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Human amniotic membrane 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.
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. The fluid contains proteins, carbohydrates, peptides, fats, amino acids, enzymes, hormones, pigments, and fetal cells. Amniotic fluid has been compared with synovial fluid, containing hyaluronan, cholesterol, and cytokines. Injection of amniotic fluid or amniotic fluid-derived cells is currently being evaluated for the treatment of osteoarthritis and plantar fasciitis.
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 (CFR) title 21, parts 1270 and 1271. Human amniotic membrane products and amniotic fluid products are included in these regulations. In 2003, ProKera® was cleared for marketing by FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). 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.”
Note: Please see policy IV-137, Bioengineered Skin and Soft Tissue Substitutes, for products unrelated to amniotic membrane and amniotic fluid.
I. Human Amniotic Membrane Grafts for Ophthalmic Conditions
II. Human Amniotic Membrane Grafts for Non-Ophthalmic Conditions
III. Experimental/Investigative Uses of Human Amniotic Membrane
V. Injection of Amniotic Fluid
Injection of amniotic fluid is considered EXPERIMENTAL/ INVESTIGATIVE for all conditions due to the lack of clinical evidence demonstrating an impact on improved health outcomes.
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Summary of Evidence
Amniotic membrane products have a history of longstanding use for the management of ophthalmologic conditions where there is limited access to autologous tissue. These products may be cryopreserved, fresh-frozen, irradiated, or lyophilized. Most are obtained directly from tissue banks and not marked by any particular manufacturer; however, there are several products marketed commercially, including Prokera®, AmbioDisk®, Ambio2®, Ambio5®, Artacent® Ocular and AmnioGraft®. The most widely studied condition with a technology assessment evaluating randomized controlled trials (RCT) evidence is use of amniotic membrane following pterygium repair. The assessment concluded, based on 4 RCTs, that conjunctival or limbal autograft was more effective than amniotic membrane. An RCT on amniotic membrane for refractory neurotrophic corneal ulcers found that outcomes following amniotic membrane graft were similar to those for conventional therapy. One RCT has shown that application of amniotic membrane in the early stages of Stevens-Johnson syndrome leads to clinically significant improvement compared to medical therapy alone. A 2012 Cochrane review found 1 RCT evaluating amniotic membrane graft for acute ocular burns. The trial suggested a benefit for amniotic membrane in the healing rate for ocular burns, but it was considered at high or uncertain risk of bias due to unequal baseline scores and lack of masking to treatment condition. A trial on amniotic membrane for the treatment of bullous keratopathy reported that there was no difference in clinical outcomes between amniotic membrane and stromal puncture. Other indications have been studied only in case series.
The evidence on amniotic and placental membrane products for the treatment of diabetic lower-extremity ulcers includes several RCTs that compared amniotic membrane to standard of care (SOC) or to an established advanced wound care product. All of these industry-sponsored studies included evaluation of wound closure as the primary outcome measure, and some included power analysis, blinded assessment of wound healing, and ITT analysis. For the amniotic membrane products evaluated in RCTs (e.g., AmnioBand® Membrane, EpiFix®, Grafix®), results indicated improved outcomes compared to SOC, and outcomes that are at least as good as the advanced wound care product Apligraf. In addition, a registry study for Biovance showed improved health outcomes, with a magnitude of benefit similar to that observed in the RCTs for other products.
Although multiple products are available for a large number of other potential uses, including treatment of lower-extremity ulcers due to venous insufficiency, osteoarthritis, plantar fasciitis, or for patients who have undergone Mohs micrographic surgery for skin cancer, clinical trial data on these products were not found in a review of the medical literature. Similarly, data on the use of injections of amniotic fluid for any indication are lacking. At this time, evidence is insufficient to demonstrate an effect on health outcomes of amniotic membrane tissue for all indications not addressed as medically necessary and appropriate.
Rationale
Use of grafts composed of amniotic chorionic membrane or chorionic tissue is an area of intense study due in part to evidence that the tissue has anti-inflammatory, antifibroblastic and antimicrobial properties. Amniotic membrane tissue is considered nonimmunogenic and has not been observed to cause substantial immune response. It is believed that these properties are retained in cryopreserved and dehydrated products, resulting in a readily available tissue with regenerative potential. Use of an amniotic membrane graft, which is fixated by sutures, is used in treatment for disorders of the corneal surface. 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. Additional indications studied in preclinical models include tendonitis, tendon repair, and nerve repair. The availability of amniotic membrane opens the possibility of regenerative medicine for an array of conditions.
The U.S. Food and Drug Administration 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. Amniotic membrane products and amniotic fluid products are included in these regulations. In 2003, ProKera® was cleared for marketing by FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). 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.” 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). 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.
Amniotic Membrane Grafts for Ophthalmologic Conditions
Neurotrophic Keratitis
In 2005, Khokhar and Natung reported on an RCT of 30 patients (30 eyes) with refractory neurotrophic corneal ulcers who were randomized to amniotic membrane transplantation (n=15) or to conventional treatment with tarsorrhaphy or bandage contact lens. At the 3-month follow-up, 11 (73.3%) of 15 patients in the amniotic membrane group showed complete epithelialization compared to 10 (66.7%) of 15 in the conventional group. This difference was not significantly significant.
