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CurrentBlue Cross Blue Shield - South DakotaPolicy 02.01.60

Amniotic Membrane and Amniotic Fluid Grafts

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Medical policy governing clinical use and coverage decisions for human amniotic membrane (HAM) and amniotic fluid products across wound care and select ophthalmic and orthopedic indications for Blue Cross Blue Shield - South Dakota members.

Policy Summary

PayerBlue Cross Blue Shield - South Dakota

PolicyAmniotic Membrane and Amniotic Fluid Grafts

Policy CodePolicy 02.01.60

Change TypeNo material clinical or coverage changes in this revision.

Effective DateMar 1, 2018

Last ReviewApr 1, 2025

Next Review DateApr 1, 2025

Key ActionVerify member benefits and obtain prior authorization documenting failure of standard conservative therapy before applying amniotic/placental membrane products.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

multiple indicationsindications reviewed

RCT evidence presentRCT evidence present

insufficient evidenceinsufficient evidence

sufficient evidenceimprove net health outcome

2018–2025evidence review period

Coverage criteria and indication-specific guidance

Indication-specific coverage conclusions

Coverage stance summarized by indication based on evidence in this section:

Diabetic lower-extremity ulcers (patch HAM/placental products): For non-healing diabetic lower-extremity ulcers (defined in trials as <20% healing after ≥2 weeks of standard care), randomized trials and multicenter registries for listed HAM/placental products demonstrated improved healing versus standard care; evidence sufficient to conclude improvement in net health outcome.

Products: Affinity, AmnioBand, Biovance, EpiCord, EpiFix, Grafix, NuShield

Venous leg ulcers: Evidence for HAM in venous leg ulcers is mixed; some RCTs and observational studies exist. EpiFix and AmnioBand Membrane may be considered medically necessary in carefully selected patients when policy criteria are met, but overall evidence is insufficient without corroborating well-designed trials.

See product-specific criteria

Ophthalmic indications — corneal ulcers/melts and select ocular surface diseases: HAM grafts (sutured or non‑sutured) improve healing for corneal ulcers and melts not responsive to initial medical therapy; selective use is supported for several ocular surface conditions depending on indication-specific evidence.

Evidence includes systematic review and RCTs for select conditions

Corneal perforation: HAM may be used as a temporary covering for corneal perforation when donor corneal tissue is not immediately available; considered a temporizing measure rather than definitive therapy.

Standard definitive therapy remains corneal transplantation

Stevens-Johnson syndrome (moderate/severe): One RCT demonstrated improved symptoms and ocular outcomes with HAM in moderate–severe SJS; evidence supports use when criteria are met.

Sharma et al., RCT (25 patients, 50 eyes)

Other indications (OA, plantar fasciitis, Mohs repair, limbal stem cell deficiency, bullous keratopathy, persistent epithelial defects): Evidence is limited or preliminary for these indications (feasibility studies, interim reports, or nonrandomized studies). Coverage may be considered in select patients when specific criteria are met, but overall evidence is insufficient to broadly conclude net health benefit.

See indication-specific criteria below

Diabetic Lower Extremity Ulcers — Covered when ALL of the following are met

Covered when ALL of the following are met for diabetic lower‑extremity ulcers

Indication: Chronic non‑healing diabetic lower‑extremity ulcer(s) documented as failing standard conservative management.failed to heal after documented SOC

Non‑healing frequently defined in trials as <20% wound area reduction after ≥2 weeks of SOC

Prior conservative care: Standard conservative management (eg, surgical debridement, complete off‑loading, appropriate dressings) attempted for at least 4 weeks prior to HAM application unless wound is clinically severe to justify immediate advanced therapy.>= 4 weeks

Document prior SOC and response

Perfusion requirement: Extremity treated has adequate blood flow documented by a palpable pedal pulse or ankle‑brachial index (ABI) > 0.70.

Venous Stasis Ulcers — Covered when ALL of the following are met

Covered when ALL of the following are met for venous stasis ulcers

Indication: Partial or full‑thickness venous stasis ulcer(s) present greater than 4 weeks duration and documented as failing standard wound therapy.> 4 weeks

Chronic VLU population consistent with trial inclusion

Prior conservative care: Documented failure of standard wound therapy including compression therapy, cleansing, debridement, infection control, and appropriate dressings.documented SOC failure

Compression and wound management must be documented

Perfusion requirement: Extremity has adequate blood flow evidenced by palpable pedal pulse or ABI > 0.70.ABI > 0.70

Ophthalmic indications (HAM grafts with/without suture) — Covered when ALL of the following are met

Covered when ALL of the following are met for ophthalmic conditions

Covered ophthalmic indications: Human amniotic membrane grafts (with or without suture) may be considered medically necessary for: neurotrophic keratitis unresponsive to conservative therapy; corneal ulcers and melts not responding to initial medical therapy; corneal perforation with active inflammation after transplant when adjunctive treatment is required; bullous keratopathy as palliation when not candidate for curative surgery; partial limbal stem cell deficiency with extensive diseased tissue; moderate or severe Stevens‑Johnson syndrome with ocular involvement; persistent epithelial defects not responding to conservative therapy; severe dry eye (DEWS 3–4) remaining symptomatic after Steps 1–3; and moderate or severe acute ocular chemical burns.

Evidence strength varies by indication (systematic review, RCTs, case series)

Conservative therapy prerequisite: For indications where conservative or initial medical therapy is standard (eg, neurotrophic keratitis, corneal ulcers/melts, persistent epithelial defects, severe dry eye), conservative measures must be tried and documented as failed prior to HAM except when clinical circumstances justify immediate use (eg, perforation without available donor tissue).document failed conservative therapy

Document specifics of prior therapies and timing

HAM with suture or glue — Covered when ALL of the following are met for pterygium and specific corneal perforation scenarios

Covered when ALL of the following are met for pterygium and specific corneal perforation scenarios

HAM with suture or glue — permitted scenarios: HAM grafts secured with suture or tissue adhesive (glue) may be considered medically necessary for: 1) corneal perforation when donor corneal tissue is not immediately available (temporizing cover); and 2) pterygium repair when there is insufficient healthy conjunctival tissue to create a conjunctival autograft.

Conjunctival autograft remains preferred for pterygium when feasible; HAM used when autograft infeasible

Documentation: Document lack of available donor corneal tissue (for temporizing perforation use) or insufficient healthy conjunctival tissue (for pterygium), the chosen fixation method (sutures or glue), and expected follow-up and definitive plan.

Include clinical justification and anticipated definitive treatment if applicable

Initial application criteria

Covered when ALL of the following are met

Population: Individual has a diabetic lower‑extremity ulcer that has failed to heal with standard of care (SOC).failed to heal after documented SOC

SOC includes debridement, appropriate dressings, offloading and compression where applicable

Intervention: Amniotic membrane or placental membrane product applied as an adjunct to SOC at intervals of every 1–2 weeks as described in evidence and product labeling.application every 1-2 weeks

Document product name, units, and application technique

Documentation: Medical record documents prior conservative therapies and failed response, baseline wound area, planned frequency of application, and criteria for re‑application or discontinuation.see definitions

Initial coverage criteria — Covered when ALL of the following are met:

Covered when ALL of the following are met:

Population and prior care: Patient has a lower‑extremity ulcer (diabetic or venous) that has failed standard of care (eg, <20% healing after >2 weeks of SOC).<20% healing after >2 weeks

Trials used run‑in criteria; document prior SOC and measured response

Intervention specifics: Treatment will be an amniotic membrane or placental membrane product applied in addition to SOC at evidence‑based intervals (typically every 1–2 weeks).application every 1-2 weeks

Products studied include Affinity, AmnioBand, Biovance, EpiCord, EpiFix, Grafix, NuShield

Outcome monitoring: Wound healing should be monitored with wound closure as the primary outcome; document number of applications and time to closure with reassessment at 4 weeks and 6–12 weeks as indicated.

Coverage criteria for amniotic/placental membrane grafts for VLUs — Covered when ALL of the following are met

Covered when ALL of the following are met

Population: Patient has a lower‑extremity venous leg ulcer that is chronic or has failed to heal with standard‑of‑care therapy.

Consistent with trial populations

Prior conservative therapy: Documentation of prior SOC for VLU, including moist or dry dressings and compression therapy, with inadequate healing documented.

