1. health and fitness
2. disease

Clinical Policy Title: Bioengineered Skin Substitutes for Ulcers and Wound Care
Clinical Policy Number: 16.03.01
Effective Date:
Initial Review Date:
Most Recent Review Date:
Next Review Date:
Dec. 1, 2013
March 21, 2013
March 19, 2014
March 2015
Policy contains:
• Bioengineered skin substitutes.
• Lower extremity ulcers.
• Pressure ulcers.
• Burns.
• Wound care.
ABOUT THIS POLICY: Arbor Health Plan has developed clinical policies to assist with making coverage determinations. Arbor Health Plan clinical
policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory
agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical
policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific
definition of “medically necessary,” and the specific facts of the particular situation are considered by Arbor Health Plan when making coverage
determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements,
the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Arbor Health Plan clinical policies are for informational
purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the
treatment decisions for their patients. Arbor Health Plan clinical policies are reflective of evidence-based medicine at the time of review. As medical
science evolves, Arbor Health Plan will update its clinical policies as necessary. Arbor Health Plan clinical policies are not guarantees of payment.
Coverage policy
Arbor Health Plan considers the use of specific bioengineered skin substitutes to be clinically proven and,
therefore, medically necessary when the following criteria are met:
Product
Coverage requirements
Apligraf®
(grafskin)
The treatment of infection-free, full-thickness, neuropathic diabetic foot ulcers (DFU)
when all of the following are met:
• The individual is under current diabetes medical management (including nutritional
support and neuropathy treatment) with evidence of stable HgbA1c levels.
• The individual has adequate circulation/oxygenation to the affected extremity as
evidenced by a palpable pulse on the foot (either dorsalis pedis or posterior tibial
artery) or an ankle brachial index (ABI) of 0.7 or greater.
• The individual is cognizant and able to participate in, or has a support system to assist
with, the follow-up care associated with the treatment of the DFU with Apligraf.
The DFU:
• Is at least 1.0 cm2 in size.
• Is free of active sinus tracts, osteomyelitis, cellulitis, eschar or necrotic tissue, or
Product
Coverage requirements
•
•
•
•
Charcot’s arthropathy; these conditions must be successfully resolved prior to skin
substitute treatment.
Extends through the dermis yet does not involve any tendon, muscle, joint capsule or
bone exposure.
Has been treated with appropriate steps to off-load pressure.
Has been present for at least three weeks.
Has been treated with conservative therapy for more than three weeks and failed to
decrease in size, OR presents as so clinically severe that it requires immediate,
aggressive therapy.
The treatment of infection-free, partial- or full-thickness venous stasis ulcers (VSU) when
all of the following are met:
• The individual is under current medical management for venous insufficiency, with
objective documentation that supports the diagnosis.
• The individual has adequate circulation/oxygenation to the affected extremity as
evidenced by a palpable pulse on the foot (either dorsalis pedis or posterior tibial
artery) or an ABI of no less than 0.65.
The VSU:
• Is at least 1.0 cm2 in size.
• Has been present for at least four weeks.
• Has been treated with conservative therapy for a minimum of four weeks and failed
to decrease in size or show any clinical indication of improvement, OR presents as so
clinically severe that it requires immediate, aggressive therapy.
Dermagraft®
Full-thickness DFU when all of the following are met:
• The individual is under current medical management for Type I or Type II diabetes
mellitus.
• The individual has adequate circulation/oxygenation to the affected extremity as
evidenced by a palpable pulse on the foot (either dorsalis pedis or posterior tibial
artery) or an ABI of 0.7 or greater.
• The individual is cognizant and able to participate in, or has a support system to assist
with, the follow-up care associated with the treatment of the DFU with Dermagraft.
The DFU characteristics include all of the following:
• Is at least 1.0 cm2 in size.
• Is free of active sinus tracts, osteomyelitis, cellulitis, eschar or necrotic tissue, or
Charcot’s arthropathy; these conditions must be successfully resolved prior to skin
substitute treatment.
• Extends through the dermis yet does not involve any tendon, muscle, joint capsule or
bone exposure.
• Has been treated with appropriate steps to off-load pressure.
• Has been present for at least three weeks.
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Product
Coverage requirements
•
Has been treated with conservative therapy for more than three weeks and failed to
decrease in size, OR presents as so clinically severe that it requires immediate,
aggressive therapy.
The treatment of infection-free, partial or full-thickness VSU when all of the following are
met:
• The individual is under current medical management for venous insufficiency, with
objective documentation that supports the diagnosis.
• The individual has adequate circulation/oxygenation to the affected extremity as
evidenced by a palpable pulse on the foot (either dorsalis pedis or posterior tibial
artery) or an ABI of no less than 0.65.
The VSU characteristics include all of the following:
• Is at least 1.0 cm2 in size.
• Has been present for at least four weeks.
• Has been treated with conservative therapy for a minimum of four weeks and failed
to decrease in size or show any clinical indication of improvement, OR presents as so
clinically severe that it requires immediate, aggressive therapy.
