Increased Cellular Dosage of Bone Marrow Aspiration Concentrate Does Not Translate to Increased Clinical Effectiveness in Knee Osteoarthritis: A Phase I Dose Escalation Study.

Introduction: Knee osteoarthritis (KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the clinical efficacy and safety of varying BMAC dosages in knee OA treatment. Methods: This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10 × 106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100 × 106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include Visual Analog Scale (VAS) for pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) for joint function recorded at baseline, 1, 3, 6, and 12 months post-intervention. Adverse events were also documented. Results: Significant clinical improvements in VAS and KOOS scores were noted across all groups at all time points compared to the baseline. However, these improvements did not significantly differ between dosage groups throughout the follow-up period. Adverse effects were minimal and primarily consisted of transient post-injection pain and effusion, with no dose-dependent increase in complications. Conclusion: BMAC treatment for knee OA is safe and demonstrates potential for significant pain relief and functional improvement, irrespective of the dosage administered within the tested range. The lack of significant differences among varying dosages suggests a plateau in therapeutic efficacy beyond a certain threshold. Further research is necessary on the long-term outcomes to optimize the dosing strategy.

Effect of Cellular Dosage of Bone Marrow Aspiration Concentrate on the Radiological Outcomes in Knee Osteoarthritis: A Phase I Dose-Escalation Study.

Introduction: Knee osteoarthritis(KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the radiological outcomes of varying BMAC dosages in knee OA treatment. Methods: This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10x106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100x106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include magnetic resonance observation of cartilage repair tissue (MOCART 2.0) score to assess the cartilage. Results: We noted significant improvement in the overall MOCART score (p = 0.027) and subchondral change sub-score (p = 0.048) and defect filling sub-score (p = 0.025) in the medium- and high-dose cohorts compared to the low-dose cohort at 1 year follow-up. Although we noted positive correlation between the clinical and radiological outcome (r = 0.43), we did not find any significant different in the clinical outcome between the treatment groups. Conclusion: BMAC for OA knee resulted in significant improvement in the radiological scores compared to the baseline. Medium and high doses of BMAC result in significantly higher radiological scores compared to low-dose BMAC at 1 year. However, the radiological improvement did not translate into functional improvement, irrespective of the dosage administered at 1 year. Further research is necessary on the long-term outcomes to understand and optimize the dosing strategy based on clinico-radiological results.

Bone Marrow Aspirate Concentrate for Treatment of Primary Knee Osteoarthritis: A Prospective, Single-Center, Non-randomized Study with 2-Year Follow-Up.

Introduction: Knee osteoarthritis (OA) is a widespread, disabling condition with no intervention to fully restore cartilage or halt progression. Bone marrow aspirate concentrate (BMAC), an autologous product from bone marrow aspiration, has shown promise as a regenerative therapy due to its cell composition and chondrogenic effects. Our study aims to assess the functional outcomes, including pain, function, satisfaction, and complications post-BMAC injection in knee OA patients. Materials and Methods: In this prospective, single-center study, 63 patients with grade II-III knee OA (Kellgren-Lawrence (K-L) scale) unresponsive to conservative management underwent BMAC injection. The procedure involved bone marrow aspiration from the anterior iliac crest, processing to obtain a concentrate, followed by intra-articular injection. Patients were followed for 24 months, assessing outcomes using the Visual Analog Scale (VAS), International Knee Documentation Committee (IKDC) score, and MOCART 2.0 score. Results: The cohort, with a slight female predominance and predominantly aged 41-50 years, majorly comprised K-L grade III OA patients. BMAC treatment resulted in significant improvements in VAS pain scores, IKDC functional scores, and MOCART 2.0 scores over the 24-month follow-up. Conclusion: BMAC injection provides significant improvement in both pain and functional outcomes at mid-term follow-up in patients with mild-to-moderate OA of the knee. Further high-quality, adequately powered, multi-center, prospective, double-blinded, randomized controlled trials with longer follow-up are necessary to justify the routine clinical use of BMAC for treatment of patients suffering with knee OA.

Efficacy of stromal vascular fraction for knee osteoarthritis: A prospective, single-centre, non-randomized study with 2 years follow-up.

