requires
pre-market approval.
Human tissue products (acellular) require no FDA clearance or approval and are intended for
homologous use only. [Title 21 Code of Federal Regulations (CFR), Section 1271.10(a) 2005]
National Government Services does not cover Class II or Human Tissue products unless otherwise
specified in an attached article or a separate LCD.
National Government Services will consider the use of Class III products eligible for coverage when used
in keeping with the FDA's approved indications for those products.
Indications:
The following general indications and limitations to Medicare coverage and payment apply to all
materials and services related to skin substitute / replacement.
Applied to wounds that have demonstrated a failed or insufficient response to no fewer than four

Page. 16 of 31
weeks of conservative wound care measures. For initial applications of skin substitutes/replacements, a
failed response to conservative measures is defined as an ulcer that has increased in size or depth or
for which there has been less than 30% closure from baseline. For the purposes of this LCD, a chronic
cutaneous ulcer is defined as a wound that has failed to proceed through an orderly and timely series
of events to produce a durable structural, functional, and cosmetic closure. A burn wound is defined as
a cutaneous wound induced by thermal, chemical, or electrical injury. An acute wound is of recent
occurrence and usually traumatic in nature.
Managed wounds should be clean and free of infection and are of reasonable size (at least 1.0 cm2 and
with adequate circulation/oxygenation to support tissue growth/wound healing as evidenced by
physical examination (presence of acceptable peripheral pulses and/or Doppler toe signals and/or ABI
of no less than 0.65).
Management of chronic wounds should include treating the underlying condition and co-morbidities,
which might include optimizing blood glucose control in patients with diabetic ulcers, ensuring
adequate nutrition status in debilitated patients, revascularization in patients with ischemic artery
disease, and pain management.
In addition to the type of dressing used in treating chronic wounds, several common principles apply to
the management of most chronic wounds:
a. Removal of dead and devitalized tissue which provides a nidus for bacterial infection (not
colonization),
b. Aggressive antibiotic treatment of peri-wound and wound infections,
c. Mechanical measures which may favorably alter local hemodynamics or ameliorate adverse
physical forces, (most common are offloading and debridement for diabetic ulcers and
compression for venous ulcers) and
d. Optimization of general nutrition.
Application of Bioengineered Skin Substitutes will be covered when the following conditions are met
and documented as appropriate for the individual patient:
1. Presence of neuropathic diabetic foot ulcers for greater than four (4) weeks' duration.
2. Presence of venous stasis ulcers of greater than three (3) months' duration that have failed to
respond to documented conservative measures for greater than two (2) months' duration.
3. Presence of neuropathic diabetic foot ulcers that have failed to respond to documented
conservative measures for greater than one (1) month's duration. These measures must include
appropriate steps to off-load pressure during treatment.
4. Presence of partial or full-thickness ulcers.
5. Measurements of the initial ulcer size, the size following cessation of any conservative
management and the size at the beginning of skin substitute treatment.
6. In all cases, the ulcer must be free of infection and underlying osteomyelitis. Documentation must
be provided that these conditions have been successfully treated and resolved prior to instituting
skin substitute treatment.
Documentation Requirements:
The patient's medical record must contain documentation that fully supports the medical necessity for
services included within this LCD. This documentation includes, but is not limited to, relevant medical
history, physical examination, and results of pertinent diagnostic tests or procedures.