Following Pterygium Repair
Results of RCTs have been reported on use of amniotic membrane following pterygium repair. In 2013, the American Academy of Ophthalmology published a technology assessment on options and adjuvants for pterygium surgery. Reviewers identified 4 RCTs comparing conjunctival or limbal autograft procedure with amniotic membrane graft, finding that conjunctival or limbal autograft was more effective than amniotic graft in reducing the rate of pterygium recurrence. The medical necessity indication is proposed based on input from specialty societies received by the Blue Cross Blue Shield Association in 2017, which is discussed below.
Stevens-Johnson Syndrome
One RCT from India (2016) assigned 25 patients (50 eyes) with acute ocular Stevens-Johnson syndrome to amniotic membrane plus medical therapy (antibiotics, steroids, or lubricants) or to medical therapy alone. The amniotic membrane was prepared locally and applied with fibrin glue rather than sutures. Application of amniotic membrane in the early stages of Stevens-Johnson syndrome resulted in improved visual acuity (p=0.042), tear breakup time (p=0.015), Schirmer test results (p<0.01) and less conjunctival congestion (p=0.03). In the amniotic membrane group at 180 days, there were no cases of corneal haze, limbal stem cell deficiency, symblepharon, ankyloblepharon, or lid-related complications. These outcomes compared with the medical therapy alone group, which had 11 (44%) of 25 cases with corneal haze (p=0.001); 6 (24%) cases of corneal vascularization and conjunctivalization (p=0.03), and 6 (24%) cases of trichiasis and metaplastic lashes.
Persistent Epithelial Defects and Ulceration
In 2004, Bouchard and John wrote a review of amniotic membrane transplantation in the management of severe ocular surface disease. They noted that amniotic membrane has been available since 1995, and has become an established treatment for persistent epithelial defects and ulceration refractory to conventional therapy. However, there was a lack of controlled studies due to rarity of the diseases and the absence of a standard therapy. They identified 661 reported cases in the peer-reviewed literature. Most cases reported assessed the conjunctival indications of pterygium, scars and symblepharon, and corneal indications of acute chemical injury and postinfectious keratitis.
Ocular Burns
A 2012 Cochrane review evaluated the evidence on amniotic membrane graft for acute ocular burns. Included in the review was a single RCT from India of 68 patients with acute ocular burns who were randomized to amniotic membrane plus medical therapy or to medical therapy alone. In the subset of 36 patients with moderate ocular burns treated within 7 days, 13 (65.0%) of 20 control eyes and 14 (87.5%) of 16 amniotic membrane -treated eyes had complete epithelialization by 21 days. There was a trend (p=0.09) toward a reduced relative risk of failure of epithelization in the treatment group. Mean logarithm of the minimum angle of resolution (logMAR) final visual acuities were 0.06 in the treatment group and 0.38 in the control group. In the subset of patients with severe ocular burns treated within 7 days, 1 (5.9%) of 17 AMT-treated eyes and 1 (6.7%) of 15 control eyes were epithelialized by day 21. There was no significant difference in final visual acuity, which was 1.77 logMAR in the treated eyes and 1.64 in the control group (p=NS). The risk of bias was considered high because of differences between the groups at baseline and because outcome assessors could not be masked to treatment. Reviewers determined that conclusive evidence supporting the treatment of acute ocular surface burns with amniotic membrane is lacking.
Bullous Keratopathy
Bullous keratopathy is characterized by stromal edema and epithelial and sub-epithelial bulla formation. In 2013, Dos Santos Paris et al. published an RCT that compared fresh amniotic membrane to stromal puncture for the management of pain in patients with bullous keratopathy. Forty patients with pain from bullous keratopathy who were either waiting for a corneal transplant or had no potential for sight in the affected eye were randomized to the 2 treatments. Symptoms had been present for approximately 2 years. amniotic membrane resulted in a more regular epithelial surface at up to 180 days follow-up, but there was no difference between the treatments related to the presence of bullae or the severity or duration of pain. Because of the similar effects on pain, the authors recommended initial use of the simpler stromal puncture procedure, with use of amniotic membrane only if pain did not resolve.
Traditionally, amniotic membrane has been fixed onto the eye with sutures or glue or placed under a bandage contact lens for a variety of ocular surface disorders. Several devices have been reported that use a ring around a cryopreserved amniotic membrane allograft that allows it to be inserted under topical anesthesia similar to insertion of a contact lens. The easier insertion may lead to more widespread use, such as dry eye disease and for healing after photorefractive keratectomy (PRK).
Dry Eye Disease
The ProKera® cryopreserved amniotic membrane device was evaluated in a 2016 series by Cheng et al. The senior author of the study (S.C.G. Tseng) holds the patent on ProKera®. This retrospective review assessed 10 patients treated with the self-retained device for moderate-to-severe dry eye disease. In this study, these 10 patients had moderate-to-severe dry eye syndrome despite conventional medical treatment. The c-amniotic membrane device was placed in 15 eyes (1 eye at a time) for a mean of 4.9 days (range, 2-8 days), after which the amniotic membrane was either dissolved or cloudy. Treatment resulted in symptomatic relief for a mean of 4.2 months (range, 0.3 to 6.8 months) after a single treatment. Symptomatic improvement was accompanied by statistically significant reductions of Ocular Surface Disease Index scores, use of topical medications, conjunctival hyperemia, corneal staining (all p <0.001) and a trend toward improved visual acuity (p=0.06).
