7.01.583 Amniotic Membrane and Amniotic Fluid

1 MEDICAL POLICY Amniotic Membrane and Amniotic Fluid BCBSA Ref. Policy: Effective Date: May 1, 2022 Last Revised: Jan. 1, 2023 Replaces: N/A RELATED MEDICAL POLICIES: Recombinant and Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions Bioengineered Skin and Soft Tissue Substitutes Orthopedic Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used with Autologous Bone Marrow) Select a hyperlink below to be directed to that section. POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY Clicking this icon returns you to the hyperlinks menu above. Introduction The Amniotic Membrane and Amniotic Fluid are structures that surround the fetus in the uterus (womb). The Fluid protects the fetus from injury. The Membrane is a thin mesh of protein and contains growth factors, stem cells, and other items crucial to a developing fetus.

2 Processing and then using the Amniotic Membrane and/or Fluid (after delivery), has been proposed to treat a number of conditions in adults. High quality medical studies show that using specific Amniotic Membrane products may be useful for treating diabetic ulcers in some cases, for specific eye conditions, and for a disorder known as Stevens-Johnson syndrome. This policy describes when these products may be considered medically necessary. Using Amniotic Membrane for other conditions or using Amniotic Fluid products is considered unproven (investigational). Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab.

3 This policy informs them about when a service may be covered. (01-01-2023) Page | 2 of 23 Policy Coverage Criteria Service Medical Necessity Treatment of nonhealing diabetic lower-extremity ulcers Treatment of nonhealing* diabetic lower-extremity ulcers using the following human Amniotic Membrane products may be considered medically necessary: Affinity AmnioBand Membrane Biovance EpiCord Epifix Grafix *Note: Nonhealing 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 ( , Zelen et al, 2015). When the above medical necessity criteria are met, the following conditions of coverage will apply: Treatment is limited to a maximum of 6 applications in 12 weeks when evidence of wound healing is present Graft applications that exceed what is reasonable and necessary as size-appropriate based on the size of the wound are considered not medically necessary (see Related Information).

4 Additional applications beyond 12 weeks are considered not medically necessary regardless of wound status. Human Amniotic Membrane grafts for ophthalmic indications Human Amniotic Membrane grafts with or without suture (Prokera , AmbioDisk ) or glue may be considered medically necessary for the treatment of ophthalmic conditions. Service Investigational Injection of micronized or particulated human Amniotic Membrane Injection of micronized or particulated human Amniotic Membrane is considered investigational for all indications, including but not limited to treatment of: Page | 3 of 23 Service Investigational osteoarthritis plantar fasciitis Injection of human Amniotic Fluid Injection of human Amniotic Fluid is considered investigational for all indications. All other human Amniotic products All other human Amniotic products ( , derived from amnion, chorion, Amniotic Fluid , umbilical cord, or Wharton s jelly) not listed above are considered investigational Other indications All other indications not listed above are considered investigational, including but not limited to treatment of lower extremity ulcers due to venous insufficiency and repair following Mohs micrographic surgery.

5 Investigational All other human Amniotic Membrane products not listed above are considered investigational, including but not limited to: AlloGen liquid AlloWrap DS or dry AltiPly AmnioAMP-MP Amnioarmor AmnioBand Particulate AmnioBind Amniocore Amniocyte Amniocyte plus Amnioexcel Amnioexcel plus AmnioFix Amnio-maxx Amnio-maxx lite AmnioMatrix injectable Amnion Bio Amniorepair Amniotext Amniotext patch Amnio Wound Amnio Wrap2 Amniply carePATCH celera Dual Membrane celera Dual Layer Cellesta Cellesta Cord Cellesta Duo Cellesta flowable amnion injectable Clarix 100 Clarix Cord 1K ClarixFlo Cogenex flowable amnion Cogenex Amniotic Membrane Corecyte Corplex Corplex P Coretext Cryo-cord cygnus cygnus Matrix Dermacyte Dermavest Novachor Novafix Novafix DL Nudyn NuShield PalinGen Membrane PalinGen XPlus PalinGen SportFlow Plurivest ProMatrX liquid Polycyte Procenta Protext Reguard Relese Restorigin Restorigin Injectable

