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Background: The delivery of therapeutic genes in sites of articular cartilage lesions using non-invasive, scaffold-guided gene therapy procedures is a promising approach to stimulate cartilage repair while protecting the cargos from detrimental immune responses, particularly when targeting chondroreparative bone marrow-derived mesenchymal stromal cells in a natural microenvironment like marrow aspirates. Methods: Here, we evaluated the benefits of providing a sequence for the cartilage-specific sex-determining region Y-type high-mobility group box 9 (SOX9) transcription factor to human marrow aspirates via recombinant adeno-associated virus (rAAV) vectors delivered by poly(ε-caprolactone) (PCL) films functionalized via grafting with poly(sodium styrene sulfonate) (pNaSS) to enhance the marrow chondrogenic potential over time. Results: Effective sox9 overexpression was observed in aspirates treated with pNaSS-grafted or ungrafted PCL films coated with the candidate rAAV-FLAG-hsox9 (FLAG-tagged rAAV vector carrying a human sox9 gene sequence) vector for at least 21 days relative to other conditions (pNaSS-grafted and ungrafted PCL films without vector coating). Overexpression of sox9 via rAAV sox9/pNaSS-grafted or ungrafted PCL films led to increased biological and chondrogenic differentiation activities (matrix deposition) in the aspirates while containing premature osteogenesis and hypertrophy without impacting cell proliferation, with more potent effects noted when using pNaSS-grafted films. Conclusions: These findings show the benefits of targeting patients’ bone marrow via PCL film-guided therapeutic rAAV (sox9) delivery as an off-the-shelf system for future strategies to enhance cartilage repair in translational applications.

In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, and sertraline, from various biological fluids. In this regard, poly(3,4-ethylenedioxythiophene)–graphene oxide (PEDOT-GO) was electrodeposited on an SPME fiber as a conductive coating, then the fiber played the acceptor-electrode role during the extraction. Thus, the immigration of the analytes under the influence of an electric field and their absorption onto the fiber coating were accomplished simultaneously. Under the optimized conditions, the limits of detection for the target analytes were acquired in the range of 0.005–0.025 µg L−1 using gas chromatography–mass spectrometry. The linearity of the method was 0.010–500 µg L−1 for the imipramine and sertraline, 0.025–500 µg L−1 for the amitriptyline, nortriptyline, and desipramine, and 1.000–250 µg L−1 for the maprotiline (R2 ≥ 0.9984). Moreover, this method provided suitable precision and fiber-to-fiber reproducibility, with RSDs ≤ 8.4%. The applicability of the proposed setup was eventually investigated for extraction of the drugs from human bone marrow aspirate, urine, plasma, and well water samples, in which satisfactory relative recoveries, from 93–105%, were obtained.

Background Transplantation of genetically modified bone marrow concentrates is an attractive approach to conveniently activate the chondrogenic differentiation processes as a means to improve the intrinsic repair capacities of damaged articular cartilage. Methods Human bone marrow aspirates were co-transduced with recombinant adeno-associated virus (rAAV) vectors to overexpress the pleiotropic transformation growth factor beta (TGF-β) and the cartilage-specific transcription factor sox9 as a means to enhance the chondroreparative processes in conditions of specific lineage differentiation. Results Successful TGF-β/ sox9 combined gene transfer and overexpression via rAAV was achieved in chondrogenically induced human bone marrow aspirates for up to 21 days, the longest time point evaluated, leading to increased proliferation, matrix synthesis, and chondrogenic differentiation relative to control treatments (reporter lacZ treatment, absence of vector application) especially when co-applying the candidate vectors at the highest vector doses tested. Optimal co-administration of TGF-β with sox9 also advantageously reduced hypertrophic differentiation in the aspirates. Conclusions These findings report the possibility of directly modifying bone marrow aspirates by combined therapeutic gene transfer as a potent and convenient future approach to improve the repair of articular cartilage lesions.