Compression therapy must be recorded

Treatment intent: Amniotic/placental membrane applied in addition to SOC at frequency approximately weekly to biweekly per product labeling and evidence.application every 1-2 weeks

Document product and application details

Step-up to Advanced Therapy — Consider advanced amniotic membrane therapy when ALL of the following are met:

Consider advanced amniotic membrane therapy when ALL of the following are met:

Step‑up to advanced therapy criteria: Wound demonstrates <40% reduction in wound area after 4 weeks of standard conservative therapy; consider advanced therapy (eg, dehydrated human amnion/chorion membrane) applied weekly or biweekly and preferably initiated early (no later than 30–45 days) for improved episode resolution and shorter treatment duration.<40% at 4 weeks

Derived from observational study and clinical consensus; early application associated with shorter treatment times

Plantar Fasciitis — Micronized HAM — adjunctive injectable criteria

Plantar fasciitis — adjunctive micronized HAM injection may be considered when ALL of the following apply:

Plantar fasciitis adjunctive therapy: Patient has plantar fasciitis refractory to standard conservative measures and is being considered for a single injection of micronized HAM; interim trial data (patient‑blinded RCT, N=145) showed greater improvements in VAS pain and Foot Functional Index at 3 months versus placebo.improvement in VAS/FFI at 3 months

Evidence limited to interim 3‑month report; longer‑term outcomes pending

Neurotrophic keratitis — evidence summary and coverage considerations

Neurotrophic keratitis with ocular surface damage or inflammation:

Neurotrophic keratitis criteria: Use of sutured HAM may be considered in individuals with neurotrophic keratitis and ocular surface damage or inflammation that does not respond to conservative therapy; note that an RCT of 30 patients showed no significant benefit of sutured HAM over tarsorrhaphy or bandage contact lens at 3 months.

Document prior conservative care and justification for HAM

Corneal ulcers and melts — covered with supportive evidence when criteria met

Corneal ulcers and melts not responding to initial medical therapy:

Corneal ulcers/melts criteria: HAM (sutured or non‑sutured) may be used when corneal ulcers or melts fail to respond to initial medical therapy; systematic review and case series report high healing rates (eg, 97% in pooled series) and vision improvement in many eyes.clinical failure of initial medical therapy

Document prior medical therapy and objective outcomes; non‑sutured HAM in office preferred when appropriate

Plantar fasciitis — interim trial evidence

Plantar fasciitis — injectable micronized HAM:

Plantar fasciitis criteria: Injection of micronized amniotic membrane may be considered for plantar fasciitis refractory to SOC when interim RCT data demonstrate clinically meaningful improvement in pain and function at 3 months; document conservative therapies tried and counsel that long‑term durability (12 months) is pending further data.

Evidence limited to interim 3‑month results (Cazzell et al.)

Corneal ulcers and melts not responsive to initial medical therapy

Covered when evidence supports use after failure of initial therapy

Corneal ulcers and melts: Use of non‑sutured amniotic membrane is supported for corneal ulcers and melts that do not respond to initial medical therapy based on systematic review and comparative case series evidence; document failed medical therapy and plan for follow‑up.evidence: systematic review and case series; clinical failure of initial medical therapy

Supports coverage for non‑sutured HAM after failed medical therapy

Corneal perforation with active inflammation after transplant — No evidence identified

No evidence identified

Corneal perforation after transplant with active inflammation: No evidence was identified to support HAM use for corneal perforation with active inflammation after corneal transplant.no supporting studies

Lack of evidence — coverage not supported by identified literature without additional data

Bullous keratopathy in patients not candidates for curative treatment — comparative evidence

Comparative evidence for bullous keratopathy

Bullous keratopathy criteria: For patients with bullous keratopathy who are not candidates for curative treatment, consider initial stromal puncture; HAM may be considered if stromal puncture fails to relieve pain or is inappropriate. An RCT found no pain advantage for HAM over stromal puncture though HAM provided a more regular epithelial surface.

Document prior simple interventions and rationale for HAM

Partial limbal stem cell deficiency — coverage consideration

Partial limbal stem cell deficiency

Partial limbal stem cell deficiency: Sutured or non‑sutured HAM may be considered in individuals with limbal stem cell deficiency when extensive diseased limbus makes selective removal insufficient; evidence consists of small case series and no RCTs.

Clinical justification should document extent of diseased tissue and prior interventions

Limbal stem cell deficiency (partial/extensive) — Covered when ALL of the following are met

Covered when ALL of the following are met for partial or extensive limbal stem cell deficiency:

Indication: Diagnosis of limbal stem cell deficiency with extensive diseased limbus where selective removal alone is insufficient.

Document extent of disease and prior treatments

Intervention: Sutured or non‑sutured HAM application (including ProKera or HAM secured with fibrin glue).

Choose modality appropriate to clinical scenario

Evidence: No randomized controlled trials; supporting evidence limited to small case series reporting variable improvements; clinical justification required to establish necessity.

Prioritize alternative definitive interventions (eg, limbal stem cell transplant) when appropriate

Moderate to severe Stevens-Johnson syndrome — Covered when ALL of the following are met

Covered when ALL of the following are met for moderate to severe Stevens-Johnson syndrome:

Indication: Diagnosis of moderate or severe Stevens‑Johnson syndrome involving the ocular surface.

Population studied in RCT

Intervention: Application of sutured or non‑sutured HAM (including cryopreserved HAM applied with fibrin glue) in addition to standard medical therapy.

c‑HAM was used in RCTs with fibrin glue

Evidence: One randomized controlled trial (25 patients, 50 eyes) demonstrated improved visual and ocular surface outcomes with HAM plus medical therapy versus medical therapy alone.

Supports efficacy for this indication

Persistent epithelial defects and ulcerations — Covered when ALL of the following are met

Covered when ALL of the following are met for persistent epithelial defects:

Indication: Persistent epithelial defects or ulcerations that have failed an adequate trial of conservative therapy (eg, topical lubricants, antibiotics, therapeutic contact lens, patching).

No RCTs identified; use based on case series and clinical practice

Intervention: Application of sutured or non‑sutured HAM as an adjunct to conservative measures to promote epithelial closure.

Document prior therapies and response

Outcome expectation: Objective aim is epithelial closure with follow‑up assessments at 1 to 3 months to document response.follow-up 1-3 months

Document outcomes and further plans if no improvement

Indication-specific evidence summaries — Use in distinct clinical scenarios when conservative therapy has failed or as adjunctive therapy

Use of HAM is considered in these distinct clinical scenarios when conservative therapy has failed or as adjunctive therapy:

Persistent epithelial defects and ulcerations: Consider HAM for persistent epithelial defects refractory to conventional medical therapy; evidence is limited (no RCTs) and based on case reports/series.no RCTs

Clinical documentation should support necessity

Severe dry eye with ocular surface damage and inflammation: Consider self‑retained or sutured HAM for moderate‑to‑severe dry eye (DEWS 2–4) not responsive to maximal medical therapy; evidence includes one small RCT and retrospective series demonstrating symptomatic and corneal improvements up to 3 months.improvement up to 3 months

Document DEWS score and prior steps attempted

Acute moderate‑to‑severe ocular chemical/thermal burns:

Acute ocular chemical/thermal burns — evidence-based considerations

Use of HAM for moderate to severe acute ocular chemical burns — evidence-based considerations

RCT evidence summary: Three randomized controlled trials (total n=197) evaluated HAM plus medical therapy versus medical therapy alone; one trial showed faster epithelial healing with HAM but no difference in final visual outcome or other major endpoints; two trials showed no benefit for epithelial healing.

Consider selective use with documentation of expected benefit

Corneal perforation (temporizing use) — sutured HAM when donor tissue not available

Use of sutured HAM for corneal perforation when donor corneal tissue is not immediately available

Temporary covering indication: HAM may be used as a temporary sutured cover for corneal perforation when corneal transplantation is the standard definitive treatment but donor corneal tissue is not immediately available.

No RCTs identified; role is temporizing until definitive tissue available

Pterygium repair (HAM when autograft infeasible) — coverage when conjunctival autograft not feasible

Use of HAM in pterygium repair when conjunctival autograft is not feasible

Pterygium repair criteria: HAM with suture or glue may be considered when there is insufficient healthy conjunctival tissue to create a conjunctival autograft; document inability to perform autograft and rationale for HAM use.

