Clinical Evaluation of Safety and Efficacy of a Central Current Good Manufacturing Practices Laboratory Produced Autologous Adipose-Derived Stromal Vascular Fraction Cell Therapy Product for the Treatment of Knee Osteoarthritis.

Knee osteoarthritis (KOA) is a prevalent condition characterized by the progressive deterioration of the entire joint and has emerged as a prominent contributor to disability on a global scale. The nature of the disease and its impact on joint function significantly limit mobility and daily activities, highlighting its substantial influence on patients' overall well-being. Stromal vascular fraction (SVF) is a heterogenous, autologous cell product, containing mesenchymal stem cells, derived from the patient's subcutaneous adipose tissue with demonstrated safety and efficacy in the treatment of KOA patients. We conducted a single-arm, open-label, multisite, FDA approved clinical study in Kellgren-Lawrence severity grade 2-4 KOA patients. The cellular product was manufactured from patient-specific lipoaspirate in a centrally located FDA-compliant manufacturing facility. Twenty-nine subjects were treated with a quality tested single intra-articular injection of GMP manufactured SVF. Adverse events, laboratory values, vital signs, and physical examination findings were monitored during the study period. Robust tolerability, without any substantial safety issues, was demonstrated. Knee pain and function, assessed through the Knee Injury and Osteoarthritis Outcome Score (KOOS), demonstrated notable improvements. These positive benefits persisted for up to 12 months, and the majority of participants expressed satisfaction. SVF from each patient was stored in a liquid nitrogen freezer for future clinical treatments. Unique to this study of autologous cells is the shipment of lipoaspirate from the clinic to a central FDA-compliant manufacturing facility for cleanroom-controlled manufacturing. The cell product characterization data demonstrate that this method produces an equivalent product in terms of cell count and viability with the added benefit of further quality assurance testing, including sterility, endotoxin, and flow cytometry, before patient administration. Clinical Trial Registration Number: NCT04043819.

A pilot study testing an Achilles tendinopathy human cadaver model using intratendinous injection of collagenase.

BACKGROUND: Achilles tendinopathy is one of the most frequently occurring soft-tissue injuries. Despite decades of research, there is still much that is unknown about the progression of tendinopathy. Animal models, such as collagenase injection, allow researchers to gain insight into disease progression and investigate clinical interventions, yet are limited in their direct application to humans. Establishment of a cadaver model of tendinopathy would provide another method of investigating clinical interventions in human tissues. The purpose of this study is to develop such a model and evaluate biomechanical changes in cadaveric Achilles tendons using ultrasound elastography. METHODS: Achilles tendons of five female foot/ankle cadavers were injected with two different concentrations (three with 10 mg/mL, two 20 mg/mL) of collagenase and incubated for 24 h. Ultrasound elastography images were collected at baseline, 16 and 24 h post-injection. Elasticity of tendons was calculated using a custom image analysis program. FINDINGS: Elasticity decreased over time in both dosage groups. In the 10 mg/mL group, mean elasticity decreased from 642 ± 246 kPa at baseline to 392 ± 38.3 kPa at 16 h and 263 ± 87.3 kPa at 24 h. In the 20 mg/mL group, mean elasticity decreased from 628 ± 206 kPa at baseline to 176 ± 152 kPa at 16 h and 188 ± 120 kPa at 24 h. INTERPRETATION: Injection of collagenase into cadaveric Achilles tendons resulted in decreases in elasticity. Decreases were observed in tendons that received injections with both 10 and 20 mg/mL collagenase dosages. Further biomechanical and histological testing is needed to evaluate this cadaveric tendinopathy.

Orthobiologic Standardization and Clinical Outcome Measurement.

There is a pressing need for the standardization of orthobiologics, considering the cellular components, concentrations, and methods of injections may vary wildly, currently without significant standards of care. There is a growing body of evidence that these factors matter significantly for patient outcomes, so it is imperative that orthobiologic constituents are measured and standardized. Cell counts may be performed for platelet-rich plasma and bone marrow aspirate-based injections, whereas adipose should have standardized processing techniques as cellular quantification is more difficult.

