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European Journal of Sport Science

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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, DOI: 10.1080/17461391.2013.878756

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 European Journal of Sport Science, 2014
http://dx.doi.org/10.1080/17461391.2013.878756

REVIEW

Medical interventions in the management of hamstring muscle injury

MATTHEW ROBINSON1 & BRUCE HAMILTON2

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
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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 (Mueller-Wohlfahrt et al., 2012). For clarity, in the

remaining discussion, we will refer to ‘hamstring
The ‘hamstrings’ comprise the diarthrodial semiten-
injury’, representing non-contact muscle injuries,
dinosus, semimembranosus and biceps femoris mus-
typically associated with a lengthening and contract-
cles and, for the sake of clarification, the phrase
ing hamstring muscle. When considering the man-
‘hamstring injury’ in this article will refer to strain
agement of a hamstring injury, there has been little
injury of the muscle belly and not the proximal or
development over the last 50 years (Copland et al.,
distal tendon. Muscle injuries account for 30–55%
2009; Hamilton, 2012). First aid and physiotherapy-
of all sporting injuries, and the hamstring group is
led rehabilitation remains the mainstay of treatment.
the most frequent muscle group involved, account-
Paradoxically, despite the limited evidence base,
ing for anywhere from 6% to 29% of all muscle
clinicians working with athletes actually have avail-
injuries in Australian football (Orchard & Seward,
able, and often use, a wide variety of adjuvant
2002), rugby, soccer/football, sprinting and basket-
therapies. While these may be considered ‘alternat-
ball. In addition, recurrence rates for hamstring
ive’, they are of increasing interest to practitioners,
injury may be as high as 30–70% (Copland, Tipton,
looking for a benefit for individual patients in
& Fields, 2009). This high prevalence and re-injury
specific situations.
rate impacts significantly on playing time, with
For all athletes, any reduction in recovery time or
professional football teams averaging 5–6 hamstring
re-injury rate for hamstring injuries would be invalu-
strains per season, and a mean loss of playing time of
able. This narrative review aims to summarise the
2–4 weeks (Linklater, Hamilton, Carmichael, Orch-
evidence for the use of known medical interventions
ard, & Wood, 2010). Subsequently, careful manage-
in the treatment of hamstring injuries in the sports
ment is required in order to ensure a rapid and safe
setting.
return to play.
Despite the high levels of clinical and academic
interest in the epidemiology and aetiology of the
Medical interventions
hamstring injury, there remain a large number of
unanswered questions. For example, even the ter- The theoretical goal of any medical intervention in
minology, classification and grading systems used in the management of any non-contact hamstring
the literature have recently been challenged 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

 2 M. Robinson & B. Hamilton

optimise inflammation; 3. maximise regeneration There remains no high-level scientific evidence for
and 4. minimise fibrosis. Through this process, an the use of enzymatic preparations in the manage-
optimal speed of safe return and minimisation of the ment of hamstring muscle injuries.
risk of re-injury will be achieved. The following will
discuss the broad range of currently available med-
Hirudoid
ical modalities that may assist in this goal.
Hirudoid is a topical heparinoid preparation, which
was a popular treatment for soft tissue ‘blood clot
Rest, ice, compression and elevation (RICE) (haematoma)’, bruising and phlebitis in the 1960s
treatment and 1970s (Hamilton, 2012). It was claimed that it
improved circulation, by dissolving small clots, and
The combination of RICE is almost universally
relieved the pain and inflammation of local throm-
applied in the initial management of hamstring
bophlebitis (McKechnie, 1972). A very basic study
injuries, with the intention of preventing further
published in 1972 reported a slight decrease in the
retraction of disrupted muscle fibres/fascicles, redu-
return to play time of footballers with unspecified
cing haematoma and interstitial fluid accumulation.
lower limb muscle, ligament or haematoma injuries
There is, however, no level 5 evidence to support
following topical administration of hirudoid
this approach (Jarvinen, Jarvinen, Kaariainen,
(McKechnie, 1972).
Kalimo, & Jarvinen, 2005). Twenty minutes of ice
There remains no high-quality evidence for the
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application, 15 minutes after contusion, was