John et al. (2017) reported on an RCT with 20 patients with moderate-to-severe dry eye disease who were treated with Prokera ®c-HAM (cryopreserved Human Amniotic Membrane) or maximal conventional treatment. The c-HAM was applied for an average of 3.4 days (range, 3-5 days), while the control group continued treatment with artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications. The primary outcome was an increase in corneal nerve density. Signs and symptoms of dry eye disease improved at both one-month and three-month follow-ups in the c-HAM group but not in the conventional treatment group. For example, pain scores decreased from 7.1 at baseline to 2.2 at 1 month and 1.0 at 3 months in the c-HAM group. In vivo confocal microscopy, reviewed by masked readers, showed a significant increase in corneal nerve density in the study group at three months, with no change in nerve density in the controls. Corneal sensitivity was similarly increased in the c-HAM group but not in controls.
The treatment outcomes in the DRy Eye Amniotic Membrane study (McDonald et al., 2018) was a retrospective series of 84 patients (97 eyes) with severe dry eye despite maximal medical therapy who were treated with Prokera® self-retained c-HAM. A majority of patients (86%) had superficial punctate keratitis. Other patients had filamentary keratitis (13%), exposure keratitis (19%), neurotrophic keratitis (2%), and corneal epithelial defect (7%). Treatment with Prokera® for a mean of 5.4 days (range, 2 to 11) resulted in an improved ocular surface and reduction in the DEWS score from 3.25 at baseline to 1.44 at 1 week, 1.45 at 1 month and 1.47 at 3 months. Ten percent of eyes required repeated treatment. There was no significant difference in the number of topical medications following c-HAM treatment. Apart from discomfort during placement, there were no adverse events. Investigators concluded that the use of cryopreserved amniotic membrane is promising to enhance the recovery of ocular surface health and reduce signs and symptoms in patients with moderate to severe dry eye disease.
The Tear Film and Ocular Surface Society (2017) published the DEWS [Dry Eye Workshop] II management and therapy report. The report evaluated the evidence on treatments for dry eye and provided a treatment algorithm for dry eye disease management, which included amniotic membrane grafts (Step 4), when other options were inadequate (Step 1-3).
Photorefractive Keratectomy
In 2016, Vlasov et al. reported on a prospective, nonrandomized controlled trial evaluating the effect of sutureless amniotic membrane (ProKera®) on corneal wound healing after photorefractive keratectomy (PRK). Forty patients (80 eyes) had PRK for myopia. After surgery, a high-oxygen-transmissible bandage contact lens was applied on the dominant eye and cryopreserved amniotic membrane on the nondominant eye. Patients were assessed daily until complete corneal re-epithelialization occurred in both eyes and then at 2 weeks and 1, 3, 6, and 12 months thereafter. The primary outcome was re-epithelialization, which was assessed daily with slit-lamp examination, fluorescein staining, and photography. The time to complete reepithelization was faster in eyes treated with a bandage contact lens (3.7 days; range, 3-7 days) than with the amniotic membrane product (4.6 days; range, 3-16 days). Initially, patients reported greater discomfort and dryness with amniotic membrane. Visual and clarity and optical quality of the cornea were similar between the amniotic membrane graft eyes and bandage contact lens eyes
Ophthalmic indications not previously addressed
Tandon, et al. (2011), published an RCT of 100 patients with chemical or thermal ocular burns. Half of the patients had moderate ocular burns and the remainder had severe burns. All but 8 had alkali or acid burns. Patients were randomized to human amniotic membrane transplantation plus medical therapy, or medical therapy alone. Epithelial healing, which was the primary outcome, was improved in the group treated with amniotic membrane, but there was no significant difference between the two groups for the final visual outcome, symblepharon formation, corneal clarity, or vascularization.
In 2005, Tamhane, et al., published an RCT (n = 44) of patients with acute moderate grade ocular burns treated with amniotic graft (N = 20) or standard medical care (n = 24). At day 1, subjective ocular discomfort scores were reduced significantly in eyes with moderate burns in the AMT group compared with controls (P = 0.05), but there was no difference between the 2 groups in eyes with severe burns. The log mean percentage reduction in size of epithelial defect by day 7 was 7.43+/-0.89 after AMT and 6.23+/-1.10 with medical treatment alone in moderate grade burns at day 7 (P = 0.01), but there was no difference between the 2 groups in eyes with severe burns. There was no overall difference in the final visual acuity, symblepharon formation, corneal vascularization, and tear function tests between the 2 groups over the next 3 months and further follow-up. Authors concluded that amniotic membrane transplantation in eyes with acute ocular burns has advantages in terms of reduction of pain and promotion of early epithelialization in patients with moderate grade burns, but not so in severe burns.
Amniotic Membrane for Ophthalmic Conditions: Clinical Input
Clinical input was sought during the 2017 review of the Blue Cross Blue Shield Association Medical Reference Policy, Amniotic Membrane and Amniotic Fluid. Clinical input was provided on behalf of the American Academy of Ophthalmology (AAO). Clinical input provided by the specialty society at an aggregate level is attributed to the specialty society. Clinical input provided by a physician member designated by the specialty society is attributed to the individual physician and is not a statement from the specialty society. Specialty society and physician respondents participating in the Blue Cross Blue Shield Association’s Evidence Street® clinical input process provide review, input, and feedback on topics being evaluated by Evidence Street. However, participation in the clinical input process by a special society and/or physician member designated by the specialty society or clinical health system does not imply an endorsement or explicit agreement with the Evidence Opinion published by BCBSA or any Blue Plan.
