Prolotherapy for chronic low back pain: a review of literature.

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 included in the review, using appropriate tools, showed how their quality has decreased over the years, reflecting the need for appropriately powered well planned and performed randomized control trials.

Assessment of safety and efficacy of intra-articular injection of stromal vascular fraction for the treatment of knee osteoarthritis-a systematic review.

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.

Two-year clinical outcomes of autologous microfragmented adipose tissue in elderly patients with knee osteoarthritis: a multi-centric, international study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine.

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 its preparation, especially in regards to regulatory compliance. The BMA Matrix represents a suitable alternative, indicated for the enhancement of tissue repair mechanisms by modulating inflammation and acting as a natural biological scaffold as well as a reservoir of cytokines and growth factors that support cell activity. Although promising, more clinical studies are warranted in order to further clarify the efficacy of this strategy.

Correction to: A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions.

The published online version contains mistake in Acknowledgment Section. The author name "Steve Gorin, M.D." should have been "Steven Gorin, D.O, M.S.Ed.".

The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review.

Introduction: Osteoarthritis (OA) often leads to symptoms such as pain, stiffness and decreased function. OA is treated with a wide range of modalities, both conservatively and surgically. Prolotherapy has been used to treat various musculoskeletal problems and has shown some promise. Sources of data: Searches of the electronic databases, PubMed, ISI web of science, PEDro and SPORTDiscus, were conducted for all Level 1-4 studies published from inception through to December 2016. Areas of agreement: Ten studies were evaluated and results show significant improvement in scores for pain, function and range of motion, both in the short term and long term. Patient satisfaction was also high in these patients (82%). Areas of controversy: Meta-analysis was not possible due to heterogeneity of outcome measures and populations. Growing points: Moderate evidence suggests that prolotherapy is safe and can help achieve significant symptomatic control in individuals with OA. Areas for developing research: Future research should focus on larger sample size, standardization of treatment protocol and basic science evidence.

A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions.

INTRODUCTION: The purpose of the present investigation is to report on detailed complications among a much larger group of 2372 orthopaedic patients treated with stem cell injections who were followed in a treatment registry for up to nine years. METHODS: All patients underwent an MSC-based, percutaneous injection treatment of an orthopaedic condition between December 2005 and September 2014 at one of 18 clinical facilities. Treated areas of the body included the knee, hip, ankle/foot, hand/wrist, elbow, shoulder, and spine. The patients were followed prospectively via enrollment in a treatment registry. Patients were followed prospectively at one, three, six and 12 months, and annually thereafter, using an electronic system, ClinCapture software. RESULTS: A total of 3012 procedures were performed on 2372 patients with follow-up period of 2.2 years. A total of 325 adverse events were reported. The majority were pain post-procedure (n = 93, 3.9 % of the study population) and pain due to progressive degenerative joint disease (n = 90, 3.8 % of the study population). Seven cases reported neoplasms, a lower rate than in the general population. The lowest rate of adverse events was observed among patients injected with BMC alone. CONCLUSION: Lowest rate of adverse events was among those patients receiving BMC injections alone, but the higher rate of AEs for BMC plus adipose and cultured cells was readily explained by the nature of the therapy or the longer follow-up. There was no clinical evidence to suggest that treatment with MSCs of any type in this study increased the risk of neoplasm.

Platelet Rich Plasma for Treatment of Rheumatoid Arthritis: Case Series and Review of Literature.

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 joints at 4 and 8 weeks after injection. There was an improvement in joint inflammation on ultrasound imaging in some patients. These effects were sustained for up to 1 year. No adverse effects were reported in any patient. PRP may be a safe and useful therapy in patients with rheumatoid arthritis who fail to respond to one or more established treatment options.

Gold-Induced Cytokine (GOLDIC®) Injection Therapy in Patient with Plantar Fasciosis: A Case Report.

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.

Nutritional, metabolic and genetic considerations to optimise regenerative medicine outcome for knee osteoarthritis.

Knee osteoarthritis (KOA) is a multifactorial degenerative disorder of joints, affecting the world's population over the age of 65 and with a higher prevalence in females. KOA is responsible for many age associated joint problems such as stiffness and pain. Conventional methods for managing KOA such as nonsteroidal anti-inflammatory drugs (NSAID) may not improve pain or alter the disease progression and may have adverse side effects. Non-pharmacological management of OA is fundamental to management of functional limitations and provides effective symptom relief but has not shown that disease progression can be altered. Regenerative medicine is a relatively new approach which aims to induce cellular regeneration and promote self-healing through minimally invasive methods. The use of regenerative medicine slowed the progression of KOA and revealed significant improvements, yet further investigations are required to optimize the outcomes. Nutritional and metabolic aspects such as supplementations, vitamins and minerals were proven to have an impact on the progression of KOA. Genetic variations are rapidly inspected to identify any potential influence of these variations in the predisposition and diagnosis of KOA. Further supporting evidence suggests the potential influence of metabolic, nutritional and genetic aspects in optimizing the outcomes of regenerative medicine in the management of KOA.

Efficacy and safety of culture-expanded, mesenchymal stem/stromal cells for the treatment of knee osteoarthritis: a systematic review protocol.

