Search Results (104)

Background: Ankle osteoarthritis (OA) differs fundamentally from knee OA: it is predominantly post-traumatic, affects younger and more active patients, and frequently arises from focal osteochondral lesions of the talus (OCLT) rather than diffuse degeneration. Cell-based and orthobiologic therapies—bone marrow aspirate concentrate (BMAC), bone marrow-derived cell transplantation (BMDC), adipose-derived mesenchymal stromal cells (ADMSCs), stromal vascular fraction (SVF), micro-fragmented adipose tissue (mFAT), and peripheral blood-derived products—have been proposed as joint-preserving options, but the evidence base has not been mapped in a way that separates degenerative post-traumatic ankle OA from focal chondral repair, or that distinguishes cells given as a standalone injection from cells given alongside a therapeutic operation. Methods: We conducted a systematic scoping review following the PRISMA-ScR framework. Human clinical studies applying cell-based therapies to post-traumatic ankle OA and/or OCLT were charted by population, cell source and preparation, mode of delivery, concomitant procedures, follow-up, and reported clinical and structural outcomes. Mode of delivery—standalone intra-articular injection versus adjunct to a concomitant surgical procedure—was pre-specified as a primary analytic axis, because it determines whether an observed effect can be attributed to the cell product at all. Given anticipated clinical and product heterogeneity and the near-absence of controlled trials of standalone injection, no meta-analysis was undertaken; the objective was to map the evidence, characterise its structure, and identify gaps. Results: Eleven clinical studies were charted. The dominant structural feature of this literature is that in nine of 11 studies the cells were co-administered with a therapeutic surgical procedure—marrow stimulation, autologous osteochondral transplantation, supramalleolar or calcaneal osteotomy, or joint debridement—so that in no charted study can the contribution of the cells be separated from that of the operation. This attribution problem, rather than any efficacy estimate, is the principal finding of the review. The remaining evidence is small, heterogeneous, and uniformly non-randomised (Level of Evidence III–V). Only two studies used standalone injection, and for degenerative post-traumatic ankle OA specifically, the standalone-injection evidence consists of a single case report. Reported clinical outcomes (AOFAS, VAS, FAOS/KOOS, Tegner) and structural surrogates (MOCART, T2-mapping, second-look arthroscopy) were generally favourable, and adverse events were mild and self-limiting; however, no study demonstrated histologically confirmed hyaline regeneration, and no adequately powered randomised trial of standalone injection for degenerative post-traumatic ankle OA was identified. Conclusions: Cell-based therapies for post-traumatic ankle OA and OCLT show promising but preliminary, hypothesis-generating signals within a fragmented evidence base in which the cellular contribution is confounded by concomitant surgery in nine of 11 charted studies; on present evidence, the field cannot claim an independent effect for the cell product. The knee OA evidence cannot be extrapolated to the ankle because of the joint’s distinct biology, aetiology, and lesion pattern. Adequately powered randomised trials of standalone intra-articular injection in well-defined degenerative post-traumatic ankle OA, using standardised product characterisation and a core outcome set with quantitative structural endpoints, are the principal advance needed. Full article

Background/Objectives: The anticoagulant used for blood collection is a fundamental but underexplored variable in platelet-rich plasma (PRP) preparation. Ethylenediaminetetraacetic acid (EDTA) and sodium citrate act on platelets through distinct calcium chelation mechanisms with potentially different consequences for PRP quality. Our group has previously demonstrated that biological and demographic variables independently modulate platelet composition in PRP; the present study extends this analysis to the pre-analytical anticoagulant variable. No prospective paired clinical study has systematically compared the effects of EDTA and sodium citrate on platelet morphological parameters in a real clinical setting. This study aimed to characterise these differences and evaluate their implications for orthobiologic therapy. Methods: A prospective within-subject paired-sample study was conducted at Instituto Cugat—Quirónsalud Barcelona (November 2025–April 2026). Twenty-six consecutive adult patients undergoing routine blood extraction prior to orthopaedic procedures had blood drawn simultaneously into K₂-EDTA and sodium citrate (3.2%) tubes. Full haematological analysis was performed on a Sysmex XN automated analyser within 30 min. Primary outcomes were mean platelet volume (MPV), platelet distribution width (PDW), large platelet ratio (P-LCR), large platelet cell count (P-LCC), and plateletcrit (PCT). Statistical comparisons used the paired t-test or Wilcoxon signed-rank test; effect sizes were quantified as Cohen’s d. Results: Seven of eight platelet-related parameters differed significantly between anticoagulants (all p < 0.001). Compared to sodium citrate, EDTA produced systematically higher MPV (+10.1%, d = 2.81), P-LCR (+25.8%, d = 2.41), P-LCC (+24.3%, d = 1.70), PDW (+13.5%, d = 1.33), PCT (+7.3%, d = 0.78), RDW-CV (+2.0%, d = 0.83), and RDW-SD (+2.6%, d = 0.80). MPV was higher with EDTA in all 26/26 paired samples without exception. Total platelet count did not differ significantly (p = 0.135). Effect sizes for all morphological parameters were large (d ≥ 0.78). Conclusions: EDTA is associated with large, reproducible, and universal platelet morphological changes consistent with calcium chelation-induced artefact, not genuine platelet hypertrophy. These artefactual changes systematically overestimate platelet size and large platelet indices by up to 26%, with direct implications for PRP quality assessment in orthobiologic medicine. Sodium citrate should remain the anticoagulant of choice for PRP preparation. Clinicians using EDTA must recognise that morphological parameters do not reflect functional platelet capacity. Full article