Page. 17 of 31
1. The medical record must document that wound treatments with skin substitutes/replacements are
accompanied by appropriate wound dressing changes during the healing period and by appropriate
compressive dressings during follow-up, including, for neuropathic diabetic foot ulcers, appropriate
steps to off-load wound pressure during the follow-up.
2. The medical record documentation must clearly document the medical necessity and performance
of the extent of site preparation procedures billed.
3. Rationale for the selection of a biological product for surgical interventions in repair of anatomic
defects or reconstruction work must be documented in the medical record and submitted to
Medicare upon request.
3. MINNESOTA DEPARTMENT OF HUMAN SERVICES (DHS):
Minnesota DHS has guidance regarding specialized wound treatment technology and specifically
addresses platelet rich plasma systems (e.g., AutoloGel, Magellan); negative pressure wound therapy
devices, and Electro-magnetic/ultrasound therapy. DHS does not address Bioengineered Skin
Substitutes in its Provider Manual or other specific provider references.
Criteria for Specialized Wound Treatment for Chronic Wounds
Authorization for specialized wound therapy for chronic wounds will be considered when a wound does
not respond to standard wound treatment for at least a 30 day period. For all wounds, documentation
and a comprehensive treatment plan, before requesting authorization for a specialized wound therapy
product, is required and includes the following:
 Wound type, including:
o Etiology and stage when appropriate
o Date of onset
o Evaluation
o Previous wound care and assessments done by a licensed medical professional
• Weekly wound measurements to assess the appropriateness of current wound treatment. If no
improvement to the wound, the wound treatment must be changed. This must be done by nursing
staff in the skilled facility or by a licensed medical professional in the home setting.
• Application of dressings to maintain a continuously moist wound environment must have been
tried prior to requesting a specialized wound therapy product (gel dressings).
• Impregnated dressings have been tried when applicable (e.g., sodium, antimicrobial, collagen
petroleum).
• Debridement of necrotic tissue - mechanical, surgical/chemical.
• Evaluation and provision for adequate nutritional status. Include both prealbumin and albumin
levels. Ideally, albumin levels are 3.5 – 5. If albumin levels are below 3.5, specialized wound therapy
may be approved if prealbumin levels are 20-40, show improvement over the previous 30 days and
if there is a nutritional plan in place written by an appropriate professional. Specialized wound
therapy will not be authorized for albumin levels below 2.8. Baseline albumin and prealbumin
levels are required and as medically necessary thereafter. If albumin levels are below 3.5, enteral
nutritional support may be covered. Refer to Enteral Nutritional Products policy.
• Moisture and incontinence have been addressed and appropriately managed.
• Compliance issues are addressed (i.e., missed medical appointments, refusing dressing changes,
repositioning, smoking, poor nutritional intake or choices).

Page. 18 of 31
• Medical intervention/correction of underlying conditions that may hinder the healing process of
the wound (i.e., local or distant infections are addressed).
• Assessment of medications that may delay healing (e.g., systemic steroids, immunosuppressive
drugs).
• Evaluation of arterial sufficiency when appropriate.
• Licensed professional (RN, LPN, PT) services in place for treatment in the home.
• Document how this request is appropriate for the type of wound being treated.
CLINICAL EVIDENCE:
SUMMARY:
There are currently a wide variety of products available for soft tissue grafting and wound treatment. These
products may be derived from allogeneic, xenographic, synthetic, or a combination of any or all of these
types of materials. All of these products are procured, produced, manufactured or processed in sufficiently
different manners that they cannot be addressed and evaluated as equivalent products. Therefore, each
product must be reviewed and judged on the basis of the available scientific evidence specific to that
product. Unfortunately, the majority of these products have no peer-reviewed, published studies available
to assist in the evaluation of their safety and efficacy. In such circumstances, products are considered
investigational and not medically necessary based on a lack of data addressing both the safety and efficacy
of the product in question. For other products, there may be one or more published studies of varying
quality.
The overall body of published evidence regarding the safety and efficacy of biological tissue-engineered
skin substitutes is limited, and at the present time does not clearly demonstrate a benefit of these products
compared with optimal standard wound care. None of the available studies provided an adequate direct
comparison of the different biological tissue-engineered skin substitute products. Additional research,
including well-designed randomized controlled or comparative studies, is needed to establish the safety,
efficacy, and comparative effectiveness of the different skin substitute products and to define appropriate
patient selection criteria.
GROUPS POLICY:
American Diabetes Association (ADA): The ADA published the findings of a consensus conference held
in April 1999 on the care of diabetic foot wounds. The statement contained a section on the evaluation
of new treatments (ADA, 1999). The following conclusions were reached:
 Any new device, dressing, or biological or pharmacological agent should be evaluated in a
consistent and rigorous manner and should not be adopted without substantial evidence of its
efficacy. New technologies include Apligraf, growth factors, electrical stimulation, cold laser, and
heat.
 The reference standard for evaluation of new treatments is the randomized controlled trial, which
should consist of a sufficient number of patients to obtain adequate statistical power.
 The relevant outcomes, wound healing and the rate of healing, depend upon ulcer severity and the
treatment regimen as well as variables such as patient compliance.
 Patient inclusion and exclusion criteria must be described, including key wound parameters (e.g.,

