CurrentBlue Cross Blue Shield - MassachusettsPolicy 643

643 Amniotic Membrane And Amniotic Fluid Prn

BCBS Massachusetts policy #643 addresses medical necessity coverage criteria, applicable settings, and coding for human amniotic membrane (HAM) products and related amniotic-derived products for commercial and Medicare members; it defines covered ophthalmic indications and diabetic lower-extremity ulcer use, lists covered and investigational HCPCS/CPT codes and required ICD-10 diagnoses, and prior authorization rules for inpatient care.

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

Policy643 Amniotic Membrane And Amniotic Fluid Prn

Policy CodePolicy 643

Change TypeProduct additions & coding clarifications

Effective Date

Next Review Date

Key ActionPrecertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.

SourceLink

POLICY UPDATE CHANGES

NuShield added to medically necessary policy statement for nonhealing diabetic lower-extremity ulcers based on RCT evidence (policy update 9/2025).

AmnioExcel added to medically necessary products for diabetic lower-extremity ulcers. Effective 1/1/2025.

Annual policy review with literature update through February 21, 2025; references added.

New investigational indication for treatment following Mohs microsurgery added in 7/2022.

Multiple historical actions clarifying coding information across many dates (1/2026, 4/2026, 10/2025, etc.).

2Primary covered clinical areas (diabetic ulcers, ophthalmic)

~100+HCPCS codes listed (covered + investigational)

Indications judged sufficient evidence / covered

10Indications judged insufficient / investigational

8Major references cited in part

Coverage Summary

BCBS Massachusetts policy #643 addresses medical necessity coverage criteria, applicable settings, and coding for human amniotic membrane (HAM) and related amniotic-derived products for commercial and Medicare members. Primary covered clinical areas are diabetic lower-extremity (nonhealing) ulcers and ophthalmic indications (multiple corneal/ocular surface conditions). The overall coverage stance is mixed: certain HAM grafts and specified patch products are considered medically necessary for defined diabetic foot ulcers and defined ophthalmic indications when criteria are met, while other uses and many injectable/amnion-derived products are designated investigational/not covered. High-level administrative notes: inpatient precertification/preauthorization is required for procedures performed inpatient, and prior authorization is handled differently for outpatient settings; coding guidance and medical necessity criteria (including required conservative-therapy failure definitions) must be documented to support coverage.

Key thresholds and policy metadata

Policy number643

StatusCURRENT

SubjectHuman Amniotic Membrane and Amniotic Fluid Products

Nonhealing diabetic wound definition< 20% decrease in wound area after at least 2 weeks of standard wound care

Persistent epithelial defect definitionFailed to close after 5 days of conservative treatment OR failed to demonstrate decrease in size after 2 days of conservative treatment

Medical Necessity Criteria

Treatment of nonhealing diabetic lower-extremity ulcers

Treatment of nonhealing diabetic lower-extremity ulcers using listed human amniotic membrane products may be considered MEDICALLY NECESSARY when ALL criteria are met:

ALL of the following

Wound type: Wound is a diabetic lower-extremity ulcer
Nonhealing definition: Nonhealing defined as less than a 20% decrease in wound area with standard wound care for at least 2 weeks<20% decrease after ≥2 weeks
Based on entry criteria for clinical trials
Product used is one of the listed human amniotic membrane products (eg, Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix, NuShield)

Coding

Covered HCPCS (when medical necessity criteria met)HCPCSCovered

Q4132	Grafix core and grafixpl core, per square centimeter
Q4133	Grafix prime, grafixpl prime, stravix and stravixpl, per square centimeter
Q4137	Amnioexcel, amnioexcel plus or biodexcel, per square centimeter
Q4151	Amnioband or guardian, per square centimeter
Q4154	Biovance, per square centimeter
Q4159	Affinity, per square centimeter
Q4160	Nushield, per square centimeter
Q4168	Amnioband, 1 mg
Q4186	Epifix, per square centimeter
Q4187	Epicord, per sq cm

1–10 of 11

1/2

Covered CPT (ocular surface placement) (when medical necessity criteria met)CPTCovered

65779	Placement of amniotic membrane on the ocular surface; single layer, sutured
65778	Placement of amniotic membrane on the ocular surface; without sutures