EpiFix®
This product from amniotic membranes was originally developed for corneal surface
indications. EpiFix is a dehydrated human amnion/chorion membrane (dHACM) allograft
and is composed of multiple layers, including a single layer of epithelial cells, a basement
membrane and an avascular connective tissue matrix. EpiFix is a minimally manipulated,
dehydrated, nonviable cellular amniotic membrane allograft that preserves and delivers
multiple extracellular matrix proteins, growth factors, cytokines and other specialty
proteins present in amniotic tissue to help regenerate soft tissue.
GRAFTJACKET® Neuropathic DFU when all of the following are met:
Regenerative
• The individual is under current diabetes medical management that includes
Tissue Matrix
documentation of an HbA1c level of 12 percent or less.
• The individual has adequate circulation/oxygenation to the affected extremity as
evidenced by a palpable pulse on the foot (either dorsalis pedis or posterior tibial
artery) or an ABI of 0. 65 or greater.
The DFU characteristics include all of the following:
• Has been present for at least three weeks.
• Is a full-thickness ulcer that extends through the dermis yet does not involve any
tendon, muscle, joint capsule or bone exposure.
• Is free of infection, active sinus tracts, osteomyelitis, cellulitis, redness, drainage,
eschar or necrotic tissue, or Charcot’s arthropathy; any of these conditions must be
successfully resolved prior to skin substitute treatment.
• The GRAFTJACKET repair is used in conjunction with conservative diabetic ulcer
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Product
Coverage requirements
measures (e.g., non-weight bearing).
OASIS®
Wound Matrix
Neuropathic DFU when all of the following are met:
• The individual is under current diabetes medical management that includes
documentation of an HbA1c level of 12 percent or less.
• Conservative wound care measures have been tried (e.g., removal of mechanical
stress).
The DFU characteristics include all of the following:
• Is infection-free.
• Has been present for at least four weeks.
• Has a viable wound bed with granulation tissue present.
• Is located on the foot or toes.
• Has no exposure of any fascia, tendon or bone.
The VSU characteristics include all of the following:
• The VSU has been present for more than one month.
• The VSU has been treated with conservative therapy (e.g., compression wraps) for
more than four weeks and has not decreased in size, has increased in size or has not
shown any clinical indication of improvement (e.g., granulation, epithelialization).
There must be documentation of baseline measurements prior to placement of the
Oasis® product.
• Chronic vascular ulcers with an ABI of 0.7 or greater in the limb receiving the Oasis
Wound Matrix.
• Partial, full-thickness or surgical wounds.
OASIS Wound Matrix is not used in individuals with any of the following (non-exhaustive)
list of conditions:
• Rheumatoid arthritis.
• Radiation therapy to the ulcer site.
• Uncontrolled congestive heart failure.
• Severe arterial disease.
• Receiving corticosteroids or immunosuppressive therapies.
• Collagen vascular disease.
• Malnutrition (albumin).
• Known allergy to porcine-derived products.
• Previous organ transplant.
• Currently undergoing hemodialysis.
• Wounds with signs of cellulitis, osteomyelitis, or necrotic or avascular ulcer beds.
• Insufficient blood supply to the ulcer (TcPO2@ < 30 mm Hg, toe or ankle brachial
index < 0.7 mmHg).
• Active Charcot joint disease or sickle-cell disease; third degree burns.
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Product
Coverage requirements
PriMatrix®
Diabetic ulcers when all of the following are met:
• The individual is under current diabetes medical management with documentation.
• Conservative wound care measures (e.g., removal of mechanical stress) have been
tried and failed.
• The ulcer has not decreased in size from baseline, has increased in size or does not
show any clinical indication of improvement (e.g., granulation, epithelialization).
• The ulcer is infection-free and osteomyelitis-free.
VSU when all of the following are met:
• The VSU has been present for greater than two months.
• The VSU has been treated with conservative therapy (e.g., surgical debridement,
compression wraps) for more than four weeks and has not decreased in size, has
increased in size or does not show any clinical indication of improvement (e.g.,
granulation, epithelialization).
• The individual has adequate arterial blood supply to support tissue growth.
• The PriMatrix is applied in conjunction with clinically adequate compression dressing.
Treatment indications include any of the following:
• Partial-thickness wounds.
• Pressure ulcers.
• Surgical wounds (e.g., dehiscence, donor sites/grafts, post-Mohs surgery, podiatric).
• Trauma wounds (e.g., abrasions, lacerations, second-degree burns,
skin tears).
• Tunneled/undermined wounds, or draining wounds.
• The individual must have adequate arterial blood supply as evidenced by ABI of 0.65
or greater in limb undergoing the procedure/application.
TheraSkin®
•
•
The application of TheraSkin must be done in conjunction with standard conservative
measures, (e.g., non-weight bearing regime).
The individual is cognizant and able to participate in, or has a support system to assist
with, the follow-up care associated with the treatment of the DFU, and/or SVU with
Theraskin.
All other uses of bioengineered skin substitutes are considered investigational and unproven, and not
medically necessary as their effectiveness has not been established in peer-reviewed professional
literature.
Limitations
Limitations apply to specific skin substitutes based upon the characteristics of each unique product or the
absence of rigorous study. The limitations for each referenced skin substitute include those listed below. All
other uses of the skin substitutes are not medically necessary.