Bone marrow aspirate concentrate (BMAC) is widely used as a source of mesenchymal stromal/stem cells (MSCs) for musculoskeletal regeneration; however, BMAC lacks essential bone marrow extracellular matrix (ECM) components, a critical component of the stem cell niche that regulates MSC survival, paracrine signaling, and regenerative capacity. We previously demonstrated that an ECM-retaining micronized bone marrow product (BMAX™) preserves pro-regenerative MSC phenotypes in vitro. Human bone marrow from a single donor was processed into conventional BMAC or BMAX™. Post-traumatic osteoarthritis was induced in immunodeficient rats using destabilization of the medial meniscus (DMM). Four weeks after surgery, animals were randomly assigned to receive intra-articular injections of BMAX™, BMAC, or phosphate-buffered saline (n = 10–12 in each group). Pain-related behavior (n = 5–6/group), histological assessment (n = 3–6/group), and micro-computed tomography (n = 4–6/group) were evaluated for up to 8 weeks after treatment. At 4 weeks after treatment, BMAC significantly increased the paw withdrawal threshold compared with PBS (p = 0.0068), whereas BMAX™ significantly reduced knee joint swelling compared with both PBS (p = 0.0235) and BMAC (p = 0.0039), and BMAX™ significantly improved knee bend scores compared with PBS (p = 0.0011). Neither treatment significantly improved OARSI histological scores at this time point. At 8 weeks after treatment, BMAX™ significantly increased the paw withdrawal threshold compared with PBS (p = 0.0305), whereas BMAC showed a non-significant trend (p = 0.0517); both treatments significantly reduced knee bend scores compared with PBS (p = 0.0027 and p = 0.0255), and BMAX™ demonstrated significantly lower knee bend scores than BMAC (p = 0.0090). BMAX™ significantly reduced knee swelling compared with PBS (p = 0.0196). Histologically, BMAX™ significantly improved OARSI scores in both the femoral condyle and tibial plateau compared with PBS (p = 0.0020 and p = 0.0003, respectively), whereas BMAC significantly improved only tibial plateau OARSI scores (p = 0.0014). Furthermore, BMAX™ demonstrated significantly lower femoral condyle OARSI scores than BMAC (p = 0.0243). Micro-computed tomography revealed that both BMAX™ and BMAC significantly reduced medial subchondral trabecular separation compared with PBS (p = 0.0340 and p = 0.0426, respectively), whereas no significant differences were observed between the two treatment groups for other bone structural parameters. In conclusion, preservation of the native bone marrow ECM was associated with improved functional outcomes and greater cartilage regeneration compared with conventional BMAC in this preclinical rat model of post-traumatic osteoarthritis. These findings support the concept that maintaining the native stem cell niche may enhance the therapeutic potential of bone marrow-derived cell therapies for osteoarthritis. Full article

