Bone Marrow Aspirate Concentrate to Treat Ankle Osteoarthritis: A Narrative Review of Progress and Challenges.

Objectives:Bone marrow aspirate concentrate (BMAC) is an autologous orthobiologic agent that has become an emerging area of interest in orthopaedic surgery. Past literature investigating hip arthroscopy outcomes revealed that patients undergoing acetabular labral repair with BMAC augmentation achieve significantly greater improvements in all PROMs at 12- and 24-month follow-up compared to a control cohort. Despite its promise, there remains a paucity of literature on BMAC’s effects on THA-free survivorship, particularly at mid-term follow-up. Furthermore, a widespread concern is the high and variable costs of BMAC augmentation. As the utilization of BMAC in clinical practice continues to rise, it is imperative that sports medicine surgeons ensure that BMAC is both efficacious and cost-effective for patients. The purpose of the present study was to investigate if BMAC is an efficacious and cost-effective adjuvant therapy for preventing mid-term conversion to THA following arthroscopic acetabular labral repair.Methods:This was a retrospective cohort study of patients < 50 years old with minimum 2-year follow-up who underwent arthroscopic repair of symptomatic acetabular labral tears. Patients were placed into BMAC or No BMAC cohorts according to whether they received BMAC at the time of repair. Besides BMAC augmentation, there were no differences in surgical technique, indications, or post-operative rehabilitation between cohorts. The primary outcome was quality-adjusted life years (QALYs) gained between BMAC and No BMAC patients, as measured by THA-free survivorship. Kaplan-Meier survival curve analysis was performed to calculate QALYs gained during the study’s time horizon, defined as the longest follow-up timepoint reached by a BMAC patient. Secondary outcomes included the incremental cost-effectiveness ratio (ICER) [Cost of Intervention #1 – Cost of Intervention #2]/[Intervention #1 QALYs – Intervention #2 QALYs], BMAC’s estimated cost to be considered a cost-effective treatment, and independent risk factors for THA-free survivorship. Our institutional OOP price for BMAC is $10,000 – inclusive of all costs associated with harvesting, processing, and application. BMAC was considered cost-effective if its ICER was below a willingness-to-pay (WTP) threshold of $50,000. Sensitivity analyses were performed to estimate BMAC cost-effectiveness at varying prices and QALYs gained.Results:358 (BMAC: 124 [34.6%] vs. No BMAC: 234 [65.4%]) patients met inclusion/exclusion criteria (Table 1 and 2). When performing an adjusted Kaplan-Meier survival analysis controlling for sex, labral tear size, and type of FAI, BMAC and No BMAC patients had 100.0% and 88.8% (P = .117) 6.16-year THA-free survival probabilities, respectively. A weighted Cox regression controlling for the same variables suggests that – while not statistically significant – No BMAC patients had a 372% increased risk of converting to THA (HR: 0.21 [0.03-1.69]; P = .144). QALYs were calculated by multiplying the survival probabilities (Figure 1) with the number of patients at risk at each THA conversion (Table 3). BMAC was associated with approximately 0.233 QALYs gained (BMAC: 6.162 vs. No BMAC: 5.929). Given the only procedural differences between cohorts was the $10,000 OOP cost of BMAC augmentation, BMAC had an ICER of $42,935.43 [BMAC Costs ($10,000)]/[QALYs Gained (0.233)]. At a WTP threshold of $50,000, BMAC was cost-effective by an ICER of $7,064.57. A sensitivity analysis controlling for a treatment price of $10,000 indicates that BMAC can be considered cost-effective if it leads to 0.200 QALYs gained. At a price of $3,000 and $5,000, BMAC must improve QALYs by 0.060 and 0.100, respectively, to be considered a cost-effective treatment.Conclusions:Given the growing volume of literature investigating the efficacy of hip arthroscopy for joint preservation, identifying adjuvant therapies with the potential to safely prolong the longevity of acetabular labral repairs and delay the progression of joint degeneration is crucial. At an institutional cost of $10,000, BMAC had an ICER of $42,935.43 and was below the WTP threshold by $7,064.57. These findings reveal that BMAC is a cost-effective treatment that has the potential to significantly improve THA-free survivorship following arthroscopic acetabular labral repair.

