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Human skin equivalents are biosynthetic and/or tissue-engineered
living skin substitutes that have evolved from the traditional allograft.
Availability and safety concerns associated with autogenic and allogeneic
skin grafts have prompted the search for a more widely available biologic
product, with structural and functional properties as close as possible to
those of natural skin. The increasing attention to skin grafts is based, in
part, on the graft's function of compensating for tissue loss by acting as
an occlusive dressing, as a skin replacement, and as a stimulus for
healing. Bioengineered tissue provides a matrix for cell migration and
delivers growth factors to the wound bed.
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The Least You Need to Know
This
article covers the use of Apligraf and Dermagraft as well as any
equivalent products yet to be released.
Dermagraft and Apligraf are both covered for neuropathic diabetic foot
ulcers of at least six weeks duration if they have not responded to 4
weeks of intensive conventional conservative therapy. The ulcers must be
located on the plantar, medial or lateral surfaces of the foot. A 12 week
(or longer) period of treatment is covered, which can include up to 3
applications of Apligraf or 8 of Dermagraft. Retreatment of the same
ulcer within a year is not covered.
Apligraf is covered for venous stasis ulcers of at least four weeks
duration if they have not responded to 4 weeks of intensive conventional
conservative therapy. A 12 week (or longer) period of treatment is
covered, which can include up to 3 applications of Apligraf. Retreatment
of the same ulcer within a year is not covered.
As these therapies are somewhat operator dependent, services must be
provided by a physician (M.D., D.O., or D.P.M.) who is skilled in the
management of chronic wounds and has appropriate training in the use of
human skin equivalents. Ulcers that are not appropriate for grafting
(e.g. active infection, systemic impairment of healing) are not covered.
Adequate perfusion to support the graft must be documented, typically by
the presence of pedal pulses and/or an Ankle Brachial Index of 0.7 or
greater.
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Keratinocytes (epidermis cellular component) from neonates are
preferentially used as the source of expanded cultured allografts. They are
better responders to mitogens than older donors and they release factors
that stimulate growth of other keratinocytes, a property that is
substantially lost by adult keratinocytes. Included among these mediators
are epidermal-derived thymocyte activating factor, interleukins,
fibronectin, and transforming growth factor-beta.
Fibroblasts (dermis cellular component) and collagen-matrix proteins
(dermis extracellular component), influence epithelial migration and
differentiation, dermoepidermal junction formation, wound contraction, and
scar formation. Dermal cells also secrete growth factors and cytokines,
which modulate cell proliferation and differentiation. Collagen synthesis
by fibroblasts forms a scaffold for cellular migration.
Skin replacements can be temporary or permanent; they can consist of only
epidermal cell components, only dermal components, or a bilayer containing
dermal and epidermal elements; they can also be synthetic, biosynthetic or
biologic.
Current biologic skin substitutes present benefits that include a
non-invasive painless grafting procedure, no requirement for anesthesia,
and outpatient (office/treatment room) performance.
Apligraf (Graftskin)
Apligraf is a biosynthetic, bi-layered living construct of cultured human
neonatal foreskin which consists of keratinocytes and fibroblasts. It is a
human skin equivalent with appearance similar to human skin that was
approved by the FDA in May 1998 for use in the treatment of venous skin
ulcers, and later approved for the treatment of neuropathic diabetic ulcers
in June 2000. It contains both dermal and epidermal components, each
housing living cells. This bioengineered product is composed of a
bovine-collagen, fibroblast-containing matrix integrated with a sheet of
stratified human epithelium. Fibroblasts taken from human neonatal foreskin
are cast in a bovine-collagen lattice, which then is seeded with epidermal
cells to produce a bilayered skin equivalent. Apligraf is metabolically,
morphologically, and biochemically similar to human skin.
The skin equivalent produces a number of cytokines and growth factors and
is immunologically well tolerated. There is no evidence of host antibody or
cell-mediated response or clinical rejection because there are no
macrophages, lymphocytes, or Langerhans' cells present in this skin
substitute. Apligraf has been shown to stimulate wound fibroblasts and to
counteract growth inhibitory activity present in chronic wound fluid.
Apligraf should be applied to a clean debrided ulcer and must be used in
conjunction with the recommended post-application compression therapy
and/or pressure off-loading.
Dermagraft
Dermagraft is a biosynthetic, dermal substitute approved by FDA in
September 2001 for use in the wound closure of diabetic foot ulcers. It
consists of cultured neonatal fibroblasts, produced by taking dermal
fibroblasts from neonatal foreskin and seeding them onto a three-dimensional
scaffold consisting of a bioabsorbable material (polyglactin mesh). The
cells grow and divide, producing collagens, extracellular matrix proteins,
and growth factors found in normal, healthy human dermis. Dermagraft is
cryopreserved to 70degrees centigrade and thawed before patient
application. This skin substitute stimulates the formation of granulation
tissue, re-epithelialization, and angiogenesis. The fibroblasts produce
collagens, fibronectin and glycosaminoglycans. They also produce transforming
growth factor Beta, which stimulates collagen formation. Fibroblasts
produce keratinocyte growth factor and secrete vascular endothelial growth
factor and hepatocyte growth factor.
Dermagraft was developed for skin replacement of full-thickness wounds. It
has no Silastic membrane, an outer silicone polymer layer that serves as an
epidermis. Mesh absorption occurs in 60-90 days.