BACKGROUND: Current osteoarthritis (OA) treatments focus on symptom relief without addressing the underlying disease process. In regenerative medicine, current treatments have limitations. In regenerative medicine, more research is needed for intra-articular stromal vascular fraction (SVF) injections in OA, including dosage optimization, long-term efficacy, safety, comparisons with other treatments, and mechanism exploration. AIM: To compare the efficacy of intra-articular SVF with corticosteroid (ICS) injections in patients with primary knee OA. METHODS: The study included 50 patients with Kellgren-Lawrence grades II and III OA. Patients were randomly assigned (1:1) to receive either a single intra-articular SVF injection (group A) or a single intra-articular ICS (triamcinolone) (group B) injection. Patients were followed up at 1, 3, 6, 12, and 24 months. Visual analog score (VAS) and International Knee Documentation Committee (IKDC) scores were administered before the procedure and at all follow-ups. The safety of SVF in terms of adverse and severe adverse events was recorded. Statistical analysis was performed with SPSS Version 26.0, IBM Corp, Chicago, IL, United States. RESULTS: Both groups had similar demographics and baseline clinical characteristics. Follow-up showed minor patient loss, resulting in 23 and 24 in groups A and B respectively. Group A experienced a notable reduction in pain, with VAS scores decreasing from 7.7 to 2.4 over 24 months, compared to a minor reduction from 7.8 to 6.2 in Group B. This difference in pain reduction in group A was statistically significant from the third month onwards. Additionally, Group A showed significant improvements in knee functionality, with IKDC scores rising from 33.4 to 83.10, whereas Group B saw a modest increase from 36.7 to 45.16. The improvement in Group A was statistically significant from 6 months and maintained through 24 months. CONCLUSION: Our study demonstrated that intra-articular administration of SVF can lead to reduced pain and improved knee function in patients with primary knee OA. More adequately powered, multi-center, double-blinded, randomised clinical trials with longer follow-ups are needed to further establish safety and justify its clinical use.

Chondroblastoma of Metacarpal Masquerading as Enchondroma - A Case Report.

Introduction: Chondroblastoma is a rare and benign bone neoplasm that accounts for <1% of all bone tumors. Chondroblastomas of the hand are extremely rare, while enchondromas are the most common bone tumor of the hand. Case Report: A 14-year-old girl had complaints of pain and swelling over the base of her thumb for 1 year. On examination, a solitary and hard swelling was palpable over the base of the thumb, with terminal restriction of first metacarpophalangeal joint movements. Radiographs revealed an expansile and lytic lesion in the epiphyseal region of the first metacarpal. Chondroid calcifications were absent. Magnetic resonance imaging showed a lesion with the hypointense signal on T1 and T2 sequences. These suggested a diagnosis of enchondroma. Excisional biopsy of the lesion, bone grafting, and Kirschner wire fixation was performed. Histological examination showed the lesion to be a chondroblastoma. No recurrence was noted at the 1-year follow-up. Conclusion: Chondroblastomas can very rarely occur in the bones of the hand. In such cases, differentiating them from enchondromas and ABCs is a challenge. Characteristic chondroid calcifications may be absent in nearly half of such cases. Curettage with bone grafting provides a good outcome with no recurrence.

Autologous platelet-rich plasma in the delayed union of long bone fractures - A quasi experimental study.

Introduction: Fractures of long bones unite without any complication except for 2%-10% which may lead to delayed or non-union of the fracture. Management of delayed union of fractures poses a great challenge for orthopaedic surgeons. Platelet-rich plasma (PRP) is an autologous blood-derived biological agent, which delivers growth factors, cytokines, and bio-micro molecules at supraphysiologic concentrations at the site of tissue injury, thus potentiating the body's healing efforts. Various studies and research have proved the osteogenic activity of PRP. The growth factors present in the PRP induce the locally available resilient progenitor or stem cells and convert the atrophic environment into a trophic environment. Materials and methods: We investigated the safety and efficacy of autologous PRP injection in the delayed union of long bone fractures. A total of 25 cases of delayed union of long bone fractures were augmented with 3 doses of autologous PRP at 3 weekly intervals and were followed up for 12 months. All the cases were documented with pre-and post-procedural and 12th -month visual analog score (VAS) and Warden's score. Results: Out of 25 cases, 21 (84.00%) cases showed good union of fracture with adequate callus formation by 10-12 weeks with 3 doses of autologous PRP injections. The mean pre-procedural VAS and Warden's score at the final follow-up showed statistically significant results (p < 0.05). No other complications were noted due to autologous PRP application among the study participants during the study period except for 3 cases (2 cases of non-union, and 1 case of implant failure). Conclusion: Results of the current study suggest that autologous injection of PRP might be a safe and effective therapeutic tool for the management of delayed union of long bone fractures.

Pseudoarthrosis of the Femur Secondary to Tuberculosis: A Rare and First Report.

