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

Policy number: MA 2.080

Effective date 7/1/2026

Policy

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.

This medical policy applies to Medicare Advantage plans offered by Capital Blue Cross and its subsidiaries.

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

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.
• 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 systematic reviews, randomized controlled trials (RCTs) and observational studies. 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. Recent systematic reviews have reported that intra-articular MSCs offer little to no pain relief for knee osteoarthritis (OA), with possible slight functional improvement and increased adverse events. For hip OA, MSCs show some benefit in pain and function but evidence is limited by small studies and inconsistent protocols. Overall, the quality of evidence is low and there is a possibility of publication bias. The strongest evidence to date is on autologous MSCs expanded from bone marrow, which includes several phase 1/2 RCTs and a phase 3 RCT (which also evaluated other cell therapies). The phase 3 trial did not indicate significant improvements with the cell therapy modalities relative to active-control intra-articular corticosteroid injections for patients with knee OA after 12 months of follow-up. Another recent phase 3 RCT evaluated autologous MSCs expanded from abdominal adipose tissue for treatment of knee OA ; this trial indicated autologous adipose-derived MSCs were more effective than matching placebo injections in improving pain, function, and other patient-reported outcomes after 6 months of follow-up. These phase 3 trials' mixed findings may be related to differences in the cell therapy modalities used, baseline cohort characteristics, and/or the use of an active vs placebo control.

Alternative methods of obtaining MSCs have been reported in a smaller number of trials and with mixed results. Current evidence regarding the application of allografts combined with stem cells for bone fusion in the extremities or spine, as well as for the treatment of nonunion, remains limited. Several early-phase, industry-sponsored trials have been reported. Clinical studies involving moldable cellular bone allografts have demonstrated high fusion rates at 12 months in lumbar, cervical, and foot and ankle procedures. These studies also note significant improvements in disability and pain scores, with few serious graft-related adverse events. However, the data are drawn primarily from nonrandomized, small-scale, and largely retrospective studies. Additional study with longer follow-up is needed to evaluate the long-term efficacy and safety of these procedures. Also, expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration approved (concentrated autologous MSCs do not require agency approval). Overall, there is a lack of clear evidence that clinical outcomes are improved. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Definitions

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.

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These polices are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding Information

Note: This list of codes is not exhaustive and may change from time to time as permitted by law or applicable clinical guidelines. The inclusion of a code in this section is not a guarantee of coverage or payment. In addition, not all covered services are eligible for separate reimbursement.

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).