Objectives:Bone marrow aspirate concentrate (BMAC) is a commonly clinically used cell source for muscular skeletal injury repair. However, it is often required multiple injections with multiple harvests which caused pain for patient. Therefore, one harvest and multiple injections will be desired, but this process requires frozen (banking) stem cells. The objective of this study is to determine whether the articular cartilage regenerative potential of BMAC will be affected by the cryopreservation technique using destabilized medial meniscus (DMM) model.Methods:Preparation of fresh and frozen BMAC. Bone marrow was drawn from patients’ iliac crest. BMAC was prepared according to the standard clinical protocol. BMAC was then split into fresh and frozen portions. For the fresh-BMAC group, 100ul of BMAC was injected into the injured knee at 4 weeks after DMM. For frozen-BMAC group, BMAC was frozen by separating cells and plasma. Briefly, BMAC was spun down, plasma was aspirated in separate tubes and frozen directly. Cells were frozen in a freezing medium with 10% DMSO for 4 weeks. When it’s time for injection, we thawed the cells, removed DMSO, combined with frozen plasma, and injected same living cell number and volume as fresh BMAC based on the cell viability after cryopreservation. In vivo osteoarthritis (OA)induction using DMM model and BMAC treatment. 12 weeks female RNU nude rats were divided into 3 groups (N=10/group), group 1, PBS; group 2, Fresh-BMAC; group 3, Frozen-BMAC. This study was approved by IACUC. All rats were subjected to DMM surgery by following the previous published method. When OA was developed at 4 weeks after surgery, PBS, Fresh BMAC and frozen BMAC were injected into the knee joints. Rats were sacrificed at 8 weeks after injection and rat knee diameter were measured before dissection. 5 rats from each group were dissected to separate femur and tibia and observed grossly and imaged. After imaging, articular cartilage was dissected for RNA extraction from both tibia plateau and femur condyle, cDNA synthesis and Q-PCR were subsequently performed. Micro-CT scan and histology: Another 5 rats from each group were fixed in formalin for 5 days and subjected to micro-CT scan for proximal tibia. After Micro-CT scanning, rat knees were decalcified using formic acid and processed and sagittal section were cut for histology. Histology was conducted according to previously described protocol [1-3].Statistical analysis: All data were analyzed using GraphPad Prism 10 software. P<0.05 was considered statistically significant.Results:Both fresh and frozen BMAC improved macroscopic core of tibia plateau cartilage. 8 weeks after BMAC treatment, we measured knee diameter. We found both fresh-BMAC and frozen-BMAC treatment decreased knee diameter of nude rats compared to PBS treated group (Fig.1A). Fresh-BMAC and frozen BMAC treatment also improved femur condyle macroscopic score, but there is no significant difference compared to PBS group (Fig.1B, C). However, both fresh and frozen BMAC significantly improved tibia plateau cartilage macroscopic score compared to PBS group, but no significant was found between Fresh-BMAC and Frozen-BMAC (Fig.1D, E). Q-PCR results showed both fresh-BMAC and frozen-BMAC treatment groups significantly decreased MMP9 mRNA expression in the injured articular cartilage (Fig.1F). Fresh-BMAC and Frozen-BMAC group also showed a trend of decreasing MMP13 expression (Fig.1G). Fresh-BMAC and frozen-BMAC treatment did not significantly affect epiphysis and subchondral bone. We performed Micro-CT scanning and quantified the epiphysis and subchondral bone microarchitecture of both lateral and medial side of tibia plateau. We found no significant difference of all bone microarchitecture parameters of lateral epiphysis, subchondral bone and medial epiphysis trabecular bone. We only found PBS group showed trend of decreasing trabecular number in the medial subchondral bone (Fig.2A-F). BMAC treatment improved histology score of tibia plateau cartilage, no difference was found between fresh and frozen BMAC. We further performed Safranin O staining to detect cartilage matrix glycosaminoglycan (GAG). We found that fresh-BMAC and frozen-BMAC groups had majority of the cartilage repaired with GAG positive cartilage when compared to PBS group. OARSI histology score quantification indicated fresh-BMAC and frozen-BMAC groups had significantly lower OARSI score than PBS group, but no significant difference between fresh and frozen BMAC treatment (Fig.3A, D). Furthermore, we performed alcian blue staining to detect hyaluronic acid and acid mucin, the result was similar as we observed in Safranin O staining (Fig.3B). Immunohistochemistry staining of collagen 2 demonstrated significant loss of collagen 2 in PBS group, while strong collagen 2 staining in was found in both chondrocytes and extracellular matrix in BMAC treated groups (Fig.3C). Importantly, no significant difference was found between fresh and frozen BMAC treatment.Conclusions:In summary, we found frozen BMAC can maintain similar function as fresh BMAC for cartilage repair after being frozen for one month.

Articular defects are a major problem with few effective treatment options. Osteochondral allograft (OCA) transplantation can be an effective treatment; however, lack of OCA bone integration can cause failure. This controlled laboratory study was designed to compare clinically applicable methods for marrow element removal and enhanced delivery of bone marrow aspirate concentrate (BMC) to OCA bone. We hypothesized that compressed carbon dioxide (CO2) treatment of OCA bone would result in significantly better marrow element removal, significantly more retention and distribution of viable osteoprogenitor cells, and significantly higher osteoinductive protein elution from OCAs compared with other preimplantation treatments. Fresh humeral heads (n = 24) were harvested and stored for 14 days, then randomly assigned to treatment based on marrow element removal and bone treatment: (standard of care [SOC]) (n = 4) - SOC high-pulse saline lavage, no BMC; (BMC) (n = 5) - saline lavage then canine BMC; (Drill + BMC) (n = 5) - 1.1 mm drill-hole immediately subchondral then saline lavage then BMC injection through drill hole; (Carb + BMC) (n = 5) - saline lavage then CO2 then BMC; or (Saline-Carb + BMC) (n = 5) - saline lavage and CO2 together then BMC. Treated OCAs were cultured for 14 days. On day 3, media were collected, centrifuged to isolate cells, and replaced. Cells were cultured for 11 days for colony forming unit (CFU) determination. OCA media were collected on days 7 and 14 of culture for analysis. On day 14, each graft was assessed for viable cell retention and distribution, and bone marrow element removal. BMC had significantly higher (p = 0.001) viable cell distribution compared with the SOC, Drill + BMC, Carb + BMC, and Saline-Carb + BMC groups. BMC and Drill + BMC had significantly higher (p < 0.05) CFUs than SOC, Carb + BMC, and Saline-Carb + BMC. Drill + BMC and Carb + BMC had the highest media concentrations of the osteoinductive biomarkers. The Carb + BMC and Saline-Carb + BMC groups were associated with significantly superior marrow element removal (p < 0.02) compared with the SOC, Drill + BMC, and BMC groups. Saline irrigation plus saturation with autogenous BMC appears to be the most advantageous preimplantation treatment for OCA transplantation.