Covered ICD-10 Diagnoses with HCPCS for diabetic ulcersICD-10Covered

E08.621	Diabetes mellitus due to underlying condition with foot ulcer
E08.622	Diabetes mellitus due to underlying condition with other skin ulcer
E09.621	Drug or chemical induced diabetes mellitus with foot ulcer
E09.622	Drug or chemical induced diabetes mellitus with other skin ulcer
E10.621	Type 1 diabetes mellitus with foot ulcer
E10.622	Type 1 diabetes mellitus with other skin ulcer
E11.621	Type 2 diabetes mellitus with foot ulcer
E11.622	Type 2 diabetes mellitus with other skin ulcer
E13.621	Other specified diabetes mellitus with foot ulcer
E13.622	Other specified diabetes mellitus with other skin ulcer

Covered ICD-10 Diagnoses for ocular CPT/HCPCSICD-10Covered

H04.121	Dry eye syndrome of right lacrimal gland
H04.122	Dry eye syndrome of left lacrimal gland
H04.123	Dry eye syndrome of bilateral lacrimal glands
H04.129	Dry eye syndrome of unspecified lacrimal gland
H11.001	Unspecified pterygium of right eye
H11.002	Unspecified pterygium of left eye
H11.003	Unspecified pterygium of eye, bilateral
H11.009	Unspecified pterygium of unspecified eye
H16.001	Unspecified corneal ulcer, right eye
H16.002	Unspecified corneal ulcer, left eye

1–10 of 25

1/3

Investigational / Not Covered HCPCSHCPCSExperimental

A2001	Innovamatrix ac, per square centimeter
A2013	Innovamatrix fs, per square centimeter
A2035	Corplex p or theracor p or allacor p, per milligram
Q4138	Biodfence dryflex, per square centimeter
Q4139	AmnioMatrix or BioDMatrix, injectable, 1 cc
Q4140	Biodfence, per square centimeter
Q4145	EpiFix, injectable, 1 mg
Q4148	Neox cord 1k, neox cord rt, or clarix cord 1k, per square centimeter
Q4150	Allowrap ds or dry, per square centimeter
Q4153	Dermavest and plurivest, per square centimeter

1–10 of 30

1/3

Policy history entries note multiple coding clarifications and product additions (for example, NuShield and AmnioExcel were added to the medically necessary product list). Inclusion of a HCPCS/CPT code in the policy or code tables does not guarantee coverage; providers should follow the policy's medical necessity criteria and the provider_actions callouts for billing rules and coding clarifications when reporting services.

Actions for Providers and Billers

Prior Authorization

Inpatient precertification required

Precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.

Documentation Required

Document conservative therapy and nonresponse

Providers must document failure of the specified conservative therapies and the durations noted in policy to justify medical necessity for ophthalmic indications and the policy’s definition of nonhealing for diabetic ulcers (less than a 20% decrease in wound area with standard wound care for at least 2 weeks).

Background and Evidence Summary

Human amniotic membrane (HAM) is harvested immediately after birth, cleaned/sterilized, and processed for clinical use by either cryopreservation or dehydration; products are formulated as patches, grafts, suspensions/particulates, or injectable preparations. HAM contains extracellular matrix components (eg, collagen, fibronectin, hyaluronic acid), growth factors, cytokines, and anti-inflammatory proteins, and is considered nonimmunogenic with anti-inflammatory and regenerative properties. Sutured HAM grafts are an established treatment for certain corneal surface disorders, while other formulations (eg, self-retained contact-lens-like inserts, injectable suspensions/particulates) are under investigation for ophthalmic and non-ophthalmic indications.

Label	Value
Diabetic lower-extremity ulcers
Multiple RCTs and multicenter registries demonstrate improved healing versus standard care for specified HAM/placental patch products (eg, Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix, NuShield); nonhealing defined as <20% decrease in wound area with standard care for ≥2 weeks
Venous leg ulcers
Three RCTs with mixed results; overall evidence insufficient to determine improvement in net health outcome
Ophthalmic - corneal ulcers/melts
Systematic review and comparative studies show high healing rates (healing in 97% of patients) and vision improvement in ~53% of eyes with sutured HAM; considered sufficient evidence for coverage when conservative therapy fails as specified

Not Covered / Investigational

The following indications are considered investigational / not covered per policy.

Concise summary of key investigational items: injections of micronized/particulated HAM for any indication (including osteoarthritis and plantar fasciitis), injection of human amniotic fluid for all indications, use of HAM/dHACM for repair following Mohs micrographic surgery, and use of HAM products for indications not listed as medically necessary such as lower-extremity ulcers due to venous insufficiency. (These items were previously included under the policy's investigational/not medically necessary sections.)

