Papers by William Murrell
Journal of Postgraduate Medicine, Education and Research, 2018
It is an exciting time in regenerative medicine. We are witness to an unprecedented explosion of ... more It is an exciting time in regenerative medicine. We are witness to an unprecedented explosion of knowledge and innovation in both basic and translational science, as well as clinical application. The great possibility of the application of biologically driven therapies holds great interest and hope from patients, practitioners, academia, and industry alike. The opportunity to cure un-curable or difficult to treat disorders and diseases captures and holds the interest of patients who are one of the key drivers for innovation. Patients are becoming keenly aware of the science and treatment options. Along with rapid availability of new therapeutics and possibly the application of unapproved treatments, worldwide regulatory bodies are under pressure to ensure treatments are safe and efficacious. The first response has been uniformly suppressive by key international regulatory bodies; followed by comprehensive legislative enactment. Currently, there is a prime opportunity for the medical community to follow recent legislative enactments and provide a comprehensive framework for self-governance. Additionally, there is an unprecedented opportunity for stakeholder collaboration and community building. The result could be a system where all who seek care have access, where medicine provides solutions and science of medicine advances unfettered, industry grows, and regulating bodies are harmonious. The future is quite bright in regenerative medicine with technology such as personalized biological products, needle-less injections, tissue targeting, gene editing, and immunotherapies as solution(s) on the horizon to address the current gap(s) in treatment. Regenerative medicine holds such great promise and excitement that many of us believe we are standing witness to a fundamental shift in the practice of medicine that could favorably alter the course of humanity. Regenerative medicine is defined as the treatment 4 of medical conditions that harnesses the human body's inherent ability to regenerate tissue at the level of cellular or organ structure, that foster cellular communication, translation, organ system refurbishment, and result in overall organism well-being. Strategies of treatment include healing response, exogenous augmentation, cellular signaling, external stimulus, and genetic influence/modification. It is here that lies the great excitement, that human beings become the source of their well-being and health. The concept is very inspiring. Specific to musculoskeletal disease we have a growing body of evidence that is supportive of innovative approaches/preparations such as platelet rich plasma for the treatment of knee osteoarthritis 1-3 , to augment rotator cuff repair 4,5 , and promising data in the area of treating tennis elbow, partial ACL (anterior cruciate ligament) tears, and plantar fasciitis with platelet based products; bone marrow derived products offer promising data for augmenting rotator cuff repair 6,7 , treating shoulder and knee osteoarthritis 8,9 , and ACL tears 10 ; adipose derived products also have promising data for treating knee osteoarthritis 11 ; and developing evidence exists for peripheral blood products for augmentation of surgically treated focal and diffuse cartilage defects in the knee with ongoing Phase IIb clinical trial in the United States 12. Although it may not seem apparent, the underlying purpose of regenerative medicine may not be just for curing a disease, but for the perfection of human organism, and possibly physical immortality. Currently, unclear and restrictive regulatory barriers in the developed world are presenting challenges for all involved, and in many cases logical and accessible treatments become inaccessible. This is not new, though we have seen this in the past 13. Recently, the United States approved the 21st Century Cures Act and accompanying Food and Drug Administration (FDA) draft guidance for Human and Cellular 5 Therapeutics/Products (HCT/P) provided another pathway for biologics that is an alternative to the standard phase pharmaceutical pathway and created a new category of biological product called regenerative medicine advanced therapy (RMAT). To date over 14 products have been approved 14 , however, it remains to be seen the actual impact on clinical practice. Although the rapid expansion of the field has outpaced regulation globally with few exceptions, existing rules have provided little guidance for both clinicians and scientists on the best way to proceed. The questions about, and definitions of, certain biologic products are currently under debate in the United Kingdom 15 , European Union 16 , India 17 , as well as Australia 18. Despite the lack of national or international harmonization of regulation, it appears that regenerative medicine moves forward and relatively newly formed societies such as the American Academy and Board of Regenerative Medicine are engaging in active dialogue with FDA; there seems to be room to influence the course of action. The regulatory, research, and clinical attention on regenerative medicine and its