How far have biological therapies come in regenerative sports medicine?

ABSTRACT

Introduction: Regular engagement in sports produces many health benefits, but also exposes to increased injury risk. The quality of medical care available is crucial not only for sports trauma but also to avoid overuse syndromes and post-traumatic degenerative conditions.

Areas covered: We provide background information on some clinical needs in sport injuries and describe the main families of biological products used in clinical practice. We also discuss limitations of the current clinical experience.

Expert opinion: Sport and exercise impairment affects different segments of the population with different needs. The exceptional demands of elite athletes and subsequent media coverage have created hype around regenerative therapies. Statistical evidence, whether weak (cell products) or moderate (PRPs), is not enough to drive medical decisions because of the heterogeneity of the biological products available and their application procedures. Moreover, the specific needs of the different segments of the population along with the available clinical evidence for each musculoskeletal condition should be considered in the decision-making process. There is urgent need to develop regenerative protocols combined with post-intervention rehabilitation, and gather meaningful clinical data on the safety and efficacy of these interventions in the different populations segments.

KEYWORDS:

• Sport injuries
• regenerative medicine
• mesenchymal stem cell (MSC)
• cell therapy
• platelet-rich plasma
• tendinopathy
• joint conditions

1. Introduction

Sports and exercise activities are recommended for all ages: they offer a myriad of health benefits to a broad range of populations, from athletes performing at the highest level, including paraolympic and able-bodied athletes, to recreational adults, the pediatric/adolescent population, or the ageing people. According to the World Health Organization (WHO), vigorous aerobic activity performed at least 75 min/week or equivalents are associated with reduced risks or mortality from all causes [1]. Different physical activity patterns are efficient (including weekend warriors) in this respect, and the all-cause mortality risk was 30% lower in active versus inactive individuals [2]. Vigorous exercise is also recommended as medicine in patients with chronic conditions, including cancer [3–5] or Alzheimer diseases [6]. Engagement in sports offers many health benefits, but also exposure to injury risks. Medical needs are different depending on the population segment. For example, in the most rapidly expanding segment of Western populations, i.e. those aged > 65, physical fitness is directly related to functional independence. At this age, overuse syndromes and degenerative sports diseases that impair movement hinder taking advantage of exercise benefits, i.e. lowering cholesterol levels, preventing muscle wasting and osteoporosis, prevention of falls [7].

On the other hand, attention is also focused on the pediatric/adolescent population and the long-term repercussions of sports injuries [8,9]. School sports associated injuries occur commonly in the upper and lower limb [10]. Joint trauma increases with sports participation [11], and often involves meniscal or anterior cruciate ligament (ACL) tears. One in every three to four young patients who return to play suffer a second ACL injury within 24 months of the original one[12], hindering their engagement in elite sport [13–16]. Recent epidemiological data demonstrate that, in the long-term, ACL and meniscal injuries are associated with seven-fold and 15-fold increase odds of total knee replacement, respectively [17].

Prevention programs toward safe participation in sports are being promoted [18]. However, the quality of medical care available is also crucial to avoid overuse syndromes and post-traumatic degenerative conditions. Future investigations in regenerative medicine therapies may help to reduce the burden of sports impairment by treating sports trauma in the first stages. These therapies include, but are not limited to, mesenchymal stromal/stem cells (MSC), placenta products, platelet-rich plasma (PRP) and other blood-derived proteins. Their use in sports medicine has exploded in efforts to augment healing, and allow individuals with ailments, including ligament and tendon ruptures, overuse injuries, cartilage trauma, and secondary degenerative conditions back to regular sport and exercise participation.

We aim to (1) provide background information on the main clinical needs in sports injuries; (2) describe the main families of biological products used in clinical settings and main concepts underlying their mechanism of action; (3) discuss limitations on the current clinical experience.

2. The emerging problem of sports injuries

The risk of an individual being injured is a complex singularity that depends on multiple factors, including the type of sport activity, the level of practice, and also on intrinsic factors, such as age, level of fitness, and genetic vulnerability. However, there is not a linear causal relationship; instead, a complex system approach, considering a web of determinants with varying interactions, is needed to identify injury pattern recognition [19]. Advances in prevention will help to develop effective programs. In parallel, development in regenerative medicine treatments is necessary to meet the current clinical needs, which differ between population segments. Below we give some data to substantiate the problem.

