BlueCross BlueShield of Tennessee Medical Policy Manual

Human Amniotic Membrane Grafts and Amniotic Fluid Injections


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.





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

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. (3:2021) Amniotic membrane and amniotic fluid (7.01.149). Retrieved March 4, 2021 from  (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

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

Tear Film and Ocular Surface Society. (2017, May). TFOS DEWS II management and therapy report. Retrieved March 6, 2019 from 

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

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 (41 articles and/or guidelines reviewed)

Wound Healing Society. (2016). WHS guidelines update: diabetic foot ulcer treatment guidelines. Retrieved March 5, 2021 from

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)




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