Premera Bluecross amniotic membrane Coverage Update

Coverage and Medical Necessity Criteria

inv-01: Diabetic lower-extremity ulcers (medically necessary products)

Treatment of nonhealing diabetic lower‑extremity ulcers

Diabetic lower‑extremity ulcer coverage: Use of listed human amniotic membrane products (Affinity; AmnioBand Membrane; Biovance; EpiCord; Epifix; Grafix; NuShield) may be considered medically necessary when the ulcer is nonhealingNonhealing = <20% decrease in wound area after >=2 weeks of standard care

When criteria are met, treatment limited to a maximum of 6 applications in 12 weeks when evidence of wound healing is present

inv-02: Ophthalmic indications (medically necessary)

Ophthalmic indications

Ophthalmic amniotic membrane grafts: Human amniotic membrane grafts with or without suture or glue may be considered medically necessary for treatment of ophthalmic conditions (e.g., neurotrophic keratitis, corneal ulcers/melts, persistent epithelial defects, post‑pterygium repair, Stevens‑Johnson syndrome)

Established practice and clinical input support coverage for these corneal surface disorders

inv-03: Investigational / Not Eligible for Coverage

Investigational products and indications

Investigational injections and other products: Injection of micronized or particulated human amniotic membrane; injection of human amniotic fluid; and all other human amniotic products not specifically listed as medically necessary are considered investigational for all indications (including but not limited to osteoarthritis, plantar fasciitis, venous insufficiency ulcers, repair after Mohs surgery)

Specific products listed in the coding investigational subsection are not eligible for coverage

inv-04: Diabetic lower-extremity ulcer — covered with criteria

Covered when ALL of the following are met (diabetic lower‑extremity ulcers):

Diabetic LE ulcers - HAM: Product is a formulation of human amniotic membrane or placental membrane (examples: Affinity; AmnioBand Membrane; AmnioExcel; Biovance; EpiCord; EpiFix; Grafix; NuShield)

RCT evidence demonstrates improved wound‑closure outcomes versus standard care for sufficiently evaluated products

Nonhealing definition: Ulcer meets nonhealing criteria: <20% reduction in wound area after ≥2 weeks of standard wound care<20% healing with ≥2 weeks of standard care

Trials used wound closure as primary outcome

inv-05: Venous lower-extremity ulcer — covered with criteria

Covered when ALL of the following are met (venous stasis ulcers):

Venous leg ulcers - HAM: Patient has a lower‑extremity ulcer due to venous insufficiency and a formulation of human amniotic membrane is used with compression bandaging as clinically appropriate

RCTs (EpiFix, AmnioBand) have shown improved wound‑closure outcomes in some trials though methodological limitations exist

inv-06: Established ophthalmic uses

Covered or established ophthalmic uses:

Ophthalmic indications examples: Sutured human amniotic membrane transplant is established for corneal surface disorders such as neurotrophic keratitis, corneal ulcers/melts, persistent epithelial defects, and related ocular surface conditions

Longstanding clinical practice and evidence support these indications

inv-07: Investigational / Insufficient evidence

Not sufficiently supported / investigational uses (insufficient evidence):

Osteoarthritis injections: Injectable human amniotic membrane or amniotic fluid for knee osteoarthritis—evidence limited to feasibility/pilot studies; insufficient to determine net health benefit

Additional larger randomized trials with longer follow‑up required

Plantar fasciitis injections: Injection of amniotic membrane for plantar fasciitis—preliminary studies including interim reports exist but evidence is insufficient to conclude improvement in net health outcome

Longer follow‑up and definitive trials needed

Reconstruction after Mohs: Use of dehydrated human amnionic/chorionic membrane for repair following Mohs surgery—evidence limited to retrospective comparative studies; prospective RCTs lacking

Current observational data are insufficient to determine net health outcome

inv-08: Adjunctive therapy for diabetic foot ulcers

Guideline-based consideration for adjunctive therapy in diabetic foot ulcers

Adjunctive therapy consideration for DFU: For diabetic foot ulcers that fail to demonstrate improvement (>50% wound area reduction) after a minimum of 4 weeks of standard wound therapy, consider adjunctive wound therapies including negative pressure therapy, biologics (PDGF, living cellular therapy, extracellular matrix products, amniotic membrane products), and hyperbaric oxygen therapy4 weeks; >50% area reduction

Choice of adjunctive therapy should be individualized based on clinical findings, availability, and cost‑effectiveness; guideline does not specify ordering of therapies

inv-09: Medically necessary — product inclusion (NuShield added)

Product inclusion update

NuShield added to medically necessary products: NuShield has been added to the list of human amniotic membrane products considered medically necessary for treatment of nonhealing diabetic lower‑extremity ulcers

Annual review 07/01/25 updated literature through Feb 21, 2025; policy statements otherwise unchanged

Graft applications that exceed what is reasonable and necessary based on the measured wound size are not covered. When the medical necessity criteria for treatment of nonhealing diabetic lower‑extremity ulcers are met, coverage is limited to a maximum of 6 applications in 12 weeks if there is evidence of wound healing; additional applications beyond 12 weeks are considered not medically necessary.

