Amniotic Membrane and Amniotic Fluid Injections for Non-Ophthalmic Applications - CAM 701149

Description
Several commercially available forms of human amniotic membrane (HAM) and amniotic fluid can be administered by patches, topical application, or injection. Amniotic membrane and amniotic fluid are being evaluated for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions.

Backgound
HUMAN AMNIOTIC MEMBRANE
Human amniotic membrane (HAM) consists of 2 conjoined layers, the amnion, and chorion, and forms the innermost lining of the amniotic sac or placenta. When prepared for use as an allograft, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated. Many products available using amnion, chorion, amniotic fluid, and umbilical cord are being studied for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions. The products are formulated either as patches, which can be applied as wound covers, or as suspensions or particulates, or connective tissue extractions, which can be injected or applied topically.

Fresh amniotic membrane contains collagen, fibronectin, and hyaluronic acid, along with a combination of growth factors, cytokines, and anti-inflammatory proteins such as interleukin-1 receptor antagonist.¹ There is evidence that the tissue has anti-inflammatory, antifibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause a substantial immune response. It is believed that these properties are retained in cryopreserved HAM and HAM products, resulting in a readily available tissue with regenerative potential. In support, 1 HAM product has been shown to elute growth factors into saline and stimulate the migration of mesenchymal stem cells, both in vitro and in vivo.²

Use of a HAM graft, which is fixated by sutures, is an established treatment for disorders of the corneal surface, including neurotrophic keratitis, corneal ulcers and melts, following pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Amniotic membrane products that are inserted like a contact lens have more recently been investigated for the treatment of corneal and ocular surface disorders. Amniotic membrane patches are also being evaluated for the treatment of various other conditions, including skin wounds, burns, leg ulcers, and prevention of tissue adhesion in surgical procedures.¹ Additional indications studied in preclinical models include tendonitis, tendon repair, and nerve repair. The availability of HAM opens the possibility of regenerative medicine for an array of conditions.

Amniotic Fluid
Amniotic fluid surrounds the fetus during pregnancy and provides protection and nourishment. In the second half of gestation, most of the fluid is a result of micturition and secretion from the respiratory tract and gastrointestinal tract of the fetus, along with urea.¹ The fluid contains proteins, carbohydrates, peptides, fats, amino acids, enzymes, hormones, pigments, and fetal cells. Use of human and bovine amniotic fluid for orthopedic conditions was first reported in 1927.³ Amniotic fluid has been compared with synovial fluid, containing hyaluronan, lubricant, cholesterol, and cytokines. Injection of amniotic fluid or amniotic fluid-derived cells is currently being evaluated for the treatment of osteoarthritis and plantar fasciitis.

Amniotic membrane and amniotic fluid are also being investigated as sources of pluripotent stem cells.¹ Pluripotent stem cells can be cultured and are capable of differentiation toward any cell type. The use of stem cells in orthopedic applications is addressed in evidence review 80152.

Regulatory Status
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. In 2017, the FDA published clarification of what is considered minimal manipulation and homologous use for human cells, tissues, and cellular and tissue-based products (HCT/Ps).⁴

HCT/Ps are defined as human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. If an HCT/P does not meet the criteria below and does not qualify for any of the stated exceptions, the HCT/P will be regulated as a drug, device and/or biological product, and applicable regulations and premarket review will be required.

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria:

"The HCT/P is minimally manipulated;
The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
Either:
1. The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
2. The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
  1. Is for autologous use;
  2. Is for allogeneic use in a first-degree or second-degree blood relative; or
  3. Is for reproductive use."

The guidance provides the following specific examples of homologous and non-homologous use for amniotic membrane:

"Amniotic membrane is used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane.
An amniotic membrane product is used for wound healing and/or to reduce scarring and inflammation. This is not homologous use because wound healing and reduction of scarring and inflammation are not basic functions of amniotic membrane.
An amniotic membrane product is applied to the surface of the eye to cover or offer protection from the surrounding environment in ocular repair and reconstruction procedures. This is homologous use because serving as a covering and offering protection from the surrounding environment are basic functions of amniotic membrane."

The FDA noted the intention to exercise enforcement discretion for the next 36 months after publication of the guidance.

In 2003, Prokera™ was cleared for marketing by the FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). The FDA determined that this device was substantially equivalent to the Symblepharon Ring. The Prokera™ device is intended “for use in eyes in which the ocular surface cells have been damaged, or underlying stroma is inflamed and scarred.”⁵ The development of Prokera, a commercially available product, was supported in part by the National Institute of Health and the National Eye Institute.

AmnioClip (FORTECH GmbH) is a ring designed to hold the amniotic membrane in the eye without sutures or glue fixation. A mounting device is used to secure the amniotic membrane within the AmnioClip. The AmnioClip currently has CE approval in Europe.

Related Policies
20116 Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Conditions
701113 Bio-Engineered Skin and Soft Tissue Substitutes
80152 Orthopedic Applications of Stem Cell Therapy

Policy
Treatment of nonhealing diabetic lower-extremity ulcers using the following human amniotic membrane products (Affinity^®, AmnioBand^® Membrane, Biovance^®, EpiCord^®, EpiFix^®, Grafix™) may be considered MEDICALLY NECESSARY.

Injection of micronized or particulated human amniotic membrane is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY for all indications, including but not limited to treatment of osteoarthritis and plantar fasciitis.

Injection of human amniotic fluid is investigational and /or unproven therefore NOT MEDICALLY NECESSARY for all indications.

All other human amniotic products (e.g., derived from amnion, chorion, amniotic fluid, umbilical cord, or Wharton's jelly) not listed above are investigational and/or unproven therefore NOT MEDICALLY NECESSARY (see policy guidelines).

All other indications not listed above are investigational/unproven therefore is considered NOT MEDICALLY NECESSARY, including but not limited to treatment of lower-extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery.

NOTE: See CAM 047 for ophthlamic indications of this technology.

Policy Guidelines
Non-healing of diabetic wounds is defined as less than a 20% decrease in wound area with standard wound care for at least 2 weeks, based on the entry criteria for clinical trials (e.g., Zelen et al. [2015]).

Tables PG1 and PG2 list the medically necessary and investigational amniotic products that have an HCPCS code.

Table PG1 Amniotic Products Listed in the Policy Statements

Trade Name	Supplier	HCPCS Code
Affinity^®	Organogenesis (previously NuTech Medical)	Q4159
AmnioBand^® Membrane	MTF Wound Care	Q4151
Biovance^®	Celularity	Q4154
Epifix^®	MiMedx	Q4186
Epicord^®	MiMedx	Q4187
Grafix^®	Osiris	Q4132, Q4133