Tuberculosis poses a major health problem worldwide, and more so in developing countries. Tuberculosis will exist for as long as there are facets of malnutrition, poor sanitation, overcrowding, and immunocompromised populations. We report a rare case of pseudoarthrosis of the femur secondary to tuberculosis. A five-year-old female child presented with swelling, discharging sinuses, and abnormal mobility in the right lower one-third of the thigh secondary to trauma seven months ago. Incision, drainage, and debridement were done, and the obtained pus showed no growth. The sample turned out to be acid-fast bacilli-positive. The patient was on anti-tubercular drugs for six months and had a protective plaster cast for about six weeks, following which knee mobilization was started. During knee mobilization, the patient underwent a forced manipulation of the lower end of the femur, and the radiograph revealed a pathological fracture for which one-and-a-half hip-spica was applied. Further radiographs revealed an un-united fracture after three months despite hip spica application, and a pseudoarthrosis of the right distal femur developed, for which non-vascularized fibular strut grafting for pseudoarthrosis of the distal third of the femur was performed and stabilized with two 2.5 mm-long K-wires supplemented with hip spica for six months. The patient was followed up regularly, and subsequent radiographs showed fibular uptake and resolution of pseudoarthrosis of the femur at the eighth-month follow-up. The patient showed complete resolution of pseudoarthrosis and an excellent functional outcome by the end of the two-year follow-up.

Current understanding of MSC-derived exosomes in the management of knee osteoarthritis.

Mesenchymal stem cell-derived exosomes (MSC-Exos) have been utilized as medicinal agents or as delivery vehicles in cartilage injuries and cartilage-based diseases. Given the ongoing emergence of evidence on the effector mechanisms and methods of the utility of the MSC-Exos in knee osteoarthritis, a comprehensive review of the current evidence is the need of the hour. Hence, in this article, we review the current understanding of the role of MSC-Exos in the management of knee osteoarthritis in view of their classification, characterization, biogenesis, mechanism of action, pathways involved in their therapeutic action, in-vitro evidence on cartilage regeneration, in-vivo evidence in OA knee models and recent advances in using MSC-Exos to better streamline future research from bench to bedside for OA knee.

Impact of the Process Variables on the Yield of Mesenchymal Stromal Cells from Bone Marrow Aspirate Concentrate.

Human bone marrow (BM) has been highlighted as a promising source of mesenchymal stromal cells (MSCs) containing various growth factors and cytokines that can be potentially utilized in regenerative procedures involving cartilage and bone. However, the proportion of MSCs in the nucleated cell population of BM is only around 0.001% to 0.01% thereby making the harvesting and processing technique crucial for obtaining optimal results upon its use in various regenerative processes. Although several studies in the literature have given encouraging results on the utility of BM aspiration concentrate (BMAC) in various regenerative procedures, there is a lack of consensus concerning the harvesting variables such as choice of anesthetic agent to be used, site of harvest, size of the syringe to be used, anticoagulant of choice, and processing variables such as centrifugation time, and speed. In this review article, we aim to discuss the variables in the harvesting and processing technique of BMAC and their impact on the yield of MSCs in the final concentrate obtained from them.

Does vehicle-based delivery of mesenchymal stromal cells give superior results in knee osteoarthritis? Meta-analysis of randomized controlled trials.

STUDY DESIGN: Meta-analysis. OBJECTIVES: We aim to analyze and compare the efficacy and safety of vehicle-based delivery of Mesenchymal Stromal Cells (MSCs) in the management of osteoarthritis of the knee from Randomized Controlled Trials (RCTs) available in the literature. MATERIALS AND METHODS: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library till August 2021 for RCTs analyzing the efficacy and safety of vehicle-based delivery of MSCs in the management of knee osteoarthritis. Visual Analog Score (VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and adverse events were the outcomes analyzed. Analysis was performed in R-platform using OpenMeta [Analyst] software. RESULTS: 21 studies involving 936 patients were included for analysis. None of the studies made a direct comparison of the direct and vehicle-based delivery of MSCs, hence we pooled the results of all the included studies of both groups and made a comparative analysis of their outcomes. Although at 6 months, both direct and vehicle-based delivery of MSCs showed significantly better VAS improvement (p = 0.002, p = 0.010), it was not consistent at 1 year for the vehicle delivery (p = 0.973). During 6 months and 12 months, direct delivery of MSCs (p < 0.001, p < 0.001) outperformed vehicle delivery (p = 0.969, p = 0.922) compared to their control based on WOMAC scores respectively. Both direct (p = 0.713) and vehicle-based delivery (p = 0.123) of MSCs did not produce significant adverse events compared to their controls. CONCLUSION: Our analysis of literature showed that current clinically employed methods of vehicle-based delivery of MSCs such as platelet-rich plasma, hyaluronic acid did not demonstrate superior results compared to direct delivery, concerning the efficacy of treatment measured by improvement in pain, functional outcomes, and safety. Hence, we urge future clinical trials to be conducted to validate the effectiveness of advanced delivery vehicles such as composite bioscaffolds to establish their practical utility in cartilage regeneration with respect to its encouraging in-vitro evidence.