Other HSE
Any other new comparable HSEs will be similarly covered by this article,
with coverage restricted to the FDA indications of the product. New
products will be added to the article as administrative updates. OrCel,
Transcyte and Dermagraft TC are included to this LCD coverage.
Indications:
1. Treatment of neuropathic diabetic foot ulcers with all the following criteria:
- Non-infected full thickness ulcers;
- Ulcers that extend through the dermis but do not involve the
tendon, muscle, joint capsule or have bone exposure;
- Ulcers that are located on the plantar, medial, or lateral
surface of the foot, including the heel;
- Ulcers free of infection, tunnels, tracts, cellulitis,
eschar, or obvious necrotic material, as this will interfere with
device adherence and wound healing;
- Ulcers of greater than six weeks duration;
- Ulcers that have not adequately responded to conventional
ulcer therapy of at least 4 weeks duration;
- Patients with documented type 1 or type 2 diabetes who are
currently receiving medical management for this condition;
- Extremity that is free of active Charcot's
Arthropathy.
2. Treatment of venous insufficiency ulcers with all the following
criteria: (Apligraf only)
- Non-infected partial or full-thickness skin ulcers;
- Ulcers which are not responding to intensive conventional
ulcer therapy of at least one month duration;
- Ulcers greater than 1 month duration (since conservative
therapy must have been tried for at least one month)
- HSE Use in conjunction with standard
therapeutic compression techniques;
A course of intensive conventional ulcer therapy is intended to signify:
- At least 4 serial physician evaluations (or a combination of
physician and nurse practitioner/physician assistant evaluations
clearly under the overall direction of the physician);
- Active debridement of necrotic tissue to promote healing (including
either wet to dry dressing, water debridement, enzymatic debridement
or selective surgical curettage) or documentation that no necrotic
tissue is present;
- Maintenance of dressings in accordance with any of the
commonly accepted current wound care practices;
- Prevention and/or eradication of secondary infection
- Non-weight bearing status
- Compressive dressings
- Routine supportive care such as
nutritional support and edema control.
Limitations of Coverage:
The frequency of the device application for both venous insufficiency
ulcers and neuropathic diabetic foot ulcers should be consistent with
patient's history and response to the device application. Repeated
application without signs of improvement or exceeding the recommended
frequency, per labeling instructions, will be denied.
1. Neuropathic Diabetic Foot Ulcers
- Use of the skin substitute is indicated for up to three
separate applications to any given ulcer (Apligraf, OrCel, Transcyte)
or eight applications (Dermagraft, Dermagraft TC);
- There should be no fewer than three weeks between
applications (Apligraf, OrCel, Transcyte), whereas
Dermagraft/Dermagraft TC should be applied weekly; and,
- If, after nine to twelve weeks of treatment and three applications
of Apligraf, OrCel or Transcyte; or eight applications of Dermagraft
or Dermagraft TC, satisfactory healing progress is not noted,
reapplication of the skin substitute is not recommended and other
treatment modalities should be considered.
- Re-treatment of the same site/ulcer within
one year is not covered.
2. Venous Stasis Ulcers
Two applications of the skin substitute are indicated. If after 12 weeks of
compression treatment and two applications of the skin substitute, a 50
percent or greater improvement is noted and documented, then re-application
of a third skin substitute will be covered. Otherwise, reapplication of the
skin substitute is not recommended and other treatment modalities should be
considered:
- There should be no fewer than six weeks between applications;
and,
- Re-treatment of the same site/ulcer within
one year is not
3. Contraindications for all ulcers
Any of the following contraindications would preclude treatment of both
venous stasis ulcers and neuropathic diabetic foot ulcers with skin
substitutes:
- ulcer showing clinical signs of active infection (i.e.,
increased exudate, odor, redness, swelling, heat, pain, tenderness to
the touch, purulent discharge);
- osteomyelitis;
- allergy to bovine collagen or hypersensitivity to any of the
components;
- inadequately treated diabetes ("adequately treated"
diabetes for purposes of this LCD would be based on documentation in
the medical record);
- uncontrolled rheumatoid arthritis and/or rheumatoid ulcers;
- other uncontrolled collagen vascular disease;
- patients who have undergone radiation
and/or chemotherapy within the month immediately preceding the skin
substitute treatment.
4. Requirement for adequate perfusion
Significant arterial insufficiency is an additional contraindication to the
placement of skin substitutes. An Ankle Brachial Index (ABI) of less than
0.7 or absent pedal pulses indicates the presence of significant arterial
insufficiency. If skin substitutes are used when such findings are present,
the medical record must contain additional test results or information that
establishes the presence of sufficient arterial blood supply to allow the
wound to heal in the presence of skin substitutes.
5. Additional applications
The use of more than three applications of Apligraf, OrCel or Transcyte; or
eight of Dermagraft or Dermagraft TC is rarely medically necessary. Any
applications beyond the norm will require extensive documentation of a
clear and unique justification for the additional procedure as this is
exceeding the usual norms of medical care.
6. Requirement for practitioner expertise
The application of all human skin equivalents is limited to physicians
(M.D., D.O. and D.P.M.) who are highly skilled in wound care management and
have experience in the use of HSE. 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.
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