Table PG2 Other Amniotic Products with HCPCS Codes

Trade Name	Supplier	HCPCS Code
Allogen	Vivex Biomedical	Q4212
AlloWrap™	AlloSource	Q4150
AmnioAMP-MP	Stratus BioSystems	Q4250
Amnioarmor™	Tissue Transplant Technology	Q4188
AmnioBand® Particulate	MTF Wound Care	Q4168
AmnioExcel®	Derma Sciences	Q4137
Amnio-maxx or Manio-maxx lite	Royal Biologics	Q4239
Amniotext	Regenerative Labs	Q4245
Amniowound	Alpha Tissue	Q4181
Amnion bio or Axomembrane	Axolotl Biologix	Q4211
Amniocore™	Stability Biologics	Q4227
Amniocyte	Predictive Biotech	Q4242
AmnioMatrix^®	Integra Life Sciences	Q4139
Amniply	International Tissue	Q4249
Amniorepair or AltiPly	Zimmer Biomet	Q4235
Amniotext patch	Regenerative Labs	Q4247
AmnioWrap2™	Direct Biologics	Q4221
Articent ac (flowable)	Tides Medical	Q4189
Artacent ac (patch)	Tides Medical	Q4190
Artacent^® Wound	Tides Medical	Q4169
Artacent^® Cord	Tides Medical	Q4126
Ascent	StimLabs	Q4213
Axolotl ambien or Axolotl Cryo	Axolotl Biology	Q4215
BioDDryFlex^®	BioD	Q4138
BioDfence™	Integra Life Science	Q4140
BioNextPATCH	BioNext Solutions	Q4228
BioWound, BioWound Plus™, BioWound XPlus™	HRT^a	Q4217
carePATCH	Extremity Care	Q4236
Cellesta/Cellesta duo	Ventris Medical	Q4184
Cellesta Cord	Ventris Medical	Q4214
Cellesta flowable	Ventris Medical	Q4185
Clarix^®	Amniox Medical	Q4156
Clarix^® Flo	Amniox Medical	Q4155
Cogenex flowable amnion	Ventris Medical	Q4230
Cogenex amniotic membrane	Ventris Medical	Q4229
Corecyte	Predictive Biotech	Q4240
Corplex	StimLabs	Q4232
Corplex P	StimLabs	Q4231
Coretext or Protext	Regenerative Labs	Q4246
Cryo-cord	Royal Biologics	Q4237
Cygnus	Vivex Biomedical	Q4170
Dermacyte	Merakris Therapeutics	Q4248
Dermavest™ or Plurivest	AediCell^a	Q4153
Derm-maxx	Royal Biologics	Q4238
Epifix Injectable	MiMedx	Q4145
Floweramnioflo	Flower Orthopedics	Q4177
Floweramniopatch	Flower Orthopedics	Q4178
Fluid flow or Fluid GF	BioLab Sciences	Q4206
Genesis	Genesis Biologics	Q4198
Guardian/AmnioBand^®	MTF Wound Care	Q4151
Interfyl^®	Celularity	Q4171
Matrion	LifeNet Health	Q4201
Neopatch or Therion	CryoLife	Q4176
Neox^® Cord	Amniox Medical	Q4148
Neox^® Flo	Amniox Medical	Q4155
Neox^® Wound	Amniox Medical	Q4156
Novachor	Organogenisis	Q4191
Novafix^®	Triad Life Sciences	Q4208
Novafix DL	Triad Life Sciences	Q4254
NuShield	Organogenesis	Q4160
PalinGen^® Membrane	Amnio ReGen Solutions	Q4173
PalinGen^® SportFlow	Amnio ReGen Solutions	Q4174
Plurivest™	AediCell	Q4153
Polycyte	Predictive Biotech	Q4241
Procenta	Lucina BioSciences	Q4244
Reguard	New Life Medical	Q4255
Restorigin	UMTB Biomedical	Q4191
Restorigin Injectable	UMTB Biomedical	Q4192
Revita	StimLabs	Q4180
Revitalon™	Medline Industries	Q4157
Surgenex, Surfactor, and Nudyn	Surgenex	Q4233
Surgicord	Synergy Biologics	Q4218
SurgiGRAFT™	Synergy Biologics	Q4183
WoundEx^®	Skye Biologics^a	Q4163
WoundEx^® Flow	Skye Biologics^a	Q4162
Woundfix, Woundfix Plus, Wounfix XPlus (see BioWound above)	HRT	Q4217
Xcellerate	Precise Bioscience	Q4234
Xwrap	Applied Biologics	Q4204

HRT: Human Regenerative Technologies; MTF: Musculoskeletal Transplant Foundation
^aProcessed by HRT and marketed under different tradename

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (quality of life), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Diabetic Lower-Extremity Ulcers
Patch or Flowable Amniotic Membrane or Placental Membrane
Clinical Context and Therapy Purpose
The purpose of patch or flowable amniotic membrane or placental membrane in patients who have diabetic lower-extremity ulcers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does amniotic membrane or placental membrane improve the net health outcome in patients with diabetic lower-extremity ulcers?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with diabetic lower-extremity ulcers that have failed to heal with the standard of care (SOC) therapy.

Interventions
The therapy being considered is an amniotic membrane or placental membrane applied every 1 to 2 weeks. It is applied in addition to the SOC.

Comparators
The following therapies are currently being used to make decisions about the healing of diabetic lower-extremity ulcers: SOC, which involves moist dressing, dry dressing, compression therapy, and offloading.

Outcomes
The primary endpoints of interest for trials of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds:

Incidence of complete wound closure
Time to complete wound closure (reflecting accelerated wound closure)
Incidence of complete wound closure following surgical wound closure
Pain control

Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCT.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
At least 7 RCTs have evaluated rates of healing with amniotic membrane grafts or placental membrane graft compared to SOC or an advanced wound therapy in patients with chronic diabetic foot ulcers (see Table 1). The number of patients in these studies ranged from 25 to 155. Human amniotic membrane (HAM) or placental membrane grafts improved healing compared to SOC by 22% (EpiCord vs. Alginate dressing) to 60% (EpiFix) in the intention-to-treat (ITT) analysis (see Table 2). In a 2018 trial, the cryopreserved placental membrane Grafix was found to be non-inferior to an advanced fibroblast-derived wound therapy (Dermagraft).

Table 1. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Active Intervention	Comparator
Serena et al. (2020)⁶	U.S.	14		76 patients with chronic (> 4 weeks) non-healing diabetic foot ulcers unresponsive to SOC and extending into dermis, subcutaneous tissue, muscle, or tendon	n = 38, Affinity	n = 38, SOC
Ananian et al. (2018)⁷	U.S.	7	2016 – 2017	75 patients with chronic (> 4 weeks) non-healing diabetic foot ulcers between 1 cm² and 15 cm²	n = 38, Grafix weekly for up to 8 weeks	n = 37, Dermagraft (fibroblast-derived) weekly for up to 8 weeks
Tettelbach et al. (2018)⁸	U.S.	11	2016 – 2018	155 patients with chronic (> 4 weeks) non-healing diabetic foot ulcers	n = 101 EpiCord plus SOC	n = 54 SOC with alginate dressing
DiDomenico et al. (2018)⁹				80 patients with non-healing (4 weeks) diabetic foot ulcers	AmnioBand Membrane plus SOC	SOC
Snyder et al. (2016)¹⁰				29 patients with non-healing diabetic foot ulcers	AmnioExcel plus SOC	SOC
Zelen et al. (2015, 2016)^11,12		4		60 patients with less than 20% wound healing in a 2 week run-in period	EpiFix	Apligraf or SOC with collagen-alginate dressing
Tettelbach et al. (2019)¹³	U.S.	14		110 patients with non-healing (4 weeks) lower extremity ulcers	EpiFix	SOC with alginate dressing
Lavery et al. (2014)¹⁴				97 patients with chronic diabetic foot ulcers	Grafix Weekly	SOC

RCT: randomized controlled trial; SOC: standard of care including debridement, nonadherent dressing, moisture dressing, a compression dressing and offloading.

Table 2. Summary of Key RCT Results

Study	Wounds Healed	Wounds Healed	Time to Complete Healing	Adverse Events and Number of Treatments
Serena et al. (2020)⁶	12 Weeks (ITT) (%)	16 Weeks (ITT) (%)	Median
N	76	76	76
Affinity	55%	58%	11 weeks
SOC	29%	29%	not attained by 16 weeks
p-value	.02	.01
HR (95% CI)		1.75 (1.16 to 2.70)
Ananian et al. (2018)⁷	8 Weeks (PP) n (%)			Patients with Index Ulcer Related Adverse Events n (%)
N	62			75
Grafix	15 (48.4%)			1 (5.9%)
Dermagraft	12 (38.7%)			4 (16.7%)
Diff (95% CI)	9.68% (−10.7 to 28.9)
Lower bound for non-inferiority	-15%
Tettlebach et al. (2018)⁸	12 Weeks (PP) n (%)	12 Weeks (ITT) n (%)		Patients with Adverse Events (% of total)
N	134	155		155
EpiCord	81 (81%)	71 (70%)		42 (42%)
SOC	29 (54%)	26 (48%)		33 (61%)
p-value	.001	.009
DiDomenico et al. (2018)⁹	6 Weeks (ITT) n (%)	12 weeks ITT n (%)	Mean Days (95% CI)
N	80	80	80
AmnioBand	27 (68)	34 (85)	37.0 (29.5 to 44.4)
SOC	8 (20)	13 (33)	67.3 (59.0 to 79.6)
HR (95% CI)		4.25 (0.44 to 0.79)
p-value	< .001	< .001	< .001
Snyder et al. (2016)¹⁰	6 Weeks (PP) Mean (95% CI)
N	21
AmnioExcel	45.5% (32.9% to 58.0%)
SOC	0%
p-value	.014
Zelen et al. (2015, 2016)^11,12	6 Weeks ITT n (%)	Wounds Healed at 12 Weeks		Weekly Treatments
N	60	100
EpiFix	19 (95%)	NR		3.4
Apligraf	9 (45%)	NR		5.9
SOC	7 (35%)	NR
HR (95% CI)		5.66; (3.03 to 10.57)
p-value	.003	< .001 vs. SOC		.003
Tettelbach et al. (2019)¹³		Wounds Healed at 12 Weeks (ITT) n(%)
N		110		110
EpiFix		38 (81)
SOC		28 (55)
p-value
Lavery et al. (2014)¹⁴		Wounds Healed at 12 Weeks		Patients With Adverse Events
N		97a	97	97
Grafix		62.0%	42.0	44.0%
SOC		21.3%	69.5	66.0%
p-value		< .001	.019	.031
Difference in wounds healed between amniotic or placental membrane and SOC	Affinity 26% AmnioBand 55% AmnioExcel 33% EpiFix 60%	Affinity 28% EpiCord 22% Grafix 41%

