Orthopedic Applications of Stem-Cell Therapy (Including Allograft and Bone Substitute Products Used with Autologous Bone Marrow)

Número de política: MA 2.080

Fecha de entrada en vigencia: 10/1/2025

Política

Mesenchymal stem cell therapy is considered investigational for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

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. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered investigational for all orthopedic applications. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Policy Guidelines

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).

Regenexx is an example of mesenchymal stem cell therapy.

AlloStem, Osteocel, Osteocel Plus, and Trinity Evolution are examples of demineralized bone matrix with stem cells.

Cross-References:

• MP 2.033 Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Non-Orthopedic Conditions
• MP 4.039 Orthopedic Applications of Platelet Rich Plasma

Product Variations

Esta política solo se aplica a ciertos programas y productos administrados por Capital Blue Cross y está sujeta a variaciones en los beneficios, como se explica en la Sección VI. Please see additional information below

FEP PPO - Refer to FEP Medical Policy Manual.

Description/Background

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are multipotent cells (also called stromal multipotent 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 bone marrow, synovium, fat, and muscle, where they can be mobilized for endogenous repair as occurs with healing of bone fractures. Tissues, such as muscle, cartilage, tendon, ligaments, and vertebral discs, show limited capacity for endogenous repair because of the limited presence of the triad of tissue functional 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 treatment of musculoskeletal disease. However, harvesting MSCs from bone marrow requires a procedure that may result in donor-site morbidity. In addition, 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.

Regulatory Status

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. MSCs are included in these regulations.

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

Concentrated autologous MSCs do not require approval by FDA. No products using engineered or expanded MSCs have been approved by 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) is a dehydrated moldable DBM scaffold (strips and cubes) that will absorb autologous bone marrow aspirate;
• Ignite^® (Wright Medical) is 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. FDA product code: MQV.

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 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 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:
• 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
• 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.

Rational

Summary of Evidence

For individuals who have cartilage defects, meniscal defects, joint fusion procedures, or osteonecrosis who receive stem cell therapy, the evidence includes small randomized controlled trials (RCTs) and nonrandomized comparative trials. Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life, and treatment-related morbidity. Use of mesenchymal stem cells (MSCs) for orthopedic conditions is an active area of research. Despite continued research into the methods of harvesting and delivering treatment, there are uncertainties regarding the optimal source of cells and the delivery method. Studies have included MSCs from bone marrow, adipose tissue, and peripheral blood. Overall, the quality of evidence is low and there is a possibility of publication bias. The strongest evidence to date is on MSCs expanded from bone marrow, which includes several phase 1/2 randomized controlled trials. Limitations in these initial trials preclude reaching conclusions, but the results to date do support future study in phase 3 trials. Alternative methods of obtaining MSCs have been reported in a smaller number of trials and with mixed results. Additional study in a larger sample of patients with longer follow-up would be needed to evaluate the long-term efficacy and safety of these procedures. Also, expanded MSCs for orthopedic applications are not FDA approved (concentrated autologous MSCs do not require agency approval). Overall, there is a lack of evidence that clinical outcomes are improved. The evidence is insufficient to determine the effects of the technology on health outcomes.

Definiciones

Allograft - a tissue graft from a donor of the same species as the recipient but not genetically identical.

Autologous - originating within an individual, (i.e., self-donation.)

Mesenchymal Stem Cells (MSC) – adult stem cells that are multipotent and can differentiate into several different specialized cell types.

Exención de responsabilidad

Las políticas médicas de Capital Blue Cross se utilizan para determinar la cobertura de tecnologías, procedimientos, equipos y servicios médicos específicos. Estas políticas médicas no constituyen un consejo médico y están sujetas a cambios según lo exija la ley o la evidencia clínica aplicable de las pautas de tratamiento independientes. Los proveedores que brindan tratamiento son individualmente responsables de los consejos médicos y el tratamiento de los miembros. These polices are not a guarantee of coverage or payment. El pago de las reclamaciones está sujeto a la determinación del programa de beneficios del miembro y la elegibilidad en la fecha del servicio, y a la determinación de que los servicios son médicamente necesarios y apropiados. El procesamiento final de una reclamación se basa en los términos del contrato que se aplican al programa de beneficios de los miembros, incluidas las limitaciones y exclusiones de beneficios. Si un proveedor o miembro tiene alguna pregunta sobre esta política médica, debe comunicarse con Servicios para proveedores o Servicios para miembros de Capital Blue Cross.

