American Medical Society for Sports Medicine Position Statement: Principles for the Responsible Use of Regenerative Medicine in Sports Medicine.

ABSTRACT: Many sports medicine physicians are currently considering introducing regenerative medicine into their practice. Regenerative medicine and the subclassification of orthobiologics are a complicated topic and have produced widely varying opinions. Although there is concern by government regulators, clinicians, scientists, patient advocacy organizations, and the media regarding the use of regenerative medicine products, there is also excitement about the potential benefits with growing evidence that certain regenerative medicine products are safe and potentially efficacious in treating musculoskeletal conditions. Sports medicine physicians would benefit from decision-making guidance about whether to introduce orthobiologics into their practice and how to do it responsibly. The purpose of this position statement is to provide sports medicine physicians with information regarding regenerative medicine terminology, a brief review of basic science and clinical studies within the subclassification of orthobiologics, regulatory considerations, and best practices for introducing regenerative medicine into clinical practice. This information will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine and orthobiologics in their practice.

Whole-Body Cryotherapy in Sports Medicine.

Cryotherapy has gained popularity among athletes across many sports. The main goals of cryotherapy, and specifically whole-body cryotherapy, are for injury prevention and counteracting negative inflammatory symptoms following athletic performance in hopes of improving recovery.

Regeneration of Skeletal Muscle After Eccentric Injury.

Eccentric-contraction-induced skeletal muscle injuries, included in what is clinically referred to as muscle strains, are among the most common injuries treated in the sports medicine setting. Although patients with mild injuries often fully recover to their preinjury levels, patients who suffer moderate or severe injuries can have a persistent weakness and loss of function that is refractory to rehabilitation exercises and currently available therapeutic interventions. The objectives of this review were to describe the fundamental biophysics of force transmission in muscle and the mechanism of muscle-strain injuries, as well as the cellular and molecular processes that underlie the repair and regeneration of injured muscle tissue. The review also summarizes how commonly used therapeutic modalities affect muscle regeneration and opportunities to further improve our treatment of skeletal muscle strain injuries.

Youth Pitcher Fatigue: Medial Elbow Laxity, Ultrasonographic Assessment of Flexor-Pronator Mass Energy Depletion, and Association With Pitch Count.

Background: Ulnar collateral ligament (UCL) injuries in youth pitchers continue to be concerning despite the institution of pitch count limits. Flexor-pronator mass fatigue can lead to diminished dynamic stability, resulting in greater stress on the UCL. Purpose/Hypothesis: To evaluate fatigue of the flexor-pronator mass by assessing changes in medial elbow laxity; noninvasively characterizing alterations in muscle glycogen; and identifying changes in subjective fatigue, strength, range of motion (ROM), pitching velocity, and accuracy with increasing pitches thrown by youth pitchers to their recommended 75-pitch count limit. It was hypothesized that, with increased pitches, medial elbow laxity would increase and that the glycogen content of the flexor-pronator mass would decrease. Study Design: Descriptive laboratory study. Methods: Healthy male pitchers aged 10 years (n = 22) threw 3 sets of 25 pitches with 12 minutes between sets (3 timepoints). Bilateral ulnohumeral joint gapping was measured by applying a standardized valgus force and utilizing ultrasound imaging. Relative changes in muscle glycogen in the bilateral flexor carpi radialis (FCR), and the flexor digitorum superficialis/flexor carpi ulnaris (FDS/FCU) muscles were measured with ultrasound software and recorded as fuel percentiles. Additional measures obtained included subjective fatigue, strength, ROM, velocity, and accuracy. Results: There were no differences in medial elbow joint-line gapping between the throwing and nonthrowing arms or between timepoints. The throwing arm demonstrated a significant decline in fuel percentile of the FCR from baseline to after 75 pitches (P = .05). There were no differences across timepoints for FDS/FCU fuel percentile values. Fatigue measurements for both arms were significantly higher at all timepoints compared with baseline (P≤ .03). Grip strength of the dominant arm after 75 pitches was decreased significantly compared with after 25 pitches (P = .02). Conclusion: Although an increase in medial elbow joint gapping was not demonstrated within the recommended 75 pitch count limit in 10-year-olds, a relative decrease in glycogen stores of the flexor-pronator mass did occur, as well as a decrease in grip strength, with increasing subjective fatigue. Clinical Relevance: This study provides a foundation for further objective testing of physiologic changes that occur with pitching to better guide pitch count limits and improve the safety of young athletes.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Autologous fat grafting for nerve regeneration and neuropathic pain: current state from bench-to-bedside.

Despite recent advances in microsurgical techniques, functional recovery following peripheral nerve injury remains slow and inadequate. Poor peripheral nerve regeneration not only leaves patients with significant impairments, but also commonly leads to the development of debilitating neuropathic pain. Recent research has demonstrated the potential therapeutic benefits of adipose-derived stem cells, to enhance nerve regeneration. However, clinical translation remains limited due to the current regulatory burdens of the US FDA. A reliable and immediately translatable alternative is autologous fat grafting, where native adipose-derived stem cells present in the transferred tissue can potentially act upon regenerating axons. This review presents the scope of adipose tissue-based therapies to enhance outcomes following peripheral nerve injury, specifically focusing on their role in regeneration and ameliorating neuropathic pain.