References

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. Updated July 21, 2020. Accessed November 23, 2025.
3. Jin WS, Yin LX, Sun HQ, et al. Mesenchymal Stem Cells Injection Is More Effective Than Hyaluronic Acid Injection in the Treatment of Knee Osteoarthritis With Similar Safety: A Systematic Review and Meta-analysis. Arthroscopy. Feb 2025; 41(2): 318-332. PMID 39154667
4. Sadeghirad B, Rehman Y, Khosraviarad A, et al. Mesenchymal stem cells for chronic knee pain secondary to osteoarthritis: A systematic review and meta-analysis of randomized trials. Osteoarthritis Cartilage. Oct 2024; 32(10): 1207-1219. PMID 38777213
5. 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
6. 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
7. Kim SH, Djaja YP, Park YB, et al. Intra-articular Injection of Culture-Expanded Mesenchymal Stem Cells Without Adjuvant Surgery in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Am J Sports Med. Sep 2020; 48(11): 2839-2849. PMID 31870444
8. Jin L, Yang G, Men X, et al. Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy: A Systematic Review and Meta-analysis. Orthop J Sports Med. Nov 2022; 10(11): 23259671221133784. PMID 36452339
9. Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. Dec 2013; 29(12): 2020-8. PMID 24286801
10. Emadedin M, Labibzadeh N, Liastani MG, et al. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. Oct 2018; 20(10): 1238-1246. PMID 30318332
11. 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: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J Transl Med. Jul 31 2018; 16(1): 213. PMID 30064455
12. 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
13. 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. Dec 2023; 29(12): 3120-3126. PMID 37994338
14. Loke RYJ, Chu Z, Liang J, et al. Allogenic MSCs are a safe and efficacious treatment for knee osteoarthritis: A systematic review of randomised controlled trials. J Exp Orthop. Jul 2025; 12(3): e70437. PMID 40980258
15. 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
16. Tangkanananukul P, Khuangsrikul S, Heebthamai D, et al. Cartilage Regeneration Potential in Early Osteoarthritis of the Knee: A Prospective, Randomized, Open, and Blinded Endpoint Study Comparing Adipose-Derived Mesenchymal Stem Cell (ADSC) Therapy Versus Hyaluronic Acid. Int J Mol Sci. Aug 31 2025; 26(17). PMID 40943401
17. Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy. Nov 2014; 30(11): 1453-60. PMID 25108907
18. 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
19. 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
20. Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. Apr 2013; 29(4): 684-94. PMID 23380320
21. 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
22. 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
23. 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
24. Vangsness CT, Farr J, Boyd J, et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. Jan 15 2014; 96(2): 90-8. PMID 24430407
25. Orthofix Announces Full Market Release and Launch of Trinity ELITE. Published July 1, 2013. Accessed November 21, 2025.
26. Wind J, Park D, Lansford T, et al. Twelve-Month Results from a Prospective Clinical Study Evaluating the Efficacy and Safety of Cellular Bone Allograft in Subjects Undergoing Lumbar Spinal Fusion. Neurol Int. Oct 26 2022; 14(4): 875-883. PMID 36412692
27. Lansford T, Park DK, Wind JJ, et al. High Lumbar Spinal Fusion Rates Using Cellular Bone Allograft Irrespective of Surgical Approach. Int J Spine Surg. Sep 12 2024; 18(4): 355-364. PMID 39054302
28. Park DK, Wind JJ, Lansford T, et al. Twenty-four-month interim results from a prospective, single-arm clinical trial evaluating the performance and safety of cellular bone allograft in patients undergoing lumbar spine fusion. BMC Musculoskelet Disord. Nov 17 2023; 24(1): 895. PMID 37978378
29. Russo A, Park DK, Lansford T, et al. Impact of surgical risk factors for non-union on lumbar spinal fusion outcomes using cellular bone allograft at 24-months follow-up. BMC Musculoskelet Disord. May 03 2024; 25(1): 351. PMID 38702654
30. Sayeed A, Jawad A, Zakko P, et al. Radiographic Fusion Outcomes for Trinity Cellular Based Allograft versus Local Bone in Posterolateral Lumbar Fusion. J Am Acad Orthop Surg Glob Res Rev. Apr 01 2024; 8(4). PMID 38648399
31. Goldman SN, Paschal GK, Mani K, et al. Efficacy of an allograft cellular bone matrix as an alternative to autograft in anterior cervical discectomy and fusion: radiological results and safety. J Spine Surg. Sep 23 2024; 10(3): 372-385. PMID 39399080
32. Donahue P. Radiographical outcomes of a cellular based allograft following foot/ankle arthrodesis in patients with risk for non-union. Orthop Rev (Pavia). 2024; 16: 115603. PMID 38562146
33. Vanichkachorn J, Peppers T, Bullard D, et al. A prospective clinical and radiographic 12-month outcome study of patients undergoing single-level anterior cervical discectomy and fusion for symptomatic cervical degenerative disc disease utilizing a novel viable allogeneic, cancellous, bone matrix (trinity evolution™) with a comparison to historical controls. Eur Spine J. Jul 2016; 25(7): 2233-8. PMID 26849141
34. Peppers TA, Bullard DE, Vanichkachorn JS, et al. Prospective clinical and radiographic evaluation of an allogeneic bone matrix containing stem cells (Trinity Evolution® Viable Cellular Bone Matrix) in patients undergoing two-level anterior cervical discectomy and fusion. J Orthop Surg Res. Apr 26 2017; 12(1): 67. PMID 28446192
35. Jones CP, Loveland J, Atkinson BL, et al. Prospective, Multicenter Evaluation of Allogeneic Bone Matrix Containing Viable Osteogenic Cells in Foot and/or Ankle Arthrodesis. Foot Ankle Int. Oct 2015; 36(10): 1129-37. PMID 25976919
36. Eastlack RK, Garfin SR, Brown CR, et al. Osteocel Plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine (Phila Pa 1976). Oct 15 2014; 39(22): E1331-7. PMID 25188591
37. Li J, Su P, Li J, et al. Efficacy and Safety of Stem Cell Combination Therapy for Osteonecrosis of the Femoral Head: A Systematic Review and Meta-Analysis. J Healthc Eng. 2021; 2021: 9313201. PMID 34608416
38. American Academy of Orthopaedic Surgeons. Management of Glenohumeral Joint Osteoarthritis Evidence-Based Clinical Practice Guideline. Updated March 23, 2020. Accessed November 25, 2025.
39. American Academy of Orthopaedic Surgeons. Management of Osteoarthritis of the Knee (Non-Arthroplasty). Updated August 31, 2021. Accessed November 25, 2025.
40. American Academy of Orthopaedic Surgeons. Management of Osteoarthritis of the Hip. Updated December 1, 2023. Accessed November 25, 2025.
41. American Academy of Orthopaedic Surgeons. Orthobiologics (Regenerative Medicine) FAQ. Updated May 2023. Accessed November 25, 2025.
42. Kaiser MG, Groff MW, Watters WC, et al. Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes as an adjunct for lumbar fusion. J Neurosurg Spine. Jul 2014; 21(1): 106-32. PMID 24980593
43. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res (Hoboken). Feb 2020; 72(2): 149-162. PMID 31908149
44. Department of Veterans Affairs/Department of Defense. VA/DoD Clinical Practice Guideline for the Non-Surgical Management of Hip & Knee Osteoarthritis. Published 2020. Accessed November 24, 2025.

Policy History

• MA 2.080
• 06/04/2025 Policy creation. Adopted complete commercial policy.
• 03/16/2026 Consensus Review. Updated background, rationale, and references. No changes to coding.

Plans issued by Capital Blue Cross and it’s subsidiaries are independent licensees of the Blue Cross Blue Shield Association. Communications issued by Capital Blue Cross in its capacity as administrator of programs and provider relations for all companies.

Health care benefit programs issued or administered by Capital Blue Cross and/or its subsidiaries, Capital Advantage Insurance Company^®, Capital Advantage Assurance Company^® and Keystone Health Plan^® Central. Independent licensees of the Blue Cross BlueShield Association. Communications issued by Capital Blue Cross in its capacity as administrator of programs and provider relations for all companies.