Coding Information

Nota: Es posible que esta lista de códigos no sea exhaustiva y que los códigos estén sujetos a cambios en cualquier momento. La identificación de un código en esta sección no denota cobertura, ya que la cobertura está determinada por los términos de la información de beneficios del miembro. Además, no todos los servicios cubiertos son elegibles para un reembolso por separado. Los códigos deben estar en orden numérico.

Investigational; therefore, not covered:

^*Use for aspiration of bone marrow for the purpose of bone grafting, other than spine surgery and other therapeutic musculoskeletal applications (e.g. Regenexx).

Referencias

1. Goldberg A, Mitchell K, Soans J, et al. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J Orthop Surg Res. Mar 09 2017; 12(1): 39. PMID 28279182
2. U.S. Food & Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use
3. Borakati A, Mafi R, Mafi P, et al. A Systematic Review And Meta-Analysis of Clinical Trials of Mesenchymal Stem Cell Therapy for Cartilage Repair. Curr Stem Cell Res Ther. Feb 23 2018; 13(3): 215-225. PMID 28914207
4. Maheshwer B, Polce EM, Paul K, et al. Regenerative Potential of Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis and Chondral Defects: A Systematic Review and Meta-analysis. Arthroscopy. Jan 2021; 37(1): 362-378. PMID 32497658
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8. Giorgino R, Alessandri Bonetti M, Migliorini F, et al. Management of hip osteoarthritis: harnessing the potential of mesenchymal stem cells-a systematic review. Eur J Orthop Surg Traumatol. Dec 2024; 34(8): 3847-3857. PMID 39254726
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10. Wakitani S, Nawata M, Tensho K, et al. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. Jan-Feb 2007; 1(1): 74-9. PMID 18038395
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16. Lamo-Espinosa JM, Mora G, Blanco JF, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. Aug 26 2016; 14(1): 246. PMID 27565858
17. Mautner K, Gottschalk M, Boden SD, et al. Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial. Nat Med. Nov 02 2023. PMID 37919438
18. Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Transplantation. Aug 2015; 99(8): 1681-90. PMID 25822648
19. Shapiro SA, Kazmerchak SE, Heckman MG, et al. A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am J Sports Med. Jan 2017; 45(1): 82-90. PMID 27566242
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21. Zaffagnini S, Andriolo L, Boffa A, et al. Microfragmented Adipose Tissue Versus Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Prospective Randomized Controlled Trial at 2-Year Follow-up. Am J Sports Med. Sep 2022: 50(11): 2881-2892. PMID 35984721
22. Kim KI, Lee MC, Lee JH, et al. Clinical Efficacy and Safety of the Intra-articular Injection of Autologous Adipose-Derived Mesenchymal Stem Cells for Knee Osteoarthritis: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial. Am J Sports Med. Jul 2023; 51(9): 2243-2253. PMID 37345256
23. Lim HC, Park YB, Ha CW, et al. Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation Versus Microfracture for Large, Full-Thickness Cartilage Defects in Older Patients: A Multicenter Randomized Clinical Trial and Extended 5-Year Clinical Follow-up. Orthop J Sports Med. Jan 2021; 9(1): 2325967120973052. PMID 33490296
24. Xiao Z, Wang X, Li C, et al. Effects of the umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis: A systematic review and meta-analysis. Medicine (Baltimore). Nov 15 2024; 103(46): e40490. PMID 39560593
25. Whitehouse MR, Howells NR, Parry MC, et al. Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study. Stem Cells Transl Med. Apr 2017; 6(4): 1237-1248. PMID 28186682
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Historial de políticas

• MA 2.080 - 06/04/2025 Policy Creation. Adopted complete commercial policy