Conjunctival autograft remains preferred when feasible; Cochrane/AAO reviews show autograft superior for recurrence reduction

Repair after Mohs microsurgery — evidence-based considerations for coverage

Summary of evidence and implications for coverage decisions:

Evidence base: No randomized controlled trials were identified for repair after Mohs microsurgery; evidence consists of nonrandomized observational studies (eg, Toman et al. 2022).

Confidence limited by retrospective design and population homogeneity

Reported comparative outcomes: Observational data reported higher complication‑free rates and fewer infections and poor scar outcomes with dHACM reconstructions compared with autologous repair in propensity‑matched analyses, but interpretation limited by study design.eg, 97.9% vs 71.3% complication‑free

Prospective comparative trials recommended

Coverage implication: Consider coverage with prior authorization and documentation that autologous repair is unsuitable or that specific reconstructive goals justify use of amniotic/placental allograft; additional prospective data would increase confidence in effectiveness.

Payer may require demonstration that alternatives are unsuitable

Evidence-supported indications — Covered when supported by trial evidence or guideline recommendation

Covered when supported by trial evidence or guideline recommendation for the specific wound type and product:

DFU evidence: Products with randomized controlled trial support showing improved healing in diabetic foot ulcers may be considered medically necessary when documented to meet policy criteria.trial evidence present

Wound Healing Society notes level 1 evidence for skin equivalents in DFU

VLU evidence: Products with corroborating RCT evidence for venous leg ulcers may be considered when policy criteria are met, recognizing some RCTs have methodological limitations requiring cautious interpretation.trial evidence present

Product‑specific RCTs referenced

Ocular surface indications: Amniotic membrane transplantation and self‑retained cryopreserved membranes are supported for a range of ocular surface disorders per ophthalmology literature and may be covered when indication‑specific criteria are met.

This policy may not apply to Federal Employee Program (FEP) members. Benefit determinations are governed by the applicable contract language in effect at the time services were rendered; exclusions, limitations, or exceptions in the member’s benefit plan may supersede the policy. Providers should verify member benefits and confirm that the service is a covered benefit prior to requesting authorization or providing treatment.

The policy designates several uses and product formats as investigational or unproven. Specifically, injection of human amniotic fluid products and injection of micronized or particulated HAM products (including investigational formulations listed in the document) are considered investigational for all indications because evidence is insufficient to show improved net health outcomes. The use of human amniotic membrane products for repair following Mohs microsurgery is also listed as investigational due to limited and nonrandomized evidence.

Products that do not meet HCT/P criteria or that are marketed without required premarket review may be excluded from coverage. The document highlights FDA actions and guidance: items marketed as amniotic fluid eyedrops without required premarket review have prompted FDA safety communications and warning letters, and non‑minimally manipulated or non‑homologous uses of amniotic products may fall outside the HCT/P regulatory pathway. Products lacking appropriate regulatory clearance or that are non‑homologous/non‑minimally manipulated may trigger denial of coverage.

No randomized trials were identified that directly compare different amniotic or placental products. The evidence base uses product‑specific RCTs and registries rather than head‑to‑head comparisons, limiting direct inferences about relative effectiveness between products. Absence of head‑to‑head comparative studies should be considered when evaluating product selection and when documenting medical necessity for a specific product.

Application of HAM or placental membrane products is described as adjunctive to standard of care (SOC) and typically applied at intervals reported in trials (weekly to every 1–2 weeks). For lower‑extremity wounds, prior conservative management must be documented (e.g., debridement, off‑loading, compression) and trials enrolled non‑healing ulcers with run‑in criteria. Documentation that SOC was attempted and the wound’s response (for example, <40% reduction in wound area at 4 weeks as a trigger to consider escalation) is expected for prior authorization and coverage review; failure to document SOC and response may jeopardize coverage.

The document lists several explicit exclusions and investigational categories although some exclusions are not reiterated in every excerpt. Notably, the policy identifies injection of amniotic fluid products and injection of micronized/particulate HAM as investigational, and it advises that use of products outside the studied indications or without trial evidence may be considered not medically necessary. Additionally, products that do not meet HCT/P regulatory criteria or that lack required premarket review are potential exclusions. Where the excerpt is silent on other exclusions, absence of supportive randomized or guideline‑level evidence may still be used to deny coverage.

A randomized controlled trial of sutured HAM for neurotrophic keratitis (n=30) found no significant benefit of sutured HAM compared with tarsorrhaphy or bandage contact lens with respect to epithelialization at 3 months. This single small RCT does not demonstrate superiority of sutured HAM over conventional therapies and is a key evidence limitation when considering sutured HAM for neurotrophic keratitis.

Codes, HCPCS/Q-code mappings, and billing guidance

Covered HAM products for diabetic lower extremity ulcersHCPCSCovered

Q4159	Affinity®
Q4151	AmnioBand® Membrane
Q4154	Biovance® tri-layer
Q4283	Biovance® 3l
Q4187	EpiCord®
Q4186	EpiFix®
Q4132	GrafixCore
Q4133	Grafix Duo
Q4304	GrafixPrime
Q4392	Grafix Plus

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Covered HAM products for venous stasis ulcersHCPCSCovered

Q4151	AmnioBand® Membrane
Q4186	EpiFix®

Coding referencemixed

See Codes table

Coding details referenced in the document's Codes table (not included in this excerpt)

Referenced HCPCS/Q-codes and code briefsmixed

Q4271	Medical Code Brief referenced
Q4270	Medical Code Brief referenced
Q4269	Medical Code Brief referenced
Q4268	Medical Code Brief referenced
Q4267	Medical Code Brief referenced
Q4266	Medical Code Brief referenced
Q4265	Medical Code Brief referenced

Covered CPT Codes (application codes)CPTCovered

15150	Tissue cultured skin autograft, trunk, arms, legs; first 25 sq cm or less.
15151	Tissue cultured skin autograft, trunk, arms, legs; additional 1 sq cm to 75 sq cm.
15152	Tissue cultured skin autograft, trunk, arms, legs; each additional 100 sq cm, or each additional 1% of body area of infants and children, or part thereof.
15155	Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; first 25 sq cm or less.
15156	Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; additional 1 sq cm to 75 sq cm.
15157	Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; each additional 100 sq cm, or each additional 1% of body area of infants and children, or part thereof.
15271	Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area.
15272	Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof.
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.
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.

Ocular and product application codesmixed

65778	Placement of amniotic membrane on the ocular surface, without sutures.
65779	Placement of amniotic membrane on the ocular surface, single layer, sutured.
65780	Ocular surface reconstruction; amniotic membrane transplantation, multiple layers.
V2790	Amniotic Membrane for Surgical Reconstruction, per procedure.
A2001	Innovamatrix ac, per square centimeter (add-on, list separately in addition to primary procedure).
A2035	Corplex p or theracor p or allacor p, per milligram.
A4100	Non-sheet form skin substitute, FDA cleared as a device, not otherwise specified.

HCPCS Q- codes and product mappings (partial)HCPCS

Q4132	Grafix CORE and GrafixPL CORE, per square centimeter (add-on).
Q4133	Grafix prime, grafixpl prime, stravix and stravixpl, per square centimeter (add-on).
Q4137	Amnioexcel, amnioexcel plus or biodexcel, per square centimeter (add-on).
Q4139	AmnioMatrix or biodmatrix, injectable, 1 cc.
Q4140	Biodfence, per square centimeter (add-on).
Q4145	Epifix, injectable, 1 mg.
Q4148	Neox cord 1k, neox cord rt, or clarix cord 1k, per square centimeter (add-on).
Q4150	AlloWrap DS or dry, per square centimeter (add-on).
Q4151	AmnioBand or Guardian, per square centimeter (add-on).
Q4153	Dermavest and Plurivest, per square centimeter (add-on).

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Additional HCPCS Q- code mappings (partial)HCPCS

Q4170	Cygnus, per square centimeter (add-on).
Q4171	Interfyl, 1 mg.
Q4173	Palingen or palingen xplus, per square centimeter.
Q4174	Palingen or promatrx, 0.36 mg per 0.25 cc.
Q4176	Neopatch or Therion, per square centimeter.
Q4177	Floweramnioflo, 0.1 cc.
Q4178	Floweramniopatch, per square centimeter.
Q4180	Revita, per square centimeter.
Q4181	Amnio wound, per square centimeter.
Q4183	Surgigraft, per square centimeter.

