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European Journal of Sport Science Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tejs20

Medical interventions in the management of hamstring muscle injury a

b

Matthew Robinson & Bruce Hamilton a

Unisports, Auckland and New Zealand

b

High Performance Sport New Zealand, Auckland, New Zealand Published online: 15 Jan 2014.

To cite this article: Matthew Robinson & Bruce Hamilton (2014) Medical interventions in the management of hamstring muscle injury, European Journal of Sport Science, 14:7, 743-751, DOI: 10.1080/17461391.2013.878756 To link to this article: http://dx.doi.org/10.1080/17461391.2013.878756

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European Journal of Sport Science, 2014 Vol. 14, No. 7, 743–751, http://dx.doi.org/10.1080/17461391.2013.878756

REVIEW

Medical interventions in the management of hamstring muscle injury

MATTHEW ROBINSON1 & BRUCE HAMILTON2

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1

Unisports, Auckland and New Zealand, and 2High Performance Sport New Zealand, Auckland, New Zealand

Abstract Acute muscle belly injuries to the semitendinosus, semimembranosus and biceps femoris (the ‘hamstring’ muscles) remain a common problem in the sporting population. Physiotherapy-led rehabilitation remains the mainstay of treatment, and the physician’s input is often minimal. Anecdotally, many different topical, oral and injectable therapies are used around the world in an effort to accelerate the healing of these injuries and to prevent their recurrence. This article reviews the evidence available to support some of the most commonly used medical therapies and the pathophysiological basis for their use. It also presents the evidence behind some of the more promising future treatments for muscle injury, including stem cell therapy, growth factor delivery and potential novel uses of current medication not traditionally used in the musculoskeletal setting. Keywords: Performance, rehabilitation, injury and prevention, medicine, musculoskeletal

Introduction The ‘hamstrings’ comprise the diarthrodial semitendinosus, semimembranosus and biceps femoris muscles and, for the sake of clarification, the phrase ‘hamstring injury’ in this article will refer to strain injury of the muscle belly and not the proximal or distal tendon. Muscle injuries account for 30–55% of all sporting injuries, and the hamstring group is the most frequent muscle group involved, accounting for anywhere from 6% to 29% of all muscle injuries in Australian football (Orchard & Seward, 2002), rugby, soccer/football, sprinting and basketball. In addition, recurrence rates for hamstring injury may be as high as 30–70% (Copland, Tipton, & Fields, 2009). This high prevalence and re-injury rate impacts significantly on playing time, with professional football teams averaging 5–6 hamstring strains per season, and a mean loss of playing time of 2–4 weeks (Linklater, Hamilton, Carmichael, Orchard, & Wood, 2010). Subsequently, careful management is required in order to ensure a rapid and safe return to play. Despite the high levels of clinical and academic interest in the epidemiology and aetiology of the hamstring injury, there remain a large number of unanswered questions. For example, even the terminology, classification and grading systems used in the literature have recently been challenged

(Mueller-Wohlfahrt et al., 2012). For clarity, in the remaining discussion, we will refer to ‘hamstring injury’, representing non-contact muscle injuries, typically associated with a lengthening and contracting hamstring muscle. When considering the management of a hamstring injury, there has been little development over the last 50 years (Copland et al., 2009; Hamilton, 2012). First aid and physiotherapyled rehabilitation remains the mainstay of treatment. Paradoxically, despite the limited evidence base, clinicians working with athletes actually have available, and often use, a wide variety of adjuvant therapies. While these may be considered ‘alternative’, they are of increasing interest to practitioners, looking for a benefit for individual patients in specific situations. For all athletes, any reduction in recovery time or re-injury rate for hamstring injuries would be invaluable. This narrative review aims to summarise the evidence for the use of known medical interventions in the treatment of hamstring injuries in the sports setting.

Medical interventions The theoretical goal of any medical intervention in the management of any non-contact hamstring muscle injury is to: 1. minimise degeneration; 2.

Correspondence: M. Robinson, Unisports, PO Box 18-067, Glen Innes, Auckland, New Zealand. E-mail: [email protected] © 2014 European College of Sport Science

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optimise inflammation; 3. maximise regeneration and 4. minimise fibrosis. Through this process, an optimal speed of safe return and minimisation of the risk of re-injury will be achieved. The following will discuss the broad range of currently available medical modalities that may assist in this goal.