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.

Adipose cellular injection in the treatment of an intrasubstance Achilles tendon defect: a case report.

Our patient presented with a 1-year history of right sided Achilles tendon pain and weakness due to partial intrasubstance tear. The injury was refractory to conservative treatment, leading to a trial injection of microfragmented adipose tissue. Progressive healing and improved function were documented on physical exam and sonographically at subsequent follow-up appointments. About 4 weeks following the injection, the patient was able to return to his regular activity level. At the 6 month follow-up appointment, the patient continued to be pain free and had resumed all prior activities without limitations. This case highlights the potential microfragmented adipose tissue has as a regenerative treatment modality for the management of partial Achilles tendon tears.

Adipose-Derived Stem Cells, Obesity, and Inflammation: A Systematic Review and Implications for Osteoarthritis Treatment.

ABSTRACT: Adipose is a known source of mesenchymal stem cells that can be used to treat musculoskeletal disorders, such as osteoarthritis. Because obesity often coexists with osteoarthritis, excess adiposity may be a useful source of mesenchymal stem cells. However, obesity is associated with systemic inflammation, which may influence the quality of adipose-derived stem cells. We performed a systematic review of the literature examining adipose-derived stem cell behavior, cytokine, and growth factor profiles from obese and nonobese patients. Two independent reviewers applied the inclusion/exclusion criteria and independently extracted data including mesenchymal stem cell count/viability/behavior, growth factor, and/or cytokine expression. Twenty-two articles met criteria for inclusion. Samples from obese patients had increased mesenchymal stem cell content (n = 6), but decreased proliferative ability (n = 3), and increased expression of interleukin 1 (n = 3), interleukin 6 (n = 3), and tumor necrosis factor α (n = 6). There was also greater macrophage content (n = 4). Weight loss normalized cellular function. In vitro behavior and quality of adipose-derived stem cell are significantly different between obese and nonobese patients. Samples from obese patients had greater adipose-derived stem cell content, lower proliferative ability, increased senescence, and increased proinflammatory cytokine expression. Differences in cellular function should be considered when using adipose to treat musculoskeletal pathology in obese and nonobese patients.

Patient registries in orthopedics and orthobiologic procedures: a narrative review.

There has been increasing evidence and growing popularity of orthobiologic treatments, such as platelet-rich plasma, bone marrow aspirate concentrate, and microfragmented adipose tissue. However, real-world data, including patient-reported pain and function outcomes, remains sparse for these procedures. Thus, collecting patient-reported outcome measures is important to evaluate the safety and efficacy of these treatments and hopefully improve patient care. Patient reported outcome measures can systematically be collected through patient registries. This narrative review serves to describe the data collection platforms and registries that obtain patient-reported outcome measures on orthobiologic procedures and provide a discussion on the benefits and limitations of registries. An internet search of the list of orthopedic registries available was conducted, and registries that collect patient-reported outcome measures for orthobiologic procedures were identified. Additional information regarding these various registries was collected by directly contacting these vendors. Publications from these registries, including case series, observational studies, and annual reports, were also reviewed. Providing this review will inform clinicians of a digital tool that can increase the efficiency of collecting outcome measures for orthobiologics and aid physicians in choosing a data collection platform.

Ultrasound-guided platelet-rich plasma injection for the treatment of recalcitrant rotator cuff disease in wheelchair users with spinal cord injury: A pilot study.

