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Bio-engineered skin and soft tissue substitutes may be derived from human tissue (autologous or allogeneic), nonhuman tissue (xenographic), synthetic materials, or a composite of these materials. Bioengineered skin and soft tissue substitutes are being evaluated for a variety of conditions, including breast reconstruction and healing lower-extremity ulcers and severe burns. Acellular dermal matrix products are also being evaluated for soft tissue repair.
Bio-engineered skin and soft tissue substitutes may be either acellular or cellular. Acellular products (eg, dermis with cellular material removed) contain a matrix or scaffold composed of materials such as collagen, hyaluronic acid, and fibronectin. Acellular dermal matrix products can differ in a number of ways, including as species source (human, bovine, porcine), tissue source (eg dermis, pericardium, intestinal mucosa), additives (eg antibiotics, surfactants), hydration (wet, freeze dried), and required preparation (multiple rinses, rehydration).
Cellular products contain living cells such as fibroblasts and keratinocytes within a matrix. The cells contained within the matrix may be autologous, allogeneic, or derived from other species (eg, bovine, porcine). Skin substitutes may also be composed of dermal cells, epidermal cells, or a combination of dermal and epidermal cells, and may provide growth factors to stimulate healing. Tissue-engineered skin substitutes can be used as either temporary or permanent wound coverings.
There are a large number of potential applications for artificial skin and soft tissue products. One large category is nonhealing wounds, which potentially encompasses diabetic neuropathic ulcers, vascular insufficiency ulcers, and pressure ulcers. A substantial minority of such wounds do not heal adequately with standard wound care, leading to prolonged morbidity and increased risk of mortality. For example, nonhealing lower-extremity wounds represent an ongoing risk for infection, sepsis, limb amputation, and death. Bio-engineered skin and soft tissue substitutes have the potential to improve rates of healing and reduce secondary complications.
The preferred outcomes for the healing of lower-extremity ulcers and burn wounds are the percentage of patients with complete wound healing and the time to complete wound healing. The percentage of patients with 50% wound healing and time to 50% wound healing have also been considered appropriate outcomes for these conditions. The percent change in wound area at 4 weeks is predictive of complete healing at 12 weeks in patients with diabetic foot ulcers. Thus, minimal improvement at 30 days can be considered as an indicator that a wound is unlikely to heal in patients with comorbidities known to affect wound healing.
Other situations in which bio-engineered skin products might substitute for living skin grafts include certain postsurgical states (eg, breast reconstruction) in which skin coverage is inadequate for the procedure performed, or for surgical wounds in patients with compromised ability to heal. Second- and third-degree burns are another situation in which artificial skin products may substitute for auto- or allografts. Certain primary dermatologic conditions that involve large areas of skin breakdown (eg, bullous diseases) may also be conditions in which artificial skin products can be considered as substitutes for skin grafts. Acellular dermal matrix (ADM) products are also being evaluated in the repair of other soft tissues including rotator cuff repair, following oral and facial surgery, hernias, and other conditions.
A large number of artificial skin products are commercially available or in development. The following summary of commercially available skin substitutes describes those products that have substantial relevant evidence on efficacy. Information on other artificial skin and soft tissue substitutes available in the United States may be found in a 2012 Technology Assessment from the Agency for Healthcare Research and Quality.
Acellular Dermal Matrix Products
Allograft acellular dermal matrix (ADM) products derived from donated human skin tissue are supplied by tissue banks compliant with standards of the American Association of Tissue Banks (AATB) and U.S. Food and Drug Administration (FDA) guidelines. The processing removes the cellular components (ie, epidermis, all viable dermal cells) that can lead to rejection and infection. ADM products from human skin tissue are regarded as minimally processed and not significantly changed in structure from the natural material; FDA classifies ADM products as banked human tissue and therefore, not requiring FDA approval.
Keramatrix® (Keraplast Research) is an open-cell foam comprised of freeze-dried keratin that is derived from acellular animal protein. In 2009, it was cleared for marketing by FDA through the 510(k) marketing process under the name of Keratec. The wound dressings are indicated in the management of the following types of dry, light, and moderately exudating partial and full-thickness wounds: pressure (stage I-IV) and venous stasis ulcers, ulcers caused by mixed vascular etiologies, diabetic ulcers, donor sites, and grafts.
Helicoll (Encol) is an acellular collagen matrix derived from bovine dermis. In 2004, it was cleared by FDA through the 510(k) process for topical wound management that includes partial and full-thickness wounds, pressure ulcers, venous ulcers, chronic vascular ulcers, diabetic ulcers, trauma wounds (eg, abrasions, lacerations, second-degree bums, skin tears), and surgical wounds including donor sites/grafts.