Background: Knee injection using either bone marrow aspirate concentrate (BMAC) or stromal vascular fraction (SVF) from adipose tissue has been shown to result in symptomatic improvement in patients with knee osteoarthritis (OA). It is still unclear whether one of these therapies is superior over the other. Purpose: To systematically report the clinical studies evaluating BMAC and SVF in the treatment of knee OA and to compare the clinical efficacy of these 2 injection therapies. Study Design: Meta-analysis; Level of evidence, 4. Methods: This meta-analysis was performed per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Studies were included if they reported the clinical outcomes after a single BMAC or SVF injection in the knee joint of patients with OA. Studies evaluating preparations of culture-expanded stem cells were excluded. A random effects model was used; the clinical efficacy of BMAC or SVF injection was assessed using the standardized mean difference (SMD) and compared. Visual analog scale (VAS) scores for pain and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) knee index were the primary outcomes. The level of statistical significance was set at P < .05. Results: Ten studies and 472 patients with knee OA who received either BMAC (233 patients) or SVF (239 patients) were included. Patients who received an injection had improved VAS outcomes (mean ± SD): from 5.8 ± 1.3 to 2.6 ± 17 for BMAC and from 6.4 ± 1.4 to 3.4 ± 0.5 for SVF. They also experienced significantly reduced pain (SMD [VAS], 2.6 for BMAC and 3.4 for SVF) and improved function (SMD [WOMAC], 1.4 for BMAC and 1.2 for SVF). However, the SVF injection had a significantly greater effect on pain reduction than did the BMAC injection (P < .0001). Based on WOMAC, the clinical effect of BMAC versus SVF knee injection in patients with knee OA was equivalent (P = .626). Results were limited by the presence of publication bias as well as variability in the preparation methods utilized in the BMAC and SVF injection protocols. Complications were reported in 50% of the BMAC studies (knee stiffness, persistent knee swelling) and 67% of the SVF studies (knee swelling, knee pain, positive SVF cultures without symptoms of infection, and bleeding at the abdominal harvest site). Conclusion: A single BMAC or SVF injection into the knee joint of patients with OA resulted in symptomatic improvement at short-term follow-up. However, SVF seemed to be more effective than did BMAC in the reduction of knee pain. There was significant variation in the BMAC and SVF injection preparation techniques used across the studies and a lack of stratification of outcomes based on the radiologic classification of OA. Therefore, these results should be taken with caution.

Despite the high prevalence of osteoarthritis (OA), there remains a need for additional therapeutic options. Cellular therapies with minimally manipulated cells such as bone marrow aspirate concentrates (BMAC) are increasingly popular in the U.S. but clear-cut evidence of efficacy has not been established. In theory, BMAC injections provide a source of stromal cells to stimulate healing in OA and ligamentous injuries; however, BMAC injections are also often associated with inflammation, short-term pain, and mobility impairment. Given that blood is known to trigger inflammation in joints, we hypothesized that removing erythrocytes [red blood cells (RBCs)] from BMAC preparations prior to intra-articular injection would improve efficacy for OA treatment. To test this hypothesis, BMAC was collected from the bone marrow of mice. Three treatment groups were pursued: (I) untreated; (II) BMAC; or (III) BMAC depleted of RBCs by lysis. Product was injected into the femorotibial joint of mice 7 days after OA had been induced by destabilization of the medial meniscus (DMM). To assess the impact of treatment on joint function, individual cage monitoring (ANY-mazeTM) and Digigait treadmill-based analyses were performed over 4 weeks. At study completion, joint histopathology was assessed and immune transcriptomes within joint tissues were compared using a species-specific NanoString panel. Significant improvements in activity, gait parameters, and histology scores were seen in animals receiving RBC-depleted BMAC compared to untreated mice; animals treated with non-depleted BMAC did not demonstrate this same extent of consistent significant improvement. Transcriptomic analysis of joint tissues revealed significant upregulation of key anti-inflammatory genes, including interleukin-1 receptor antagonist (IRAP), in mice treated with RBC-depleted BMAC compared to animals treated with non-RBC depleted BMAC. These findings indicate that RBC depletion in BMAC prior to intra-articular injection improves treatment efficacy and reduces joint inflammation compared to BMAC.