Context/Objective: Wheelchair users with spinal cord injury (SCI) have a high risk of developing shoulder pain, caused by rotator cuff disease. Platelet-rich plasma (PRP) is a potential treatment after conservative treatments fail and prior to surgical intervention; however, it has not been tested in wheelchair users who have recalcitrant shoulder pain associated with rotator cuff disease. The objective of this pilot project was to test the safety and potential treatment effect of an ultrasound-guided PRP injection for shoulder pain in the aforementioned population.Design: Prospective, quasi-experimental.Setting: Clinical research center.Participants: Six wheelchair users with SCI (3 paraplegia, 3 tetraplegia) who had chronic shoulder pain due to rotator cuff disease (presence of anterior shoulder pain, positive physical examination tests for rotator cuff disease, and tendinopathy demonstrated by ultrasound) and failed at least six months of conservative treatment.Interventions: Ultrasound-guided PRP injection into pathological shoulder tendons, targeting the supraspinatus. Subjects were provided a standardized stretching and strengthening program and were followed for 4, 8, 12, and 24 weeks post-intervention with outcomes collected at each time-point.Outcome Measures: Wheelchair User's Shoulder Pain Index (WUSPI); pain Numerical Rating Scale (NRS); physical and ultrasound examinations for supraspinatus tendinopathy; 5-point patient global impression of change (PGIC).Results: WUSPI (69.9%, P < 0.001), NRS (49.6%, P < 0.01), and physical exam scores (35.7%, P < 0.01) decreased 24 weeks after treatment. Participants reported overall improvement in their status as a result of the treatment. No adverse events were noted, and no changes in ultrasound markers for tendinopathy were observed.Conclusion: A single, ultrasound-guided PRP injection into the supraspinatus tendon, followed by a stretching and strengthening exercise program, was safe and provided improvements in shoulder pain outcome measures in this sample for 24 weeks. Lack of blinding, short-term follow-up, and a suitable control group warrant a larger randomized controlled trial.Trial Registration: NCT01355549.

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.

Delay to TKA in Patients Treated with a Multimodal Approach Using High Molecular Weight, Biologically Derived Hyaluronic Acid.

BACKGROUND: The primary objective of this study was to determine the effect of single versus multiple rounds of intra-articular hyaluronic acid (IA-HA) in delaying the need for total knee arthroplasty (TKA) in patients with knee OA, and if additional benefits were seen when used in conjunction with other multimodal treatment options. METHODS: This study was a retrospective claims analysis of a large commercial database containing more than 100 million patients with continuous coverage from October 1, 2010 through September 30, 2015. Time to TKA for patients who received one course of Euflexxa (IA-BioHA) were compared to patients who received two or more courses of IA-BioHA and patients who received no IA-HA. Assessment of multimodal treatment effects was done between the following groups: IA-BioHA injections alone, IA-BioHA and bracing, IA-BioHA and corticosteroid injection, and IA-BioHA with both corticosteroids and bracing. RESULTS: A total of 26,727 patients were included in the analysis of treatment courses, and 31,034 in the analysis of multimodal treatment combinations. The use of IA-BioHA demonstrated a delay of TKA that was prolonged with repeated courses of treatment (1.411 years, interquartile range [IQR]: 1.44). The greatest delay to TKA was observed for the patients who had received all three treatment options (1.5 years, IQR: 1.52) in the multimodal analysis. CONCLUSIONS: These results confirm that treatment of knee OA should consider the use of multimodal therapy instead of focusing on individual treatment options. Additionally, the use of repeated courses of IA-BioHA should be considered for prolonged benefit for patients with symptomatic knee OA.

Use of Bone Marrow Concentrate to Treat Pain and Musculoskeletal Disorders: An Academic Delphi Investigation.

