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Stem Cells in Orthopedics: a Comprehensive Guide for the General Orthopedist

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Stem Cells in Orthopedics: a Comprehensive Guide for the General Orthopedist A Review Paper Stem Cells in Orthopedics: A Comprehensive Guide for the General Orthopedist Bryan M. Saltzman, MD, Benjamin D. Kuhns, MD, MS, Alexander E. Weber, MD, Adam Yanke, MD, and Shane J. Nho, MD, MS Abstract The use of biologic adjuvants in the treat- the vast majority of studies have featured ment of operative and nonoperative ortho- small sample sizes and limited duration of pedic injuries continues to expand in concert follow-up. In addition, a number of important with our understanding of the acute and questions remain regarding the clinical safe- chronic healing process of musculoskeletal ty, treatment delivery, and overall efficacy injuries. Stem cell treatments in orthopedics of stem cell augmentation of injured tissue are among the most commonly explored in orthopedics. The objective of the current options, and have found varying levels of review is to present a broad overview of the success in promoting osseous and soft tissue current state of stem cell treatments healing. Basic science and translational in orthopedic surgery, with an emphasis on studies have demonstrated the potential for soft tissue healing. This review of stem cell broad application of stem cells in the treat- treatment covers the basic science behind ment of a growing number of musculoskel- biologic augmentation, advantages of the etal injuries. Emerging clinical studies have various stem cell sources, preclinical results, also provided promising results, although and current and future clinical applications. iologic use in orthopedics is a continuously and (4) release of immune regulators and growth evolving field that complements technical, factors.2 Mesenchymal stem cells (MSCs) have Banatomic, and biomechanical advancements garnered the most attention in the field of surgery in orthopedics. Biologic agents are receiving due to their ability to differentiate into the tissues increasing attention for their use in augmenting of interest for the surgeon.3 This includes both healing of muscles, tendons, ligaments, and bone marrow-derived mesenchymal stem cells osseous structures. As biologic augmentation (bm-MSCs) and adipose-derived mesenchymal strategies become increasingly utilized in bony stem cells (a-MSCs). These multipotent stem cells and soft-tissue injuries, research on stem cell use in adults originate from mesenchymal tissues, in- in orthopedics continues to increase. Stem cell- cluding bone marrow, tendon, adipose, and muscle based therapies for the repair or regeneration of tissue.4 They are attractive for clinical use because muscle and tendon represent a promising technol- of their multipotent potential and relative ease of ogy going forward for numerous diseases.1 growth in culture.5 They also exert a paracrine effect Stem cells by definition are undifferentiated cells to modulate and control inflammation, stimulate en- that have 4 main characteristics: (1) mobilization dogenous cell repair and proliferation, inhibit apop- during angiogenesis, (2) differentiation into special- tosis, and improve blood flow through secretion of ized cell types, (3) proliferation and regeneration, chemokines, cytokines, and growth factors.6,7 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. 280 The American Journal of Orthopedics ® July/August 2016 www.amjorthopedics.com Questions exist regarding the best way to ad- a lower immunogenicity, which allows allogeneic minister stem cells, whether systematic adminis- use.11 Safety has been preliminarily demonstrated tration is possible for these cells to localize to the in use thus far; Centeno and colleagues12 found no tissue in need, or more likely if direct application neoplastic tissue generation at the site of stem cell to the pathologic area is necessary.8,9 A number injection after 3 years postinjection for a cohort of of sources, purification process, and modes of de- patients who were treated with autologous bm- livery are available, but the most effective means MSCs for various pathologies. Self-limited pain and of preparation and administration are still under swelling are the most commonly reported adverse investigation. The goal of this review is to illus- events after use.13 However, long-term data are trate the current state of knowledge surrounding lacking in many instances to definitively suggest stem cell