Several commercially available forms of human amniotic membrane (HAM) and amniotic fluid can be administered by grafts, topical application or injection. There are many products available using amnion, chorion, amniotic fluid, and umbilical cord that 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 surface disorders.
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, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated.
HAM grafts used for certain ocular surface disorders (e.g., AmnioGraft®) have been shown to be effective in promoting healing. Traditionally they have been fixated with sutures or glue or secured under a bandage contact lens. Self-contained or ringed devices (e.g. AmbioDisk™, ProKera®) with no sutures, glue, or bandage lens needed allow for application in an office setting rather than as an outpatient.
Amniotic fluid injections have been proposed as treatment for certain orthopedic uses (e.g. osteoarthritis, plantar fasciitis. When administered by injection. (e.g., AmnioMatrix®, Clarix® Flo) human amniotic tissue is micronized, or reduced in particle size to a form that can be suspended in liquid. HAM injections are being evaluated for the treatment of a variety of conditions, including tendonitis, plantar fasciitis, cartilage damage, and for alleviation of pain and stiffness in individuals with osteoarthritis.Note: This policy addresses human amniotic/chorionic membrane products and amniotic fluid products only, for other bioengineered skin and soft tissue products please refer to the Bioengineered Skin and Soft Tissue Substitutes medical policy.
Human amniotic membrane grafts for the treatment of lower-extremity diabetic skin ulcers are considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Human amniotic membrane grafts (e.g. AmnioGraft®, ProKera®, AmbioDisk™) for the treatment of certain ophthalmic indications are considered medically necessary if the medical appropriateness criteria are met (See Medical Appropriateness below.)
amniotic membrane grafts, for the treatment of all other ophthalmic
conditions/diseases is considered investigational,
Injection of micronized or particulated human amniotic membrane fluid and/or amniotic fluid for the treatment of all conditions/diseases, including but not limited to treatment of osteoarthritis and plantar fasciitis, is considered investigational.
Human amniotic membrane grafts are considered medically appropriate if ANY ONE of the following criteria is met:
For the treatment of non-healing (less than a 20% decrease in wound area after 2 weeks of standard care) diabetic lower-extremity skin ulcers if ANY ONE of the following products are used:
GrafixCore™ (Grafix® PL Core)
GrafixPrime™ (Grafix ® PL Prime)
For the treatment of ophthalmic conditions with suture, glue, or bandage contact lens (e.g., AmbioGraft®) for ANY ONE of the following:
Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment
Pterygium (i.e., ‘surfers eye’ is a pinkish, triangular tissue growth on the cornea) repair
For the treatment of ophthalmic conditions with or without suture or glue (e.g., AmbioGraft®, ProKera®, AmbioDisk™) for ANY ONE of the following:
Neurotrophic keratitis (degenerative disease of the cornea caused by damage of the trigeminal nerve) that has not responded to conservative therapy (e.g., pressure patching, therapeutic contact lens, topical lubricants, or topical antibiotics)
Corneal ulcers (open sore on the cornea, usually as the result of an infection) that have not responded to conservative therapy (e.g., patching, therapeutic contact lens, or topical antimicrobial agents)
Corneal perforation when there is active inflammation after corneal transplant requiring adjunctive treatment
Corneal epithelial defects (e.g. mechanical trauma, ultraviolet burns, systemic disorders leading to corneal dryness, Limbal stem cell deficiency, neurotrophic diseases causing incomplete lid closure) that have ANY ONE of the following:
Failed to decrease in size after two (2) days of conservative treatment
Failed to close completely after five (5) days of conservative treatment (conservative treatment includes at least one of the following: topical lubricants, topical antibiotics, therapeutic contact lens, or patching)
Bullous keratopathy as a palliative measure in individuals who are not candidates for curative treatment (e.g., endothelial or penetrating keratoplasty)
Partial limbal stem cell deficiency with extensive diseased tissue where selective removal alone is not sufficient
Keratolysis or corneal melts (sterile melting of the cornea, may occur following cataract extraction)
Stevens-Johnson syndrome (severe skin reaction to certain medications)
Moderate or severe acute ocular chemical burn
Severe dry eye with ocular surface damage and inflammation that remains symptomatic after treatment with ONE or MORE of the following:
Warm compresses on the lids
Ocular lubricants and/or ointments
Prescription drugs to manage dry eye disease (such as topical antibiotics, topical corticosteroids, topical secretagogues, oral secretagogues, oral macrolide or tetracycline antibiotics
Therapeutic contact lens, either soft or rigid
Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.
Literature on human amniotic membrane injection for regenerative medicine is at a very early stage. Additional studies with larger sample sizes and longer follow-up are needed to permit conclusions. Therefore, this technology remains investigational for applications other than lower extremity diabetic skin ulcers and certain surface ocular disorders.
Agency for Healthcare Research and Quality (AHRQ). (2020, February). Skin substitutes for treating chronic wounds. Retrieved March 23, 2020 from http://www.ahrq.gov.