use of a topical heparinoid preparation in the
observed to reduce post-capillary leakage, and to
treatment of hamstring muscle injuries.
inhibit the ‘rolling’ and endothelial adhesion of
leucocytes for 5 hours (Deal, Tipton, & Rosen-
crance, 2002). Unanswered questions remain, how- Non-steroidal anti-inflammatories
ever, including the best muscle length at which to
The eventual functional recovery of injured muscle is
cool, the use of movement during cooling, and the
dependent upon an appropriate inflammatory
duration and frequency of treatment.
response (Mishra, Fridén, Schmitz, & Lieber,
1995). However, the neutrophil infiltration and the
associated ‘respiratory burst’ may also cause second-
Enzymatic preparations
ary damage to the muscle (Toumi, F’Guyer, & Best,
Post-injury intramuscular injections of hyaluroni- 2006) and inhibition of this respiratory burst results
dase, an enzyme that breaks down and inactivates in less myofibre damage 24 hours post-injury (Brick-
hyaluronic acid, were frequently used between the son et al., 2003). This suggests that there
1950s and 1970s. A 1950s review of soft tissue may be a benefit from minimising certain aspects of
injuries proposed its use for the rapid elimination of the inflammatory phase and non-steroidal anti-
accumulated fluid, via the breakdown of granulation inflammatories (NSAIDs) have been shown to reduce
tissue (Gartland & McAusland, 1954). A 1954 inflammation observable on magnetic resonance
review describes hyaluronidase as a ‘spreading fac- imaging (MRI) in muscles following exercise-induced
tor’ to ‘disperse inflammatory exudate’ and advo- injury (Baldwin, Stevenson, & Dudley, 2001). Fur-
cated the injection of 20–30 ml, with local thermore, clinical studies have suggested an early
anaesthetic, into the centre of the injured area 24– improvement in recovery from pain, attenuated
48 hours post-injury. The regression of the swelling strength loss and no reduction in the eventual tensile
was described as ‘striking’ and ‘unbelievable’ and a strength of the muscle resulting from short-term
subjective improvement was reported (Delarue, NSAID use (Baldwin et al., 2001). However, experi-
1954). Similarly, a rapid reduction of the swelling mental models have demonstrated conflicting out-
following muscle trauma and a ‘rapid return to comes, with delayed muscle regeneration, increased
normal function’ was observed in a collection of fibrosis and functional impairment (Almekinders,
case reports (Gartland & McAusland, 1954). 1999; Linklater et al., 2010). Furthermore, depletion
The use of Chymoral (a mix of trypsin and of macrophages and Prostaglandin E2 (PGE2) has
chymotrypsin) and Varidase (a mix of streptokinase been shown to decrease satellite cell differentiation,
and streptodornase) was recommended in the 1970s muscle fibre growth and muscle regeneration (Smith,
for muscle injury, to decrease swelling and bruising Kruger, Smith, & Myburgh, 2008). Traditionally, the
(Merry, 1970). Individual enzymatic preparations, use of NSAIDs has been touted to potentially
such as trypsin, chymotrypsin, streptokinase and increase bleeding in a hamstring injury, although
streptodornase have also been used both intramus- there is no evidence for this. This concern is abated
cularly and orally, despite limited evidence of clinical by the use of specific COX2 inhibition which, while
benefit (Hamilton, 2012). having reduced bleeding potential, has still been
 Medical interventions for hamstring muscle injury 3

