BlueCross BlueShield of Tennessee Medical Policy Manual

Orthopedic Applications of Stem Cell Therapy


Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various musculoskeletal tissues. 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. Potential uses of MSCs for orthopedic applications include treatment of damaged bone, cartilage, ligaments, tendons and intervertebral discs. However, the ability to induce cell division and differentiation without adverse effects, such as the formation of neoplasms, remains a significant concern.

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 individuals.

Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials with MSCs and/or bioactive molecules such as growth factors. It is believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold or matrix, such as demineralized bone matrix (e.g., Vitoss® Bioactive Foam Bone Graft Substitute, CopiOs® Bone Void Filler, DBX® Demineralized bone matrix putty), culture conditions for tissue-specific induction, and implantation techniques that provide appropriate biomechanical support and stimulation.




This technology continues in the early stages of development. There remains a lack of evidence to determine if clinical outcomes are improved. The small randomized and nonrandomized comparative trials provide insufficient evidence to evaluate the effect on health outcomes.


Akgun, I., Unlu, M., Erdal, O., Ogut, T., Erturk, M., Ovali, E., et al. (2015). Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Archives of Orthopedic and Trauma Surgery, 135 (2), 251-263. Abstract retrieved January 18, 2017 from PubMed database.

American Academy of Orthopaedic Surgeons. (2009; last confirmed 2014).The treatment of glenohumeral joint osteoarthritis – guideline and evidence report. Retrieved October 17, 2018 from

American Association of Neurological Surgeons. (2014). 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. Retrieved October 18, 2018 from Journal of Neurosurgery Spine, 21 (1), 106-132.

BlueCross BlueShield Association. Evidence Positioning System. (1:2018). Orthopedic applications of stem-cell therapy (including allografts and bone substitutes used with autologous bone marrow) (8.01.52). Retrieved October 17, 2018 from  (38 articles and/or guidelines reviewed)

Borakati, A., Mafi, R., Mafi, P., & Khan, W.S. (2018). A systematic review and meta-analysis of clinical trials of mesenchymal stem cell therapy for cartilage repair. Current Stem Cell Research and Therapy, 13 (3), 215-225. Abstract retrieved October 18, 2018 from PubMed database.

Goldberg, A., Mitchell, K., Soans, J., Kim, L., & Zaidi, R. (2017). The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. Journal of Orthopaedic Surgery and Research, 12 (1), 39. (Level 1 evidence)

Pak, J., Lee, J., Park, K., Park, M., Lang, L., & Lee, S. (2017). Current use of autologous adipose tissue derived stromal vascular fraction cells for orthopedic applications. Journal of Biomedical Science, 24 (9). (Level 2 evidence)

Shapiro, S.A., Kazmerchak, S.E., Heckman, M.G., Zubair, A.C., & O’Connor, M.I. (2017). A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. American Journal of Sports Medicine, 45 (1), 82-90. Abstract retrieved October 18, 2018 from PubMed database.

Vega, A., Martin-Ferrero, M., Del Canto, F., Alberca, M., Garcia, V., Munar, A., et al. (2015). Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation, 99 (8), 1681-1690. Abstract retrieved January 18, 2017 from PubMed database.

Winifred S. Hayes, Inc. Medical Technology Directory. (2015, December; last search update November 2017). Autologous stem cell therapy for treatment of avascular necrosis of the hip. Retrieved October 17, 2018 from  (61 articles and/or guidelines reviewed)

Wong, K.L., Lee, K.B., Tai, B.C., Law, P., Lee, E.H., & Hui, J.H. (2013). 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, 29 (12), 2020-2028. Abstract retrieved January 18, 2017 from PubMed database.




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