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Further HCPCS Q- product codes (extended list)HCPCS

Q4198	Genesis amniotic membrane, per square centimeter (add-on).
Q4201	Cygnus matrix, per square centimeter.
Q4204	Matrion, per square centimeter.
Q4205	Xwrap, per square centimeter.
Q4206	Membrane graft or membrane wrap, per square centimeter.
Q4208	Fluid flow or fluid GF, 1 cc.
Q4209	Novafix, per square centimeter.
Q4211	Amnion bio or Axobiomembrane, per square centimeter.
Q4212	Allogen, per cc.
Q4213	Ascent, 0.5 mg.

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Q4198 mappingsHCPCS

Q4198 = Q4220	Genesis amniotic membrane, per square centimeter mapped to BellaCell HD or Surederm (add-on; list separately)
Q4198 = Q4221	Genesis amniotic membrane, per square centimeter mapped to Amniowrap2 (add-on; list separately)

Q4224 mappingsHCPCS

Q4224 = Q4225	Human health factor 10 amniotic patch (hhf10-p), per square centimeter = Amniobind or Dermabind TL (add-on)
Q4224 = Q4227	HHF10-P per sq cm = Amniocore (add-on)
Q4224 = Q4229	HHF10-P per sq cm = Cogenex amniotic membrane (add-on)
Q4224 = Q4230	HHF10-P per sq cm = Cogenex flowable amnion, per 0.5 cc (add-on)
Q4224 = Q4232	HHF10-P per sq cm = Corplex, per sq cm (add-on)
Q4224 = Q4233	HHF10-P per sq cm = Surfactor or Nudyn, per 0.5 cc (add-on)
Q4224 = Q4234	HHF10-P per sq cm = Xcellerate, per sq cm (add-on)
Q4224 = Q4235	HHF10-P per sq cm = Amniorepair or Altiply, per sq cm (add-on)
Q4224 = Q4236	HHF10-P per sq cm = Carepatch, per sq cm (add-on)
Q4224 = Q4237	HHF10-P per sq cm = Cryo-cord, per sq cm (add-on)

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Q4249 / Q4267 mappingsHCPCS

Q4249 = Q4250	Amniply, topical, per sq cm = AmnioAmp-mp, per sq cm (add-on)
Q4249 = Q4251	Amniply, topical, per sq cm = Vim, per sq cm (add-on)
Q4249 = Q4252	Amniply, topical, per sq cm = Vendaje, per sq cm (add-on)
Q4249 = Q4253	Amniply, topical, per sq cm = Zenith amniotic membrane, per sq cm (add-on)
Q4249 = Q4254	Amniply, topical, per sq cm = Novafix dl, per sq cm (add-on)
Q4249 = Q4255	Amniply, topical, per sq cm = Reguard, topical, per sq cm (add-on)
Q4249 = Q4256	Amniply, topical, per sq cm = Mlg complete, per sq cm (add-on)
Q4249 = Q4257	Amniply, topical, per sq cm = Relese, per sq cm (add-on)
Q4249 = Q4258	Amniply, topical, per sq cm = Enverse, per sq cm (add-on)
Q4249 = Q4259	Amniply, topical, per sq cm = Celera dual layer or celera dual membrane, per sq cm (add-on)

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Q4267/Q4286 mappings continuedHCPCS

Q4267 = Q4271	NeoStim DL = Complete FT, per sq cm (add-on)
Q4267 = Q4272	NeoStim DL = Esano A, per sq cm (add-on)
Q4267 = Q4273	NeoStim DL = Esano AAA, per sq cm (add-on)
Q4267 = Q4274	NeoStim DL = Esano AC, per sq cm (add-on)
Q4267 = Q4275	NeoStim DL = Esano ACA, per sq cm (add-on)
Q4267 = Q4276	NeoStim DL = Orion, per sq cm (add-on)
Q4267 = Q4278	NeoStim DL = Epieffect, per sq cm (add-on)
Q4267 = Q4279	NeoStim DL = Vendaje AC, per sq cm (add-on)
Q4267 = Q4280	NeoStim DL = Xcell amnio matrix, per sq cm (add-on)
Q4267 = Q4281	NeoStim DL = Barrera SL or Barrera DL, per sq cm (add-on)

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Nudyn / Grafix mappingsHCPCS

Q4286 = Q4293	Nudyn SL/W = Acesso DL, per sq cm (add-on)
Q4286 = Q4294	Nudyn SL/W = Amnio quad-core, per sq cm (add-on)
Q4286 = Q4295	Nudyn SL/W = Amnio tri-core amniotic, per sq cm (add-on)
Q4286 = Q4296	Nudyn SL/W = Rebound matrix, per sq cm (add-on)
Q4286 = Q4297	Nudyn SL/W = Emerge matrix, per sq cm (add-on)
Q4286 = Q4298	Nudyn SL/W = Amnicore pro, per sq cm (add-on)
Q4286 = Q4299	Nudyn SL/W = Amnicore pro+, per sq cm (add-on)
Q4286 = Q4300	Nudyn SL/W = Acesso TL, per sq cm (add-on)
Q4286 = Q4301	Nudyn SL/W = Activate matrix, per sq cm (add-on)
Q4286 = Q4302	Nudyn SL/W = Complete ACA, per sq cm (add-on)

1–10 of 12

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Grafix / Caregraft mappingsHCPCS

Q4304 = Q4306	Grafix plus = American Amnion AC, per sq cm (add-on)
Q4304 = Q4307	Grafix plus = American Amnion, per sq cm (add-on)
Q4304 = Q4308	Grafix plus = Sanopellis, per sq cm (add-on)
Q4304 = Q4309	Grafix plus = Via matrix, per sq cm (add-on)
Q4304 = Q4310	Grafix plus = Procenta, per 100 mg (add-on)
Q4304 = Q4311	Grafix plus = Acesso, per sq cm (add-on)
Q4304 = Q4312	Grafix plus = Acesso AC, per sq cm (add-on)
Q4304 = Q4313	Grafix plus = Dermabind FM, per sq cm (add-on)
Q4304 = Q4314	Grafix plus = Reeva FT, per sq cm (add-on)
Q4304 = Q4315	Grafix plus = Regenelink amniotic membrane allograft, per sq cm (add-on)

1–10 of 17

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Caregraft / Simpligraft and remaining mappingsHCPCS

Q4322 = Q4324	Caregraft = Amniotx, per sq cm (add-on)
Q4322 = Q4325	Caregraft = Acapatch, per sq cm (add-on)
Q4322 = Q4326	Caregraft = Woundplus, per sq cm (add-on)
Q4322 = Q4327	Caregraft = Duoamnion, per sq cm (add-on)
Q4322 = Q4328	Caregraft = Most, per sq cm (add-on)
Q4322 = Q4329	Caregraft = Singlay, per sq cm (add-on)
Q4322 = Q4330	Caregraft = Total, per sq cm (add-on)
Q4322 = Q4331	Caregraft = Axolotl graft, per sq cm (add-on)
Q4322 = Q4332	Caregraft = Axolotl dualgraft, per sq cm (add-on)
Q4322 = Q4333	Caregraft = Ardeograft, per sq cm (add-on)

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Conservative treatment duration — key values

Minimum conservative treatment duration>= 4 weeks of standard conservative management (eg, debridement, off-loading, standard dressings) before HAM for diabetic or venous ulcers

Exception for clinically severe woundsImmediate aggressive therapy allowed when wound is clinically severe (document rationale)

Application frequency expectationAdjunctive HAM application typically every 1–2 weeks (weekly to biweekly per product evidence)

Prior authorization, documentation, and billing actions for providers

Prior Authorization

Verify benefits / contact customer service

Prior authorization/verification of benefits likely required per payer rules and contract language; providers should contact customer service for specifics.

Documentation Required

Prior approval & required documentation expected

Prior approval is not applicable per the policy header, but the medical record is expected to contain the documentation listed under Required Documentation before application of a skin substitute for diabetic or venous ulcers.

