Mesenchymal stem cells (MSCs) are progenitor cells located in the bone marrow that may develop into connective tissue and bone (Shen, 2005). Mesenchymal stem cell therapy refers to the procurement (through autologous or cadaveric allogeneic bone marrow stem cell harvest) of MSCs, processing and subsequent infusion or implantation of the MSCs into various anatomic areas to promote healing or regeneration of damaged cartilage or bone. This document addresses the use of MSC therapy for regeneration in orthopedic (e.g., cartilage or bone) indications.

Note: For additional information please see the following:

• TRANS.00022 Autologous Cell Therapy for the Treatment of Damaged Myocardium
• TRANS.00036 Stem Cell Therapy for Peripheral Vascular Disease
• SURG.00011 Autologous, Allogeneic, Xenographic, Synthetic and Composite Products for Wound Healing and Soft Tissue Grafting
• SURG.00059 Recombinant Human Bone Morphogenetic Protein
• SURG.00093 Treatment of Osteochondral Defects of the Knee and Ankle 

Investigational and Not Medically Necessary:

Mesenchymal stem cell therapy is considered investigational and not medically necessary for treatment of orthopedic indications.

Tendon, ligament, cartilage and bone defects have typically been surgically repaired and may be augmented by utilizing autologous grafts, cadaveric allografts or synthetic grafts. However, there have been limitations to the graft sources such as comorbid conditions, and limited autologous grafts as well as graft failures. Therefore, alternative regenerative technologies continue to be investigated.

Various agents and techniques to procure and expand mesenchymal stem cells to achieve sufficient numbers for infusion or implantation are being studied and utilized in proprietary processes for diverse orthopedic indications. The processing of cadaveric allogeneic donor MSCs typically involves proprietary techniques and combination of MSCs with various transport medium. However, there is a paucity of randomized controlled trials in humans to support the safety and efficacy of using mesenchymal stem cell therapy for orthopedic indications, including cartilage and ligament repair and bone regeneration.

At this time, the medical evidence supporting the use of mesenchymal stem cells for orthopedic indications is limited to a series of animal studies and small case series without long-term follow-up results. This novel approach has not demonstrated in randomized controlled trials an improved and durable health outcome benefit over standard therapies.

In a pilot study of seven individuals with skeletal defects of the femur and tibia, Kitoh (2004) used mesenchymal stem cells in a gel suspension during ten distraction osteogenesis procedures to lengthen limbs. The goal was to reduce the treatment period and complications, which included pin loosening, pin track infections, delayed consolidation, joint contractures and fractures. Only three individuals were assessable after pin removal. The authors compared results from two of the three mesenchymal transplant individuals, to eight historic cases treated at the same institution, with an average healing index of 22.0 days/centimeter (cm) and 37.8 days/cm, respectively. The investigators noted the healing index is "based on various parameters such as the patient's age, amount of length gained, and the location of the osteotomy." Additional study is required to determine the optimal amount and type of mesenchymal stem cells for transplantation, and to evaluate long-term outcomes.

Wakitani and colleagues (2004) conducted a pilot study using autologous bone marrow mesenchymal cell therapy to repair nine full-thickness cartilage defects in the patello-femoral joints of three individuals. The assessment of clinical symptoms were rated with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC score), with zero being the worst and one hundred being the best rating. IKDC scores improved for all three individuals during the follow-up period ranging from 7 to 20 months after receiving mesenchymal therapy. In all three cases, the investigators were unable to confirm the material covering the defects was in fact hyaline cartilage resulting from mesenchymal cell therapy.

Currently, there are ongoing clinical trials to investigate the effects of mesenchymal stem cell therapy in open tibial fractures, lumbar fusion, osteoarthritis, cartilage defects and meniscectomy (U.S. National Institutes of Health).