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Product
Details
Apligraf
A single application of Apligraf may be all that is
required to affect wound healing in those DFUs and
VSUs that are likely to improve with this therapy.
Additional applications, when less than a 50 percent
“take” is observed, are limited to a total of four for
the same initially qualified ulcer (for a total of five
applications).
• Additional applications beyond five in a oneyear period are generally not considered
reasonable or medically necessary.
• Retreatment within one year following the
last successful Apligraf application is
generally not considered reasonable or
medically necessary.
• Retreatment of an ulcer wound, following
unsuccessful treatment that consisted of
two failed Apligraf applications, is not
considered reasonable or medically
necessary.
Dermagraft
A single application of Dermagraft may be all that is
required to affect wound healing in those DFUs that
are likely to improve with this therapy. Additional
applications of Dermagraft are limited to a total of
seven for the same initially qualified DFU (for a total
of eight applications).
• Additional applications beyond eight in a
one-year period are generally not
considered reasonable, proven or medically
necessary.
• Retreatment within one year following the
last successful Dermagraft application is
generally not considered proven or
medically necessary.
EpiFix, Mimedx,
Epifix should not be used for areas of active or
latent infection; or if there is a risk of complications.
Treatment with EpiFix for conditions beyond FDA
approved indications are not covered, as there is
insufficient peer-reviewed medical literature to
support a conclusion of medical necessity.
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GRAFTJACKET, OASIS, TheraSkin, PriMatrix
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Theraskin
•
All of the skin substitute products contained
in this policy are to be used in a manner
supported by their respective, specific FDA
labeling.
Medicare part B accepts the U.S. Food and
Drug Administration's (FDA) classification
and description of any bioengineered skin
substitute. The FDA has regulated most skin
substitutes as medical devices. However,
some are regulated as human tissue and are
therefore subject to the rules and
regulations of banked human tissue, not the
FDA approval process.
The medical record must clearly state the
skin substitute product is being used in an
office- or clinic-based, comprehensive,
organized wound management program.
The application of bioengineered skin
substitutes is limited to clinicians who are
highly skilled in wound care management
and have experience in the use of
bioengineered skin substitutes for the
treatment of wounds. The success of the
procedure is somewhat dependent on the
skill of the performing provider; therefore,
the provider may be subject to a post
payment peer review in order to verify
his/her qualifications.
Debridement and ulcer/wound preparation
are considered a part of the material
application procedure.
Additional applications of the same
bioengineered skin substitute occur with
two weeks between applications for VSUs,
and there should be no fewer than three
weeks between applications for neuropathic
DFUs, except when more frequent
applications are either a part of the FDA
product specific labeling instructions, or are
clearly supported by medical record
documentation of medically reasonable and
necessary indications.
Treatment with TheraSkin is usually
expected to last no more than 12 weeks for
any ulcer that initially qualifies for
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treatment. Reapplication of TheraSkin
within one week for the same ulcer is not
considered reasonable or medically
necessary:
Retreatment with TheraSkin when the initial
application has resulted in no decrease in
size or increase in granulation tissue,
epithelialization or progress towards closing
is not considered reasonable or medically
necessary.
Retreatment within one year following the
last successful application with TheraSkin is
not considered reasonable or medically
necessary.
Retreatment of an ulcer following an
unsuccessful treatment consisting of two
failed TheraSkin applications is not
considered reasonable or medically
necessary.
Additional limitations for bioengineered skin substitutes
• All of the skin substitute products contained in this policy are to be used in a manner supported by
their respective, specific FDA labeling.
• Medicare part B accepts the U.S. Food and Drug Administration's (FDA) classification and
description of any bioengineered skin substitute. The FDA has regulated most skin substitutes as
medical devices. However, some are regulated as human tissue and are therefore subject to the
rules and regulations of banked human tissue, not the FDA approval process.
• The medical record must clearly state that the skin substitute product is being used in an office- or
clinic-based, comprehensive, organized wound management program.
• The application of bioengineered skin substitutes is limited to clinicians who are highly skilled in
wound care management and have experience in the use of bioengineered skin substitutes for the
treatment of wounds. The success of the procedure is somewhat dependent on the skill of the
performing provider; therefore, the provider may be subject to a post-payment peer review in
order to verify his/her qualifications.
• Debridement and ulcer/wound preparation are considered a part of the material application
procedure.
• Additional applications of the same bioengineered skin substitute occur with two weeks between
applications for VSUs and at least three weeks between applications for neuropathic DFUs, except
when more frequent applications are either a part of the FDA product-specific labeling instructions
or are clearly supported by medical record documentation of medically reasonable and necessary
indications.
NOTE: The following codes are not reimbursed under Medicaid fee schedule in Nebraska:
• The application of tissue cultured allogenic skin substitute or dermal substitute for use on
lower limb, includes the site preparation and debridement if performed; first 25 sq cm or
less [required when billing (CPT G0440); this includes site preparation.
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•
Application of tissue cultured allogenic skin substitute or dermal substitute for use on lower
limb, includes the site preparation and debridement if performed; first 25 sq cm or less
[required when billing, each additional 25 sq. cm. (CPT G0441); this includes site
preparation.
The application of skin substitute, Apligraf®, per square centimeter (HCPCS Q4101).
