LCD L39128: Amniotic and Placental-Derived Product Injections and/or Applications for Musculoskeletal Indications, Non-Wound

This is a NON-coverage policy for all amniotic membrane, amniotic fluid, or other placental-derived product injections and/or applications as a means of managing musculoskeletal injuries, joint conditions, and all other conditions not stated below.

This guidance does NOT include discussion on burns, wounds, or ophthalmic conditions.

NOTE: For information on stem cell transplantation please see the Centers for Medicare & Medicaid Services (CMS) National Coverage Determination (NCD) §110.23 Stem Cell Transplantation.

Introduction

Amniotic and placental-derived products are known to possess certain beneficial characteristics. These products have been identified as a source of stem cells. Stem cells, by definition, have the capability to differentiate into any cell of an organism as well as the capability of self-renewal. 1 In addition, the extracellular matrix (ECM) of placental and amniotic-based tissues are rich in collagen, glycoproteins, proteoglycans, fibroblasts, as well as many cytokines and growth factors thought to promote healing with a lower risk of low immunologic reaction.

Based on these characteristics, amniotic and placental-derived products are currently being studied and heavily marketed as allografts that serve as:

• scaffolds for tissue engineering

• membrane covering certain burns, wounds, and ophthalmic corneal injuries

• micronized/particulate products suspended in an aqueous material to be applied topically or injected into joints, tendons, ligaments

• applications or injections performed intra-operatively to promote post-operative healing

These amniotic and placental-derived products are further being investigated for a multitude of indications, including but not limited to musculoskeletal conditions involving joint pain and back pain, chronic pain in general, dental conditions, alopecia, wounds, burns, and a plethora of others. In the quest to find alternative non-operative treatments for certain musculoskeletal conditions, the emergence of a class of substances being marketed as “orthobiologics” has become more prevalent in the pharmaceutical market. “Orthobiologics” are biological products aimed at treating musculoskeletal conditions to heal injury/trauma and/or slow down degenerative conditions if not effectuate regeneration of tissues. 2 The result ideally would be decreased pain and increased function. One such category of orthobiologics involves the incorporation of human amniotic and placental-derived products.

The amniotic and placental-derived products are obtained from the placenta of donors, usually, immediately post caesarean-section at full term, and screened for transmittable diseases. These products are made up of varying combinations of amniotic membrane, amniotic fluid, chorionic membrane, umbilical cord, umbilical cord blood, and what is known as Wharton’s jelly. 3

Definitions:

The Placenta is a multi-layered circulatory temporary organ that supplies food and oxygen to the fetus during pregnancy. The multiple layers of the placenta include the:

• Amnion - the innermost membrane that surrounds the fetus during gestation

• Chorion - outermost membrane that surrounds the fetus during gestation

Amniotic fluid is the fluid surrounding the fetus within the amnion.

Umbilical cord is the cord connecting the fetus to the placenta comprised of the umbilical vein, arteries, allantois, and yolk sac embedded in Wharton’s jelly.

Wharton’s Jelly is a gelatinous soft connective tissue derived from extra-embryonic mesoderm within the umbilical cord. 4

The amniotic membrane itself is divided into 3 histologic layers:

• A single epithelial layer

• A thick basement membrane

• An avascular stromal (mesenchymal) layer 5,6,7,8

The avascular stromal layer is further divided into 3 layers: 6,7,8

• The Compact layer

• The middle Fibroblast layer

• The Spongy layer

The Spongy Layer , loosely connected to the chorionic membrane, is highly concentrated with proteoglycans and glycoproteins, including hyaluronic acid (HA), as well as type I, III, and IV collagen. 5,6,8,9

The middle Fibroblast layer is made up of type I, III, V, and VI collagen. 6,8,9

The Compact layer that sits adjacent to the basement membrane is composed of collagen types I, III, V, and VI, along with fibronectin. 5,9

The basement membrane anchors the epithelial layer and contains collagen types IV, V and VII, fibronectin, laminin, and HA. 6,10

Adjacent to the basement membrane and in immediate contact with the amniotic fluid is the single layer of epithelial cells. Amniotic epithelial cells produce type III and IV collagen, glycoproteins such as laminin and fibronectin, which in turn form the basement membrane. 5

The amniotic membrane’s purpose is to house and physically protect the fetus, but some additional functions include regulation of the pH of the amniotic fluid, transportation of water and soluble material between the mother and fetus, and the synthesis of numerous growth factors and cytokines. The amniotic membrane also secretes anti-inflammatory proteins. All of this results in these tissues having anti-inflammatory, anti-microbial, anti-fibroblastic, and non-immunogenic properties.

