biological therapies in regenerative sports medicinepilarmartinescudero.es/octnov16/biological...
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REVIEW ARTICLE1
2 Biological Therapies in Regenerative Sports Medicine
3 Isabel Andia1• Nicola Maffulli2,3
45 � Springer International Publishing Switzerland 2016
6 Abstract Regenerative medicine seeks to harness the
7 potential of cell biology for tissue replacement therapies,
8 which will restore lost tissue functionality. Controlling and
9 enhancing tissue healing is not just a matter of cells, but
10 also of molecules and mechanical forces. We first describe
11 the main biological technologies to boost musculoskeletal
12 healing, including bone marrow and subcutaneous fat-
13 derived regenerative products, as well as platelet-rich
14 plasma and conditioned media. We provide some infor-
15 mation describing possible mechanisms of action. We
16 performed a literature search up to January 2016 searching
17 for clinical outcomes following the use of cell therapies for
18 sports conditions, tendons, and joints. The safety and effi-
19 cacy of cell therapies for tendon conditions was examined
20 in nine studies involving undifferentiated and differentiated
21 (skin fibroblasts, tenocytes) cells. A total of 54 studies
22 investigated the effects of mesenchymal stem-cell (MSC)
23 products for joint conditions including anterior cruciate
24 ligament, meniscus, and chondral lesions as well as
25 osteoarthritis. In 22 studies, cellular products were injected
26 intra-articularly, whereas in 32 studies MSC products were
27 implanted during surgical/arthroscopic procedures. The
28 heterogeneity of clinical conditions, cellular products, and
29approaches for delivery/implantation make comparability
30difficult. MSC products appear safe in the short- and mid-
31term, but studies with a long follow-up are scarce.
32Although the current number of randomized clinical stud-
33ies is low, stem-cell products may have therapeutic
34potential. However, these regenerative technologies still
35need to be optimized.
36
3738Key Points 39
4142
43Biologics, including adult cells, platelet-rich plasma,
44and conditioned media, are under investigation for
45regenerative purposes in sports medicine.
46Cell therapies under clinical assessment include
47dermal fibroblasts, tenocytes, chondrocytes, and
48various products containing stem cells, mainly bone
49marrow concentrate, stromal vascular fraction, bone
50marrow-derived mesenchymal stem cells, and
51adipose stem cells.
52The use of adult cell therapies is safe. Most articles
53report improvement in clinical outcomes, but overall
54the quality of evidence is low, with the absence of
55adequately powered controlled clinical trials. 56
57
581 Introduction
59Impairment of biological and mechanical homeostasis is
60common in orthopedic sports medicine where muscu-
61loskeletal tissues are often subjected to excessive stresses
A1 & Isabel Andia
A3 1 Regenerative Medicine Laboratory, BioCruces Health
A4 Research Institute, Cruces University Hospital, Pza Cruces
A5 12, 48903 Barakaldo, Spain
A6 2 Department of Musculoskeletal Disorders, University of
A7 Salerno School of Medicine and Dentistry, Salerno, Italy
A8 3 Queen Mary University of London, Barts and the London
A9 School of Medicine and Dentistry Centre for Sports and
A10 Exercise Medicine, Mile End Hospital, 275 Bancroft Road,
A11 London E1 4DG, England
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Sports Med
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62 and multiple injuries. Major injuries in athletes result in a
63 high incidence of chronic problems such as osteoarthritis
64 (OA), for which effective treatments are not yet available
65 [1]. Both acute and chronic sports lesions have promoted a
66 surge of novel biological therapies aiming to improve the
67 quality of life of athletes and active individuals.
68 Currently, most expectations in regenerative sports
69 medicine are focused on the potential of cell therapies,
70 typically adult mesenchymal stromal/stem cells (MSCs).
71 Regenerative medicine seeks to harness the potential of cell
72 biology for re-establishment of lost tissue functionality.
73 However, controlling and enhancing musculoskeletal tissue
74 regeneration is not just a matter of cells. Molecules, cells,
75 and mechanical forces are hardwired and cooperate in
76 healing mechanisms. For example, platelet-rich plasma
77 (PRP), an autologous regenerative technology, is based on
78 the delivery of a pool of growth factors and cytokines with
79 tissue healing potential, and has been widely used in sports
80 medicine settings aiming to enhance tissue healing [2].
81 Both PRP and adult MSCs are physiological means to
82 combat injury. In this context, regenerative medicine seeks
83 to enhance these endogenous resources to help tissue
84 homeostasis prevail over hostile microenvironments.
85 Regenerative technologies, both allogeneic and autolo-
86 gous, have emerged as an industry, and the potential
87 market is expected to reach US$8 billion by 2020 [3, 4].
88 Orthopedics and sports medicine are among the areas that
89 will have the greatest applications. Athletes (professional
90 and recreational) seek novel regenerative medicine inter-
91 ventions to heal injuries, and to rapidly resume their
92 desired sports activities. Cell therapies are offered in sev-
93 eral stem-cell centers around the world, not only for sports
94 injuries [5], but also to treat devastating illnesses including
95 cerebral palsy, Alzheimer disease, or multiple sclerosis,
96 among others. Medical tourism is an internet-driven busi-
97 ness, mediating a rapid expansion of stem-cell clinics,
98 mostly in countries with permissive regulatory conditions
99 [6].
100 However, stem-cell therapies are still in their first stages
101 of implementation, and much research is still necessary
102 before they can meet the hope that has been put on them.
103 To refrain from pursuing unproven expensive cell thera-
104 pies, the International Society for Stem Cell Research
105 (ISSCR) offers clear information about disproved efficacy
106 and associated risks (ISSCR, 2013) [7]. Also, a set of
107 performance guidelines is available for responsible
108 administration of stem-cell therapies (ISSCR, 2008) [8].
109 Aiming to provide an update for healthcare profession-
110 als interested in regenerative therapies, we address what is
111 known about the composition of cell-based products (i.e.,
112 adult mesenchymal stromal/stem-cell products) and other
113 differentiated cell therapies, their combination with PRP,
114 and the assumptions or paradigms on which to base their
115mechanisms of action. We also review the current literature
116about clinical outcomes following the use of cell therapies
117in sports medicine for tendon and joint conditions.
1182 Regenerative Medicine Technologies
1192.1 Regenerative Medicine Products
120The three main regenerative medicine injectable products
121undergoing investigation for tissue healing are (1) most
122importantly, cells, which drive healing mechanisms; (2)
123PRP; and (3) conditioned media (CM) from cells (Fig. 1).
124In general, cells or other regenerative products for mus-
125culoskeletal injuries are delivered locally. This is in con-
126trast to the systemic route of administration in some other
127pathologies, such as systemic lupus erythematosus [9].
1282.1.1 Cellular Products
129Cell therapies include a broad range of subtypes, from
130injectable mixtures of cell populations, as is the case with
131bone marrow concentrate (BMC), and stromal vascular
132fraction (SVF), to refined MSC preparations with trilin-
133eage differentiation capacity and characteristic surface
134proteins. Despite these specific features, there are not
135unequivocal markers of cell quality and functional effi-
136cacy in vivo. Furthermore, comparability between inter-
137trial clinical outcomes can be hindered because of vari-
138ability in the quality of MSCs associated with fabrication
139reagents and procedures. Central to progress in the field is
140a description of manufacturing procedures and the
141development of products based on standardized parame-
142ters. Therefore, for laboratory-expanded cells, authors are
143encouraged to provide specific in-process data, such as
144initial yield (9106)/days at passage zero (P0), passage 2
145(P2) cumulative population doublings, and P2 epitopes
146(?/-) [10].
147As an alternative, tissue-specific biopsies can be har-
148vested and differentiated cells, such as chondrocytes for
149cartilage, and tenocytes or skin fibroblasts for tendon
150conditions, are implanted after 3–4 weeks of growth
151in vitro. Presently, the main interest is focused on injecting
152cells and PRPs; both are mostly used on an autologous
153basis to avoid any host immune responses.
154Hereinafter, we address the main characteristics of bone
155marrow and fat-derived regenerative products as well as
156PRP and CM.
1572.1.1.1 Stromal Vascular Fraction and Adipose Stromal/
158Stem Cells Adipose tissue can be considered the richest
159source of stem cells in our body. A simple adipose graft has
160been injected in joint conditions as an adjuvant to BMC.
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161Alternatively, adipose tissue can be fractionated into
162mature adipocytes, blood, and the SVF (Fig. 2). In 1964,
163Rodbell [11] isolated SVF for the first time using prote-
164olytic enzymes and centrifugation. SVF can be obtained in
165a few hours using kits and following commercial protocols,
166without altering the relevant biological characteristics of
167the cells. SVF is a fresh product prepared at the point of
168care but qualifies as an advanced therapy medicinal product
169(ATMP) because it involves the use of proteolytic enzymes
170to obtain a cell suspension. This cell suspension is then
171centrifuged and the cell pellet is termed SVF. Thus, the use
172of SVF for orthopedic conditions requires Food and Drug
173Administration (FDA) and institutional review board (IRB)
174approval.
175The injection of these preparations provides the host
176tissue with a heterogeneous cell population including
177hematopoietic stem cells, endothelial cells, and adipose-
178derived stromal/stem cells representing 2–10 % of SVF.
179CD34? cells (angiogenic cells) are present in large num-
180bers and could compose up to 63 % of SVF [12, 13].
181Overall, CD34? cells constitute the main part of the stem-
182cell niche, and may also favorably influence modulation of
183neovascularization. Vascularization is crucial in early
184healing mechanisms to provide oxygen and nutrients for
185the metabolic needs of activated cells but it is downregu-
186lated in the later stages of healing.
187Alternatively, to improve purity and obtain a larger
188number of MSCs, SVF can be culture expanded (Fig. 2a).
189Zuk et al. [14], pioneered the characterization of multipo-
190tent stem cells from human fat-derived SVF, currently
191named ASCs (adipose stromal/stem cells).
192The International Society for Cellular Therapy (ISCT)
193has proposed four criteria for adult mesenchymal stem-cell
194characterization: (1) plastic adherence, (2) at least tri-lin-
195eage differentiation capabilities, (3) expression of CD73,
196CD90, and CD105, and (4) lack of expression of CD14,
197CD11b, CD34, CD45, CD19, CD79, and human leukocyte
198antigen–antigen D related [14].
199Interestingly, the potential of ASCs is independent of
200the anatomical fat source [15]. However, ASCs from aged
201people are less proliferative, and can be of lower quality,
202because of telomere shortening and DNA damage, com-
203promising their clinical success [16].
2042.1.1.2 Bone Marrow Concentrates, and Bone-Marrow-
205Derived Mesenchymal Stromal/Stem Cells Bone marrow
206aspirates, from the iliac crest or other sites, can be pro-
207cessed (most often by centrifugation) at the point of care to
208concentrate the nucleated cells of the marrow, which
209contain various populations of progenitors (Fig. 2b). This
210‘fresh’ product obtained through minimal manipulation is
211named BMC or BMAC, bone marrow concentrate or bone
Fig. 1 Current regenerative technologies for musculoskeletal inju-
ries. a Adult mesenchymal stromal cells, also known as mesenchymal
stem cells (MSCs), which are cells with high proliferative and self-
renewal capabilities, adhesive to plastic surfaces, showing specific
cell surface proteins, and with potential to differentiate in at least
three lineages including bone, cartilage, and adipose tissue. b Platelet-
rich plasma (PRP) that consists of a pool of signaling proteins
including growth factors, cytokines, and other adhesive proteins
involved in healing mechanisms (the list is not exhaustive). c Con-
ditioned culture media (CM), which contain biologically active
molecules secreted by cells in vitro; these molecules affect cell
functions. ADAMTS A disintegrin-like and metalloprotease with
thrombospondin, ADP adenosine diphosphate, ADSC adipose stem
cells, BM-MSCs bone marrow-derived mesenchymal stem cells, CCL
chemokine (C-C motif) ligand, CTGF connective tissue growth
factor, FGF fibroblastic growth factor, HGF hepatocyte growth
factor, HSC hematopoietic stem cells, IGF insulin growth factor,
MMP matrix metalloproteinase, MSCs mesenchymal stem cells, PAI
plasminogen activator inhibitor, PBP platelet basic protein, PDGF
platelet-derived growth factor, PF platelet factor, PRP platelet-rich
plasma, SDF stromal cell-derived factor, TGF transformed growth
factor, TSP thrombospondin, VEGF vascular endothelial growth
factor
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212 marrow aspirate concentrate. Most cells are CD34? heme
213 progenitors, and very few (0.01–0.001 %) are multipotent
214 MSCs [17]. A subpopulation that only retains chondro-
215 genic potential has also been identified, making them
216 particularly attractive for joint conditions [18].