The application of skin substitute, Oasis wound matrix, per square centimeter (HCPCS
Q4102).
The application of skin substitute, Dermagraft, per square centimeter (HCPCS Q4106)
The application of Graftjacket®, per square centimeter (HCPCS Q4107).
The application of skin substitute, Primatrix®, per square centimeter (HCPCS Q4110).
The application of TheraSkin, per square centimeter (HCPCS Q4121).
The application of EpiFix, per square centimeter (HCPCS Q4131)
Alternative covered services
Physician and surgical visits, vacuum assisted wound closure, conservative diabetic foot care, conservative
venous stasis ulcer wound care, compression therapy, and pneumatic compression.
Please also see the summary of evidence table (pages 7 – 8).
Background
The skin is the largest organ of the body and provides various functions, such as protection from harmful
bacteria, excessive water loss, excretion and temperature regulation. It is composed of two layers, the
epidermis and the dermis. The epidermis is the layer that comes into direct contact with the environment
and depends upon the dermal layer for numerous structures and support; among these are connective
tissue, vasculature to supply nutrients, sensory receptors and glandular activity. When these functions of
the skin are disrupted it may become damaged and prone to develop wounds or infections. Ultraviolet sun
rays, age and certain disease processes may cause detrimental changes to the skin.
Skin grafts have a history of being used to replace damaged or absent areas of dermal tissue associated
with disease or injury. Skin grafts may be full thickness (FTSG), involving all the layers of the skin, or splitthickness skin grafts (STSG) that involve the epidermis and a limited amount of the dermis. Autologous skin
grafts, or auto grafts, use portions of an individual's own skin and are the least prone to tissue rejection.
Though autologous grafts are excellent material for wound repair, their use is dependent upon the amount
of healthy skin available. Skin harvesting procedures are painful, invasive and may add stress to an already
compromised individual. Temporary skin is provided by the use of allografts, from other human donors, or
xenografts, tissue from another animal species such a porcine (pig) or bovine (cow). These temporary skin
grafts must be replaced with an autograft.
Bioengineered skin substitutes were developed to address the problems encountered with the use of
allografts, autografts and xenografts. These products are known by names such as tissue-engineered skin
substitutes, skin alternatives and skin equivalents. Bioengineered products contain natural or synthetic
matrix scaffolds composed of fibroblast or keratinocyte cells that provide a mechanically stable framework
and tissue infiltration. Human skin substitutes are manufactured using selected human cells that are placed
into a matrix and provided with nutrients for the cells to grow into the desired tissue. Skin substitutes have
been developed to meet the needs of individuals with insufficient skin for grafting. They are designed to
temporarily assume the functions of the dermal layers until an individual’s own skin repairs itself or until a
skin replacement is found.
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Bioengineered skin substitutes are approved for use in certain types of non-healing wounds and have been
used for a variety of chronic wounds with the aim of reducing infection and promoting faster healing —
beneficial clinical effects associated with complete wound closure. Venous stasis ulcers and diabetic foot
ulcers are two types of chronic, non-healing wounds that affect all types of demographic groups.
Bioengineered skin substitutes are classified into four main groups:
1. Human- and human/animal-derived bioengineered skin substitutes regulated through FDA
premarket approval process (PMA) or humanitarian device exemption (HDE).
2. Human-derived bioengineered skin substitutes regulated as human cells, tissues, and cellular and
tissue-based products.
3. Animal-derived bioengineered skin substitutes regulated through FDA 510(k) process.
4. Biosynthetic bioengineered skin substitutes regulated through FDA 510(k) process.
Apligraf (grafskin) and Dermagraft are human/animal-derived bioengineered skin substitutes regulated
through FDA premarket approval process (PMA) or humanitarian device exemption (HDE) as a
manufactured viable bilaminate. Apligraf is a composite, bilayered product derived from human neonatal
foreskin in a bovine matrix. Studies confirm that Apligraf combined with compression therapy improves
healing times for venous stasis wounds. Dermagraft is a dermal replacement derived from human neonatal
foreskin fibroblasts, and is FDA-approved for use in diabetic foot ulcers (DFU).
EpiFix is amniotic membrane used for diabetic foot ulcers. Amniotic membranes are obtained post-partum,
cleaned, sterilized and dehydrated for storage. The FDA classifies these as banked human tissue and
regulates them under Section 361 of the Public Health Services Act.
GRAFTJACKET Regenerative Tissue Matrix, EpiFix and TheraSkin are human-derived bioengineered skin
substitutes regulated as human cells, tissues, and cellular and tissue-based products. GRAFTJACKET
Regenerative Tissue Matrix is derived from cadaver skin and has been studied for use in individuals with
DFUs. EpiFix is derived from amniotic cell lines.
OASIS Wound Matrix and PriMatrix are animal-derived bioengineered skin substitutes regulated through
FDA 510(k) processes. OASIS Wound Matrix is a natural extracellular matrix derived from porcine small
intestinal submucosa that replaces the human body's absent or damaged extracellular matrix. It contains
collagen, elastin, etc., is compatible with human tissue and has FDA approval for use in the treatment of
partial- and full-thickness wounds, such as diabetic ulcers, venous stasis ulcers and other surgical wounds.