Medical record must document failed conservative measures or clinical severity justifying immediate aggressive therapy
Document lack of wound size/depth improvement or absence of granulation/epithelialization
Record frequency of application and that product was applied per manufacturer's instructions

Background and clinical context

Human amniotic membrane (HAM) and amniotic‑derived products are available in multiple formulations — sheet/patch grafts (sutured or self‑retained), cryopreserved and dehydrated placental membranes, topical preparations, and injectable/micronized suspensions — and are being evaluated across wound care, ophthalmic, and selected orthopedic indications. The clinical intent is typically to provide a biologic scaffold with growth factors and anti‑inflammatory properties to promote epithelialization and reduce inflammation; in wound trials these products have been studied as an adjunct to standard of care with application frequencies reported as weekly to every 1–2 weeks. Evidence quality varies by indication: randomized controlled trials support certain diabetic foot and venous ulcer applications and select ophthalmic indications, while other uses rely on limited, nonrandomized, or interim data.

Definitions and key terms

HAM / placental membrane products — examples and product list

Named commercial HAM/placental productsAffinity®, AmnioBand® Membrane, Biovance®, EpiCord®, EpiFix®, Grafix™ (GrafixCore/Duo/Prime/Plus), NuShield

Forms availablePatch (sheet), flowable/flowable injectable, and placental membrane formulations referenced in trials and product lists

Use casesProducts listed are those evaluated in RCTs and considered for diabetic and select venous ulcer indications when criteria met

Non-healing diabetic lower-extremity ulcer — trial definition (<20% healing after 2 weeks SOC)

Trial definition of non‑healing DLUsUlcer showing <20% healing after at least 2 weeks of standard of care (run‑in) used as RCT inclusion criterion

Run‑in requirement

Policy Summary

PayerBlue Cross Blue Shield - South Dakota

PolicyAmniotic Membrane and Amniotic Fluid Grafts

Policy CodePolicy 02.01.60

Change TypeNo material clinical or coverage changes in this revision.

Effective DateMar 1, 2018

Last ReviewApr 1, 2025

Next Review DateApr 1, 2025

Key ActionVerify member benefits and obtain prior authorization documenting failure of standard conservative therapy before applying amniotic/placental membrane products.

SourceLink

On This Page

Required to support healing potential

Product and application: Application of an indicated HAM/placental product listed in policy (eg, Affinity, AmnioBand, Biovance, EpiCord, EpiFix, Grafix, NuShield) applied as an adjunct to SOC at intervals consistent with evidence (typically every 1–2 weeks).application every 1-2 weeks

Document product, units, and application technique per manufacturer instructions

Documentation and monitoring: Medical record documents prior SOC, failed response, planned frequency of HAM application, objective wound measurements (baseline area and percent area reduction at 4 weeks), and plan for reassessment and retreatment or discontinuation.assess wound area reduction at 4 weeks

Use validated wound closure endpoints; document number of applications and outcomes

To ensure adequate perfusion prior to advanced graft use

Product and application: Application of an indicated HAM product for VLUs (eg, AmnioBand Membrane or EpiFix) applied in addition to SOC at intervals consistent with evidence (approximately weekly to biweekly).application every 1-2 weeks

Document product, units, and application technique per manufacturer instructions

Documentation and monitoring: Medical record documents prior SOC, wound measurements, number and frequency of HAM applications, and objective reassessment with wound area reduction recorded at 4 weeks.assess at 4 weeks

Wound area reduction <40% at 4 weeks may trigger step‑up consideration

Application modality: Select sutured, glued, or non‑sutured (self‑retained) HAM modality appropriate to the clinical scenario; non‑sutured (office) application is preferred to avoid surgical delay when clinically appropriate.

Sutured or glued HAM used when tissue fixation required (eg, perforation, pterygium repair)

Documentation and follow-up: Document indication, prior therapies, details of HAM product and fixation method, baseline and follow-up measures (eg, epithelial healing, visual acuity), and planned reassessment at 1–3 months as clinically appropriate.follow-up at 1-3 months

Use validated ocular outcome measures where available

Record number of applications and objective outcomes

Outcomes timeframe: Clinical expectation of complete wound closure or meaningful healing within 6–12 weeks based on trial endpoints and FDA guidance; monitor and document progress accordingly.6-12 weeks for healing assessment

Use standardized wound closure endpoints

assessed at 6–12 weeks

Trials reported closure at 6–12 weeks

Wound area reduction <40% at 4 weeks OR clinical judgment that healing trajectory has stalled, prompting consideration of advanced therapy (eg, DHACM).

<40% area reduction at 4 weeks

Observational and expert guidance support step‑up when <40% reduction

HAM plus medical therapy may speed epithelial healing in some trials but overall RCT evidence is mixed; consider HAM selectively in moderate‑to‑severe burns after clinical judgment and documentation of expected benefit.

Three RCTs (n=197) with mixed results

clinical indication per ophthalmology literature

Follow DEWS II stepwise care for severe dry eye

Ankle‑brachial index (ABI) — key values

Minimum perfusion requirement (ABI)> 0.70 ankle‑brachial index (ABI) or presence of palpable pedal pulse to demonstrate adequate blood flow

Assessment methodABI measurement or documentation of palpable pedal pulses in treated extremity

ApplicabilityRequired for both diabetic lower‑extremity ulcers and venous stasis ulcers before HAM application

Wound area reduction at 4 weeks — monitoring & trigger

4‑week wound response monitoringMeasure percent wound area reduction at 4 weeks from start of SOC to assess need to escalate to advanced therapy

Primary wound outcomes timeframeClinical trials use complete wound closure and time to closure with assessments at 6–12 weeks; document baseline area and follow‑up

Documentation to support step‑upRecord baseline wound area, percent area reduction at 4 weeks, number/frequency of HAM applications, and plan if <40% reduction

4‑week wound area reduction threshold

4‑week reduction threshold prompting step‑upLess than 40% reduction in wound area at 4 weeks of standard care — trigger to consider advanced therapy (eg, DHACM)

Clinical judgment clauseStep‑up may also be based on clinician assessment of a stalled healing trajectory even if percentage threshold ambiguous

Timing for early AT applicationEarly DHACM application (no later than 30–45 days) with weekly/biweekly follow-up associated with improved episode resolution

Wound surface area billing thresholds — codes by wound area

CPT application code — first 25 sq cm15271: application of skin substitute graft to trunk/arms/legs, total wound surface area up to 100 sq cm; first 25 sq cm or less

CPT application code — each additional 25 sq cm15272: each additional 25 sq cm wound surface area (list separately in addition to primary procedure)

CPT application codes — larger area increments15273: first 100 sq cm (or 1% body area infants/children); 15274: each additional 100 sq cm

Tissue cultured skin autograft codes (face/complex sites)15155–15157: tissue cultured skin autograft codes for face/scalp/hand/foot and additional area increments

Prior Authorization

PA when requesting amniotic/placental membrane as adjunct to SOC

Application of amniotic or placental membrane products is described as an adjunct to standard of care applied every 1 to 2 weeks; coverage decisions should require documentation of SOC and planned treatment frequency.

Therapy applied every 1–2 weeks as an adjunct to SOC
Document that application frequency aligns with evidence (weekly to biweekly)

Prior Authorization

Confirm indication and SOC failure with PA

Prior authorization should confirm the ulcer type (diabetic or venous), document failure of prior standard of care (run‑in criteria such as <20% healing after ≥2 weeks), and note the planned application schedule (every 1–2 weeks) as adjunctive therapy.

Confirm ulcer classification (diabetic vs venous)
Provide run‑in evidence of failed SOC (e.g., <20% healing after >2 weeks)
Specify planned application frequency (weekly to biweekly)

Prior Authorization

Recommend PA for advanced allograft requests

Prior authorization is appropriate when advanced therapies such as dehydrated human amnion/chorion membrane (dHACM) are requested for chronic venous or diabetic ulcers after SOC has failed; include timing relative to diagnosis and rationale for early versus delayed advanced therapy.

Document why advanced allograft is needed after SOC failure
If early application is requested, include timing (e.g., within 30–45 days) and justification

Note

No explicit PA codes specified in this excerpt

The document does not list explicit prior authorization codes or mandatory PA rules in the cited sections; billing/coding mappings are provided separately.