CI: confidence interval; DIFF: difference; HR: hazard ratio; ITT: intention-to-treat; NR: not reported; PP: per-protocol; RCT: randomized controlled trial; SOC: standard of care.
^a. Power analysis indicated that 94 patients per arm would be needed. However, after a prespecified interim analysis at 50% enrollment, the blinded review committee recommended the trial is stopped due to the efficacy of the treatment.

Limitations in study design and conduct are shown in Table 3. Studies without notable limitations reported power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and ITT analysis. Limitations from the RCT with AmnioExcel (Snyder et al, 2016) ^10, preclude conclusions for this product.

Table 3. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Serena et al. (2020)⁶	3. The randomization process and allocation concealment were not described	1, 2. No blinding of patients or investigators. Assessors were blinded		1. Although ITT analysis, there was substantial missing data for depth and volume with the digital analysis system.
Ananian et al. (2018)⁷		2, 3. No blinding for outcomes assessment
Tettelbach et al. (2018)⁸		1, 2, 3. No blinding
DiDomenico et al. (2018)⁹
Snyder et al. (2016)¹⁰				1. There was high loss to follow-up with discontinuation of 8 of 29 participants	1. Power analysis was not reported
Zelen et al. (2015, 2016)^11,12				1. Thirteen of 35 patients in the SOC group exited the study at 6 weeks due to less than 50% healing, which may have affected the 12-week results.
Tettelbach et al. (2019)¹³		1, 2. No blinding of patients or investigators. Assessors were blinded
Lavery et al. (2014)¹⁴

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
ITT: intention to treat; SOC: standard of care.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Prospective Single-Arm or Registry Studies
Prospective single-arm or registry studies are described in Tables 4 and 5.

Smiell et al. (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types; about a third (n=47) were diabetic foot wounds.¹⁵ Of those treated, 28 ulcers had failed prior treatment with advanced biologic therapies. For all wound types, 41.6% closed within a mean time of 8 weeks and a mean of 2.4 amniotic membrane applications.

In 2016, Frykberg et al. reported treatment of complex chronic wounds (exposed tendon or bone) with Grafix. With the cryopreserved placental membrane applied weekly for up to 16 weeks, 59% of wounds closed with a mean time to closure of 9 weeks.¹⁶

Table 4. Summary of Prospective Single-Arm Studies or Registry Characteristics

Study	Study Design	Participants	Treatment Delivery
Smiell et al. (2015)¹⁵	Multicenter Registry	Various chronic wounds: 47 diabetic foot wounds, 20 pressure ulcers, and 89 venous ulcers; 28 had failed prior treatment with advanced biologic therapies (Apligraf, Dermagraft, or Regranex)	Biovance
Frykberg et al. (2016)¹⁶	Prospective multi-center single-arm study	31 patients with chronic complex diabetic foot wounds with exposed tendon or bone	Grafix weekly until closure or 16 weeks

Table 5. Summary of Prospective Single-Arm Studies or Registry Results

Study	Treatment	Wounds Closed	Mean Time to Closure	Number of Applications
Smiell et al. (2015)¹⁵	Biovance	41.6%	8 weeks	2.4
Frykberg et al. (2016)¹⁶	Grafix	59.3%	9 weeks	9

Section Summary: Diabetic Lower-Extremity Ulcers
For individuals who have non-healing diabetic lower-extremity ulcers who receive a patch or flowable formulation of HAM or placental membrane (i.e., Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix), the evidence includes RCTs. The RCTs evaluating amniotic and placental membrane products for the treatment of non-healing (< 20% healing with ≥ 2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM with standard care or with an established advanced wound care product. These trials used wound closure as the primary outcome measure, and some included power analysis, blinded assessment of wound healing, and ITT analysis. For the HAM products that have been sufficiently evaluated (i.e., Affinity, AmnioBand Membrane, Biovance, EpiCord, EpiFix, Grafix), results have shown improved outcomes compared with standard care, and outcomes that are at least as good as an established advanced wound care product. Improved health outcomes in the RCTs are supported by multicenter registries. No studies were identified that compared different amniotic or placental products, and indirect comparison between products is limited by variations in the patient populations.

Lower-Extremity Ulcers Due to Venous Insufficiency
Amniotic Membrane
Clinical Context and Therapy Purpose
The purpose of amniotic membrane or placental membrane in patients who have lower-extremity ulcers due to venous insufficiency is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does amniotic membrane or placental membrane improve the net health outcome in patients with venous ulcers?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with lower-extremity venous ulcers that have failed to heal with SOC therapy.

Interventions
The therapy being considered is amniotic membrane or placental membrane applied every 1 to 2 weeks. It is applied in addition to the SOC.

Comparators
The following therapies are currently being used to make decisions about the healing of venous ulcers: SOC, which involves moist dressing, dry dressing, and compression therapy.

Outcomes
The primary endpoints of interest for trials of wound closure are as follows, consistent with guidance from the FDA for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds:

Incidence of complete wound closure
Time to complete wound closure (reflecting accelerated wound closure)
Incidence of complete wound closure following surgical wound closure
Pain control

Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Two RCTs, both with EpiFix, were identified on HAM for venous leg ulcers. Serena et al. (2014) reported on an industry-sponsored multicenter open-label RCT that compared EpiFix d-HAM plus compression therapy with compression therapy alone for venous leg ulcers (see Tables 6 and 7).¹⁷ The primary outcome in this trial was the proportion of patients with 40% wound closure at 4 weeks, which was achieved by about twice as many patients in the combined EpiFix group compared with the control group (see Table 8). However, a similar percentage of patients in the combined EpiFix group and the control group achieved complete wound closure during the 4-week study. There was no significant difference in healing for wounds given 1 versus 2 applications of amniotic membrane (62% vs. 63%, respectively). Strengths of this trial included adequate power and ITT analysis with last observation carried forward. Limitations included the lack of blinding for wound evaluation and use of 40% closure rather than complete closure. A 2015 retrospective study of 44 patients from this RCT (31 treated with amniotic membrane) found that wounds with at least 40% closure at 4 weeks (n=20) had a closure rate of 80% by 24 weeks; however, this analysis did not take into account additional treatments after the 4-week randomized trial period.

A second industry-sponsored, multicenter, open-label RCT (Bianchi et al. [2018; 2019]) evaluated the time to complete ulcer healing following weekly treatment with EpiFix d-HAM plus compression therapy or compression wound therapy alone (see Tables 6 and 7).^18,¹⁹ Patients treated with EpiFix had a higher probability of complete healing by 12 weeks, as adjudicated by blinded outcome assessors (hazard ratio, 2.26; 95% CI, 1.25 to 4.10; p = .01), and improved time to complete healing, as assessed by Kaplan-Meier analysis. In per-protocol analysis, healing within 12 weeks was reported for 60% of patients in the EpiFix group and 35% of patients in the control group (p < .013) (see Table 8). Intent-to-treat analysis found complete healing in 50% of patients in the EpiFix group compared to 31% of patients in the control group (p = .0473). There were several limitations of this trial (see Tables 8 and 9). In the per-protocol analysis, 19 (15%) patients were excluded from the analysis, and the proportion of patients excluded differed between groups (19% from the EpiFix group vs. 11% from the control group). There was also a difference between the groups in how treatment failures at 8 weeks were handled. Patients in the control group who did not have a 40% decrease in wound area at 8 weeks were considered study failures and treated with advanced wound therapies. The ITT analysis used last-observation-carried-forward for these patients and sensitivity analysis was not performed to determine how alternative methods of handling the missing data would affect results. Kaplan-Meier analysis suggested a modest improvement in the time to heal when measured by ITT analysis, but may be subject to the same methodological limitations.