Methods
Searches
Arbor Health Plan searched PubMed and the databases of:
• UK National Health Services Centre for Reviews and Dissemination.
• Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other evidencebased practice centers.
• The Centers for Medicare & Medicaid Services.
The search terms were “skin substitutes” and “wound care.”
We included:
• Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater
precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined
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transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are
thus rated highest in evidence-grading hierarchies.
Guidelines based on systematic reviews.
Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost
studies), reporting both costs and outcomes — sometimes referred to as efficiency studies — which
also rank near the top of evidence hierarchies.
Overview of the literature — systematic reviews/guidelines and economic analyses for bioengineered
skin substitutes: reverse chronological order and then alphabetically by first author.
Summary of findings
While the methodologic quality of the literature is generally poor, it has recently improved sufficiently for
cautious conclusions that skin substitutes are safe and at least as effective as standard treatments.
Citation
Content
Hayes (2013)
OASIS Wound Matrix for lower extremity ulcers:
• 3 RCTs and one quasi.
• Low-quality evidence for improved healing.
Hoogewerf (Cochrane;
2013)
Topical treatment for facial burns:
• RCTs, 1980 ‒ 2012.
• Five trials (119 subjects) — two for antimicrobial agents, three for skin
substitutes.
• All high risk of bias.
• Insufficient evidence.
Wasiak (Cochrane;
2013)
Dressings for superficial and partial thickness burns:
• RCTs; 2012.
• Thirty trials — generally poor quality.
• Trials too heterogeneous for conclusions.
Snyder (AHRQ; 2012)
Skin substitutes for chronic wounds:
• Eighteen RCTs — 12 DFU; six VSU; one pressure ulcer.
• Overall moderate/low quality.
Buchberger (2011)
Growth factors and active skin substitutes for non-infected diabetic foot ulcers:
• Publications since 1990.
• Could be alternatives to standard wound treatment alone but weak evidence
precludes firm conclusions.
UK National Institute
for Clinical Excellence
(NICE) (2011)
Inpatient management of diabetic foot problems:
• Economic evaluations — Feb 2010.
• Hospitals should have multi-disciplinary foot care teams (diabetologist and
nurse specialist, surgeon, podiatrist, tissue viability nurse, and access to other
specialist services) for diabetics with foot ulcers.
• Wound dressing choice should take into account clinical assessment of wound,
patient preferences and acquisition cost.
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Citation
Content
•
NOT recommended: dermal or skin substitutes, autologous platelet-rich plasma
gel, regenerative wound matrices, growth factors, hyperbaric oxygen.
Hayes (2010)
Skin substitutes for wound healing (limited number of moderate quality RCTs):
• Apligraf — in conjunction with standard therapy for non-infected chronic lower
extremity ulcers for whom standard therapy is ineffective.
• Biobrane — pediatric patients with non-infected partial thickness burns < 25%
of body surface area.
• Dermagraft — in conjunction with standard therapy for DFUs > 3 weeks and not
responsive to standard therapy alone.
Barber (Australian
Safety and Efficacy
Register of New
Interventional
Procedures - Surgical
[ASERNIP-S]; 2008)
Flack (2008)
Skin substitutes for diabetic foot ulcers and venous leg ulcers:
• RCTs; July 2008.
• 18 poor/moderate quality trials (1,909 subjects).
• Products with dermal component may improve healing.
Barber (ASERNIP-S ;
2006)
Bioengineered skin substitutes for wound management:
• Evidence based rated average; limited by small sample sizes, short follow up
time and general lack of methodologic rigor for all three indications (epidermal,
dermal or both).
• Safety — suggests that substitutes at least as safe as standard therapies for
diabetic foot ulcers and venous leg ulcers but data insufficient for long-term
outcomes judgment.
Pham (ASERNIP-S;
2006)
Bioengineered skin substitutes for burns:
• RCTs — 2006.
• Insufficient evidence.
Economic evaluation: closure of partial thickness facial burns with bioactive skin
substitute:
• Effectiveness based on one low-quality RCT (34 subjects, no power calculation
or randomization methods reported).
• Skin substitutes cost-effective compared to current practice.
Demling (2002)
Economic evaluation: Vacuum-assisted wound closure vs. alternatives including
Apligraf and Dermagraft for diabetic foot ulcers:
• Markov model; one year horizon and data from RCTS.
• No studies directly compared VAC to skin substitutes but VAC appears to be
more effective and less expensive than alternatives.
Glossary
Reapplication — An additional application of a skin substitute to the same ulcer within the same treatment
period.
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Retreatment — A new treatment period in which the same ulcer is treated again because the initial
treatment was apparently unsuccessful.
Related policies
Arbor Health Plan Utilization Management program description.
References
Professional society guidelines/other:
American College of Foot and Ankle Surgeons. Diabetic foot disorders. Oct 2006.
Barber C, Watt A, Pham CT, et al. Bioengineered skin substitutes for the management of wounds: a
systematic review. Stepney: Australian Safety and Efficacy Register of New Interventional Procedures Surgical (ASERNIP-S). ASERNIP-S Report No. 52.2006.
Hayes, Inc. Oasis Wound matrix. Health Technology Brief. Reviewed 12/24/2013.