Osteoarthritis (OA) is characterized by interactions among inflammatory and extracellular matrix mediators that may not be fully captured through individual evaluation. This study investigated the multivariate organization and temporal dynamics of selected mediators in a lipopolysaccharide-challenged in vitro canine OA cartilage–synovium explant coculture system treated with platelet-rich gel supernatant (PRGS) and platelet-poor gel supernatant (PPGS). Tissue explants obtained from six dogs were exposed to PRGS or PPGS at 25% and 50% concentrations. Interleukin-1β (IL-1β), IL-10, transforming growth factor beta 1, platelet-derived growth factor BB, and hyaluronic acid were quantified at 1 and 48 h. Principal component analyses (PCA) were performed using both individual mediator concentrations and biologically relevant mediator ratios, which were intended to capture the balance among inflammatory, regulatory, GF-related, and matrix-associated responses beyond absolute mediator concentrations alone, and principal component scores were evaluated using linear mixed-effects models. Mediator-based PCA revealed that variability was distributed across multiple dimensions, with significant treatment, time, and treatment × time effects detected in different principal components. Ratio-based PCA concentrated a larger proportion of total variance within the first two components (81.1%) than mediator-based PCA (61.4%) and identified treatment- and time-related effects involving regulatory and matrix-associated mediator balances. Ratio-derived PCA showed greater structural stability across resampling analyses than the mediator-based approach. PRGS 50% generated the most pronounced multivariate separation, particularly within components associated with GF- and matrix-related mediator profiles. These findings indicate that biologically relevant mediator ratios provide complementary information regarding the organization of inflammatory and regenerative responses in this experimental system. Full article

Musculoskeletal pain is driven by degenerative conditions such as osteoarthritis or intervertebral disk degeneration. This creates a major burden on health systems and patient quality of life. Platelet-rich plasma (PRP) is an orthobiologic that contains platelets and growth factors which promote angiogenesis, modulate inflammation, and support tissue repair. Mechanobiology is central in the healing process, where mechanical loading regulates cellular behavior through mechanotransduction pathways including integrin/FAK and RhoA/ROCK. This use of signaling pathways allows for regeneration along multiple different tissue types. Evidence suggests that PRP and mechanical loading may act together to promote tissue repair, with PRP-derived signals interacting with biomechanical cues to enhance fibroblast activation, remodeling, and regenerative responses. There is variability in PRP preparation, rehabilitation protocols, and tissue-specific responses, which all highlight the need for a more standardized and guided treatment strategy. Understanding the interplay between PRP-derived biologic signaling and mechanobiologic pathways may help inform the development of more standardized, tissue-specific regenerative treatment strategies and could potentially contribute to improved clinical outcomes in patients with musculoskeletal pain. Full article

Knee osteoarthritis is commonly managed with intra-articular therapies that differ widely in composition, mechanism, and clinical persistence, yet the duration of their benefit is discussed inconsistently, which limits practical comparison between ozone, hyaluronic acid, platelet-derived products, and cell-rich orthobiologics. In this narrative review we examine the mechanism-driven temporal behavior of these therapies, focusing on the physicochemical, biomechanical, biological, and regenerative factors that influence how long a clinical response persists. By temporal hierarchy we mean the mechanistically informed pattern by which therapies differ in the duration of their physicochemical presence, biological activity, and clinical benefit, not a ranking of efficacy or a claim of equivalence. Read against this definition, ozone occupies the shortest end of the spectrum; conventional hyaluronic acid shows intermediate persistence; modified hyaluronic acid hydrogels may extend activity through improved rheology and enzymatic resistance; platelet-rich plasma and injectable platelet-rich fibrin provide more sustained biological signaling; and bone marrow aspirate concentrate and stromal vascular fraction may act over longer periods through trophic and paracrine pathways. Heterogeneity in study design, patient selection, and outcome reporting still limits firm conclusions, and standardized reporting of product characteristics and time-related endpoints will be essential to validate or refine the proposed framework. Full article