Two additional studies, one with Amnioband and a second with Artacent, are listed on clinicaltrials.gov as completed in 2018, but results have not been published (see Table 14)

Table 6. Summary of Key RCT Characteristics

					Interventions
Study	Countries	Sites	Dates	Participants	Active	Comparator
Serena et al. (2014)¹⁷	U.S.	8	2012 – 2014	84 patients with a full-thickness chronic VLU between 2 and 20 cm2 treated for at least 14 d	1 (n = 26) or 2 (n = 27) applications of EpiFix plus standard wound therapy (n = 53)	Standard wound therapy (debridement with alginate dressing and compression) (n = 31)
Bianchi et al. (2018, 2019)^18,19	U.S.	15	2015 – 2017	128 patients with a full-thickness VLU of at least 30-d duration	Weekly EpiFix plus moist wound therapy plus compression (n = 64 ITT; 52 PP)	Moist wound therapy plus compression (n = 64 ITT; 57 PP)

ITT: Intent-to-treat; PP: per-protocol; RCT: randomized controlled trial; VLU: venous leg ulcer.

Table 7. Summary of Key RCT Results

Study	Percent With 40% Wound Closure at 4 Weeks	Percent With Complete Wound Closure at 4 Weeks	Complete Wound Closure at 12 Weeks n (%)		Complete Wound Closure at 16 Weeks n (%)
			PP	ITT	PP	ITT
Serena et al. (2014)¹⁷
EpiFix	62	11.3
Control	32	12.9
p-Value	.005
Bianchi et al. (2018, 2019 )^18,19
EpiFix			31 (60)	32 (50)	37 (71)	38 (59)
Control			20 (35)	20 (31)	25 (44)	25 (39)
p-Value			.013	.047	.007	.034

ITT: Intent-to-treat; PP: per protocol; RCT: randomized controlled trial.

Table 8. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Serena et al. (2014)¹⁷
Bianchi et al. (2018, 2019 )^18,19					1. Advanced wound therapy was allowed in the control group before the primary endpoint was reached.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aPopulation key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 9. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Serena et al. (2014)¹⁷
Bianchi et al. (2018, 2019 )^18,19		1. Open-label with blinded assessors		1. Unequal exclusion of patients in the 2 groups in the per-protocol analysis.3. Advanced wound therapy was allowed in the control group before the primary endpoint was reached

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^bBlinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Biovance
As described above, Smiell et al. (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types; about half (n = 89) were venous ulcers.¹⁵ Of the 179 treated, 28 (16%) ulcers had failed prior treatment with advanced biologic therapies. For all wound types, 41.6% closed within a mean time of 8 weeks and a mean of 2.4 amniotic membrane applications. However, without a control group, the percentage of wounds that would have healed with SOC is unknown.

Section Summary: Lower-Extremity Ulcers Due to Venous Insufficiency
The evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix. One RCT reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and the SOC. A second RCT evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression. Although a significant difference in complete healing was reported, interpretation is limited by the differential loss to follow-up and exclusions between groups. Although a subsequent publication reported ITT analysis, the handling of missing data differed between the groups and sensitivity analysis was not performed. The methodological flaws in the design, execution, and reporting of both of these RCTs limit inference that can be drawn from the results. Two additional studies with other HAM products have been completed but not published, raising further questions about the efficacy of HAM for lower-extremity ulcers due to venous insufficiency. Therefore, corroboration with well-designed and well-conducted RCTs evaluating wound healing in patients with venous leg ulcers is needed to demonstrate efficacy. The corroborating RCTs should report ITT and sensitivity analysis, with analysis of all patients, including those who were off treatment or had protocol deviations and exclusions.

Osteoarthritis
ReNu™ Knee Injection in Patients with Osteoarthritis
In 2016, a feasibility study (N = 6) was reported of cryopreserved human amniotic membrane (c-HAM) suspension with amniotic fluid-derived cells for the treatment of knee osteoarthritis.²⁰ A single intra-articular injection of the suspension was used, with follow-up at 1 and 2 weeks and at 3, 6, and 12 months posttreatment. Outcomes included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scale, and a numeric pain scale. Statistical analyses were not performed for this small sample. No adverse events, aside from a transient increase in pain, were noted. RCTs are in progress.

A trial with 200 participants was completed in February 2019 (see Table 14). No publications from this trial have been identified.

Section Summary: Osteoarthritis
Current evidence is insufficient to support definitive conclusions on the utility of c-HAM in the treatment of knee osteoarthritis.

Plantar Fasciitis
Clinical Context and Therapy Purpose
The purpose of micronized amniotic membrane in patients who have plantar fasciitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does injectable amniotic membrane improve the net health outcome in patients with plantar fasciitis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with plantar fasciitis that has failed to heal with SOC therapy.

Interventions
The therapy being considered is micronized amniotic membrane. It is applied in addition to the SOC.

Comparators
The following therapies are currently being used to make decisions about the healing of plantar fasciitis: corticosteroid injections and SOC, which involves offloading, night-splinting, stretching, and orthotics.

Outcomes
The primary endpoints of interest for trials of plantar fasciitis are as follows: Visual Analog Score (VAS) for pain and function measured by the Foot Functional Index.

Acute effects of HAM injection may be measured at 2 to 4 weeks. The durability of treatment would be assessed at 6 to 12 months.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Consistent with a "best available evidence approach," within each category of study design, studies with larger sample sizes and longer durations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
One systematic review and 2 randomized pilot studies were identified on the treatment of plantar fasciitis using an injection of micronized HAM.

Systematic Review
A 2016 network meta-analysis of 22 RCTs (total N=1216 patients) compared injection therapies for plantar fasciitis.²¹ In addition to c-HAM and micronized d-HAM/chorionic membrane, treatments included corticosteroids, botulinum toxin type A, autologous whole blood, platelet-rich plasma, nonsteroidal anti-inflammatory drugs, dry needling, dextrose prolotherapy, and polydeoxyribonucleotide. Placebo arms included normal saline, local anesthetic, sham dry needling, and tibial nerve block. Analysis indicated d-HAM had the highest probability for improvement in pain and composite outcomes in the short-term, however, this finding was based only on a single RCT. Outcomes at 2 to 6 months (7 RCTs) favored botulinum toxin for pain and patient recovery plan for composite outcomes.

Randomized Controlled Trials
Zelen et al. (2013) reported a preliminary study with 15 patients per group (placebo, 0.5 cc, and 1.25 cc) and 8-week follow-up.²² A subsequent RCT by Cazell et al. (2018) enrolled 145 patients and reported 3-month follow-up (see Table 10).²³ In Cazzell et al. (2018) amniotic membrane injection led to greater improvements in the VAS for pain and the Foot Functional Index between baseline and 3 months (see Table 11) compared to controls. VAS at 3 months had decreased to 17.1 in the AmnioFix group compared to 38.8 in the placebo control group, which would be considered a clinically significant difference.

Table 10. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Active Intervention	Comparator Intervention
Cazzell et al. (2018)²³; AIPF004 (NCT02427191)	U.S.	14	2015 – 2018	Adult patients with plantar fasciitis with VAS for pain > 45	n = 73; Single injection of AmnioFix 40 mg/ml	n = 72; Single injection of saline

NCT02427191: Micronized dHACM Injection as Compared to the Saline Placebo Injection in the Treatment of Plantar Fasciitis; RCT: randomized controlled trial; VAS: visual analog score.