Permacol™ (Covidien) is xenogeneic and composed of cross-linked porcine dermal collagen. Cross-linking improves the tensile strength and long-term durability, but decreases pliability.
PriMatrix™ (TEI Biosciences) is a xenogeneic ADM processed from fetal bovine dermis. It was cleared for marketing by FDA through the 510(k) process for partial- and full-thickness wounds; diabetic, pressure, and venous stasis ulcers; surgical wounds; and tunneling, draining, and traumatic wounds. FDA product code: KGN.
SurgiMend® PRS (TEI Biosciences) is a xenogeneic ADM processed from fetal bovine dermis. This product is currently undergoing an FDA-regulated investigational device exemption trial for breast reconstruction.
Strattice™ Reconstructive Tissue Matrix (LifeCell Corp.) is a xenogenic non-cross-linked porcine-derived ADM. There are pliable and firm versions, which are stored at room temperature and come fully hydrated.
Oasis™ Wound Matrix (Cook Biotech) is a xenogeneic collagen scaffold derived from porcine small intestinal mucosa. In 2000, it was cleared for marketing by FDA through the 510(k) process for the management of partial- and full-thickness wounds, including pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled undermined wounds, surgical wounds, trauma wounds, and draining wounds. FDA Product code: KGN.
Amniotic Membrane Products
Amniotic membrane consists of two conjoined layers, the amnion and chorion, and forms the innermost lining of the amniotic sac or placenta. It is harvested immediately after birth, cleaned, sterilized, and either fresh frozen or dehydrated. Human amniotic membrane is considered minimally processed and not significantly changed in structure from the natural material; FDA classifies it as banked human tissue and, therefore, it does not require FDA approval. Amniotic membrane sheet products include Affinity™ (NuTech Medical), AlloWrap™ (AlloSource), AmnioBand and GUARDIAN (Musculoskeletal Transplant Foundation), AmnioGraft® (Bio-Tissue), BioDfence™ and BioDDryFlex® (BioD), Biovance® (Alliqua Biomedical), Dermavest™ and Plurivest™ (Aedicell), EpiFix® (dehydrated- MiMedix), Neox®1000 (Amniox® Medical), Grafix® Prime and Grafix® Core (cryopreserved; Osiris), NuShield™ (NuTech Medical), and Revitalon™ (previously known as AmnioClear; Medline Industries). Injectable amniotic membrane products, such as AmnioFix® (MiMedix), are discussed in the Amniotic Membrane and Amniotic Fluid Injections medical policy.
Living Cell Therapy
Apligraf® (Organogenesis) is a bilayered living cell therapy composed of an epidermal layer of living human keratinocytes and a dermal layer of living human fibroblasts. Apligraf® is supplied as needed, in 1 size, with a shelf-life of 10 days. In 1998, it was approved by FDA for use in conjunction with compression therapy for the treatment of noninfected, partial- and full-thickness skin ulcers due to venous insufficiency and in 2001 for full-thickness neuropathic diabetic lower-extremity ulcers nonresponsive to standard wound therapy.
Dermagraft® (Organogenesis) is composed of cryopreserved human-derived fibroblasts and collagen derived from newborn human foreskin and cultured on a bioabsorbable polyglactin mesh scaffold. Dermagraft has been approved by FDA for repair of diabetic foot ulcers. FDA product code: PFC.
TheraSkin® (Soluble Systems) is a cryopreserved human skin allograft composed of living fibroblasts and keratinocytes and an extracellular matrix in epidermal and dermal layers. TheraSkin® is derived from human skin allograft supplied by tissue banks compliant with the AATB and FDA guidelines. It is considered a minimally processed human cell, tissue, and cellular- and tissue-based product by FDA.
Epicel® (Genzyme Biosurgery) is a cultured epithelial autograft and is FDA-approved under a humanitarian device exemption (HDE) for the treatment of deep dermal or full-thickness burns comprising a total body surface area of 30% or more. It may be used in conjunction with split-thickness autografts or alone in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. FDA product code: OCE.
OrCel™ (Forticell Bioscience; formerly Composite Cultured Skin) is an absorbable allogeneic bilayered cellular matrix, made of bovine collagen, in which human dermal cells have been cultured. It was approved by FDA premarket approval for healing donor site wounds in burn victims and under an HDE for use in patients with recessive dystrophic epidermolysis bullosa undergoing hand reconstruction surgery to close and heal wounds created by the surgery, including those at donor sites. FDA product code: ODS.