6 Revita Revitalon Signature APatch Surfactor Surgenex, Page | 4 of 23 Artacent AC (flowable) Artacent AC (patch) Artacent Cord Artacent Wound Ascent Axobiomembrane Axolotl Ambient Axolotl Cryo Axolotl DualGraft Axolotl Graft Biodexcel BioDFence BioDFence DryFlex BioDMatrix injectable BioNext PATCH BioSkin BioSkin Flow BioWound BioWound Plus BioWound Xplus Derm-maxx Enverse Epifix Injectable FlowerAmnioFlo (liquid) FlowerAmnioPatch Fluid Flow liquid Fluid GF liquid Genesis Amniotic Membrane Human Health Factor 10 Amniotic patch (hhf10-p), per square centimeter InnovaMatrix Advanced Care Interfyl Keroxx Matrion Membrane Graft Membrane Wrap MLG-CompleteTM NeoPatch Neox 100 Neox Cord 1k Neox Cord-RT Neox Flo Neox Wound SurgiCORD SurGraft SurgiGRAFT SurgiGRAFT -DUAL Therion TAG Vendaje Vim WoundEx WoundEx Flow WoundFix WoundFix Plus WoundFix Xplus Xcellerate Xwrap Zenith Note: HRT: Human Regenerative Technologies; MTF Musculoskeletal Transplant Foundation a Processed by HRT and marketed under different tradename Documentation Requirements The patient s medical records submitted for review should document that medical necessity criteria are met.

7 The record should include clinical documentation of: Diagnosis/condition History and physical examination documenting the severity of the condition Name of product to be used Previous therapy attempted and for how long The size (measurements) of the affected area to be treated Coding Page | 5 of 23 Code Description HCPCS Reviewed for Medical Necessity Q4132 Grafix Core and GrafixPL Core, per sq cm Q4133 Grafix PRIME, GrafixPL PRIME, Stravix and StravixPL, per square centimeter Q4151 AmnioBand or Guardian, per sq cm Q4154 Biovance , per sq cm Q4159 Affinity , per sq cm Q4186 Epifix , per square centimeter Q4187 EpiCord , per square centimeter Investigational (Not Eligible for Coverage) Q4100 Skin substitute, not otherwise specified Q4137 AmnioExcel , AmnioExcel Plus or Biodexcel, per sq cm Q4138 BioDFence DryFlex, per sq cm Q4139 AmnioMatrix or BioDMatrix, injectable, 1 cc. Q4140 BioDFence , per sq cm Q4145 EpiFix , injectable, 1 mg Q4148 Neox Cord 1k, Neox Cord RT, or Clarix Cord 1K, per sq cm Q4150 AlloWrap DS or dry, per square centimeter Q4153 Dermavest and Plurivest , per sq cm Q4155 Neox Flo or Clarix Flo , 1 mg Q4156 Neox 100 or Clarix 100, per sq cm Q4157 Revitalon , per sq cm Q4160 Nushield , per sq cm Q4162 WoundEx Flow, BioSkin Flow, cc Q4163 WoundEx, , BioSkin, , per sq cm Q4168 AmnioBand , 1 mg (Particulate)

8 Page | 6 of 23 Code Description Q4169 Artacent wound, per sq cm Q4170 cygnus per sq cm Q4171 Interfyl , 1 mg Q4173 PalinGen or PalinGen XPlus, per sq cm Q4174 PalinGen or ProMatrX, mg per cc Q4176 Neopatch or therion, per square centimeter Q4177 FlowerAmnioFlo , cc Q4178 FlowerAmnioPatch, per sq cm Q4180 Revita , per sq cm Q4181 Amnio Wound, per sq cm Q4183 SurgiGRAFT , per square centimeter Q4184 Cellesta or Cellesta Duo, per square centimeter Q4185 Cellesta flowable amnion (25 mg per cc); per cc Q4188 AmnioArmor , per square centimeter Q4189 Artacent AC, 1 mg (flowable) Q4190 Artacent AC, per square centimeter (patch) Q4191 Restorigin , per square centimeter Q4192 Restorigin , 1 cc (injectable) Q4194 Novachor , per square centimeter Q4198 Genesis Amniotic Membrane , per square centimeter Q4199 cygnus matrix, per sq cm Q4201 Matrion, per sq cm Q4202 Keroxx ( g/cc), 1 cc Q4204 XWRAP, per square centimeter Q4205 Membrane Graft or Membrane Wrap, per sq cm Q4206 Fluid Flow or Fluid GF, 1 cc Page | 7 of 23 Code Description Q4208 Novafix , per sq cm Q4209 SurGraft , per sq cm Q4210 Axolotl Graft or Axolotl DualGraft , per sq cm Q4211 Amnion Bio or AxoBioMembrane, per sq cm Q4212 AlloGen , per cc Q4213 Ascent, mg Q4214 Cellesta Cord , per sq cm Q4215 Axolotl Ambient or Axolotl Cryo , mg Q4216 Artacent Cord, per sq cm Q4217 WoundFix , BioWound , WoundFix Plus, BioWound Plus, WoundFix Xplus or BioWound Xplus, per sq cm Q4218 SurgiCORD, per sq cm Q4219 SurgiGRAFT -DUAL, per sq cm Q4221 Amnio Wrap2 , per sq cm Q4224 Human Health Factor 10 Amniotic patch (hhf10-p), per square centimeter (new code effective 4/1/22) Q4225 AmnioBind, per square centimeter (new code effective 4/1/22)