Table 11. Summary of Key RCT Results

Study	Change in VAS-Pain Between Baseline and 3 mo (95% CI)	Change in FFI-R Between Baseline and 3mo (95% CI)	Patients with Adverse Events up to 3 mo n(%)	Patients with Serious Adverse Events up to 3 mo n(%)
Cazzell et al. (2018)²³; AIPF004	N = 145	N = 145	N = 145	N = 145
AmnioFix	54.1 (48.3 to 59.9)	35.7 (30.5 to 41.0)	30 (41.1%)	1 (0.6%)
Placebo	31.9 (24.8 to 39.1)	22.2 (17.1 to 27.4)	39 (54.2%)	3 (1.8%)
Diff (95% CI)	22.2 (13.1 to 31.3)	13.5 (6.2 to 20.8)
p-Value	< .001	< .001

CI: confidence interval; FFI-R: Foot Function Index; RCT: randomized controlled trial; VAS: visual analog score.

Limitations in relevance and design and conduct of this publication are described in Tables 12 and 13. The major limitation of the study is the short-term follow-up, which the authors note is continuing to 12 months. The extended follow-up will be reported in a separate publication.

Table 12. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Cazzell et al. (2018)²³; AIPF004			3. Placebo injections were used. A control delivered at a similar intensity as the investigational treatment would be corticosteroid injections.		1, 2. Follow-up to 12 mo will be reported in a subsequent publication.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Cazzell et al. (2018)²³; AIPF004		1. Single blinded trial, although outcomes were self-reported by blinded patients		1. Only the first 3 months of 12-month follow-up were reported.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Plantar Fasciitis
The evidence on injection of amniotic membrane for the treatment of plantar fasciitis includes preliminary studies and a larger (N = 145) patient-blinded comparison of micronized injectable-HAM and placebo control. Injection of micronized amniotic membrane resulted in greater improvements in VAS for pain and the Foot Functional Index compared to placebo controls. The primary limitation of the study is this is an interim report of 3 months' results. The authors noted that 12-month follow-up will be reported in a subsequent publication. No additional publications have been identified as of the latest update.

Repair Following Mohs Microscopic Surgery
Clinical Context and Therapy Purpose
The purpose of repair with human amniotic membrane in patients who have undergone Mohs microsurgery for skin cancer is to provide a treatment option that is an alternative to or an improvement on existing procedures.

The question addressed in this evidence review is: Does amniotic membrane improve the net health outcome in patients requiring repair following Mohs microsurgery?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who require reconstruction following Mohs microsurgery for skin cancer on the head, neck, face, or dorsal hand.

Interventions
The therapy being considered is repair following Mohs microsurgery with human amniotic membrane. It is proposed as a nonsurgical alternative to cutaneous repair in cosmetically sensitive areas such as the head, neck, face, or dorsal hand.

Comparators
Comparators of interest include surgical repair using autologous tissue (eg, local flaps and full-thickness skin grafts) and healing without surgery. Second intention healing (i.e., the wound is left open to heal by granulation, contraction, and epithelialization) is a nonsurgical option for certain defects.

Incidence of complete wound closure
Time to complete wound closure (reflecting accelerated wound closure)
Incidence of complete wound closure following surgical wound closure
Pain control

Complete ulcer healing with advanced wound therapies may be measured at 6 to 12 weeks.

In trials comparing human amniotic membrane to surgical repair in patients post-Mohs microscopic surgery, other important outcomes are postprocedure morbidity and mortality, surgical complications, development of a non-healing wound, and quality of life.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Consistent with a "best available evidence approach," within each category of study design, studies with larger sample sizes and longer durations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
No RCTs were identified for this indication.

Nonrandomized Studies
Toman et al. (2022) conducted an observational study that compared repair using a dehydrated human amnion/chorion membrane product (Epifix) with surgical repair using autologous tissue in patients who underwent same-day repair following Mohs microsurgery for removal of skin cancer on the face, head, or neck (Table 14).³⁹ Propensity-score matching using retrospective data from medical records was used to identify 143 matched pairs. The primary endpoint was the incidence of postoperative morbidity, including the rate of infection, bleeding/hematoma, dehiscence, surgical reintervention, or development of a nonhealing wound. Postoperative cosmetic outcomes were assessed at 9 months or later and included documentation of suboptimal scarring, scar revision treatment, and patient satisfaction.

Results are summarized in Table 15, and study limitations in Tables 16 and 17. A greater proportion of patients who received dHACM repair experienced zero complications (97.9% vs. 71.3%; p < .0001; relative risk 13.67; 95% CI 4.33 to 43.12). Placental allograft reconstructions developed less infection (p = .004) and were less likely to experience poor scar cosmesis (P < .0001). Confidence in these findings is limited, however, by the study's retrospective design and potential for bias due to missing data. Additionally, the study's relevance is limited due to a lack of diversity in the study population and no comparison to non-surgical treatment options.

Table 14. Nonrandomized Study of Dehydrated Human Amnion/Chorion Membrane for Repair Following Mohs Microsurgery — Characteristics

Study	Study Type	Country	Dates	Participants	Repair using dHACM	Repair using autologous tissue	Follow-Up
Toman et al. (2022)³⁹	Retrospective, observational Propensity-score matching used to identify matched pairs	U.S.	2014 – 2018	Patients who underwent Mohs microsurgery for removal of a basal or squamous cell carcinoma and required same day repair for moderate- to high-risk defects on the face, head, and neck. Mean age 78.0 years; 76.9% male 100% white	n = 143	n = 143	Unclear; 9 months or later for postoperative cosmetic outcomes.

dHACM: dehydrated human amnionic/chorionic membrane.

Table 15. Nonrandomized Study of Dehydrated Human Amnion/Chorion Membrane for Repair Following Mohs Microsurgery — Results

Study	dHACM repair n = 143	Autogolous tissue Repair n = 143	P
Toman et al. (2022)³⁹
Experienced no complications, n (%)	140 (97.9)	102 (71.3)	< .0001
Infection, n (%)	3 (2.0)	15 (10.0)	.004
Bleeding or hematoma, n (%)	0 (0.0)	7 (5.0)	.015
Wound dehiscence, n (%)	0 (0.0)	4 (3.0)	.122
Surgical reintervention, n (%)	0 (0.0)	11 (8.0)	.0007
Nonhealing wound, n (%)	0 (0.0)	5 (3.5)	.060
Poor scar cosmesis, n (%)	0 (0.0)	21 (15.0)	< .0001
Scar revision, n (%)	0 (0.0)	14 (9.8)	< .0001
Follow-up visits, mean (SD)	3.4 (1.6)	2.5 (1.1)	< .0001
Days to discharge, mean (SD)	30.7 (16.9)	30.3 (22.9)	.840

SD: standard deviation; dHACM: dehydrated human amnionic/chorionic membrane.

Table 16. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Duration of Follow-up^e
Toman et al. (2022)³⁹	4. Study participants were 100% white, over two-thirds male		2. No comparison to non-surgical options (e.g., second intention healing)	1. Not all outcomes mentioned in methods had results reported (e.g., patient satisfaction with scar appearance)

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aPopulation key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4. Enrolled populations do not reflect relevant diversity; 5. Other.
^bIntervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^cComparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^dOutcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 17. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Toman et al. (2022)³⁹	1. Not randomized	1, 2. Not blinded		7. Data extracted from medical records could be incomplete/ inaccurate; 10 of 153 patients excluded because no match identified

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^bBlinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^cSelective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^dData Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^ePower key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^fStatistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Repair Following Mohs Microscopic Surgery
A retrospective observational study found a higher complication-free rate in 143 propensity score-matched pairs of patients who had received autologous tissue or dHACM repair following Mohs microsurgery for skin cancer on the face, head, or neck. This study was limited by its retrospective design. Additional evidence from well-designed and conducted prospective studies is needed.