shown to decrease the number of neutrophils and muscle injuries, reported pain relief almost immedi-
macrophages present in a muscle lesion (Bondesen, ately after intramuscular injection of dexamethasone
Mills, Kegley, & Pavlath, 2004; Shen, Li, Tang, and bupivacaine and each returned to full-speed
Cummins, & Huard, 2005). However, COX2 inhibi- pitching at 19, 22 and 22 days, respectively, with no
tion has also been shown to increase the levels of re-injuries reported. The authors state that by com-
transforming growth factor beta-1 (TGFβ-1) and as a parison, similar injuries were anticipated to have a
result, fibrosis is increased in a dose- and duration- typical return to play time of 42–70 days (Stevens,
dependent manner (Shen et al., 2005). Crain, Akizuki, & Beaulieu, 2010).
Following ‘freeze’-type injury to mouse muscle, In contrast to these published clinical series, in vivo
COX2 inhibitors reduced myofibre regeneration if models studying cortisone use in muscle injury have
started three days prior to the injury, but not if they alternative implications. Intramuscular administra-
were started seven days post-injury (Bondesen et al., tion of methylprednisolone following contusion of
2004). After muscle laceration in mice, administra- rat muscle resulted in a delayed inflammatory
tion of a COX2 inhibitor resulted in an initial delay response, increased numbers of polymorphonuclear
in the regeneration of myofibres, and in inferior cells and macrophages, residual necrotic tissue and
regeneration at five weeks (Shen et al., 2005). decreased fibroblasts and myotubes at day seven
In Australian-rules footballers, no correlation was post-injury. By day 14, there remained disruption of
observed between NSAID use in the first three days the normal tissue architecture and marked muscle
post-injury and either a return to play within three atrophy (Beiner, Jokl, Cholewicki, & Panjabi, 1999).
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weeks or injury recurrence (Warren, Gabbe, Schnei- Further studies suggest that intramuscular corticos-
der-Kolsky, & Bennell, 2010) and in another group teroid injection is associated with muscle atrophy
of sportspeople from an assortment of sports no and disruption of the normal muscle architecture
additional benefit was found from adding NSAID to (Linklater et al., 2010). Immediate intramuscular
physiotherapy following injury (Reynolds, Noakes, administration of corticosteroid after eccentric mus-
Schwellnus, Windt, & Bowerbank, 1995). Further- cle injury in mice caused reduced levels of Inter-
more, with respect to pain management, swelling, leukin 1β and TGFβ-1 at day 3, compared with non-
strength and endurance, placebo or simple analgesia treated mice, and tetanic and single-twitch tension
are as effective as NSAIDs (Almekinders, 1999; values were actually equal to treated, sham-injured
Copland, Tipton, & Fields, 2009). mice by day 3 (Hakim et al., 2005). By contrast,
There remains debate about the merits of NSAIDs untreated, injured mice achieved comparable con-
following hamstring muscle injury, but the known tractile function after seven days, suggesting a short-
negative consequences of NSAIDs on muscle regen- term attenuation of strength loss with corticosteroid
eration, would support the preferential use of simple administration immediately following injury.
analgesia rather than NSAIDs in the initial phase of The use of corticosteroids in hamstring muscle
injury. injury, while supported by limited clinical series, has
been shown in vivo studies to result in significant
deficits in normal muscle structural regeneration.
Corticosteroids
Further high-quality clinical trials are required prior
In the 1970s, a daily dose of prednisone (20 mg) was to any clinical recommendation being made.
recommended in the initial phase of muscle injuries,
to reduce inflammation (Merry, 1970). In 2000, a
Traumeel
retrospective study of 58 National Football League
players with an acute, discrete lesion in the ham- Traumeel is a homoeopathic remedy but one which
string muscle belly, reported remarkable results after allegedly contains traces of botanical and mineral
the intramuscular administration of 4 mg of dex- ingredients (Casper & Foerstel, 1986). It may be
amethasone less than 72 hours post-injury (Levine, used topically, orally or infiltrated directly into a
Bergfeld, Tessendorf, & Moorman, 2000). Six hamstring injury and is claimed to both decrease the
players were able to return to play immediately and release of pro-inflammatory mediators and increase
the mean time to return to play was 7.6 days (range the release of anti-inflammatory cytokines (Linklater
0–24). Additional treatment with ice, massage, et al., 2010; Zenner & Metelmann, 1992). In
ultrasound and electrical stimulation continued for addition, it allegedly has a number of additional
up to 65 days but no complications were recorded. properties, including analgesia, anti-haemorrhagic,
The muscles reportedly regained normal strength anti-viral, accelerated wound healing, prevention of
and appearance, although no isokinetic testing or venous stasis and increased cell respiration, although
imaging was performed and this study has a number its mechanism of action remains to be clarified
of significant limitations. Similarly, a 2010 case (Lussignoli, Bertani, Metelmann, Bellavite, & Con-
series of three baseball pitchers with internal oblique forti, 1999). A survey of 348 physicians using
 4 M. Robinson & B. Hamilton