217 Because of the huge interest in using BMC as ‘therapy’,
218 the performance of different commercial systems is com-
219 pared in terms of cell recovery, stem/progenitor cells
220 (CD34?), and colony-forming units (CFU-F); that is,
221 MSCs [19].
222 Alternatively, mononuclear cells can be isolated by
223 density gradient centrifugation, and cultured on plastic
224 surfaces to remove hematopoietic mononuclear cells.
225 Adherent MSCs are then expanded for several generations.
226 Since cells are isolated from the niche that controls their
227 phenotype (i.e., other cells, cytokines, extracellular matrix
228 [ECM], molecular forces, and so on), following substantial
229manipulation, both bone marrow-derived mesenchymal
230stem cells (BM-MSCs) and ASCs are therefore considered
231an ATMP as ruled in the EU Directive no. 1394/2007 [20].
232Similarly, in the USA, ATMPs are regulated by CBER (the
233Center for Biologics Evaluation and Research). These
234treatments are only allowed via an IRB approval protocol.
2352.1.1.3 Peripheral Blood Progenitor Cells Peripheral
236blood progenitor cells (PBPC) are CD34? cells collected in
237apheresis procedures typically after treating the patient
238with a granulocyte colony-stimulating factor (G-CSF) or
239granulocyte–macrophage colony-stimulating factor (GM-
240CSF) [21]. Currently, PBSC are used as a source of stem
241cells in the hematopoietic reconstitution. In addition,
242PBSCs can be harvested and cryopreserved. This product is
243injected within tendons and in the joint cavity to enhance
244tissue healing.
Fig. 2 Regenerative products obtained from adipose tissue and bone
marrow. a Adipose tissue. Common steps to process cells from
lipoaspirates/adipose tissue include washing, enzymatic digestion/
mechanical disruption, and centrifugal separation for isolation of SVF
as a pellet at the bottom of the tube. Purity can be improved and a
higher number of MSCs can be prepared in sizeable doses after a few
weeks of ex-vivo expansion. The latter involves substantial manip-
ulation (more than ‘minimal manipulation’), thus is considered as an
advanced therapy from a regulatory point of view. This fact involves
additional complexity and a considerable increase in costs. b Bone
marrow. Common steps to process cells from bone marrow include
centrifugation and cell-culture expansion of plastic-adherent cells.
ISCT criteria to define adult MSCs: MSCs express CD73, CD90, and
CD105. MSCs lack expression of hematopoietic lineage markers
c-kit, CD14, CD11b, CD34, CD45, CD19, CD79, and human
leukocyte antigen (HLA)-DR. ASCs meet the majority of ISCT’s
criteria for MSCs but it has been found that ASCs can exist as
CD34?, CD31-, CD104b-, smooth muscle actin cells. ASCs adipose
stem cells, BMC bone marrow concentrate, EPC endothelial progen-
itor cells, HSC hematopoietic stem cells, ISCT International Society
for Cellular Therapy, MSCs mesenchymal stem cells, SVF stromal
vascular fraction
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245 2.1.2 Platelet-Rich Plasma Technologies
246 PRP is a plasma preparation with a number of platelets
247 above the normal level in blood, generally obtained after
248 centrifugation of peripheral blood. PRP contains a complex
249 molecular mixture including signaling and adhesive pro-
250 teins. At present, it is evident that the therapeutic effect of
251 PRPs in tissue healing is not only attributed to growth
252 factors, but also to a myriad of chemokines and other
253 cytokines actively involved in tissue-repair processes,
254 including cell proliferation, differentiation, migration,
255 angiogenesis, and the synthesis of ECM [22]. Importantly,
256 PRPs also trigger synthesis of neurotrophic and angiogenic
257 factors by local cells, thereby amplifying the initial effect
258 [23].
259 Combining PRP with cell therapies provides a con-
260 trolled milieu for cells. In addition, PRPs can function as
261 both cell carriers and cytokine delivery systems. In fact,
262 upon plasmatic fibrinogen cleavage and polymerization by
263 thrombin action, the newly developed fibrin constitutes a
264 suitable adhesive scaffold for cell delivery [24]. Platelets
265 embedded within this fibrin scaffold slowly release the
266 molecular pool stored in the alpha granules as well as other
267 small molecules contained in dense granules [25]. What
268 makes PRP attractive is the delivery system embodied by
269 fibrin that confines molecules and cells to the chosen site.
270 The molecular characterization of PRPs is challenging
271 and varies quantitatively from one individual PRP to
272 another and from one formulation to another [26]. Up to
273 now, it has been impossible to establish quality criteria for
274 PRP products, because there is not enough information
275 about which are the main molecules responsible for the
276 therapeutic effect in each specific tissue condition.
277 Although the initial paradigm of PRP actions was based on
278 platelet number, currently we know that most PRP effects
279 are the consequence of activation of migratory and local
280 cells [27].
281 More research is necessary to describe how PRP influ-
282 ences the regenerative actions of MSCs. For example, it
283 was recently shown that PRP could favor stemness, and
284 prolongs survival of transplanted cells [28–30]. In addition,
285 PRP can control secretory function [31] in different man-
286 ners depending on PRP formulation and cell phenotype.
287 Van Pham et al. [32] studied the behavior of the mixture of
288 human ASCs obtained from SVF of ten individuals and
289 expanded with PRP. In addition, ASCs were re-suspended
290 in 3 mL of human PRP, after which the product was
291 implanted into a cartilage injury in immunodeficient mice.
292 This study showed that PRP efficiently stimulated ASC
293 proliferation, and does not change the marker expression of
294 ASCs, but it modifies the expression of SOX-9 (SRY [sex
295 determining region Y]-Box 9), collagen type 2, and
296aggrecan. Also, PRP reduces vascular endothelial growth
297factor (VEGF) expression by ASC [32].
2982.1.3 Conditioned Media
299A less investigated product to be used for regenerative
300purposes is the conditioned culture media (CM). While
301growing in vitro, cells release to the extracellular milieu a
302pool of cytokines, chemokines, growth factors (including
303transforming growth factors [TGF-a, TGF-b], hepatocyte
304growth factor [HGF], epidermal growth factor [EGF],
305fibroblast growth factor [FGF-2], insulin growth factor
306[IGF-1], VEGF, angiopoietin [ANGPT-1], among others),
307as well as matricellular proteins, enzymes, microvesicles/
308exosomes, messenger RNAs (mRNAs), and microRNAs
309[33] (Fig. 1c). The source of CM is cells cultured in vitro
310under specific consistent protocols. CM is composed from
311the soluble molecular components of cell secretome, which
312can be tailored for specific therapeutic actions. Actually,
313the therapeutic potential of CM is based on one of the
314paradigms of MSC actions: the trophic and paracrine
315effects on local cells.
316A major advantage of CM is that it can be easily man-
317ufactured, sterilized, packaged, and stored, and thus can
318constitute an ‘off-the-shelf’ stem-cell product.
319The therapeutic value of the stem-cell CM is under
320research [34, 35]. Numerous patent applications have been
321filed in recent times (i.e., US2012/0276215A1). For
322example, an ongoing clinical trial [36] in OA is assessing
323the safety and feasibility of trophic factors from umbilical
324cord mesenchymal stem cells.
3252.2 The Mechanism of Action of Regenerative
326Medicine Products
327There are a number of conditions in which regenerative
328medicine products, in particular MSCs, have been inves-
329tigated, and thousands of articles have been published on
330this topic. Consistent with the complexity of these prod-
331ucts, extensive literature from the past decades indicates
332that regenerative medicine products modulate almost every
333facet of repair mechanisms (Fig. 3).
334When injected systemically, the assumption that MSCs
335home to the relevant tissue and replace injured cells was
336based on both their migratory and differentiation capacities
337[37, 38]. Site-directed implantation (i.e., cells loaded in col-
338lagen membranes [or other scaffolds] placed within chondral
339or osteochondral defects) can also influence cell fate. In
340addition to tri-lineage differentiation capacity (i.e., bone,
341cartilage, and fat), adult MSCs further differentiate to tendon
342or ligament in the presence of environmental molecular cues
343including ligament/tendon-derived matrix [39].
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344 Why tissue engraftment rarely occurs after the local
345 injection of cells is unknown. Several authors [40, 41]
346 speculate that cell engraftment is hindered because the host
347 tissue is not adequately conditioned, and does not provide
348 normal trophic signals to implanted cells. This can happen
349 especially in degenerative diseases such as OA or
350 tendinopathy, in which the microenvironment could be
351 deprived of nutrients and exposed to high concentrations of
352 proteases such as A disintegrin and metalloprotease with
353 thrombospondin (ADAMTS), metalloproteinases (MMPs)
354 [42], and detrimental pro-inflammatory cytokines such as
355 interleukin-1b (IL-1b) and tumor necrosis factor (TNF-a)
356 [43].
357 An alternative hypothesis currently being investigated
358 focused on the trophic paracrine and autocrine actions of
359 MSCs. Secreted growth factors, chemokines, and cytokine
360 factors include TGF-a, TGF-b, HGF, IL-6, EGF, FGF-2,
361 IGF-1, and VEGF [44, 45]. Cells can also limit tissue
362 destruction and enhance repair by means of anti-apoptotic,
363 proliferative, and angiogenic actions [46–48].
364 The therapeutic potential of MSC secretome is the rea-
365 son to believe that CM may mimic the effects of cells.
366 Similar trophic actions are advocated for the pool of
367 growth factor and cytokines delivered by PRP [49]. A
368 potential role for MSCs is the mobilization and activation
369 of the local niche. Similarly, PRP can optimize the local
370 niche, and progenitors within a tendon can be stimulated to
371 proliferate and differentiate [50].
372Recent literature has emphasized the role of MSCs as
373modulators of excessive inflammation [51, 52]. MSCs
374activated by local inflammatory molecules (i.e., TNF-a,
375IL-1b, and interferon gamma [IFN-c]) secrete
376immunomodulatory factors including inducible nitric
377oxide synthase (iNOS), monocyte chemotactic protein 1
378(MCP-1), interleukin 1 receptor antagonist (IL-1Ra),
379and prostaglandin E2 (PGE2) [53]. PGE2 favors macro-
380phage transition from M1 to M2 and the synthesis of
381anti-inflammatory IL-10 [54, 55]. Interestingly, when
382MSCs are activated by inflammatory cytokines present
383in the local milieu, they secrete TNFa-stimulated gene
3846, TNFa-inducible protein 6 (TSG-6) that suppresses
385inflammation through a negative feedback loop on
386inflammatory toll-like receptor/nuclear factor kappa-b
387DNA-binding subunit (TLR/NF-jb) pathways [56, 57].
388Actually, TSG-6 has been proposed as a marker of MSC
389quality and functional efficacy in modulating sterile
390inflammation [54].
391Whether a single allogeneic MSC product can be used
392for all musculoskeletal conditions, and have similar effi-
393cacy to autologous MSCs, is unknown. But, assuming that
394aging of MSCs reduces their regenerative capabilities
395[58, 59], allogeneic MSCs may overcome this limitation.
396Ready-to-use MSCs are a feasible option because they
397escape immune recognition as they do not express HLA
398class 2 antigens and express moderate detectable levels of
399HLA class 1 antigen [60, 61]. However, once implanted,
Fig. 3 Mechanism of action of cell therapies: while still unclear,
several hypotheses have been proposed. Differentiated cells are
injected or implanted within tissue lesions to (1) engraft, synthesize
ECM molecules, integrate with the surrounding tissue, and return
tissue to homeostasis conditions and full functional capabilities.