Hayes, Winifred S. Directory Report. Biosynthetic tissue‐engineered skin substitutes for wound healing.
January 14, 2010.
Institute for Clinical Systems Improvement (ICSI). Pressure ulcer prevention and treatment protocol.
Bloomington(MN): Institute for Clinical Systems Improvement (ICSI). 2012.
National Institute for Health and Clinical Excellence (NICE). CG 119 Diabetic foot problems: Inpatient
management of diabetic foot problems. 2011.
National Pressure Ulcer Advisory Panel. Pressure ulcer treatment recommendations. In: Prevention and
treatment of pressure ulcers: clinical practice guideline. Washington, DC: National Pressure Ulcer Advisory
Panel. 2009: 51 – 120.
Pham CT, Maddern G, Greenwood J, Cleland H, Woodruff P. Bioengineered skin substitutes for the
management of burns: a systematic review. Stepney, S. Australia: Royal Australasian College of Surgeons,
Australian Safety and Efficacy Register of new Interventional Procedures - Surgical (ASERNIP-S). Report No.
46. 2006.
Snyder DL, Sullivan N, Schoelles KM. Skin substitutes for treating chronic wounds. Technology assessment
report. Prepared by the ECRI Institute Evidence-based Practice Center under contract to the Agency for
Healthcare Research and Quality (AHRQ), Rockville, MD. (Contract No: HHSA 290-2007-10063. December
18, 2012.
United States Department of Health and Human Services. Agency for Healthcare Research and Quality
(AHRQ). Technology Assessment Program. Negative Pressure Wound Therapy Devices. November 12, 2009.
Peer-reviewed references:
Barber C, Watt A, Pham C, et al. Influence of bioengineered skin substitutes on diabetic foot ulcer and
venous leg ulcer outcomes. Journal of Wound Care.2008; 17(12):517 – 27.
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Brem H, Kirsner R, Boulton A. Protocol for treatment of diabetic foot ulcers. American Journal of Surgery.
2004; 187: (5).
Buchberger A, Follmann M, Freyer D, Huppertz H, Ehm A, Wasem J. The evidence for the use of growth
factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): a health
technology assessment (HTA). Clinical Endocrinology and Diabetes.2011; 119(8):472 – 9.
Brigido SA. The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity
wounds: a prospective 16-week pilot study. Int Wound J. 2006 Sep; 3(3):181 – 7,
Brigido SA, Schwartz E, McCarroll R, Hardin-Young J. Use of an acellular flowable dermal replacement
scaffold on lower extremity sinus tract wounds: a retrospective series. Foot Ankle Spec. 2009 Apr; 2(2):67 –
72.
Curran MP, Plosker GL. Bilayered bioengineered skin substitute (Apligraf): a review of its use in the
treatment of venous leg ulcers and diabetic foot ulcers. Biodrugs. 2002;16(6):439 – 55.
Demling RH, Niezgoda JA, Haraway GD, Mostow EN. Small intestinal submucosa wound matrix and full
thickness venous ulcers: preliminary results. Wounds. 2004; 16:18 – 22.
Demling RH, DeSanti L. Closure of partial thickness facial burn with a bioactive skin substitute in the major
burn population decreases the cost of care and improves outcome. Wounds.2002; 14(6):230 – 4.
Department of Health and Human Services. Oversight of tissue banking. Jan 20, 2001. Available at URL
address: http://www.oig.hhs.gov/. Accessed March 30, 2014.
Driver VR, Hanft J, Fylling CP, Beriou JM, AutoloGel™ Diabetic Foot Ulcer Study Group. A prospective,
randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers.
Ostomy Wound Manage. 2006 Jun; 52(6):68 – 70, 72, 74 passim.
Edmonds M; European and Australian Apligraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of
neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009 Mar; 8(1):11 – 18.
Flack S, Apelqvist J, Keith M, Trueman P, Williams D. An economic evaluation of VAC therapy compared with
wound dressings in the treatment of diabetic foot ulcers. Journal of Wound Care.2008; 17(2):71 – 8.
Game FL, Hinchliffe RJ, Apelqvist J, et al. A systematic review of interventions to enhance the healing of
chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev. 2012 Feb; 28 Suppl 1:119 – 41.
Hayes Inc. Hayes Medical Technology Directory Report. Biosynthetic tissue‐engineered skin substitutes for
wound healing. Lansdale, Pa: Hayes, Inc. February 21, 2012.
Ho C, Tran K, Hux M, Sibbald G, Campbell K. Artificial skin grafts in chronic wound care: a meta-analysis
of clinical efficacy and a review of cost-effectiveness. HealthPoint®. Oasis Matrix. 2011.[Technology reports
no 52]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2005.
Hoogewerf CJ, Van Baar ME, Hop MJ, Niewenhuis MK, Oen IMMH, Middelkoop E. Topical treatments for
facial burns. Cochrane Database of Systematic Reviews. 2013. Issue 1.
14
Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. In: The
Cochrane Library, Issue 1. Chichester, UK: John Wiley & Sons, Ltd.; 2000. Updated 2009.