related products suggests they are here to stay. The market has grown quite significantly overall from 2012 through 2016 by nearly 100% according to the actualized by the stem cell therapy index (SCTI) 19. With the acceptance of cellular therapies, comes a prime opportunity for practitioners in the space to collaborate and create self-imposed standards for regulation and harmony across practices. This can be done by peer-to-peer knowledge and best practice sharing; creating the required processes for defining the conditions that have the most evidence for treatment, determining the best candidates for treatment, candidate assessment and selection, and informed consent. Additionally, creating standard operating procedures (SOPs) for sample collection and handling, cellular processing, 6 treatment administration, outcome and adverse event management and reporting are opportunities in the industry. Guidelines are currently
Regenerative Treatments in Sports and Orthopedic Medicine
COVID-19 is a raging pandemic with cases, hospitalizations and deaths surging. Prevention has foc... more COVID-19 is a raging pandemic with cases, hospitalizations and deaths surging. Prevention has focused to date on mask wearing, social distancing, and the development of vaccines. Novel mitigation strategies, however, are needed to combat the pandemic optimally.There was an epidemic of inactivity in 2020 partially because of government recommendations to stay indoors and the mandated closure of gyms. Vitamin D deficiency is also a common worldwide problem, especially for persons of color. These two issues are contributing to the severity of the pandemic and should be addressed.
Muscle and Tendon Injuries
Introduction: A new procedure using uniquely designed gold particles to stimulate the production ... more Introduction: A new procedure using uniquely designed gold particles to stimulate the production of various protective and regenerative proteins in patients own blood (GOLDIC®) was investigated. This study was designed to evaluate the effect of four consecutive GOLDIC® injections in human patients with Achilles tendinopathy.
In orthopedic surgery there has been a never-ending quest to improve surgical outcome and the pat... more In orthopedic surgery there has been a never-ending quest to improve surgical outcome and the patient’s experience. Progression has been marked by the refinement of surgical techniques and instruments and later by enhanced diagnostic imaging capability, specifically magnetic resonance. Over time implant optimization was achieved, along with the development of innovative minimally invasive arthroscopic technical skills to leverage new versions of classic procedures and implants to improve short-term patient morbidity and initial, mid-term, and long-term patient outcomes. The use of regenerative and/or biological adjuncts to aid the healing process has followed in the drive for continual improvement, and major breakthroughs in basic science have significantly unraveled the mechanisms of key healing and regenerative pathways. A wide spectrum of primary and complementary regenerative treatments is becoming increasingly available, including blood-derived preparations, growth factors, bon...
British medical bulletin, 2021
INTRODUCTION Low back pain is common and imposes major societal burdens for patient suffering and... more INTRODUCTION Low back pain is common and imposes major societal burdens for patient suffering and costs. Prolotherapy injections are used for musculoskeletal conditions including tendinopathies, osteoarthritis and low back pain to enhance soft-tissue healing. This review aims to clarify the place of prolotherapy in chronic low back pain (CLBP). SOURCES OF DATA Using multiple databases, a systematic search was performed to identify studies detailing the use of prolotherapy to manage CLBP. A total of 12 articles was included in the present work. AREAS OF AGREEMENT Considering the level of evidence and the quality of the studies assessed using the modified Coleman Score, prolotherapy is an effective management modality for CLBP patients in whom conservative therapies failed. AREAS OF CONTROVERSY The presence of co-interventions and the clinical heterogeneity of the work contributes to confound the overall conclusions. GROWING POINTS AND AREAS FOR RESEARCH The analysis of the studies in...
Most orthopaedic intervention for trauma or pathological processes is unambiguous. However, when ... more Most orthopaedic intervention for trauma or pathological processes is unambiguous. However, when venturing into the realm of treatment for degenerative conditions or soft tissue injuries the indication for treatment has mostly been supported by level 3 evidence in the top orthopaedic surgery journals.1 In the past few of decades it has been concerning to see a growing number of treatments designed for end-stage disease being applied to younger individuals. As life expectancy increases, the risks of multiple revision interventions are likely and from a public health standpoint, more expensive, and predictably unsustainable. Enter the possibility of minimally invasive interventions with lower morbidity and, if properly utilized, adding critical time prior to end-stage disease intervention.