MSCs can (1) engraft the tissue provided that the conditions of the
host tissue are favorable for differentiation; (2) modulate the
inflammatory response; (3) provide trophic and antiapoptotic factors;
(4) interact with the progenitor niche. ECM extracellular matrix, EGF
endothelial growth factor, HGF hepatocyte growth factor, IDO
indoleamine 2,3-dioxygenase, IFN interferon, IGF insulin growth
factor, IL interleukin, MCP monocyte chemotactic protein, MSCs
mesenchymal stem cells, PDGF platelet-derived growth factor, PGE2
prostaglandin E2, SDF stromal cell-derived factor, TGF transforming
growth factor, TLR toll-like receptor, TNF tumor necrosis factor,
TSG-6 TNFa-stimulated gene 6, TNFa-inducible protein 6, VEGF
vascular endothelial growth factor
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400 allogeneic MSCs can differentiate into local cells, and can
401 activate the host immune response [62]. The presence of
402 immunogenicity after cell differentiation can decrease their
403 therapeutic effect. Current knowledge supports the theory
404 that MSCs are immune evasive and not immune privileged,
405 an issue that requires further scientific clarification.
406 Efficacy doses of regenerative medicine products are
407 unknown. Regenerative medicine products are biological
408 response modifiers in contrast to pharmaceutical agents or
409 recombinant proteins. This means that they induce further
410 cellular and molecular changes over time. However,
411 because of their perception as drugs, MSC doses for
412 expanded cells are measured in the millions or billions of
413 cells, and initially calculated based on the recipient’s body
414 weight for systemic or intrathecal routes of administration
415 [63]. Intralesional delivery compared with systemic
416 administration has the advantage that cells arrive directly at
417 the target tissue, avoiding cell losses that may occur during
418 migration. Doses of PRP are measured as concentration of
419 platelets or multiples of platelets relative to the number in
420 peripheral blood.
4213 Regenerative Therapies in Clinical Practice
422To obtain more precise information about the clinical
423outcomes following cell therapies, we conducted a narra-
424tive review, categorizing the studies included in the review
425by target tissue and underlying pathology. We excluded
426studies examining the efficacy of autologous chondrocyte
427implantation (ACI) because they have been recently
428reviewed [64]. For the same reason, we did not review PRP
429studies [2, 65, 66].
4303.1 Search Strategy
431The review methodology is shown in Fig. 4. Articles were
432categorized according to condition, and whether the
433experimental cell product was applied by injection or at
434surgery. Additionally, studies were categorized according
435to whether fresh ‘stem-cell-based products’ (same-day
436procedures) or laboratory-expanded cells for 3–4 weeks
437were used. Data relating to experimental design, condition,
438patient population, as well as specific cell product,
Literature search (from 1980 to January week 4, 2016)Databases: PubMed, EMBASE, Web of ScienceLimits: human clinical, therapyResearch areas: orthopedics, sports medicine, rheumatology
Search criteriaClinical studies or registry data involving the use of cell therapies in tendon and joint pathologies, written inEnglish language and published in peer reviewed journals. Case reports were excluded
Search terms combined: Tendon, lesion, injury, healing, regeneration, rotator cuff, supraspinatus, patellar tendon, Achilles tendon, epicondylitisJoint, knee, hip, ankle, cartilage, meniscus, ligament, osteoarthritisCell therapy, stem cells, adipose stem cell, bone marrow stem cells, stromal cell, peripheral blood progenitor cells
Clinical studies with cell products for joint conditions, N=54
Conservative management, N=22
Surgical/arthroscopic implantation, N=32
Clinical studies with cell products for tendon conditions, N=10
Fig. 4 Review methodology
for cell therapies in tendons and
joints
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439 intervention type, and clinical outcomes were extracted and
440 tabulated (Tables 1, 2, 3).
441 3.2 Results
442 Nine clinical studies used autologous cells obtained from
443 different sources to treat tendon conditions [67–76]
444 (Table 1). In addition, we identified 22 studies in which
445 laboratory-expanded MSCs (n = 11) [77–88] or stem-cell-
446 derived products (n = 11) were injected intra-articularly
447 [89–99] (Table 2). Thirty-two studies performed arthro-
448 scopic/surgical delivery of cells [24, 101–133]; nine of
449 these studies used laboratory-expanded cells [100–108]
450 while stem-cell-derived products were used in 23 studies
451 [24, 109–133] (Table 3).
4523.2.1 Tendon Conditions
453Studies examining the efficacy and safety of cell therapies
454in tendon conditions are shown in Table 1 [67–76]. Cell
455therapies consisted of culture-expanded tenocytes [70, 71]
456or skin fibroblasts [67, 74]; also, BMC [68, 69, 72], SVF
457[76], and PBPC [73] have been used in five case series.
458A pioneer study was conducted in Australia by Wang
459et al. [70, 71], who implanted 2–5 9 106 autologous
460tenocytes, obtained from patellar tendon biopsies and fur-
461ther expanded in vitro, within the lateral epicondyle by
462ultrasound-guided injections with no peppering in 20
463patients with recalcitrant tendinopathy. No donor-site
464complication was found at follow-up. Outcome scores
465included visual analog scale (VAS), decreasing from 5.73
Table 1 Tendinopathies conservatively treated with cell therapies [67–76]
Study (year) Study design, N/patient
population
Intervention/follow-up Outcome measurements/follow-up/results
Epicondylitis (N = 4)
Connell et al.
(2009) [67]
Case series, N = 12 Injection, skin-derived cells,
expanded
6 months: 11/12 patients had satisfactory outcomes
Decrease in tear number, new vessels and tendon
thickness
Moon et al.
(2008) [68]
Case series, N = 26, lateral
and/or medial, recalcitrant to
conservative treatments
BMC ? pucaine after arthroscopic
debridement
8 weeks, 6 months: VAS, MEPS, no complications.
Pain reduction, improvement in MEPS at 8 weeks
and 6 months
Singh et al.
(2014) [69]
Case series, N = 30 patients,
first episode tendinopathy
BMC, 4–5 mL ? 1 mL 2 %
lidocaine
PREE, 2, 6 and 12 weeks, significant improvement in
functional outcome at all time points
Wang et al.
(2013, 2015)
[70, 71]
Case series, recalcitrant
patients, N = 20
Injection, autologous expanded
tenocytes 2–5 9 106 cells
1 year, VAS decrease, quick DASH improvement,
UEFS decrease and grip strength improved, MRI
improved. Effect maintained at 4.5 years
Shoulder (N = 2)
Centeno et al.
(2015) [72]
Case series, 115 shoulders in
102 patients, tears \1.5 cm
and shoulder OA
Preinjection with hypertonic
dextrose, BM-MSCs 4.7 9 108
cells
DASH, NPS, MCID defined as 2 point reduction in
NPS and 10 points in DASH
Ellera Gomes
et al. (2012)
[73]
Cases series, complete rotator
cuff tears
Conventional rotator cuff repair
plus PBMN cell injection into
tendon borders
Significant increase in UCLA at 12 months, MRI
integrity in all tendons 14/14, one patient relapsed
after 2 years
Patellar tendon (N = 2)
Clarke et al.
(2011) [74]
RCT, N = 46 patients, 60
patellar tendons
Expanded dermal fibroblasts
(2 mL) ? PRP versus PRP ?
medium without cells (2 mL)
Improvement VISA-P, 6 weeks, 3 and 6 months.
Reduction of hypoechogenicity and tear size in both
groups at 6 months. Increased thickness in cell group
Pascual-
Garrido et al.
(2012) [75]
Case series, N = 5 patients,
refractory patellar
tendinopathy
Non-expanded BMC 5 years: significant improvement in Tegner and KOOS
(all sub-scales). 7/8 patients would have the
procedure again
Achilles tendon (N = 1)
Tate-Oliver
and
Alexander
(2013) [76]
Case series, N = 3, partial
thickness interstitial tears
US-guided percutaneous
infiltration of (SVF ? PRP[49)
Patients returned to full activities after12 weeks, US at
12 months showed restoration of normal tendon
structure, improvement maintained at 3–4 years.
Increase in discomfort 3–4 days after infiltration
BMC bone marrow concentrate, BM-MSCs bone marrow-derived mesenchymal stem cells, DASH Disabilities of the Arm, Shoulder and Hand,
KOOS Knee injury and Osteoarthritis Outcome Score, MCID minimal clinically important differences, MEPS Mayo Elbow Performance Score,
MRI magnetic resonance imaging, NPS Numeric Pain Scale, OA osteoarthritis, PBMN peripheral blood mononuclear cells, PRP platelet-rich
plasma, PREE Patient-Rated Elbow Evaluation, RCT randomized controlled trial, SVF stromal vascular fraction, UCLA UCLA Shoulder Rating
Scale, UEFS Upper Extremity Functional Scale, US ultrasound, VAS visual analog scale, VISA-P Victorian Institute of Sports Assessment–
Patellar
I. Andia, N. Maffulli
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
Ta
ble
2C
on
serv
ativ
em
anag
emen
t:in
ject
ion
so
fce
llp
rod
uct
sin
join
tco
nd
itio
ns
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Inje
ctio
no
fex
pan
ded
mes
ench
ym
alst
emce
lls
(N=
11
)[7
7–8
8]
Cen
ten
oet
al.
(20
15
)[7
7]
Cas
ese
ries
,A
CL
tear
s,N
=1
0,
gra
de
1,
2,
3
tear
s
Inje
ctio
n,
pre
-in
ject
ion
of
3–
5m
Lo
f1
2.5
%d
extr
ose
?0
.1%
lid
oca
ine
inn
orm
alsa
lin
ein
toth
eA
CL
2–
5
day
sp
rio
rto
69
49
10
6B
M-M
SC
s/2
.7m
Lin
ject
ion
1,
3,
6,
and
12
mo
nth
s,V
AS
dec
reas
e1
.7,
p=
0.2
5,
LE
FS
incr
ease
23
.3,p
=0
.03
,se
lf-r
ated
imp
rov
emen
t8
6.7
%,7
/10
pat
ien
tssh
ow
edim
pro
vem
ents
inat
leas
t4
/5m
easu
rem
ents
(VA
S,
LE
FS
,F
RI,
sub
ject
ive
%im
pro
vem
ent
and
MR
I)
Cen
ten
oan
d
Fre
eman
(20
14
)
[78
]
Co
ntr
oll
edst
ud
y,
sev
ere
carp
om
etac
arp
alO
A,
n=
6p
atie
nts
trea
ted
and
n=
10
un
trea
ted
con
tro
ls,
chro
nic
Inje
ctio
no
f5
.76
91
06
BM
-MS
Cs
11
.8m
on
ths
afte
rce
llin
filt
rati
on
imp
rov
emen
to
f6
0%
,
wh
erea
s1
9%
inth
eco
ntr
ol
gro
up
.V
AS
red
uct
ion
63
%an
d
freq
uen
cyan
dd
ura
tio
no
fp
ain
dec
reas
edb
y4
1.7
%an
d
83
.3%
.N
oco
mp
lica
tio
ns
amo
ng
trea
ted
pat
ien
ts
Cen
ten
oet
al.
(20
11
)[7
9]
Co
ntr
oll
edst
ud
y,
kn
eeO
A,
n=
6
exp
erim
enta
l,n
=1
0co
ntr
ols
.S
etti
ng
:
inte
rven
tio
nal
pai
np
ract
ice
Inje
ctio
n,
5.7
69
10
6B
M-M
SC
sex
pan
ded
wit
h
pla
tele
tly
sate
At
12
mo
nth
s,6
0%
imp
rov
emen
tin
trea
tmen
tg
rou
p(9
5%
CI
22
–9
9)
and
19
%in
the
con
tro
lg
rou
p(9
5%
CI
-1
10
to7
3);
p=
0.0
03
,p
ain
dec
reas
e,fr
equ
ency
,an
dd
ura
tio
n
Dav
atch
iet
al.
(20
11
)[8
0]
Cas
ese
ries
,k
nee
OA
,N
=4
Inje
ctio
n,
auto
log
ou
sex
pan
ded
BM
-MS
Cs
8–
99
10
6
cell
s
VA
S,
wal
kin
gti
me
top
ain
imp
rov
edin
�p
atie
nts
,n
um
ber
of
stai
rsth
eyw
ere
able
tocl
imb
imp
rov
edsi
gn
ifica
ntl
y
Em
aded
inet
al.
