Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage loss, inflammation, and joint dysfunction. With profound effects on joint function and quality of life, OA imposes a substantial socio-economic burden. As of now, OA remains incurable, lacking approved medications, regenerative therapies, or procedures that can halt the progressive destruction of the joint. Intraarticular (IA) injections have emerged as a cornerstone in the management of knee OA, offering localized minimally invasive therapeutic options. Traditional IA therapies, including corticosteroids and hyaluronic acid (HA), primarily aim to reduce pain but lack regenerative capacity. Biologic IA therapies for knee OA including autologous blood-derived products like platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC) and mesenchymal stromal cells (MSCs) have become more commonly used. Finally, newer IA therapies such as fibroblast growth factor 18 and gene therapy are being investigated. In this review, we highlight the current evidence around IA injections for the treatment of knee OA.

Bone marrow aspirate concentrate (BMAC) is an autologous regenerative therapy enriched with mesenchymal stem cells (MSCs) and bioactive growth factors, offering potential disease-modifying effects in knee osteoarthritis (OA). Compared to conventional intra-articular treatments, including hyaluronic acid (HA), platelet-rich plasma (PRP), and corticosteroids, BMAC promotes cartilage regeneration, modulates inflammation, and enhances subchondral bone remodeling. Clinical evidence suggests that BMAC provides short- to mid-term symptomatic relief and functional improvement, with some studies indicating a potential to delay total knee arthroplasty (TKA). However, findings remain inconsistent, and long-term efficacy compared to PRP or autologous conditioned serum (ACS) is yet to be firmly established. Variability in BMAC preparation methods, injection protocols (single vs. repeated administration, intra-articular vs. subchondral delivery), and patient selection criteria complicates its clinical application, highlighting the need for standardized guidelines. Additionally, economic feasibility and cost-effectiveness concerns limit its widespread adoption. This review synthesizes current clinical evidence, evaluates optimal administration strategies, and explores future directions for improving treatment standardization and patient-specific therapy. Future research should prioritize well-designed, multicenter randomized controlled trials (RCTs) with long-term follow-up to confirm the sustained efficacy and therapeutic potential of BMAC in OA management.

Bone tissue, the second most transplanted tissue after blood, is utilized in over 2.2 million bone grafts annually to address various bone-related conditions including fractures, tumors, bone infections, scoliosis, congenital defects, osteoporosis, osteoarthritis, and osteogenesis imperfecta. According to incomplete statistics, $4.3 billion was spent on bone graft materials in 2015 alone, with projections suggesting this figure may reach $66 billion by 2026. The limited availability of autogenous bone graft considered the gold standard due to their three critical biological properties: osteoconduction, osteoinduction, and osteogenesis-alongside the increasing global aging population, may be contributing to this rising expenditure. Furthermore, advancements in biomaterials and engineering technologies have created opportunities for the exploration of new bone graft substitutes. In this review, we will examine the fundamental structure of natural bone and the characteristics of ideal bone graft, highlighting common bone graft materials currently available, such as true bone ceramics, decalcified bone matrix, freeze-dried bone and demineralized freeze-dried bone, bioactive glasses, bone marrow aspirate concentrate, polymer nanocomposites, which have different characteristics in osteogenic, osteoconductivity, osteoinductivity, biocompatibility, mechanical properties, and resorption. How to utilize its advantages to maximize the osteogenic effect will be the focus of this review, and some of the current challenges in the field of bone grafting will be identified, outlining potential directions for future development. In conclusion, the choice of bone graft is critical to bone repair and regeneration, and a comprehensive understanding of the advantages and disadvantages of bone graft materials can improve the effectiveness of related surgical interventions.

Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms.

To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials.

We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis.

Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant-reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events.

We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, weight loss and exercise) (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet-rich plasma injections (two trials), oral acetaminophen (paracetamol) (one trial), non-steroidal anti-inflammatory drugs plus physical therapy plus hyaluronic acid injection (one trial) and stem cell injection plus intra-articular co-intervention versus co-intervention alone (three trials) in people with osteoarthritis of the knee. Trials were predominantly small, with sample sizes ranging from 6 to 252 participants, with only two trials having more than 100 participants. The average age of participants across trials ranged from 51 to 66 years, and symptom duration varied from one to 10 years. Placebo-controlled trials were largely free from bias, while most trials without a placebo control were susceptible to performance and detection biases. Here, we limit reporting to the main comparison, stem cell injection versus placebo injection. Compared with placebo injection, stem cell injection may slightly improve pain and function up to six months after treatment. Mean pain (0 to 10 scale, 0 no pain) was 4.5 out of 10 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I2 = 80%; 7 studies, 445 participants). Mean function (0 to 100 scale, 0 best function) was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I2 = 82%; 7 studies, 432 participants). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injection, because the certainty of the evidence was very low. Mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I2 = 96%; 2 studies, 288 participants) at up to six months follow-up. At the end of follow-up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (risk ratio (RR) 1.29, 95% CI 1.10 to 1.53; I2 = 0%; 4 trials, 348 participants). We downgraded the evidence to low certainty for pain and function due to indirectness (as the source, method of preparation and dose of stem cells varied across studies), and suspected publication bias (up to three larger RCTs have been conducted but withdrawn prior to reporting of results). For quality of life and treatment success, we further downgraded the evidence to very low certainty due to imprecision in addition to indirectness and suspected publication bias. We are uncertain of the potential harms associated with stem cell injection, as there were very low event rates for serious adverse events. At the end of follow-up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.72, 95% CI 0.20 to 2.64; I2 = 0%; 7 trials, 461 participants) and there were no reported withdrawals due to adverse events. We downgraded the evidence to very low certainty due to indirectness, suspected publication bias and imprecision. Radiographic progression was not assessed in any of the included studies.

Compared with placebo injections and based upon low-certainty evidence, stem cell injections for people with knee osteoarthritis may slightly improve pain and function. We are uncertain of the effects of stem cell injections on quality of life or the number who report treatment success. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.

Bone marrow mononuclear cells (BMMNCs) are becoming a promising cell therapy in regeneration medicine. BMMNCs are now obtained by density gradient centrifugation (DGC) in clinical practice, which is complicated and greatly influenced by human manipulation.

Our objective is to develop a simple and safe method to isolate BMMNCs.

Bone marrow was aspirated from nine minipigs. The optimal hypotonic sodium chloride (NaCl) concentration was first investigated based on the BMMNCs viability and lysis efficiency tests. Afterward, three different methods (ammonium chloride (NH4Cl) lysis, hypotonic NaCl lysis, and DGC) were used for BMMNCs isolation. Nucleated cell yield, residual red blood cells (RBCs) level, BMMNCs viability, apoptotic cell percentage, and colony-forming ability were measured in three groups. Cell morphology, cell phenotype, proliferative capacity, and osteogenic, adipogenic, and chondrogenic lineage differentiation potential of the bone marrow mesenchymal stem cells (BMSCs) were compared in three groups.

0.3% NaCl lysis group had optimal cell viability and lysis efficiency and the 0.3% NaCl lysis group had higher cell yield and lower RBCs remaining in BMMNCs compared to the DGC group. The BMSCs harvested from the NH4Cl lysis group had the worst proliferation ability. The NaCl lysis group was not inferior to the other two groups in terms of other biological characteristics of BMMNCs/BMSCs.