BACKGROUND: Acute and degenerative musculoskeletal disorders are among the most common etiologies of disability worldwide. Recently, there has been interest in the field of regenerative medicine to bridge the gap between conservative and surgical management of these conditions. Autologous bone marrow concentrate is one type of injectate that has increased in popularity over the last few decades. Though there is promising evidence supporting its efficacy, standard of care practice guidelines to govern the appropriate use and implementation of such technology are currently lacking. OBJECTIVES: The aim of this article is to report findings from a survey administered using the Delphi technique to a group of physicians using bone marrow concentrate in practice to determine best practice consensus regarding optimization of patient safety and education. STUDY DESIGN: Delphi panel technique. SETTING: The study was first announced at a national meeting and continued remotely across the United States via 4 rounds of online surveys. METHODS: An initial panel of 30 expert members was convened and a 5-member steering committee was established. Four rounds of consensus questionnaires totaling 11 unique questions were distributed. Ten questions included a 5-point Likert scale from "Strongly Agree" to "Strongly Disagree," and one question had a selection of 5 options regarding minimum level of evidence required. The anonymized aggregate results of each round were shared with the group prior to voting in the subsequent round in accordance with the Delphi process. Consensus was defined as 80% agreement of the statements indicating either "Strongly Agree" or "Agree" for the 10 questions with the Likert Scale and 80% agreement among 2 of 5 choices in the question regarding levels of evidence. RESULTS: Three invited participants were excluded by the second round of questions due to lack of response in a timely manner, leaving 27 physicians queried. Nine of the 11 questions met criteria for > 80% consensus. Areas of agreement included importance of a treatment registry, candidacy grading, expanded informed consent, scientific accuracy in advertising, institutional review board approval for novel uses, performance of procedures by only licensed physicians or mid-level providers with direct physician oversight, use of image guidance for injections, data submission for publication in peer reviewed literature, and a minimum requirement of case-series level of evidence for use of bone marrow concentrate in musculoskeletal medicine. The 2 areas that did not meet criteria for consensus included online publishing of individual clinic data and standards around cell counting for dosing. LIMITATIONS: The Delphi panel of experts was convened on a voluntary basis rather than a nomination process. Our panel of experts were all physicians who use bone marrow concentrate in practice, therefore it is possible that a different panel of experts within other disciplines would reach different conclusions. CONCLUSIONS: There is significant consensus among a panel of physicians performing bone marrow concentrate injections regarding best practice guidelines for musculoskeletal conditions.

A pilot study to evaluate micro-fragmented adipose tissue injection under ultrasound guidance for the treatment of refractory rotator cuff disease in wheelchair users with spinal cord injury.

CONTEXT/OBJECTIVES: Wheelchair users with chronic shoulder pain have few options after conservative treatments fail. This pilot study's purpose was to establish safety and treatment effects of micro-fragmented adipose tissue (MFAT) injections under ultrasound guidance for treatment of refractory shoulder pain caused by rotator cuff disease in wheelchair users with spinal cord injury (SCI) to prepare for a larger trial. DESIGN: Pilot clinical trial. SETTING: Rehabilitation hospital outpatient clinic. PARTICIPANTS: Ten wheelchair users with chronic SCI who had moderate-to-severe shoulder pain caused by refractory rotator cuff disease (diagnosed via ultrasound) for greater than 6 months. INTERVENTIONS: Ultrasound-guided injections of MFAT into the pathologic rotator cuff tendons and other abnormal shoulder structures (e.g. acromioclavicular and glenohumeral joints; subacromial bursa). OUTCOME MEASURES: 6- and 12-month changes in 11-point Numerical Rating Scale (NRS); Wheelchair User's Shoulder Pain Index (WUSPI); Brief Pain Inventory pain interference items (BPI-I7); Patient Global Impression of Change (PGIC); ultrasound and physical exams; and adverse events. CONCLUSIONS: There were no significant adverse events throughout the study period. WUSPI, NRS, and BPI-I7 scores were significantly lower 6 and 12 months post-procedure (P < .05). Of those who remained in the trial, clinically meaningful changes (≥30% decrease) in WUSPI, NRS, and BPI-I7 scores were observed in 77.8%, 77.8%, and 66.7% of participants, respectively. All but one participant reported improvement in clinical status. MFAT injection under ultrasound guidance is potentially a safe and efficacious treatment for refractory shoulder pain caused by rotator cuff disease in wheelchair users with SCI. A larger, randomized controlled trial has been initiated.Trial registration: ClinicalTrials.gov identifier: NCT03167138.