(20
12
)[8
1]
Cas
ese
ries
,k
nee
OA
,N
=6
fem
ales
req
uir
ing
pro
sth
esis
Inje
ctio
n,
20
–2
49
10
6B
M-M
SC
,su
spen
ded
insa
lin
e
seru
man
din
ject
edu
nd
erfl
uo
rosc
op
y
No
adv
erse
even
ts,
pai
n,
fun
ctio
nal
stat
us,
and
wal
kin
g
dis
tan
ceim
pro
ved
at6
mo
nth
sb
ut
the
effe
ctsl
igh
tly
dec
reas
edat
12
mo
nth
s.M
RI
sho
wed
incr
ease
inca
rtil
age
thic
kn
ess,
exte
nsi
on
of
the
rep
air
tiss
ue
ov
erth
esu
bch
on
dra
l
bo
ne
and
dec
reas
ein
the
size
of
sub
cho
nd
ral
edem
ain
3/6
pat
ien
ts
Joet
al.
(20
14
)
[82
]
Cas
ese
ries
,k
nee
OA
,N
=1
8In
ject
ion
,A
d-M
SC
sth
ree
dif
fere
nt
do
ses,
19
10
7
cell
s;5
91
07
cell
s;1
91
08
cell
s
Imp
rov
emen
tV
AS
,W
OM
AC
at6
mo
nth
s,cl
inic
al,
rad
iolo
gic
al,
arth
rosc
op
ic,
and
his
tolo
gic
alev
alu
atio
ns
sho
wed
resu
lts
inth
eh
igh
-do
seg
rou
p.
Th
esi
zeo
fca
rtil
age
def
ect
dec
reas
edin
the
med
ial
fem
ora
lco
nd
yle
san
dti
bia
l
pla
teau
on
the
hig
h-d
ose
gro
up
.H
yal
ine
cart
ilag
eo
n
his
tolo
gy
Kim
etal
.(2
01
5)
[83
]
Co
ho
rtst
ud
y,
n=
20
pat
ien
tstr
eate
dw
ith
MS
Cs
?P
RP
inje
ctio
nv
sn
=2
0m
atch
ed
pat
ien
tsim
pla
nte
dar
thro
sco
pic
ally
wit
h
MS
Cs
?P
RP
MS
Cs
iso
late
dfr
om
SV
Fan
dex
pan
ded
.A
rth
rosc
op
ic
imp
lan
tati
on
vs
inje
ctio
n
At
28
.6m
on
ths
IKD
Can
dT
egn
erb
ette
rin
the
imp
lan
tati
on
than
inje
ctio
ng
rou
p.
ICR
Sg
rad
eas
sess
edar
thro
sco
pic
ally
,
bet
ter
inth
eim
pla
nta
tio
ng
rou
p,
p=
0.0
41
Oro
zco
etal
.
(20
13
),(2
01
4,
2-y
ear
foll
ow
-
up
)[8
4,
85]
Cas
ese
ries
,k
nee
OA
,N
=1
2In
ject
ion
,au
tolo
go
us
40
91
06
BM
-MS
CM
RI
at1
yea
r,2
7%
dec
reas
eo
fp
oo
rca
rtil
age
area
s,6
8–
78
%
imp
rov
emen
tin
alg
ofu
nct
ion
alin
dex
So
ler
Ric
het
al.
(20
15
)[8
6]
Cas
ese
ries
,k
nee
OA
,K
-L:
II–
IV,
N=
50
pat
ien
ts
Inje
ctio
nau
tolo
go
us
40
91
06
BM
-MS
CL
equ
esn
e,W
OM
AC
,V
AS
,M
RI,
sig
nifi
can
tre
du
ctio
nin
pai
n
at6
and
12
mo
nth
sp
ost
-tre
atm
ent.
VA
Sd
ecre
ased
sig
nifi
can
tly
.T
ota
lW
OM
AC
dec
reas
eat
12
mo
nth
sb
ut
no
t
sig
nifi
can
t.P
oo
rca
rtil
age
ind
exu
sed
toq
uan
tify
T2
map
pin
g
sho
wed
pro
mis
ing
ou
tco
mes
in7
4%
of
pat
ien
tsat
12
mo
nth
s
Biologics for Sports Injuries
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
Ta
ble
2co
nti
nu
ed
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Van
gsn
ess
etal
.
(20
14
)[8
7]
RC
T,
surg
ical
lyre
mo
ved
men
isca
lti
ssu
e,
N=
55
pat
ien
ts,
inje
ctio
ns
7–
10
day
saf
ter
par
tial
med
ial
men
isce
cto
my
Sin
gle
kn
eein
ject
ion
,5
09
10
6al
log
enei
cM
SC
s,1
50
91
06
allo
gen
eic
MS
Cs
wit
hH
Aas
veh
icle
,co
ntr
ol
gro
up
HA
inje
ctio
n
No
ecto
pic
tiss
ue
form
atio
n,
at1
2m
on
ths
incr
ease
dm
enis
cal
vo
lum
e(u
pto
15
%)
in2
4%
pat
ien
tsin
gro
up
A(l
ow
er
do
se)
and
6%
pat
ien
tsin
gro
up
B(h
igh
erce
lld
ose
)
p=
0.0
22
),n
op
atie
nt
inth
eco
ntr
ol
gro
up
.S
ign
ifica
nt
red
uct
ion
inp
ain
asm
easu
red
by
VA
S.
Ev
iden
ceo
fm
enis
cus
reg
ener
atio
nin
pat
ien
tsw
ho
rece
ived
cell
s
Veg
aet
al.
(20
15
)[8
8]
RC
T,
kn
eeO
Ase
ver
ity
II–
IVK
-L,
n=
15
per
gro
up
Inje
ctio
n/a
llo
gen
eic
40
91
06
BM
-MS
Cs
vs
HA
(60
mg
sin
gle
do
se)
VA
S,
Leq
ues
ne,
WO
MA
C,
6an
d1
2m
on
ths.
No
dif
fere
nce
sin
pai
nb
etw
een
gro
up
sex
cep
tfo
rV
AS
at1
2m
on
ths,
Leq
ues
ne
and
WO
MA
Cd
ecre
ased
on
lyin
exp
erim
enta
lg
rou
p.
77
%
pat
ien
tssa
tisfi
edin
the
cell
gro
up
and
38
%in
the
con
tro
l
gro
up
.N
ose
rio
us
adv
erse
even
ts.
MR
IT
2re
lax
atio
n
mea
sure
men
tssh
ow
edca
rtil
age
qu
alit
yim
pro
vem
ent
inth
e
MS
Cg
rou
p
Inje
ctio
no
fS
VF
and
/or
BM
C(N
=1
1)
[89
–9
9]
Bu
iet
al.
(20
14
)
[89
]
Cas
ese
ries
,k
nee
,N
=2
1S
VF
?P
RP
8.5
mo
nth
s,im
pro
vem
ent
inV
AS
,fu
nct
ion
,an
dM
RI
Cen
ten
oet
al.
(20
14
)[9
0]
Cas
ese
ries
,k
nee
OA
,N
=4
24
kn
ees,
earl
y
stag
e
Inje
ctio
nB
M-M
SC
stw
od
ose
sn
=1
85
do
se[
49
10
8an
dn
=2
24
do
se\
49
10
8IK
DC
,V
AS
;1
,3
,6
mo
nth
san
d1
yea
r;b
ette
rw
ith
hig
her
do
se,
p\
0.0
01
Cen
ten
oet
al.
(20
14
)[9
1]
Reg
istr
yd
ata,
kn
eeO
A,
84
0p
roce
du
res
Inje
ctio
n,
61
6B
MC
and
22
4B
MC
?ad
ipo
seL
EF
Sin
crea
se,
NP
Sd
ecre
ase,
add
itio
no
fad
ipo
seti
ssu
en
o
ben
efit.
Ad
ver
seev
ents
6%
inB
MA
Cg
rou
pan
d8
.9%
in
BM
C?
adip
ose
Fo
do
ran
d
Pau
lset
h(2
01
6)
[92
]
Cas
ese
ries
,k
nee
OA
(K-L
I–II
I),
N=
6
pat
ien
ts,
8k
nee
s
Inje
ctio
nS
VF
,1
4.1
91
06
nu
clea
ted
cell
s3
mo
nth
san
d1
yea
rim
pro
vem
ent
inW
OM
AC
and
VA
S.
MR
I
at3
mo
nth
s,n
od
etec
tab
led
iffe
ren
ces
Gib
bs
etal
.
(20
15
)[9
3]
Cas
ese
ries
,k
nee
OA
,N
=4
pat
ien
ts,
N=
7
join
ts
Inje
ctio
n,
SV
F?
PR
P2
,3
,6
,8
,an
d1
2m
on
ths,
KO
OS
,g
etu
pan
dg
ote
st,
stai
r
clim
bin
gte
stre
turn
edto
no
rmal
Kim
etal
.(2
01
4)
[94
]
Cas
ese
ries
,k
nee
OA
K-L
I–IV
,N
=4
1
pat
ien
ts(7
5k
nee
s)
Inje
ctio
n,
BM
C?
fat
3,
6,
12
mo
nth
s.S
ign
ifica
nt
imp
rov
emen
tin
VA
S,
IKD
C,
SF
-
36
,m
ore
effe
ctiv
ein
earl
yO
A
Ko
het
al.
(20
13
)
[95
]
Cas
ese
ries
,k
nee
OA
,N
=1
8S
VF
fro
min
frap
atel
lar
pad
inje
cted
(1.1
89
10
6)
wit
h
PR
P,
two
inje
ctio
ns
PR
P1
.28
91
06
pla
tele
t/lL
3m
on
ths,
1an
d2
yea
rs,
WO
MA
C,
Ly
sho
lm,
VA
S.
Imp
rov
emen
tin
MR
Ian
dcl
inic
alsc
ore
s.Im
pro
vem
ent
rela
ted
ton
um
ber
of
inje
cted
cell
s
Ko
han
dC
ho
i
(20
12
)[9
6]
Kn
eeca
rtil
age
def
ects
,re
tro
spec
tiv
e
com
par
ativ
est
ud
y
SV
F?
PR
Pv
ersu
sP
RP
(SV
Fis
fro
min
frap
atel
lar
pad
)
16
.4m
on
ths
VA
S,
Ly
sho
lm,
Teg
ner
bet
ter
inS
VF
?P
RP
Oli
ver
etal
.
(20
15
)[9
7]
Cas
ese
ries
,k
nee
OA
,N
=7
0p
atie
nts
,K
-L:
II–
IV
3m
LB
MC
?2
ml
lip
oas
pir
ate
in0
.00
12
5%
lid
oca
ine
3an
d6
mo
nth
s,K
OO
Ssu
b-s
core
sim
pro
ved
bu
tn
ot
sig
nifi
can
tly
Pak
etal
.(2
01
3)
[98
]
Ch
on
dro
mal
acia
pat
ella
e,N
=3
SV
F?
PR
P3
mo
nth
s,V
AS
,F
RI,
RO
M,
MR
Ip
ain
and
fun
ctio
n
imp
rov
emen
t,an
dM
RI
evid
ence
of
cart
ilag
ere
gen
erat
ion
I. Andia, N. Maffulli
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
466to 1.21, and the shortened version of the Disabilities of the
467Arm, Shoulder and Hand (Quick DASH questionnaire),
468improving from 45.88 to 6.61, after 1 year. In addition, the
469Upper Extremity Functional Scale (UEFS) decreased sig-
470nificantly from a mean value of 31.73 to 9.21, and grip
471strength improved from a mean value of 19.85 to 46.60.
472The cell treatment was unsuccessful in one patient who
473opted for surgery after 3 months. Magnetic resonance
474imaging (MRI) score improved significantly at 1 year
475compared with baseline (p \ 0.001). Durability of the
476therapeutic effects was maintained at a mean 4.5-year
477follow-up [71].