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Rest, ice, compression and elevation (RICE) treatment The combination of RICE is almost universally applied in the initial management of hamstring injuries, with the intention of preventing further retraction of disrupted muscle fibres/fascicles, reducing haematoma and interstitial fluid accumulation. There is, however, no level 5 evidence to support this approach (Jarvinen, Jarvinen, Kaariainen, Kalimo, & Jarvinen, 2005). Twenty minutes of ice application, 15 minutes after contusion, was observed to reduce post-capillary leakage, and to inhibit the ‘rolling’ and endothelial adhesion of leucocytes for 5 hours (Deal, Tipton, & Rosencrance, 2002). Unanswered questions remain, however, including the best muscle length at which to cool, the use of movement during cooling, and the duration and frequency of treatment.

Enzymatic preparations Post-injury intramuscular injections of hyaluronidase, an enzyme that breaks down and inactivates hyaluronic acid, were frequently used between the 1950s and 1970s. A 1950s review of soft tissue injuries proposed its use for the rapid elimination of accumulated fluid, via the breakdown of granulation tissue (Gartland & McAusland, 1954). A 1954 review describes hyaluronidase as a ‘spreading factor’ to ‘disperse inflammatory exudate’ and advocated the injection of 20–30 ml, with local anaesthetic, into the centre of the injured area 24– 48 hours post-injury. The regression of the swelling was described as ‘striking’ and ‘unbelievable’ and a subjective improvement was reported (Delarue, 1954). Similarly, a rapid reduction of the swelling following muscle trauma and a ‘rapid return to normal function’ was observed in a collection of case reports (Gartland & McAusland, 1954). The use of Chymoral (a mix of trypsin and chymotrypsin) and Varidase (a mix of streptokinase and streptodornase) was recommended in the 1970s for muscle injury, to decrease swelling and bruising (Merry, 1970). Individual enzymatic preparations, such as trypsin, chymotrypsin, streptokinase and streptodornase have also been used both intramuscularly and orally, despite limited evidence of clinical benefit (Hamilton, 2012).

There remains no high-level scientific evidence for the use of enzymatic preparations in the management of hamstring muscle injuries. Hirudoid Hirudoid is a topical heparinoid preparation, which was a popular treatment for soft tissue ‘blood clot (haematoma)’, bruising and phlebitis in the 1960s and 1970s (Hamilton, 2012). It was claimed that it improved circulation, by dissolving small clots, and relieved the pain and inflammation of local thrombophlebitis (McKechnie, 1972). A very basic study published in 1972 reported a slight decrease in the return to play time of footballers with unspecified lower limb muscle, ligament or haematoma injuries following topical administration of hirudoid (McKechnie, 1972). There remains no high-quality evidence for the use of a topical heparinoid preparation in the treatment of hamstring muscle injuries. Non-steroidal anti-inflammatories The eventual functional recovery of injured muscle is dependent upon an appropriate inflammatory response (Mishra, Fridén, Schmitz, & Lieber, 1995). However, the neutrophil infiltration and the associated ‘respiratory burst’ may also cause secondary damage to the muscle (Toumi, F’Guyer, & Best, 2006) and inhibition of this respiratory burst results in less myofibre damage 24 hours post-injury (Brickson et al., 2003). This suggests that there may be a benefit from minimising certain aspects of the inflammatory phase and non-steroidal antiinflammatories (NSAIDs) have been shown to reduce inflammation observable on magnetic resonance imaging (MRI) in muscles following exercise-induced injury (Baldwin, Stevenson, & Dudley, 2001). Furthermore, clinical studies have suggested an early improvement in recovery from pain, attenuated strength loss and no reduction in the eventual tensile strength of the muscle resulting from short-term NSAID use (Baldwin et al., 2001). However, experimental models have demonstrated conflicting outcomes, with delayed muscle regeneration, increased fibrosis and functional impairment (Almekinders, 1999; Linklater et al., 2010). Furthermore, depletion of macrophages and Prostaglandin E2 (PGE2) has been shown to decrease satellite cell differentiation, muscle fibre growth and muscle regeneration (Smith, Kruger, Smith, & Myburgh, 2008). Traditionally, the use of NSAIDs has been touted to potentially increase bleeding in a hamstring injury, although there is no evidence for this. This concern is abated by the use of specific COX2 inhibition which, while having reduced bleeding potential, has still been