Traumeel to treat 3241 patients revealed a large muscle tears (Lee et al., 2011) but there is no further
number of proposed indications for its use, with evidence available.
intramuscular injection the most frequently used There remains no high-level scientific evidence in
method of administration (Zenner & Metelmann, the English language literature for the use of Active-
1992). While allegedly utilised in all preparations for gin preparations in the management of hamstring
a wide range of musculoskeletal conditions (Stock, muscle injuries.
1988), there remains no high-quality research asses-
sing its efficacy and a significant placebo effect
Mesotherapy
cannot be ruled out.
Advocates of Traumeel for hamstring muscle Mesotherapy involves multiple subcutaneous injec-
injuries recommend the use of intramuscular admin- tions of a mixture of homoeopathic and pharma-
istration into, and surrounding, the injury site ceutical medication, as well as vitamins, plant
immediately and for several days following the injury extracts and other substances and is used widely in
(Mueller-Wohlfahrt, 2007). However, a number of some parts of Europe, North Africa and the Middle
poorly conducted studies fail to provide convincing East, for the relief of musculoskeletal pain and the
evidence to support its use (Bohmer & Ambrus, treatment of injuries. A review of the use of
1992; Mihoc, 1986). One such study, in which the mesotherapy, published by the Italian society for
controls were not matched, purported to reveal mesotherapy, continually referred more to the tech-
accelerated reduction in post-traumatic soft tissue nique of intradermal administration rather than to
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swelling with the combined administration of oral the exact ‘drug’ or ‘active substances’ delivered
and intramuscular Traumeel (Casper & Foer- (Mammucari, Gatti, Maggiori, & Sabato, 2012).
stel, 1986). Nevertheless, it reported positive results for the
Despite the lack of high-quality evidence to sup- treatment of a number of various injuries. There
port its use, it apparently continues to be adminis- appeared to be no consensus on what mix of drugs
tered for a great many conditions. However, there were to be used, although in the illustrated algorithm
remains no high-level scientific evidence for the use a mixture of NSAID and muscle relaxant was
of Traumeel preparations in the management of recommended (Mammucari et al., 2012).
hamstring muscle injuries. There remains no high-level scientific evidence for
the use of mesotherapy techniques in the manage-
ment of hamstring muscle injuries.
Actovegin
Actovegin is a deproteinised calf blood haemodiasy- Anabolic agents
late, used for over 60 years in Europe for a variety of Beta 2 agonists, along with anabolic steroids and
conditions including acute stroke, post-partum growth factors such as insulin-like growth factor 1
haemorrhage, bone fracture and topically for ulcer (IGF1), are growth-promoting agents with potent
treatment (Lee, Rattenberry, Connelly, & Nokes, anabolic effects on skeletal muscle. Administration
2011). It is proposed to contain electrolytes, trace of Fenoterol to mice after myotoxic injury resulted in
elements, amino acids, nucleosides and carbohyd- enhanced regeneration and more rapid recovery of
rate and fat metabolites but no growth factors or force production when compared to controls (Beitzel
hormones (Lee et al., 2011). It is suggested that the et al., 2004). Clenbuterol accelerates macrophage
amino acids contained within it increase muscle fibre migration, satellite cell activation, myotube forma-
synthesis (Linklater et al., 2010) but studies attempt- tion and revascularisation, as well increasing the size
ing to identify the active ingredients in Actovegin of muscle fibres in transplanted skeletal muscle in
have been inconclusive (Lee et al., 2011). mice (Roberts & McGeachie, 1992). Intramuscular
Despite the lack of scientific evidence, the use of administration of Formoterol, five days post-
Activegin for hamstring muscle injury is advocated myotoxic injury, was seen to improve muscle mass
by some practitioners, to increase muscle regenera- and force generation above that of non-injected mice
tion and reduce scarring (Mueller-Wohlfahrt, 2007). only at day 7 post-injury (Ryall et al., 2008).
Indeed, in some areas, its use is considered so Similarly, the anabolic steroid Nandrolone is asso-
routine in the management of muscle injuries, that ciated with more rapid healing and restoration of
it has been used as a control treatment (Wright- muscle twitch force after contusion injury (Beiner
Carpenter, Klein, et al., 2004). A pilot study with et al., 1999). A 40% increase in maximal tetanic
limited subjects and a poor methodology reported a force is also seen at six weeks post-Bupivucaine
significant difference in subjective recovery and the muscle injury with weekly Nandrolone injections,
return to play time in athletes following the intra- when compared to an untreated control group of
muscular administration of Actovegin into grade I castrated mice (Hite, Baltgalvis, & Sato, 2009); and
 Medical interventions for hamstring muscle injury 5