The optimal concentration for hypotonic NaCl lysis to obtain BMMNCs is 0.3%. Compared with NH4Cl lysis and DGC, the 0.3% NaCl lysis may be a safe, appropriate, and low-cost method for BMMNCs isolation.

This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Bone tissue engineering (BTE) has emerged as a promising approach to address large bone defects caused by trauma, infections, congenital malformations, and tumors. This review focuses on scaffold design, cell sources, growth factors, and vascularization strategies, highlighting their roles in developing effective treatments. We explore the complexities of balancing mechanical properties, porosity, and biocompatibility in scaffold materials, alongside optimizing mesenchymal stem cell delivery methods. The critical role of growth factors in bone regeneration and the need for controlled release systems are discussed. Vascularization remains a significant hurdle, with strategies such as angiogenic factors, co-culture systems, and bioprinting under investigation. Mechanical challenges, tissue responses, and inflammation management are examined, alongside gene therapy's potential for enhancing osteogenesis and angiogenesis via both viral and non-viral delivery methods. The review emphasizes the impact of patient-specific factors on bone healing outcomes and the importance of personalized approaches. Future directions are described, emphasizing the necessity of interdisciplinary cooperation to advance the field of BTE and convert laboratory results into clinically feasible solutions.

Osteoarthritis, a degenerative joint disease, requires innovative therapies due to the limited ability of cartilage to regenerate. Since mesenchymal stem cells (MSCs) provide a cell source for chondrogenic cells, we hypothesize that chemicals capable of enhancing the chondrogenic potential of MSCs with transforming growth factor-beta (TGFβ) in vitro may similarly promote chondrogenesis in articular cartilage in vivo.

Chemical compounds that enhance the TGFβ signaling for chondrogenesis were investigated utilizing mesenchymal stem cells derived from human induced pluripotent stem cells. The mechanisms of action underlying the identified compound were explored in vitro, and its therapeutic effects were validated in vivo using a mouse model of exercise-induced osteoarthritis.

Hydroxycitric acid (HCA) emerged as the lead compound. In vitro, HCA effectively enhanced chondrogenesis by inhibiting ATP citrate lyase, inducing citrate and alpha-ketoglutarate (α-KG), while reducing cytosolic acetyl coenzyme A (Ac-CoA). This induction of α-KG promoted collagen prolyl-4-hydroxylase activity, boosting hydroxyproline production and matrix formation. The reduction of Ac-CoA attenuated the inhibitory effect of β-catenin on mitochondrial activity by diminishing its acetylation. In vivo, orally administered HCA accumulated in joint tissues of mice and histological examination demonstrated newly synthesized cartilage tissues in damaged area. Analysis of joint tissue extracts revealed a downregulation of Ac-CoA and an upregulation of citrate and α-KG, accompanied by a systemic increase in an anabolic biomarker.

HCA demonstrates promise as an osteoarthritis therapy by enhancing chondrogenic differentiation. Its ability to modulate crucial metabolic pathways and facilitate cartilage repair suggests potential for clinical translation, addressing a critical need in the treatment of osteoarthritis.

To establish consensus statements via a modified Delphi process about ethics, transparency, regulation, and best practices for the use of orthobiologics in clinical practice for musculoskeletal pathology.

A consensus process on the regulation of orthobiologics at the provider level was conducted using a modified Delphi technique. Twenty orthopaedic surgeons, sports medicine physicians, or basic scientists participated. Each participant was a Biologic Association member organization representative and asked to participate because of their active interest in the field of orthobiologics. Levels of consensus were delineated according to the number of votes for each statement: no consensus, <80%; consensus, 80% to 89%; strong consensus, 90% to 99%; unanimous, 100%.

The 26 consensus statements on orthobiologics resulted in 14 achieving unanimous consensus, 8 achieving strong consensus, 3 achieving consensus, and 1 did not achieve consensus. Overall, 85% of the statements reached either a unanimous or strong consensus. Of the statements regarding communication and transparency, 9 reached unanimous consensus, including information to convey and helpful tools to describe current orthobiologics, persistent misinformation, use of the word "stem cells," "off-label" use, and problems with the present regulatory environment. Five statements discussing the regulation of novel orthobiologics achieved unanimous consensus. These statements highlighted research regulation, safety, and suggested improvements to regulatory issues. The statement that did not achieve any consensus was on the regulatory processes that should be in place by an institution providing novel orthobiologic treatments. No statement reached a unanimous agreement on cost or ethical considerations.

This study successfully identified key consensus statements emphasizing the importance of ethics, transparency, and regulation in the use of orthobiologics, with 85% of statements reaching unanimous or strong consensus. These findings underscore the need for standardized communication, improved regulatory frameworks, and enhanced safety measures while highlighting persistent challenges in addressing cost and ethical considerations.

Level V, expert opinion.

Knee osteoarthritis (OA) is a common degenerative joint condition and a major cause of disability in the general population.

Recent published literature identified from PubMed, EMBASE, Google Scholar, and Scopus.

Orthobiological therapies try to regenerate articular cartilage and stop the progression of the degenerative lesion. Intra-articular injections of biological derivates have been increasingly used in the last decade.

The indications for the use of bone marrow aspirate concentrate (BMAC) are still unclear.

We systematically reviewed the current literature on BMAC in the management of knee OA, giving an update on the current indications for the selection of the ideal patient and the preparations and efficacy of BMAC compared to other biological alternatives.

BMAC is a valuable source of mesenchymal stem cells, offering potential benefits in attenuating the inflammatory pathway associated with knee OA. Intra-articular injection of BMAC has shown effectiveness in clinical trials improving functional outcomes of knee OA patients. The superiority of BMAC over other orthobiological treatments cannot be assessed because of conflicting results.

Knee osteoarthritis (OA) is a chronic articular disease characterized by the progressive degeneration of cartilage and bone tissue, leading to the appearance of subchondral cysts, osteophyte formation, and synovial inflammation. Conventional treatments consist of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and glucocorticoids. However, the prolonged use of these drugs causes adverse effects. NSAIDs, for instance, are known to be nephrotoxic, increasing the damage to articular cartilage. New therapies capable of accelerating the process of tissue regeneration and repair are being discussed, such as the use of orthobiologics that are naturally found in the body and obtained through minimally invasive collection and/or laboratory manipulations. Bone marrow aspirate (BMA) and bone marrow aspirate concentrate (BMAC) are both rich in hematopoietic stem cells, mesenchymal stem cells (MSCs), and growth factors (GFs) that can be used in the healing process due to their anabolic and anti-inflammatory effects. The aim of this literature review is to assess the efficacy of BMA and BMAC in the treatment of knee OA based on the favorable results that researchers have obtained with the use of both orthobiologics envisaging an accelerated healing process and the prevention of OA progression.

Injectable platelet-rich fibrin (iPRF), a liquid form of PRF that is prepared from peripheral blood without anticoagulants, promotes tissue wound healing and regeneration. The present study focused on iPRF-like bone marrow aspirate concentrate (iBMAC) prepared without anticoagulant, and the regenerative potential of iPRF and iBMAC was compared in vitro.

iPRF and iBMAC were prepared from the same New Zealand white rabbits. The cytocompatibility and regenerative potential of each concentrate were evaluated using primary rabbit gingival fibroblasts and osteoblasts.