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Medical interventions for hamstring muscle injury shown to decrease the number of neutrophils and macrophages present in a muscle lesion (Bondesen, Mills, Kegley, & Pavlath, 2004; Shen, Li, Tang, Cummins, & Huard, 2005). However, COX2 inhibition has also been shown to increase the levels of transforming growth factor beta-1 (TGFβ-1) and as a result, fibrosis is increased in a dose- and durationdependent manner (Shen et al., 2005). Following ‘freeze’-type injury to mouse muscle, COX2 inhibitors reduced myofibre regeneration if started three days prior to the injury, but not if they were started seven days post-injury (Bondesen et al., 2004). After muscle laceration in mice, administration of a COX2 inhibitor resulted in an initial delay in the regeneration of myofibres, and in inferior regeneration at five weeks (Shen et al., 2005). In Australian-rules footballers, no correlation was observed between NSAID use in the first three days post-injury and either a return to play within three weeks or injury recurrence (Warren, Gabbe, Schneider-Kolsky, & Bennell, 2010) and in another group of sportspeople from an assortment of sports no additional benefit was found from adding NSAID to physiotherapy following injury (Reynolds, Noakes, Schwellnus, Windt, & Bowerbank, 1995). Furthermore, with respect to pain management, swelling, strength and endurance, placebo or simple analgesia are as effective as NSAIDs (Almekinders, 1999; Copland, Tipton, & Fields, 2009). There remains debate about the merits of NSAIDs following hamstring muscle injury, but the known negative consequences of NSAIDs on muscle regeneration, would support the preferential use of simple analgesia rather than NSAIDs in the initial phase of injury. Corticosteroids In the 1970s, a daily dose of prednisone (20 mg) was recommended in the initial phase of muscle injuries, to reduce inflammation (Merry, 1970). In 2000, a retrospective study of 58 National Football League players with an acute, discrete lesion in the hamstring muscle belly, reported remarkable results after the intramuscular administration of 4 mg of dexamethasone less than 72 hours post-injury (Levine, Bergfeld, Tessendorf, & Moorman, 2000). Six players were able to return to play immediately and the mean time to return to play was 7.6 days (range 0–24). Additional treatment with ice, massage, ultrasound and electrical stimulation continued for up to 65 days but no complications were recorded. The muscles reportedly regained normal strength and appearance, although no isokinetic testing or imaging was performed and this study has a number of significant limitations. Similarly, a 2010 case series of three baseball pitchers with internal oblique

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muscle injuries, reported pain relief almost immediately after intramuscular injection of dexamethasone and bupivacaine and each returned to full-speed pitching at 19, 22 and 22 days, respectively, with no re-injuries reported. The authors state that by comparison, similar injuries were anticipated to have a typical return to play time of 42–70 days (Stevens, Crain, Akizuki, & Beaulieu, 2010). In contrast to these published clinical series, in vivo models studying cortisone use in muscle injury have alternative implications. Intramuscular administration of methylprednisolone following contusion of rat muscle resulted in a delayed inflammatory response, increased numbers of polymorphonuclear cells and macrophages, residual necrotic tissue and decreased fibroblasts and myotubes at day seven post-injury. By day 14, there remained disruption of the normal tissue architecture and marked muscle atrophy (Beiner, Jokl, Cholewicki, & Panjabi, 1999). Further studies suggest that intramuscular corticosteroid injection is associated with muscle atrophy and disruption of the normal muscle architecture (Linklater et al., 2010). Immediate intramuscular administration of corticosteroid after eccentric muscle injury in mice caused reduced levels of Interleukin 1β and TGFβ-1 at day 3, compared with nontreated mice, and tetanic and single-twitch tension values were actually equal to treated, sham-injured mice by day 3 (Hakim et al., 2005). By contrast, untreated, injured mice achieved comparable contractile function after seven days, suggesting a shortterm attenuation of strength loss with corticosteroid administration immediately following injury. The use of corticosteroids in hamstring muscle injury, while supported by limited clinical series, has been shown in vivo studies to result in significant deficits in normal muscle structural regeneration. Further high-quality clinical trials are required prior to any clinical recommendation being made. Traumeel Traumeel is a homoeopathic remedy but one which allegedly contains traces of botanical and mineral ingredients (Casper & Foerstel, 1986). It may be used topically, orally or infiltrated directly into a hamstring injury and is claimed to both decrease the release of pro-inflammatory mediators and increase the release of anti-inflammatory cytokines (Linklater et al., 2010; Zenner & Metelmann, 1992). In addition, it allegedly has a number of additional properties, including analgesia, anti-haemorrhagic, anti-viral, accelerated wound healing, prevention of venous stasis and increased cell respiration, although its mechanism of action remains to be clarified (Lussignoli, Bertani, Metelmann, Bellavite, & Conforti, 1999). A survey of 348 physicians using