The Use of Recombinant Human Growth Hormone to Protect Against Muscle Weakness in Patients Undergoing Anterior Cruciate Ligament Reconstruction: A Pilot, Randomized Placebo-Controlled Trial.

BACKGROUND: Anterior cruciate ligament (ACL) tears are common knee injuries. Despite undergoing extensive rehabilitation after ACL reconstruction (ACLR), many patients have persistent quadriceps muscle weakness that limits their successful return to play and are also at an increased risk of developing knee osteoarthritis (OA). Human growth hormone (HGH) has been shown to prevent muscle atrophy and weakness in various models of disuse and disease but has not been evaluated in patients undergoing ACLR. HYPOTHESIS: Compared with placebo treatment, a 6-week perioperative treatment course of HGH would protect against muscle atrophy and weakness in patients undergoing ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 19 male patients (aged 18-35 years) scheduled to undergo ACLR were randomly assigned to the placebo (n = 9) or HGH (n = 10) group. Patients began placebo or HGH treatment twice daily 1 week before surgery and continued through 5 weeks after surgery. Knee muscle strength and volume, patient-reported outcome scores, and circulating biomarkers were measured at several time points through 6 months after surgery. Mixed-effects models were used to evaluate differences between treatment groups and time points, and as this was a pilot study, significance was set at P < .10. The Cohen d was calculated to determine the effect size. RESULTS: HGH was well-tolerated, and no differences in adverse events between the groups were observed. The HGH group had a 2.1-fold increase in circulating insulin-like growth factor 1 over the course of the treatment period (P < .05; d = 2.93). The primary outcome measure was knee extension strength, and HGH treatment increased normalized peak isokinetic knee extension torque by 29% compared with the placebo group (P = .05; d = 0.80). Matrix metalloproteinase-3 (MMP3), which was used as an indirect biomarker of cartilage degradation, was 36% lower in the HGH group (P = .05; d = -1.34). HGH did not appear to be associated with changes in muscle volume or patient-reported outcome scores. CONCLUSION: HGH improved quadriceps strength and reduced MMP3 levels in patients undergoing ACLR. On the basis of this pilot study, further trials to more comprehensively evaluate the ability of HGH to improve muscle function and potentially protect against OA in patients undergoing ACLR are warranted. REGISTRATION: NCT02420353 ( ClinicalTrials.gov identifier).

Pathogenesis and Management of Tendinopathies in Sports Medicine.

OBJECTIVE: Tendinopathy is a major clinical problem in sports medicine and is often difficult to treat. Traditional therapeutic approaches have focused on reducing inflammation, yet research suggests that little to no inflammation is present in the tendons that fail to heal. The purpose of this review was to evaluate the effectiveness of the available treatment options for tendinopathy and to inform best clinical practices. DESIGN: A narrative review. METHODS: A comprehensive search of electronic databases (PubMed, Google Scholar and Web of Science) was conducted to identify relevant studies through June 2016. Studies were deemed relevant if they were published in English and contained original research on the management of tendinopathy in humans. RESULTS: Studies varied in methodological quality and were often limited by small sample size and lack of sufficient control groups. Critical evaluation of the literature suggests that physical therapy with or without eccentric exercise should be considered a first-line treatment. Corticosteroids and nonsteroidal anti-inflammatory drugs provide short-term symptomatic relief, but long-term efficacy has not been demonstrated. Inconsistent results do not support the routine use of prolotherapy, platelet-rich plasma injections and topical nitric oxide patches. Operative intervention should be reserved until conservative measures fail or an obvious operative lesion is present. CONCLUSIONS: While numerous therapeutic modalities exist for tendinopathy in the athlete, the ideal treatment protocol has not been clearly defined. The development of new targeted therapies for tendinopathy is likely to follow a greater understanding of the cellular and molecular mechanisms that underlie its pathogenesis.

Local cryotherapy minimally impacts the metabolome and transcriptome of human skeletal muscle.

Cryotherapy is commonly used in the treatment of skeletal muscle injuries. However, the data to support the use of cryotherapy is inconclusive, and the biochemical etiology of cryotherapy in human skeletal muscle remains largely unknown. We therefore sought to determine how a clinically-relevant dose of cryotherapy would impact the transcriptome and metabolome of skeletal muscle. Eight healthy male subjects (age 24.7 ± 4.5 years, BMI 22.2 ± 1.6) received a 15 minute bout of local cryotherapy, delivered via ice cup massage over the anterolateral thigh. This resulted in an 85% decrease in skin temperature and a predicted 27% reduction in intramuscular temperature. The contralateral side served as a non-treated control. Two hours after cryotherapy, muscle biopsies were obtained to analyze changes in the transcriptome, metabolome, and activation of p38 MAPK, ERK1/2, Akt, and p70S6K proteins. No changes were detected in the transcriptome between control and cooled muscles. Cryotherapy reduced levels of hexose sugars and hypoxanthine by 1.3%, but no statistically different changes were observed in 60 additional metabolites. Overall, no differences in phosphorylated p38 MAPK, ERK1/2, Akt, and p70S6K were observed. A clinically relevant dose of cryotherapy produced negligible acute biochemical and molecular changes in the skeletal muscle of human subjects.