Both gingival fibroblasts and osteoblasts treated with each concentrate exhibited excellent cell viability. Interestingly, compared to cells treated with iPRF, cells treated with iBMAC demonstrated significantly greater migration potential. Furthermore, higher mRNA levels of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and collagen I (COL1) were observed in gingival fibroblasts treated with iBMAC than in those treated with iPRF. Compared with osteoblasts treated with iPRF, osteoblasts treated with iBMAC exhibited greater differentiation potential, as indicated by increased osteocalcin (OCN) expression and mineralization capability.

The results of the in vitro study suggest that, compared with iPRF, iBMAC may promote wound healing and bone regeneration more effectively. However, further preclinical and clinical studies are needed to confirm the regenerative potential of iBMAC in the body.

Despite being recognized as a safe procedure with minimal reported complications, injecting autologous bone marrow aspirate concentrate (BMAC) as an adjuvant to arthroscopic partial meniscectomy (APM) for symptomatic patients with meniscal tears and concomitant knee osteoarthritis (OA) has not been studied in randomized controlled trials.

To compare patient-reported outcome measure (PROM) scores and radiographic outcomes in symptomatic patients with meniscal tears and concomitant mild knee OA who underwent APM with and without an autologous BMAC injection administered at the time of surgery.

Randomized controlled trial; Level of evidence, 1.

Enrolled patients aged ≥18 years determined to have a symptomatic meniscal tear with concomitant mild knee OA suitable for APM and meeting inclusion and exclusion criteria were randomized into 2 groups: BMAC and control (no BMAC). The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 1 year postoperatively. Secondary endpoints included radiographic outcomes (Kellgren-Lawrence grade) at 1 year postoperatively and various PROM scores, including those for the IKDC, Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale, and Veterans RAND 12-Item Health Survey, at 3 months, 6 months, 1 year, and 2 years after meniscectomy.

Of the 95 enrolled patients, 83 (87.4%) were included for final analysis. No significant differences were found between the groups with regard to patient characteristics, intraoperative variables, concomitant procedures, preoperative PROM scores, or preoperative radiographic findings. At 1 year postoperatively, the BMAC group failed to demonstrate significantly better IKDC scores (P = .687) or radiographic outcomes (P > .05 for all radiographic measures) compared with the control group. Secondary PROM scores also did not significantly differ between the groups (P > .05 for all PROMs). However, there were higher achievement rates of the minimal clinically important difference for the KOOS Sport (100.0% vs 80.0%, respectively; P = .023) and KOOS Symptoms (92.3% vs 68.0%, respectively; P = .038) at 1 year postoperatively in the BMAC group than in the control group. All PROMs, excluding the VR-12 mental score, showed significant improvements compared with baseline at all postoperative time points for both the BMAC and control groups.

The addition of an autologous BMAC injection during APM did not result in significant changes in IKDC scores or radiographic outcomes at the 1-year postoperative mark. Secondary PROM scores were generally comparable between the 2 groups, but there was higher minimal clinically important difference achievement for the KOOS Sport and KOOS Symptoms at 1 year postoperatively in the BMAC group. In patients with symptoms consistent with a meniscal tear who had concomitant mild OA, the addition of BMAC to arthroscopic debridement did not affect the outcome.

NCT02582489 (ClinicalTrials.gov).

Placental-derived allografts have been of interest as a potential nonsurgical treatment to reduce pain and improve function in knee osteoarthritis (OA). The purpose of this study was to evaluate the effect of single and repeat injection of amniotic suspension allograft (ASA) on pain, function, and cytokine levels using a destabilization of the medial meniscus (DMM) rat model of OA. Post-DMM surgery, animals were treated with a single injection of either ASA, vehicle, or triamcinolone, or repeated injection of either ASA or vehicle. Behavioral testing including knee swelling, pain threshold, dynamic weight bearing (DWB), and gait analysis were evaluated during the in-life phase. Postsacrifice, histopathology and serum and synovial fluid analyses were evaluated. Significant improvements in both DWB differentials and pain threshold were seen in response to repeated injection of ASA, while a single injection of ASA and triamcinolone resulted in significant improvements in pain threshold. Histopathology analysis found no significant differences regardless of treatment compared to vehicle, except for an increase in synovitis following repeated injection of ASA. A single injection of ASA and triamcinolone resulted in increased anti-inflammatory cytokines; repeated ASA injection resulted in significant increases in several immune-modulating factors relevant to OA. When comparing the impact of single and repeat ASA treatments on behavioral testing, repeated injection provided significant additional improvements in both pain and function. This study provides evidence demonstrating the impact of a second injection while also providing additional data for evaluating the use of ASA as a nonsurgical treatment for knee OA.

Advanced cell therapies emerged as promising candidates for treatment of knee articular diseases, but robust evidence regarding their clinical applicability is still lacking.

To assess the efficacy and safety of advanced mesenchymal stromal cells (MSC) therapy for knee osteoarthritis (OA) and chondral lesions.

Systematic review of randomized controlled trials conducted in accordance with Cochrane Handbook and reported following PRISMA checklist. GRADE approach was used for assessing the evidence certainty.

25 randomized controlled trials that enrolled 1048 participants were included. Meta-analyses data showed that, compared to viscosupplementation (VS), advanced MSC therapy resulted in a 1.91 lower pain VAS score (95 % CI -3.23 to -0.59; p < 0.00001) for the treatment of knee OA after 12 months. Compared to placebo, the difference was 0.99 lower pain VAS points (95 % CI -1.94 to -0.03; p = 0.76). According to the GRADE approach, the evidence was very uncertain for both comparisons. By excluding studies with high risk of bias, there was a similar size of effect (VAS MD -1.54, 95 % CI -2.09 to -0.98; p = 0.70) with improved (moderate) certainty of evidence, suggesting that MSC therapy probably reduces pain slightly better than VS. Regarding serious adverse events, there was no difference from advanced MSC therapy to placebo or to VS, with very uncertain evidence.

Advanced MSC therapy resulted in lower pain compared to placebo or VS for the treatment of knee OA after 12 months, with no difference in adverse events. However, the evidence was considered uncertain.

Currently, there is a lack of studies with good methodological structure aiming to evaluate the real clinical impact of advanced cell therapy for knee OA. The present study was well structured and conducted, with Risk of Bias, GRADE certainty assessment and sensitivity analysis. It explores the translational aspect of the benefits and safety of MSC compared with placebo and gold-standard therapy to give practitioners and researchers support to expand this therapy in their practice.

CRD42020158173. Access at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173.

To evaluate procedural heterogeneity, patient-reported outcomes (PROs), and complications following geniculate artery embolization (GAE) for knee osteoarthritis (OA).

A literature search was performed using PubMed, Embase, and Scopus databases from inception to August 2023 according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Human clinical studies reporting PROs following GAE for treatment of knee OA were included, and a qualitative comparison across PROs, procedural descriptions, and complications was performed. Study quality was assessed using the Cochrane Collaboration's risk of bias tool and the Methodological Index for Non-Randomized Studies criteria. The primary outcome measures included changes in PROs at 12 months and variances in procedural methodology.