Most common sports injuries involve chondral and traumatic osteochondral defects (OCD) in the knee and ankle. In addition, there is strong dominance of overuse conditions, i.e. injuries produced along a continuum, without identification of any punctual event responsible for the condition. These conditions are the result from an imbalance caused by continuous mechanical load induced damage and the ability of tissue to remodel and repair itself. Unfortunately, most overuse injuries have little capacity for reversibility once a threshold of tissue degeneration is surpassed.

The affected body region is often sport specific, especially in athletes competing at the highest levels. A systematic review including 11 studies revealed 36% (2.4–75%) prevalence of full-thickness focal chondral defects, as diagnosed via magnetic resonance imaging (MRI) or arthroscopy [20]. The analysis included a total of 931 subjects, of whom 40% athletes were former players in the National Basketball Association (NBA) and the National Football League (NFL). Managing the problem at this stage would hinder progress of deterioration and development of secondary osteoarthritis (OA). The prevalence of secondary knee and hip OA in former professional soccer players is higher than in matched controls [21]. Likewise, hip OA is more common in elite athletes competing in impact sports (i.e. soccer, handball, track, and field or hockey) than in those participating in high-level long distance running [22].

Elite track and field athletes often suffer injuries in the knee and lower leg, i.e. Achilles tendon, ankle, and foot/toe [23,24]. Also, the patellar and Achilles tendons are a source of problems in pivoting sports and in runners. Similarly, the lower back is one of the most common injured sites in golf, followed by the elbow/forearm, and shoulder/upper arm [25]. Poor swing mechanics and too much play or training are the most common causes of injury. Upper extremity conditions, such as deficits in the glenohumeral joint, are common in overhead throwers, i.e. baseball at all playing levels [26].

Therapeutic approaches can range from rehabilitation to surgery, and are contingent on patients’ needs, i.e. the time of season, sport, performance limitations, and concomitant pathology. Regenerative treatments aim to provide new tissue with mechanical and physical properties indistinguishable from the original one. This translates to absence of relapses after an athletic injury, a potential decrease in overuse injuries and can avoid many problems associated with subsequent changes in lifestyle.

3. Regenerative treatments for sports impairment

The main regenerative technologies currently being investigated in the context of sports injuriesare cell therapies [27], and specific blood derivatives on the basis of their concentration and physiological balance of healing and/or anti-inflammatory factors [28]. Also, the use of placenta products is capturing attention [29]. In the context of musculoskeletal injuries, these products are often referenced as orthobiologics. As the topic of the emerging regenerative technologies is already broad we will focus on cell therapies and blood-derived formulations, mainly PRPs.

3.1. Tissue-specific cells

Musculoskeletal tissues have limited ability for regeneration because of the lack of endogenous cells able to drive regeneration and the scarce vascularity. Thus, the initial goal of cell therapies was to transplant living cells to engraft the tissue and generate high-quality extracellular matrix (ECM). The quality of the regenerated/repaired ECM is of paramount importance in sports: it should confer flexibility and the ability to sustain high tensile loads, allowing return to full sport activities without relapses.

The concept of replacement therapy is straightforward with chondrocyte (for full thickness cartilage defects) or tenocyte therapies for tendon conditions. Both modalities of adult differentiated cell therapy are already in the market. Autologous chondrocyte implantation (ACI), for focal cartilage defects, dates back to the early 90s [30]. The way chondrocytes are delivered has evolved from implantation of freely suspended or carried in fibrin glue (ACI) to matrix-embedded (MACI). However, this approach is indicated for patients less than 50 years with focal chondral defects. To avoid these drawbacks, the use of allogeneic chondrocytes obtained from polydactily children is under investigation in Phase III clinical trials [31]. This therapy contains non-transduced and transduced chondrocytes expressing high levels of transforming growth factor β1 (TGF-β1), aiming to enhance ECM synthesis [32] (Invossa®, TissueGene Inc.). However, the recent long term report of an accurately performed randomized controlled trial shows that, 15 years from the index procedure, the long term results of microfracture and ACI in the knee were equally disappointing, with more total knee replacements needed in the ACI than in the microfracture group.