Injuries and disorders of the musculoskeletal system cause pain and loss of function, thereby lea... more Injuries and disorders of the musculoskeletal system cause pain and loss of function, thereby leading to disability. The goal of rehabilitation medicine is to restore function in individuals with disability. This Update presents evidence from studies published from March 2016 to February 2017 in the area of orthopaedic rehabilitation. Articles from the American Journal of Physical Medicine & Rehabilitation, The American Journal of Sports Medicine, Archives of Physical Medicine and Rehabilitation, The BMJ, The Clinical Journal of Pain, JAMA, The Journal of Bone & Joint Surgery, The Journal of Pain, the Journal of Shoulder and Elbow Surgery, The New England Journal of Medicine, Pain Medicine, Physical Therapy, PM&R, and Spine were considered. We screenedmanuscript titles and abstracts and included articles that were considered to be of high impact and value to readers.
International Orthopaedics
The aim of this study is to evaluate the outcomes of autologous microfragmented adipose tissue (M... more The aim of this study is to evaluate the outcomes of autologous microfragmented adipose tissue (MFAT) injection in elderly patients with knee osteoarthritis (OA). We hypothesized that MFAT knee infiltration for the treatment of knee OA would yield good clinical results out to two years follow-up. Multi-centric, international, open-label study conducted by orthopedic surgery, and/or regenerative medicine facilities utilizing patient registries. Subjects recruited for eligibility. The primary outcome measure was Knee Injury and Osteoarthritis Outcome Score (KOOS). Outcomes and patient factors were compared to baseline, at six, 12, and 24 months. Statistical models were used to assess KOOS subscores and probability of exceeding the Minimally Clinically Important Difference (MCID) or Patient Acceptable Symptom State (PASS), and to assess the effect of the treatment variables on KOOS - Pain. Seventy-five patients, 120 primary treatments, mean age 69.6 years, (95%CI 68.3–70.9), BMI 28.4 (95%CI 27.3–29.6), with KL grade 2 to 4 knee OA treated with a single MFAT injection. KL grades 2 (15.1%), 3 (56.3%), and 4 (28.6%), with 20.8% of knees having previously undergone surgery. Patients with KL grade 2 disease had the best results in KOOS - Pain (P = 0.001), at six, 12, and 24 months. Including advanced KL grade 3 and 4 osteoarthritis patients, significant functional and quality of life success was seen in 106/120 treatments (88.3%, 66 patients) at all follow-up time points. Fourteen treatments (11.7%, 9 patients) failed prior to the study endpoint. This study shows that a single-dose MFAT injection leads to clinical, functional, and quality of life improvement at two years in elderly patients, in KL grades 2 to 4 of knee osteoarthritis. These findings provide evidence that this treatment modality could be a safe and effective option to other commonly available treatments in carefully selected patients.
International Orthopaedics
Purpose Stromal vascular fraction (SVF) as an injectable regenerative therapy for knee osteoarthr... more Purpose Stromal vascular fraction (SVF) as an injectable regenerative therapy for knee osteoarthritis (OA) has gained recent popularity. However, there is no clear consensus on the outcomes of such treatment. We systematically reviewed available evidence on the use of SVF injection in the treatment of knee OA. Methods The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with keyword search in PubMed, Scopus, and the Cochrane Library Database and related article search in Google Scholar. Clinical studies demonstrating effects of SVF in knee OA and published in English literature were included. Risk of bias assessment was done with modified Coleman Methodology Scoring (CMS). Results Eleven studies (9 prospective, 2 retrospective) that contributed to 290 knees in 200 patients were included. Two studies that contributed to 3718 knee injections were excluded from pooled analysis and were scrutinized separately. Majority of patients reported improvement in pain, range of motion (ROM), functional rating, six metre walking distance, and functional outcome scores. There was no major donor-site morbidity. There was only one reported case of knee joint infection and no case of tumour formation in relation to SVF injection. Discussion Intra-articular injection of SVF can be a simple, affordable, and minimally invasive treatment that could serve as an interim option for patients who failed other conservative and arthroscopic options. Conclusion Intra-articular injection of SVF is a safe and effective technique for the management of knee OA. However, comparative Level I studies are needed to support the use of adjuvants with SVF and also to compare the use of SVF (with or without adjuvants) with ADMSCs, PRP, and bone marrow concentrate.