A total of 17 studies, consisting of 533 patients and 620 knees, were identified. The reported mean improvement at 12 months for visual analog scale for pain and Western Ontario and McMaster Universities Arthritis Index scores ranged from 10 to 59 and 35.3 to 47, respectively. At 12 months, median improvements were observed in Knee injury and Osteoarthritis Outcome Score subscales such as Pain (range, 8.3-19.5), Quality of Life (15.49-25.0), Sport (7.5-26.3), and Symptoms (1.8-25.0). Decreasing minimal clinically important difference (MCID) achievement was observed between the 3-month and 6-month follow-up points. Patients with advanced OA and degenerative findings on magnetic resonance imaging exhibited lower rates of MCID achievement. Transient adverse events occurred in up to 80% of patients. Limited evidence from serial magnetic resonance imaging assessments suggests that GAE improves levels of synovitis. Significant heterogeneity exists among the GAE methodology as 4 different definitions of technical success, 4 distinct embolization targets, and use of 5 embolization agents were noted.

GAE results in short-term improvements in pain and function with decreasing MCID achievement observed after 3 to 6 months. Patients with severe OA also demonstrate lower rates of MCID achievement. A high rate of transient complications is reported, including skin discoloration and access site hematomas. Significant protocol heterogeneity exists, which contributes to variable outcomes.

Level IV, systematic review of Level IV studies.

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.

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.

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.

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.

Hip osteoarthritis (OA) is one of the leading causes of disability and morbidity worldwide. It is estimated to affect 9.2% individuals globally with age over 45 years. Conventional treatment modalities have limitations and side-effects. To overcome these limitations, over the last decade, there has been an increased interest in the use of orthobiologics derived from autologous sources including platelet-rich plasma (PRP), bone-marrow aspirate concentrate (BMAC) and adipose tissue derived formulations. This review qualitatively presents the in-vitro, pre-clinical, clinical and on-going clinical studies exploring the safety and efficacy of BMAC for management of hip OA.

The electronic database search was done through PubMed, Embase, Web of Science, Scopus, ProQuest and Google Scholar till February 2024. The search terms used were "osteoarthritis" OR "hip osteoarthritis" OR "orthobiologics" OR "efficacy or use of orthobiologic treatment" OR "bone-marrow concentrate" OR "bone-marrow aspirate concentrate", AND "BMAC". The inclusion criteria were clinical studies of any level of evidence written in the English language, published till February 2024, evaluating the safety and efficacy of intra-articular administration of BMAC for the management of hip OA.

A total of 5 studies were included in this review for qualitative data synthesis. The total number of patients who participated in the study was 182, ranging from 4 to 112 in a single study. No adverse events were reported throughout the duration of the study. In addition, intra-articular administration of BMAC led to reduced pain, and improved function and overall quality of life (QoL).

The results from this review demonstrated that administration of BMAC is safe and potentially efficacious in terms of reducing pain, improving function and overall QoL of patients with hip OA in short- and mid-term average follow-up based on the included studies. Nonetheless, more adequately powered, multi-center, prospective, double-blind, non-randomized and randomized controlled trials with long-term follow-up are warranted to establish long-term safety and efficacy of BMAC for management of hip OA and justify its routine clinical use.

Bone marrow mononuclear cells (BMMNCs) have great potential in bone regenerative therapy. The main method used today to obtain BMMNCs is Ficoll density gradient centrifugation. However, the centrifugal force for this isolation method is still suboptimal.

To determine the optimal centrifugal force in Ficoll density gradient centrifugation of bone marrow (BM) to achieve high stem/progenitor cell content BMMNCs for regenerative therapy.

BM was aspirated from nine minipigs and divided into three groups according to different centrifugal forces (200 g, 300 g and 400 g). Immediately after BMMNCs were obtained from each group by Ficoll density gradient centrifugation, residual red blood cell (RBC) level, nucleated cell counting, viability and flow cytometric analyses of apoptosis and reactive oxygen species (ROS) generation were measured. The phenotypic CD90 and colony formation analyses of BMMNCs of each group were performed as well. Bone marrow-derived mesenchymal stem cells (BMSCs) were harvested at passage 2, then morphology, cell phenotype, proliferation, adipogenic, chondrogenic and osteogenic lineage differentiation potential of BMSCs from each group were compared.

The 300 g centrifugal force was able to isolate BMMNCs from BM with the same efficiency as 400 g and provided significantly higher yields of CD90+ BMSCs and fibroblastic colony-forming units of BMSC (CFU-f(BMSC)), which is more crucial for the regenerative efficacy of BMMNCs. Meanwhile, 200 g hosted the most RBC contamination and minimum CFU-f (BMSC) yield, which will be disadvantageous for BMMNC-based cell therapy. As for in vitro cultured BMSCs which were isolated from BMMNCs by different centrifugal forces, no significant differences were found on morphology, cell proliferation rate, phenotypic marker, adipogenic, chondrogenic and osteogenic differentiation potential.

300 g may be the optimal centrifugal force when using Ficoll density gradient centrifugation to isolate BMMNCs for bone regenerative therapy.

This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

To compare the efficacy of common intra-articular injections used in the treatment of knee osteoarthritis, including corticosteroid (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and bone marrow aspirate concentrate (BMAC), with a minimum follow-up of 6-months.

A literature search was conducted using the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in August 2022 in the following databases: PubMed/MEDLINE, Scopus, Cochrane Database of Controlled Trials, and the Cochrane Database of Systematic Reviews. Level I to II randomized clinical trials with a minimum follow-up of 6 months that investigated the treatments of interest were included. Patient-reported outcome scores for pain and function at baseline and at latest follow-up were extracted, and the change in scores was converted to uniform 0 to 100 scales. Arm-based Bayesian network meta-analysis using a random-effects model was created to compare the treatment arms in pain and function.

Forty-eight studies comprising a total of 9,338 knees were included. The most studied intra-articular injection was HA (40.9%), followed by placebo (26.2%), PRP (21.5%), CS (8.8%), and then BMAC (2.5%). HA and PRP both led to a significant improvement in pain compared with placebo. HA, PRP, and BMAC all led to a significant improvement in function scores when compared with placebo. Surface under the cumulative ranking curves (SUCRAs) of the interventions revealed that PRP, BMAC, and HA were the treatments with the highest likelihood of improvement in both pain and function, with overall SUCRA scores of 91.54, 76.46, and 53.12, respectively. The overall SUCRA scores for CS and placebo were 15.18 and 13.70, respectively.

At a minimum 6-month follow-up, PRP demonstrated significantly improved pain and function for patients with knee osteoarthritis compared with placebo. Additionally, PRP exhibited the highest SUCRA values for these outcomes when compared with BMAC, HA, and CS.

Level II, meta-analysis of Level I to II studies.