Bianchi, C., Cazzell, S., Vayser, D., Reyzelman, A.M., Dosluoglu, H., Tovmassian, G., et al. (2018). A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix®) allograft for the treatment of venous leg ulcers. International Wound Journal, 15 (1), 114-122. (Level 1 evidence)
BlueCross BlueShield Association. Evidence Positioning System. (6:2020) Amniotic membrane and amniotic fluid (7.01.149). Retrieved January 22, 2021 from http://www.evidencepositioningsystem.com. (91 articles and/or guidelines reviewed)
Cheng, A., Zhao, D., Chen, R., Yin, Han., Tighe, S., et al. (2016). Accelerated restoration of ocular surface health in dry eye disease by self-retained cryopreserved amniotic membrane. Ocular Surface, 14 (1), 56–63. (Level 4 evidence)
Farr, J. & Cohen, S. (2016). Subchondroplasty® as an emerging treatment option for sports-related subchondiral stress fractures. ASPETAR: Sports Medicine Journal, Vol. 5, page 284-291. (Level 4 evidence)
Fonseca, EC., Rocha, EM., & Arruda, GV. (2018). Comparison among adjuvant treatments for primary pterygium: A network meta-analysis. A British Journal of Ophthalmology, 102 (6), 748-756. Abstract retrieved March 23, 2020 from PubMed database.
Frykberg, R., Gibbons, G., Walters, J., Wukich, D., & Milstein, F. (2016) 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. International Wound Journal, ISSN 1742-4801. (Level 2 evidence)
Gheorghe, A., Pop, M., Burcea, M., & Serban, M. (2015). New clinical application of amniotic membrane transplant for ocular surface disease. Journal of Medicine and Life, 9 (2), 177-179. (Level 5 evidence)
Hanselman, A., Tidwell, J. & Santrock, R. (2015). Cryopreserved Human Amniotic Membrane Injection for Plantar Fasciitis: A Randomized, Controlled, Double-Blind Pilot Study. Foot & Ankle International, 36 (2), 151-158. (Level 2 evidence)
Hirche, C., Senghaas, A., Fischer, S., Hollenbeck, S., Kremer, T. & Kneser, U. (2016). Novel use of a flowable collagen-glycosaminoglycan matrix (Integra™ Flowable Wound Matrix) combined with percutaneous cannula scar tissue release in treatment of postburn malfunction of the hand--A preliminary 6 month follow-up. Burns, 42 (1), 1-7. Abstract retrieved March 15, 2018 from PubMed database.
Johnson, E., Marshall, J., & Michael, G. (2016). A comparative outcomes analysis evaluating clinical effectiveness in two different human placental membrane products for wound management. Wound Repair and Regeneration, e-published DOI:10.1111/wrr.12503. (Level 3 evidence)
Lavery, L., Fulmer, J., Shebetka, K., Regulski, M., Vayser, D., Fried, D, et al. (2014). The efficacy and safety of Grafix® for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. International Wound Journal, ISSN 1742-4801. (Level 2 evidence)
Liu, J., Li, l. & Li, X. (2019). Effectiveness of cryopreserved amniotic membrane transplantation in corneal ulceration: a meta-analysis. Cornea, [e-published ahead of print] doi: 10.1097/ICO. Abstract retrieved March 5, 2019 from PubMed database.
McGaughy, A., Gupta, P., Fekrat, S. & Scott, I. (2015). In office use of amniotic membrane.Eyenet. 31-32. (Level 5 evidence)
National Institute for Health and Clinical Excellence (NICE). (2019, October). Diabetic foot problems: prevention and management. Retrieved March 23, 2020 from http://www.nice.org.uk.
Serena, T., Carter, M., Lam, T., Sabo, M., & DiMarco, D. (2014). 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 and Regeneration, 22, 688-692. (Level 2 evidence)
Serena, T., Yaakov, R., Moore, S., Cole, W., Coe, S., Snyder, R., et al (2019). A randomized controlled clinical trial of a hypothermically stored amniotic membrane for use in diabetic foot ulcers. Journal of Comparative Effectiveness Research, 9 (1), 23-24. (Level 2 evidence)
Smiell, J., Treadwell, T., Hahn, H., & Hermans, M. (2015). Real-world experience with a decellularized dehydrated human amniotic membrane allograft. Wounds, 27 (6), 158-69. Abstract retrieved April 4, 2018 from PubMed database.
Society of Vascular Surgery. (2016, February). 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. Retrieved January 25, 2021 from https://vascular.org.
Tear Film and Ocular Surface Society. (2017, May). TFOS DEWS II management and therapy report. Retrieved March 6, 2019 from www.theocularsurface.com.
U. S. Food and Drug Administration. (2003, December). Center for Devices and Radiologic Health. 510(k) Premarket Notification Database. K032104 (ProKera™). Retrieved May 23, 2017 from http://www.fda.gov.
Vines, J. B., Aliprantis, A. O., Gomoll, A. H., & Farr, J. (2015). Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. Journal of Knee Surgery, 2015, Dec 18, [E-pub ahead of print]. Abstract retrieved June 28, 2016 from PubMed database.
Winifred S. Hayes, Inc. Medical Technology Assessment. (2019, September; last update search December 2020). Grafix cryopreserved placental membrane (Osiris Technologies Inc.) for treatment of chronic foot ulcers in patients with Diabetes Mellitus. Retrieved January 22, 2021 from www.Hayesinc.com/subscribers. (41 articles and/or guidelines reviewed)
Zelen, C. M., Gould, L., Serena, T., Carter, M., Keller, J. & Li, W. (2014). 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. International Wound Journal, ISSN 1742-4801. (Level 2 evidence)
ORIGINAL EFFECTIVE DATE: 12/12/2015
MOST RECENT REVIEW DATE: 3/11/2021
Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.
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