The preparation of platelet-rich plasma (PRP) requires precise density-based centrifugation of anticoagulated whole blood to achieve an optimal hematologic bioformulation while enhancing platelet recovery efficiency. Commercial PRP systems exhibit substantial heterogeneity in processing architecture, with variable platelet yields and inconsistent cellular composition profiles. In this clinical PRP device evaluation, 70 sequential samples sourced from two independent clinical facilities were used to evaluate the performance characteristics of the XCELL 60 mL single-spin centrifugation platform. Two different PRP preparations were consistently prepared as per physician preferences: PRP-1 and PRP-2. The main differences between these two preparations were the concentration of leukocytes and reduction in red blood cells. The system was evaluated based on critical PRP performance metrics. The results demonstrated the following: (1) A consistent 8-fold increase in platelet concentration relative to baseline whole blood was achieved. (2) The average platelet capture rate (PCR) was 83%. (3) The total available platelets (TAPs) in the PRP specimen produced from both groups combined were 10.8 ± 2595 billion platelets within a final product volume of 6 mL. (4) Hematocrit values were reduced to <2–6% across sites (reduction of 94% and 84% in RBCs, respectively). Finally, (5) a customizable leukocyte content (20.9–25.4 × 10⁹/L) was achieved without comprising platelet yield. This single-spin centrifugation architecture achieved performance parity with historically preferred double-spin systems while reducing the processing time and number of preparation steps. Engineering analysis established that high-precision platelet recovery and bioformulation control are achievable through optimized single-spin centrifugal design, enabling standardized therapeutic dosing for autologous regenerative medicine applications. Full article

Background: Osteoarthritis involves the degeneration of cartilage, subchondral bone, and the synovial membrane, often associated with rotator cuff (RC) tears, causing pain and functional limitations. While non-surgical treatments can provide relief, surgery is sometimes necessary. Autologous adipose-derived mesenchymal stem cells (ADMSCs) have shown promise in tissue repair. Objective: This study compared clinical outcomes between patients treated with arthroscopic RCR alone and those treated with RCR combined with intra-articular AdMSC injection. Methods: This retrospective study included 61 patients. Group A (n = 30) underwent standard RCR, while Group B (n = 31) received RCR combined with intra-articular ADMSC injections. Participants had comparable baseline age, BMI, height, CMS, and VAS scores. Shoulder function was assessed using the Constant–Murley Score, and pain intensity was assessed using the visual analog scale at baseline, 3, 6, and 12 months. Statistical significance was set at p < 0.05. Results: At 3 months, Group B showed lower VAS scores than Group A (13.09 ± 8.34 vs. 25.14 ± 13.57, p < 0.001), while CMSs did not differ significantly (70.55 ± 23.46 vs. 63.01 ± 24.33, p = 0.223). At 6 months, Group B showed better VAS and CMSs than Group A (VAS: 5.31 ± 4.38 vs. 23.74 ± 15.72, p < 0.001; CMS: 83.29 ± 18.98 vs. 65.66 ± 11.58, p < 0.001). At 12 months, Group B maintained better VAS and CMSs than Group A (VAS: 4.45 ± 5.67 vs. 18.34 ± 12.65, p < 0.001; CMS: 85.55 ± 13.12 vs. 66.36 ± 9.38, p < 0.001). Conclusions: In this preliminary retrospective non-randomized cohort, AdMSC use as an adjunct to arthroscopic rotator cuff repair was associated with better pain and functional scores over 12 months. Because of the retrospective design and lack of imaging follow-up, these findings should be interpreted as clinical associations and require confirmation in randomized studies. Full article

Chronic joint disease is a major cause of lameness and reduced performance in sport horses and is characterized by persistent synovial inflammation and protease-mediated matrix degradation. This exploratory prospective pilot study investigated clinical outcomes and synovial biomarker changes following intra-articular administration of an α-2-macroglobulin plasma-derived preparation. Twenty client-owned sport horses were observed in the treatment group (n = 10) or a comparison group (n = 10) and monitored for up to 180 days under field conditions. Clinical outcomes were assessed longitudinally, while synovial fluid was analyzed at baseline and 30 days post-treatment only in treated horses. Mixed-effects analysis showed significant group × time interactions for American Association of Equine Practitioners (AAEP) lameness score, flexion test response, and joint effusion. Treated horses showed early and sustained improvement in clinical scores, whereas minimal changes were observed in the comparison group. At 30 days, treated horses exhibited consistent within-subject reductions in synovial total protein, total nucleated cell count, polynuclear cell percentage, pro-inflammatory cytokines (PGE₂, TNF-α, IL-6, IL-1β), matrix metalloproteinases (MMP-9, MMP-13), sulphated glycosaminoglycans, and neurogenic mediators (NGF, Substance P). These findings indicate a coherent pattern of clinical improvement associated with parallel changes in synovial biomarkers in treated horses. However, as longitudinal biomarker data were not collected in the comparison group, these observations should be interpreted as exploratory and do not establish causality. The observed findings support the rationale for further investigation of protease-targeted approaches in equine joint disease. Full article