For tendon conditions, an autologous tenocyte implantation technology (Ortho-ATI®, Orthocell) is under investigation [33,34]. These therapies involve a two-step procedure: first the harvesting of healthy tissue from the patient/recipient and subsequent cell culture to obtain millions of cells for implantation in a second intervention. Alternatively, instead of differentiated cell injection/implantation, MSCs injection protocols may provide an adjuvant treatment option for sports conditions.

3.2. Adult mesenchymal stromal/stem cells

Initially, the goal of MSC based therapies was to promote implanted cells to differentiate into tissue-specific cells for functional regeneration. Theoretically, MSC therapies can assist tissue regeneration first engrafting the tissue, and, secondly, inducing a pro-regenerative environment through the secretion of cytokines and other active molecules. Because MSC differentiation and engraftment rarely occurs, the therapeutic benefits of MSC can be produced through anti-inflammatory and immune-modulatory paracrine mechanisms [33]. In fact, repair occurs through complex interactions of cell phenotypes in the presence of changing molecular environments. Importantly, MSC therapies rely on the ability and functionality of host cells.

These therapies can be applied in different ways: first using heterogeneous cell mixtures with low abundance of MSCs, i.e. bone marrow concentrate (BMC) and stromal vascular fraction (SVF) of adipose tissue, and secondly using purified, laboratory expanded MSCs [27].

3.3. Heterogeneous cell formulations: BMC and SVF

BMC and SVF contain mesenchymal stem/stromal cells within their niche. The niche is a native microenvironment that contains different cell phenotypes and molecular signals, which drive the fate of MSC. Although SVF and BMC are named as mesenchymal stem cell therapies, not only in protocol marketing, but also in research [34], in reality these products contain very few MSCs. Only about 0.001–0.01% and 2–10% of mononuclear cells fulfill MSC properties in BMC and SVF respectively, and are compatible with the definition of stem cell phenotype, provided by international societies, International Society Cell & Gene Therapy (ISCT), and International Federation for Adipose Therapeutics and Science (IFATS), i.e. a specific profile of membrane molecular markers, and in vitro differentiation abilities (chondrocytes, osteoblast, adipocytes) [35, 36].

Both BMC and SVF therapies can be easily implemented at the point of care on an autologous basis, as the donor and the recipient are one and the same. Bone marrow from the iliac crest is easily harvested in arthroscopic procedures, and has been the choice in most cell interventions for focal cartilage defects. Conceptually, subchondral bone microfractures were the precursor to BMC implantation. Their goal was to liberate and stimulate MSCs migration from subchondral bone to the cartilage defect. At present, SVF and BMC are used either as an adjuvant to augment this procedure or as a substitute to such microfractures [37,38]. Recent data in horses indicate that implanting BMC without microfractures can have similar outcomes to microfractures [39]. BMC is however more efficient when implanted on the chondral defect through arthroscopy compared to intra-articular injections of BMC [40].

From a regulatory point of view, BMC can be easily used in clinical practice because it fulfills two mandatory conditions: first, it is obtained through minimal manipulation, and second, the application is homologous, and ‘it performs the same basic functions.’ Therefore, several protocols and kits to prepare BMC are marketed (Harvest SmartPReP2, EnCyte Apex Biologix, Arthrex Angel flow cytometry bone marrow concentrate system. BMAC Harvest Smart PrepP2 System, MarrowStim concentration kit, Biomet, Concemo Proteal).

On the other hand, some regulatory bodies (i.e. Food and Drug Administration, FDA) discuss whether or not ‘homologous use’ applies for intra-articular or intratendinous SVF administration. Adipose tissue is an easily available source of mesenchymal stem cells, and novel devices to prepare SVF are rapidly expanding. Importantly, the properties of adipose stromal cells (ADSCs) are independent of the anatomical harvest site [41]. Processing adipose tissue to obtain SVF can be performed through enzymatic or mechanical treatment. The former involves the use of collagenase or mixture of enzymes to optimize the yield of nucleated cells [42]. Different protocols and automated/semiautomated devices are available commercially (Tissue Genesis Icellator Cell Isolation System, Sepax Technology, GID SVF platform, Medi-KanLipokit, StromaCell by Microaire, the CytoriCellution System). Non-enzymatic methods fit into ‘minimal manipulation’ thus regulation is easier to fulfill. Instead, cell products obtained through enzymatic digestion are considered as an advanced therapy in some countries (i.e. U.S.A.) and heavily regulated. There is also concern among clinicians about the presence of residual collagenase in the final product.