Prior Authorization

PA: document failed conservative therapy / trial evidence for ophthalmic uses

For ophthalmologic indications, prior authorization should require documentation that conservative therapy was tried and failed (or trial evidence supports use), or note when an indication is supported only by interim trial data.

Show prior conservative/initial medical therapy and its duration
For plantar fasciitis, note that evidence may be interim (3-month results)

Prior Authorization

PA: document failed medical therapy or ineligibility for simpler procedures

Prior authorization for HAM in corneal ulcers/melts or bullous keratopathy should cite failure of initial medical therapy or ineligibility/unsuitability of simpler procedures (e.g., stromal puncture) before approving HAM.

Document unsuccessful response to initial medical therapy for corneal ulcers/melts
For bullous keratopathy, document attempted stromal puncture or rationale why it is not appropriate

Prior Authorization

PA: confirm specific indication (e.g., extensive limbal disease)

Prior authorization should confirm the specific ophthalmic indication (for example, limbal stem cell deficiency with extensive diseased tissue not amenable to selective removal) when requesting HAM.

Specify diagnosis and extent of diseased limbus
Explain why selective removal alone is insufficient

Prior Authorization

PA: state ophthalmic indication and prior therapies tried

When requesting prior authorization for HAM, note the indication such as chemical/thermal burn, severe dry eye with ocular surface damage, or persistent epithelial defect refractory to conservative therapy, and include prior treatments and anticipated HAM treatment duration.

Document prior conservative treatments attempted (Steps 1–3 for dry eye per DEWS II)
Provide anticipated duration and application details of HAM

Prior Authorization

PA recommended for ocular HAM used as temporizing cover or when autograft infeasible

Prior authorization is recommended when HAM is used as a temporizing cover for corneal perforation or as graft material in pterygium repair when conjunctival autograft is not feasible; include documentation of lack of donor corneal tissue or insufficient conjunctival tissue.

For corneal perforation, document unavailability of donor corneal tissue
For pterygium repair, document insufficiency of healthy conjunctival tissue for autograft

Prior Authorization

PA recommended for post‑Mohs amniotic membrane repair

Prior authorization should specify use of human amniotic/chorionic membrane for reconstruction following Mohs microsurgery and note that supporting evidence is from retrospective observational data with limitations.

Document that autologous repair is unsuitable or rationale for choosing dHACM
Cite observational evidence (e.g., Toman et al. 2022) and note study limitations

Prior Authorization

Product‑specific prior authorization (reference code briefs/HTAs)

Prior authorization for some products may be product‑specific; reference the product‑specific medical code briefs and HTA summaries cited in the policy when seeking approval.

Reference Q‑code medical code briefs (examples listed in policy)
Include any HTA or Hayes briefs cited to support medical necessity

Billing Rule

Report procedures using specified CPT and HCPCS/Q‑codes

Providers must report procedures using the listed CPT application codes and corresponding HCPCS/Q‑codes for amniotic/placental membrane and skin substitute products when billing for application procedures.

Use appropriate CPT application codes (e.g., 15271–15274 range) for skin substitute application
Report corresponding Q‑codes for specific products as listed in the policy

Billing Rule

Use policy code‑to‑product mappings when billing

Code-to-product mappings in the policy must be used when billing; this section does not itself establish prior authorization requirements.

Map billed product to the appropriate add‑on Q‑code and unit (per sq cm or per cc)
List Q‑codes separately in addition to the primary procedure as applicable

Step Therapy

Conservative therapy prerequisite before HAM

For wound indications, HAM products are considered medically necessary only after an adequate trial of standard conservative management (typically ≥4 weeks) has been attempted unless the wound is clinically severe.

Conservative management examples: debridement, off‑loading, standard dressings, compression where appropriate
Document exceptions for immediate aggressive therapy if clinically severe

Step Therapy

Require trial of standard conservative management (≥4 weeks)

HAM is medically necessary for wound indications only after a trial of standard conservative management for at least 4 weeks (unless immediate aggressive therapy is justified).

Run‑in criteria used in trials: e.g., <20% healing after ≥2 weeks
Document ABI > 0.70 or palpable pedal pulses for adequate perfusion

Step Therapy

Document attempt of conventional non‑surgical therapies

Conventional non‑surgical therapies (edema control, infection control, debridement, off‑loading, compression) should be attempted and documented prior to advanced biologic graft application.

Document control of edema, infection management, appropriate debridement
For venous ulcers, document diligent use of compression therapy

Step Therapy

SOC required before initiating advanced HAM therapy

Patient must have received standard of care therapy before initiation of HAM/placental membrane; studies enrolled ulcers that failed SOC and applications are adjunctive.

Confirm prior SOC and evidence of failed response before approving advanced therapy

Step Therapy

Step‑up when <40% wound area reduction at 4 weeks

Evidence and expert guidance support stepping up to advanced therapy when wound area reduction is less than 40% at 4 weeks of SOC; consider DHACM earlier (within 30–45 days) when clinically indicated.

Trigger for step‑up: <40% wound area reduction at 4 weeks
Early DHACM (≤30–45 days) with weekly/biweekly applications associated with shorter treatment duration

Step Therapy

Clinical pathway: early DHACM (30–45 days) and <40% step‑up rule

Clinical pathways referenced support early DHACM application within 30–45 days in some studies; step‑up to advanced therapy is recommended when wound area reduction is <40% at 4 weeks.

Document timing of advanced therapy relative to diagnosis
Record number and frequency of applications (mean ~4.8 applications reported in observational study)

Step Therapy

Consider tarsorrhaphy and bandage contact lens before sutured HAM

Before approving sutured HAM for some ocular indications, consider tarsorrhaphy and bandage contact lens as comparators; documentation should show these standard therapies were considered or attempted.

Document whether tarsorrhaphy or bandage contact lens was attempted or why not appropriate

Step Therapy

Prefer stromal puncture before HAM for bullous keratopathy

For bullous keratopathy, stromal puncture is preferred as an initial, simpler procedure; HAM may be considered if pain does not resolve after stromal puncture.

Document attempt of stromal puncture and persistent symptoms before HAM

Step Therapy

Consider limbal stem cell transplant / medical therapy before HAM

Consider limbal stem cell transplant or medical therapy before approving HAM for limbal stem cell deficiency; document why these comparators are not appropriate when seeking authorization.

Explain why limbal stem cell transplant or other medical options are unsuitable

Step Therapy

Document trials of conservative medical therapies before HAM

Conservative medical therapies (topical lubricants, antibiotics, therapeutic contact lens, patching; for dry eye: artificial tears, cyclosporine, serum tears, steroids, NSAIDs) are standard comparators and should be tried prior to HAM when appropriate.

Document duration and response to topical and systemic conservative therapies
For dry eye, follow DEWS II stepwise management before considering HAM

Step Therapy

Prefer autograft for pterygium; use HAM only if autograft infeasible

For pterygium repair, conjunctival or limbal autograft is preferred to reduce recurrence; HAM should be used when autograft is not feasible and documentation should explain why.

Document insufficiency of healthy conjunctival tissue for autograft
Reference RCTs/Cochrane review supporting autograft superiority when applicable

Step Therapy

Consider autologous repair or second‑intention healing before HAM

Consider comparator options (autologous tissue repair, local flaps, full‑thickness grafts, or second‑intention healing) before authorization for reconstructive uses; document why these alternatives are not appropriate if requesting HAM.

Explain why surgical autologous repair or second‑intention healing are unsuitable

Step Therapy

Follow stepwise guideline approaches (DEWS II) before HAM

Follow guideline stepwise algorithms (e.g., DEWS II for dry eye) where advanced or surgical options like HAM are considered only after earlier steps have failed.

Document progression through DEWS II steps and persistent symptoms before HAM
For dry eye, confirm Steps 1–3 attempted prior to Step 4 interventions

Note

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Prior Authorization

Verify member benefits and contract exclusions

Providers should verify member benefits and applicable contract language; Wellmark will determine medical necessity only if the benefit exists and no contract exclusions apply.

Confirm member coverage and any contract exclusions before submitting PA or billing

Documentation Required

Required documentation before product application

Prior to application, the medical record must document failed conservative measures (or justify immediate aggressive therapy), lack of wound size/depth improvement, evidence of venous insufficiency when applicable, and frequency of application.