Background Application of genetically modified bone marrow concentrates in articular cartilage lesions is a promising approach to enhance cartilage repair by stimulating the chondrogenic differentiation processes in sites of injury. Method In the present study, we examined the potential benefits of transferring the proliferative and pro-chondrogenic basic fibroblast growth factor (FGF-2) to human bone marrow aspirates in vitro using the clinically adapted recombinant adeno-associated virus (rAAV) vectors to monitor the biological and chondrogenic responses over time to the treatment compared with control ( lacZ ) gene application. Results Effective, significant FGF-2 gene transfer and expression via rAAV was established in the aspirates relative to the lacZ condition (from ~ 97 to 36 pg rhFGF-2/mg total proteins over an extended period of 21 days). Administration of the candidate FGF-2 vector led to prolonged increases in cell proliferation, matrix synthesis, and chondrogenesis but also to hypertrophic and terminal differentiation in the aspirates. Conclusion The present evaluation shows the advantages of rAAV-mediated FGF-2 gene transfer to conveniently modify bone marrow concentrates as a future approach to directly treat articular cartilage lesions, provided that expression of the growth factor is tightly regulated to prevent premature hypertrophy in vivo.

Human bone marrow (BM) is a kind of source of mesenchymal stem cells (MSCs) as well as growth factors and cytokines that may aid anti-inflammation and regeneration for various tissues, including cartilage and bone. However, since MSCs in BM usually occupy only a small fraction (0.001%) of nucleated cells, bone marrow aspirate concentrate (BMAC) for cartilage pathologies, such as cartilage degeneration, defect, and osteoarthritis, have gained considerable recognition in the last few years due to its potential benefits including disease modifying and regenerative capacity. Although further research with well-designed, randomized, controlled clinical trials is needed to elucidate the exact mechanism of BMAC, this may have the most noteworthy effect in patients with osteoarthritis. The purpose of this article is to review the general characteristics of BMAC, including its constituent, action mechanisms, and related issues. Moreover, this article aims to summarize the clinical outcomes of BMAC reported to date.

Purpose The fracture stage of non-traumatic osteonecrosis (ON stage 3) of the femoral head (ONFH) has an unfavourable prognosis frequently requiring total hip replacement (THR). The percentage could be lowered after core decompression. In earlier non-fracture ON stages, implantation of autologous bone marrow aspirate concentrate (BMAC) improved the effect of core decompression. The purpose was to evaluate the effect of BMAC in addition to core decompression in stage 3 ONFH. Methods A double blind RCT was conducted comparing two groups: core decompression plus saline injection or core decompression plus BMAC implantation. Both patients and assessors were blinded to the treatment assignments. Evaluations were done at baseline, three, six, 12, and 24 months, including pain (VAS), WOMAC, side-effects, radiological evolution including ARCO subclassifications, together with possible THR requirement. The primary endpoint was the need for THR. The second endpoints included the clinical symptoms such as pain and functional ability and the progression of the ON lesions as well as the appearance of osteoarthritis features (ARCO stage 4). Both groups included 23 hips (19 patients). Results No differences were found between the groups for THR requirements, clinical tests, and radiological evolution. In both groups, 15/23 hips needed THR. The radiological evolution of the ONFH lesions in term of location, extension, surface collapse, and dome depression was moderate in both groups and was not correlated with the need of THR. Conclusions Implantation of BMAC after core decompression did not produce any improvement of the evolution of ONFH stage 3. Level of evidence I.