Orthopaedic Journal of Sports Medicine
NeuroLogica, education payments from Arthrex, faculty/speaker fees from Linvatec, and consulting ... more NeuroLogica, education payments from Arthrex, faculty/speaker fees from Linvatec, and consulting fees from Linvatec, Trice Medical, and Flexion Therapeutics. B.J.S. has received honoraria from Trice Medical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.
International Journal of Molecular Sciences
The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alte... more The rise in musculoskeletal disorders has prompted medical experts to devise novel effective alternatives to treat complicated orthopedic conditions. The ever-expanding field of regenerative medicine has allowed researchers to appreciate the therapeutic value of bone marrow-derived biological products, such as the bone marrow aspirate (BMA) clot, a potent orthobiologic which has often been dismissed and regarded as a technical complication. Numerous in vitro and in vivo studies have contributed to the expansion of medical knowledge, revealing optimistic results concerning the application of autologous bone marrow towards various impactful disorders. The bone marrow accommodates a diverse family of cell populations and a rich secretome; therefore, autologous BMA-derived products such as the “BMA Matrix”, may represent a safe and viable approach, able to reduce the costs and some drawbacks linked to the expansion of bone marrow. BMA provides —it eliminates many hurdles associated with...
International Orthopaedics
1 Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy 2 Firs... more 1 Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy 2 First Moscow State Medical University, Sechenov University, Moscow, Russia 3 Abu Dhabi Knee and Sports Medicine, Healthpoint Hospital, Abu Dhabi, United Arab Emirates 4 Department of Orthopedic Surgery, Division of Surgery, William Beaumont Army Medical Center, Ft. Bliss, TX, USA 5 Department of Orthopaedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 6 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele – Milan, Italy https://doi.org/10.1007/s00264-020-04934-x
Indian Journal of Orthopaedics
A novel technique of cultivating autologous blood with gold particles; then separating the gold p... more A novel technique of cultivating autologous blood with gold particles; then separating the gold particles and cells from the serum and injecting the conditioned serum into affected plantar fascia. A first-time report of the safety and efficacy in treatment of recalcitrant plantar fasciosis in an Olympic equestrian. A single patient with clinical signs, symptoms and ultrasound evidence of plantar fasciosis was treated with four intra-ligamentous GOLDIC® injection therapy. The Olympic jumper was evaluated by Visual Analog Scale (VAS), Foot and Ankle Disability Index (FADI), and Global Rating of Change (GRoC) score(s) before injection and at 6-month follow-up. VAS, FADI, and GRoC scores showed substantial and marked improvement clinically. The subject was able to return to sport without limitations after 8 weeks. The initial result demonstrates that the treatment regimen is safe, and efficacious. The subject demonstrated reduction of pain, and improved function that allowed return to high level competition.