Background:Osteoarthritis (OA) poses a significant global burden, with conventional treatments like corticosteroid and hyaluronic acid (HA) injections commonly used. Emerging injectable biologics, including bone marrow aspirate concentrate (BMAC), show promise in OA management.Purpose:To investigate the clinical efficacy of BMAC injection compared with other injection treatments for knee OA.Study Design:Systematic review; Level of evidence, 1.Methods:A systematic review was conducted using PubMed, Embase, Cochrane Library, and Google Scholar to identify randomized controlled trials with Level 1 evidence that compared the clinical efficacy of BMAC with other injections. The visual analog scale for pain and the Pain subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) were used as clinical scores representing pain. For functional assessment, the Western Ontario and McMaster Universities Osteoarthritis Index and the International Knee Documentation Committee subjective form were used. For studies comparing BMAC with HA, each clinical score was standardized to pain and function scales based on the minimal clinically important difference (MCID).Results:Eight studies, consisting of a total of 937 patients, were included. Patients treated with BMAC showed a significant improvement in clinical scores compared with baseline, starting at 1 month postinjection. For pain scores at 6-month (P = .033) and 12-month follow-up (P = .011), BMAC demonstrated favorable results over HA, with a statistically significant difference. However, these differences did not exceed the MCID. When BMAC was compared with other injections, no significant differences were observed in the degree of clinical score improvement. No serious adverse events or events significantly associated with BMAC compared with other treatments were reported.Conclusion:BMAC injections demonstrated effectiveness in providing pain relief and functional improvement for patients with knee OA. When BMAC was compared with other intra-articular injection options, distinct differences surpassing the MCID were not evident. Further research is deemed necessary to investigate the role of BMAC in the treatment of knee OA.

Background:Approximately 47 million people in the United States have been diagnosed with arthritis. Autologous platelet-rich plasma (PRP) injections have been documented to alleviate symptoms related to knee osteoarthritis (OA) in randomized controlled trials, systematic reviews, and meta-analyses. Autologous bone marrow aspirate concentrate (BMC) injections have also emerged as a treatment option for knee OA, with a limited clinical evidence base.Purpose:To compare the efficacy of BMC to PRP for the treatment of knee OA regarding pain and function at multiple time points up to 12 months after an injection. We hypothesized that BMC will be more effective in improving outcomes in patients with knee OA.Study Design:Randomized controlled trial; Level of evidence, 2Methods:A total of 90 participants aged between 18 and 80 years with symptomatic knee OA (Kellgren-Lawrence grades 1-3) were randomized into 2 study groups: PRP and BMC. Both groups completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subjective International Knee Documentation Committee (IKDC) questionnaires before and 1, 3, 6, 9, and 12 months after a single intra-articular injection of leukocyte-rich PRP or BMC.Results:There were no statistically significant differences in baseline IKDC or WOMAC scores between the 2 groups. All IKDC and WOMAC scores for both the PRP and BMC groups significantly improved from baseline to 1 month after the injection (P < .001). These improvements were sustained for 12 months after the injection, with no difference between PRP and BMC at any time point.Conclusion:Both PRP and BMC were effective in improving patient-reported outcomes in patients with mild to moderate knee OA for at least 12 months; neither treatment provided a superior clinical benefit. Autologous PRP and BMC showed promising clinical potential as therapeutic agents for the treatment of OA, and while PRP has strong clinical evidence to support its efficacy, BMC has limited support. This study did not prove BMC to be superior to PRP, providing guidance to clinicians treating OA. It is possible that the results were affected by patients knowing that there was no control group.Registration:NCT03289416 (ClinicalTrials.gov identifier).

Objectives: There continues to be a general lack of consensus regarding the optimal treatment for osteochondral lesions of the talus (OLTs). Microfracture, once considered the gold-standard, has been associated with poor long-term results due to the formation of biomechanically inferior reparative fibrocartilage as opposed to hyaline cartilage. Particulate allogenic cartilage extracellular matrix offers a promising solution as an adjuvant therapy; however, there is currently minimal objective evidence to indicate its effect on post-operative outcomes. This study compares post-operative radiographic and clinical outcomes following treatment of OLTs with an adjuvant mixture of particulate cartilage extracellular matrix and bone marrow aspirate concentrate (BMAC) against outcomes following microfracture with or without BMAC. Methods: Patients diagnosed with an OLT and treated by a fellowship-trained orthopedic surgeon were screened for inclusion. Those whose surgical intervention included microfracture, microfracture augmented with BMAC alone, or microfracture augmented with a mixture of BMAC and particulate allogenic cartilage extracellular matrix were eligible for this case-control study. Lesion size, location, and concurrent injuries were recorded following retrospective chart review. Foot and Ankle Outcome Scores (FAOS) were collected pre-operatively and at a minimum of 1 year post-operatively through the prospective Registry database at the authors’ institution. Modified magnetic resonance observation of cartilage repair tissue (MOCART) scoring evaluated the structural quality of repaired lesions on MRIs collected greater than six months post-operatively. Differences in post-operative MOCART and FAOS scores were evaluated using ANOVA tests. Results: Forty-seven patients treated with microfracture alone, forty-seven treated with microfracture augmented by BMAC, and fifty-two treated with an adjuvant mixture of particulate allogenic cartilage extracellular matrix and BMAC were identified at a minimum of 2 years post-operatively. Average MOCART scores were significantly different between treatment groups (p=0.03). At an average follow-up of 10.86 months, patients who received adjunctive therapy had an average MOCART score of 73.5 ± 11.13. At an average follow-up of 23.06 months and 43.6 months respectively, patients treated with microfracture and BMAC and microfracture alone scored 63.33 ± 22.23 and 55 ± 23.92. There was no detectable statistically significant difference in post-operative FAOS scores between treatment groups. With respect to revision surgery, two patients (3.84%) originally treated with adjuvant particulate cartilage extracellular matrix and BMAC have required a secondary surgery as opposed to nine patients (9.57%) treated with microfracture and BMAC or microfracture alone. Conclusion: Increases in post-operative FAOS scores compared to pre-operative FAOS scores for all treatment groups indicate patients’ function and symptoms improved regardless of intervention received. However, significantly higher MOCART scores for the particulate cartilage extracellular matrix and BMAC treatment group suggest adjuvant treatment may help achieve better post-operative fill and structural integrity. Thus, long-term outcomes and the quality of reparative tissues may be improved through use of adjuvant treatments such as particulate allogenic cartilage extracellular matrix and BMAC.