3.4. Laboratory expanded mscs

MSCs can be selectively isolated according to their adhesive properties in vitro from different sources, including the synovium, Hoffa fat, SVF, and BMC [43–45]. Subsequently, they can be expanded under specific conditions until the necessary number is obtained for cell transplantation. However, products are not unique, as different laboratory protocols can produce MSCs with different properties. In fact, regenerative therapies are governed by the axiom ‘the process is the product.’ Cell conditioning procedures can involve gene modifications, treating cells in hypoxia, 3D culture conditions, or addition of cytokines [46]. Interestingly, MSCs obtained from BMC or SVF have different differentiation capabilities to bone and fat but do not differ in their chondrogenic potential [47].

Commonly, intralesional delivery is performed in orthopedic sports injuries. However, different medical problems entail different ways of administration. For example, in concussion and traumatic brain injuries, SVF administered systemically by venous perfusion is being investigated (NCT02959294).

3.5. Emerging cell-based regenerative strategies

While MSC therapies aim to create a pro-regenerative environment through paracrine interactions, at least two other promising regenerative medicine approaches are investigated. First, to harness the intrinsic capacities of the endogenous progenitor pool, chemically synthesized small molecules that trigger the progenitor stem cell pool, such as kartogenin, are under investigation [48,49]. These molecules can stimulate proliferation and differentiation of the endogenous pool [50]. The goal of these developments is not only the treatment of degenerative conditions secondary to sports injuries, but also preventive, i.e. articular application after ACL and meniscus ruptures.

Second, based on the hypothesis that senescent cells may hinder repair, local clearance of senescent cells by pharmacological or gene approaches and their repercussion in solving degenerative conditions are being investigated [51].

3.6. Blood derived products

The most popular blood derived products are PRPs. They were introduced at the beginning of the millennium in elite sports, aiming to decrease the time to return to competition without well controlled clinical data of efficacy, but because of their safety profile. Still, PRP use for musculoskeletal conditions is an off-label application. Commonly, they are prepared using commercial kits and protocols, but different protocols can produce different products, mainly pure PRP and leukocyte-rich PRP (L-PRP). Classification systems for PRPs in sports medicine have been proposed [52]. Currently, efforts toward a minimal description of products and procedures are mandatory in order to establish relationships between formulations and clinical indications [53]. A similar initiative is taking place in cell therapy reporting [54].

For degenerative joint conditions, further injectable products, though less extensively investigated, are blood-derived protein mixtures, such as APS (Zimmer Biomet), Orthokine®, or Arthrokinex^TM [55]. They are believed to be anti-inflammatory because of the high concentration of soluble receptors for inflammatory proteins, including interleukin 1 receptor antagonist (IL-1ra), soluble receptor for IL-1 (sIL-1RII), soluble receptor for tumor necrosis factor (sTNF-RII).

Furthermore, α2-macroglobulin (Cytonics Corp.) is an abundant plasma protein with anti-catabolic actions (against MMPs and ADAMTs) [56] and its therapeutic potential in OA is under research (NCT01613833) for both primary OA and secondary posttraumatic/overuse OA.

3.7. Placenta products

The use of amniotic fluid concentrates in 68 patients with different articular conditions dates back to 1938 [57]. Currently, placenta derivatives are available as off-the-shelf products to supplement tissue healing resources based on their content of various growth factors, in addition to structural collagens (types I, III, IV, V, and VII), laminin, fibronectin, proteoglycans, and hyaluronan. Amnion-derived human allografts are immune privileged, as they do not express major histocompatibility complex (MHC) class II antigens.

A review of clinical studies using these products has been recently published [28]. The level of scientific evidence is however low, and only three case series have examined the benefits of injectable tissue matrix allografts [58] in plantar fasciopathy and Achilles tendinopathy, or used them as an adjunct to surgery; all studies report positive results and no adverse events. However, when injections of cryopreserved amniotic membrane were compared to corticosteroids (CS) in a pilot RCT, there were no differences, or, as expected, better short-term outcomes in the CS group [59].