A Narrative Review Evaluating Extracorporeal Shockwave Therapy as a Potential Regenerative Treatment for Musculoskeletal Conditions in Military Personnel.

INTRODUCTION: Extracorporeal shockwave therapy (ESWT) has a wide variety of clinical applications ranging from urology to orthopedics. Extracorporeal shockwave therapy is of particular interest to military medicine in the treatment of diverse musculoskeletal injuries, including recalcitrant tendinopathy. Much of the evidence for ESWT is from studies in the civilian population, including athletes. A few investigations have been conducted within military personnel. Musculoskeletal conditions within military personnel may contribute to pain and physical limitations. Optimal functional outcomes could be achieved through ESWT. The purpose of this narrative review is to summarize the current evidence on the efficacy of ESWT the in management of lower extremity musculoskeletal injuries in the military. Further, we explore the relative efficacy of ESWT compared to regenerative medicine procedures, including studies with treatment using platelet-rich plasma. MATERIALS AND METHODS: A literature review was performed in April 2020 to identify studies evaluating the use of ESWT for lower extremity conditions commonly observed in military personnel, including plantar fasciitis, Achilles tendinopathy, patellar tendinopathy, medial tibial stress syndrome, and knee arthritis. The literature search was completed by two researchers independently, using PubMed and Embase databases and same search terms. Disagreements were adjudicated by a senior author. Due to the paucity of relevant search results, the search term parameters were expanded to incorporate active participants. RESULTS: Two studies evaluated the use of ESWT in a military population for lower extremity injuries. This included a randomized control trial in active military with medial tibial stress syndrome and an unblinded retrospective study for the chronic plantar fasciitis condition. Both studies in the military had favorable outcomes in the use of ESWT compared to other treatment arms. The remaining studies predominantly included athletes. Although heterogeneity on the quality of the studies may prevent meta-analysis and limit the generalization of the findings, the majority of studies demonstrated an improvement in pain and return to activity using ESWT. Two studies using platelet-rich plasma as a treatment arm identified similar short-term outcomes compared to ESWT for Achilles tendinopathy and patellar tendinopathy. CONCLUSION: Our findings suggest that ESWT is a safe and well-tolerated intervention with positive outcomes for lower extremity conditions commonly seen in the military. The few studies comparing ESWT to PRP suggest regenerative benefits similar to orthobiologics in the shorter term. More robust quality designed research may enable the evaluation of ESWT efficacy within the military population. In summary, the use of ESWT may provide pain reduction and improved function in active populations with lower extremity musculoskeletal injuries. Further research in the military is needed to evaluate shockwave efficacy in order to advance musculoskeletal care and improve outcomes.

Pain and functional outcomes of the sacroiliac joint after platelet-rich plasma injection: a descriptive review.

The purpose of this manuscript is to highlight and review the status of literature regarding efficacy of platelet-rich plasma (PRP) in the treatment of sacroiliac joint (SIJ) dysfunction. A review of the literature on PRP interventions on the SIJ or ligaments was performed. Seven studies had improvements in their respective primary end point and demonstrated a strong safety profile without any serious adverse events. Only five articles demonstrated clinical efficacy of >50% in their primary outcome measures. There appears to be inconsistent and insufficient evidence for a conclusive recommendation for or against SIJ PRP. There is a need for adequately powered well-designed, standardized, double-blinded randomized clinical trials to determine the effectiveness of PRP in SIJ-mediated pain.

Corticosteroids: Review of the History, the Effectiveness, and Adverse Effects in the Treatment of Joint Pain.