Document failed conservative measures or that wound is clinically severe
Record venous insufficiency evidence (DVT history or duplex ultrasound)
Specify application frequency and immobilization per manufacturer's instructions

Documentation Required

Document prior SOC failure and failed response

Document prior failure of standard of care wound therapies (moist/dry dressings, compression, off‑loading) and objective evidence of unsuccessful treatment before applying amniotic/placental membrane products.

Show no reduction or increase in ulcer size/depth despite SOC
Include details of debridement, off‑loading, and compression use

Documentation Required

Document ulcer type and SOC trial results

Document that the ulcer is a lower‑extremity diabetic or venous ulcer, that it is non‑healing after an adequate trial of SOC (e.g., >2 weeks with <20% healing), and the planned application frequency (every 1–2 weeks).

Specify ulcer type and run‑in trial results (percent healing and duration)
Record planned HAM application schedule (weekly to biweekly)

Documentation Required

Include prior SOC treatments and wound characteristics

Include prior SOC treatments and wound characteristics in documentation: prior dressings, compression, debridement, off‑loading, baseline wound area, and perfusion status (ABI or palpable pulses).

Baseline wound area and perfusion measures (ABI > 0.70 if applicable)
List prior treatments and their durations

Documentation Required

Document timepoint endpoints (4‑week, 12‑week) and application counts

Document study‑relevant endpoints and timelines where available: baseline wound area, percent area reduction at 4 weeks, number and frequency of HAM applications, and 12‑week healing outcomes.

Record percent area reduction at 4 weeks (for step‑up decisions)
Track healing status at 6–12 weeks as trial endpoints

Documentation Required

Document specific clinical indication for HAM

Document the specific indication when requesting ocular HAM (e.g., neurotrophic keratitis, corneal ulcer/melt not responding to initial medical therapy, or plantar fasciitis trial status).

State precise ocular diagnosis and prior therapies attempted
For plantar fasciitis, document prior conservative care and trial evidence

Documentation Required

Document clinical history and prior ophthalmic therapy

Include clinical history and prior therapy details for corneal ulcers/melts: prior medical therapy attempts, clinical course, and any prior interventions (e.g., attempted stromal puncture).

Detail prior topical/systemic treatments and durations
Describe prior procedural interventions and outcomes

Documentation Required

Document baseline and follow‑up ocular outcomes

Document clinical outcomes with objective measures: baseline and follow‑up visual acuity, corneal/epithelial healing assessments, and timing of follow‑up (approximately 1–3 months).

Record VA and epithelial healing status at baseline and follow‑up
Include dates of follow‑up assessments (1–3 months)

Documentation Required

Document DEWS score and prior maximal therapy for severe dry eye

For severe dry eye, document baseline DEWS score and prior maximal medical therapy (artificial tears, cyclosporine A, serum tears, antibiotics, steroids, NSAIDs) before HAM application.

Record DEWS score and duration of symptoms
List prior maximal medical therapies and response

Documentation Required

Document indication (corneal perforation, burn, pterygium repair) when requesting HAM

Ensure documentation supports the indication such as corneal perforation, acute chemical/thermal ocular burn, or pterygium repair with insufficient conjunctival tissue when requesting HAM.

Describe the specific ocular event (e.g., burn, perforation) and prior management
State why alternative definitive or autologous treatments are not possible

Documentation Required

Document Mohs reconstruction details for prior authorization

Document reconstruction following Mohs microsurgery with details: wound risk category (moderate‑ to high‑risk defect), product used (e.g., dHACM/Epifix), and comparator considerations if applicable.

Specify Mohs defect location and risk category
Name the product used and units applied; explain why autologous repair was not chosen

Documentation Required

Cite supporting clinical evidence (RCTs, trials) in PA

Cite relevant randomized controlled trials, trial identifiers, and published outcomes for the specific amniotic/placental product used when seeking authorization.

Include RCT references and outcome data supporting the product choice

Billing Rule

Use correct CPT/HCPCS/ICD codes when reporting services

Use appropriate CPT, HCPCS, revenue, and ICD diagnosis codes to report provider services for application of skin substitutes and amniotic/placental products.

Select correct CPT application code for wound surface area (e.g., 15271–15274)
Map product to the correct Q‑code and billed unit

Billing Rule

Document product name and billed units to match Q‑code mapping

Documentation should support the use of an amniotic membrane or related product as an add‑on to a primary procedure and specify the product name and billed unit (per sq cm, per 0.5 cc, or per cc) to match the mapped Q‑code.

State product name, formulation, and units applied
Ensure billed units align with policy mappings (per sq cm, per 0.5 cc, per cc)

Denial Risk

Verify benefits — contract language governs determinations

Benefit determinations are based on the applicable contract language in effect at the time services were rendered; verify benefits and consider exclusions/limitations that may apply.

Denial Risk

Denial risk for repeated application without improvement

Repeated application to the same wound within the same treatment period without signs of improvement may be denied.

Document objective evidence of improvement before re‑application or justify retreatment as a new treatment period

Denial Risk

Regulatory noncompliance may trigger denial

Products marketed or distributed without required premarket review (for example, certain amniotic fluid eyedrops) raise significant safety concerns and may trigger regulatory action that affects coverage.

Confirm product regulatory status; products lacking required oversight may be excluded

Denial Risk

Denial risk if use does not align with studied indications

Use of HAM/placental membrane is studied for non‑healing diabetic lower‑extremity ulcers (commonly defined in trials as <20% healing after ≥2 weeks of SOC); claims for populations not matching studied indications may be at risk for denial.

Ensure patient population matches trial inclusion/run‑in criteria when seeking coverage

Denial Risk

Denial risk for VLUs without documented SOC failure

Use of amniotic/placental membrane is intended for patients with lower‑extremity venous ulcers that have failed to heal with SOC; therapies applied without documentation of SOC failure may be denied.

Denial Risk

Evidence limitations may lead to denial or additional review

Evidence limitations and methodological flaws in available studies may be cited as reasons for coverage denials or additional review for some indications.

Denial Risk

Interim evidence for plantar fasciitis may affect coverage decisions

Use of HAM for plantar fasciitis is supported only by interim 3‑month results from a blinded trial; lack of longer follow‑up or additional publications may lead to coverage uncertainty.

Note interim nature of evidence when requesting PA for plantar fasciitis

Denial Risk

Evidence gap — corneal perforation after transplant

No evidence was identified for HAM for corneal perforation with active inflammation after corneal transplant; lack of supporting evidence may trigger coverage denial for that indication.

Denial Risk

Evidence limitation risk for limbal stem cell deficiency

Lack of randomized controlled trial evidence for HAM in limbal stem cell deficiency may lead to requests for additional documentation of medical necessity or denial.

Denial Risk

Denial risk when conservative therapy not exhausted for persistent defects

Persistent epithelial defects and ulcerations lack RCT evidence; use when conservative therapy has not been exhausted may be denied.

Denial Risk

Corneal perforation — temporizing use only

Use of HAM for corneal perforation is considered temporizing only when donor corneal tissue is not immediately available; application as definitive therapy may be denied.

Denial Risk

Evidence limitations may trigger prior authorization denial

Evidence for some reconstructive indications is limited to nonrandomized retrospective data; lack of high‑quality prospective trials may lead to medical necessity denial if randomized evidence is required.

Denial Risk

Evidence‑based coverage risk for unsupported products/indications

Lack of randomized controlled trials or guideline‑level support for a specific product or indication may lead to noncoverage decisions.

Denial Risk

Coding / claim filing risk

Failure to use the appropriate CPT, HCPCS, revenue, or ICD diagnosis codes when reporting services may result in claim processing issues or denial.

Ensure correct mapping of product to Q‑code and use correct CPT skin substitute application codes

Billing Rule

Add‑on billing requirement — report Q‑codes separately with correct units

Billing Q‑codes that are listed as add‑on but not reported separately in addition to the primary procedure or billed with incorrect units may trigger claim processing issues or denials.