with higher, supraphysiological doses (6 mg/kg), to perform athletic activity at 100% of competition
increased numbers of muscle fibres are seen at both level. All injuries were grouped together and the
three and six weeks (Hite et al., 2009). There are no study concluded that there was a mean reduction of
well-documented studies on the effect of anabolic six days in return to play with autologous condi-
steroids on recovery following muscle injury in tioned serum, compared to controls (Wright-
humans, but one could assume that similar benefits Carpenter, Klein, et al., 2004).This study has a
may be encountered. number of limitations which restrict its interpretation.
Anabolic agents such as beta 2 agonists, anabolic While an exciting area for musculoskeletal medi-
steroids, isolated growth factors and hormones such as cine, there remain a large number of unanswered
growth hormone all have important clinical roles in questions related to the potential use of manipulated
medicine but have a significant side effect profile autologous blood products in hamstring muscle
associated with their use. Given the potential for abuse injury, and ultimately there remains little scientific
in a performance-enhancing manner, and their pro- evidence for the use of autologous blood products in
hibition by the World Anti-Doping Agency (WADA) hamstring muscle strain injuries.
for elite athletes, their use in self-limiting injuries such
as hamstring muscle strains is not indicated.
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy (HBOT) is administered
Platelet-rich plasma/autologous conditioned
by placing the patient in a chamber containing 100%
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serum
oxygen, which is typically pressurised to 1.5–3.0
Platelet-rich plasma (PRP) is an autologous concen- times atmospheric pressure at sea level for periods
tration of platelets, promoted for a wide variety of between 60 minutes and 120 minutes once or twice
musculoskeletal conditions including muscle injur- a day (Bennett, Best, Babul-Wellar, & Taunton,
ies. While the benefit to muscle regeneration of 2005). At two times absolute atmosphere, the blood
individual recombinant growth factors such as nerve oxygen content is reportedly increased by 2.5% and
growth factor, basic fibroblast growth factor (FGF) tissue oxygen tension is increased 10-fold (Staples,
and IGF-1 are well recognised (Menetrey et al., Clement, Taunton, & McKenzie, 1999) and it is
2000), it is not clear if this benefit translates to the often recommended for decompression sickness, air
use of PRP. embolism, carbon monoxide poisoning and after
In vivo, the repeated administration of activated severe burns and crush injuries. HBOT remains
PRP to rat muscle strains resulted in a significant popular for the treatment of musculoskeletal injuries
increase in isometric force at day 3 following a single in the elite sporting population, although there
strain injury and at day 7 and day 14 following a appears to be no consensus on its validity, or the
repeated strain injury. However, both treated and optimal treatment regime (Staples & Clement,
non-treated groups ultimately returned to full 1996). It is also unclear how quickly after the injury
strength at the same time (Hammond, Hinton, the treatment should be initiated or what the dura-
Curl, Muriel, & Lovering, 2009). Two limited case tion should be; however, exposure to HBOT within
reports suggest a benefit from PRP infiltration post- 4–6 hours after injury has been shown to be most
muscle strain, but these are inconclusive (Hamilton, effective in controlling tissue ischemia in a skin flap
Knez, Eirale, & Chalabi, 2010; Karli & Robin- reperfusion model (Zamboni, Roth, Russell, &
son, 2012). Smoot, 1992). In one of the few studies, 70 human
Similarly, autologous conditioned serum, has been subjects were randomised to a five-day treatment
shown to be effective for skeletal muscle healing, period with HBOT or control (21% oxygen) after an
demonstrating increased regeneration of muscle intense eccentric leg exercise programme (Staples,
fibres, satellite cell activation and angiogenesis in 1996). There was enhanced recovery of eccentric
rats and a shorter return to play time in humans strength after HBOT, although the treated and
(Wright-Carpenter, Klein, et al., 2004; Wright- untreated groups perceived similar levels of muscle
Carpenter, Opolon, et al., 2004). In one study, 18 soreness.
athletes with an MRI-confirmed grade II strain of HBOT has been reported to stimulate fibroblasts,
various muscles underwent alternate day adminis- promote granulation tissue formation and revascu-
tration of autologous conditioned serum into the site larisation, while inhibiting the inflammatory
of injury. The control group received Traumeel and response in injured muscle (Best, Loitz-Ramage,
Actovegin injections and all participants also con- Corr, & Vanderby, 1998). However, in an animal-
sumed an oral ‘antiphlogistic’. Athletes partook in a model gastrocnemius crush injury, HBOT did not
physiotherapy rehabilitation programme until isoki- improve functional or morphologic measures of
netic testing revealed an attainment of ≥90% of the muscle recovery when compared with the untreated
strength of the contralateral limb and they were able controls (Nelson, Wolf, & Li, 1994). By contrast,
 6 M. Robinson & B. Hamilton