The American Academy of Orthopaedic Surgeons (2007) provides information on stem cells:

Bone marrow stromal cells are mesenchymal stem cells that, in the proper environment, can differentiate into cells that are part of the musculoskeletal system. They can help to form trabecular bone, tendon, articular cartilage, ligaments and part of the bone marrow.

At this point, stem cell procedures in orthopaedics are still at an experimental stage. Most procedures are performed at research centers as part of controlled clinical trials.

In a systematic review by Longo and colleagues (2011), the use of MSC therapy for repair of tendon injuries "are at an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion."

Although results of small case series suggest that MSC therapy may improve regeneration of bone or tissue in orthopedic indications, the lack of adequate controls, randomization and blinding and the small sample sizes preclude definitive conclusions regarding the net health benefit of MSC therapy.

MSCs are being investigated as a regenerative biologic agent because of the ability to differentiate into multiple tissue types and to self-renew (Bonab, 2006). The MSC population in bone marrow is estimated at 1 in 3.1 x10⁴ mononuclear cells, and is even lower in cord blood or peripheral blood (Bonab, 2006). Although other sources for MSCs have been identified, the bone marrow is currently the primary source of procurement.

Mesenchymal stem cell therapy has been proposed as a treatment option for orthopedic indications that include torn cartilage, osteoarthritis, and bone grafting. The proposed benefits of mesenchymal stem cell therapy are improved healing and possible avoidance of surgical procedures with protracted recovery times.

Optimal materials or grafts that promote bone growth and healing require the following properties (Shen, 2005):

• Osteogenic:  contains osteoprogenitor cells that can lay down a new bone matrix
• Osteoinductive:  provides signals required to induce differentiation of MSCs into mature osteoblasts
• Osteoconductive:  passive scaffolding to promote vascular invasion and bone apposition on the surface for new bone formulation

The available data has not yet established that mesenchymal stem cells, when infused or transplanted into an area, can 1) truly regenerate by incorporating themselves into the native tissue, surviving, and differentiating or 2) promote the preservation of injured tissue and tissue remodeling.

Currently, the risks of mesenchymal stem cell therapy for the treatment of orthopedic indications are unknown. Insufficient data has been reported to allow a proper understanding of how this technology may affect individuals either in the short or long term. However, there are known risks related to the various methods utilized to harvest mesenchymal stem cells from the bone marrow, including pain and hemorrhage.

Stem cells: A type of cell from which other types of cells develop.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

 Peer Reviewed Publications: 

1. Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006; 7:14.
2. Kitoh H, Kitakoji T, Tsuchiya H, et al. Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis-a preliminary result of three cases. Bone. 2004; 35(4):892-898.
3. Longo UG, Lamberti A, Maffulli N, Denaro V. Tissue engineered biological augmentation for tendon healing: a systematic review. Br Med Bull. 2011; 9831-59.
4. Noth U, Steinert AF, Tuan RS. Technology Insight: Adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol. 2008; 4(7):371-380.
5. Rai B, Lin JL, Lim ZX, et al. Differences between in vitro viability and differentiation and in vivo bone-forming efficacy of human mesenchymal stem cells cultured on PCL-TCP scaffolds. Biomaterials. 2010; 31(31):7960-7970.
6. Shen FH, Samartzis D, An HS. Cell technologies for spinal fusion. Spine J. 2005; 5(6 Suppl):231S-239S.
7. Wakitani S, Mitsuoka T, Nakamura N, et al. Autologous bone marrow and stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004; 13(5):595-600.

1. American Academy of Orthopaedic Surgeons. Stem cells and orthopaedics. Last reviewed September 2007. Available at: http://orthoinfo.aaos.org/topic.cfm?topic=A00501. Accessed on May 26, 2011.
2. National Cancer Institute. Available at: http://www.cancer.gov. Accessed on May 26, 2011.
3. U.S National Institutes of Health. Stem Cell Information. Available at: http://stemcells.nih.gov/info/glossary.asp. Accessed on May 26, 2011.

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