Input supported the use of sutured or glued amniotic membrane for neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Those providing input had low confidence that sutureless amniotic membrane performed as well or better than sutured amniotic membrane.
In 2019, the Blue Cross Blue Shield Association sought input from practicing ophthalmologists 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 the case of corneal perforation when corneal tissue is not immediately available, the opinions of the ophthalmologists surveyed was that while corneal tissue is the preferred graft material in these cases, HAM alone may be a reasonable temporizing alternative when corneal tissue is not available. Because of the rare nature of these cases, large RTCs have not been performed. Clinical series and case reports supporting the efficacy of HAM for corneal perforation were provided, including a case series by Kim, et al. (2009), in which 10 patients with corneal perforations were treated with fibrin glue-assisted augmented amniotic membrane (AM). The mean ulceration diameter was 2.7 ± 0.95 mm (range, 2–5 mm). All patients retained their own globes after the procedure and had well-formed deep anterior chambers, and 90% of patients showed complete epithelialization over the AM. The mean re-epithelialization time was 14.9 ± 4.9 days (range 10–24 days). No eyes showed evidence of infection or recurrent corneal melting during the follow-up period. This surgical method was very helpful in stabilizing the wound in the early postoperative period. Rodríguez-Ares, et al. (2004), reported on 15 patients with corneal perforations of different sizes, with multiple causes. Two layers of amniotic membrane (for microperforations) or 3–4 layers (for the other groups) were trimmed to the size of the ulcer and sutured in place with interrupted 10-0 nylon sutures. Mean epithelialization time was 3.7 weeks (range 2–6). Mean time to recovery of corneal stroma thickness was 10.1 weeks (range 7–15). In all cases, ocular inflammation subsided within 2–5 weeks. The treatment was judged successful in 73% (11/15) of eyes. Three of the 4 unsuccessful treatments were of perforations 3 mm or more in diameter; of the 5 eyes with perforations of more than 1.5 mm in diameter, only 2 were treated successfully. Investigators concluded that multilayer AMT is effective for treating corneal perforations with diameter less than 1.5 mm. The technique may be a good alternative to penetrating keratoplasty, especially in acute cases in which graft rejection risk is high.
Hick, et al. (2005) reported on a study of 33 eyes from 32 patients in which amniotic membrane transplantation with corneal ulcers refractive to conventional treatment. Fourteen ulcers were perforated and received fibrin glue and amniotic membrane. Overall success was observed in 80% (27/33 eyes) of the cases, with success rates of 87.5% (14/16 eyes), 70% (7/10 eyes), 85.7% (6/7 eyes) in groups 1, 2, and 3, respectively. The ulcers healed in a mean time of 3.6 ± 1.6 weeks and the follow-up was 14.8 ± 9.9 months. Failure was noted in 6 eyes with severe neurotrophic keratitis, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and Acanthamoeba keratitis. Grafts with fibrin sealant showed a success rate of 92.9 % (13/14 eyes) compared to 73.7% (14/19 eyes) for amniotic grafts alone. In patients with severe limbal damage, a success rate of only 20% (1/5) was observed. Investigators concluded that amniotic membrane transplant is a viable option in the treatment of corneal ulcers of various depths and etiologies. The techniques lead to rapid reconstruction of the corneal surface and can give a good functional outcome result or allow keratoplasty to be done in more favorable conditions. Solomon and associates described the outcome of amniotic membrane transplantation for nontraumatic corneal perforations, descemetoceles, and deep ulcers on 34 eyes of 33 consecutive patients. Three or 4 layers of amniotic membrane were applied over the ulcer bed and anchored with 10-0 nylon interrupted or running sutures. A large amniotic membrane piece was used as a patch to cover the entire corneal surface. Main outcome measures were the formation of anterior chamber depth, epithelialization of the grafts, and stability of the corneal stromal thickness. Mean follow-up period was 8.1 ± 5.7 (ranging from 2-23) months. A successful result was observed in 28 of 34 eyes (82.3%). Of the successful cases, 23 eyes needed one AMT procedure, whereas 5 eyes needed two procedures to achieve a successful result. In five eyes, a subsequent definitive surgical procedure such as penetrating keratoplasty or lid surgery was needed. Failure was observed in six eyes with rheumatoid arthritis, neurotrophic keratopathy, or graft melting. Conclusions were that amniotic transplantation is an effective method for managing nontraumatic corneal perforations and descemetoceles; it may serve as permanent therapy or as a temporizing measure until definitive reconstruction can be performed. In addition, it may be beneficial in countries where corneal tissue availability is limited.
Diabetic Lower Extremity Ulcers
At least six randomized controlled trials have evaluated rates of healing with amniotic membrane grafts or placental membrane graft compared to standard of care (SOC) of an advanced wound therapy in patients with chronic diabetic foot ulcers. The number of patients in these studies ranged from 25 to 155. Human amniotic membrane 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. In a 2018 trial, the cryopreserved placental membrane Grafix was found to be non-inferior to an advanced fibroblast-derived wound therapy (Dermagraft).