478Connell et al. [67] studied the effect of autologous
479fibroblasts, prepared from skin biopsies, on recalcitrant
480epicondylitis in 12 patients. Six months after cell injec-
481tions, 11 of 12 patients showed decreased tear number and
482tendon thickness as assessed by ultrasound (US) [66].
483Moon et al. [68] investigated the effect of BMC in 26
484patients with medial or lateral epicondylitis, and reported a
485reduction in pain and enhanced functionality at 6 months.
486Centeno et al. [72] reported the effects of BMC injection
487for the treatment of supraspinatus tears and shoulder OA in
488a prospective multi-site registry study. Eighty-one rotator
489cuff tears and 34 patients with shoulder OA followed
490needle injection treatment with BMC containing PRP and
491platelet lysate; the nucleated cell count in BMC was an
492average of 4.7 9 108 cells. Of note, tendons were previ-
493ously treated with hypertonic dextrose in order to condition
494the host tissue. DASH scores decreased by an average of
49552.6 % (p \ 0.001) and numeric pain scale decreased by
49644.2 % (p \ 0.001). The reduction of disability and pain
497started at the first month after treatment. Improvement
498continued for up to 2 years.
499The efficacy of autologous fibroblast injections com-
500bined with PRP was examined in a randomized clinical
501trial (RCT) involving 46 patients and 60 patellar tendons
502[74]. The experimental group showed better functional
503outcomes than the control group treated with PRP injec-
504tions. A reduction of hypoechogenicity and tear size was
505reported in both groups, but tendons treated with cells
506displayed increased thickness. In a case series, Pascual-
507Garrido et al. [75] injected eight patients with refractory
508patellar tendinopathy with BMC and followed them for up
509to 5 years. Seven of the eight patients were satisfied with
510the procedure, and significant improvements were seen in
511Tegner and Knee injury and Osteoarthritis Outcome Score
512(KOOS).
513Significant improvements were reported except for
514patients with bilateral pathology. SVF combined with PRP
515was injected in three patients with partial thickness inter-
516stitial tears in their Achilles tendon [76]. Restoration of a
517normal tendon structure was reported after 12 months, and
518the improvement was maintained for 3–4 years.Ta
ble
2co
nti
nu
ed
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Pak
etal
.(2
01
3)
[99
]
Cas
ese
ries
,O
A,
N=
91
pat
ien
ts.
Hip
n=
22
;
kn
een
=7
4;
ank
len
=2
;lo
wb
ack
n=
2
SV
F?
HA
?ac
tiv
ated
PR
P?
thre
ein
ject
ion
so
f
acti
vat
edP
RP
wee
kly
wit
hin
am
on
th
Mea
nfo
llo
w-u
p2
6m
on
ths,
sig
nifi
can
td
ecre
ase
inV
AS
at1
and
3m
on
ths.
Pai
nan
dsw
elli
ng
1d
ayaf
ter
SV
F?
HA
?
acti
vat
edP
RP
in3
7%
of
pat
ien
ts.
Saf
ety
asse
ssm
ent:
infe
ctio
n0
%,
tum
or
0%
,te
no
syn
ov
itis
/ten
do
nit
is2
2%
,
neu
rolo
gic
1%
hem
orr
hag
icst
rok
e2
wee
ks
afte
rth
e
pro
ced
ure
AC
Lan
teri
or
cru
ciat
eli
gam
ent,
Ad
-MS
Cs
adip
ose
-der
ived
mes
ench
ym
alst
emce
lls,
BM
AC
bo
ne
mar
row
asp
irat
eco
nce
ntr
ate,
BM
-MS
Cs
bo
ne
mar
row
-der
ived
mes
ench
ym
alst
emce
lls,
BM
C
bo
ne
mar
row
con
cen
trat
e,C
Ico
nfi
den
cein
terv
al,
FR
IF
un
ctio
nal
Rat
ing
Ind
ex,
HA
hy
alu
ron
icac
id,
ICR
SIn
tern
atio
nal
Car
tila
ge
Res
earc
hS
oci
ety
,IK
DC
Inte
rnat
ion
alK
nee
Do
cum
enta
tio
n
Co
mm
itte
e,K
-LK
ellg
ren
-Law
ren
cesc
ore
,K
OO
SK
nee
inju
ryan
dO
steo
arth
riti
sO
utc
om
eS
core
,L
EF
SL
ow
erE
xtr
emit
yF
un
ctio
nal
Sca
le,
MR
Im
agn
etic
reso
nan
ceim
agin
g,
MS
C
mes
ench
ym
alst
emce
ll,
NP
SN
um
eric
Pai
nS
cale
,O
Ao
steo
arth
riti
s,P
RP
pla
tele
t-ri
chp
lasm
a,R
CT
ran
do
miz
edco
ntr
oll
edtr
ial,
RO
Mra
ng
eo
fm
ov
emen
t,S
VF
stro
mal
vas
cula
rfr
acti
on
,V
AS
vis
ual
anal
og
scal
e,W
OM
AC
Wes
tern
On
tari
oan
dM
cMas
ter
Un
iver
siti
esO
steo
arth
riti
sIn
dex
Biologics for Sports Injuries
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
Ta
ble
3S
urg
ical
(art
hro
sco
py
/art
hro
tom
y)
imp
lan
tati
on
of
cell
pro
du
cts
injo
int
con
dit
ion
s
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Su
rgic
al/a
rth
rosc
op
icim
pla
nta
tio
no
fex
pan
ded
MS
Cs
(N=
9)
[10
0–
10
8]
Ak
gu
net
al.
(20
15
)[1
00
]
Pro
spec
tiv
era
nd
om
ized
pil
ot
stu
dy
,N
=1
4,
kn
ee,
full
thic
kn
ess
cho
nd
ral
lesi
on
s[
2cm
2M
ini-
arth
roto
my
m-A
MI
vs
m-A
CI.
MS
Cs
har
ves
ted
fro
msy
no
via
and
exp
and
ed/c
ho
nd
rocy
tes
har
ves
ted
and
exp
and
ed
6,
12
,an
d2
4m
on
ths,
m-A
MI
gro
up
bet
ter
for
all
KO
OS
sub
-sca
les
than
m-A
CI
(pai
n,
sym
pto
ms,
AD
L,
spo
rt/r
ec).
MR
Iat
24
mo
nth
sm
-AM
Iex
cell
ent
and
m-A
CI
gro
up
go
od
.B
on
em
arro
wed
ema
sig
nal
dec
reas
edto
no
rmal
in
m-A
MI.
No
com
pli
cati
on
s
Hal
eem
etal
.
(20
10
)[1
01
]
Cas
ese
ries
,k
nee
cho
nd
ral
lesi
on
sN
=5
pat
ien
ts
full
-th
ick
nes
sd
efec
ts,
3–
10
cm2
Art
hro
sco
py
15
91
06
BM
-MS
Cs
?P
R-fi
bri
ng
lue
(7.7
91
08
pts
/mL
)2
91
06
cell
s/cm
2co
ver
ed
wit
hp
erio
stea
lfl
ap
All
pat
ien
tsim
pro
ved
ICR
Ssc
ore
at6
,1
2m
on
ths,
seco
nd
loo
kar
thro
sco
py
in2
pat
ien
tssh
ow
edn
earl
yn
orm
al
join
ts;
MR
Io
f3
pat
ien
tssh
ow
edco
mp
lete
def
ect
fill
,2
pat
ien
tssh
ow
edin
com
ple
teco
ng
ruit
y
Ko
het
al.
(20
14
)
[10
2]
Cas
ese
ries
,N
=3
7k
nee
s,ch
on
dra
lle
sio
ns
2.3
–8
.9
cm2
2.5
–6
.19
10
6M
SC
sfr
om
SV
FIm
pro
ved
IKD
C,
Teg
ner
.IC
RS
gra
din
gat
2n
dlo
ok
76
%o
f
kn
ees
rate
dab
no
rmal
Lee
etal
.(2
01
2)
[10
3]
Pro
spec
tiv
eco
ho
rtst
ud
y,
kn
eech
on
dra
lle
sio
nN
=3
5p
atie
nts
arth
rosc
op
icm
icro
frac
ture
?
ou
tpat
ien
tin
ject
ion
of
10
7B
M-M
SC
s?
2m
LH
A
ver
sus
N=
35
MS
Cs
imp
lan
ted
ino
pen
surg
ery
VA
S,
IKD
C,
Ly
sho
lm,
sig
nifi
can
tim
pro
vem
ents
inb
oth
gro
up
sat
24
mo
nth
s
Nej
adn
iket
al.
(20
10
)[1
04
]
Ob
serv
atio
nal
coh
ort
stu
dy
,k
nee
cho
nd
ral
lesi
on
s,
N=
72
Art
hro
tom
yto
imp
lan
tce
lls
N=
36
pat
ien
tsA
CI
vs
N=
36
BM
-MS
C,
2-s
tag
ep
roce
du
re.
BM
-
der
ived
MS
Cs
and
cho
nd
rocy
teex
pan
sio
n
IKD
C,
ICR
S,
SF
-36
,L
ysh
olm
,T
egn
er.
No
dif
fere
nce
s
bet
wee
ng
rou
ps
Saw
etal
.(2
01
3)
[10
5]
RC
T,
kn
ee,
gra
de
3–
4ch
on
dra
lle
sio
ns
N=
50
pat
ien
ts,
25
per
gro
up
Su
bch
on
dra
ld
rill
ing
and
5in
ject
ion
so
fH
Av
s
PB
PC
?H
A(o
nce
per
wee
k)
atse
rial
vis
its
po
st-
surg
ery
6m
on
ths
afte
rsu
rger
y1
inje
ctio
np
er
wee
kfo
r3
wee
ks
No
dif
fere
nce
sb
etw
een
gro
up
sat
24
-mo
nth
IKD
C.
No
no
tab
lead
ver
seef
fect
s.1
6p
atie
nts
per
gro
up
had
his
tolo
gy
and
2n
dlo
ok
arth
rosc
op
yIC
RS
his
tolo
gic
sco
re,
MR
Isc
ans
at1
8m
on
ths,
sig
nifi
can
tly
bet
ter
inth
e
exp
erim
enta
lg
rou
p
Sek
iya
etal
.
(20
15
)[1
06
]
Cas
ese
ries
,k
nee
,si
ng
leca
rtil
age
lesi
on
of
the
fem
ora
lco
nd
yle
,N
=1
0(5
pat
ien
tsu
nd
erw
ent
con
com
itan
tA
CL
reco
nst
ruct
ion
amo
ng
wh
om
2
had
men
iscu
ssu
turi
ng
)
Ex
pan
ded
syn
ov
ial
MS
Cs
wit
hau
tolo
go
us
seru
m
for
14
day
s,ar
thro
sco
pic
imp
lan
tati
on
on
the
def
ect
MR
Iim
pro
ved
fro
m1
.0±
0.3
to5
.0±
0.7
p=
0.0
05
,
his
tolo
gy
per
form
edo
n2
nd
loo
kar
thro
sco
py
on
4p
atie
nts
sho
wed
hy
alin
eca
rtil
age
in3
pat
ien
tsan
dfi
bro
us
cart
ilag
e
in1
pat
ien
t,L
ysh
olm
no
chan
ge,
Teg
ner
76
±7
bef
ore
and
95
±3
afte
r.A
ver
age
foll
ow
-up
52
mo
nth
s
Teo
etal
.(2
01
2)
[10
7]
Cas
ese
ries
,p
atel
lar
OC
D,
ado
lesc
ent
pat
ien
ts,
mea
n
age
16
.8y
ears
N=
20
auto
log
ou
sch
on
dro
cyte
s,N
=3
pat
ien
ts
cult
ure
dB
M-M
SC
6,
12
,an
d2
4m
on
ths.
Mea
nIK
DC
sco
re,
Teg
ner
-Ly
sho
lm
ou
tco
mes
,an
dL
ysh
olm
-Gil
lqu
ist
scal
eim
pro
ved
fro
m4
5,
2.5
,an
d5
0,
resp
ecti
vel
yat
surg
ery
to7
5,
4,
and
70
,
resp
ecti
vel
y,
at2
4-m
on
thfo
llo
w-u
p.