Chondromalacia patellae (CMP) is a widespread cause of patellofemoral pain syndrome (PFPS), which manifests as anterior knee pain and functional limitations. Current treatments frequently fail to give long-term relief, necessitating the exploration of new therapeutic techniques. Recent research has demonstrated the efficacy of Bone Marrow Aspirate Concentrate (BMAC) therapy, which utilizes the regeneration characteristics of mesenchymal stem cells (MSCs) and growth factors. We present the case of a 36-year-old male patient with Grade III CMP who was resistant to conservative treatment but was successfully treated with BMAC therapy. Detailed methods for BMAC preparation, such as double centrifugation and growth factor analysis, are presented. At six and 12 weeks after therapy, the patient showed significant improvements in pain and functional results, as well as enhanced levels of growth factors and CD34+ cells in the BMAC. This study provides insights into the regeneration potential of BMAC therapy and highlights its promising role in managing chondral abnormalities. Larger clinical trials and standardization of BMAC preparation procedures are necessary for establishing its effectiveness and consistency as a standard treatment approach for CMP.

Osteoarthritis (OA) is an incapacitating and one of the most common physically degenerative conditions with an assorted etiology and a highly complicated molecular mechanism that to date lacks an efficient treatment. The capacity to design biological networks and accurately modify existing genomic sites holds an apt potential for applications across medical and biotechnological sciences. One of these highly specific genomes editing technologies is the CRISPR/Cas9 mechanism, referred to as the clustered regularly interspaced short palindromic repeats, which is a defense mechanism constituted by CRISPR associated protein 9 (Cas9) directed by small non-coding RNAs (sncRNA) that bind to target DNA through Watson-Crick base pairing rules where subsequent repair of the target DNA is initiated. Up-to-date research has established the effectiveness of the CRISPR/Cas9 mechanism in targeting the genetic and epigenetic alterations in OA by suppressing or deleting gene expressions and eventually distributing distinctive anti-arthritic properties in both in vitro and in vivo osteoarthritic models. This review aims to epitomize the role of this high-throughput and multiplexed gene editing method as an analogous therapeutic strategy that could greatly facilitate the clinical development of OA-related treatments since it's reportedly an easy, minimally invasive technique, and a comparatively less painful method for osteoarthritic patients.

This comprehensive review provides an in-depth analysis of platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) as potential treatments for knee osteoarthritis. It explores their mechanisms of action, clinical efficacy, safety considerations, and the importance of personalised treatment approaches. The review highlights promising findings regarding the ability of PRP and BMAC to alleviate symptoms, improve joint function, and potentially slow disease progression. It emphasises the need for further research into long-term outcomes, direct comparative studies, protocol standardisation, biomarker identification, and cost-effectiveness assessments to enhance clinical practice. While the review does not directly compare PRP and BMAC, it provides valuable insights into their respective roles in knee osteoarthritis management. The review aims to contribute to evidence-based advancements in regenerative therapies for knee osteoarthritis by addressing critical research priorities and refining treatment strategies.

Regenerative techniques combined with core decompression (CD) are commonly used to treat osteonecrosis of the femoral head (ONFH). However, no consensus exists on regeneration therapy combined with CD that performs optimally. Therefore, we evaluated six regenerative therapies combined with CD treatment using a Bayesian network meta-analysis (NMA).

We searched PubMed, Embase, Cochrane Library, and Web of Science databases. Six common regeneration techniques were categorized into the following groups with CD as the control group: (1) autologous bone graft (ABG), (2) autologous bone graft combined with bone marrow aspirate concentrate (ABG + BMAC), (3) bone marrow aspirate concentrate (BMAC), (4) free vascular autologous bone graft (FVBG), (5) expanded mesenchymal stem cells (MSCs), and (6) platelet-rich plasma (PRP). The conversion rate to total hip arthroplasty (THA) and progression rate to femoral head necrosis were compared among the six treatments.

A total of 17 literature were included in this study. In the NMA, two of the six treatment strategies demonstrated higher response in preventing the progression of ONFH than CD: MSCs (odds ratio [OR]: 0.098, 95% confidence interval [CI]: 0.0087-0.87) and BMAC (OR: 0.27, 95% CI: 0.073-0.73). Additionally, two of the six treatment strategies were effective techniques in preventing the conversion of ONFH to THA: MSCs (OR: 0.062, 95% CI: 0.0038-0.40) and BMAC (OR: 0.32, 95% CI: 0.1-0.074). No significant difference was found among FVBG, PRP, ABG + BMAC, ABG, and CD in preventing ONFH progression and conversion to THA (P > 0.05).

Our NMA found that MSCs and BMAC were effective in preventing ONFH progression and conversion to THA among the six regenerative therapies. According to the surface under the cumulative ranking value, MSCs ranked first, followed by BMAC. Additionally, based on our NMA results, MSCs and BMAC following CD may be necessary to prevent ONFH progression and conversion to THA. Therefore, these findings provide evidence for the use of regenerative therapy for ONFH.

Biomaterials augmented with Bone Marrow Aspirate Concentrate (BMAC) are becoming increasingly utilized in the cartilage treatment. However, the potential role of cellular parameters in the intraoperatively applied BMAC have yet to be elucidated.

(A) To evaluate clinical outcomes and safety of a combined single-step approach with scaffolds (fibrin glues, collagen gels, collagen-hydroxyapatite membrane) and filtered Bone Marrow Aspirate (fBMA) for the treatment of osteochondral lesions of the talus (OLTs). (B) To identify significant factors for postoperative improvements, considering cellular parameters as potential predictors.

All the patients operated on due to OLTs by the combination above were selected from the hospital registry database (35 pts, years 16-55, and minimally 1 year follow-up). Treatment outcomes were followed clinically with Patient-reported outcome measures (PROMs), and by pursuing serious adverse events (SAE) and graft failures (GF). Cellular parameters of the injected fBMA were determined. Pre- and postoperative PROMs values were compared to evaluate postoperative improvements. Multivariable regression models were applied to identify potential factors (demographics, medical history, joint and lesion characteristics, scaffold type, surgical and cellular parameters) that predict the treatment outcomes.

At the mean follow-up of 32.2 (12.5) months, all Foot and Ankle Outcome Score (FAOS) and European Quality of Life in Five Dimensions Three-Level (EQ-5D-3 L) values improved significantly. 4 (11%) SAE (3 arthrofibrosis, one hardware removal), and 3 (9%) GF occurred. Female gender and concomitant procedures were the main negative predictors for postoperative outcomes. The number of fibroblast colony forming units (CFU-F) or their proportion among total nucleated cells (CFU-F/TNC) were positively correlated with the improvements of some PROMs.

Scaffolds augmented with fBMA proved as an adequate and safe approach for OLTs treatment. Cellular parameters seem to influence the treatment outcomes, thus further attention should be given to the intraoperatively applied products.

Level IV.

Orthobiologics are rapidly growing in use given their potential to augment healing for multiple musculoskeletal conditions. Orthobiologics consist of a variety of treatments including platelet-rich plasma and stem cells that provide conceptual appeal in providing local delivery of growth factors and inflammation modulation. The lack of standardization in nomenclature and applications within the literature has led to a paucity of high-quality evidence to support their frequent use. The purpose of this review was to describe the current landscape of orthobiologics and the most recent evidence regarding their use.