BACKGROUND: Corticosteroids have been used for the past 70 years in the treatment of various musculoskeletal conditions. This includes its use for joint pain such as rheumatoid arthritis and osteoarthritis. OBJECTIVES: A narrative review of the literature from its initial discovery to the present day to summarize the research of corticosteroids for joint pain to determine the safety and effectiveness of this commonly used and prescribed medication. METHODS: A review of the literature was performed regarding the effectiveness and side effects of corticosteroids for joint and osteoarthritis conditions. RESULTS: The current evidence would suggest that the use of corticosteroids provides moderate short-term benefit for reducing pain and improving functioning. These benefits generally last several weeks without long-term effectiveness. In addition to its limited short-term effectiveness, there are multiple potential adverse effects including toxicity to articular cartilage and numerous systemic side effects such as increases in blood glucose levels, a reduction in immune function, and an increased risk of infections. LIMITATIONS: English only articles were reviewed. No attempt was made to perform a formal statistical or meta-analysis. CONCLUSIONS: The current evidence would suggest that the use of corticosteroids provides moderate evidence for short-term pain reduction and improvement in function. There are multiple potential adverse effects, such as toxic damage to articular cartilage, as well as numerous systemic side effects, including a reduction in immune function and an increased risk of infection, of which physicians need to be aware.

Platelet-Rich Plasma Applications for Achilles Tendon Repair: A Bridge between Biology and Surgery.

Achilles tendon ruptures are very common tendon ruptures and their incidence is increasing in modern society, resulting in work incapacity and months off sport, which generate a need for accelerated and successful therapeutic repair strategy. Platelet-rich plasma (PRP) is emerging as adjuvant human blood-derived constructs to assist Achilles tendon rupture treatment. However, myriad PRP preparation methods in conjunction with poor standardization in the modalities of their applications impinge on the consistent effectiveness of clinical and structural outcomes regarding their therapeutic efficacy. The purpose of this review is to provide some light on the application of PRP for Achilles tendon ruptures. PRP has many characteristics that make it an attractive treatment. Elements such as the inclusion of leukocytes and erythrocytes within PRP, the absence of activation and activation ex vivo or in vivo, the modality of application, and the adjustment of PRP pH can influence the biology of the applied product and result in misleading therapeutic conclusions. The weakest points in demonstrating their consistent effectiveness are primarily the result of myriad PRP preparation methods and the poor standardization of modalities for their application. Selecting the right biological scaffold and applying it correctly to restitutio ad integrum of ruptured Achilles tendons remains a daunting and complex task.

Clinical evaluation of micro-fragmented adipose tissue as a treatment option for patients with meniscus tears with osteoarthritis: a prospective pilot study.

PURPOSE: The management of knee pain secondary to meniscal tears with osteoarthritis is limited by the poor inherent healing potential of the meniscus. Previous studies have reported on the benefit of autologous micro-fragmented fat as a therapeutic for various knee pathologies. The goal of this prospective pilot study was to determine the safety and potential treatment effect of micro-fragmented adipose tissue injection for patients with knee pain secondary to osteoarthritis and meniscal tears who have failed conservative management. METHODS: Twenty subjects with knee pain secondary to osteoarthritis with associated meniscal tear after failed conservative management were enrolled in the study. Numeric Pain Scale (NPS) and Knee Injury and Osteoarthritis Outcome Scale (KOOS) following ultrasound-guided intra-meniscal and intra-articular micro-fragmented adipose tissue injections were examined at three, six and 12 months. RESULTS: The mean NPS revealed a significant decrease in patient pain at the 1-year time point compared with baseline (5.45 to 2.21, p < .001). Similarly, overall, mean KOOS symptoms significantly improved from 57.7 to 78.2 (p < .001), with all 4 KOOS subscales demonstrating significant improvement at the final one year follow-up. One subject developed uncomplicated cellulitis at the harvest site which was treated with oral antibiotics. Other complications were minor and mostly limited to adipose harvest. CONCLUSION: This study demonstrated that micro-fragmented adipose tissue injected directly into a torn meniscus and knee joint using ultrasound guidance represents a safe and potentially efficacious treatment option for patients with knee pain suffering from degenerative arthritis and degenerative meniscal tears. A larger, randomized, controlled trial is warranted to determine efficacy. TRIAL REGISTRATION: Clinicaltrials.org Identifier: NCT03714659.