Top investigational/clinical indications (compact)

Nonhealing diabetic lower-extremity ulcersMultiple RCTs and registries show improved healing vs standard care for listed HAM/placental patch products; considered medically necessary when prior standard care has failed

Corneal ulcers and meltsSystematic review and comparative studies show high healing rates; sutured HAM considered medically necessary when not responding to initial conservative therapy

Severe dry eye (DEWS 3–4)RCT and case series show symptom reduction and corneal surface improvement with self-retained HAM; considered medically necessary when steps 1–3 have failed

Definitions

Definitions:

Nonhealing (diabetic wounds): Less than a 20% decrease in wound area with standard wound care for at least 2 weeks.

Persistent epithelial defect: Failed to close completely after 5 days of conservative treatment or failed to demonstrate decrease in size after 2 days of conservative treatment.

HAM: Human amniotic membrane; placental membrane products derived from amnion/chorion.

dHACM: Dehydrated human amnion/chorion membrane allograft (example product: EpiFix).

Revision History

7/2022added

New investigational indication for treatment following Mohs microsurgery added; investigational statement and coding clarification implemented.

1/1/2025clarified

AmnioExcel added to the list of medically necessary products for the treatment of nonhealing diabetic lower-extremity ulcers; effective 1/1/2025; coding clarified.

9/2025clarifiedLatest

NuShield added to the medically necessary policy statement for treatment of nonhealing diabetic lower-extremity ulcers based on RCT evidence (policy update 9/2025); coding clarified; annual policy review with literature update through February 21, 2025; references added.

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

Policy643 Amniotic Membrane And Amniotic Fluid Prn

Policy CodePolicy 643

Change TypeProduct additions & coding clarifications

Effective Date

Next Review Date

Key ActionPrecertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.

SourceLink

On This Page

Products listed in policy and supported by RCTs/registries

Ophthalmic indications - HAM grafts with or without suture (MEDICALLY NECESSARY)

Human amniotic membrane grafts with or without suture may be considered MEDICALLY NECESSARY for the following ophthalmic indications when conservative therapy fails as specified:

Ophthalmic indications (with/without suture)

Neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy
Conservative therapy may include 5 days of pressure patching, therapeutic contact lens, topical lubricants, and topical antibiotics (policy-specified)
Corneal ulcers/melts: Corneal ulcers and melts that do not respond to initial conservative therapy
Conservative therapy may include 2 days of patching, therapeutic contact lens, and topical antimicrobial agents (policy-specified)
Corneal perforation (post-transplant): Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment
Bullous keratopathy as a palliative measure in individuals not candidates for curative treatment (eg, endothelial or penetrating keratoplasty)
Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient
Stevens-Johnson syndrome: Moderate or severe Stevens-Johnson syndrome
RCT evidence (25 patients/50 eyes) supports improved symptoms/function
Persistent epithelial defects that do not respond to conservative therapy
Persistent epithelial defect = failed to close after 5 days of conservative treatment or failed to decrease after 2 days; conservative treatment may include 5 days of topical lubricants, topical antibiotics, therapeutic contact lens, or patching
Severe dry eye (DEWS 3 or 4) with ocular surface damage and inflammation that remains symptomatic after Steps 1-3 of dry eye disease management algorithm
Policy references RCT and case series showing benefit for self-retained HAM
Acute ocular chemical burn: Moderate or severe acute ocular chemical burn

Ophthalmic indications - HAM grafts with suture or glue (MEDICALLY NECESSARY)

Human amniotic membrane grafts with suture or glue may be considered MEDICALLY NECESSARY for:

Ophthalmic indications (suture or glue)

Corneal perforation (temporary): Corneal perforation when corneal tissue is not immediately available
HAM may provide temporary coverage when corneal tissue not available (policy-specified)
Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft

Not Medically Necessary / Investigational

The following are considered INVESTIGATIONAL for all indications reviewed herein:

Investigational items

Other ophthalmic indications: Human amniotic membrane grafts for all ophthalmic indications not specifically listed above
Injection - HAM particulate: Injection of micronized or particulated human amniotic membrane for all indications (including osteoarthritis and plantar fasciitis)
Policy states injection of micronized/particulate HAM is investigational for all indications
Injection - amniotic fluid: Injection of human amniotic fluid for all indications
Policy states injection of amniotic fluid is investigational for all indications
Other amniotic-derived products: All other human amniotic products (derived from amnion, chorion, amniotic fluid, umbilical cord, Wharton's jelly) not listed as medically necessary
Mohs repair: Use of HAM products for indications reviewed herein not listed as medically necessary, including lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery
New investigational indication for Mohs repair added in policy history; policy lists Mohs repair as investigational

Medically Necessary / Sufficient Evidence Indications

Covered when evidence is sufficient to determine improvement in net health outcome:

Sufficient evidence indications

Diabetic lower-extremity ulcers: Nonhealing diabetic lower-extremity ulcers (patch formulation of HAM or placental membrane) when prior standard care has failedNonhealing = <20% decrease after ≥2 weeks
RCTs and multicenter registries showed improved outcomes vs standard care; specified products include Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix, NuShield
Corneal ulcers/melts (sutured HAM): Corneal ulcers and melts that do not respond to initial medical therapy (sutured HAM)
Systematic review/case series and nonrandomized comparative study showed high healing rates; evidence sufficient
Stevens-Johnson syndrome: Moderate or severe Stevens-Johnson syndrome (HAM)
One RCT (25 patients/50 eyes) found improved symptoms and function vs medical therapy; evidence sufficient
Severe dry eye with ocular surface damage and inflammation not responding to conservative therapy (self-retained HAM)
RCT and large case series showed symptom reduction and corneal surface improvement; evidence sufficient
Corneal perforation (temporary coverage): Corneal perforation when corneal tissue is not immediately available (sutured HAM as temporary coverage)
Evidence sufficient to determine improvement as temporary measure

Insufficient Evidence / Investigational Indications

Not covered / investigational when evidence is insufficient to determine improvement in net health outcome:

Insufficient evidence / investigational

Venous insufficiency ulcers: Lower-extremity ulcers due to venous insufficiency (patch HAM)
3 RCTs with mixed results; overall evidence insufficient
Knee osteoarthritis (injection): Knee osteoarthritis (injection of HAM or amniotic fluid suspension/particulate)
Feasibility/pilot study only; evidence insufficient
Plantar fasciitis (injection): Plantar fasciitis (injection of amniotic membrane)
Preliminary studies and interim report (N=145) with promising results but evidence insufficient pending full data
Neurotrophic keratitis (sutured HAM): Neurotrophic keratitis with ocular surface damage/inflammation not responding to conservative therapy (sutured HAM)
RCT (30 patients) showed no benefit vs tarsorrhaphy/bandage contact lens; evidence insufficient
Corneal perforation (post-transplant): Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment (HAM)
No comparative evidence identified; insufficient
Bullous keratopathy as palliative measure in patients not candidates for curative treatment (eg, keratoplasty) (HAM)
RCT showed no advantage over stromal puncture; insufficient
Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient (HAM adjunctive to removal)
No comparative trials; insufficient evidence
Persistent epithelial defects and ulceration that do not respond to conservative therapy (HAM)
No comparative trials; insufficient evidence
Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft (HAM)
Systematic reviews show conjunctival/limbal autograft more effective than HAM for recurrence; evidence insufficient
Mohs repair: Repair following Mohs micrographic surgery using human amniotic/chorionic membrane (dHACM, EpiFix)
Retrospective comparative study with improved complication and cosmesis outcomes but observational design limits conclusions; evidence insufficient

Documentation Required

Support prior conservative therapy/failure for ophthalmic and wound indications

Document that conservative therapy was attempted and failed when using HAM for ophthalmic indications where the policy specifies 'does not respond to conservative therapy' (examples: neurotrophic keratitis — e.g., 5 days of patching/therapeutic contact lens/topical lubricants/antibiotics; corneal ulcers/melts — e.g., 2 days of patching/therapeutic contact lens/topical antimicrobials; persistent epithelial defects per the policy definition).

Documentation Required

Specify product and formulation

When seeking coverage for diabetic lower‑extremity ulcers, document the specific patch product and formulation used (policy lists examples such as Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix, NuShield) because the evidence base and medically necessary statement reference specific products.

Billing Rule

Report services with appropriate codes and modifiers

Providers should report all services using current industry‑standard procedure, revenue, and diagnosis codes, including modifiers where applicable; inclusion of a code in the policy does not guarantee coverage — the medical necessity criteria in the policy must be met.

Billing Rule

Coding clarifications required

Policy history repeatedly indicates coding information was clarified; providers and billers must follow the insurer’s coding guidance (coding specifics appear elsewhere in the policy and have been clarified multiple times in the policy history).

Persistent epithelial defectsListed but evidence limited; policy requires failure of conservative therapy (definition provided) before HAM use

Mohs micrographic surgery repairInvestigational — retrospective comparative study shows fewer complications but evidence insufficient; added investigational indication in 7/2022

Multiple (1/2026, 4/2026, 10/2025, etc.)clarified

Multiple historical actions clarifying coding information across many dates; coding clarifications but no other clinical policy statement changes except noted product additions.

1/2025revised

Annual policy review with literature update through January 3, 2024; references updated (AmnioExcel addition noted as effective 1/1/2025).