Co
mp
lica
tio
ns
incl
ud
ep
erio
stea
lh
yp
ertr
op
hy
ob
serv
edin
2p
atie
nts
Wo
ng
etal
.
(20
13
)[1
08
]
RC
T,
un
ico
mp
artm
enta
lk
nee
OA
and
gen
uv
aru
m,
n=
28
pat
ien
tsce
lls
?H
Av
sn
=2
8co
ntr
ols
HT
O?
mic
rofr
actu
re?
BM
-MS
Cs
(in
ject
edp
ost
-
op
)v
sH
TO
?m
icro
frac
ture
.E
xp
and
edB
M-
MS
Cs
wer
ein
ject
edaf
ter
22
day
s
MO
CA
RT
adju
sted
by
age,
at1
yea
rb
ette
rin
the
cell
gro
up
.
Teg
ner
,L
ysh
olm
,IK
DC
cell
trea
tmen
tad
ded
imp
rov
emen
t
Art
hro
sco
pic
imp
lan
tati
on
of
no
n-e
xp
and
edce
lls
(N=
23
)[2
4,
10
9–
13
3]
Bu
da
etal
.(2
01
6)
[10
9]
Cas
ese
ries
,o
steo
cho
nd
ral
lesi
on
so
fth
eta
lus
and
ank
leO
A,
N=
56
BM
C?
PR
F,
arth
rosc
op
ico
ro
pen
-fiel
dsu
rger
y,
bo
ne
fill
ing
wit
hd
emin
eral
ized
bo
ne
mat
rix
in
sele
cted
case
s
12
,2
4,
and
36
mo
nth
s’fo
llo
w-u
p,
clin
ical
imp
rov
emen
t
asse
ssed
by
AO
FA
Sat
3ti
me
po
ints
.M
RI
in2
2p
atie
nts
,
MO
CA
RT
rev
eale
dco
mp
lete
deg
ree
of
fill
ing
wit
hb
on
e
edem
ain
mo
stp
atie
nts
.1
6/5
6re
qu
ired
ano
ther
inte
rven
tio
n(f
ailu
res)
ano
ther
trea
tmen
t
I. Andia, N. Maffulli
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
Ta
ble
3co
nti
nu
ed
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Bu
da
etal
.(2
01
5)
[11
0]
RC
T,
ank
le,
ost
eoch
on
dra
lle
sio
ns
of
the
talu
s,
N=
80
,4
0p
erg
rou
p
AC
Iv
sB
MC
?P
RP
arth
rosc
op
icd
ebri
dem
ent
48
mo
nth
sM
RI,
MO
CA
RT
sim
ilar
inb
oth
gro
up
s,cl
inic
al
ou
tco
mes
sim
ilar
inb
oth
gro
up
s
Bu
da
etal
.(2
01
5)
[11
1]
Ret
rosp
ecti
ve
stu
dy
,k
nee
,h
emo
ph
ilia
cp
atie
nts
,
N=
5
BM
Ctr
ansp
lan
tati
on
,sy
no
vec
tom
y,
arth
rosc
op
ic
deb
rid
emen
t
24
mo
nth
s,A
OF
AS
imp
rov
emen
tan
dM
RI
MO
CA
RT
sig
ns
of
cart
ilag
ere
gen
erat
ion
Bu
da
etal
.(2
01
4)
[11
2]
Cas
ese
ries
,an
kle
,N
=6
4p
atie
nts
,p
ost
-tra
um
atic
typ
eII
foca
lle
sio
ns
tala
rd
om
e
BM
C?
[po
rcin
eco
llag
enp
ow
der
?P
RP
]o
rB
MC
?[H
Am
emb
ran
e?
PR
P]
6,
12
,1
8,
and
24
mo
nth
s,fi
nal
foll
ow
-up
72
mo
nth
s,
AO
FA
Sim
pro
vem
ent
no
dif
fere
nce
sb
etw
een
bo
th
scaf
fold
s.6
0/6
4p
atie
nts
par
tici
pat
ein
low
-im
pac
tsp
ort
s
at4
.8m
on
ths
and
49
/64
pat
ien
tsin
hig
h-i
mp
act
spo
rtat
11
.9m
on
ths
Bu
da
etal
.(2
01
0,
20
13
)
[11
3,
11
4]
Cas
ese
ries
,k
nee
ost
eoch
on
dra
lle
sio
ns,
N=
30
pat
ien
ts,
28
wit
hp
ost
-tra
um
atic
lesi
on
s,G
rad
eII
-IV
and
2p
atie
nts
wit
ho
steo
cho
nd
riti
sd
isse
can
s
BM
C,
con
cen
trat
edfr
om
60
to6
mL
soak
edin
to
HA
mem
bra
ne,
imp
lan
ted
arth
rosc
op
ical
lyan
d
cov
ered
wit
hP
RP
6,
12
,1
8,
24
,3
6m
on
ths,
IKD
C,
KO
OS
sig
nifi
can
t
imp
rov
emen
t.M
RI,
MO
CA
RT
sco
re(6
and
12
mo
nth
s)
sho
wed
asso
ciat
ion
wit
hK
OO
Ssc
ore
,re
gen
erat
ion
of
sub
cho
nd
ral
bo
ne
and
cart
ilag
e,h
isto
log
yin
2p
atie
nts
sho
wed
typ
eII
coll
agen
and
pro
teo
gly
can
s
En
eaet
al.
(20
15
)
[11
5]
Cas
ese
ries
,k
nee
,fo
cal
cho
nd
ral
lesi
on
s,2
.5cm
2M
icro
frac
ture
wit
hco
llag
enim
mer
sed
inB
MC
12
mo
nth
s,m
acro
sco
pic
asse
ssm
ent,
all
rep
airs
app
ear
alm
ost
no
rmal
.C
lin
ical
imp
rov
emen
t.N
oad
ver
seef
fect
s
Gia
nn
ini
etal
.
(20
09
,2
01
3)
[11
6,
11
7]
Cas
ese
ries
,o
steo
cho
nd
ral
lesi
on
so
fth
eta
lus,
N=
49
pat
ien
ts
BM
C?
scaf
fold
2,3
,an
d4
yea
rsA
OF
AS
imp
rov
edan
dco
rrel
ated
wit
hM
RI
fin
din
gs
Go
bb
iet
al.
(20
11
)[1
18
]
Cas
ese
ries
,k
nee
,g
rad
eIV
cho
nd
ral
lesi
on
s,si
ze
9.2
cm2,
N=
15
pat
ien
ts,
6/1
5h
adm
ult
iple
cho
nd
ral
lesi
on
s
BM
C?
coll
agen
I/II
Im
atri
x6
,1
2,
and
24
mo
nth
s,im
pro
vem
ent
inIK
DC
,K
OO
S,
Ly
sho
lm,T
egn
er,S
F-3
6.M
RI
sho
wed
cart
ilag
e-li
ke
tiss
ue
cov
erin
gle
sio
ns
Kas
emk
ijw
atta
na
etal
.(2
01
1)
[11
9]
Cas
ese
ries
,N
=2
,g
rad
e3
–4
ICR
Scl
assi
fica
tio
nA
rth
rosc
op
icim
pla
nta
tio
nB
M-M
SC
s?
3D
coll
agen
30
mo
nth
s,n
oco
mp
lica
tio
ns,
sig
nifi
can
tim
pro
vem
ent
KO
OS
,IK
DC
.D
efec
tfi
ll,
stif
fnes
san
din
corp
ora
tio
nto
adja
cen
tca
rtil
age
asas
sess
edin
arth
rosc
op
y
Kim
etal
.(2
01
5)
[24
]
Ret
rosp
ecti
ve
coh
ort
stu
dy
,k
nee
N=
54
pat
ien
ts(5
6
kn
ees)
iso
late
dfu
llth
ick
nes
sca
rtil
age
lesi
on
sK
-L
1–
2
37
pat
ien
ts(3
9k
nee
s)S
VF
wit
ho
ut
scaf
fold
,1
7
pat
ien
ts=
kn
ees,
SV
F?
fib
rin
glu
e
28
.6m
on
ths
IKD
Can
dT
egn
erim
pro
ved
,n
od
iffe
ren
ces
bet
wee
ng
rou
ps.
At
2n
dlo
ok
arth
rosc
op
y,
bet
ter
ICR
S
gra
de
ing
rou
p2
Kim
etal
.(2
01
5)
[12
0]
Ret
rosp
ecti
ve
case
seri
es,
kn
eeN
=4
9p
atie
nts
(55
kn
ees)
iso
late
dfu
llth
ick
nes
sca
rtil
age
lesi
on
sK
-L
1–
2
SV
FS
ign
ifica
nt
dif
fere
nce
sin
clin
ical
ou
tco
mes
amo
ng
the
age
and
lesi
on
size
gro
up
.A
ge[
60
yea
rsan
dle
sio
nsi
ze
[6
cm2
sho
wed
po
or
ou
tco
mes
Kim
etal
.(2
01
6)
[12
1]
Cas
ese
ries
,is
ola
ted
kn
eech
on
dra
lle
sio
ns,
K-L
gra
de
1–
2,
N=
24
pat
ien
ts
Art
hro
sco
pic
deb
rid
emen
tS
VF
?fi
bri
ng
lue
24
mo
nth
s,IK
DC
and
Teg
ner
sig
nifi
can
tim
pro
vem
ent,
MR
I
MO
CA
RT
sig
nifi
can
tim
pro
vem
ent
Kim
etal
.(2
01
3)
[12
2]
Cas
ese
ries
,N
=4
5p
atie
nts
[5
0y
ears
ank
le,
ost
eoch
on
dra
lle
sio
ns
of
the
talu
s
Art
hro
sco
pic
mar
row
stim
ula
tio
n,
N=
35
pat
ien
ts
(37
ank
les)
vs
BM
Cin
ject
ion
?ar
thro
sco
pic
mar
row
stim
ula
tio
n
21
.8m
on
ths,
Ro
les
and
Mau
dsl
eyb
ette
rw
ith
ou
tB
MC
,
Teg
ner
bet
ter
inB
MC
gro
up
Kim
etal
.(2
01
4)
[12
3]
Co
ho
rtst
ud
y,
N=
49
pat
ien
ts,
50
ank
les,
ost
eoch
on
dra
lle
sio
ns
of
the
talu
s
Art
hro
sco
py
N=
26
OC
stim
ula
tio
n,
N=
24
OC
stim
ula
tio
nan
dS
VF
All
clin
ical
ou
tco
mes
(VA
S,
AO
FA
S,
Teg
ner
,M
OC
AR
T)
imp
rov
edin
MS
Cg
rou
pco
mp
ared
wit
hco
ntr
ols
Biologics for Sports Injuries
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
Ta
ble
3co
nti
nu
ed
Stu
dy
(yea
r)S
tud
yd
esig
n,
con
dit
ion
,N
/pat
ien
tp
op
ula
tio
nIn
terv
enti
on
/cel
lp
rod
uct
Ou
tco
me
mea
sure
men
ts/f
oll
ow
-up
/res
ult
s
Ko
het
al.
(20
16
)
[12
4]
Pro
spec
tiv
era
nd
om
ized
tria
lIC
RS
gra
de
III/
IV,
sym
pto
mat
icca
rtil
age
def
ect[
3cm
2o
nth
efe
mo
ral
con
dy
le
AD
SC
?fi
bri
ng
lue
?m
icro
frac
ture
vs
mic
rofr
actu
re
MR
Iat
24
mo
nth
s,co
mp
lete
cart
ilag
eco
ver
age
in6
5%
of
exp
erim
enta
lg
rou
pv
s4
5%
inth
eco
ntr
ol
gro
up
.K
OO
S
bet
ter
inex
per
imen
tal
gro
up
bu
tn
od
iffe
ren
ces
insu
b-
sco
res,
2n
dlo
ok
arth
rosc
op
yan
dh
isto
log
ysh
ow
edn
o
dif
fere
nce
sb
etw
een
gro
up
s
Ko
het
al.