Amniotic products have been identified as sources of stem cells. Both the amniotic epithelial layer (maternal derived cells) and mesenchymal (avascular stromal) layer derived from the embryonic mesoderm contain their respective stem cells that can differentiate into multiple cell lines, including myocytes, osteocytes, and chondrocytes. 8,9 Amniotic fluid also is found to contain amniotic mesenchymal stem cells. 7

The chorionic membrane connected adjacent to the mother’s endometrium during the development of the fetus, umbilical cord, Wharton’s jelly, and umbilical cord blood have also been found to contain mesenchymal stem cells. 7,11

Under normal conditions, placental tissues are collected via aseptic technique during cesarean section. From there, protocols vary as to how the tissues are harvested, prepared, preserved, and stored. Testing is also required to ensure these tissues do not carry any communicable diseases transmittable from donor to recipient.

Because the spongy layer loosely connects the amniotic membrane to the chorionic membrane, these 2 layers are easily separated upon initial harvesting by blunt dissection. 10 Other than ease of separation between amniotic and chorionic membranes, the following steps in processing the tissues into the desired form vary based on which portions of the placental tissues are utilized, what sterilization processes (if any) are undertaken, and what method of preservation is used. Common methods of preservation include cryopreservation, lyophilization (freeze-drying), glycerol-preservation, γ (gamma)-sterilization, low heat dehydration, and vitrification, to name a few. 5,8,9,10

A process called “Decellularization” may be used in which the layer of amniotic epithelial cells is removed from the collected amniotic membrane, leaving behind the valuable ECM components. By removing all cellular components, it is thought that there is less possibility of eliciting an immunogenic response. 3,10 Different decellularization processes are available. Finally, preparation in the form of sheets, cutting into small particulates, processing into a liquid form, along with re-suspension in varying solutions are additional steps that may occur in order to reach the desired final product.

Depending on the methods utilized, the processing of placental and amniotic-based tissues into their final form will affect the viability of cellular components, growth factors, and other valuable properties that these tissues are known for. To date, there are significant differences that exist in the processing of different placental and amniotic-based tissue products. 3,5 Further complicating matters, some manufacturers have their own “proprietary” manufacturing processes, which make it impossible to determine if there is any consistency and standardization in the final product form, characteristics, properties, and components.

Further complicating matters is the fact that there is no standard formulation, dose, or frequency of administration available or considered standard of care in treatment with these types of products.

Despite this lack of standardization in composition, dosing, or administration, numerous amniotic and placental-derived products are flooding the market for use in treatment of musculoskeletal conditions. These conditions include, but are not limited to tendon/ligament injuries, musculoskeletal injuries, cartilage damage, osteoarthritis, (or pain related of these conditions) as well as an adjunct in orthopedic surgical treatments. In light of the lack of standardization of composition, the remainder of this Local Coverage Determination (LCD) will use the term amniotic and placental-derived products to mean ANY product derived from ANY combination of amniotic membrane/chorion/placenta/Wharton’s jelly/umbilical cord/amniotic fluid/umbilical cord blood.

Although amniotic and placental-derived products are marketed to treat certain musculoskeletal conditions, there is only a paucity of accompanying human clinical trials available regarding safety and efficacy.

Literature Inclusion/Exclusion Protocol

A comprehensive literature search of PubMed was performed. Only full text published studies of the musculoskeletal conditions listed below were included. Individual papers within systematic reviews were analyzed. Relevant clinical studies with at least 10 patients per group not included in the systematic reviews were also reviewed. Four level I randomized controlled trial (RCT) studies were identified and analyzed for certainty of evidence and risk of bias. There were 6 systematic reviews and 2 meta-analyses examined. These included studies that were already identified with the search parameters. Eleven non-randomized studies were reviewed. Weakness in the literature included lack of standardization of these products, heterogeneous applications (or intended uses), variations in length of treatment/follow up, lack of comparators/controls, and high risk of bias due to lack of blinding, allocation concealment, publication bias, as well as conflicts of interests by authors. While there was a trend toward a positive benefit for amniotic and placental-derived product injections, the evidence is insufficient to determine efficacy or safety for musculoskeletal indications. While studies did not report adverse effects other than pain with injections, they were not adequately powered or designed to access safety and long-term outcomes.

NOTE: The musculoskeletal conditions listed below were the currently identified conditions discussed within that resulting body of evidence. Other musculoskeletal conditions not singled out in this evidentiary analysis section were those without a critical mass of reviewable literature.