Advances in Shoulder Surgery, May 2, 2018
Rotator cuff disease accounts for 10% of all shoulder pain and major shoulder disability, with li... more Rotator cuff disease accounts for 10% of all shoulder pain and major shoulder disability, with limited information concerning the natural history and treatment approaches for the disorder. Our objective is to assess the available evidence for the efficacy and morbidity of commonly used systemic medications, physiotherapy, and injections alongside evaluating any negative long-term effects. Although there is conflicting literature, there appears to be some consensus on the best indicators for choosing to treat a full-thickness tears (FTT) non-operatively to reduce pain and improve function. The risks associated with these tears include the potential of the progression of the tear, a diminished healing potential due to age or longer symptom duration, muscle atrophy, and fatty infiltration. The indications for surgery following conservative treatment are becoming more defined, and an outline regarding what scenarios warrant a transition from an initial conservative treatment plan has been developed. The developing benefits of using mesenchymal stem cells (MSCs) and other biologics have the potential to be disruptive to current treatment protocols in the approaches to healing rotator cuff tears (RCTs). With improved imaging modalities, diagnostic accuracy, and sensitivity, practitioners of the future will hopefully be able to intervene earlier in the disease pathogenesis cycle.
Case Reports in Rheumatology
Platelet-rich plasma (PRP) is an autologous blood product with platelets above circulating levels... more Platelet-rich plasma (PRP) is an autologous blood product with platelets above circulating levels and releases several growth factors after activation. PRP may help to decrease joint inflammation by modulating synovial cell proliferation and differentiation and inhibition of catabolic pathways in various articular conditions. Though PRP has shown good efficacy in osteoarthritis and other musculoskeletal conditions such as synovitis, epicondylitis, skeletal muscle injuries, and tendinopathy, there is limited experience for the use of PRP in patients with rheumatoid arthritis. Precise mechanisms of action of PRP are not known. We present clinical experience for treatment with PRP (2–4 ml) in four patients with rheumatoid arthritis who had inadequate response and persistent pain and inflammation with intra-articular steroids. Irrespective of past and ongoing treatments and duration of disease, all patients showed improvement in the visual analog scale and disease activity score of 28 j...
Journal of Postgraduate Medicine, Education and Research
It is an exciting time in regenerative medicine. We are witness to an unprecedented explosion of ... more It is an exciting time in regenerative medicine. We are witness to an unprecedented explosion of knowledge and innovation in both basic and translational science, as well as clinical application. The great possibility of the application of biologically driven therapies holds great interest and hope from patients, practitioners, academia, and industry alike. The opportunity to cure un-curable or difficult to treat disorders and diseases captures and holds the interest of patients who are one of the key drivers for innovation. Patients are becoming keenly aware of the science and treatment options. Along with rapid availability of new therapeutics and possibly the application of unapproved treatments, worldwide regulatory bodies are under pressure to ensure treatments are safe and efficacious. The first response has been uniformly suppressive by key international regulatory bodies; followed by comprehensive legislative enactment. Currently, there is a prime opportunity for the medical community to follow recent legislative enactments and provide a comprehensive framework for self-governance. Additionally, there is an unprecedented opportunity for stakeholder collaboration and community building. The result could be a system where all who seek care have access, where medicine provides solutions and science of medicine advances unfettered, industry grows, and regulating bodies are harmonious. The future is quite bright in regenerative medicine with technology such as personalized biological products, needle-less injections, tissue targeting, gene editing, and immunotherapies as solution(s) on the horizon to address the current gap(s) in treatment. Regenerative medicine holds such great promise and excitement that many of us believe we are standing witness to a fundamental shift in the practice of medicine that could favorably alter the course of humanity. Regenerative medicine is defined as the treatment 4 of medical conditions that harnesses the human body's inherent ability to regenerate tissue at the level of cellular or organ structure, that foster cellular communication, translation, organ system refurbishment, and result in overall organism well-being. Strategies of treatment include healing response, exogenous augmentation, cellular signaling, external stimulus, and genetic influence/modification. It is here that lies the great excitement, that human beings become the source of their well-being and health. The concept is very inspiring. Specific to musculoskeletal disease we have a growing body of evidence that is supportive of innovative approaches/preparations such as platelet rich plasma for the treatment of knee