Background   The use of bone morphogenic protein (BMP-2) in adult spine deformity (ASD) surgery remains controversial more than two decades following its approval for clinical application in spine surgery. This study was performed to assess outcomes in patients undergoing ASD surgery with BMP application compared with a combination of bone marrow aspirate, cancellous bone chips and i-Factor. Methods This was a retrospective cohort study. ASD patients were stratified by use of intra-operative BMP (BMP +) or not (BMA + I) and surveyed for the development of complications and mechanical failure. Quality of life gained following the procedure was evaluated using quality-adjusted life years (QALYs). Cost was calculated using the PearlDiver database and CMS definitions. Multivariable analyses (ANCOVA) and logistic regression were used to adjust for confounding. Results 512 patients were included (60% BMP +). At baseline, BMP + patients were older (62.5 vs 60.8 years, p  < 0.010). Radiographic and quality-of-life metrics did not differ at follow up timepoints (all p > 0.05). BMP use was associated with higher supplemental rod use (OR: 7.0, 1.9 – 26.2, p  = 0.004), greater number of levels fused (OR: 1.1, 1.03 – 1.17, p  = 0.003) and greater neurological complications (OR: 5.0, 1.3 – 18.7, p  = 0.017). Controlling for rod use and levels fused, BMP use was not associated with a lower risk of mechanical complications (OR 0.3, 95% CI: 0.2 – 3.0, p  = 0.353), rod breakage (OR: 3.3, 0.6 – 18.7, p  = 0.182) or implant failure (OR: 0.3, 0.04 – 1.51). At 2 years, the BMP + cohort exhibited higher overall costs ($108,062 vs $95,144, p  = 0.002), comparable QALYs (0.163 vs 0.171, p  = 0.65) and higher cost per QALY ( p  = 0.001) at two years. Conclusions In this analysis, BMP-2 application was not associated with superior outcomes when compared to a less costly biologic alternative (bone marrow aspirate + cancellous bone chips + i-Factor) following ASD surgery. The use of BMP-2 in ASD surgery appears to have reduced cost-efficacy at two years postoperatively.

Purpose Fracture healing encompasses a succession of dynamic multifactorial metabolic events, which ultimately re-establishes the integrity of the biomechanical properties of the bone. Up to 10% of the fractures occurring annually will need additional surgical procedures because of impaired healing. The aim of this article is to review the current literature regarding the use of bone marrow aspirate concentrate (BMAC) and its effectiveness in the management of bone defects. Methods We have included all published clinical literature investigating the development, techniques and applications of BMAC. Language, design and risk of bias did not deter the initial inclusion of any study. Our search was exclusively limited to studies involving human subjects. A PRISMA compliant search was carried out as published in 2009. This included the online databases: PubMed, EMBASE, clinical trial.gov and the Cochrane library from 1960 to the end of May 2015. MeSH terms used included: “Bone” AND “Marrow” AND “Aspirate” AND “Concentrate” AND “Bone Defects” AND “NONUNION”. Eligible studies were independently appraised by two authors using the Critical Appraisal Skills Program checklist. For the purpose of narrative review, relevant studies were included irrespective of methodology or level of evidence. Results Thirty-four of the 103 (48 PubMed and 55 EMBASE) results yielded by the preliminary search were included. Exclusions included three duplicate records, six letters, 17 non-orthopaedics related studies and four records irrelevant to our search topic. The CASP appraisal confirmed a satisfactory standard of 31 studies. They all had clearly defined objectives, were well designed and conducted appropriately to meet them. The published studies reported the use of BMAC in non-union and fracture healing (15 studies), bone defects (nine studies), spine fusion (two studies), distraction osteogensis (two studies) and complications related to the use of BMAC (seven studies). Conclusions Stem cells found in BMAC have the potential to self-renew, undertake clonal expansion and differentiate into different musculoskeletal tissues. The commercial processing of BMAC needs to be optimized in order to achieve a consistent end product, which will provide predicable and translatable results. The future potential of cell characterization in order to determine the optimum cell for repair/regeneration of bone also needs to be explored. Level of Evidence: Systematic Review of minimum level IV studies.