after eccentric stretch injury, rabbit muscle fibre and a clinically relevant benefit is yet to be estab-
damage was reduced at seven days and less of a lished (Gharaibeh et al., 2012).
difference in muscle torque strength was seen
between injured and non-injured legs when compar-
Surgical repair
ing five days of HBOT to non-HBOT rabbits (Best
et al., 1998). Caution is advised, however, when Although the surgical repair of grade III proximal
extrapolating these experimental findings to the hamstring tendon injuries (‘complete tears’) is fairly
treatment of athletes, as there are no clinical studies common, some suggest that repair of grade II strains
to support these findings. ‘may provide benefit’ if there is large intramuscular
A Cochrane review assessed the effect of HBOT haematoma, a partial tear of over 50% of the muscle
on delayed-onset muscle soreness and concluded diameter or if there is persistent knee extension pain
that there may actually be a short-term increase in at 4–6 months post-injury (Jarvinen et al., 2005).
pain with its use (Bennett et al., 2005) and, despite Suturing of lacerated muscle results in reduced
some promising results, there remains limited sci- scarring, compared to immobilisation alone (Huard
entific evidence for the use of HBOT in hamstring et al., 2002).
muscle strain injuries.
The future

Antifibrotic agents Myoblast transplantation has been attempted in

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mice but only 1–5% of cells survive and it is