List add‑on Q‑codes separately and bill correct units (per sq cm, per 0.5 cc, per cc)

Trials required documented SOC and assessment of percent healing during run‑in before enrollment

Documentation expectationMedical record should show SOC details and measured percent healing over run‑in period

Wagner Grading System (diabetic ulcer)

Wagner grading categoriesGrade 1: Superficial; Grade 2: Extension to tendon/joint without abscess/osteomyelitis; Grade 3: Deep with abscess/osteomyelitis; Grade 4: Gangrene of forefoot; Grade 5: Extensive gangrene

Clinical useWagner grades commonly used to characterize diabetic foot ulcer severity in assessments and studies

DocumentationRecord Wagner grade when relevant to clinical assessment and coverage justification

Failed Response / Unsuccessful treatment definition

Definition of failed/unsuccessful treatmentAn ulcer that has failed to respond to documented appropriate wound‑care measures, increased in size/depth, or shows no improvement (no granulation/epithelialization) over 2–4 weeks past start of therapy

Clinical implicationFailed response must be documented before advanced HAM/placental membrane application per policy criteria

Record elementsInclude wound measurements, debridement history, infection control, off‑loading/compression use, and duration of nonresponse

Re-Application vs Retreatment definitions

Re‑application definitionAdditional application of a skin substitute to the same ulcer within the same treatment period

Retreatment definitionA new treatment period where the same ulcer is treated again because the initial treatment failed

Billing/authorization relevanceDistinguishing re‑application vs retreatment should be documented for prior authorization and claims review

Non-healing ulcer (trial entry) — definition used in RCTs

Non‑healing ulcer (trial entry) — common definitionLess than approximately 20% wound area reduction after a run‑in period (commonly ≥2 weeks) on standard of care

Run‑in measurementTrials measured percent area reduction during run‑in to confirm non‑healing status prior to randomization

DocumentationBaseline and run‑in wound area measurements should be in the medical record to support eligibility

Standard of Care (SOC) — what SOC includes

Standard of Care (SOC) componentsDebridement, nonadherent or moisture dressings, compression where appropriate, and off‑loading

SOC for VLUsConservative wound management including moist/dry dressings plus compression therapy (eg, multilayer dressings or compression stockings >20 mmHg)

DocumentationMedical record should document SOC measures used and patient adherence where applicable

Standard of Care (SOC) for VLUs — conservative wound management and compression

SOC for venous leg ulcersConservative wound management plus compression therapy; HAM/placental membrane applied as adjunct to SOC

Application frequencyEvidence describes HAM applied approximately weekly to biweekly when used as adjunct to SOC

Prior documentationRequire documentation of failed SOC (duration and treatments) before advanced therapy for VLUs

dHACA / DHACM — definition and application frequency

dHACA / DHACM definitionDehydrated human amnion and chorion allograft (eg, EpiFix, AmnioBand) used as advanced wound therapy

Application frequencyApplied weekly or biweekly in clinical practice and trials (eg, FPFU paradigm)

Typical episode useObservational data report mean ~4.8 DHACM applications per VLU episode when used early

Advanced therapy (AT) / DHACM / dHACA — definition and typical application cadence

Advanced therapy (AT) definitionAdvanced biologic therapy such as DHACM/dHACA applied after failed SOC to promote healing

Typical cadenceWeekly to biweekly applications; earlier application (within 30–45 days) associated with shorter treatment duration in observational data

Evidence contextAT evaluated in RCTs and observational studies with endpoints at 4 and 12 weeks (area reduction and closure)

Primary outcomes for plantar fasciitis trials — VAS and Foot Functional Index

Primary outcomes in plantar fasciitis trialsVisual Analog Scale (VAS) for pain and Foot Functional Index (function) with acute effects at 2–4 weeks and durability at 6–12 months

Timing of assessmentAcute effects measured 2–4 weeks; trial durability assessed at 6–12 months (interim reports may present 3‑month data)

DocumentationRecord baseline and follow‑up VAS and Foot Functional Index scores when using micronized HAM injection

HAM (human amniotic membrane) — forms and uses

HAM forms and usesSutured or non‑sutured (self‑retained) ocular grafts and micronized injectable forms for non‑ocular indications

Ophthalmic applicationHAM can be sutured, glued, or self‑retained (eg, ProKera) for ocular surface disorders

Therapeutic intentAimed to promote epithelial healing and reduce inflammation on ocular surface or wound bed

Conservative/initial medical therapy — examples

Conservative/initial medical therapy examplesTarsorrhaphy, bandage contact lens, topical lubricants, antibiotics, therapeutic contact lens, patching; for wounds: debridement, dressings, compression, off‑loading

Role before HAMConservative therapies should be attempted and documented before considering HAM for most indications

DocumentationSpecify prior conservative treatments and duration in medical record for prior authorization

Bullous keratopathy definition

DefinitionBullous keratopathy is characterized by stromal edema and epithelial and subepithelial bulla formation

Clinical relevanceDescribes the ocular condition for which HAM may be considered as palliation when curative surgery not appropriate

Populations addressed — list of clinical populations

Populations addressed (examples)Corneal perforation when donor tissue unavailable; corneal ulcers/melts not responding to initial therapy; bullous keratopathy when not curative; partial limbal stem cell deficiency with extensive diseased tissue

ScopePolicy applies to wound care and select ophthalmic and orthopedic indications described in evidence summaries

Extensive diseased limbus definition

Extensive diseased limbusLimbal stem cell deficiency presentation where selective removal of diseased tissue alone is insufficient and more extensive intervention is required

Clinical implicationMay justify use of sutured or non‑sutured HAM when alternatives inadequate

c-HAM — cryopreserved human amniotic membrane definition

c‑HAM definitionCryopreserved human amniotic membrane prepared for application, sometimes applied with fibrin glue rather than sutures

Typical useSelf‑retained or short‑duration applications (eg, ProKera) reported in ocular trials

DEWS score — dry eye severity scoring

DEWS score purposeReport of the International DEWS assesses 9 domains (scale 1–4); scores 2–4 indicate moderate‑to‑severe dry eye

Use in policyBaseline DEWS and follow‑up assessments recommended when considering HAM for severe dry eye

sutured or glued HAM — definition

Sutured or glued HAM definitionHuman amniotic membrane applied to ocular surface or surgical site and secured by sutures or tissue adhesive (glue)

IndicationsUsed for corneal perforation temporizing, pterygium repair when autograft not feasible, and other ocular surface reconstructions

relevant population — corneal perforation when donor tissue unavailable

Relevant population — corneal perforationIndividuals with corneal perforation when corneal tissue is not immediately available (HAM as temporizing cover)

Evidence noteNo RCTs identified for definitive use; role described as temporary measure until donor tissue available

dHACM — dehydrated human amnion/chorion membrane product definition

dHACM definitionDehydrated human amnion/chorion membrane product (example: EpiFix) used for wound repair

Clinical evaluationdHACM evaluated in RCTs and observational studies for diabetic and venous leg ulcers

Second-intention healing — definition

Second‑intention healingAllowing a wound to heal by granulation, contraction, and epithelialization rather than primary surgical closure

Comparator relevanceSecond‑intention healing is a nonsurgical comparator in Mohs repair contexts

cellular and acellular skin equivalents / placental membrane products — definition

Cellular and acellular skin equivalents definitionBiologic grafts derived from amnion/chorion or umbilical cord tissues, cellular or decellularized, providing growth factors and scaffold to stimulate wound healing

Relation to HAMThese products are referenced alongside HAM products in wound‑healing guideline evidence and RCTs

DEWS II — Dry Eye Workshop II algorithm reference

DEWS II referenceDry Eye Workshop II provides a 4‑step management algorithm guiding when advanced therapies (including HAM) are considered

Clinical implicationHAM considered after failure of earlier DEWS steps (eg, lubricants, prescription therapies, in‑office procedures)

Human placental/amnion/umbilical products — definition

Human placental/amnion/umbilical products — definitionBiologic allografts derived from amniotic membrane, placental membrane, or umbilical cord used as wound coverings or injectables for wound healing

Product formsSheet grafts, flowable/injectable preparations, and cryopreserved/ dehydrated variants cited in literature

FDA communications — safety notifications and warning letters

FDA communications referencePublic safety notifications and warning letters (eg, FDA public safety notification on amniotic fluid eyedrops and warning letters) are cited for regulatory context

Coverage impactProducts marketed without required premarket review or not meeting HCT/P criteria may be subject to regulatory action affecting coverage

Provider actionClinicians should review FDA notices for specific products in use