BACKGROUND: Osteoarthritis is a progressive multifactorial condition of the musculoskeletal system with major symptoms including pain, loss of function, damage of articular cartilage and other tissues in the affected area. Knee osteoarthritis imposes major individual and social burden, especially with the cost and complexity of surgical interventions. Mesenchymal stem/stromal cells have been indicated as a treatment for degenerative musculoskeletal conditions given their capacity to differentiate into tissues of the musculoskeletal system. METHODS: A systematic search will be conducted in Medline, Embase, Cochrane Library, Scopus and relevant trial databases of English, Japanese, Korean, German, French, Italian, Spanish and Portuguese language papers published or in press to June 2018, with no restrictions on publication year applied. References will be screened and assessed for eligibility by two independent reviewers as per PRISMA guidelines. Cohort, cross-sectional or case controlled studies will be included for the analysis. Data extraction will be conducted using a predefined template and quality of evidence assessed. Statistical summaries and meta-analyses will be performed as necessary. DISCUSSION: Results will be published in relevant peer-reviewed scientific journals and presented at national or international conferences by the investigators. TRIAL REGISTRATION: The protocol was registered on the PROSPERO international prospective register of systematic reviews prior to commencement, CRD42018091763 .

Quality in practice: implementation of a clinical outcomes registry in regenerative medicine.

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 decision-making 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.

Alternatives to Biologics in Management of Knee Osteoarthritis: A Systematic Review.

BACKGROUND: Knee osteoarthritis (KOA) is a common condition encountered by physicians. KOA is addressed by a wide array of modalities including a number of nonbiological treatments. METHODS: PubMed, ISI Web of Science, and SPORTDiscus were searched for level 1 to 4 studies published from inception to August 2017. RESULTS: A total of 18 studies were evaluated and results demonstrated moderate supporting evidence for prolotherapy and limited evidence for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin. Evidence for local anesthetic agents was conflicting. CONCLUSION: There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin in improving pain and function. There is conflicting evidence for the use of local anesthetic agents in patients with KOA.

Concepts in regenerative medicine: Past, present, and future in articular cartilage treatment.

Regenerative medicine is emerging with great interest and hope from patients, industry, academia, and medical professionals. Cartilage regeneration, restoration, or repair is one of the prime targets that remains largely unsolved, and many believe that regenerative medicine can possibly deliver solutions that can be widely used to address the current gap(s) in treatment. In the United States, Europe, Australia, and India the regulation of regenerative based treatments has become a big debate. Although the rules and regulations remain unclear, clinicians that are interested should carry-on with the best available guidelines to ensure safety and compliance during delivery in clinical practice to avoid regulatory infraction. Many have made significant investment of time, resources, and facilities in recent years to provide new regenerative treatment options and advance medical care for patients. Instead of reinventing the wheel, it would be more efficient to adopt currently accepted standards and nomenclature borrowed from transplantation science, and cord blood storage industries. The purposes of this article are to provide some historical background to the field of regenerative medicine as it applies to cartilage, and how this field has developed. This will be followed by a separate discussion on regulatory oversight and input and how it has influenced access to care. Furthermore, we discuss current clinical techniques and progress, and ways to deliver these treatments to patients safely, effectively, and in a cost sensitive manner, concluding with an overview of some of the promising regenerative techniques specific to cartilage.

Initial treatment of complete rotator cuff tear and transition to surgical treatment: systematic review of the evidence.

BACKGROUND: rotator cuff tear affects many people. Natural history, and evidence for non-operative treatment remains limited. Our objective is to assess evidence available for the efficacy and morbidity of commonly used systemic medications, physiotherapy, and injections alongside evaluating any negative long-term effects. METHODS: a systematic search was performed of PubMed, Cochrane, EMBASE and CINAHL dates (1 January 1960 - 1 December 2014), search terms: 'rotator cuff tear', 'natural history', 'atraumatic', 'injection', 'physiotherapy' or 'physical therapy', 'injection', 'corticosteroid', 'PRP', 'MSC', risk of conservative treatment', and 'surgical indication'. RESULTS: eleven studies were included. The mean Coleman Methodology Score modified for conservative therapy is 69.21 (range 88-44) (SD 12.31). This included 2 RCTs, 7 prospective, and 2 retrospective studies. Evidence suggests it is safe to monitor symptomatic rotator cuff tears, as tear size and symptoms are not correlated with pain, function, and/or ultimate outcome. CONCLUSIONS: complete rotator cuff tears may be effectively treated with injections, exercise in the short and intermediate terms respectively. Negative effect of corticosteroids on rotator cuff tissue has not been demonstrated. Timing to end conservative treatment is unknown, but likely indicated when a patient demonstrates increased weakness and loss of function not recoverable by physiotherapy.

Regenerative treatments to enhance orthopedic surgical outcome.

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, bone marrow preparations, and stem cells. This is a new era in the application of biologically active material, and it is transforming clinical practice by providing effective supportive treatments either at the time of the index procedure or during the postoperative period. Regenerative treatments are currently in active use to enhance many areas of orthopedic surgery in an attempt to improve success and outcome. In this review we provide a comprehensive overview of the peer-reviewed evidence-based literature, highlighting the clinical outcomes in humans both with preclinical data and human clinical trials involving regenerative preparations within the areas of rotator cuff, meniscus, ligament, and articular cartilage surgical repair.