Stem cell therapy for musculoskeletal conditions

Status: Decision completed

Policy context

Stem cell therapy for joint pain is an outpatient procedure that begins with collection of stem cells from a patient (autologous) or from another person (allogeneic). The cells may be cultured or concentrated and then injected into the affected area. The topic is proposed based on concerns related to the safety, efficacy, and value for stem cell injections for musculoskeletal pain.

Primary criteria ranking

  • Safety = High
  • Efficacy = High
  • Cost = High
Documents (2020 assessment)

Assessment timeline (2020)

  • Draft key questions published: September 19, 2019
  • Public comment period: September 19 to October 2, 2019
  • Final key questions published: October 18, 2019
  • Draft report published: December 31, 2019
  • Public comment period: December 31 to January 29, 2019
  • Final report published: February 19, 2020
  • HTCC public meeting: June 12, 2020


Stem cells are the basis of all tissues and organs in the body. Their ability to "self-renew" (i.e. they can give rise to multiple cells of the same kind) for long periods of time and to differentiate into mature cells with specific functions are part of normal physiologic processes for replacing injured tissues and cells. These properties of stem cells make them attractive, promising approaches for treating a variety of medical conditions. Use of stem cell therapies has been referred to a part of "regenerative medicine" by some. Musculoskeletal tissues that have a limited capacity for endogenous repair include vertebral discs, cartilage, tendons, ligaments and muscle. For many orthopedic conditions, effective nonsurgical treatment options are limited. Thus, there has been much interest in the use of stem cell therapy to stimulate repair and regeneration for such conditions. Tissue engineering and use of stem cells have been active areas of research for the treatment of orthopedic and musculoskeletal conditions.

The NIH defines stem cells as "different from other kinds of cells in the body. All stem cells have three general properties: they are capable of dividing and renewing themselves for long periods of time, they are unspecialized; and they can give rise to specialized cell types". Stem cell types are often described as embryonic stem cells (obtained at the earliest developmental stages), somatic stem cells (also referred to as adult or tissue-specific stem cells), and recently, induced pluripotent stem cells which are engineered from specialized cells. Embryonic stem cells are able to generate any type of cell and are referred to as pluripotent. Under the right conditions, they can be replicated and cultured in this undifferentiated state. Induced pluripotent cells are a topic of ongoing research; their production involves the engineering or "reprograming" of adult cells to behave like pluripotent embryonic stem cells. In contrast, tissue-specific, (adult, somatic) stem cells have differentiated into specialized cells that may produce some or all of the mature cell types contained in a specific organ or tissue. These are termed multipotent and are often found deep within tissues of organs that continuously replenish themselves. Because adult stem cells are rare in mature tissues and a variety of other cell types are included in the sampling process, identification, isolation and growth of adult stem cells in laboratory settings is required; methods for expansion and culturing cells in sufficient numbers for transplantation are not well developed. Stem cell sources may be autogenic or allogenic. 

Tissue specific (adult, somatic) stem cells have been most commonly described related to the treatment of musculoskeletal pain conditions of interest for this HTA and will be the focus. Mesenchymal stem cells (MSCs) are generally defined as multipotent adult stem cells that have potential to differentiate in to various musculoskeletal tissues and have been most commonly described. The accuracy and use of the term "mesenchymal stem cell" has been questioned. MSCs are isolated from the connective tissue surrounding organs and other tissues called stroma, prompting some scientist to suggest that "mesenchymal stromal cells" may be a more accurate name. The International Society for Cell Therapy (ISCT) has defined mesenchymal stromal cells as multipotent progenitor cells derived from nonhematopoietic tissues (e.g. bone marrow, fat and synovium) that are plastic adherent, express certain cell markers but not others and are capable of differentiating into bone, cartilage and fat forming cells. Such cells may have immunomodulary and anti-inflammatory properties as well which may support and stimulate cells to enhance repair processes. Cells meeting the ISCT criteria for must be cultured in the laboratory. MSCs were first identified in bone marrow and demonstrated an ability to make bone, cartilage and fat cells. They have since been grown from other tissues such as adipose tissue, the amnion, Wharton's jelly and the umbilical cord as well as muscle, synovial membrane and tendons. There are only a small number of stem cells in organs and tissues and their ability to divide is limited; thus they must be cultured and manipulated to produce sufficient quantities for treatment. Processes for procuring and expanding autologous and allogenic MCS are often proprietary. The characteristics of MSCs depend the source within the body as well as how they are isolated and cultured. While a variety of cells have been categorized as MSCs, in the literature there is lack of clarity regarding specific cell characteristics and markers for accurate categorization. In addition, there is not a full understanding of whether the cells are actually stem cells or what cell types that they are capable of creating. MSCs are usually harvested via bone marrow aspirate for orthopedic applications. The procedure for harvesting cells may result in donor site morbidity to include pain and bleeding, however. Adipose tissue is the next most common source of MCSs for musculoskeletal applications. Age impacts the number of viable cells and their ability to differentiate. The bioactivity is of MSCs variable. MSCs are used as a stand-alone therapy in the form of an injection or in combination with scaffolds. (Viganò, 2016)

In addition to lack of consistency in terminology related to stem cells  in general and mesenchymal cells in particular, there is substantial inconsistency across the orthopedic literature relative to reporting preparation, processing, composition and delivery of bone marrow aspirate products and other MSC sources. Minimum reporting standards for clinical studies of cell-based therapies have recently been proposed.

Proposed applications of SCT for orthopedic use and soft-tissue musculoskeletal injuries include the following:

  • Bone-joint injuries (e.g. fractures, bone defects, nonunion, spinal fusion)
  • Cartilage defects, osteoarthritis
  • Ligament and tendon injuries (e.g. including ACL and MCL lesions, rotator cuff lesions and Achilles tendon rupture)
  • Other: meniscopathy, femoral head osteonecrosis, osteogenesis imperfecta

Short-term and long term harms or adverse events have not been well studied and the risk of using MSC therapy is unknown. Potential safety concerns in addition to the potential failure of cells to work as expected include administration site reactions or infection, ability of cells to migrate from placement sites and differentiate into inappropriate cell types or excessive multiplication and tumor growth.

The U.S. Food and Drug Administration (FDA) regulates tissues and human cells intended for implantation, infusion, or transplantation via the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271. The regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) is described as a tiered, risk-based approach which includes consideration of whether the cell source is from structural tissue (e.g. adipose, cartilage) or cells/nonstructural tissues as well as the processing, degree of manipulation and whether the HCT/P is intended for homologous use. The following articles are not considered HCT/Ps:  Minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow). Examples of minimally manipulated autologous cell preparations for which FDA approval is not needed include bone marrow concentrate, adipose stromal ,or stromal vascular fraction and placental tissue fragments.

Culture-expanded connective tissue cells, including MSCs, muscle-derived cells, adipose-derived cells, and cartilage-derived cells for orthopedic applications are not FDA-approved.

In general, the range of clinical conditions or diseases for which stem cells have proven to be effective is very small. Many stem cell based treatments are new and considered experimental. In general, the most frequently used stem cells for therapy have been blood stem cells. Hematopoietic stem cell transplantation (from bone marrow) has been successfully used to treat patients with leukemia, lymphoma and some inherited blood disorders. Grafting of tissues derived from or maintained by stem cells has also been used to treat some bone, skin and corneal conditions. While there have been a large number of pre-clinical studies related to musculoskeletal applications of stem cell therapy, the evidence from methodologically rigorous clinical studies may be sparse.