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Traumeel to treat 3241 patients revealed a large number of proposed indications for its use, with intramuscular injection the most frequently used method of administration (Zenner & Metelmann, 1992). While allegedly utilised in all preparations for a wide range of musculoskeletal conditions (Stock, 1988), there remains no high-quality research assessing its efficacy and a significant placebo effect cannot be ruled out. Advocates of Traumeel for hamstring muscle injuries recommend the use of intramuscular administration into, and surrounding, the injury site immediately and for several days following the injury (Mueller-Wohlfahrt, 2007). However, a number of poorly conducted studies fail to provide convincing evidence to support its use (Bohmer & Ambrus, 1992; Mihoc, 1986). One such study, in which the controls were not matched, purported to reveal accelerated reduction in post-traumatic soft tissue swelling with the combined administration of oral and intramuscular Traumeel (Casper & Foerstel, 1986). Despite the lack of high-quality evidence to support its use, it apparently continues to be administered for a great many conditions. However, there remains no high-level scientific evidence for the use of Traumeel preparations in the management of hamstring muscle injuries.

muscle tears (Lee et al., 2011) but there is no further evidence available. There remains no high-level scientific evidence in the English language literature for the use of Activegin preparations in the management of hamstring muscle injuries. Mesotherapy Mesotherapy involves multiple subcutaneous injections of a mixture of homoeopathic and pharmaceutical medication, as well as vitamins, plant extracts and other substances and is used widely in some parts of Europe, North Africa and the Middle East, for the relief of musculoskeletal pain and the treatment of injuries. A review of the use of mesotherapy, published by the Italian society for mesotherapy, continually referred more to the technique of intradermal administration rather than to the exact ‘drug’ or ‘active substances’ delivered (Mammucari, Gatti, Maggiori, & Sabato, 2012). Nevertheless, it reported positive results for the treatment of a number of various injuries. There appeared to be no consensus on what mix of drugs were to be used, although in the illustrated algorithm a mixture of NSAID and muscle relaxant was recommended (Mammucari et al., 2012). There remains no high-level scientific evidence for the use of mesotherapy techniques in the management of hamstring muscle injuries.

Actovegin Actovegin is a deproteinised calf blood haemodiasylate, used for over 60 years in Europe for a variety of conditions including acute stroke, post-partum haemorrhage, bone fracture and topically for ulcer treatment (Lee, Rattenberry, Connelly, & Nokes, 2011). It is proposed to contain electrolytes, trace elements, amino acids, nucleosides and carbohydrate and fat metabolites but no growth factors or hormones (Lee et al., 2011). It is suggested that the amino acids contained within it increase muscle fibre synthesis (Linklater et al., 2010) but studies attempting to identify the active ingredients in Actovegin have been inconclusive (Lee et al., 2011). Despite the lack of scientific evidence, the use of Activegin for hamstring muscle injury is advocated by some practitioners, to increase muscle regeneration and reduce scarring (Mueller-Wohlfahrt, 2007). Indeed, in some areas, its use is considered so routine in the management of muscle injuries, that it has been used as a control treatment (WrightCarpenter, Klein, et al., 2004). A pilot study with limited subjects and a poor methodology reported a significant difference in subjective recovery and the return to play time in athletes following the intramuscular administration of Actovegin into grade I