Summary of Evidence
Diabetic Lower-Extremity Ulcers
For individuals who have non-healing diabetic lower-extremity ulcers who receive a patch or flowable formulation of HAM or placental membrane (i.e., Affinity, AmnioBand Membrane, AmnioExcel, Biovance, EpiCord, EpiFix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The RCTs evaluating amniotic and placental membrane products for the treatment of non-healing (< 20% healing with ≥ 2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM with standard care or with an established advanced wound care product. These trials used wound closure as the primary outcome measure, and some used power analysis, blinded assessment of wound healing, and intention-to-treat analysis. For the HAM products that have been sufficiently evaluated (i.e., Affinity, AmnioBand Membrane, Biovance, EpiCord, EpiFix, Grafix), results have shown improved outcomes compared with standard care, and outcomes that are at least as good as an established advanced wound care product. Improved health outcomes in the RCTs are supported by multicenter registries. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Lower-Extremity Ulcers Due to Venous Insufficiency
For individuals who have lower-extremity ulcers due to venous insufficiency who receive a patch or flowable formulation of HAM, the evidence includes 2 RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The published evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix. One RCT reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and the standard of care. A second RCT evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression, but interpretation is limited by methodologic concerns. Two additional studies with other HAM products have been completed but not published, raising further questions about the efficacy of HAM for venous insufficiency ulcers. Therefore, corroboration with well-designed and well-conducted RCTs evaluating wound healing is needed to demonstrate efficacy for this indication. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Osteoarthritis
For individuals who have knee osteoarthritis who receive an injection of suspension or particulate formulation of HAM or amniotic fluid, the evidence includes a feasibility study. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The pilot study assessed the feasibility of a larger RCT evaluating HAM injection. Additional trials, which will have a larger sample size and longer follow-up, are needed to permit conclusions on the effect of this treatment. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Plantar Fasciitis
The evidence on injection of amniotic membrane for the treatment of plantar fasciitis includes preliminary studies and a larger (N = 145) patient-blinded comparison of micronized injectable-HAM and placebo control. Injection of micronized amniotic membrane resulted in greater improvements in the visual analog score for pain and the Foot Functional Index compared to placebo controls. The primary limitation of the study is that this is an interim report with 12-month results pending. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Repair Following Mohs Micrographic Surgery
For individuals who have undergone Mohs micrographic surgery for skin cancer on the face, head, neck, or dorsal hand who receive human amniotic/chorionic membrane, the evidence includes a nonrandomized, comparative study and no RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. A retrospective analysis using data from medical records compared a dehydrated human amnionic/chorionic membrane product (dHACM, Epifix) to repair using autologous surgery in 143 propensity-score matched pairs of patients requiring same-day reconstruction after Mohs microsurgery for skin cancer on the head, face, or neck. A greater proportion of patients who received dHACM repair experienced zero complications (97.9% vs. 71.3%; p < .0001; relative risk 13.67; 95% CI 4.33 to 43.12). Placental allograft reconstructions developed less infection (p=.004) and were less likely to experience poor scar cosmesis (p < .0001). This study is limited by its retrospective observational design. Well-designed and conducted prospective studies are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2019 Input
Clinical input was sought to help determine whether the use of human amniotic membrane graft either without or with suture fixation for several ophthalmic conditions would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 2 respondents, including 1 specialty society-level response and 1 physician-level response identified through specialty societies including physicians with academic medical center affiliations.

Clinical input supported the use of amniotic membrane in individuals with the following indications:

Neurotrophic keratitis with ocular surface damage and inflammation that does not respond to conservative therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.
Corneal ulcers and melts that do not respond to initial medical therapy. Non-sutured HAM in an office setting would be preferred to avoid a delay in treatment associated with scheduling a surgical treatment.
Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment.
Bullous keratopathy and who are not candidates for curative treatment (e.g., endothelial or penetrating keratoplasty) as an alternative to stromal puncture.
Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient.
Persistent epithelial defects and ulcerations that do not respond to conservative therapy.
Severe dry eye with ocular surface damage and inflammation that does not respond to conservative therapy.
Moderate or severe acute ocular chemical burn.
Corneal perforation when corneal tissue is not immediately available.
Pterygium repair when there is insufficient healthy tissue to create a conjunctival autograft.

Further details from clinical input are included in the appendix.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Society for Vascular Surgery et al.
In 2016, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine made the following recommendation: "For DFUs [diabetic foot ulcers] that fail to demonstrate improvement (> 50% wound area reduction) after a minimum of 4 weeks of standard wound therapy, we recommend adjunctive wound therapy options. These include negative pressure therapy, biologics (platelet-derived growth factor [PDGF], living cellular therapy, extracellular matrix products, amnionic membrane products), and hyperbaric oxygen therapy. Choice of adjuvant therapy is based on clinical findings, availability of therapy, and cost-effectiveness; there is no recommendation on ordering of therapy choice."⁴⁰

Wound Healing Society
In 2016, the Wound Healing Society updated their guidelines on diabetic foot ulcer treatment.⁴¹ The Society concluded that there was level 1 evidence that cellular and acellular skin equivalents improve diabetic foot ulcer healing, noting that, “healthy living skin cells assist in healing DFUs [diabetic foot ulcers] by releasing therapeutic amounts of growth factors, cytokines, and other proteins that stimulate the wound bed.” References from 2 randomized controlled trials on amniotic membrane were included with references on living and acellular bioengineered skin substitutes.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 18.

Table 18. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04457752^a	A Randomised Controlled Multicentre Clinical Trial, Evaluating the Efficacy of Dual Layer Amniotic Membrane (Artacent^®) and Standard of Care Versus Standard of Care Alone in the Healing of Chronic Diabetic Foot Ulcers	124	Dec 2022
NCT03390920^a	Evaluation of Outcomes With Amniotic Fluid for Musculoskeletal Conditions	200	Jun 2030
NCT04612023	A Prospective, Double-Blinded, Randomized Controlled Trial of an Amniotic Membrane Allograft Injection Comparing Two Doses (1 mL and 2 mL Injection) and a Placebo (Sterile Saline) in the Treatment of Osteoarthritis of the Knee	90	Jul 2022
NCT04553432^a	Dry Eye OmniLenz Application of Omnigen Research Study	70	Jul 2022
NCT04599673	Prospective Analysis of Intraoperative AMNIOGEN^® Injection in Patients With Rotator Cuff Tear	100	Sep 2022
NCT04636229^a	A Phase 3 Prospective, Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy of Amniotic Suspension Allograft (ASA) in Patients With Osteoarthritis of the Knee	474	Dec 2023
NCT03864939	Randomized Pilot Study to Improve Postprostatectomy Incontinence and Potency by Application of Dried Human Amnion Graft	328	Apr 2025
NCT03855514^a	A Prospective, Multicenter, Randomized, Controlled Clinical Study Of NuShield^® and Standard of Care (SOC) Compared to SOC Alone For The Management Of Diabetic Foot Ulcers	200	Dec 2021
Unpublished
NCT02609594^a	A Multi-center Randomized Controlled Clinical Trial Evaluating Two Application Regimens of Amnioband Human Amniotic Membrane and Standard of Care vs. Standard of Care Alone in the Treatment of Venous Leg Ulcers	240	Dec 2018 (status unknown)
NCT02838784^a	The Efficacy and Safety of Artacent™ for Treatment Resistant Lower Extremity Venous and Diabetic Ulcers: A Prospective Randomized Study	134	Dec 2018 (status unknown)
NCT03441607^a	Safety & Efficacy of Micronized Human Amnion Chorion Membrane Biologic (mHACMb) FloGraft (Micronized Human Amnion Chorion Membrane)^® in Adults With Pain Due to Osteoarthritis of the Knee	320	Mar 2019 (status unknown)
NCT02318511^a	An Investigation of ReNu™ Knee Injection: Monitoring the Response of Knee Function and Pain in Patients With Osteoarthritis	200	Feb 2019 (completed)
NCT03379324^a	A Prospective, Randomized Study Comparing Outcomes Following Arthroscopic Double-row Rotator Cuff Repair With and Without the Addition of a Cryopreserved, Liquid, Injectable Amnion Allograft	260	Sep 2019 (status unknown)
NCT03414268^a	A Phase 3, Prospective, Double-Blinded, Randomized Controlled Trial of the Micronized dHACM Injection As Compared To Saline Placebo Injection In The Treatment Of Plantar Fasciitis	276	Apr 2021 (active, not recruiting)
NCT02982226^a	A Comparative Study of Injectable Human Amniotic Allograft (ReNu™) Versus Corticosteroids for Plantar Fasciitis: A Prospective, Randomized, Blinded Study	150	Apr 2021 (active, not recruiting)
NCT03414255^a	A Phase 3, Prospective, Double-Blinded, Randomized Controlled Trial Of The Micronized dHACM Injection As Compared To Saline Placebo Injection In The Treatment Of Achilles Tendonitis	158	May 2021 (active, not recruiting)
NCT03485157^a	A Phase 2B, Prospective, Double-blinded, Randomized Controlled Trial of the Micronized Human Amnion Chorion Membrane Injection as Compared to Saline Placebo Injection in the Treatment of Osteoarthritis of the Knee	466	Oct 2021

NCT: national clinical trial.
^aDenotes industry-sponsored or cosponsored trial.