Ongoing research in placenta derived products includes three trials, with two therapies being investigated for knee OA, NCT03337243 and NCT03028428. The latter involves the administration of 10⁷ placenta derived mesenchymal stem cell, with HA as the comparator. Likewise, the use of amniotic fluid to treat various musculoskeletal conditions is being examined (NCT03390920).

4. Are there research evidences for optimal decision-making?

Preclinical research supports the efficacy of MSC in tendon and articular conditions based on the anti-inflammatory and anti-catabolic effect of these therapies. However, current data derived from clinical research are insufficient to establish specific indications and recommendations [60,61]. In fact, media and direct internet marketing have raised expectations around regenerative sports medicine claiming that MSC therapies accelerate return to play without surgery in elite athletes. These therapies do not have marketing approval because of insufficient clinical research. We briefly describe the current scientific evidence of MSC products and PRPs, based on accurate statistical synthesis of clinical trials. Protocols for injection varied (i.e. injecting intra-, peri-, or within the bursa) as did treatment regimens, and can be part of success/failures [62].

4.1. Tendinopathies

The most common overuse tendinopathies include rotator cuff and elbow in the upper body and patellar and Achilles tendons, in the lower limb.

There are no clinical trials examining the efficacy of MSC therapies for patellar tendinopathy, only a small case series with eight patients and 5 year follow-up reporting ‘promising results’ after BMC injection [63]. PRP is superior to ESWT or dry needling according to a recent synthesis of quantitative data from two randomized studies [64].

In tendinopathy of the main body of the Achilles tendon, intratendinous injection of SVF has been compared with PRP in a RCT involving a total of 44 patients with 6 months follow-up. Both treatments produced good clinical outcomes, and SVF was superior in the short-term (15–30 days), but after 6 months there were no differences between the treatments [65].

Regarding PRP therapies, the injection of 4 mL of PRP associated with eccentric exercises was not superior to saline [66]. In a comparison of three treatment regimens combined with eccentric exercise, four injections of PRP (2 weeks apart), one high volume image guided injection (HVIGI) of saline + local anesthetic + CS or few drops of subcutaneous saline, pain reduction was higher in the HVIGI and PRP groups than placebo at all time points, tendon thickness and intra-tendon vascularity decreased in the HVIGI and PRP groups but not in the placebo group. HVIGI was more effective than PRP at 12 weeks but not at 24 weeks [67] .

Plantar fasciopathy is an overuse injury of the plantar fascia. Data analysis from nine RCTs, comparing PRP versus CS but with small sample sizes (total 430 patients) and limited quality, did not identify statistically significant differences in pain reduction and functional scores after 4 or 12 weeks [68]. However, PRP exhibited better efficacy than the steroid treatment after 24 weeks.

There are no RCT examining the efficacy of MSC products in epicondylopathy, merely one case series showing significant clinical improvements after local injection of BMC in 30 patients [69]. Interestingly, allogeneic ADSC injected with fibrin showed clinical and structural improvements, with no adverse events in a safety and feasibility study [70]. PRP was compared with CS in eight studies, without differences in pain reduction in the short term (2–4 weeks) [71]. However, PRP was superior to steroids at 6 months and 1 year. These results confirm previous network meta-analysis comparing PRP, autologous blood and CS [72]. However, PRP was not effective in patients with first episode epicondylopathy in a RCT [73].

Conservative management of rotator cuff with cell therapies is unexplored. BMC injections reduced pain and improved function in a case series involving 115 patients with glenohumeral OA with or without rotator cuff tear [74].

Association of PRP to rotator cuff surgery has no clear benefits [75]. Moreover, post-operative injections of PRP at 7 and 14 days after rotator cuff surgery did not provide relevant benefits, i.e. enhanced clinical, re-tear rates, or radiological outcomes at 3.5 years [76].

Three recent meta-analyses have pooled all tendon conditions together and analyzed whether or not PRP decreases pain and improves function. Fitzpatrick et al. [77] analyzed 18 RCTs (1066 patients) including PRP, PPP, autologous blood, and autologous conditioned plasma (ACP) injections and concluded that a single ultrasound guided injection of L-PRP is effective in reducing pain.