Page. 19 of 31
area and depth), ulcer duration, and presence of infection, neuropathy, and/or ischemia.
 All patients in controlled trials must receive standardized wound care, including off-loading, a
defined debridement protocol, and evaluation of patient compliance with the protocol.
 Primary study endpoints should include the proportion of patients with complete wound healing,
as defined by the Wound Healing Society, within a specific time frame. Secondary endpoints
include time to healing, velocity of wound healing, rate of recurrence, quality of life, and cost-
effectiveness.
Wound Healing Society (WHS): An advisory panel convened by the WHS published guidelines for the
treatment of arterial insufficiency ulcers in 2006. This panel concluded that "extracellular matrix
replacement therapy appears to be promising for mixed ulcers and may have a role as an adjuvant
agent in arterial ulcers, but further study is required." The WHS guideline also stated that "despite the
existence of animal studies, case series, and a small number of RCTs to support biomaterial use for
pressure ulcers, diabetic ulcers, and venous ulcers, there are no studies specifically on arterial ulcers.
Therefore, studies in arterial ulcers must be conducted before the recommendation can be made"
(Hopf et al., 2006). A second advisory panel published guidelines for the treatment of acute wounds.
The panel concluded that when an excised burn with a total burn surface area (TBSA) is so large that
donor sites for split-thickness skin grafts are not enough, permanent skin substitutes can be used as
skin replacement with no fear of rejection. In addition, the third panel advised that nonimmunogenic
skin substitutes might also serve as permanent skin replacement with no fear of rejection. Temporary
biologic, synthetic, biosynthetic, or bioengineered dressings are not sufficient to provide permanent
burn wound closure, but they can allow for the wound to be free of infection until the permanent
wound heals completely (Franz et al., 2008). In a set of guidelines published in 2006 for the treatment
of chronic wounds, an advisory panel concluded that various skin substitutes or biologically active
dressings are emerging that provide temporary wound closure and serve as a source of stimuli (e.g.,
growth factors) for healing of venous ulcers (Robson et al., 2006).
Association for the Advancement of Wound Care (AAWC): In 2005, the AAWC presented a summary
algorithm for venous ulcer care that recommends use of dressings that maintain a moist environment.
If no healing is seen in 30 days, the algorithm recommends biologic dressings, including matrix
dressings (AAWC, 2005).
American College of Foot and Ankle Surgeons (ACFAS): In a clinical practice guideline on diabetic foot
disorders, the ACFAS makes general references to active or interactive dressings. This guideline
concludes that "although these products are commonly used in clinical practice, they have not yet been
conclusively shown to expedite wound healing" (Frykberg, 2002).
American Podiatric Medical Association (APMA): The APMA includes Oasis Wound Matrix in its list of
therapeutic products that have been evaluated and granted the APMA "seal of approval" (APMA,
2009).
American Society of Plastic Surgeons (ASPS): The ASPS clinical practice guidelines for management of
chronic lower extremity wounds advise that appropriate dressings be used to maintain a moist
environment, and state that the available evidence does not support the superiority of any particular
dressing material. The guideline mentions that bioactive dressings, including topical antimicrobials,
bioengineered composite skin equivalent, bilaminar dermal regeneration template, and recombinant
human growth factor, are all products that can be considered (ASPS, 2007).
Wound, Ostomy and Continence Nurses Society (WOCN): The WOCN has released a set of guidelines

Page. 20 of 31
for the management of wounds and use of Oasis Wound Matrix product (WOCN, 2006).
APPLICABLE CODES:
The Current Procedural Terminology (CPT®) codes and HCPCS codes listed in this policy are for reference purposes only.
Listing of a service or device code in this policy does not imply that the service described by this code is a covered or
non-covered health service. The inclusion of a code does not imply any right to reimbursement or guarantee claims
payment. Other medical policies and coverage determination guidelines may apply.
HCPCS Code Description