Amniotic allografts are intended for single‑patient use. All unused material must be discarded and should not be reused or transferred to another individual; failure to discard unused single‑patient allograft material may result in noncoverage or claim denial. Providers should document product name/size used and disposal of unused material in the medical record.

Injection of micronized or particulated human amniotic membrane and injection of human amniotic fluid are considered investigational for all indications. Specifically, injectable formulations proposed for osteoarthritis lack sufficient evidence from adequately powered randomized trials to establish net health benefit and are therefore not eligible for coverage.

The FDA has raised safety and regulatory concerns about some marketed amniotic‑derived products that have not undergone required premarket review. Examples include a 2024 public safety notification regarding amniotic fluid eyedrops marketed without required premarket review and FDA statements that use of amniotic membrane for bone regeneration or for wound healing to reduce scarring/inflammation is not considered a homologous use. Such products may be subject to additional regulatory oversight and pose potential safety risks.

This medical policy does not apply to Medicare Advantage; providers and members with Medicare Advantage plans should consult plan documents or member services for coverage determination.

Applications that exceed size‑appropriate amounts for the wound or that exceed the policy's specified application limits (for example, more than 6 applications in 12 weeks when healing is evident) are considered not medically necessary and are not covered.

Use of amniotic membrane products or injectable amniotic‑derived formulations for indications not explicitly listed as medically necessary in this policy (for example, many products and indications listed in the Investigational/Not Eligible for Coverage section) is considered investigational and not covered.

Current evidence for injectable formulations of HAM or amniotic fluid for conditions such as knee osteoarthritis and plantar fasciitis is limited to feasibility or preliminary studies. The available data are insufficient to conclude an improvement in net health outcome, and these injectable indications are therefore considered not proven/insufficient evidence for coverage.

Products marketed without the FDA's required premarket review or those used in non‑homologous ways (per FDA examples) raise safety and regulatory concerns. Such regulatory noncompliance may affect coverage determinations and could result in denial if the product is not appropriately regulated or cleared.

Coding, Measurement, and Quantity Limits

Reviewed for Medical Necessity (selected)HCPCS

Q4132	Grafix Core and GrafixPL Core, per square centimeter (add-on, list separately in addition to primary procedure)
Q4133	Grafix PRIME, GrafixPL PRIME, Stravix and StravixPL, per square centimeter (add-on, list separately in addition to primary procedure)
Q4151	AmnioBand or Guardian, per square centimeter (add-on, list separately in addition to primary procedure)
Q4154	Biovance, per square centimeter (add-on, list separately in addition to primary procedure)
Q4159	Affinity, per square centimeter (add-on, list separately in addition to primary procedure)
Q4160	Nushield, per square centimeter (add-on, list separately in addition to primary procedure)
Q4186	Epifix, per square centimeter (add-on, list separately in addition to primary procedure)
Q4187	EpiCord, per square centimeter (add-on, list separately in addition to primary procedure)

Additional HCPCS codes listedHCPCS

Q4100	Skin substitute, not otherwise specified (e.g., AmnioFix)
Q4137	AmnioExcel, AmnioExcel Plus or Biodexcel, per square centimeter (add-on)
Q4140	BioDFence, per square centimeter (add-on)
Q4145	EpiFix, injectable, 1 mg
Q4168	AmnioBand, 1 mg (Particulate)
Q4171	Interfyl, 1 mg
Q4176	Neopatch or Therion, per square centimeter (add-on)
Q4180	Revita, per square centimeter (add-on)
Q4192	Restorigin, 1 cc (injectable)
Q4204	XWRAP, per square centimeter (add-on)

Other codes mentionedHCPCS

A2035

Corplex P or Theracor P or Allacor P, per milligram

G-codes (new effective 04/01/26)HCPCS

G0681	Application of a premarket approval (PMA), 510(k), 361 HCT/P non-sheet form skin substitute for a wound surface area up to 100 sq cm; first 25 sq cm or less (new code effective 04/01/26)
G0682	Application of a PMA/510(k)/361 HCT/P non-sheet form skin substitute for a wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area (list separately) (new code effective 04/01/26)
G0683	Application of a PMA/510(k)/361 HCT/P non-sheet form skin substitute graft for a wound surface >=100 sq cm; first 100 sq cm (new code effective 04/01/26)
G0684	Application of a PMA/510(k)/361 HCT/P non-sheet form skin substitute graft for a wound surface >=100 sq cm; each additional 100 sq cm wound surface area (list separately) (new code effective 04/01/26)

HCPCS Q-codes (sample start)HCPCS

Q4271	Complete FT, per square centimeter (add-on, list separately in addition to primary procedure)
Q4272	Esano a, per square centimeter (add-on, list separately in addition to primary procedure)