Objectives:Bone marrow aspirate concentrate (BMAC) is one type of orthobiologic that has gained increased popularity over the last decade for a variety of orthopedic procedures. Multiple factors have been demonstrated to influence the MSCs concentration and chondrogenic potential in BMA and thus BMAC, ranging from aspiration location to amount extracted to peripheral blood platelet count. Some studies have suggested that age may affect chondrogenic potential of BMAC derived MSCs but may not affect initial MSC concentration. Therefore, the purpose of this study was to 1) investigate the concentration value and variance BMAC content and 2) investigate the effects of donor age, sex, and other demographic factors on the amount of MSCs as measured by flow cytometry in bone marrow aspirate concentrate (BMAC).Methods:A review of patients who underwent BMAC treatment as part of a clinical trial were enrolled and complete BMAC flow cytometry data were included in analysis. Chart review was performed to identify patient demographic factors to determine their relationship to flow cytometry cell count. Flow cytometry was performed on both patient bone marrow aspirate (BMA) and BMAC samples to identify multipotent MSC phenotype defined as cell-surface co-expression of the antigens CD105, CD73, and CD90 (≥95% positive) and the absence of hematopoietic lineage markers CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR (≤2% positive). The ratio of cells in BMA: BMAC samples was calculated, and Spearman correlations and Kruskall-Wallis tests were used to determine the relationship of cell concentration to demographic factors.Results:A total of 80 patients were included in analysis (49% male, mean age: 49.93±12.17 years). Mean concentration of BMA and BMAC was 2,048.13±2,004.14 MSCs/mL and 5618.87±7568.54 MSC/mL, respectively, with a mean BMAC:BMA ratio of 4.35 ± 2.09 (Figure 1). A significantly higher MSC concentration was observed in the BMAC samples (P=0.005). No patient demographic factors (age, sex, height, weight, BMI, smoking status) significantly impacted MSC concentration in the BMAC samples.Conclusions:This study validates that BMAC concentrates and increases MSCs from BMA approximately four-fold. In addition, in opposition to our hypothesis, no demographic factors affected the final number of MSCs observed with flow cytometry analysis. These preliminary results suggest that BMAC successfully concentrates BMA and provides a higher number of MSCs. Baseline patient characteristics likely have minimal effects on the number and concentration of MSCs in BMAC, and therefore may not limit patient selection for BMAC for clinical use.Figure 1.Distribution of the ratio of BMAC to BMA

Background and objectives: Cartilage regeneration using mesenchymal stem cells (MSCs) has been attempted to improve articular cartilage regeneration in varus knee osteoarthritis (OA) patients undergoing high tibial osteotomy (HTO). Bone marrow aspirate concentrate (BMAC) and human umbilical cord blood-derived MSCs (hUCB-MSCs) have been reported to be effective. However, whether BMAC is superior to hUCB-MSCs remains unclear. This systematic review and meta-analysis aimed to determine the clinical efficacy of cartilage repair procedures with BMAC or hUCB-MSCs in patients undergoing HTO. Materials and Methods: A systematic search was conducted using three global databases, PubMed, EMBASE, and the Cochrane Library, for studies in which the clinical outcomes after BMAC or hUCB-MSCs were used in patients undergoing HTO for varus knee OA. Data extraction, quality control, and meta-analysis were performed. To compare the clinical efficacy of BMAC and hUCB-MSCs, reported clinical outcome assessments and second-look arthroscopic findings were analyzed using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results: The present review included seven studies of 499 patients who received either BMAC (BMAC group, n = 169) or hUCB-MSCs (hUCB-MSC group, n = 330). Improved clinical outcomes were found in both BMAC and hUCB-MSC groups; however, a significant difference was not observed between procedures (International Knee Documentation Committee score; p = 0.91, Western Ontario and McMaster Universities OA Index; p = 0.05, Knee Society Score (KSS) Pain; p = 0.85, KSS Function; p = 0.37). On second-look arthroscopy, the hUCB-MSC group showed better International Cartilage Repair Society Cartilage Repair Assessment grade compared with the BMAC group (p < 0.001). Conclusions: Both BMAC and hUCB-MSCs with HTO improved clinical outcomes in varus knee OA patients, and there was no difference in clinical outcomes between them. However, hUCB-MSCs were more effective in articular cartilage regeneration than BMAC augmentation.