Ananian, et al. (2018), conducted a prospective, randomized single-blind study comparing the efficacy of viable cryopreserved placental membrane (vCPM) and human fibroblast-derived dermal substitute (hFDS) for chronic diabetic foot ulcers at 7 centers (n = 62). Patients were randomized in a 1:1 ratio to receive weekly treatments of vCPM or HFDA for up to 8 applications or until wound closure was achieved. Primary endpoint was the proportion of patients who achieved complete closure of the index wound (defined as 100% reepithelialization as determined by the investigator) by the end of treatment. Additional endpoints included the proportion of patients who achieved complete wound closure for wounds ≤ 5 cm2 and > 5 cm2, time to closure, number of grafts used to achieve wound closure, proportion of patients who achieved a 50% or greater reduction in wound size by day 28, percent area reduction (PAR) of nonclosed wounds at day 56, and per-patient product cost during the course of treatment. Safety endpoints included number and types of adverse events (AEs). Investigators concluded that vCPM was not inferior to hFDS for the proportion of patients achieving complete wound closure (9.68, 90% CI: [10.67, 28.94]). However, preliminary findings show that vCPM may have better outcomes for wounds ≤ 5 cm2 : 81.3% (13/16) of wounds in the vCPM group vs. 37.5% (6/16) of wounds in the hFDS group reached complete closure at the end of treatment (p = 0.0118).
Tettelbach, et al. (2019), reported on a randomized controlled trial conducted at 14 wound centers in the United States to confirm the efficacy of dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of chronic lower extremity ulcers in persons with diabetes. Patients with lower extremity ulcers of a least 4 weeks duration were entered into a 2-week study run-in phase and treated with alginate wound dressings and appropriate offloading. Those with less than or equal to 25% wound closure after run-in were randomly assigned to receive weekly dHACM application in addition to offloading or standard of care with alginate wound dressings, for 12 weeks. 110 patients were included in the intent-to-treat (ITT) analysis, with n = 54 in the dHACM group and n = 56 in the no-dHACM group. Of the participants, 98 completed the study per protocol, with 47 receiving dHACM and 51 not receiving dHACM. The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per-protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT-70% versus 50%, P = 0.0338, per-protocol-81% versus 55%, P = 0.0093). A Kaplan-Meier analysis was performed to compare the time-to-healing performance with/without dHACM, showing a significantly improved time to healing with the use of allograft, log-rank P < 0.0187. Cox regression analysis showed that dHACM-treated subjects were more than twice as likely to heal completely within 12 weeks than no-dHACM subjects (HR: 2.15, 95% confidence interval 1.30-3.57, P = 0.003). At the final follow up at 16 weeks, 95% of dHACM-healed ulcers and 86% of healed ulcers in the no-dHACM group remained closed. These results confirm that dHACM is an efficacious treatment for lower extremity ulcers in a heterogeneous patient population.
Tettelbach, et al. (2019) published a prospective, multicenter randomized controlled comparative study involving the epiCord allograft in the treatment of diabetic foot ulcers. 155 patients with a confirmed diagnosis of Type 1 or Type 2 diabetes, presenting with a 1 to 15 cm2 ulcer were randomized 2:1 to receive a weekly application of EpiCord (n = 101) or standardized therapy with alginate wound dressing, non-adherent silicone dressing, absorbent non-adhesive hydropolymer secondary dressing, and gauze bandage (n = 54). Study visits were conducted for 12 weeks. At each visit, the ulcer was cleaned and debrided as necessary, measured, and photographed prior to application of treatment group-specific dressings. The primary study end point was the percentage of complete closure of the study ulcer within 12 weeks. Data for randomised subjects meeting study inclusion criteria were included in an intent-to-treat (ITT) analysis. Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40). ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord-treated and 26 of 48 (54%) for alginate-treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate-treated ulcers, P < 0.0001. These results demonstrate the safety and efficacy of EpiCord as a treatment for non-healing DFUs.
In 2016, the Wound Healing Society updated their guidelines on diabetic foot ulcer treatment. 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 dehydrated amniotic membrane were included with references on living and acellular bioengineered skin substitutes. Also 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.”
Affinity ® vs Standard of Care
Serena, et al., (2020) published a randomized controlled trial (n = 76) across 14 centers that assessed clinical outcomes associated with the use of hypothermically stored amniotic membrane (HSAM) plus standard of care (SOC) compared with SOC alone. SOC consisted of debridement, infection elimination, use of dressing, and offloading by total contact casting. HSAM-treated ulcers were compared with SOC-treated ulcers by analyses that determined frequency of wound closure. The trial investigated the comparative effectiveness of HSAM and SOC versus SOC alone over a 16-week study period. Primary analyses were frequency of and time to wound closure by 16 weeks, including 12 weeks in the treatment phase and 4 weeks in the follow-up phase. Ulcer area (cm2), depth (mm) and volume (cm3) were measured using digital planimetry. At both 12 weeks and 16 weeks, the unadjusted end point of wound closure was significantly greater for HSAM-treated ulcers than SOC (55 vs 29%, p=0.02 at 12 weeks and 58 vs 29%, p=0.01 at 16 weeks). The median time to wound closure was 11 weeks for HSAM-treated ulcers; for SOC-treated ulcers, the median time to wound closure was not obtained because 50% of patients in the SOC group failed to demonstrate wound closure by the end of the study at 16 weeks.