9 Q4227 AmnioCore per sq cm Q4228 BioNext PATCH, per sq cm Q4229 Cogenex Amniotic Membrane , per sq cm Q4230 Cogenex Flowable Amnion, per cc Q4231 Corplex P, per cc Q4232 Corplex, per sq cm Q4233 SurFactor or NuDyn , per cc Q4234 XCellerate , per sq cm Q4235 AMNIOREPAIR or AltiPly , per sq cm Q4236 carePATCH, per sq cm Page | 8 of 23 Code Description Q4237 Cryo-Cord , per sq cm Q4239 Amnio-Maxx or Amnio-Maxx Lite, per sq cm Q4240 CoreCyte , for topical use only, per cc Q4241 PolyCyte , for topical use only, per cc Q4242 AmnioCyte Plus , per cc Q4244 Procenta , per 200 mg Q4245 AmnioText , per cc Q4246 CoreText or ProText , per cc Q4247 Amniotext patch, per sq cm Q4248 Dermacyte Amniotic Membrane Allograft, per sq cm Q4249 AMNIPLY , for topical use only, per square centimeter Q4250 AmnioAmp-MPMP , per square centimeter Q4251 Vim, per sq cm Q4252 Vendaje, per sq cm Q4253 Zenith Amniotic Membrane , per sq cm Q4254 Novafix DL, per square centimeter Q4255 REGUaRD, for topical use only, per square centimeter Q4256 MLG-Complete, per square centimeter (new code effective 4/1/22) Q4257 Relese, per square centimeter (new code effective 4/1/22) Q4258 Enverse, per square centimeter (new code effective 4/1/22) Q4259 Celera Dual Layer or Celera Dual Membrane , per sq cm (new code effective 7/1/22) Q4260 Signature APatch, per sq cm (new code effective 7/1/22) Q4261 TAG, per sq cm (new code effective 7/1/22) Q4262 Dual Layer Impax Membrane , per sq cm (new code effective 1/1/2023) Q4263 SurGraft TL, per sq cm (new code effective 1/1/2023) Q4264 Cocoon Membrane , per sq cm (new code effective 1/1/2023) Page | 9 of 23 Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).

10 HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS). Related Information Epifix Sizing Guidelines The allograft is intended for single-patient use only. All unused material should be discarded. Multiple sizes are available in a wide range of sheet and mesh configurations covering wounds To determine the measure of a wound in square centimeters multiply the length of the wound by the width of the wound in centimeters. ( , 10 cm in length x 5 cm in width =50 cm2) Here is a sample of the package standard sizes for Epifix: Table 2. Epifix Sample of Package Standard Sizes Item Number Size & Description GS-5024 24 mm disk GS-5330 3 cm x 3 cm sheet (9 sq cm) GS-5350 3 cm x 5 cm sheet (15 sq cm) GS-5460 4 cm x 6 cm sheet (24 sq cm) GS-5560 5 cm x 6 cm sheet (30 sq cm) GS-5770 7 cm x 7 cm sheet (49 sq cm) ES-3500 3 cm x 5 cm mesh sheet (15 sq cm) ES-4400 4 cm x cm mesh sheet (18 sq cm) ES-5500 5 cm x cm mesh sheet ( sq cm) Source: (Accessed March 28, 2022).