Chondral and osteochondral lesions encompass several acute or chronic defects of the articular cartilage and/or subchondral bone. These lesions can result from several different diseases and injuries, including osteochondritis dissecans, osteochondral defects, osteochondral fractures, subchondral bone osteonecrosis, and insufficiency fractures. As the cartilage has a low capacity for regeneration and self-repair, these lesions can progress to osteoarthritis. This study provides a comprehensive overview of the subject matter that it covers. PubMed, Scopus and Google Scholar were accessed using the following keywords: "chondral lesions/defects of the femoral head", "chondral/cartilage lesions/defects of the acetabulum", "chondral/cartilage lesions/defects of the hip", "osteochondral lesions of the femoral head", "osteochondral lesions of the acetabulum", "osteochondral lesions of the hip", "osteochondritis dissecans," "early osteoarthritis of the hip," and "early stage avascular necrosis". Hip osteochondral injuries can cause significant damage to the articular surface and diminish the quality of life. It can be difficult to treat such injuries, especially in patients who are young and active. Several methods are used to treat chondral and osteochondral injuries of the hip, such as mesenchymal stem cells and cell-based treatment, surgical repair, and microfractures. Realignment of bony anatomy may also be necessary for optimal outcomes. Despite several treatments being successful, there is a lack of head-to-head comparisons and large sample size studies in the current literature. Additional research will be required to provide appropriate clinical recommendations for treating chondral/osteochondral injuries of the hip joint.

Bone marrow aspirate concentrate can be used as an additive to surgical treatment of osteochondral lesions of the talus. This systematic literature review aims to study the effect of the additional use of bone marrow aspirate concentrate on top of a surgical treatment for osteochondral lesions of the talus on clinical outcomes compared to surgical treatment alone.

An online literature search was conducted using PubMed (Medline), Embase (Ovid), and the Cochrane library for all studies comparing a surgical intervention with bone marrow aspirate concentrate, with a surgical intervention without bone marrow aspirate concentrate. The methodological quality was rated according to the methodological index for non-randomised studies checklist. The primary outcome measure were clinical outcomes. Secondary outcome measures consisted of revision rate, complication rate, radiographic outcome measures and histological analyses. Subgroups were created based on type of surgical intervention used in the studies. If multiple articles were included in a subgroup, a linear random-effects model was used to compare the bone marrow aspirate concentrate-augmented group with the control group.

Out of 1006 studies found, eight studies with a total of 718 patients were included. The methodological quality, assessed according to the methodological index for non-randomised studies checklist, was weak. A significantly better functional outcome measures (p < 0.05) was found in the subgroup treated with bone marrow stimulation + bone marrow aspirate concentrate compared to the group treated with bone marrow stimulation alone, based on three non-blinded studies. No significant differences regarding clinical outcomes were found in the subgroups comparing matrix-induced autologous chondrocyte implantation with matrix-induced bone marrow aspirate concentrate, osteochondral autologous transplantation alone with osteochondral autologous transplantation + bone marrow aspirate concentrate and autologous matrix-induced chondrogenesis plus peripheral blood concentrate vs. matrix-associated stem cell transplantation bone marrow aspirate concentrate.

There is insufficient evidence to support a positive effect on clinical outcomes of bone marrow aspirate concentrate as an additive to surgical treatment of osteochondral lesions of the talus. However, based on the safety reports and initial results, sufficiently powered, patient- and researcher-blinded, prospective randomised controlled trials are justified and recommended. Until then, we advise not to implement a therapy (addition of bone marrow aspirate concentrate) without clinical evidence that justifies the additional costs involved.

Level III.

This study aimed to describe a surgical procedure for the management of corticosteroid-induced osteonecrosis of the femoral head (ONFH) and report its clinical results. The technique included harvesting a bone plug from the lateral femoral neck, core decompression, and bone marrow aspirate concentrate (BMAC) application; the procedure was completed by press-fit insertion of the autologous bone plug in the debrided area. Autologous bone plug-sliding with core decompression and bone marrow concentrate aspirate application provides good clinical outcomes in the management of ONFH. A retrospective review was performed using records of patients operated on between October 2019 and June 2021. Only patients with Ficat-Arlet stage-2 ONFH, who underwent the procedure described, were included. Twenty- nine hips (18 patients) were included and evaluated clinically and radiologically. Clinical evaluation included the Harris hip score (HHS) and Visual analogue scale (VAS) for pain, while radiological evaluation included direct radiographs. The average age was 39.8 years (± 11.7, range: 24-65 years). The average follow-up was 13.5 months (± 3.4, range: 8-19 months). There were improvements in the VAS pain and Harris hip scores in all patients. Average HHS increased from 61.90 to 87.45 (p < 0.001), while the average VAS pain score decreased from 7.14 to 3.27 (p < 0.001). No complications were encountered in any of the patients during the follow-up. None of the patients had femoral head collapse on the latest radiograph or required total hip replacement. The combination of the novel autologous bone plug-sliding method with conventional regenerative methods is a successful treatment choice for ONFH.

Patellar chondral lesions can be particularly challenging to manage in younger and more active populations.

To synthesize, organize, and summarize the results and complication rates of various patellar cartilage restoration techniques.

Systematic review; Level of evidence, 4.

We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the Medline, Embase, Scopus, and Cochrane databases. Studies were included that reported on surgical treatment of patellar chondral defects with ≥5 patients and 12 months of follow-up data. Relevant demographic data from the included studies were extracted, and patient-reported outcome scores, visual analog scale for pain results, return-to-sport rate, complications, and concomitant procedures were documented.

There were 24 studies that met the inclusion criteria, with a total of 575 patients (male, n = 239; female, n = 336). In total, 6 surgical techniques were utilized. In 9 studies, the surgical procedure of choice was osteochondral autograft transplantation (OAT); 8 studies evaluated autologous chondrocyte implantation (ACI); 3 evaluated advanced microfracture/autologous matrix-induced chondrogenesis; 1 evaluated osteochondral allograft transplantation (OCA); 1 evaluated particulate juvenile articulated cartilage; and 2 evaluated a synthetic osteochondral graft. No uniform functional outcome score or assessment was utilized across studies. OAT was predominantly used for smaller chondral lesions (<2 cm²) and demonstrated minimal complication rates and satisfactory outcome scores. Advanced microfracture techniques showed promise, with improvement in outcome scores and zero complications. Matrix-induced ACI consistently exhibited higher mean improvement in the measured outcome scores and resulted in fewer complications when compared with previous generations of ACI.

OAT and ACI were the most studied procedures for isolated patellar chondral defects. Advanced microfracture techniques showed promise, but indications (ie, size) and variability in techniques need to be elucidated in higher-level studies. Further prospective studies comparing OCA and matrix-induced ACI for larger patellar defects are necessary to determine the superior technique.

The use of biologic materials in orthopaedics (orthobiologics) has gained significant attention over the past years. To enhance the body of the related literature, this review article is aimed at summarizing these novel biologic therapies in orthopaedics and at discussing their multiple clinical implementations and outcomes.

This review of the literature presents the methods, clinical applications, impact, cost-effectiveness, and outcomes, as well as the current indications and future perspectives of orthobiologics, namely, platelet-rich plasma, mesenchymal stem cells, bone marrow aspirate concentrate, growth factors, and tissue engineering.