AmnioBand® vs Standard Care
AmnioBand® Membrane was compared with standard of care (SOC) for the treatment of nonhealing (minimum 4 weeks) diabetic foot ulcers in an industry-sponsored, multicenter trial by DiDomenico et al. (2016). Forty patients were randomized to SOC or to SOC plus weekly applications of the dehydrated placental allograft for up to 12 weeks. Healing was determined by the principal investigator at each institution and confirmed by an independent and blinded panel of 6 physicians. This study was adequately powered to detect a difference of 45% between groups in the primary outcome (the proportion of wounds healed at 6 weeks). Complete healing by 6 weeks was observed for 70% (14/20) of wounds treated with the dehydrated placental matrix compared with 15% (3/20) of wounds treated by SOC alone (p=0.001). The odds ratio for healing was 17 (95% confidence interval [CI], 3.1 to 93; p=0.001). At 12 weeks, complete healing was observed for 85% (17/20) of wounds in the AmnioBand group compared with 25% (5/20) in the SOC group. Mean time to heal for wounds treated with amniotic membrane was 36 days (95% CI, 27 to 46 days) compared to 70 days (95% CI, 59 to 81 days; p<0.001) with standard care. The number needed to treat to achieve healing at 12 weeks was 1.7 (95% CI, 1.2 to 2.8). Strengths of this study included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and intention-to-treat (ITT) analysis.
AmnioExcel® vs Standard Care
AmnioExcel® dehydrated human amniotic membrane was compared with standard care in an industry-sponsored, open-label multicenter RCT (N=29) by Snyder et al. Randomization was performed by computer module and stratified by site and wound area. The primary outcome was the percentage of patients with complete wound closure at 6 weeks. The per protocol population included 11 patients in the AmnioExcel® group and 10 in the SOC group. For the ITT population, 33% (95% CI, 25.0% to 46.4%) of patients in the AmnioExcel® group achieved wound closure by 6 weeks compared to 0% of the SOC group (p=0.017). In the per protocol analysis, 45.5% of patients treated with AmnioExcel® achieved wound closure by 6 weeks compared to 0% in the SOC arm (p=0.008) with a 95% confidence interval of the responder ratio of 32.9% to 58.0% (p=0.014). Power analysis was not described, and 8 patients withdrew early (4 in each group), raising questions about the reliability of the effect size.
Biovance®
In 2015, Smiell et al. reported on an industry-sponsored, multicenter registry study of Biovance dehydrated amniotic membrane for the treatment of various chronic wound types, including 47 diabetic foot wounds, 20 pressure ulcers, and 89 venous ulcers. This study examined the effectiveness of dehydrated amniotic membrane in a real-world setting. The size of the wounds at baseline ranged from less than 2 cm2 (35.4% of wounds) to over 25 cm2 (9.0% of wounds). Ninety-eight percent were on the lower extremities. Twenty-eight ulcers had failed prior treatment with advanced biologic therapies (Apligraf®, Dermagraft®, or Regranex®), including 10 diabetic foot wounds. For all wound types, 41.6% closed, with a mean time to closure of 8 weeks and a mean of 2.4 amniotic membrane applications. In the subgroup of 112 patients who practiced good wound care, including offloading or compression therapy as indicated, 49.6% of wounds closed by a mean of 7.4 weeks. Wounds that had not closed during the observation period decreased in size by a mean of 46.6%.
EpiFix® vs Standard Care
In 2013, Zelen et al. reported an industry-sponsored, nonblinded, RCT comparing use of EpiFix® dehydrated amniotic membrane (n=13) with SOC (n=12) for diabetic foot ulcers of at least 4 weeks in duration. EpiFix® was applied every 2 weeks if the wound had not healed, with weekly dressing changes comprised of nonadherent dressing, moisture retentive dressing, and a compression dressing. Standard moist wound dressing was changed daily. After 4 weeks of treatment, EpiFix® treated wounds had reduced in size by a mean of 97% compared with 32% for the SOC group. Healing rate, defined as complete epithelialization of the open area of the wound, was 77% for EpiFix® compared with 0% for SOC. After 6 weeks of treatment, wound sizes were reduced by 98.4% with EpiFix® treatment compared with -1.8% for SOC. The healing rate was 92% with EpiFix® compared with 8% with SOC alone. At trial conclusion, unhealed wounds from the control group were treated with EpiFix®. The mean duration of foot ulcers at the beginning of treatment was 19.4 weeks (range, 6.0-54 weeks) for the combined group. Follow-up was available at 9 to 12 months after primary healing in 18 of 22 eligible patients. Examination of these 18 patients found that 17 (94.4%) wounds remained fully healed.
EpiFix® vs Apligraf®
EpiFix® was compared with Apligraf® (living cell therapy) in a multicenter RCT published in 2016 by Zelen et al. Sixty patients were randomized to treatment with EpiFix®, Apligraf®, or standard wound care. Although patients and site investigators could not be blinded due to differences in products, wound healing was verified by 3 independent physicians who evaluated photographic images. Median wound size was 2.0 cm2 (range, 1.0-9.0 cm2 ) and median duration of the index ulcer was 11 weeks (range, 5-54 weeks). After 6 weekly treatments, the mean percent wound area healed was 97.1% for EpiFix®, 80.9% for Apligraf®, and 27.7% for SOC; 95% of wounds had healed completely in the EpiFix® group compared with 45% treated with Apligraf® and 35% who received standard wound care (p=0.003). The estimated median time to wound closure, based on Kaplan-Meier analysis, was 13 days for EpiFix® compared with 49 days for both Apligraf® and SOC (p<0.001).
