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DESCRIPTIONMesenchymal 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.
MSCs are multipotent cells (also called stromal multipotent cells) that possess the ability to 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. Bone-marrow aspirate is considered to be 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 an additional 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.
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. 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) has stated:
"A major challenge posed by SC [stem-cell] therapy is the need to ensure their efficacy and safety. Cells manufactured in large quantities outside their natural environment in the human body can become ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune reactions, or growth of unwanted tissue.”
Concentrated autologous MSCs do not require approval by FDA.
Demineralized bone matrix (DBM), which is processed allograft bone, is considered minimally processed tissue and does not require FDA approval. At least 4 commercially available DBM products are reported to contain viable stem cells:
Whether these products can be considered minimally manipulated tissue is debated. A product would not meet the criteria for FDA regulation part 1271.10 if it is dependent upon the metabolic activity of living cells for its primary function. Otherwise, a product would be considered a biologic product and would need to demonstrate safety and efficacy for the product’s intended use with an investigational new drug and Biologics License Application (BLA).
Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some products currently available are:
Other commercially available products are intended to be mixed with bone marrow aspirate and have received 510(k) clearance, such as:
No products using engineered or expanded MSCs have been approved by the FDA for orthopedic applications.
In 2008, the FDA determined that the mesenchymal stem cells sold by Regenerative Sciences for use in the Regenexx™ procedure would be considered drugs or biological products and thus require submission of a New Drug Application (NDA) or Biologics Licensing Application (BLA) to the FDA. In 2014, a federal appellate court upheld FDA’s power to regulate adult stem cells as drugs and biologics and ruled that the Regenexx cell product fell within FDA’s authority to regulate human cells, tissues, and cellular and tissue-based products (HCT/Ps). To date, no NDA or BLA has been approved by the FDA for this product. As of 2015, the expanded stem-cell procedure is only offered in the Cayman Islands. Regenexx™ network facilities in the U.S. provide same-day stem-cell and blood platelet procedures, which do not require FDA approval.
Related medical policies include Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions and Autologous Chondrocyte Implantation and Other Cell-based Treatments of Focal Articular Cartilage Lesions.
POLICYMesenchymal 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.
This policy does not address unprocessed allograft bone.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY07/22/2010: 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 added.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.01.52
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.