Currently available studies have used variable methods of research including biologic materials as well as patient populations and outcome measurements, therefore making comparison of studies difficult. Key features for the study and use of orthobiologics include minimal invasiveness, great healing potential, and reasonable cost as a nonoperative treatment option. Their clinical applications have been described for common orthopaedic pathologies such as osteoarthritis, articular cartilage defects, bone defects and fracture nonunions, ligament injuries, and tendinopathies.

Orthobiologics-based therapies have shown noticeable clinical results at the short- and mid-term. It is crucial that these therapies remain effective and stable in the long term. The optimal design for a successful scaffold remains to be further determined.

Solid bone marrow aspirate concentrate (sBMAC) is harvested from bone marrow aspirate without anticoagulants by a centrifugation protocol similar to that for platelet-rich fibrin (PRF) prepared from peripheral blood. It was hypothesized that sBMAC could accelerate not only wound healing but also bone regeneration because of the abundant growth factor (GF) releases from enriched bone marrow cells. The purpose of the present study was to investigate skin wound healing and bone regenerative potential of sBMAC compared with arterial blood-derived PRF (Ar-PRF) and venous blood-derived PRF (Ve-PRF) in a skin defect and calvarial bone defect model in rabbits. GF release assays revealed significantly higher release of transforming growth factor-β (TGF-β), alkaline phosphatase (ALP), and osteocalcin (OCN) from sBMAC compared with PRFs for 24 h. In the skin defect animal model, sBMAC and PRFs promoted wound bed angiogenesis and re-epithelization in skin defect sites with higher collagen 1 synthesis, cytokeratin AE1/AE3, vascular endothelial growth factor (VEGF) expressions on week 1. Furthermore, a calvarial defect assay revealed that sBMAC promoted new bone formation with a sufficient bone marrow structure similar to that of intact bone in the bone defects. Ar-PRF achieved the second highest bone closure and new bone volume but yielded new bone that was thinner than the intact bone. In conclusion, sBMAC treatment might be a good option instead of PRF as an adjuvant therapy for both skin and bone tissue regeneration therapies in certain clinical situations. Impact statement Solid bone marrow aspirate concentrate (sBMAC) is new type of clot material prepared from bone marrow aspirate. The present study for the first time showed that sBMAC significantly accelerated both skin wound healing and bone formation in the defects, compared with conventional platelet-rich fibrin in rabbit experiment models.

To assess the effectiveness of intra-articular injection of bone marrow concentrate (BMC) under ultrasound (US) guidance in the treatment of patellofemoral osteoarthritis (OA), with clinical and volumetric magnetic resonance (MR) imaging follow-up.

This retrospective study included 96 consecutive patients referred for US-guided intra-articular injection of BMC for symptomatic patellofemoral OA for which conservative treatment had failed. A control group of 21 patients with symptomatic patellofemoral OA was included for comparison. Data on International Knee Documentation Committee (IKDC), Visual Analog Scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores as well as volumetric MR imaging (using T2 mapping sequence) were collected before and 12 months after injection, and the results were compared.

No technical adverse events were noted during bone marrow aspiration, BMC preparation, or intra-articular injection of BMC. No clinical adverse events were reported during long-term follow-up. All mean scores improved between baseline and 12 months after intra-articular injection of BMC (VAS 5.5 to 3.6, P < .0001; WOMAC 36.8 to 22.2, P < .0001; and IKDC 41.8 to 58.2, P < .0001). MR imaging at 1 year of follow-up after BMC treatment showed no statistically significant difference in hyaline cartilage volume compared with that at the baseline (P = .690), suggesting stabilization of the cartilage degradation process. In contrast, the group of untreated patients showed a significant decrease in the cartilage volume (P = .001), corresponding to a cartilage loss of 6.9%.

The results suggest that intra-articular injection of BMC under US guidance could be a promising option for the treatment of symptomatic patellofemoral OA and could promote the preservation of healthy residual cartilage volume.

Intra-articular bone marrow concentrate (BMC) and aspirate (BMA) injections have been used with mixed results to treat osteoarthritis (OA). Given the various aspiration and concentration methods available for preparing bone marrow, more data are needed to identify the optimal bone marrow harvesting techniques to treat OA.

This retrospective cohort study examined the effect of using low-volume BMAs harvested using the Marrow Cellution™ (MC) device on 160 patients (262 knees) suffering from pain due to knee OA, KL grades 2-4, that did not respond to conservative treatment. Changes in visual analog scores (VAS) for overall daily activity were examined over a six-month time frame in these patients (63.5 ± 0.97 years of age; 48.1% male). In addition, changes in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Patient Global Impression of Change (PGIC scores) were examined over the same time frame in a smaller subset of patients (95 patients including 172 knees).

There was a statistically significant improvement in VAS scores for overall daily activity 6 months postprocedure in the study population, 7.29 ± 0.27 vs. 3.76 ± 0.34 (p < 0.0001), as well as statistically significant improvements in WOMAC scores, 49.3 ± 4.27 vs. 66.3 ± 4.08 (p < 0.0001). On the individual level, 71% of the cases displayed VAS improvements and 61% of the cases displayed WOMAC improvements that exceeded levels previous studies determined to be the minimal clinically important difference (MCID) for knee OA treatments. The improvements in WOMAC scores were also seen in both the WOMAC pain subscore, 52.2 ± 4.39 vs. 72.2 ± 4.36 (p < 0.0001) and the WOMAC function subscore, 51.6 ± 4.67 vs. 69.0 ± 4.36 (p < 0.0001). In addition, the PGIC scores measuring patient satisfaction improved from 4.03 ± 0.26 at 6 weeks postprocedure to 4.65 ± 0.28 at 6 months postprocedure (p < 0.0001).

Knee OA patients treated with MC BMA intra-articular injections exhibited significant reductions in VAS pain scores and significant improvements in WOMAC scores that exceeded the minimal clinically important difference thresholds. In addition, reductions in VAS pain scores and improvements in WOMAC scores correlated with higher PGIC scores.

Currently, there are no effective clinical or experimental treatments to fully restore the function of the torn acetabular labrum. To fill the gap, here, we report the finding of progenitor cells in labral tissue, which can be recruited and stimulated to repair torn acetabular labral tissue. This study aimed to develop a biomolecule releasing bioadhesive which can speed up labral tissue healing by eliciting autologous labral progenitor cellular responses. A click chemistry-based bioadhesive, capable of releasing biomolecules, was synthesized to exert ~3× adhesion strength compared with fibrin glue. Via the release of platelet-derived growth factor (PDGF), the adhesive was shown to actively recruit and stimulate the proliferation of labral progenitor cells to the tear sites and within the adhesive. Finally, the ability of this biomolecules-releasing adhesive designed to promote labral tissue regeneration was evaluated using discarded human acetabular labrum tissue compared with surgical suture ex vivo. Histological analysis shows that PDGF-releasing bioadhesive yielded significantly more labrum cell responses and extracellular matrix protein (proteoglycan and collagen) production at the tear tissue site than surgical suture controls. The results confirm that the new PDGF-releasing bioadhesive can activate the responses of autologous labral progenitor cells to significantly improve labral tissue regeneration. Clinical significance: These PDGF-releasing bioadhesives may serve as a new and effective tool for repairing and regenerating acetabular labrum tears.