The quality of the scar formation and re-modelling considered more effective to use muscle-derived
of the injured muscle tissue is one of the most stem cells (MDSC), as they have high regenerative
important determinants of muscle function and risk potential (Ota et al., 2011). Intramuscular adminis-
of re-injury (Linklater et al., 2010). Fibrosis prevents tration of MDSC into the injured tibialis anterior
the full recovery of strength in lacerated muscle muscle of mice at four days post-contusion increased
(Sato et al., 2003) and in hamstring injuries, the goal angiogenesis, myogenesis and strength at two weeks
is to minimise scar formation. Numerous agents are compared to injured mice injected with saline (Ota
known to reduce scar tissue formation, typically et al., 2011). Furthermore, less fibrosis was seen
through inhibition of TGFβ-1 activity. Relaxin, following administration at seven days, possibly by
Gamma interferon, Decorin, Suramin and Losartan avoiding the peak TGFβ-1 levels at day 2–3.
have been shown to inhibit fibrosis and improve Transplantation of MDSC, genetically modified
regeneration (Bedair, Karthikeyan, Quintero, Li, & to produce increased amounts of growth factor, was
Huard, 2008; Huard, Li, & Fu, 2002; Gharaibeh seen to promote healing in bones and ligaments and
et al., 2012; Jarvinen et al., 2005). While most of to recruit other stem cells to the site of injury
these drugs remain experimental in nature, and (Jarvinen et al., 2005). MDSC transplantation may
hence of little clinical relevance, Losartan (an act via the paracrine effect of vascular endothelial
Angiotensin II (AT2) receptor antagonist) is avail- growth factor (VEGF) release, as early revascularisa-
able for clinical use in hypertension management. tion and regeneration is observed to occur even in
Pathologic fibrosis has been linked with AT2 (an the absence of donor cell differentiation. The same
end-product of the angiotensin converting enzyme benefit may therefore be gained simply by adminis-
[ACE] pathway), and the use of either ACE inhibi- tering VEGF (Gharaibeh et al., 2012).
tors or AT2 blockers has been shown to reduce One major potential drawback to transplantation
fibrosis in many tissues (Bedair et al., 2008). is the need to harvest MDSC 2 weeks prior to injury
Increased AT2 receptor expression is observed in and the lack of information regarding the long-term
injured skeletal muscle (Bedair et al., 2008). By teratogenicity of the transplanted tissue (Ota et al.,
antagonising these receptors, and thus modulating 2011). Some success has, however, been gained
TGFβ-1, Losartan results in a time- and dose- from transplanting human adipose-derived stem
dependent increase in muscle regeneration and cells (ADSC) into the injured muscles of immuno-
decrease in fibrosis post-laceration in mice (Bedair suppressed mice, resulting in a significant increase in
et al., 2008). Patients using ACE inhibitors have also the number of ADSC-derived muscle fibres, and this
been shown to have reduced age-related sarcopaenia is an area for future consideration (Goudenege et al.,
and elite endurance athletes with genetically novel 2009). There are, however, currently no high-quality
AT2 metabolism are known to have increased studies to support the use of stem cells for muscle
skeletal muscle function (Onder, Vedova, & regeneration or for gene delivery in humans.
Pahor, 2006). We have already explored the effects of exogen-
There are no published clinical studies on the ously administered growth factors on healing tissue
effect of AT2 inhibitors on muscle injury in humans but a more effective method of increasing local
 Medical interventions for hamstring muscle injury 7

growth factor concentration may be by introducing Conclusion

vectors carrying the genes responsible for their
As clinicians we have a duty not to cause harm
production. FGF gene products stimulate endothe-
during our pursuit of optimal muscle injury man-
lial, smooth muscle and myoblast cells (Doukas
agement. We must at all times proceed with caution
et al., 2002) and, although direct delivery of the
and practice evidence-based medicine. There is a
FGF2 protein was not observed to induce myotube
regeneration and arteriogenesis in an ‘excisional dearth of high-quality interventional studies on
wound’ to a mouse muscle, delivery of the FGF2 treatment of the acute hamstring strain and this is a
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