Background: Knee osteoarthritis is the most common musculoskeletal progressive disorder that affects nearly 303 million people worldwide. This condition prevails in 10% males and 13% females among the elders above 60. Although there is conventional nonsurgical and surgical treatment available for knee osteoarthritis, there is a fascinating interest in bone marrow aspirate concentrate (BMAC) as well as adipose-derived mesenchymal stem cells (AD-MSC), including enzymatically treated stromal vascular fraction (SVF) and mechanically treated (microfat/nanofat) injections among physicians. Hence, this systematic review aims to determine the efficacy of BMAC and AD-MSCs (enzyme and mechanically treated) injections for knee osteoarthritis treatment. Methods: A systematic review was performed on the following data sources (PubMed, Scopus, Google Scholar, EMBASE, and Cochrane Library) published on March 31, 2021. The keywords or MeSH terms include 'Knee Osteoarthritis with 'Bone marrow aspirate concentrate' OR 'BMAC' or with 'Adipose-derived mesenchymal stem cells (AD-MSC)' or with 'Stromal vascular fraction' OR 'SVF' or 'Mechanically treated AD-MSC (mfat/nanofat)'. In addition, the retrieved articles were further reviewed to identify relevant research studies. Results: The authors reviewed and tabulated data based on the year of study, study type, therapy protocol, patient population, outcome measures, and interpretation. Among the 382 records screened, 43 studies (16 on BMAC and 27 on AD-MSCs) were included in the systematic review study. Among them, only 5 were randomized controlled trials. These selected studies demonstrated short-term positive outcomes such as improvement in knee pain and function with no adverse side effects. Moreover, researchers reported varied administration methods of BMAC or AD-MSC either as standalone or in combination with other conservative procedures such as PRP (Platelets Rich Plasma), HA (Hyaluronic acid), or surgery. Conclusions: BMAC and AD-MSC (enzymatically and mechanically treated) injections prove safer and more efficacious in patients with knee osteoarthritis for a shorter duration of 2 years. However, the available literature lacks high-quality studies with no varied clinical settings and long-term follow-up of more than two years.

Background: In the last decade, regenerative therapies have become one of the leading disease modifying options for treatment of knee osteoarthritis (OA). Still, there is a lack of trials with a direct comparison of different biological treatments. Our aim was to directly compare clinical outcomes of knee injections of Bone Marrow Aspirate Concentrate (BMAC), Platelet-rich Plasma (PRP), or Hyaluronic acid (HA) in the OA treatment. Methods: Patients with knee pain and osteoarthritis KL grade II to IV were randomized to receive a BMAC, PRP, and HA injection in the knee. VAS, WOMAC, KOOS, and IKDC scores were used to establish baseline values at 1, 3, 6, 9, and 12 months. All side effects were reported. Results: A total of 175 patients with a knee osteoarthritis KL grade II-IV were randomized; 111 were treated with BMAC injection, 30 with HA injection, and 34 patients with PRP injection. There were no differences between these groups when considering KL grade, BMI, age, or gender. There were no serious side effects. The mean VAS scores after 3, 7, 14, and 21 days showed significant differences between groups with a drop of VAS in all groups but with a difference in the BMAC group in comparison to other groups (p < 0.001). There were high statistically significant differences between baseline scores and those after 12 months (p < 0.001) in WOMAC, KOOS, KOOS pain, and IKDC scores, and in addition, there were differences between these scores in the BMAC group in comparison with other groups, except for the PRP group in WOMAC and the partial IKDC score. There were no differences between the HA and PRP groups, although PRP showed a higher level of clinical improvement. Conclusions: Bone marrow aspirate concentrate, Leukocyte rich Platelet Rich Plasma, and Hyaluronic acid injections are safe therapeutic options for knee OA and provide positive clinical outcomes after 12 months in comparison with findings preceding the intervention. BMAC could be better in terms of clinical improvements in the treatment of knee OA than PRP and HA up to 12 months. PRP provides better outcomes than HA during the observation period, but these results are not statistically significant. More randomized controlled trials and high quality comparative studies are needed for direct correlative conclusions.