As the population ages, the incidence and prevalence of musculoskeletal degeneration, such as osteoarthritis, increase. While the currently accepted treatment options provide symptomatic and functional improvement, they do not halt the progression of osteoarthritis. This results in the eventual need for surgery for many patients with advanced osteoarthritis. Due to the seemingly inevitable progression of OA, many clinicians and researchers have shifted their focus to regenerative therapies. Orthobiologics, a specific type of regenerative therapy designed to treat orthopedic conditions, has been gaining traction in recent years due to the utilization of autologous biological substances and synthetic peptides in healing musculoskeletal injuries and degenerative conditions. Orthobiologics can be distinguished into one of four classes: cell-based, biologic fluids-based, matrix-based, molecular-based, and based on their composition. In this review, key examples of each class, mechanism of action, and current clinical data for each agent are examined. Limitations of current orthobiologics involve a lack of standardization in the preparation and administration of each agent, as well as uniformity in assessment endpoints across different clinical studies. Lastly, we will discuss future directions of orthobiologics as a therapy for the treatment of osteoarthritis. Full article

Temporomandibular joint osteoarthritis (TMJ-OA) is a multifactorial degenerative disorder characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic inflammation, leading to pain and functional impairment in affected individuals. Despite its clinical impact, effective disease-modifying treatments remain limited, highlighting the need for innovative therapeutic approaches for treating this condition in the future. This manuscript examines the biological rationale, clinical applications, and therapeutic potential of platelet-rich plasma (PRP) and injectable platelet-rich fibrin (i-PRF) in the management of TMJ-OA. As autologous platelet-derived biomaterials, PRP and i-PRF contain high concentrations of growth factors and bioactive molecules that can modulate inflammatory responses and support tissue repair. PRP is associated with a relatively rapid release of these mediators, whereas i-PRF forms a fibrin matrix that may enable a more sustained release profile. Current clinical evidence suggests that both therapies show potential to contribute to pain reduction and may facilitate improvements in mandibular function. However, substantial heterogeneity in preparation protocols, study designs, and outcome measures limits the comparability and generalizability of these findings to the general population. Overall, PRP and i-PRF represent promising, minimally invasive regenerative strategies for managing TMJ-OA. Full article

Mesenchymal stromal/stem cells (MSCs) are increasingly investigated as intra-articular therapies for equine osteoarthritis (OA), although most studies have focused on allogeneic or combination-based approaches. Evidence supporting the use of autologous MSCs as a stand-alone treatment remains limited. The present study evaluated the safety and clinical evolution following intra-articular administration of autologous muscle-derived MSCs (mdMSCs) in horses with naturally occurring chronic OA. Thirteen horses with confirmed clinical disease were included. Each affected joint received a single injection, with the administered cell dose adapted to joint size (1 × 10⁷ or 2 × 10⁷ cells). Clinical assessments were conducted at baseline and at 6 and 12 weeks post-treatment using the American Association of Equine Practitioners (AAEP) lameness scale, together with a joint inflammation score and a composite total clinical score (TCS). Clinical scores decreased over time, with statistically significant improvements observed at both follow-up time points. Seven of thirteen horses met the predefined responder criteria based on AAEP improvement, including complete resolution of lameness in several cases. The treatment was well tolerated, with only mild and transient local reactions that resolved without intervention. These results indicate that intra-articular administration of autologous mdMSCs is associated with clinically relevant improvement in horses with chronic OA. Full article