C9354 Acellular pericardial tissue matrix of nonhuman origin (Veritas), per sq cm
C9358 Dermal substitute, native, nondenatured collagen, fetal bovine origin (SurgiMend Collagen
Matrix), per 0.5 sq cm
C9360 Dermal substitute, native, nondenatured collagen, neonatal bovine origin (SurgiMend Collagen
Matrix), per 0.5 sq cm
C9363 Skin substitute (Integra Meshed Bilayer Wound Matrix), per square cm
C9364 Porcine implant, Permacol, per sq cm
C9366 EpiFix, per sq cm
C9367 Skin substitute, Endoform Dermal Template, per sq cm
C9368 Grafix core, per square centimeter
C9369 Grafix prime, per square centimeter
Q4100 Skin substitute, not otherwise specified
Q4101 Apligraf, per sq cm
Q4102 Oasis wound matrix, per sq cm
Q4103 Oasis burn matrix, per sq cm
Q4104 Integra bilayer matrix wound dressing (BMWD), per sq cm
Q4105 Integra dermal regeneration template (DRT), per sq cm
Q4106 Dermagraft, per sq cm
Q4107 GRAFTJACKET, per sq cm
Q4108 Integra matrix, per sq cm
Q4110 PriMatrix, per sq cm
Q4111 GammaGraft, per sq cm
Q4112 Cymetra, injectable, 1 cc
Q4113 Graft Jacket Xpress injectable1 cc
Q4113 Graft Jacket Xpress injectable1 cc
Q4114 Integra flowable wound matrix, injectable, 1 cc
Q4115 AlloSkin, per square centimeter
Q4116 AlloDerm, per square centimeter
Q4117 HYALOMATRIX, per sq cm
Q4118 MatriStem micromatrix, 1 mg
Q4119 MatriStem Wound Matrix, PSMX, RS, or PSM, per sq cm
Q4120 MatriStem burn matrix, per sq cm
Q4121 TheraSkin, per sq cm
Q4122 Dermacell per square centimeter
Q4123 Alloskin RT, per square centimeter
Q4124 Oasis ultra tri‐layer wound matrix, per square centimeter

Page. 21 of 31
Q4125 Arthroflex, per square centimeter

Q4126 MemoDerm, DermaSpan, TranZgraft or InteguPly, per sq cm
Q4127 TalyMED, per square centimeter
Q4128 FlexHD, AllopatchHD, or Matrix HD, per sq cm
Q4129 Unite Biomatrix, per square centimeter
Q4130 Strattice TM, per square centimeter
Q4131 EpiFix, per sq cm
Q4132 Q4132 Grafix core, per sq cm
Q4133 Grafix prime, per sq cm
Q4134 hMatrix, per sq cm
Q4135 Mediskin, per sq cm
Q4136 E‐Z Derm, per sq cm
CPT® Code Description
15002-15005 Surgical preparation codes for skin replacement surgery
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 wound surface area
15272 Application of 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)
15273 Application of 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
15274 Application of 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)
15275 Application of 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
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)
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
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 in addition to code for primary
procedure)
15777 Implantation of biologic implant (e.g., acellular dermal matrix) for soft tissue reinforcement (e.g.,
breast, trunk) (List separately in addition to code for primary procedure)
ICD‐9 PCS Code Description
86.67 Free skin graft; Dermal regenerative graft
ICD‐10 PCS Code Description
0HR0XJ3 Replacement of Scalp Skin with Synthetic Substitute, Full Thickness, External Approach
0HR0XJ4 Replacement of Scalp Skin with Synthetic Substitute, Partial Thickness, External Approach

Page. 22 of 31
0HR0XJZ Replacement of Scalp Skin with Synthetic Substitute, External Approach