(20
15
)
[12
5]
Cas
ese
ries
,k
nee
cho
nd
ral
lesi
on
sN
=3
0p
atie
nts
[6
5y
ears
Art
hro
sco
pic
lav
age
and
inje
ctio
no
f4
.29
10
7S
VF
cell
sw
ith
3m
LP
RP
2y
ears
,V
AS
and
fun
ctio
nim
pro
vem
ent,
16
/30
pat
ien
ts
foll
ow
ed2
nd
loo
kar
thro
sco
py
:3
kn
ees
no
rmal
cart
ilag
e,
7n
ewca
rtil
age
par
tial
lyco
ver
edth
ed
efec
t,4
kn
ees
un
cert
ain
chan
ge,
and
2k
nee
sfa
iled
hea
lin
g.
5/3
0
wo
rsen
edK
-Ld
egre
eat
2y
ears
Ko
het
al.
(20
14
)
[12
6]
Pro
spec
tiv
eco
mp
arat
ive
stu
dy
,k
nee
Su
rger
yH
TO
?P
RP
vs
HT
O?
PR
P?
MS
CL
ysh
olm
,K
OO
S,
VA
S.
Gre
ater
imp
rov
emen
tin
VA
San
d
KO
OS
for
pai
nan
dsy
mp
tom
sin
the
MS
C?
PR
Pg
rou
p.
Art
hro
sco
pic
eval
uat
ion
sho
wed
fib
roca
rtil
age
cov
erag
ein
50
%o
fM
SC
s?
PR
Pan
d1
0%
of
the
pat
ien
tsin
PR
P
gro
up
Kry
chet
al.
(20
16
)[1
27
]
Co
ho
rtst
ud
y,
kn
ee,
full
thic
kn
ess
cart
ilag
ed
efec
ts
N=
46
Sca
ffo
ld?
BM
AC
,N
=1
2;
scaf
fold
?P
RP
,
N=
23
;sc
affo
ldco
ntr
ol
N=
11
12
mo
nth
s,M
RI
scaf
fold
?B
MA
Cim
pro
ved
mat
ura
tio
n
wit
hg
reat
erfi
llan
dT
2v
alu
escl
ose
rto
hy
alin
eca
rtil
age
Mic
hal
eket
al.
(20
15
)[1
28
]
Cas
ese
ries
,m
ult
icen
ter,
ost
eoar
thri
tis,
11
28
pat
ien
ts,
18
56
join
ts(h
ips
and
kn
ees)
,5
03
pat
ien
tsca
nd
idat
es
for
tota
ljo
int
arth
rop
last
y
SV
F?
PR
P3
,6
,1
2m
on
ths
KO
OS
/HO
OS
.8
0.6
and
91
%o
fp
atie
nts
imp
rov
ed[
50
%at
3-m
on
than
d1
2-m
on
thfo
llo
w-u
p.
4/5
03
pat
ien
tsre
qu
ired
tota
lh
ipre
pla
cem
ent
Saw
etal
.(2
01
5)
[12
9]
Cas
ese
ries
,k
nee
,N
=8
pat
ien
ts,
ICR
SG
rad
e4
lesi
on
s
Op
enw
edg
eH
TO
and
5w
eek
lyin
ject
ion
so
f
PB
SC
s?
HA
(8:2
),3
add
itio
nal
inje
ctio
ns
at
inte
rval
s6
,1
2,
and
18
mo
nth
s
His
tolo
gy
at2
nd
loo
kar
thro
sco
py
,IC
RS
vis
ual
asse
ssm
ent
scal
em
ean
12
74
(13
40
isn
orm
alca
rtil
age)
.N
oin
fect
ion
s
Sk
ow
ron
ski
etal
.
(20
13
)[1
30
]
Cas
ese
ries
,IC
RS
gra
de
III–
IVca
rtil
age
lesi
on
sin
the
kn
ee,
N=
54
pat
ien
ts
BM
C?
coll
agen
1an
d5
yea
rs,
Ly
sho
lm,
KO
OS
,V
AS
.A
t1
yea
r,2
5p
oin
ts
imp
rov
emen
tin
KO
OS
and
35
po
ints
inL
ysh
olm
Sil
va
etal
.(2
01
4)
[13
1]
RC
T,
ten
do
n–
bo
ne
atta
chm
ent,
AC
Lre
con
stru
ctio
n,
n=
20
exp
erim
enta
lg
rou
p,
n=
23
con
tro
lg
rou
p
Art
hro
sco
py
,A
CL
reco
nst
ruct
ion
,3
mL
BM
C,
1.5
mL
inje
cted
inth
eg
raft
and
1.5
mL
inje
cted
wit
hin
the
bo
ne
tun
nel
,w
ith
ou
tir
rig
atio
n
MR
Iat
3m
on
ths,
no
dif
fere
nce
sb
etw
een
gro
up
sin
SN
Rin
the
up
per
and
low
erin
terz
on
es
Wak
itan
iet
al.
(20
02
,2
01
1)
[13
2,
13
3]
Cas
ese
ries
,k
nee
,N
=4
1p
atie
nts
,4
5k
nee
s,ce
ll
tran
spla
nta
tio
np
erfo
rmed
in1
98
8
BM
-MS
CS
afet
y:
11
yea
rsan
d5
mo
nth
sfo
llo
w-u
p,
no
tum
ors
,n
o
infe
ctio
ns
AC
Lan
teri
or
cru
ciat
eli
gam
ent,
AC
Iau
tolo
go
us
cho
nd
rocy
teim
pla
nta
tio
n,
AM
Iau
tolo
go
us
mes
ench
ym
alst
em-c
ell
imp
lan
tati
on
,A
OF
AS
Am
eric
anO
rth
op
edic
Fo
ot
and
An
kle
Sco
re,
AD
SC
adip
ose
stem
cell
s,B
MA
Cb
on
em
arro
was
pir
ate
con
cen
trat
e,B
MC
bo
ne
mar
row
con
cen
trat
e,B
M-M
SC
sb
on
em
arro
w-d
eriv
edm
esen
chy
mal
stem
cell
s,H
Ah
yal
uro
nic
acid
,H
OO
SH
ipIn
jury
and
Ost
eoar
thri
tis
Ou
tco
me
Sco
re,
HT
Oh
igh
tib
ial
ost
eoto
my
,IC
RS
Inte
rnat
ion
alC
arti
lag
eR
esea
rch
So
ciet
y,
IKD
CIn
tern
atio
nal
Kn
eeD
ocu
men
tati
on
Co
mm
itte
e,K
-LK
ellg
ren
-Law
ren
ce
sev
erit
ysc
ore
,K
OO
SK
nee
inju
ryan
dO
steo
arth
riti
sO
utc
om
eS
core
,M
OC
AR
Tm
agn
etic
reso
nan
ceo
bse
rvat
ion
of
cart
ilag
ere
pai
rti
ssu
e,M
RI
mag
net
icre
son
ance
imag
ing
,M
SC
sm
es-
ench
ym
alst
emce
lls,
OA
ost
eoar
thri
tis,
OC
Do
steo
cho
nd
riti
sd
isse
can
s,P
BP
Cp
erip
her
alb
loo
dp
rog
enit
or
cell
s,P
RF
pla
tele
t-ri
chfi
bri
n,
PR
Pp
late
let-
rich
pla
sma,
RC
Tra
nd
om
ized
con
tro
l
tria
l,S
F-3
6S
ho
rtF
orm
-36
,S
NR
sig
nal
-to
-no
ise
rati
o,
SV
Fst
rom
alv
ascu
lar
frac
tio
n,
VA
Sv
isu
alan
alo
gsc
ale
I. Andia, N. Maffulli
123Journal : Large 40279 Dispatch : 21-9-2016 Pages : 22
Article No. : 620h LE h TYPESET
MS Code : SPOA-D-16-00093 h CP h DISK4 4
RE
VIS
ED
PRO
OF
519 Cell replacement treatment associated with PRP can be
520 useful in severe degenerative cases in which PRP alone is
521 insufficient to reverse the progression. Moreover, PRP is a
522 good adjuvant to cell therapies, as it enhances cell survival
523 and proliferation, and helps to confine cells at the delivery
524 site. Clarke et al. [74] have compared dermal fibroblasts ?
525 PRP versus PRP alone. A reduction in hypoechogenicity
526 and tear size was found in both groups, though increased
527 thickness was more evident in the cell group.
528 Further research to identify the best cell source and
529 treatment regimens is needed. Moreover, design of cell
530 therapies should be tailored according to anatomical area;
531 that is, the main body of the tendon or the enthesis. Precise
532 needle delivery is important. As novel cell tracking systems
533 are developed, we will be able to visualize whether cells
534 integrate in the host tissue, and thus the ultimate fate of the
535 implanted cells can be clarified [134].
536 Table 4 shows a summary of advantages and disad-
537 vantages of the different types of cells being examined in
538 clinical studies, and the development stages in tendon and
539 joint conditions following the IDEAL framework. The
540 latter includes four stages of therapy development descri-
541 bed as idea, exploration, assessments, and large data sets
542 [135].
543 3.2.2 Joint Conditions
544 Peeters et al. [136] assessed the safety of intra-articular
545 delivery of MSC products either by injection or surgical
546 implantation. They analyzed 844 interventions, and repor-
547 ted two related adverse events, one infection and one
548 pulmonary embolism, and two non-related adverse events,
549 one prostate cancer and one Schwannoma. Minor events
550 included pain, swelling, and dehydration. Most clinical
551 studies do not refer explicitly to adverse events, but when
552 these were considered, minor self-resolving adverse events
553 were reported. Follow-up as long as 11 years has been
554 maintained in one study including 41 patients (45 knees)
555 treated with BMC, and no tumors have been reported
556 [132, 133]. Moreover, a multicenter analysis of adverse
557 events in 2372 patients undergoing adult autologous stem-
558 cell therapy corroborated the safety of MSC-based thera-
559 pies [137].
560 We have classified clinical studies into needle injection
561 delivery (Table 2), or surgical/arthroscopic delivery
562 (Table 3). In addition, we have grouped studies according
563 to regulatory criteria as expanded MSCs (i.e., more than
564 minimal manipulation), ‘advanced therapy’ or fresh cell
565 products, interventions performed on the same day (i.e.,
566 SVF [qualified as ATMP]), or BMC. Based on current
567 clinical studies, there is equal interest in freshly isolated
568 mixed-cell populations (BMC, SVF), and culture-expanded
569 mesenchymal stromal/stem cells.
5703.2.2.1 Needle Injection Delivery
5713.2.2.1.1 Intra-Articular Injections of Culture-Expanded
572Mesenchymal Stem Cells. Anterior Cruciate Ligament
573Intraligamentous injection of BM-MSCs improved the
574integrity of anterior cruciate ligament (ACL) with grade
5751–3 tears in seven of ten patients, as determined by analysis
576of images using Image J software [77].
577Meniscus An RCT by Vangsness et al. [87] reported the
578safety and efficacy of two doses of cells: 50 and 150 mil-
579lion allogeneic BM-MSCs suspended in hyaluronic acid
580(HA), and injected intra-articularly 7–10 days following
581meniscectomy. According to outcome data, surgically
582removed meniscal tissue was regenerated, cartilage surface
583protected, and joint damage decreased. The number of
584patients with increased meniscal volume was five of 54
585patients (four from the group that received the lower dose
586of cells, and one from the higher dose group) at 12 months
587post-procedure. Only three patients maintained the
588increased meniscal volume at 2 years (mean percentage 18;
58995 % CI 4.0–45.6). Other ongoing trials are examining the
590efficacy of autologous MSCs in meniscus injury grade 3
591[138], and also autologous BMC injection in patients
592undergoing partial or complete meniscectomy [139].
593Cartilage Lesions and Osteoarthritis The needle injec-
594tion technique (intra-articular cell injection) was used in 22
595studies [77–99] (Table 2). Eleven studies examined the
596effect of intra-articular injections of in vitro expanded
597MSCs. Cell doses ranged from 5.76 9 106 to 400 9 106
598cells.
599Both RCTs [87, 88] used donor-derived (allogeneic)
600BM-MSCs and used the cell vehicle, HA, as control. Vega
601et al. [88] included 30 patients who were randomized to
602either allogeneic BM-MSCs (n = 15), or a single high-
603molecular weight HA injection (n = 15).