Introduction: Orthobiologics such as Platelet-Rich Plasma (PRP) and Injectable Platelet-Rich Fibrin (i-PRF) have emerged as promising tools in regenerative medicine. However, the lack of methodological standardization and the still limited comparative characterization between these products represent significant barriers to their optimized clinical application. This comparative laboratory study aimed to characterize and differentiate PRP and i-PRF, focusing on their cellular composition, obtained volume, and total Platelet-Derived Growth Factor (PDGF-BB) content. Materials and Methods: This study was conducted with 34 individuals meeting standard blood donation criteria. Peripheral blood samples were collected from all participants. PRP was obtained using a modified double-spin centrifugation protocol, whereas i-PRF was prepared using a modified low-speed centrifugation technique. Cellularity (platelet and leukocyte counts), final produced volume, and total PDGF-BB content were assessed using complete blood count analysis and an enzyme-linked immunosorbent assay (ELISA), respectively. Statistical analysis was performed using Linear Mixed Models (LMMs). Results: Both protocols resulted in significant increases in platelet and leukocyte concentrations compared to baseline values. PRP showed significantly higher platelet and leukocyte concentrations compared with i-PRF, as well as markedly higher PDGF-BB levels. In contrast, i-PRF yielded a substantially greater final volume and enabled a higher absolute delivery of total leukocytes, whereas PRP delivered a greater absolute number of platelets. In exploratory analyses, female sex, the presence of comorbidities, and increased abdominal circumference were associated with variations in product volume and cellular composition. Discussion: These findings indicate that PRP and i-PRF exhibit distinct biological profiles in terms of cellularity, volume, and total PDGF-BB content. Whether these laboratory differences translate into distinct clinical outcomes remains unknown. The results should therefore be viewed as hypothesis-generating: they suggest that PRP and i-PRF may not be interchangeable, and that future randomized clinical trials are needed to define product-specific indications based on the target tissue and desired biological mechanism. Full article

Background/Objectives: Knee osteoarthritis (OA) is a common degenerative joint disease for which conservative treatments often provide limited long-term benefit. Adipose-derived stromal cells delivered as stromal vascular fraction (SVF) represent a minimally invasive orthobiological approach with potential anti-inflammatory and regenerative effects. This study aimed to evaluate the clinical effectiveness and safety of intra-articular autologous SVF therapy and to explore patient- and treatment-related factors influencing outcomes over one year. Methods: This single-center retrospective study included 48 patients with knee OA Kellgren–Lawrence (KL) grade II–III treated with a single intra-articular injection of autologous SVF between June 2020 and February 2022. Clinical outcomes were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline and at 3 and 12 months post-treatment. Associations between clinical outcomes and age, sex, body mass index (BMI), OA grade, and administered cell dose were analyzed. Results: Significant improvements were observed in all KOOS domains at 3 months post-treatment (p < 0.001). At 12 months, improvements remained significant across domains, although Symptom scores showed slight attenuation. Higher administered cell dose was associated with greater improvement in KOOS Quality of Life (CFU-F indicators, r_s = 0.41–0.45, p < 0.01) and Sport and Recreation (TNC indicators, r_s = 0.36–0.38, p < 0.05) at 12 months, while younger age predicted greater QoL improvement and normal BMI was associated with better Symptom outcomes. Radiographic OA severity did not significantly influence treatment response, and sex-related differences were minimal. No serious adverse events were recorded. Discussion: SVF therapy was associated with sustained functional improvement and demonstrated a favorable safety profile in patients with moderate knee OA. Although demographic and treatment-related factors showed limited influence, cell dose, BMI, and age may affect selected outcomes. Prospective controlled studies with larger cohorts and longer follow-up are required to optimize patient selection and treatment protocols. Conclusions: These findings suggest that autologous SVF therapy may represent a safe and effective complementary treatment option for patients with moderate knee osteoarthritis seeking alternatives to more invasive interventions; however, these results should be confirmed in prospective controlled studies. Full article

Type 2 diabetes mellitus (T2DM) affects approximately 10–25% of patients undergoing orthopedic procedures and is associated with impaired tissue healing, increased complication rates, and reduced responsiveness to orthobiologic therapies, including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cell (MSC) preparations. The underlying mechanisms include advanced glycation end-product accumulation, NF-κB-driven chronic inflammation, Nrf2 pathway impairment, mitochondrial dysfunction, and epigenetic diabetic memory, collectively compromising both orthobiologic product quality and the tissue microenvironment. Emerging, predominantly mechanistic evidence suggests that targeted nutritional interventions, including bioactive compounds targeting mitochondrial biogenesis pathways, anti-inflammatory dietary patterns, and specific micronutrients, may modulate these pathological processes and potentially improve orthobiologic outcomes. This narrative review synthesizes evidence from diabetic pathophysiology, orthobiologic outcomes research, and nutritional science to propose a conceptual clinical framework for regenerative medicine optimization in T2DM patients. Critical knowledge gaps are identified, and a research agenda is proposed. The proposed framework, based primarily on mechanistic and preclinical evidence, should be interpreted as a foundation for research prioritization and hypothesis generation rather than as a clinical protocol. Rigorous randomized trials directly evaluating nutritional optimization in orthobiologic therapy for diabetic patients are required before evidence-based recommendations can be established. Full article