Biobrane®/Biobrane-L (Smith and Nephew) is a biosynthetic wound dressing constructed of a silicon film with a nylon fabric partially imbedded into the film. The fabric creates a complex 3-dimensional structure of trifilament thread, which chemically binds collagen. Blood/sera clot in the nylon matrix, adhering the dressing to the wound until epithelialization occurs. FDA product code: FRO.
Integra® Dermal Regeneration Template (marketed as Omnigraft Dermal Regeneration Matrix; Integra LifeSciences) is a bovine, collagen/glycosaminoglycan dermal replacement covered by a silicone temporary epidermal substitute. It was approved by FDA for use in postexcisional treatment of life-threatening full-thickness or deep partial-thickness thermal injury where sufficient autograft is not available at the time of excision or not desirable because of the physiologic condition of the patient. Integra™ Matrix Wound Dressing and Integra™ meshed Bilayer Wound Matrix are substantially equivalent skin substitutes approved by FDA through the 510(k) process for other indications. Integra® Bilayer Wound Matrix (Integra LifeSciences) is designed to be used in conjunction with negative pressure wound therapy. The meshed bilayer provides a flexible wound covering and allows drainage of wound exudate. FDA product code: MDD.
TransCyte™ (Advanced Tissue Sciences) consists of human dermal fibroblasts grown on nylon mesh, combined with a synthetic epidermal layer and was approved by FDA in 1997. TransCyte is intended as a temporary covering over burns until autografting is possible. It can also be used as a temporary covering for some burn wounds that heal without autografting.
Suprathel® (PolyMedics Innovations) is a synthetic copolymer membrane fabricated from a tripolymer of polylactide, trimethylene carbonate, and s-caprolactone. It is used to provide temporary coverage of superficial dermal burns and wounds. Suprathel® is covered with gauze and a dressing that is left in place until the wound has healed.
Breast reconstructive surgery using allogeneic acellular dermal matrix products* (ie, AlloDerm®, AlloMax™, DermaMatrix™, FlexHD®, GraftJacket®; see Policy Guidelines) may be considered medically necessary,
Treatment of chronic, noninfected, full-thickness diabetic lower-extremity ulcers using the following tissue-engineered skin substitutes may be considered medically necessary:
Treatment of chronic, noninfected, partial- or full-thickness lower-extremity skin ulcers due to venous insufficiency, which have not adequately responded following a 1-month period of conventional ulcer therapy, using the following tissue-engineered skin substitutes may be considered medically necessary:
Treatment of dystrophic epidermolysis bullosa using the following tissue-engineered skin substitutes may be considered medically necessary:
Treatment of second- and third-degree burns using the following tissue-engineered skin substitutes may be considered medically necessary:
All other uses of the bio-engineered skin and soft tissue substitutes listed above are considered investigational.
All other skin and soft tissue substitutes not listed above are considered investigational, including, but not limited to:
Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Clinical input indicated that the various acellular dermal matrix (ADM) products used in breast reconstruction have similar efficacy. The products listed are those that have been identified for use in breast reconstruction. Additional ADM products may become available for this indication.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY5/2001: Approved by Medical Policy Advisory Committee (MPAC)
4/10/2002: Code Reference section updated, HCPCS J7340 added
4/18/2002: Type of Service and Place of Service deleted
5/30/2002: Code Reference section updated, ICD-9 280.82, 459.81, 459.89, 707.0, 707.10, 707.11, 707.12, 707.13, 707.14, 707.15, 707.19, 707.8, 707.9, 891.0, 891.1, 891.2, 892.0, 892.1, 892.2, 893.0, 893.1, 893.2, 894.0, 894.1, 894.2 added
8/1/2003: ICD-9 diagnosis code 433.9 typo corrected, ICD-9 diagnosis code ranges 443.0-443.9, 707.0-707.9, 891.0-894.2 listed separately
2/12/2004: Code Reference section updated; ICD-9 diagnosis code 443.0, 443.1, 443.21, 443.22, 443.23, 443.24, 443.29, 443.81, 443.89, 443.9 deleted; HCPCS C1305, Q0185 deleted
3/22/2005: Code Reference section updated, ICD-9 diagnosis code 707.0 5th digit with effective date of 10/1/2004 added, HCPCS J7343 with effective date of 1/1/2005 added
8/1/2005: Code Reference section updated, CPT 15342, 15343 added, ICD-9 diagnosis code 250.80, 250.81 with note "use additional code to identify any associated ulceration (i.e., 707.10-707.9)" added, ICD-9 diagnosis 707.10-707.9 description revised, ICD-9 diagnosis code 891.0, 891.1, 891.2, 892.0, 892.1, 892.2, 893.0, 893.1, 893.2, 894.0, 894.1, 894.2 deleted
03/08/2006: Coding updated. CPT/HCPCS 2006 revisions added to policy
11/16/2006: Policy updated. Updates approved by Medical Policy Advisory Committee (MPAC). Added ICD-9 code 756.81
12/27/2006: Code Reference section updated per the 2007 CPT/HCPCS revisions
5/14/07: Policy reviewed, no changes
12/17/07: Coding updated. CPT/HCPCS 2008 revisions added to policy.