HCPCS Q-codes (continued)HCPCS

Q4273	Esano aaa, per square centimeter (add-on, list separately in addition to primary procedure)
Q4274	Esano ac, per square centimeter (add-on, list separately in addition to primary procedure)
Q4275	Esano aca, per square centimeter (add-on, list separately in addition to primary procedure)
Q4276	Orion, per square centimeter (add-on, list separately in addition to primary procedure)
Q4278	Epieffect, per square centimeter (add-on, list separately in addition to primary procedure)
Q4279	Vendaje AC, per square centimeter (add-on, list separately in addition to primary procedure)
Q4280	Xcell amnio matrix, per square centimeter (add-on, list separately in addition to primary procedure)
Q4281	Barrera sl or barrera dl, per square centimeter (add-on, list separately in addition to primary procedure)
Q4282	Cygnus dual, per square centimeter (add-on, list separately in addition to primary procedure)
Q4283	Biovance tri-layer or biovance 3l, per square centimeter (add-on, list separately in addition to primary procedure)

Mixed HCPCS descriptors including per 100 mgHCPCS

Q4310	Procenta, per 100 mg
Q4311	Acesso, per square centimeter (add-on, list separately in addition to primary procedure)
Q4312	Acesso AC, per square centimeter (add-on, list separately in addition to primary procedure)

HCPCS Q-codes with new effective datesHCPCS

Q4368	AmchoThick, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 07/01/25)
Q4369	AmnioPlast 3, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 07/01/25)
Q4370	AeroGuard, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 07/01/25)
Q4383	Axolotl Graft Ultra, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 10/01/25)
Q4399	Summit FX, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 01/01/26)
Q4400	Polygon3 membrane per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 01/01/26)
Q4418	Biolab membrane wrap flow, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 04/01/26)
Q4420	Nuform, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 01/01/26)

HCPCS add-on codes (new)HCPCS

Q4439	Instagraft, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 04/01/26)
Q4440	Curamatrix, per square centimeter (add-on, list separately in addition to primary procedure) (new code effective 04/01/26)

Product sizing/specifications (informational)mixed

Sample sizes

Product package sizes listed for Epifix, AmnioBand, Grafix, Biovance, Epicord, NuShield, Affinity (size-to-cm2 conversions provided)

Listed HCPCS/CPT codes (history shows many additions)HCPCS | mixed

Q4249
Q4250
Q4251
Q4252
Q4253
Q4254
Q4255
Q4256
Q4257
Q4258

1–10 of 111

1/12

HCPCS/Q and other codes referenced in historyHCPCS

Q4265
Q4266
Q4267
Q4268
Q4269
Q4270
Q4271
Q4272
Q4273
Q4274

1–10 of 169

1/17

Nonhealing wound definition — threshold

Nonhealing wound definitionLess than a 20% decrease in wound area with standard wound care for at least 2 weeks

Clinical trial basisDefinition based on entry criteria for relevant clinical trials (e.g., Zelen et al., 2015)

Applies toDiabetic lower‑extremity ulcers when evaluating eligibility for HAM products listed as medically necessary

Maximum applications

What Providers Must Do

Prior Authorization

Confirm coding and prior authorization

Verify HCPCS/CPT coding and any plan-specific prior authorization (PA) requirements before submitting claims. Many product-specific Q-codes and new add-on HCPCS codes have future effective dates — confirm the code effective date and whether PA is required under the member's plan.

Check code effective dates for newly added Q-codes (several have future effective dates 07/01/25, 10/01/25, 04/01/26).
Confirm whether the member's benefit requires prior authorization for the specific HCPCS/CPT code and product.
Verify PA requirements for new HCPCS add-on codes effective 04/01/26 (e.g., codes noted in coding updates).

Denial Risk

Applications must be size-appropriate and within policy limits

Applications that exceed size-appropriate use or the policy maximum are not medically necessary. Ensure the number and size of applications billed are reasonable based on wound measurements and the policy limits.

Background and Clinical Context

Human amniotic membrane (HAM) is composed of the amnion and chorion and contains extracellular matrix components, growth factors, and anti‑inflammatory proteins; products are processed (cryopreserved or dehydrated) into grafts, membranes, or other forms. Processing methods and product formulations vary by manufacturer, and some products are intended as coverings (homologous use for ocular surface protection) while others are advanced as wound or regenerative therapies.

Definitions and Abbreviations

Nonhealing (diabetic lower-extremity ulcer) — definition

Nonhealing definition (DEFINITIONS)Less than a 20% decrease in wound area with standard wound care for at least 2 weeks

Clinical trial basisDefinition derived from entry criteria used in clinical trials for diabetic lower‑extremity ulcers

Use caseUsed to determine eligibility for medically necessary HAM products for diabetic lower‑extremity ulcers

Abbreviations

HRTHuman Regenerative Technologies (HRT)

MTFMusculoskeletal Transplant Foundation (MTF)

Context

OpenPayer

Human amniotic membrane and amniotic fluid products for wound and ophthalmic indications

Coverage and Medical Necessity Criteria

Coding, Measurement, and Quantity Limits

What Providers Must Do

Background and Clinical Context

Definitions and Abbreviations