Bryan M. Saltzman, MD, Benjamin D. Kuhns, MD, MS, Alexander E. Weber, MD, Adam Yanke, MD, and Shane J. Nho, MD, MS
Authors’ Disclosure Statement: Dr. Saltzman reports that he receives royalties from Nova Science Publishers and Postgraduate Institute for Medicine. Dr. Yanke reports that he receives research support from Arthrex and NuTech. Dr. Nho reports that he receives research support from Allosource, Arthrex, Athletico, DJ Orthopaedics, Linvatec, Miomed, Smith & Nephew, and Stryker; is on the editorial/governing board of The American Journal of Orthopedics; is on the board of the American Orthopaedic Society for Sports Medicine and the Arthroscopy Association of North America; is a paid consultant for Ossur and Stryker; and receives publishing royalties from Springer. The other authors report no actual or potential conflict of interest in relation to this article.
The use of biologic adjuvants in the treatment of operative and nonoperative orthopedic injuries continues to expand in concert with our understanding of the acute and chronic healing process of musculoskeletal injuries. Stem cell treatments in orthopedics are among the most commonly explored options, and have found varying levels of success in promoting osseous and soft tissue healing. Basic science and translational studies have demonstrated the potential for broad application of stem cells in the treatment of a growing number of musculoskeletal injuries. Emerging clinical studies have also provided promising results, although the vast majority of studies have featured small sample sizes and limited duration of follow-up. In addition, a number of important questions remain regarding the clinical safety, treatment delivery, and overall efficacy of stem cell augmentation of injured tissue in orthopedics. The objective of the current review is to present a broad overview of the current state of stem cell treatments in orthopedic surgery, with an emphasis on soft tissue healing. This review of stem cell treatment covers the basic science behind biologic augmentation, advantages of the various stem cell sources, preclinical results, and current and future clinical applications.
Biologic use in orthopedics is a continuously evolving field that complements technical, anatomic, and biomechanical advancements in orthopedics. Biologic agents are receiving increasing attention for their use in augmenting healing of muscles, tendons, ligaments, and osseous structures. As biologic augmentation strategies become increasingly utilized in bony and soft-tissue injuries, research on stem cell use in orthopedics continues to increase. Stem cell-based therapies for the repair or regeneration of muscle and tendon represent a promising technology going forward for numerous diseases.1
Stem cells by definition are undifferentiated cells that have 4 main characteristics: (1) mobilization during angiogenesis, (2) differentiation into specialized cell types, (3) proliferation and regeneration, and (4) release of immune regulators and growth factors.2 Mesenchymal stem cells (MSCs) have garnered the most attention in the field of surgery due to their ability to differentiate into the tissues of interest for the surgeon.3 This includes both bone marrow-derived mesenchymal stem cells (bm-MSCs) and adipose-derived mesenchymal stem cells (a-MSCs). These multipotent stem cells in adults originate from mesenchymal tissues, including bone marrow, tendon, adipose, and muscle tissue.4 They are attractive for clinical use because of their multipotent potential and relative ease of growth in culture.5 They also exert a paracrine effect to modulate and control inflammation, stimulate endogenous cell repair and proliferation, inhibit apoptosis, and improve blood flow through secretion of chemokines, cytokines, and growth factors.6,7
Questions exist regarding the best way to administer stem cells, whether systematic administration is possible for these cells to localize to the tissue in need, or more likely if direct application to the pathologic area is necessary.8,9 A number of sources, purification process, and modes of delivery are available, but the most effective means of preparation and administration are still under investigation. The goal of this review is to illustrate the current state of knowledge surrounding stem cell therapy in orthopedics with a focus on osteoarthritis, tendinopathy, articular cartilage, and enhancement of surgical procedures.
Important Considerations
Common stem cell isolates include embryonic, induced pluripotent, and mesenchymal formulations (Table 1). MSCs can be obtained from multiple sites, including but not limited to the adult bone marrow, adipose, muscular, or tendinous tissues, and their use has been highlighted in the study of numerous orthopedic and nonorthopedic pathologies over the course of the last decade. Research on the use of embryonic stem cells in medical therapy with human implications has received substantial attention, with many ethical concerns by those opposed, and the existence of a potential risk of malignant alterations.8,10 Amniotic-derived stem cells can be isolated from amniotic fluid, umbilical cord blood, or the placenta and thus do not harbor the same social constraints as the aforementioned embryonic cells; however, they do not harbor the same magnitude of multi-differentiation potential, either.4
Adult MSCs are more locally available and easy to obtain for treatment when compared with embryonic and fetal stem cells, and the former has a lower immunogenicity, which allows allogeneic use.11 Safety has been preliminarily demonstrated in use thus far; Centeno and colleagues12 found no neoplastic tissue generation at the site of stem cell injection after 3 years postinjection for a cohort of patients who were treated with autologous bm-MSCs for various pathologies. Self-limited pain and swelling are the most commonly reported adverse events after use.13 However, long-term data are lacking in many instances to definitively suggest the absence of possible complications.
Basic Science
Stem cell research encompasses a wide range of rapidly developing treatment strategies that are applicable to virtually every field of medicine. In general, stem cells can be classified as embryonic stem cells (ESCs), induced pluripotent stem (iPS) cells, or adult-derived MSCs. ESCs are embryonic cells derived typically from fetal tissue, whereas iPS cells are dedifferentiated from adult tissue, thus avoiding many of the ethical and legal challenges imposed by research with ESCs. However, oncogenic and lingering politico-legal concerns with introducing dedifferentiated ESCs or iPS cells into healthy tissue necessitate the development, isolation, and expansion of multi- but not pluripotent stem cell lines.14 To date, the most advantageous and widely utilized from any perspective are MSCs, which can further differentiate into cartilage, tendon, muscle, and bony tissue.7,15,16
MSCs are defined by their ability to demonstrate in vitro differentiation into osteoblasts, adipocytes, or chondroblasts, adhere to plastic, express CD105, CD73, and CD90, and not express CD43, CD23, CD14 or CD11b, CD79 or CD19, or HLA-DR.17 Porada and Almeida-Porada18 have outlined 6 reasons highlighting the advantages of MSCs: 1) ease of isolation, 2) high differentiation capabilities, 3) strong colony expansion without differentiation loss, 4) immunosuppression following transplantation, 5) powerful anti-inflammatory properties, and 6) their ability to localize to damaged tissue. The anti-inflammatory properties of MSCs are particularly important as they promote allo- and xenotransplantation from donor tissues.19,20 MSCs can be isolated from numerous sources, including but not limited to bone marrow, periosteum, adipocyte, and muscle.21-23 Interestingly, the source tissue used to isolate MSCs can affect differentiation capabilities, colony size, and growth rate (Table 2).24 Advantages of a-MSCs include high prevalence and ease of harvest; however, several animal studies have shown inferior results when compared to bm-MSCs.25-27 More research is needed to determine the ideal source material for MSCs, which will likely depend in part on the procedure for which they are employed.27