References

Parolini O, Soncini M, Evangelista M, et al. Amniotic membrane and amniotic fluid-derived cells: potential tools for regenerative medicine?. Regen Med. Mar 2009; 4(2): 275-91. PMID 19317646
Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. Oct 2013; 10(5): 493-500. PMID 23902526
Shimberg M, Wadsworth K. The use of amniotic-fluid concentrate in orthopaedic conditions. J Bone Joint Surg. 1938;20(I):167-177.
U.S. Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff. 2017 https://www.regulations.gov/document?D=FDA-2017-D-6146-0003 Accessed January 10, 2022
Food and Drug Administration. 510(k) Summary: ProKeraTM Bio-Tissue Inc. (K032104). 2003; https://www.accessdata.fda.gov/cdrh_docs/pdf3/K032104.pdf. Accessed January 10, 2022.
Serena TE, Yaakov R, Moore S, et al. A randomized controlled clinical trial of a hypothermically stored amniotic membrane for use in diabetic foot ulcers. J Comp Eff Res. Jan 2020; 9(1): 23-34. PMID 31691579
Ananian CE, Dhillon YS, Van Gils CC, et al. A multicenter, randomized, single-blind trial comparing the efficacy of viable cryopreserved placental membrane to human fibroblast-derived dermal substitute for the treatment of chronic diabetic foot ulcers. Wound Repair Regen. May 2018; 26(3): 274-283. PMID 30098272
Tettelbach W, Cazzell S, Sigal F, et al. A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. Int Wound J. Feb 2019; 16(1): 122-130. PMID 30246926
DiDomenico LA, Orgill DP, Galiano RD, et al. Use of an aseptically processed, dehydrated human amnion and chorion membrane improves likelihood and rate of healing in chronic diabetic foot ulcers: A prospective, randomised, multi-centre clinical trial in 80 patients. Int Wound J. Dec 2018; 15(6): 950-957. PMID 30019528
Snyder RJ, Shimozaki K, Tallis A, et al. A Prospective, Randomized, Multicenter, Controlled Evaluation of the Use of Dehydrated Amniotic Membrane Allograft Compared to Standard of Care for the Closure of Chronic Diabetic Foot Ulcer. Wounds. Mar 2016; 28(3): 70-7. PMID 26978860
Zelen CM, Gould L, Serena TE, et al. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. Dec 2015; 12(6): 724-32. PMID 25424146
Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J. Apr 2016; 13(2): 272-82. PMID 26695998
Tettelbach W, Cazzell S, Reyzelman AM, et al. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics. Int Wound J. Feb 2019; 16(1): 19-29. PMID 30136445
Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. Oct 2014; 11(5): 554-60. PMID 25048468
Smiell JM, Treadwell T, Hahn HD, et al. Real-world Experience With a Decellularized Dehydrated Human Amniotic Membrane Allograft. Wounds. Jun 2015; 27(6): 158-69. PMID 26061491
Frykberg RG, Gibbons GW, Walters JL, et al. A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane. Int Wound J. Jun 2017; 14(3): 569-577. PMID 27489115
Serena TE, Carter MJ, Le LT, et al. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. Nov-Dec 2014; 22(6): 688-93. PMID 25224019
Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix (R) ) allograft for the treatment of venous leg ulcers. Int Wound J. Feb 2018; 15(1): 114-122. PMID 29024419
Bianchi C, Tettelbach W, Istwan N, et al. Variations in study outcomes relative to intention-to-treat and per-protocol data analysis techniques in the evaluation of efficacy for treatment of venous leg ulcers with dehydrated human amnion/chorion membrane allograft. Int Wound J. Jun 2019; 16(3): 761-767. PMID 30864259
Vines JB, Aliprantis AO, Gomoll AH, et al. Cryopreserved Amniotic Suspension for the Treatment of Knee Osteoarthritis. J Knee Surg. Aug 2016; 29(6): 443-50. PMID 26683979
Tsikopoulos K, Vasiliadis HS, Mavridis D. Injection therapies for plantar fasciopathy ('plantar fasciitis'): a systematic review and network meta-analysis of 22 randomised controlled trials. Br J Sports Med. Nov 2016; 50(22): 1367-1375. PMID 27143138
Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis--a feasibility study. Foot Ankle Int. Oct 2013; 34(10): 1332-9. PMID 23945520
Cazzell S, Stewart J, Agnew PS, et al. Randomized Controlled Trial of Micronized Dehydrated Human Amnion/Chorion Membrane (dHACM) Injection Compared to Placebo for the Treatment of Plantar Fasciitis. Foot Ankle Int. Oct 2018; 39(10): 1151-1161. PMID 30058377
Suri K, Kosker M, Raber IM, et al. Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. Eye Contact Lens. Sep 2013; 39(5): 341-7. PMID 23945524
Liu J, Li L, Li X. Effectiveness of Cryopreserved Amniotic Membrane Transplantation in Corneal Ulceration: A Meta-Analysis. Cornea. Apr 2019; 38(4): 454-462. PMID 30702468
Yin HY, Cheng AMS, Tighe S, et al. Self-retained cryopreserved amniotic membrane for treating severe corneal ulcers: a comparative, retrospective control study. Sci Rep. Oct 12 2020; 10(1): 17008. PMID 33046729
Paris Fdos S, Goncalves ED, Campos MS, et al. Amniotic membrane transplantation versus anterior stromal puncture in bullous keratopathy: a comparative study. Br J Ophthalmol. Aug 2013; 97(8): 980-4. PMID 23723410
Kheirkhah A, Casas V, Raju VK, et al. Sutureless amniotic membrane transplantation for partial limbal stem cell deficiency. Am J Ophthalmol. May 2008; 145(5): 787-94. PMID 18329626
Pachigolla G, Prasher P, Di Pascuale MA, et al. Evaluation of the role of ProKera in the management of ocular surface and orbital disorders. Eye Contact Lens. Jul 2009; 35(4): 172-5. PMID 19474753
Sharma N, Thenarasun SA, Kaur M, et al. Adjuvant Role of Amniotic Membrane Transplantation in Acute Ocular Stevens-Johnson Syndrome: A Randomized Control Trial. Ophthalmology. Mar 2016; 123(3): 484-91. PMID 26686968
Bouchard CS, John T. Amniotic membrane transplantation in the management of severe ocular surface disease: indications and outcomes. Ocul Surf. Jul 2004; 2(3): 201-11. PMID 17216092
John T, Tighe S, Sheha H, et al. Corneal Nerve Regeneration after Self-Retained Cryopreserved Amniotic Membrane in Dry Eye Disease. J Ophthalmol. 2017; 2017: 6404918. PMID 28894606
McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018; 12: 677-681. PMID 29670328
Tandon R, Gupta N, Kalaivani M, et al. Amniotic membrane transplantation as an adjunct to medical therapy in acute ocular burns. Br J Ophthalmol. Feb 2011; 95(2): 199-204. PMID 20675729
Eslani M, Baradaran-Rafii A, Cheung AY, et al. Amniotic Membrane Transplantation in Acute Severe Ocular Chemical Injury: A Randomized Clinical Trial. Am J Ophthalmol. Mar 2019; 199: 209-215. PMID 30419194
Tamhane A, Vajpayee RB, Biswas NR, et al. Evaluation of amniotic membrane transplantation as an adjunct to medical therapy as compared with medical therapy alone in acute ocular burns. Ophthalmology. Nov 2005; 112(11): 1963-9. PMID 16198422
Kaufman SC, Jacobs DS, Lee WB, et al. Options and adjuvants in surgery for pterygium: a report by the American Academy of Ophthalmology. Ophthalmology. Jan 2013; 120(1): 201-8. PMID 23062647
Clearfield E, Muthappan V, Wang X, et al. Conjunctival autograft for pterygium. Cochrane Database Syst Rev. Feb 11 2016; 2: CD011349. PMID 26867004
Toman J, Michael GM, Wisco OJ, et al. Mohs Defect Repair with Dehydrated Human Amnion/Chorion Membrane. Facial Plast Surg Aesthet Med. Jan-Feb 2022; 24(1): 48-53. PMID 34714143
Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. Feb 2016; 63(2 Suppl): 3S-21S. PMID 26804367
Lavery LA, Davis KE, Berriman SJ, et al. WHS guidelines update: Diabetic foot ulcer treatment guidelines. Wound Repair Regen. Jan-Feb 2016; 24(1): 112-26. PMID 26663430