0HR0XK3 Replacement of Scalp Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR0XK4 Replacement of Scalp Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR1XJ3 Replacement of Face Skin with Synthetic Substitute, Full Thickness, External Approach
0HR1XJ4 Replacement of Face Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR1XJZ Replacement of Face Skin with Synthetic Substitute, External Approach
0HR1XK3 Replacement of Face Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR1XK4 Replacement of Face Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR4XJ3 Replacement of Neck Skin with Synthetic Substitute, Full Thickness, External Approach
0HR4XJ4 Replacement of Neck Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR4XJZ Replacement of Neck Skin with Synthetic Substitute, External Approach
0HR4XK3 Replacement of Neck Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR4XK4 Replacement of Neck Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR5XJ3 Replacement of Chest Skin with Synthetic Substitute, Full Thickness, External Approach
0HR5XJ4 Replacement of Chest Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR5XJZ Replacement of Chest Skin with Synthetic Substitute, External Approach
0HR5XK3 Replacement of Chest Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR5XK4 Replacement of Chest Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR6XJ3 Replacement of Back Skin with Synthetic Substitute, Full Thickness, External Approach
0HR6XJ4 Replacement of Back Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR6XJZ Replacement of Back Skin with Synthetic Substitute, External Approach
0HR6XK3 Replacement of Back Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR6XK4 Replacement of Back Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR7XJ3 Replacement of Abdomen Skin with Synthetic Substitute, Full Thickness, External Approach
0HR7XJ4 Replacement of Abdomen Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR7XJZ Replacement of Abdomen Skin with Synthetic Substitute, External Approach
0HR7XK3 Replacement of Abdomen Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR7XK4 Replacement of Abdomen Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HR8XJ3 Replacement of Buttock Skin with Synthetic Substitute, Full Thickness, External Approach
0HR8XJ4 Replacement of Buttock Skin with Synthetic Substitute, Partial Thickness, External Approach
0HR8XJZ Replacement of Buttock Skin with Synthetic Substitute, External Approach
0HR8XK3 Replacement of Buttock Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HR8XK4 Replacement of Buttock Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HRAXJ3 Replacement of Genitalia Skin with Synthetic Substitute, Full Thickness, External Approach

Page. 23 of 31
0HRAXJ4 Replacement of Genitalia Skin with Synthetic Substitute, Partial Thickness, External Approach
0HRAXJZ Replacement of Genitalia Skin with Synthetic Substitute, External Approach
0HRAXK3 Replacement of Genitalia Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HRAXK4 Replacement of Genitalia Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HRBXJ3 Replacement of Right Upper Arm Skin with Synthetic Substitute, Full Thickness, External
Approach
0HRBXJ4 Replacement of Right Upper Arm Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRBXJZ Replacement of Right Upper Arm Skin with Synthetic Substitute, External Approach
0HRBXK3 Replacement of Right Upper Arm Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRBXK4 Replacement of Right Upper Arm Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRCXJ3 Replacement of Left Upper Arm Skin with Synthetic Substitute, Full Thickness, External Approach
0HRCXJ4 Replacement of Left Upper Arm Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRCXJZ Replacement of Left Upper Arm Skin with Synthetic Substitute, External Approach
0HRCXK3 Replacement of Left Upper Arm Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRCXK4 Replacement of Left Upper Arm Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRDXJ3 Replacement of Right Lower Arm Skin with Synthetic Substitute, Full Thickness, External
Approach
0HRDXJ4 Replacement of Right Lower Arm Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRDXJZ Replacement of Right Lower Arm Skin with Synthetic Substitute, External Approach
0HRDXK3 Replacement of Right Lower Arm Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRDXK4 Replacement of Right Lower Arm Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HREXJ3 Replacement of Left Lower Arm Skin with Synthetic Substitute, Full Thickness, External Approach
0HREXJ4 Replacement of Left Lower Arm Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HREXJZ Replacement of Left Lower Arm Skin with Synthetic Substitute, External Approach
0HREXK3 Replacement of Left Lower Arm Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HREXK4 Replacement of Left Lower Arm Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRFXJ3 Replacement of Right Hand Skin with Synthetic Substitute, Full Thickness, External Approach
0HRFXJ4 Replacement of Right Hand Skin with Synthetic Substitute, Partial Thickness, External Approach
0HRFXJZ Replacement of Right Hand Skin with Synthetic Substitute, External Approach
0HRFXK3 Replacement of Right Hand Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HRFXK4 Replacement of Right Hand Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRGXJ3 Replacement of Left Hand Skin with Synthetic Substitute, Full Thickness, External Approach