In 2015, Kirsner et al. reported an industry-sponsored observational study comparing the effectiveness of Apligraf® and EpiFix® in a real-world setting. Data were obtained from a wound care‒specific database from 3000 wound care facilities. The database included 1458 diabetic ulcers treated for the first time in 2014 with Apligraf® (n=994) or EpiFix® (n=464). Using the same criteria as the 2015 study by Zelen (described above), data were included on the treatment of 226 diabetic foot ulcers from 99 wound care centers. Selection criteria for foot wounds included size between 1 cm2 and 25 cm2, duration of 1 year or less, and wound reduction of 20% or less in the 14 days prior to treatment. Although wounds for the 2 groups were comparable at baseline, the rationale for using a particular product was not reported. One hundred sixty-three wounds were treated with Apligraf® (mean, 2.5 applications) and 63 were treated with EpiFix® (mean, 3.5 applications, p=0.003). By week 24, 72% of wounds treated with Apligraf® and 47% of wounds treated with EpiFix® had closed (p=0.01). Median time to closure was 13.3 weeks for Apligraf® and 26.0 weeks for EpiFix® (p=0.01). This study is at risk of selection bias in determining treatment assignment.
Grafix® vs Standard Care
Grafix® cryopreserved placental membrane was compared with standard wound care in a 2014 multicenter RCT. Strengths of this trial included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and ITT analysis. Ninety-seven patients with chronic diabetic foot ulcers were randomized to Grafix® or to standard wound therapy, both administered once a week for up to 12 weeks. Power analysis indicated that 94 patients per arm would be needed. However, after prespecified interim analysis at 50% enrollment, the blinded review committee recommended that the trial be stopped due to efficacy of the treatment. ITT analysis from the blinded evaluation phase showed a significant increase in the proportion of patients achieving the primary outcome of wound closure by 12 weeks (62.0% vs 21.3%, p <0.001) and a decrease in the median time to complete wound closure (42.0 days vs 69.5 days, p=0.019). Safety evaluation found that fewer Grafix® treated patients and a decrease in the median time to complete wound closure (42.0 days vs 69.5 days, p=0.019). Safety evaluation found that fewer Grafix® treated patients experienced at least 1 adverse event (44.0% vs 66.0%, p=0.031) or had wound-related infections (18.0% vs 36.2%, p=0.044), with a trend toward fewer hospitalizations related to infections (6% vs 15%, p=0.15).
Lower Extremity Ulcers due to Venous Insufficiency
In August 2021, ECRI published a Clinical Evidence Assessment on Neox® Flo Wound Matrix (Amniox Medical, Inc.) for Treating Chronic Wounds. Neox® Flo is a sterile, cryopreserved, particulate human placental tissue allograft intended to facilitate healing of partial- and full-thickness acute and chronic wounds. This publication focused on Neox® Flo’s safety and efficacy in the treatment of chronic wounds. ECRI reported that the evidence was inconclusive, as no published studies that examined Neox® Flo’s safety and efficacy were identified.
Similarly, ECRI examined NuShield Placental Allograft (Organogenesis, Inc) for treating burns. NuShieldTM, a sterilized, dehydrated allograft derived from human placental tissue, purportedly reduces inflammation, scar tissue formation, and promotes wound healing, As with Neox® Flo, ECRI identified no published studies that examined the safety and efficacy of NuShieldTM.
EpiFix®
In 2014, Serena et al. reported on an industry-sponsored multicenter open-label RCT that compared EpiFix® amniotic membrane plus compression therapy to compression therapy alone for venous leg ulcers. Ulcers were included if they were chronic (>1 month in duration); extended through the full thickness of the skin but not down to muscle, tendon, or bone; and had been treated with compression therapy for at least 14 days. Eighty-four participants were enrolled and assigned to a single EpiFix® allograft (n=26), 2 allografts (n=27), or compression therapy alone (n=31). The primary outcome (proportion of patients with 40% wound closure at 4 weeks) was achieved by 62% in the combined EpiFix groups and by 32% in the control group (p=0.005). During the 4-week trial period, 6 (11.3%) patients in the combined EpiFix® group and 4 (12.9%) in the control group achieved complete wound closure. Secondary outcomes, which evaluated the use of 1 versus 2 applications of amniotic membrane, showed no significant difference in outcomes (62% vs 63%). Strengths of this study 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 account for additional treatments after the 4-week randomized trial period.
A second industry-sponsored multicenter open-label RCT, (Bianchi et al., 2017), evaluated the time to complete ulcer healing following weekly treatment with EpiFix® d-HAM and compression therapy or compression therapy with standard dressing. 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=0.01), and improved time to complete healing, as assessed by Kaplan-Meier analysis. Healing within 12 weeks was reported for 60% of patients in the EpiFix® group and 35% of patients in the control group. There were several limitations of this trial. Nineteen (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). Also, the trial did not use the ITT analysis. Had all excluded patients been considered treatment failures, the difference between groups would have been 17% (48% wound healing for EpiFix® vs 31% for controls). There was also a difference between the groups in how treatment failures at eight weeks were handled. Patients in the control group who did not have a 40% decrease in wound area at eight weeks were considered study failures and treated with advanced wound therapies. Although the trialists noted that only 1 patient from this group had healed by weeks 12 and 16, reporting is unclear about how many patients from the d-HAM group would have been considered treatment failures at 8 weeks using the same cutoff.