Chen et al. [78] pooled data from 21 RCTs, with a total of 1031 participants. Overall, long-term follow-up results showed significantly less pain in the PRP group compared with the control group. However, substantial heterogeneity was reported at baseline and different time-point follow-ups. Miller et al. [79] included 16 RCTs with a minimum follow-up of three months. PRP was more effective than controls in reducing pain with a moderate effect size (0.47, 95%CI (0.22–0.72, p < 0.001)) and moderate heterogeneity.

Overall, meta-analyses evaluating only PRP injections (not arthroscopic augmentation) favor the use of PRP to reduce pain and enhance function. However, this conclusion is barely supported by the studies taken individually. Miller et al. [79] attributed the discrepancy to the fact that studies are underpowered (median 35 patients per group) to detect the effect size. According to their meta-analysis, a sample size of 73 patients per group would be required to be able to detect differences.

4.2. Joint conditions

Biological products have been used to augment arthroscopic procedures in the ankle, knee and hip. The goal is not only to restore cartilage integrity but also to avoid propagation of cartilage destruction and progression to OA. The safety of MSC products was examined in case series and registry data with long term follow-up [80,81]. A systematic review including 844 interventions with a 21-month follow-up showed intra-articular MSC injections to be safe [82]. Similarly, the safety of SVF+ PRP injections was reported in 91 patients with a follow up of 26 months [83].

Microfracture has been the gold standard for regulatory bodies; ACI is the treatment reference for young patients with focal cartilage defects. Novel regenerative treatments aim to enhance the clinical results obtained with these therapies. BMC has been compared to ACI in few studies. In a prospective comparative trial, MACI was compared with BMC implantation [84]. The latter may be more favorable than MACI (81% vs. 76% complete filling of the defect), and it is a cheaper one-step intervention. Accordingly, [BMC+ PRP] versus ACI implantation in osteochondral lesions of the talus [85] provided similar structural and clinical outcomes. Matrix-assisted MSC (in vitro expanded MSC) implantation has also been compared with MACI in a randomized study including 14 patients with full-thickness cartilage defects greater than 2 cm². After 2 years, results were good for both cell grafts, but slightly better with MSCs [86].

There is no high-quality research, merely case series in which BMC or SVF are used as adjuvants to arthroscopy (reviewed in [27] and [87]. An RCT [88] showed that outcomes after microfractures were better if patients received PRP 6–24 h after the index procedure.

Likewise, osteochondral lesions of the talus have been treated conservatively with BMC, but the evidence is weak, merely based on case series and one RCT using HA as comparator [89,90].

OA involves diffuse cartilage lesions, often with meniscal damage; advanced deterioration involves sclerotic bone, reduced intra-articular space and subchondral bone marrow edema, which is often the source of pain. Most clinical trials do not discriminate specific OA phenotypes (i.e. secondary or idiopathic). Shapiro et al. [91] examined the safety and efficacy of intra-articular injections ofBMC in a randomized study involving 25 patients with bilateral OA. After 6 months, there were no complications, and all patients experienced a decrease in pain without differences between BMC or saline. Pain relief after saline injection has been confirmed in a meta-analysis of 32 studies involving 1705 patients [92]. Intra-articular injections of laboratory-expanded MSC were investigated in meniscal regeneration after meniscectomy using HA as control, with modest results. The efficacy of allogeneic BM-MSC injections yield better clinical and imaging outcomes compared with HA injections.

Two meta-analyses published in 2017 examine the efficacy of PRP injections. Shen et al. [93] included 14 RCT (1423 individuals) and data revealed that PRP was more effective than other treatments at 12 months in terms of pain reduction and functional improvement. Accordingly, Dai et al.. [94] included 10 RCTs (level 1) 1069 patients at 6 months; HA and PRP were similar but at 12 months PRP was more effective than HA or saline exceeding the minimally clinically important difference.

5. Conclusion

The needs of conservative treatments for sports impairment have accelerated the clinical use of biological therapies, without sufficient clinical research substantiating their effectiveness. Further knowledge about the mechanism of action of these biological products is needed to optimize the products and clinical procedures. The wide range of clinical indications, that biological therapies are considered for, and the great heterogeneity of products/protocols make advances difficult.