Page. 24 of 31
0HRGXJ4 Replacement of Left Hand Skin with Synthetic Substitute, Partial Thickness, External Approach
0HRGXJZ Replacement of Left Hand Skin with Synthetic Substitute, External Approach
0HRGXK3 Replacement of Left Hand Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HRGXK4 Replacement of Left Hand Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
0HRHXJ3 Replacement of Right Upper Leg Skin with Synthetic Substitute, Full Thickness, External
Approach
0HRHXJ4 Replacement of Right Upper Leg Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRHXJZ Replacement of Right Upper Leg Skin with Synthetic Substitute, External Approach
0HRHXK3 Replacement of Right Upper Leg Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRHXK4 Replacement of Right Upper Leg Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRJXJ3 Replacement of Left Upper Leg Skin with Synthetic Substitute, Full Thickness, External Approach
0HRJXJ4 Replacement of Left Upper Leg Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRJXJZ Replacement of Left Upper Leg Skin with Synthetic Substitute, External Approach
0HRJXK3 Replacement of Left Upper Leg Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRJXK4 Replacement of Left Upper Leg Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRKXJ3 Replacement of Right Lower Leg Skin with Synthetic Substitute, Full Thickness, External
Approach
0HRKXJ4 Replacement of Right Lower Leg Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRKXJZ Replacement of Right Lower Leg Skin with Synthetic Substitute, External Approach
0HRKXK3 Replacement of Right Lower Leg Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRKXK4 Replacement of Right Lower Leg Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRLXJ3 Replacement of Left Lower Leg Skin with Synthetic Substitute, Full Thickness, External Approach
0HRLXJ4 Replacement of Left Lower Leg Skin with Synthetic Substitute, Partial Thickness, External
Approach
0HRLXJZ Replacement of Left Lower Leg Skin with Synthetic Substitute, External Approach
0HRLXK3 Replacement of Left Lower Leg Skin with Nonautologous Tissue Substitute, Full Thickness,
External Approach
0HRLXK4 Replacement of Left Lower Leg Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRMXJ3 Replacement of Right Foot Skin with Synthetic Substitute, Full Thickness, External Approach
0HRMXJ4 Replacement of Right Foot Skin with Synthetic Substitute, Partial Thickness, External Approach
0HRMXJZ Replacement of Right Foot Skin with Synthetic Substitute, External Approach
0HRMXK3 Replacement of Right Foot Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HRMXK4 Replacement of Right Foot Skin with Nonautologous Tissue Substitute, Partial Thickness,
External Approach
0HRNXJ3 Replacement of Left Foot Skin with Synthetic Substitute, Full Thickness, External Approach

Page. 25 of 31
0HRNXJ4 Replacement of Left Foot Skin with Synthetic Substitute, Partial Thickness, External Approach
0HRNXJZ Replacement of Left Foot Skin with Synthetic Substitute, External Approach
0HRNXK3 Replacement of Left Foot Skin with Nonautologous Tissue Substitute, Full Thickness, External
Approach
0HRNXK4 Replacement of Left Foot Skin with Nonautologous Tissue Substitute, Partial Thickness, External
Approach
CPT® is a registered trademark of the American Medical Association.
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POLICY HISTORY:
DATE ACTION/DESCRIPTION
01/30/2013 New Policy 2013M0011A. Reviewed by Interim Medical Policy Committee.
03/28/2013 Quality Improvement Advisory and Credentialing Council (QIACC).
11/15/2013 Published to UCare.org
07/01/2015 Policy Update:
• Added applicable ICD-10 codes to the Coding Section. The list of codes may not be
all-inclusive and does not denote coverage.
• Policy identification number updated to 2015M0011A.
09/14/2015 Policy Revision:
Approved by the Medical Policy Committee (MPC).
 Changed some products from investigative to medically necessary and proven
 Added products
 Policy identification number updated to 2015M0011B.
09/24/2015 Quality Improvement Advisory and Credentialing Council (QIACC).
03/24/2016 Policy Update: Added applicable HCPCS codes.

Page. 31 of 31

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Clinical & Quality Management MEDICAL POLICY

BIOENGINEERED SKIN SUBSTITUTES

Table of Contents: Page: Cross Reference Policy:

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COVERAGE RATIONALE / CLINICAL CONSIDERATIONS:

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• Sufficient autograft tissue is not available at the time of excision, OR

Epifix® is considered MEDICALLY NECESSARY for the treatment of:

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o Non-weight bearing regimen

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INVESTIGATIONAL AND NOT MEDICALLY NECESSARY:

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COMPOSITE MATRICES DERIVED FROM HUMAN KERATINOCYTES, FIBROBLASTS AND BOVINE OR

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HCPCS Code Description

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Q4125 Arthroflex, per square centimeter

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0HR0XJZ Replacement of Scalp Skin with Synthetic Substitute, External Approach

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Document Format (PDF) from the AAWC Web site.

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https://www.uptodate.com/home/index.html. Accessed September 9, 2015.

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