Objectives:Preliminary findings in the literature suggest that treatment with bone marrow aspirate concentrate (BMAC) at the time of hip arthroscopy is a potentially viable solution to improve outcomes in patients with cartilage degradation concomitant to acetabular labral tearing; however, functional scores to date have not eclipsed 24 months. Therefore, the present study compares minimum five-year outcomes in patients treated with or without BMAC augmentation to address chondral damage during arthroscopic labral repair.Methods:This is a case-control study analyzing prospectively collected data in patients who underwent acetabular labral repair from a single surgeon between May 2014 and January 2019. Patients were stratified into either the 1) BMAC cohort or the 2) control cohort depending on whether or not BMAC was used to address chondrolabral junction breakdown secondary to femoroacetabular impingement (FAI) and labral tearing during surgery. Patients were only included for data analysis if they: 1) underwent primary acetabular labral repair on their affected hip and 2) completed PROMs preoperatively and at 60 months after surgery. Exclusion criteria consisted of: 1) previous ipsilateral hip arthroscopy; 2) labral debridement; 3) a lateral center edge angle (LCEa) of <20º; and 4) <5 years of follow-up. Univariate analyses were performed using unpaired t test and chi-square/Fisher exact test as appropriate to draw baseline comparisons between groups. Informed by these unadjusted analyses, primary regressions included the following variables as fixed effects to compare PROMs at each timepoint via mixed-effect modeling: time (months), BMAC augmentation, BMAC*time interaction, age, sex, osteoplasty procedure performed, and intraoperative breakdown of chondrolabral junction. Statistical analysis was performed using R Version 4.2.1 or SPSS Version 29.0.2.0 and P < 0.05 was considered significant.Results:81 hips were included for analysis: 39 from the BMAC cohort and 42 from the control cohort. Univariate analyses demonstrated similar baseline characteristics between both groups with regard to BMI (BMAC: mean=39.0kg/m2 ± SD of 3.9kg/m2 versus no BMAC: 25.3kg/m2 ± 4.4; p=0.856); Tönnis angle (1.4º ± 7.9º vs. 2.6º ± 7.2º; p=0.502), lateral center edge angle (LCEa) (35.5º ± 7.2º vs. 35.7º ± 6.2º; p=0.879); and alpha angle (54.3º ± 14.9º versus 50.3º ± 16.6º; p=0.262) (Tables 1&2). In the adjusted analysis, patients treated with and without BMAC experienced similar PROMs at enrollment, 3 months, and 6 months, with the exception of iHOT-33 at enrollment (BMAC: mean = 48.3 [95% CI = 39.5, 57.0] versus no BMAC: 38.1 [30.1, 46.1]; p = 0.033) (Table 3). At 12 months, patients treated with BMAC demonstrated significantly higher HOS-ADL scores than those without (92.7 [86.8, 98.7] versus 85.7 [80.2, 91.2]; p = 0.037); however, mHHS, iHOT-33, and HOS-SS scores were similar at this timepoint (p > 0.05). At 24 months, patients treated with BMAC reported significantly higher mHHS (91.7 [85.7, 97.7] versus 82.1 [76.6, 87.6]; p = 0.004), iHOT-33 (86.3 [77.5, 95.1] versus 74.2 [66.2, 82.2]; p = 0.012), and HOS-ADL (93.9 [87.9, 99.8] versus 85.0 [79.6, 90.5]; p = 0.008) scores. This trend continued at 60 months, as patients treated with BMAC showed significantly higher mHHS (95.5 [89.6, 100.0] versus 83.9 [78.4, 89.4]; p < 0.001), iHOT-33 (91.5 [82.7, 100.0] versus 78.3 [70.2, 86.3]; p = 0.006), and HOS-SS (87.7 [75.7, 99.7] versus 71.4 [60.4, 82.4]; p = 0.012) scores. These results held in the unadjusted sensitivity analyses (Figure 1).Conclusions:Patients who underwent BMAC augmentation during arthroscopic labral repair outperformed patients who underwent labral repair alone without BMAC. This difference started to manifest at 12 months postoperatively and steadily increased in contrast until 5 years after surgery. These findings remain consistent with short-term reports and add mid-term outcomes to the growing body of literature that describes the patient-reported effect of BMAC as an adjuvant therapy during hip arthroscopy.