Articular cartilage (AC) injuries do not heal primarily and large lesions progress to degenerative osteoarthritis. Osteochondral allograft transplantation is an effective surgical treatment but is limited by the lack of donor tissue availability. Fresh allografts can be stored hypothermically up to 28-45 days after which the tissue is no longer viable for transplantation. Vitrification is a method of cryopreservation with the potential to extend the storage time of AC. A specific protocol has been demonstrated to preserve high chondrocyte viability; however, its effect on various mechanical properties of the extracellular matrix (ECM) remains unknown and is the focus of this initial study. Porcine AC was subject to a defined vitrification protocol, using fresh and frozen samples as positive and negative controls, respectively; n = 20 for all three groups. Unconfined compression testing was used to assess mechanical properties of the tissue under rapid load, stress relaxation, and equilibrium conditions. The stress relaxation time constants (modeled with a 2-term Prony series) τ1 and τ2 were significantly lower for frozen (p = 0.014, p < 0.001) and vitrified (p = 0.009, p = 0.003) tissue compared to fresh, with no differences between frozen and vitrified samples (p = 0.848 and 0.105 for τ1 and τ2, respectively). These values indicate that frozen and vitrified samples relaxed more rapidly than fresh, which may suggest altered matrix composition and permeability post-treatment. These results represent the initial study in our experimental path to evaluate differences in mechanical properties of vitrified tissues.

Intra-articular injections of autologous, minimally manipulated, cell therapies such as bone marrow concentrate (BMC) to treat knee osteoarthritis (OA) may delay or prevent future total knee arthroplasty (TKA). Arthroplasty has the known and substantial risk of venous thromboembolism (VTE) and requires routine prophylaxis, whereas the VTE risk associated with knee BMC injections is unknown. We report on the rate of VTE from a large orthobiologics patient registry and assess whether knee BMC procedures require routine prophylaxis.

A retrospective analysis of knee osteoarthritis cases tracked in a treatment registry and treated at 72 clinical sites with BMC from 2007 to 2020 who were not prophylactically anticoagulated was performed to identify adverse events (AEs) associated with VTE. Treating physicians were contacted to improve discovery of possible occurrences of VTE.

Twenty cases (0.16%) of VTE were identified from the registry of 12,780 knee BMC treatments. These events were less frequent than the published data demonstrate for anticoagulated TKA patients.

Based on the rates of VTE from our retrospective treatment registry analysis compared to the risk of medication-induced haemorrhage, routine prophylactic anticoagulation is not recommended for intra-articular knee BMC procedures. Further research into safety and efficacy of BMC treatment for knee OA is warranted.

NCT03011398, retrospectively registered.

Bone marrow aspirate concentrate (BMAC) has emerged as a therapeutic option for symptomatic knee osteoarthritis (OA).

To systematically review the literature to evaluate the efficacy of isolated BMAC injection in the treatment of OA of the knee joint.

Systematic review; Level of evidence, 4.

A systematic review was performed by searching the PubMed, Embase, and Cochrane Library databases up to July 2020 to identify human studies that assessed the clinical outcomes of isolated BMAC injection for the treatment of knee OA. The electronic search strategy used was "bone marrow aspirate concentrate knee osteoarthritis."

Eight studies met the inclusion criteria, including a total of 299 knees with a mean follow-up of 12.9 months (range, 6-30 months). Of all patient-reported outcomes assessed across studies, 34 of 36 (94.4%) demonstrated significant improvement from baseline to latest follow-up (P < .05). Five studies evaluating numerical pain scores (visual analog scale and Numeric Rating Scale) reported significant improvements in pain level at final follow-up (P < .01). However, 3 comparative studies evaluating BMAC in relation to other therapeutic injections failed to demonstrate the clinical superiority of BMAC.

The BMAC injection is effective in improving pain and patient-reported outcomes in patients with knee OA at short- to midterm follow-up. Nevertheless, BMAC has not demonstrated clinical superiority in relation to other biologic therapies commonly used in the treatment of OA, including platelet-rich plasma and microfragmented adipose tissue, or in relation to placebo. The high cost of the BMAC injection in comparison with other biologic and nonoperative treatment modalities may limit its utility despite demonstrable clinical benefit.

This article is dedicated to the use of orthobiologic therapies in the management of early osteoarthritis in middle-aged athletes. Understanding a patient's presenting symptoms, physical examination, imaging results, and goals is of critical importance in applying orthobiologic therapies. The field of orthobiologics is expanding at a rapid pace, and the clinical studies examining the utility of each treatment lag behind the direct-to-consumer marketing that leads to these products being used. Here we provide a review of the available treatments, emerging treatments, and the current literature supporting or refuting their use. Currently studied orthobiologics include autologous and allogenic cell therapies, autologous blood products, hyaluronic acid, gene therapies, Wnt inhibitors, and a variety of systemic treatments.

Bone marrow aspirate concentrate (BMAC) therapy has been spotlighted as a promising regenerative tool with its abundant source of mesenchymal stromal cells (MSCs) and growth factors. The spectrum of the utility of BMAC therapy has been expanding day by day to harness the potential for varied therapeutic purposes. In the due course of its evolution, it is often essential to have a comprehensive summary of progress to have a greater understanding and refine our future directives. With technological developments such as data mining, graphic drawing and information analytics combined with computational statistics, visualization of scientific metrology has become a reality. With this newer perspective, we intend to use scientometric tools including text mining, cocitation analysis, keyword analysis and cluster network analysis to perform thematic trend mapping and hotspot analysis of the literature on BMAC therapy and evaluate its progress in the management of osteoarthritis.

Platelet-rich fibrin (PRF) prepared from venous blood is used in the clinic to improve soft tissue wound healing. Nevertheless, arterial blood or bone marrow aspirate might also be a candidate for the source of PRF-like concentrates. The purpose of the present study was to investigate blood/bone marrow aspirate concentrates obtained from arterial blood, venous blood, and bone marrow aspirate to determine its respective regenerative potential in vitro. Arterial blood-derived PRF (Ar-PRF), venous blood-derived PRF (Ve-PRF), and solid bone marrow aspirate concentrate (sBMAC) were prepared from New Zealand white rabbits. Each clot was evaluated for its cytocompatibility and regenerative potential on primary rabbit gingival fibroblasts and osteoblasts. Both gingival fibroblasts and osteoblasts treated with each concentrate showed excellent viability. Interestingly, the sBMAC-treated cells demonstrated significantly greater migratory potential than the other treatment groups. Furthermore, higher mRNA levels of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF) and collagen I (COL1) in gingival fibroblasts were observed in sBMAC group compared with Ar-PRF and Ve-PRF groups. Greater osteoblast differentiation potential, including higher osteocalcin (OCN) expression and mineralization potential, was found in osteoblasts treated with sBMAC. However, minor differences between the behaviors of cells treated with Ar-PRF and Ve-PRF were observed. In conclusion, sBMAC might be a new candidate for promoting wound healing and bone regeneration. Further preclinical and clinical experiments are necessary to prove the regenerative potential of sBMAC in the body.

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.