Coding Section

Codes	Number	Description
CPT		No code
HCPCS	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
	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
	Q4151	AmnioBand or Guardian, per square centimeter
	Q4153	Dermavest and Plurivest, per square centimeter
	Q4154	Biovance, per square centimeter
	Q4155	Neoxflo or Clarixflo, 1 mg
	Q4156	NEOX 100 or CLARIX 100, per square centimeter
	Q4157	Revitalon, per square centimeter
	Q4159	Affinity, per square centimeter
	Q4160	NuShield, per square centimeter
	Q4162	WoundEx Flow, BioSkin Flow, 0.5 cc
	Q4163	WoundEx, BioSkin, per square centimeter
	Q4168	Amnioband, 1 mg
	Q4169	Artacent wound, per square centimeter
	Q4170	Cygnus, per square centimeter
	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 (revised 7/1/2020)
	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
	Q4184	Cellesta or cellesta duo, per square centimeter
	Q4185	Cellesta flowable amnion (25 mg per cc); per 0.5 cc
	Q4186	Epifix, per square centimeter
	Q4187	Epicord, per square centimeter
	Q4188	Amnioarmor, per square centimeter
	Q4189	Artacent ac, 1 mg
	Q4190	Artacent ac, per square centimeter
	Q4191	Restorigin, per square centimeter
	Q4192	Restorigin, 1 cc
	Q4194	Novachor, per square centimeter
	Q4198	Genesis amniotic membrane, per square centimeter
	Q4201	Matrion, per square centimeter
	Q4204	Xwrap, per square centimeter
	Q4205	Membrane graft or membrane wrap, per square centimeter
	Q4206	Fluid flow or fluid GF, 1 cc
	Q4208	Novafix, per square cenitmeter
	Q4209	Surgraft, per square centimeter )
	Q4210	Axolotl graft or axolotl dualgraft, per square centimeter
	Q4211	Amnion bio or Axobiomembrane, per square centimeter
	Q4212	Allogen, per cc
	Q4213	Ascent, 0.5 mg
	Q4214	Cellesta cord, per square centimeter
	Q4215	Axolotl ambient or axolotl cryo, 0.1 mg
	Q4216	Artacent cord, per square centimeter
	Q4217	Woundfix, BioWound, Woundfix Plus, BioWound Plus, Woundfix Xplus or BioWound Xplus, per square centimeter
	Q4218	Surgicord, per square centimeter
	Q4219	Surgigraft-dual, per square centimeter
	Q4220	BellaCell HD or Surederm, per square centimeter
	Q4221	Amniowrap2, per square centimeter
	Q4227	Amniocore, per square centimeter (new eff 7/1/20)
	Q4228	BioNextPATCH, per square centimeter (new eff 7/1/20)
	Q4229	Cogenex amniotic membrane, per square centimeter (new eff 7/1/20)
	Q4230	Cogenex flowable amnion, per 0.5 cc (new eff 7/1/20)
	Q4231	Corplex P, per cc (new eff 7/1/20)
	Q4232	Corplex, per square centimeter (new eff 7/1/20)
	Q4233	Surfactor or Nudyn, per 0.5 cc (new eff 7/1/20)
	Q4234	Xcellerate, per square centimeter (new eff 7/1/20)
	Q4235	Amniorepair or altiply, per square centimeter (new eff 7/1/20)
	Q4236	carePATCH, per square centimeter (new eff 7/1/20)
	Q4237	Cryo-cord, per square centimeter (new eff 7/1/20)
	Q4238	Derm-maxx, per square centimeter (new eff 7/1/20)
	Q4239	Amnio-maxx or Amnio-maxx lite, per square centimeter (new eff 7/1/20)
	Q4240	Corecyte, for topical use only, per 0.5 cc (new eff 7/1/20)
	Q4241	Polycyte, for topical use only, per 0.5 cc (new eff 7/1/20)
	Q4242	Amniocyte plus, per 0.5 cc (new eff 7/1/20)
	Q4244	Procenta, per 200 mg (new eff 7/1/20)
	Q4245	Amniotext, per cc (new eff 7/1/20)
	Q4246	Coretext or Protext, per cc (new eff 7/1/20)
	Q4247	Amniotext patch, per square centimeter (new eff 7/1/20)
	Q4248	Dermacyte Amniotic Membrane Allograft, per square centimeter (new eff 7/1/20)
	Q4249	Amniply, for topical use only, per square centimeter (eff 10/01/2020)
	Q4250	Amnioamp-mp, per square centimeter (eff 10/01/2020
	Q4251 (effecitve 10/01/2021)	Vim, per square centimeter
	Q4252 (effecitve 10/01/2021)	Vendaje, per square centimeter
	Q4253 (effecitve 10/01/2021)	Zenith amniotic membrane, per square centimeter
	Q4254	Novafix dl, per square centimeter (eff 10/01/2020)
	Q4255	Reguard, for topical use only, per square centimeter (eff 10/01/2020)
ICD-10-CM	E08.621-E08.622; E09.621-E09.622; E10.621-E10.622; E11.621-E11.622: E13.621-E13.622	Diabetes codes with foot ulcer or other skin ulcer
	H04.121-H04.129	Dry eye syndrome code range
	H11.001-H11.069	Pterygium of eye code range
	H16.001-H16.079	Corneal ulcer code range (includes perforation)
	H16.231-H16.239	Neurotrophic keratoconjunctivitis code range
	H18.10-H18.13	Bullous Keratopathy code range
	H18.30	Unspecified corneal membrane change (includes epithelial)
	H18.52	Epithelial (juvenile) corneal dystrophy
	H18.59	Other hereditary corneal dystrophies
	H18.831-H18.839	Recurrent erosion of cornea code range
	H18.891-H18.899	Other specified disorders of the cornea code range (includes limbal stem cell deficiency)
	I87.2	Venous insufficiency
	L51.1	Stevens-Johnson syndrome
	M17.10-M17.9	Osteoarthritis of the knee code range
	M72.2	Plantar fasciitis
	T26.10-T26.12	Burn of cornea and conjunctival sac code range
	T26.50-T26.52	Corrosion of cornea and conjunctival sac code rang
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
Type of service	Medicine
Place of service	Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

History From 2015 Forward

03/06/2023	Annual review, no change to policy intent. Updating policy, guidelines and background to update with current products on market.
03/08/2022	Annual review, adding policy statement regarding Mohs procedure. Also updating description, guidelines, rationale and references.
01/01/2022	Interim review to add Neox100 and Neox 1k as supported products for diabetic foot ulcer care.
10/20/2021	Updating coding section adding codes Q4251, Q4252, Q4253 effective 10/01/2021. No other changes made.
03/02/2021	Annual review, no change to policy intent. Updating description, regulatory status, guidelines, rationale, references and coding.
11/06/2020	Interim review to remove different policy guidelines related to sutured vs non sutured use of this technology. Also removing verbiage for ocular conditions and directing readers to CAM 047 for ocular uses. Updating title. No other changes made.
03/04/2019	Annual review, no change to policy intent. Updating regulatory status.
03/28/2018	Annual review, policy verbiage updated to include specific investigational items. Also updating background, description, guidelines, rationale, references and coding.
03/09/2017	Interim review, moving coverage criteria for patch formulations of amniotic membrane from policy 701113 to this policy. Updating background, description, policy , guidelines, regulatory status, rationale and references.
07/12/2016	Annual review, no change to policy intent. Updating background, description, guidelines, rationale, references and coding.
07/21/2015	NEW POLICY

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Amniotic Membrane and Amniotic Fluid Injections for Non-Ophthalmic Applications - CAM 701149

Table PG1 Amniotic Products Listed in the Policy Statements