Objectives:Fresh osteochondral allograft transplantation (OCA), which transfers viable, mature hyaline cartilage and subchondral bone into full-thickness chondral defects, has demonstrated good long-term results in the knee. However, incomplete osseous trabecular integration of allograft bone with the host bone is correlated with inferior patient-reported outcomes (Williams et al, JBJS, 2007) and can lead to graft failure. As a result, augmentation of OCA with bone marrow aspirate concentrate (BMAC) has been hypothesized to improve osseous incorporation of the allograft compared to OCA alone. The purpose of this study was to compare the appearance of osseous integration at the host-graft junction on magnetic resonance imaging (MRI) in patients treated with BMAC+OCA versus patients treated with OCA alone.Methods:Between February 2013 and June 2016, 29 patients with full-thickness cartilage defects were treated with BMAC+OCA (n = 10) or OCA alone (n = 19) and followed prospectively with an MRI at approximately 12 months after surgery. Intraoperatively, bone marrow aspirate was harvested from the ipsilateral iliac crest (Magellan, Arteriocyte), and the allograft plug was soaked in BMAC prior to implantation. No patients received a concomitant meniscus allograft transplantation, realignment osteotomy, or anterior ligament reconstruction. Bone, cartilage, and ancillary features on postoperative MRI were assessed and graded using the Osteochondral Allograft MRI Scoring System (OCAMRISS) by a blinded musculoskeletal radiologist. This is a system that scores subchondral bone plate congruity, bone marrow signal intensity, osseous integration, and cystic changes of the graft and host-graft junction as part of the bone features assessment (Meric et al, Cartilage, 2015) (Table 1). Comparisons of demographic characteristics and OCAMRISS scores between groups were performed with the Mann-Whitney test.Results:The mean ages of the BMAC and control groups were 32.9 and 33.4 years, respectively (p = 0.95). Males comprised 60% of the BMAC group and 68% of the control group (p = 0.70). MRIs for the BMAC and control groups were obtained at a mean of 11.2 (range, 9-14) and 11.3 (range, 8-15) months after surgery, respectively (p = 0.87). Mean total OCAMRISS scores were not significantly different between groups (BMAC - 7.8, control - 8.0; p = 0.93). Furthermore, mean bone (BMAC - 2.3, control - 2.8; p = 0.22), cartilage (BMAC - 3.3, control - 3.0; p = 0.55), and ancillary (BMAC - 2.2, control - 2.3; p = 0.92) feature scores were not significantly different between groups. Imaging for 5 patients (50%) in the BMAC and 11 patients (59%) in the control groups (p = 0.71) demonstrated a persistent discernible cleft without crossing trabeculae at the host-graft junction (Figure 1). Almost all grafts (over 90%) demonstrated persistent subchondral marrow edema relative to the epiphyseal bone.Conclusion:The addition of autogenous BMAC to OCA did not enhance osseous integration and bony features at the host-graft junction compared to OCA alone at 12 months. Although more MRI follow-up of patients treated with BMAC+OCA is needed to confirm this finding, these results suggest that any augmentative biologic effect of BMAC for OCA, if one exists, is likely to be small.Table 1.Osteochondral Allograft Magnetic Reponance Imaging Scoring System (OCAMRISS) (adapted from Metric et al) MRI FeatureMRI ScoreBone Features1. Subchondral bone plate congruity of graft and host-graft junction0: Intract and flush; 1: Disrupted or not flush by >1 subchondral thickness 2. Subchondral bone marrow signal intensity of graft relative to epiphyseal bone0: Normal; 1: Abnormal (bone marrow edema pattern or hypointensity on all sequences) 3. Osseous integration at host-graft junction0: Crossing trabeculae; 1: Discernible cleft 4. Presence of cystic changes of graft and host-graft junction0: Absent; 1: PresentCartilage Features5. Cartilage signal of graft0: Normal; 1: Altered intensity (either hypointense of hyperintense, but not fluid); 2: Fluid signal intensity on all sequences 6. Cartilage “fill” of graft (percentage of volume)0: 76-100%; 1: 51-75% or >100%; 2: <50% 7. Cartilage edge integration at host-graft junction0: No discernible boundary; 1: Discernible boundary; 2: Discernible fissure >1 mm 8. Cartilage surface congruity of graft and host-graft junction0: Flush; 1: <50% offset of host cartilage; 2: >50% offset of host cartilage 9. Calcified cartilage integrity of graft0: Intract, thin, and smooth; 1: Altered (disrupted, thickened or blurred)Ancillary Features10. Opposing cartilage0: Normal; 1: Abnormal (bone marrow edema pattern or hypointensity on all sequences) 11. Meniscal tears0: Absent; 1: Present 12. Synovitis0: Absent; 1: Present 13. Fad pad scarring0: Absent; 1: PresentFigure 1.Representative 12-month coronal and sagittal MRI sections in a (A,B) 20-year-old male, demonstrating crossing trabeculae and minimal subchondral marrow edema, and (C,D) 16-year-old-male, demonstrating discernible clefts at the host-graft junction and significant subchondral marrow edema. Both were treated with BMAC+OCA

Background: Intra-articular (IA) platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) injections have shown efficacy and safety in treating osteoarthritis (OA). However, the effectiveness and mechanisms of combined intraosseous (IO) administration of these orthobiologics have yet to be explored. Purpose/Hypothesis: The purpose of this study was to evaluate the effect on pain, cartilage, synovium/infrapatellar fat pad (IFP), and subchondral bone in rat knee OA, comparing isolated IA with combined IA and IO (IA+IO) injections of PRP or BMAC. It was hypothesized that combined injections would be superior to sole IA injections. Study Design: Controlled laboratory study. Methods: A total of 48 rats were divided into 6 groups: sham (only joint puncture during OA induction with IA+IO saline injection treatment) and 5 groups with OA induction, control (IA+IO saline injection), PRP (IA PRP+IO saline injection), BMAC IA (IA BMAC+IO saline injection), PRP IA+IO (IA+IO PRP injection), and BMAC IA+IO (IA+IO BMAC injection). OA was induced by IA injection of monosodium iodoacetate (MIA). Rats were administered different orthobiologics according to their grouping 3 weeks after the MIA injection. Pain changes were evaluated using the weightbearing ratio assay at weeks 3, 4, 5, 7, and 9 after OA induction. Rats were euthanized at week 9 for gross, radiological, histological, immunohistochemical, and immunofluorescence assessments of cartilage, synovium, and subchondral bone. Results: Compared with the control group, all orthobiologics injection groups had reduced joint pain. Compared with IA injection, IA+IO injections provided superior pain relief by suppressing calcitonin gene-related peptide and substance P in both the synovium/IFP and subchondral bone. IA+IO injections slowed the progression of subchondral bone lesions by inhibiting CD31hiEmcnhi vessel formation and excessive osteoclast and osteoblast turnover while preserving subchondral bone microarchitecture, slowing cartilage degeneration. However, IA+IO injections did not outperform isolated IA injections in reducing synovitis and synovium/IFP fibrosis. Compared with PRP, BMAC exhibited superior inhibition of pain-related mediators, but no significant differences were observed in synovitis suppression, infrapatellar fat pad fibrosis, and subchondral bone protection. Conclusion: IA+IO injections of orthobiologics were more effective in relieving pain, slowing cartilage degeneration, and inhibiting abnormal vascularization and remodeling compared with isolated IA injections. BMAC showed superior pain relief in the synovium/IFP and subchondral bone compared with PRP. Further research is needed to optimize PRP and BMAC components for enhanced efficacy in OA management. Clinical Relevance: Our findings contribute to advancing the understanding of pain relief mechanisms and support the endorsement of IO injection of orthobiologics for the treatment of OA and joint pain.