Orthopedic Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used with Autologous Bone Marrow)

POLICY NUMBER

A.8.01.52

DESCRIPTION

Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various musculoskeletal tissues. Potential uses of MSCs for orthopedic applications include treatment of damaged bone, cartilage, ligaments, tendons, and intervertebral discs.

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are multipotent cells (also called multipotent stromal cells) that can differentiate into various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs are associated with the blood vessels within the bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with the healing of bone fractures. Tissues such as cartilage, tendon, ligaments, and vertebral discs, show limited capacity for endogenous repair because of the limited presence of the triad of functional tissue components: vasculature, nerves, and lymphatics. Orthobiologics is a term introduced to describe interventions using cells and biomaterials to support healing and repair. Cell therapy is the application of MSCs directly to a musculoskeletal site. Tissue engineering techniques use MSCs and/or bioactive molecules such as growth factors and scaffold combinations to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues.

Bone marrow aspirate is considered the most accessible source, and thus, the most common place to isolate MSCs for the treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires a procedure that may result in donor-site morbidity. Also, the number of MSCs in bone marrow is low, and the number and differentiation capacity of bone marrow-derived MSCs decreases with age, limiting their efficiency when isolated from older patients.

In vivo, the fate of stem cells is regulated by signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, culture conditions for tissue-specific induction, and implantation techniques that provide appropriate biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors), and implantation techniques, each preparation must be individually examined.

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, Title 21, parts 1270 and 1271. Mesenchymal stem cells (MSCs) are included in these regulations.

The regulatory status of the stem cell or stem cell-containing products addressed in this policy is summarized below.

Concentrated autologous MSCs do not require approval by the FDA. No products using engineered or expanded MSCs have been approved by the FDA for orthopedic applications.

The following products are examples of commercialized demineralized bone matrix (DBM) products. They are marketed as containing viable stem cells. In some instances, manufacturers have received communications and inquiries from the FDA related to the appropriateness of their marketing products that are dependent on living cells for their function. The following descriptions are from the product literature.

• Allostem® (AlloSource) is a partially demineralized allograft bone seeded with adipose-derived MSCs.

• Map3® (RTI Surgical) contains cortical cancellous bone chips, DBM, and cryopreserved multipotent adult progenitor cells (MAPC®).

• Osteocel Plus® (NuVasive) is a DBM combined with viable MSCs isolated from allogeneic bone marrow.

• Trinity Evolution Matrix™ (Orthofix) is a DBM combined with viable MSCs isolated from allogeneic bone marrow.

• Other products contain DBM alone and are designed to be mixed with bone marrow aspirate:

  • Fusion Flex™ (Wright Medical): a dehydrated moldable DBM scaffold (strips and cubes) that will absorb autologous bone marrow aspirate.

  • Ignite® (Wright Medical): an injectable graft with DBM that can be combined with autologous bone marrow aspirate.

A number of DBM combination products have been cleared for marketing by the FDA through the 510(k) process.

Tables 1 and 2 provide a representative sample of these products, differentiated by whether they must be mixed with autologous MSCs.

Table 1. Examples of Demineralized Bone Matrix Products Cleared by the FDA that Do Not Require Mixing with Autologous MSCs

FDA: U.S. Food and Drug Administration; MSCs: mesenchymal stem cells.

Table 2. Examples of Demineralized Bone Matrix Products Cleared by the FDA that Require Mixing with Autologous MSCs

FDA: U.S. Food and Drug Administration; MSCs: mesenchymal stem cells.

In 2020, the FDA updated their guidance on "Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use."

Human cells, tissues, and cellular and tissue-based products (HCT/P) 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.

An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria:

"1) The HCT/P is minimally manipulated;

 2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;

3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and

4) Either:

i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or

ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:

a) Is for autologous use;

b) Is for allogeneic use in a first-degree or second-degree blood relative; or

c) Is for reproductive use."

The FDA does not consider the use of stem cells for orthopedic procedures to be homologous use.

Related medical policies include  Recombinant and Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions and Autologous Chondrocyte Implantation for Focal Articular Cartilage Lesions .

POLICY

Mesenchymal stem cell therapy is considered investigational for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue.

Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, are considered investigational for all orthopedic applications.

Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered investigational for all orthopedic applications.

POLICY EXCEPTIONS

None 

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

This policy does not address unprocessed allograft bone or products that do not require mixing with stem cells (product examples are shown in Tables 1 and 2 for informational purposes).

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

07/22/2010: Approved by Medical Policy Advisory Committee

06/22/2011: Policy reviewed; no changes.

05/09/2012: Policy reviewed; no changes.

09/03/2013: Policy description updated regarding available products. Added the following investigational policy statement: Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM) with stem cells, is considered investigational for all orthopedic applications.

07/09/2014: Policy reviewed; description updated regarding DBM products. Policy statement unchanged.

08/03/2015: Code Reference section updated for ICD-10.

11/12/2015: Policy title changed from "Orthopedic Applications of Stem Cell Therapy" to "Orthopedic Applications of Stem Cell Therapy (Including Allograft and Bone Substitute Products Used With Autologous Bone Marrow." Policy description updated regarding available products. Added the following policy statement: Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered investigational for all orthopedic applications. Policy guidelines updated to state that this policy does not address unprocessed allograft bone. Investigative definition updated.

03/09/2016: Policy title changed from "Orthopedic Applications of Stem Cell Therapy (Including Allograft and Bone Substitute Products Used with Autologous Bone Marrow)" to "Orthopedic Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used With Autologous Bone Marrow)." Policy reviewed; no changes.

05/26/2016: Policy number A.8.01.52 added.

08/14/2017: Policy description updated regarding FDA regulations and products. Policy statements unchanged.

02/13/2018: Policy description updated. Policy statements unchanged.

03/18/2019: Policy reviewed; no changes.

02/26/2020: Policy description updated regarding FDA regulations for human cells, tissues, and cellular and tissue-based products. Policy statements unchanged.

03/29/2021: Policy description updated regarding devices and FDA guidance. Policy statements unchanged.

02/21/2022: Policy reviewed; no changes.

03/13/2023: Policy reviewed; no changes.

02/27/2024: Policy description updated regarding examples of demineralized bone matrix products. Policy statements unchanged. Policy Guidelines updated to clarify that this policy does not address unprocessed allograft bone or products that do not require mixing with stem cells.

04/08/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 8.01.52 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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