Anabolic agents Beta 2 agonists, along with anabolic steroids and growth factors such as insulin-like growth factor 1 (IGF1), are growth-promoting agents with potent anabolic effects on skeletal muscle. Administration of Fenoterol to mice after myotoxic injury resulted in enhanced regeneration and more rapid recovery of force production when compared to controls (Beitzel et al., 2004). Clenbuterol accelerates macrophage migration, satellite cell activation, myotube formation and revascularisation, as well increasing the size of muscle fibres in transplanted skeletal muscle in mice (Roberts & McGeachie, 1992). Intramuscular administration of Formoterol, five days postmyotoxic injury, was seen to improve muscle mass and force generation above that of non-injected mice only at day 7 post-injury (Ryall et al., 2008). Similarly, the anabolic steroid Nandrolone is associated with more rapid healing and restoration of muscle twitch force after contusion injury (Beiner et al., 1999). A 40% increase in maximal tetanic force is also seen at six weeks post-Bupivucaine muscle injury with weekly Nandrolone injections, when compared to an untreated control group of castrated mice (Hite, Baltgalvis, & Sato, 2009); and

Medical interventions for hamstring muscle injury

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with higher, supraphysiological doses (6 mg/kg), increased numbers of muscle fibres are seen at both three and six weeks (Hite et al., 2009). There are no well-documented studies on the effect of anabolic steroids on recovery following muscle injury in humans, but one could assume that similar benefits may be encountered. Anabolic agents such as beta 2 agonists, anabolic steroids, isolated growth factors and hormones such as growth hormone all have important clinical roles in medicine but have a significant side effect profile associated with their use. Given the potential for abuse in a performance-enhancing manner, and their prohibition by the World Anti-Doping Agency (WADA) for elite athletes, their use in self-limiting injuries such as hamstring muscle strains is not indicated. Platelet-rich plasma/autologous conditioned serum Platelet-rich plasma (PRP) is an autologous concentration of platelets, promoted for a wide variety of musculoskeletal conditions including muscle injuries. While the benefit to muscle regeneration of individual recombinant growth factors such as nerve growth factor, basic fibroblast growth factor (FGF) and IGF-1 are well recognised (Menetrey et al., 2000), it is not clear if this benefit translates to the use of PRP. In vivo, the repeated administration of activated PRP to rat muscle strains resulted in a significant increase in isometric force at day 3 following a single strain injury and at day 7 and day 14 following a repeated strain injury. However, both treated and non-treated groups ultimately returned to full strength at the same time (Hammond, Hinton, Curl, Muriel, & Lovering, 2009). Two limited case reports suggest a benefit from PRP infiltration postmuscle strain, but these are inconclusive (Hamilton, Knez, Eirale, & Chalabi, 2010; Karli & Robinson, 2012). Similarly, autologous conditioned serum, has been shown to be effective for skeletal muscle healing, demonstrating increased regeneration of muscle fibres, satellite cell activation and angiogenesis in rats and a shorter return to play time in humans (Wright-Carpenter, Klein, et al., 2004; WrightCarpenter, Opolon, et al., 2004). In one study, 18 athletes with an MRI-confirmed grade II strain of various muscles underwent alternate day administration of autologous conditioned serum into the site of injury. The control group received Traumeel and Actovegin injections and all participants also consumed an oral ‘antiphlogistic’. Athletes partook in a physiotherapy rehabilitation programme until isokinetic testing revealed an attainment of ≥90% of the strength of the contralateral limb and they were able