therapy in orthopedics with a focus on the absence of possible complications. osteoarthritis, tendinopathy, articular cartilage, and enhancement of surgical procedures. Basic Science Stem cell research encompasses a wide range of Important Considerations rapidly developing treatment strategies that are Common stem cell isolates include embryonic, in- applicable to virtually every field of medicine. In duced pluripotent, and mesenchymal formulations general, stem cells can be classified as embryonic (Table 1). MSCs can be obtained from multiple stem cells (ESCs), induced pluripotent stem (iPS) sites, including but not limited to the adult bone cells, or adult-derived MSCs. ESCs are embryonic marrow, adipose, muscular, or tendinous tissues, cells derived typically from fetal tissue, whereas and their use has been highlighted in the study of iPS cells are dedifferentiated from adult tissue, numerous orthopedic and nonorthopedic patholo- thus avoiding many of the ethical and legal chal- gies over the course of the last decade. Research lenges imposed by research with ESCs. However, on the use of embryonic stem cells in medical oncogenic and lingering politico-legal concerns therapy with human implications has received with introducing dedifferentiated ESCs or iPS cells substantial attention, with many ethical concerns into healthy tissue necessitate the development, by those opposed, and the existence of a potential isolation, and expansion of multi- but not pluripo- risk of malignant alterations.8,10 Amniotic-derived tent stem cell lines.14 To date, the most advanta- stem cells can be isolated from amniotic fluid, um- geous and widely utilized from any perspective are bilical cord blood, or the placenta and thus do not MSCs, which can further differentiate into carti- harbor the same social constraints as the afore- lage, tendon, muscle, and bony tissue.7,15,16 mentioned embryonic cells; however, they do not MSCs are defined by their ability to demonstrate harbor the same magnitude of multi-differentiation in vitro differentiation into osteoblasts, adipo- potential, either.4 cytes, or chondroblasts, adhere to plastic, express Adult MSCs are more locally available and easy CD105, CD73, and CD90, and not express CD43, to obtain for treatment when compared with CD23, CD14 or CD11b, CD79 or CD19, or HLA- embryonic and fetal stem cells, and the former has DR.17 Porada and Almeida-Porada18 have outlined Table 1. Advantages and Disadvantages of Stem Cells by Source Stem Cell Type Source Advantages Disadvantages Embryonic stem cells Embryonic tissue Pluripotent to all 3 germ layers; mesoderm, Oncogenic potential, endoderm, ectoderm allogenic rejection, ethical and legal constraints Induced pluripotent stem Adult somatic tissue Pluripotent, decreased ethical concerns Oncogenic potential, cells transfected with embryonic due to adult source, no allogenic rejection modest induction yield transcription factors Mesenchymal stem cells Multiple fetal and adult tissue Can differentiate into tissues of interest: bone, Limited differentiation (umbilical cord, umbilical cartilage, and tendon; immunosuppressive capacity, modest yield blood, placenta, skin, allowing for allo- and xeno-transplantation from host tissue bone marrow, blood vessels, adipose, synovium, periosteum, dental pulp) www.amjorthopedics.com July/August 2016 The American Journal of Orthopedics ® 281 Stem Cells in Orthopedics: A Comprehensive Guide for the General Orthopedist 6 reasons highlighting the advantages of MSCs: alleviated in part with the advent of 3-dimensional 1) ease of isolation, 2) high differentiation capabil- printing and the ability to more precisely alter scaf- ities, 3) strong colony expansion without differ- fold architecture.14,33 Additional limitations include entiation loss, 4) immunosuppression following ensuring MSC purity and differentiation potential transplantation, 5) powerful anti-inflammatory following harvesting and expansion. At present, properties, and 6) their ability to localize to dam- the use of tissue engineering with MSCs is prom- aged tissue. The anti-inflammatory properties of ising but it remains a nascent technology with MSCs are particularly important as they promote additional preclinical studies required to confirm allo- and xenotransplantation from donor tis- implant efficacy and safety. sues.19,20 MSCs can be isolated from numerous sources, including but not limited to bone marrow, Clinical Entities periosteum, adipocyte, and muscle.21-23 Interest- Osteoarthritis ingly, the
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