Karr JC. Retrospective comparison of diabetic foot ulcer and venous stasis ulcer healing outcome between a
dermal repair scaffold (PriMatrix) and a bilayered living cell therapy (Apligraf). Adv Skin Wound Care. 2011
Mar; 24(3):119 – 25.
Kirsner RS, Warriner R, Michela M, Stasik L, Freeman K. Advanced biological therapies for diabetic foot
ulcers. Arch Dermatol. 2010 Aug;146(8):857 – 62.
Landsman AS, Cook J, Cook E, et al. A Retrospective Clinical Study of 188 Consecutive Patients to Examine
the Effectiveness of a Biologically Active Cryopreserved Human Skin Allograft (TheraSkin®) on the
Treatment of Diabetic Foot Ulcers and Venous Leg Ulcers. Foot Ankle Spec. 2011 Feb; 4(1):29 – 41.
Límová M. Active wound coverings: bioengineered skin and dermal substitutes. Surg Clin North Am. 2010
Dec; 90(6):1237 – 55.
Marston W, Hanft J, Norwood P, Pollak R. The efficacy and safety of Dermagraft in improving the healing of
chronic diabetic foot ulcers. Diabetes Care. 2003 Jun; 26(6):1701 – 5.
Martin BR, Sangalang M, Wu S, Armstrong DG. Outcomes of allogenic acellular matrix therapy in treatment
of diabetic foot wounds: an initial experience. Int Wound J. 2005 Jun; 2(2):161 – 5.
Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D. Effectiveness of an extracellular matrix graft (OASIS
Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. Journal of Vascular
Surgery. 2005; 41(5):837 – 43.
Niezgoda JA, Van Gils CC, Frykberg RG, Hodde JP. Randomized clinical trial comparing OASIS Wound Matrix
to Regranex Gel for diabetic ulcers. Adv Skin Wound Care. 2005 Jun; 18(5 Pt 1):258 – 66.
Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft.
Eur J Vasc Endovasc Surg. 2004 Jun; 27(6):666 – 72.
Organogenesis Inc. Apligraf. Prescribing information. 2010. Novartis. Available
at: http://www.apligraf.com/professional/. Accessed March 30, 2014.
Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers: a phase II
randomized, double-blind, placebo-controlled study. Wound Repair Regen. 1999 May – Jun; 7(3):141 – 7.
Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue
matrix compared to standard wound management in healing diabetic foot ulcers: a prospective,
randomised, multicentre study. Int Wound J. 2009 Jun; 6(3):196 – 208.
Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound
dressing in the treatment of difficult-to-heal wounds of mixed arterial/venous etiology. Adv Skin Wound
Care. 2010; 23(1):34 – 38.
Steinberg JS, Edmonds M, Hurley DP Jr, King WN. Confirmatory data from EU study supports Apligraf for the
treatment of neuropathic diabetic foot ulcers. J Am Podiatr Med Assoc. 2010 Jan – Feb; 100(1):73 – 7.
15
Teng YJ, Li YP, Wang JW, et al. Bioengineered skin in diabetic foot ulcers. Diabetes Obes Metab. 2010 Apr;
12(4):307 – 15.
U.S. Food and Drug Administration (FDA). Apligraf (Graftskin) for venous ulcers — P950032. Jan 29, 1998.
Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/P950032b.pdf. Accessed March 30, 2014.
FDA Approval Notice, May 22, 1998 (Apligraf®); September 28, 2002 FDA Approval Notice, September 28,
2001 (Dermagraft®).
U.S. Food and Drug Administration (FDA). Theraskin — K090812, approval letter. July30, 2009. Available
at: http://www.accessdata.fda.gov/cdrh_docs/pdf9/K090812.pdf. Accessed March 30, 2014.
United States Department of Health and Human Services. Agency for Healthcare Research and Quality
(AHRQ). Technology Assessment Program. Skin Substitutes for Treating Chronic Wounds. December 22,
2011.
U.S. Food and Drug Administration (FDA). Apligraf (Graftskin) for diabetic foot ulcers — P950032. Mar 8,
2000. Available at URL address: http://www.accessdata.fda.gov/cdrh_docs/pdf/P950032S016b.pdf
Accessed March 30, 2014.
Wasiak J, Cleland H, Campbell F, Spinks A. Dressings for superficial and partial thickness burns. Cochrane
Database of Systematic Reviews. 2013;3.
Wright Medical Technologies. GraftJacket Regenerative Tissue Matrix. 2011. Available
at: http://www.wmt.com/physicians/prescribing/documents/LC_GJ_121P0129_IFU_T12.pdf. Accessed
March 30, 2014.
Clinical trials
Systematic reviews cover trials published through 2010.
Centers for Medicare & Medicaid Services (CMS) national coverage determination
As of the writing of this policy, the Centers for Medicare & Medicaid Services (CMS), has a longstanding
National Care Determination (NCD) 270.5, for Porcine Skin and Gradient Pressure Dressings. [CMS Website].
Available at: http://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=139&ncdver=1&DocID=270.5&bc=gAAAAAgAAAAAAA%3d%3d&. Accessed March 30,
2014.