Purpose This study had two primary aims: (1) to evaluate the clinical efficacy of fluoroscopically-guided subchondral autologous bone marrow aspirate concentrate (BMAC) injection for reducing pain and improving function in patients with knee osteoarthritis (OA)-associated bone marrow lesions (BMLs), we hypothesized significant improvements across validated outcome measures at 12 months; and (2) to assess early radiologic changes in BML severity using MRI, hypothesizing a significant reduction in MOAKS scores at 3 months. Secondary aims evaluated subgroup differences by age and body mass index (BMI), with age stratified as ≤ 50, 50–60, 60–70, and > 70 years, and hypothesizing superior outcomes in younger patients and those with lower BMI. Methods Retrospective evaluation of consecutive patients aged ≥ 18 years, with symptomatic knee OA and MRI-confirmed femoral or tibial subchondral BMLs, who underwent treatment between September 2022 and March 2024, with 12-month follow-ups ending in March 2025. Inclusion required BMI 18–30 kg/m 2 , neutral/varus limb alignment without deformity, intact cruciate ligaments/menisci, and no intra-articular injections within 12 months. Exclusion criteria included infection, BMI > 30 kg/m 2 , ligament/meniscal injuries, or prior cellular therapy. Autologous BMAC was harvested from the posterior superior iliac crest, concentrated via density gradient centrifugation, and injected subchondrally under C-arm fluoroscopy. Primary outcomes included the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Visual Analog Scale (VAS) at baseline and at 1, 3, 6, and 12 months. The secondary outcome was the MRI Osteoarthritis Knee Score (MOAKS) at baseline and at 3 months. Repeated measures ANOVA/Friedman tests were used; p  < 0.05 was considered significant. Results 62 patients (mean age 57.7 ± 12.9 years; 56.5% female; mean BMI 24.4 ± 3.7 kg/m 2 ; 12-month follow-up) demonstrated significant improvements across all KOOS subscales ( p  < 0.001), WOMAC ( p  < 0.001), and VAS ( p  < 0.001) versus baseline. MOAKS scores reduced significantly at 3 months ( p  < 0.001). Patients with BMI < 24 kg/m 2 showed superior KOOS-pain improvement at 12 months ( p  = 0.043) and within this group, MOAKS scores significantly improved at 3 months ( p  < 0.001). Patients ≤ 60 years exhibited greater VAS reduction at 1 month ( p  = 0.021) than those > 70 years. Conclusion In this retrospective case series, fluoroscopically guided subchondral BMAC injection was associated with significant and sustained clinical improvement in pain and function over 12 months, alongside an early reduction in MRI-detected bone marrow lesion severity at 3 months. Because MRI assessment was limited to the early postoperative period, no conclusions can be drawn regarding the durability of structural changes or lesion resolution. These findings are encouraging and warrant confirmation in randomized controlled trials incorporating longer-term and quantitative MRI follow-up. Level of Evidence IV

Purpose The aim of this study was to evaluate the clinical and imaging findings up to 24 months of follow-up in patients treated with combined subchondral and intra-articular bone marrow aspirate concentrate (BMAC) injections for the treatment of knee osteoarthritis (OA). Methods Thirty consecutive patients (19 males, 11 females) aged between 40 and 75 years (mean age 56.4 ± 8.1 years) with unilateral symptomatic knee OA (Kellgren–Lawrence 2–3) were included in the study. Patients were treated with combined intra-articular and subchondral bone BMAC injections (total 9 ml) under fluoroscopic control. IKDC subjective score, VAS for pain, KOOS, and EQ-VAS were prospectively evaluated up to 24 months. Radiographs were performed at baseline and at 24 months after the procedure. MRI was evaluated with the WORMS score at baseline, 6–12 months, and 24 months of follow-up. The statistical analysis was performed using SPSS v.19.0 and for all tests p  < 0.05 was considered significant. Results No major complications and a 13% failure rate were reported. The IKDC subjective score remained stable from 62.6 ± 19.4 at 12 months to 63.4 ± 17.1 at 24 months (both p  < 0.0005 compared to baseline, 40.5 ± 12.5). Similar improvements were reported for all KOOS subscales, while EQ-VAS did not report any significant improvement. VAS pain worsened from 3.0 ± 1.9 at 12 months to 4.4 ± 1.8 at the final follow-up ( p  = 0.0001), although remaining lower compared to the baseline value of 6.3 ± 1.8 ( p  = 0.002). The radiographic evaluation did not reveal signs of improvement or deterioration of the OA grade. The MRI findings showed a worsening in marginal osteophytes and synovitis, but a significant reduction of bone marrow edema at 24 months ( p  < 0.0005). Conclusion Combined intra-articular and subchondral BMAC injections provided clinical and imaging benefits up to 24 months for the treatment of symptomatic knee OA, with durable clinical results, a low failure rate, and a significant reduction of bone marrow edema.