Biovance®
In 2015, Smiell et al. reported on an industry-sponsored, multicenter registry study of Biovance® dehydrated amniotic membrane for the treatment of various chronic wound types; about half (n=89) were venous ulcers. 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. Corroboration with well-designed and well-conducted RCTs evaluating wound healing is needed to demonstrate efficacy. The corroborating RCTs should report ITT analysis, with analysis of all patients, including those who were off treatment or had protocol deviations and exclusions. While per protocol analysis can supplement the results, it is not sufficient to determine the effect of the treatment on health outcomes.
Osteoarthritis
In September 2020, Hayes, Inc, published a Health Technology Assessment on the use of amniotic allografts for tendon and ligament injuries. The finding of this body determined that the available studies do not provide sufficient evidence to evaluate the effectiveness of amniotic allografts for the treatment or prevention of tendon and ligament injuries. Therefore, a rating of D2, reflecting a very low quality of evidence that is insufficient to draw conclusions regarding the efficacy and safety for the indications addressed. Substantial uncertainty remains due to a small body of evidence and the absence of well-designed clinical trials. Similarly, an Evolving Evidence Review, also published in September 2020, concluded that there was minimal support for the use of amniotic allografts for the treatment of knee osteoarthritis. According to the analysis, a small body of poor-quality evidence suggests the injection of amniotic allografts to the intra-articular space is associated with improvements in pain and function with minimal adverse events; however, data from 2 randomized controlled trials do not show clear benefits over placebo injection with saline. Publication of good-quality studies comparing amniotic allografts with placebo and other active treatments will inform the potential role of amniotic allografts in the treatment of knee osteoarthritis.
ReNu™
A feasibility study (N=6) of cryopreserved human amniotic membrane suspension with amniotic fluid‒derived cells (ReNuTM) for the treatment of knee osteoarthritis was reported in 2016. A single intraarticular 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 effects, aside from a transient increase in pain, were noted.
Plantar Fasciitis
One systematic review and 2 randomized pilot studies were identified on the treatment of plantar fasciitis using injection of micronized amniotic membrane. A 2016 network meta-analysis of 22 RCTs (total N=1216 patients) compared injection therapies for plantar fasciitis. In addition to cryopreserved amniotic membrane and micronized dehydratic amniotic membrane amniotic/ chorionic membrane, treatments included corticosteroids, botulinum toxin type A, autologous whole blood, platelet-rich plasma (PRP), nonsteroidal anti-inflammatory drugs, dry needling, dextrose prolotherapy, and polydeoxyribonucleotide. Placebo arms included normal saline, local anesthetic, sham dry needling, and tibial nerve block. The minimum clinically important difference (MCID) was defined as -9 mm on a visual analog scale (VAS), which is substantially lower than the 30% or 20-mm decrease in VAS score for pain more typically used. Secondary outcomes included total and sub scores for the Foot Health Status Questionnaire (FHSQ), with an MCID defined as 7 on the FHSQ function and 9 on the FHSQ general foot health subscales. Overall, risk of bias was low for randomization and blinding of participants, high for blinding of personnel, and uncertain for allocation concealment and outcome reporting. Analysis found amniotic membrane had the highest probability for improvement in pain and composite outcomes in the short term. However, this finding was based only on 1 RCT. When the efficacy of amniotic membrane was compared to corticosteroid injections, the mean difference in VAS score was a modest at -7.32 out of 100 (95% CI, -11.2 to -3.38) and the mean difference in the FHSQ score was 31.2 (95% CI, 13.9 to 48.6). Outcomes at 2-to-6 months (7 RCTs) favored botulinum toxin for pain and PRP for composite outcomes.
One small (N=23), industry-sponsored, double-blind study found similar improvements with injection of amniotic membrane (Clarix® Flo) compared with corticosteroid injection. Another industry-sponsored, patient-blinded study by Zelen et al. (N=45) compared injection of saline to dehydrated amniotic membrane (AmnioFix®) 0.5 mL or 1.25 mL in patients with symptoms recalcitrant to conservative treatment. In the 2 amniotic membrane groups, scores on the American Orthopaedic Foot and Ankle Society hindfoot scale improved by about 50 points over the 8 weeks of the study compared with 10 points for controls (p <0.001). FACES pain scores decreased from 8.7 out of 10 at baseline to 0.8 at 8 weeks with amniotic membrane, compared with a decrease from 8.0 to 4.6 for controls (p <0.001). Longer follow-up is ongoing.
Surgical wound management
Mohs micrographic surgery
Toman, et al. (2022), conducted an observational study that compared repair using a dehydrated human amnion/chorion membrane product (dHACM, 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. 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. 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 observational design. 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. Additional evidence from well-designed and conducted prospective studies is needed.
In July 2021, ECRI published a Clinical Evidence Assessment, Stravix® Cryopreserved Placental Tissue (Osiris Therapeutics, Inc.) for Treating Surgical Wounds. As with other skins substitutes, Stravix® is intended as a substitute for skin autografts when harvesting skin is infeasible, impractical, or risky to the patient. In this report, ECRI concluded that there are too data available to draw conclusions as to the effectiveness of Stravix®. As with other products, controlled studies are needed for comparison with autografts and other skins substitutes.
In September 2021, ECRI also evaluated the use of AlloWrap®, a Clinical Evidence Assessment, as a tissue barrier for onlay or wrapping to reduce or prevent postoperative adhesions. This publication reported that there were no data available upon which to evaluate the use of AlloWrap® for preventing postsurgical adhesion.
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