604Overall, all case series that evaluated injections of cul-
605ture-expanded MSCs involved few patients and showed
606moderately good results, with no safety problems.
6073.2.2.1.2 Needle Injection Delivery of Stromal Vascular
608Fraction or Bone Marrow Concentrate. Freshly prepared
609SVF combined with PRP was injected in 113 knees, 22
610hips, two ankles and two lower backs, and outcomes
611reported in five cases series [89, 93, 95, 96, 98], and the
612combination PRP ? HA in one study [99]. In addition, one
613registry data study [91] reported outcomes after 840 knee
614injections, 616 knees injected with BMC, and 224 knees
615with a mixture of BMC and fat. The addition of fat to BMC
616showed no benefit [91]. Mean reported improvement was
61746.8 % in patients receiving BMC and 39.3 % in patients
618receiving BMC plus lipoaspirate. There were no differ-
619ences between patients undergoing bilateral versus unilat-
620eral procedures. Kim et al. also injected BMC and fat in 75
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621 knees, and reported better outcomes in patients with early
622 OA [94]. Pak et al. [99] reported on 100 joints (74 knees,
623 22 hips, 2 lower backs, and 2 ankles) in 91 patients injected
624 with SVF (10 mL) combined with PRP (2 mL buffy coat)
625 ? HA (1 mL 0.5 %). Patients returned for four additional
626 PRP injections (freshly prepared, one injection per week),
627 and the treatment lasted 1 month. Patients were followed
628 for up to 30 months (by phone). VAS improved signifi-
629 cantly at 1 and 3 months after treatment. Complications
630 included pain and swelling secondary to injection in 37 %
631of joints and 22 % of patients reported tendonitis/
632tenosynovitis; no infections were reported. One patient
633suffered a hemorrhagic stroke 2 weeks after the procedure,
634but this was considered not related to the procedure, as the
635frequency of this event in the general population is 1 %.
636No tumors were found.
637Gibbs et al. [93] treated four patients (seven joints) with
638SVF and PRP, followed by rehabilitation for 4 months.
639Pain and quality of life, as measured using KOOS,
640improved significantly; mobility returned to normal.
Table 4 Summary of advantages and disadvantages of the different types of cells being examined in clinical studies
Cell-based
product
Tissue
source
Procedure Regulation Advantages Disadvantages IDEAL
framework
Tenocytes Tendon Tissue biopsy
Laboratory
expansion
ATMP Easy and minimally
invasive access. Very
proliferative cells
Limited information about
functionality of transplanted cells.
High cost
2a
Dermal
fibroblasts
Skin Tissue biopsy
Laboratory
expansion
ATMP Easy and minimally
invasive access. Very
proliferative cells
No information about phenotypic
changes towards tenocytic lineage.
High cost
2a
Chondrocytes Cartilage Tissue biopsy
Laboratory
expansion
ATMP FDA approved.
Carticel�commercially
available
Unavailability of tissue. Low yield.
Dedifferentiation. High cost
4
BMC Bone
marrow
Aspiration
Centrifugation
Tissue Delivery of nucleated
cells (minimally
manipulated). Point of
care processing
technology same day
Heterogeneous product. Low MSC
number. Better results if matrix
supported and arthroscopic
implantation
2b
SVF Adipose
tissue
Lipoaspiration
Digestion
Centrifugation
ATMP Fresh product. Point of
care processing
technology same-day
procedure
Heterogeneous product. Limited
understanding of mechanism of
action
2d
Fat graft Adipose
tissue
Tissue harvest
Separation from oil
and liquid
Tissue Used to augment BMC
tissue graft prepared at
point of care
Inflammatory effects when mixed
with BMC
2a
PBPC Peripheral
blood
G-CSF or GM-CSF
treatment
Apheresis procedure
Blood
product
Can be harvested and
cryopreserved
Very few studies. Insufficient
information on mechanism of
action
2a
BM-MSCs Bone
marrow
Aspiration
Centrifugation
Cell selection
Cell expansion
ATMP Can be cryopreserved.
Allogeneic or
autologous. Well
characterized
Age-related changes in cells lead to
regenerative decline. BM-MSC
yield depends on harvesting
procedure. High cost. Ectopic bone
formation in tendon
2a
ASCs Adipose
tissue
Lipoaspiration
Digestion
Centrifugation
Cell selection
Cell expansion
ATMP MSC potentiality
independent of the
harvest site. Can be
cryopreserved
Different cell sub-populations. High
cost
2a
IDEAL framework [136]: stage 1, idea; 2a development, small number of reports; 2b exploration, increased number of reports and patients per
report, registries; 3 assessments, RCTs, multicenter studies, analysis of large data sets
ASCs adipose stem cells, ATMP Advanced Therapy Medicinal Product, BMC bone marrow concentrate, BM-MSCs bone marrow-derived
mesenchymal stem cells, FDA Food and Drug Administration, G-CSF granulocyte colony-stimulating factor, GM-CSF granulocyte-macrophage
colony-stimulating factor, MSCs mesenchymal stem cells, PBPC peripheral blood precursor cells, RCT randomized clinical trial, SVF stromal
vascular fraction
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641 As an alternative to bone marrow and subcutaneous fat,
642 Koh et al. [95] used the infrapatellar pad as a source for
643 MSCs and injected a mean of 1.18 9 106 cells with 3 mL
644 of PRP; patients experienced a significant reduction in
645 Western Ontario and McMaster Universities Osteoarthritis
646 Index (WOMAC) (from 49.9 to 30), an improvement in
647 Lysholm score, and significant pain reduction (VAS).
648 Improvements in MRI scores were also reported
649 (p \ 0.001).
650 3.2.2.2 Surgical/Arthroscopic Delivery
651 3.2.2.2.1 Culture-Expanded Mesenchymal Stem
652 Cells. Tendon–bone healing following ACL reconstruc-
653 tion remains an unresolved issue of ACL surgery. Filling
654 the bone tunnels with PRP does not speed up tendon-to-
655 bone integration [140]. Recently, a randomized trial was
656 performed to assess the suitability of fresh BMC in tendon–
657 bone healing [131]. However, there were no differences
658 between cell-treated patients and controls, as assessed by
659 MRI.
660 Ten studies described the implantation of culture-ex-
661 panded MSCs during arthroscopy or open surgery for
662 chondral lesions or OA [96, 100–108] (Table 3). Interest-
663 ingly, Kim et al. examined the potential differences
664 between arthroscopic implantation of cells, and site-di-
665 rected delivery by injection: arthroscopic implantation was
666 more accurate and produced better clinical and imaging
667 results [83].
668 Intra-articular delivery of MSCs with arthroscopic pro-
669 cedures was performed in debridement, microfractures
670 [103], management of patellar osteochondritis dissecans
671 (OCD) [107], or microfracture with high tibial osteotomy
672 [108]. MSCs were in some studies just implanted in the
673 defect using periosteal flaps or embedded in scaffolds such
674 as collagen [112], HA [103, 105], PRP-fibrin [102], or
675 fibrin glue [24].
676 One controlled study [100] used ACI as control for AMI
677 (autologous mesenchymal stem cell implantation), with
678 better results in the AMI group. In five case series, joints
679 were treated with synovium-derived MSCs [106], infrap-
680 atellar-derived MSCs [96], and BM-MSCs [101, 107, 108].
681 3.2.2.2.2 Stem-Cell-Based Products: Arthroscopic Deliv-
682 ery of Stromal Vascular Fraction, Bone Marrow Concen-
683 trate or Peripheral Blood Progenitor Cells. Surgical
684 implantation of non-expanded cells has been performed in
685 23 studies (Table 3). Of these, seven studies involved
686 osteochondral lesions of the talus [109, 110, 112, 116, 117,
687 122, 123] and seven studies used SVF [24, 120, 121,
688 123–125, 128]; another study [129] used PBPCs and the
689 other 15 studies used BMC [109–119, 122, 126, 127,
690 130–133]. In several studies, cells were used as an adjuvant
691to surgical interventions including microfracture or sub-
692chondral drilling [115, 122–124], arthroscopic debridement
693with or without synovectomy [110, 111, 121], arthroscopic
694lavage [125], and open-wedge high tibial osteotomy
695[126, 129].
696Histology and second-look arthroscopies after cell
697intervention have been evaluated in several studies
698[125, 126, 141]. Koh et al. examined 16 knees after
699arthroscopic lavage combined with injection of SVF [125].
700On second look, three knees were considered very positive
701(normal cartilage appearance), seven were rated positive
702(new cartilage partially covered the defect), four knees
703were rated neutral (uncertain change), and two patients
704experienced failed healing. Moreover, 37 knees were
705examined after MSC intervention by the same authors, and
706were evaluated using International Cartilage Research
707Society (ICRS) grading. Results showed that 2/37 were
708normal, 7/37 were nearly normal (grade II), 20/37 were
709abnormal (graded III), and 8/37 were severely abnormal
710(graded IV). High bone mass index (BMI) and large lesions
711were predictors of poor clinical outcomes. The same
712authors [126] evaluated at second look (median 19.8
713months post-surgery) patients that followed high tibial
714osteotomy (HTO) with SVF ? PRP or HTO ? PRP, and
715results revealed that patients in the SVF ? PRP group
716showed more regenerative changes as assessed by the
717Kanamiya grading system [126]. In four of the five patients
718treated with 7–8 mL of PBPC ? 2 mL HA, Saw et al.
719[141] found regenerated cartilage integrated with sur-
720rounding tissue. Histology showed predominance of type II
721collagen, particularly in deeper layers with collagen type I
722in the superficial layer. These findings, together with the
723columnar morphology of cells, could reveal features of
724hyaline cartilage [141]. However, to date, control of the
725fate of adult MSCs within the joint is far below expecta-
726tions, with the regenerated tissue having features of fibro-
727cartilage and a lack of architectural organization [142].
7284 Conclusions
729This review of the recent literature indicates that several
730different cell phenotypes, including tendon, skin, or mes-
731enchymal stem cells, can be suitable for tendon conditions,
732with applications performed most often with ultrasound-
733guided percutaneous injections. Indeed, the complexity of
734articular conditions has shifted research from autologous
735chondrocyte implantation to the use of a variety of mes-
736enchymal stromal cell products. MSCs are applied not only
737for the treatment of chondral defects, but also for those of
738ligaments and the meniscus, and to reduce joint degener-
739ation and reduce the burden of OA. Cells can engraft joint
740tissues especially at lesion sites. However, multipotency
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741 may not be the major determinant of success, and repair
742 may rely on a combination of differentiation ability and
743 paracrine effects able to stimulate the ability of exogenous
744 cells to promote endogenous healing mechanisms. A
745 moderate amount of basic science work shows that the
746 approach may work, and a sizeable amount of animal work
747 shows that MSCs and other biological interventions seem
748 to have some effect. However, translational work in human
749 medicine is lacking, and the small volume of well per-
750 formed work in humans shows that essentially these ther-
751 apies, though based on sound basic science findings, do not
752 seem to work particularly well for clinical purposes.
753 It is likely that opportunities for developing effective
754 treatment for musculoskeletal tissues will arise only after
755 the secrets of MSCs have been unveiled. When trans-
756 planting cells, the conditions of the host tissue are of high
757 functional importance as differentiation into suitable cell
758 phenotypes can be inhibited by inflammatory factors pro-
759 duced by the host tissue/organ. The anti-inflammatory
760 properties of PRP can help prevent environmental hostility.
761 Numerous hurdles need to be overcome as cell therapy
762 progresses. On the one hand, technical challenges associ-
763 ated with robust cell manufacturing at reduced costs are
764 mandatory. On the other hand, use of these technologies
765 will require identifying and understanding the hetero-
766 geneity of stem-cell products as well as specific features of
767 disease stage and progression. In this context, identification
768 of biomarkers can serve not only to assess changes in tissue
769 quality, but also to subgroup patients and tailor biological
770 interventions according to specific pathological processes.771
772 Compliance with Ethical Standards
773 Funding No sources of funding were used to assist in the preparation774 of this article.
775 Conflict of interest Nicola Maffulli and Isabel Andia declare that776 they have no conflicts of interest relevant to the content of this review.
777 References
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