Local coverage determinations
National Government Services, Inc. (NGS). Local Care Determination (LCD). L26003. Biological Products for
Wound Treatment and Surgical interventions. Original 12/01/2007. Revised 01/25/2013. Available
at: http://www.cms.gov/medicare-coverage-database/details/lcddetails.aspx?LCDId=26003&ContrId=179&ver=47&ContrVer=1&SearchType=Advanced&CoverageSelection=
Local&PolicyType=Final&s=41&CntrctrType=8&KeyWord=Biologic+products+for+wound&KeyWordLookUp
=Title&KeyWordSearchType=Exact&kq=true&bc=IAAAABAAAAAAAA%3d%3d&. Accessed March 30, 2014.
Novitas Solutions, Inc. Local Care Determination (LCD). L27549. Human Skin Equivalents (HSE) — Use in the
Treatment of Chronic Cutaneous Ulcer Wounds. Original 07/11/2008. Revised 04/01/2012. Available
16
at: http://www.cms.gov/medicare-coverage-database/details/lcddetails.aspx?LCDId=27549&ContrId=161&ver=77&ContrVer=2&DocID=L27549&bc=gAAAAAgAAAAAAA%3d
%3d&. Accessed March 30, 2014.
Wisconsin Physician Services (WPS). Local Care Determination (LCD). L30135. Application of bioengineered
skin substitutes. [WPS Website]. Original 8/16/2009. Revised 01/01/2013. Available
at: http://www.cms.gov/medicare-coverage-database/details/lcddetails.aspx?LCDId=30135&ContrId=143&ver=61&ContrVer=1&Date=01%2f01%2f2014&DocID=L30135&bc
=iAAAAAgAAAAAAA%3d%3d&. Accessed March 30, 2014.
Commonly submitted codes
Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not
an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill
accordingly.
CPT Code
Description
Comment
11042
Debridement, subcutaneous tissue (includes epidermis and dermis, if
performed); first 20 sq. cm or less
11043
Debridement, muscle and/or fascia (includes epidermis and dermis, if
performed); first 20 sq. cm or less
11044
Debridement, bone (includes epidermis and dermis , subcutaneous tissue,
muscle and/or fascia, if performed); first 20 sq. cm or less
11045
Debridement, subcutaneous tissue (includes epidermis and dermis, if
performed); each additional 20 sq. cm or part thereof (list separately in addition
to code for primary procedure
11046
Debridement, muscle and/or fascia (includes epidermis, dermis, and
subcutaneous tissue, if performed): each additional 20 sq. cm, or part thereof (list
separately in addition to code for primary procedure
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
Apligraf, GraftJacket,
TheraSkin
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)
Apligraf, GraftJacket,
TheraSkin
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
Apligraf, GraftJacket,
TheraSkin
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)
Apligraf, GraftJacket,
TheraSkin
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
Dermagraft,
GraftJacket, Oasis
17
100 sq. cm; first 25 sq. cm or less wound surface area
Wound Matrix,
TheraSkin
15276
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; each additional 25 sq. cm wound surface area, or part thereof (List
separately in addition to code for primary procedure)
Dermagraft,
GraftJacket, Oasis
Wound Matrix,
TheraSkin
15277
Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears,
orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area
greater than or equal to 100 sq. cm; first 100 sq. cm wound surface area, or 1%
of body area of infants and children
Dermagraft,
GraftJacket, Oasis
Wound Matrix,
TheraSkin
15278
Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears,
orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area
greater than or equal to 100 sq. cm; each additional 100 sq. cm wound surface
area, or part thereof, or each additional 1% of body area of infants and children,
or part thereof (List separately in addition to code for primary procedure)
Dermagraft,
GraftJacket, Oasis
Wound Matrix,
TheraSkin
G0440
G0441
HCPCS Code
Q4101
Q4102
Q4106
Q4107
Q4110
Q4121
Q4131
ICD-9 Code
250.80
Application of tissue cultured allogenic skin substitute or dermal substitute for use
on lower limb, includes the site preparation and debridement if performed; first 25
sq. cm or less [required when billing
Medicare; do not use CPT codes]
Each additional 25 sq. cm
Description
Includes site
preparation for
Ampligraf & Dermagraft
Physician service only
[required when billing
Medicare; do not use
CPT codes]
Physician service only
Comment
Skin substitute, Oasis wound matrix, per square centimeter
Apligraf, supplied in 44
sq. cm. equals 44 units.
Oasis Wound Matrix
Skin substitute, Dermagraft, per square centimeter
Dermagraft
GraftJacket, per square centimeter
GraftJacket
Skin substitute, PriMatrix, per square centimeter
Primatrix
TheraSkin, per square centimeter
TheraSkin
EpiFix, per square centimeter
EpiFix
Description
Comment
Skin substitute, Apligraf, per square centimeter
Diabetic skin ulcer (type II or unspecified diabetes)
18
250.81
Diabetic skin ulcer (type 1)
250.82
Diabetic skin ulcer (type 11 or unspecified, uncontrolled)
250.83
Diabetic skin ulcer (type 1, uncontrolled)
707.14
Ulcer of heel and midfoot
707.15
Ulcer of toes
249.80
Secondary diabetes skin ulcer, (not stated as uncontrolled)
249.81
Secondary diabetes skin ulcer, uncontrolled
454.0
Venous stasis ulcer leg
941.2-x-945.2X
Second degree burns
Add 5th digit for location
19