9/3/2008: Added ICD-9 codes 250.60 - 250.63
9/22/2008: Annual ICD-9 updates effective 10-1-2008 applied
12/24/2008: Code reference section updated per 2009 CPT/HCPCS revisions
6/30/2009: New HCPC codes Q4115 and Q4116 added to covered table.
03/09/2011: Removed the following deleted codes from the Code Reference section: 15342, 15343, J7340, J7343, J7345 - J7349.
04/24/2013: Policy reviewed; no changes.
11/03/2014: Policy title changed from "Apligraf for Wound Healing" to "Bio-Engineered Skin and Soft Tissue Substitutes." Policy description updated to reflect scope of policy. Policy statement udpated to list medically necessary products and their covered indications, as well as the products that are considered investigational.
12/31/2014: Added the following new 2015 HCPCS codes to the Code Reference section: Q4150, Q4151, Q4152, Q4153, Q4154, Q4155, Q4156, Q4157, Q4158, Q4159, and Q4160.
04/30/2015: Policy statement revised to add that EpiFix is considered medically necessary for treatment of diabetic foot ulcers. Updated listing of investigational skin and soft tissue substitutes in the policy statement. Policy guidelines updated to add medically necessary and investigational definitions. Code Reference section updated to add CPT Codes 15271, 15272, 15273, 15274, 15275, 15276, 15277, and 15278 to the Covered Codes table. Added HCPCS codes Q4128 and Q4131 to the Covered Codes table. Removed deleted procedure codes Q4109, 15170, 15171, 15175, 15176, 15340, 15341, 15360, 15361, 15365, and 15366 from the Code Reference section. HCPCS codes Q4103, Q4104, Q4108, Q4110, Q4111, and Q4115 moved to the Investigational Codes section and also added HCPCS codes Q4112 - Q4114, and Q4117 - Q4127, and Q4129 - Q4149 to the Investigational Codes table per the investigational policy statement. Added ICD-9 diagnosis codes 174.0 - 174.9, 233.0, 941.30 - 941.39, 941.40 - 941.49, 941.50 - 941.59, 942.30 - 942.39, 942.40 - 942.49, 942.50 - 942.59, 943.30 - 943.39, 943.40 - 943.49, 943.50 - 943.59, 944.30 - 944.38, 944.40 - 944.48, 944.50 - 944.58, 945.30 - 945.39, 945.40 - 945.49, 945.50 - 945.59, 946.3 - 946.5, 948.00 - 948.99, 949.3 - 949.5, V10.3, and V45.71 to the Covered Codes table. Removed diagnosis code 756.81 from the Covered Codes table. Deleted outdated references from the Sources section.
08/31/2015: Medical policy revised to add ICD-10 codes.
12/31/2015: Code Reference section updated to add new 2016 HCPCS codes Q4161, Q4162, Q4163, Q4164, and Q4165 to the investigational codes table. Code description revised for HCPCS code Q4153.
05/31/2016: Policy number added.
12/31/2016: Policy description updated regarding artificial skin and soft tissue substitutes. Policy statement regarding treament of diabetic lower-extremity ulcers updated to add Integra® Dermal Regeneration Template and Amniotic Membrane Graft (including Biovance® and Grafix™) as medically necessary. Removed TransCyte™ as medically necessary for treatment of second and third degree burns, as it is no longer commercially available. Investigational list of skin and soft tissue substitutes updated to add, remove, and revise product names. Policy guidelines updated for clarification regarding acellular dermal matrix products. Code Reference section updated to move the following HCPCS codes from investigational to covered, effective 01/01/2017: Q4132, Q4133, and Q4154. Added new 2017 HCPCS codes Q4166, Q4167, Q4168, Q4169, Q4170, Q4171, Q4172, Q4173, Q4174, and Q4175 to the investigational codes table. Revised code descriptions for HCPCS codes Q4105 and Q4131.
Blue Cross Blue Shield Association policy # 7.01.113
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.