osteoarthritis 1-3 , to augment rotator cuff repair 4,5 , and promising data in the area of treating tennis elbow, partial ACL (anterior cruciate ligament) tears, and plantar fasciitis with platelet based products; bone marrow derived products offer promising data for augmenting rotator cuff repair 6,7 , treating shoulder and knee osteoarthritis 8,9 , and ACL tears 10 ; adipose derived products also have promising data for treating knee osteoarthritis 11 ; and developing evidence exists for peripheral blood products for augmentation of surgically treated focal and diffuse cartilage defects in the knee with ongoing Phase IIb clinical trial in the United States 12. Although it may not seem apparent, the underlying purpose of regenerative medicine may not be just for curing a disease, but for the perfection of human organism, and possibly physical immortality. Currently, unclear and restrictive regulatory barriers in the developed world are presenting challenges for all involved, and in many cases logical and accessible treatments become inaccessible. This is not new, though we have seen this in the past 13. Recently, the United States approved the 21st Century Cures Act and accompanying Food and Drug Administration (FDA) draft guidance for Human and Cellular 5 Therapeutics/Products (HCT/P) provided another pathway for biologics that is an alternative to the standard phase pharmaceutical pathway and created a new category of biological product called regenerative medicine advanced therapy (RMAT). To date over 14 products have been approved 14 , however, it remains to be seen the actual impact on clinical practice. Although the rapid expansion of the field has outpaced regulation globally with few exceptions, existing rules have provided little guidance for both clinicians and scientists on the best way to proceed. The questions about, and definitions of, certain biologic products are currently under debate in the United Kingdom 15 , European Union 16 , India 17 , as well as Australia 18. Despite the lack of national or international harmonization of regulation, it appears that regenerative medicine moves forward and relatively newly formed societies such as the American Academy and Board of Regenerative Medicine are engaging in active dialogue with FDA; there seems to be room to influence the course of action. The regulatory, research, and clinical attention on regenerative medicine and its related products suggests they are here to stay. The market has grown quite significantly overall from 2012 through 2016 by nearly 100% according to the actualized by the stem cell therapy index (SCTI) 19. With the acceptance of cellular therapies, comes a prime opportunity for practitioners in the space to collaborate and create self-imposed standards for regulation and harmony across practices. This can be done by peer-to-peer knowledge and best practice sharing; creating the required processes for defining the conditions that have the most evidence for treatment, determining the best candidates for treatment, candidate assessment and selection, and informed consent. Additionally, creating standard operating procedures (SOPs) for sample collection and handling, cellular processing, 6 treatment administration, outcome and adverse event management and reporting are opportunities in the industry. Guidelines are currently
Annals of Translational Medicine
Background: The aim of this didactic article is to describe the implementation of a clinical outc... more Background: The aim of this didactic article is to describe the implementation of a clinical outcomes registry within a clinical setting for musculoskeletal regenerative medicine. A patient-centred clinical registry, designed and implemented into the practice of a musculoskeletal clinic specializing in regenerative medicine. Methods: A focus on patient outcomes at all levels of the patient journey was established to monitor and continually improve care. The registry was designed to monitor the diagnosis, treatment and outcomes of musculoskeletal pathologies of the shoulder, elbow, hip, knee, foot and spine presenting to the clinic. Specifically, the registry was designed for surveillance, tracking, and reporting of efficacy and adverse events of cellular-based therapies. Results: The registry has completed its implementation phase and is now in a pilot period to confirm data collection processes and user feedback. Initial findings indicate suboptimal data entry compliance in key areas that were rectified by refining data fields, reimaging within existing operating systems, and linkage to external supporting documents. Conclusions: The key impacts of the registry implementation have been to (I) redefine criteria for treatment success and failure within the area of biologic treatments in musculoskeletal practice; (II) instigate discussion, and document standardized treatment pathways, clinical handover processes and shared decisionmaking with patients; and (III) act as a catalyst to target deficiencies in staff knowledge and skills in the areas of patient management and interaction, clinical documentation and administration processes. A practice registry provides a platform for monitoring treatment safety and efficacy in the context of biologic therapies in musculoskeletal medicine. Registries of this kind will contribute to ongoing discourse regarding best value treatments in the musculoskeletal context.
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Papers by William Murrell