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to perform athletic activity at 100% of competition level. All injuries were grouped together and the study concluded that there was a mean reduction of six days in return to play with autologous conditioned serum, compared to controls (WrightCarpenter, Klein, et al., 2004).This study has a number of limitations which restrict its interpretation. While an exciting area for musculoskeletal medicine, there remain a large number of unanswered questions related to the potential use of manipulated autologous blood products in hamstring muscle injury, and ultimately there remains little scientific evidence for the use of autologous blood products in hamstring muscle strain injuries. Hyperbaric oxygen therapy Hyperbaric oxygen therapy (HBOT) is administered by placing the patient in a chamber containing 100% oxygen, which is typically pressurised to 1.5–3.0 times atmospheric pressure at sea level for periods between 60 minutes and 120 minutes once or twice a day (Bennett, Best, Babul-Wellar, & Taunton, 2005). At two times absolute atmosphere, the blood oxygen content is reportedly increased by 2.5% and tissue oxygen tension is increased 10-fold (Staples, Clement, Taunton, & McKenzie, 1999) and it is often recommended for decompression sickness, air embolism, carbon monoxide poisoning and after severe burns and crush injuries. HBOT remains popular for the treatment of musculoskeletal injuries in the elite sporting population, although there appears to be no consensus on its validity, or the optimal treatment regime (Staples & Clement, 1996). It is also unclear how quickly after the injury the treatment should be initiated or what the duration should be; however, exposure to HBOT within 4–6 hours after injury has been shown to be most effective in controlling tissue ischemia in a skin flap reperfusion model (Zamboni, Roth, Russell, & Smoot, 1992). In one of the few studies, 70 human subjects were randomised to a five-day treatment period with HBOT or control (21% oxygen) after an intense eccentric leg exercise programme (Staples, 1996). There was enhanced recovery of eccentric strength after HBOT, although the treated and untreated groups perceived similar levels of muscle soreness. HBOT has been reported to stimulate fibroblasts, promote granulation tissue formation and revascularisation, while inhibiting the inflammatory response in injured muscle (Best, Loitz-Ramage, Corr, & Vanderby, 1998). However, in an animalmodel gastrocnemius crush injury, HBOT did not improve functional or morphologic measures of muscle recovery when compared with the untreated controls (Nelson, Wolf, & Li, 1994). By contrast,

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after eccentric stretch injury, rabbit muscle fibre damage was reduced at seven days and less of a difference in muscle torque strength was seen between injured and non-injured legs when comparing five days of HBOT to non-HBOT rabbits (Best et al., 1998). Caution is advised, however, when extrapolating these experimental findings to the treatment of athletes, as there are no clinical studies to support these findings. A Cochrane review assessed the effect of HBOT on delayed-onset muscle soreness and concluded that there may actually be a short-term increase in pain with its use (Bennett et al., 2005) and, despite some promising results, there remains limited scientific evidence for the use of HBOT in hamstring muscle strain injuries.

and a clinically relevant benefit is yet to be established (Gharaibeh et al., 2012). Surgical repair Although the surgical repair of grade III proximal hamstring tendon injuries (‘complete tears’) is fairly common, some suggest that repair of grade II strains ‘may provide benefit’ if there is large intramuscular haematoma, a partial tear of over 50% of the muscle diameter or if there is persistent knee extension pain at 4–6 months post-injury (Jarvinen et al., 2005). Suturing of lacerated muscle results in reduced scarring, compared to immobilisation alone (Huard et al., 2002).

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The future Antifibrotic agents The quality of the scar formation and re-modelling of the injured muscle tissue is one of the most important determinants of muscle function and risk of re-injury (Linklater et al., 2010). Fibrosis prevents the full recovery of strength in lacerated muscle (Sato et al., 2003) and in hamstring injuries, the goal is to minimise scar formation. Numerous agents are known to reduce scar tissue formation, typically through inhibition of TGFβ-1 activity. Relaxin, Gamma interferon, Decorin, Suramin and Losartan have been shown to inhibit fibrosis and improve regeneration (Bedair, Karthikeyan, Quintero, Li, & Huard, 2008; Huard, Li, & Fu, 2002; Gharaibeh et al., 2012; Jarvinen et al., 2005). While most of these drugs remain experimental in nature, and hence of little clinical relevance, Losartan (an Angiotensin II (AT2) receptor antagonist) is available for clinical use in hypertension management. Pathologic fibrosis has been linked with AT2 (an end-product of the angiotensin converting enzyme [ACE] pathway), and the use of either ACE inhibitors or AT2 blockers has been shown to reduce fibrosis in many tissues (Bedair et al., 2008). Increased AT2 receptor expression is observed in injured skeletal muscle (Bedair et al., 2008). By antagonising these receptors, and thus modulating TGFβ-1, Losartan results in a time- and dosedependent increase in muscle regeneration and decrease in fibrosis post-laceration in mice (Bedair et al., 2008). Patients using ACE inhibitors have also been shown to have reduced age-related sarcopaenia and elite endurance athletes with genetically novel AT2 metabolism are known to have increased skeletal muscle function (Onder, Vedova, & Pahor, 2006). There are no published clinical studies on the effect of AT2 inhibitors on muscle injury in humans