6. Expert opinion

To meet the clear demand of sports-related injuries, biological products are used with multiple aims, mainly to accelerate healing and restore function. Advances in this field are based on the scientific understanding of molecular and cell biology in tissue healing processes. Exogenous stem cells can be implanted to take the role of resident cells. In addition, these cells can secrete multiple paracrine factors which stimulate new ECM synthesis by resident cells, through trophic actions (chondrocytes, tenocytes). Alternatively, molecular pools combined in a physiological balance (blood-derived products or placenta products) can modulate angiogenesis, and enhance cell migration and tissue anabolism, thereby activating repair mechanisms. However, current knowledge is insufficient to trigger specific mechanisms in a temporal and spatial manner and refine therapeutic approaches. Thus, biological treatments are indicated broadly according to vague goals.

The urgent needs to speed recovery in elite athletes, and media coverage of anecdotic celebrity cases, have produced hype around these regenerative therapies [95]. Direct to consumer marketing of stem cell treatment through the Internet has been the focus of criticism, because of claims of benefits without supporting clinical trials [96]. Matthews et al. [97] recorded a list of public sports figures seeking for stem cell therapies abroad, and examined the use athletes to advertise the validity of the therapies. Hype in marketing stem cell therapies is associated with phrases, such as ‘cutting-edge’ and ‘breakthrough,’ and with stories that highlight the benefits. This helps to explain why SVF and BMC are named as mesenchymal stem cell therapies, not only in protocol marketing, but also in research: in reality these products contain very few MSCs. In fact, their therapeutic potential might be attributed to other components of the product which are rarely mentioned, including endothelial progenitor cells, hematopoietic stem cells, immune cells (monocytes and macrophages, regulatory T cells) or pericytes. Experimental research is needed to understand the true protagonists of the therapeutic benefits.

Sports physicians and orthopedic surgeons have embraced PRP therapies with little understanding of the nature of the product and mechanism of action [98]. PRP could have some similarities with ‘ultra-filtered extracts of calf blood’ (Actovegin) that form part of sports medicine therapeutic armamentarium. Although initially PRP was perceived as doping because, among the thousands of molecules it contains, a few were present in the World Anti-Doping Agency (WADA) list, the ban was lifted by 2010. In contrast with stem cell therapy propaganda, the media coverage of PRP displays relatively few of phrases like ‘cutting edge technology’ or ‘breakthrough’ [99]. PRP therapies, when presented to the public in the context of sports, most often claim to shorten recovery times, as they are purported to accelerate and promote healing [99].

During the last couple of decades, sports medicine has matured and evolved toward an evidence-based science. The specific needs of the different segments of the population along with the available clinical evidence for each musculoskeletal condition should be considered in the decision-making process. Unfortunately, the current statistical evidence, whether weak (cell products) or moderate (PRPs), is not enough to drive medical decisions because of the heterogeneity of products and application procedures.

Further advances driven by an interdisciplinary collaboration between experimental researchers, physiologists, rehabilitation, and orthopedic surgeons and sports physicians among others will be necessary to exploit the potential of biological therapies.

Article highlights

• Sports and exercise induced ailments affect a broad range of individuals, from athletes performing at the highest level, including paralympic and able bodied athletes, to recreational adults, the pediatric/adolescent population, or the ageing people.

• The main regenerative technologies currently used in the clinic in the context of sports injuries are cell therapies, placenta products and specific blood derivatives, mainly platelet-rich plasma, on the basis of their concentration of healing and/or anti-inflammatory factors.

• Local application of mesenchymal stem/stromal cell products is safe, but high-quality translational research is needed to shape effective clinical protocols able to exploit the capacity of cells to support tissue repair and alleviate the effects of tissue degeneration, either by engrafting the tissue or by paracrine actions.

• Despite the hype created by media around mesenchymal stem/stromal cell therapies, they cannot be recommended for sports trauma or overuse injuries (mainly tendinopathy and joint conditions) because of the lack of outcome data from good quality trials.

• Research on PRP therapies points to a moderate effect on pain and functional recovery in tendinopathy and osteoarthritis. However, evidences are not sufficient to make clinical decisions, given the heterogeneity of products and patient variability.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Instituto de Salud Carlos III ISCIII cofunded with FEDER funds [PI13/01707].