Myoblast transplantation has been attempted in mice but only 1–5% of cells survive and it is considered more effective to use muscle-derived stem cells (MDSC), as they have high regenerative potential (Ota et al., 2011). Intramuscular administration of MDSC into the injured tibialis anterior muscle of mice at four days post-contusion increased angiogenesis, myogenesis and strength at two weeks compared to injured mice injected with saline (Ota et al., 2011). Furthermore, less fibrosis was seen following administration at seven days, possibly by avoiding the peak TGFβ-1 levels at day 2–3. Transplantation of MDSC, genetically modified to produce increased amounts of growth factor, was seen to promote healing in bones and ligaments and to recruit other stem cells to the site of injury (Jarvinen et al., 2005). MDSC transplantation may act via the paracrine effect of vascular endothelial growth factor (VEGF) release, as early revascularisation and regeneration is observed to occur even in the absence of donor cell differentiation. The same benefit may therefore be gained simply by administering VEGF (Gharaibeh et al., 2012). One major potential drawback to transplantation is the need to harvest MDSC 2 weeks prior to injury and the lack of information regarding the long-term teratogenicity of the transplanted tissue (Ota et al., 2011). Some success has, however, been gained from transplanting human adipose-derived stem cells (ADSC) into the injured muscles of immunosuppressed mice, resulting in a significant increase in the number of ADSC-derived muscle fibres, and this is an area for future consideration (Goudenege et al., 2009). There are, however, currently no high-quality studies to support the use of stem cells for muscle regeneration or for gene delivery in humans. We have already explored the effects of exogenously administered growth factors on healing tissue but a more effective method of increasing local

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Medical interventions for hamstring muscle injury growth factor concentration may be by introducing vectors carrying the genes responsible for their production. FGF gene products stimulate endothelial, smooth muscle and myoblast cells (Doukas et al., 2002) and, although direct delivery of the FGF2 protein was not observed to induce myotube regeneration and arteriogenesis in an ‘excisional wound’ to a mouse muscle, delivery of the FGF2 gene via an adenoviral vector was seen to do so (Doukas et al., 2002). This suggests that gene transfer may induce more complex fibre and vessel healing pathways. Administration of an IGF-producing viral vector to mice increased growth factor levels and also improved muscle healing and strength (Gharaibeh et al., 2012). Conversely, in another study, introduction of GF genes via intramuscular adenoviral vector was not seen to be beneficial in mouse laceration models (Huard et al., 2002). An alternative administration method, electroporation delivery of IGF1 DNA to lacerated hamstrings of mice stimulated increased regeneration of muscle fibres at two weeks and increased fibre diameter at four weeks (Takahashi et al., 2003). There was no observed increase in serum IGF1, only in the local muscle, suggesting that this method of gene delivery may not have unwanted systemic effects.

Summary There is an increasing arsenal of medical interventions available for the treatment of hamstring injury; however the majority of medical interventions lack a substantial evidence base, and continue to be used on a personal experiential level only. Traditionally, sports medicine literature has ignored many of the practices being performed by practitioners working with high-level athletes. As a result, the medical management of the hamstring muscle injury has progressed little in the last 50 years (Hamilton, 2012). Novel treatment regimens such as antifibrotic agents and PRP, both of which have a sound pathophysiological basis and in vitro evidence, offer some hope to enhancing our medical management of hamstring injuries. Converting the observed tissuelevel healing properties of the various interventions into clinically relevant improvements in the athlete’s recovery and function may pose an additional challenge that may be explored with further clinical trials. Further confounding the difficulties of clinical research are the ongoing limitations in the understanding of the aetiology, pathophysiology, terminology and grading of hamstring muscle injuries. Only when these are further delineated will the benefit of any medical interventions be established.

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