Mechanisms of treatment effects using allogeneic, umbilical cord-derived mesenchymal stromal stem cells (MSCs) in knee osteoarthritis: a pharmacological clinical study protocol.

BACKGROUND: Knee osteoarthritis (KOA) presents a prevalent orthopedic condition causing substantial impairment in the quality of life and imposing a significant societal and economic burden. Mesenchymal stromal/stem cells (MSCs), known for their regenerative properties and immunomodulatory effects, have emerged as a promising therapeutic avenue in regenerative medicine. Despite MSCs' therapeutic potential, their precise mechanisms of action in KOA remain underexplored. METHODS: Conducted as a randomized, open-label clinical trial, 20 patients will be enrolled, with 10 in the intervention group and 10 in the control group. The primary focus will be to explore the molecular mechanisms associated with MSC therapy. Biomarkers and gene expressions related to cartilage metabolism, inflammation, immune modulation, and pain in the synovial fluid, blood, and tissue samples will be analyzed. Patients will undergo pre- and post-treatment evaluations using patient-reported outcome measures (PROMs) and comprehensive clinical assessments. DISCUSSION: This is an exploratory study with the goal to provide comprehensive insights into the therapeutic effects of MSCs on a molecular level, potentially paving the way for optimized and more effective MSC-based therapies in the management of KOA, as well as furthering the development of novel treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06078059. Registered on 5 October 2023.

A Biomimetic Osteochondral Scaffold Augmented With Filtered Bone Marrow Aspirate for the Treatment of Joint Surface Lesions in the Knee.

BACKGROUND: Multilayered osteochondral scaffolds are becoming increasingly utilized for the repair of knee joint surface lesions (KJSLs). However, the literature on predictive factors is rather limited. PURPOSE: To (1) evaluate the clinical outcomes and safety of a combined single-step approach using a biomimetic collagen-hydroxyapatite scaffold (CHAS) and filtered bone marrow aspirate (fBMA) for the treatment of KJSLs and (2) identify significant predictors of the treatment outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All patients who underwent surgery because of a KJSL (size ≥1.5 cm2; International Cartilage Regeneration & Joint Preservation Society grades 3-4) using the combination above were selected from a hospital registry database (100 patients; minimum 2-year follow-up). Patient characteristics, medical history, knee joint and lesion status, intraoperative details, and cellular parameters of the injected fBMA were collected. The arthroscopic evaluation of chondral and meniscal tissue quality in all knee compartments was performed using the Chondropenia Severity Score. Treatment outcomes were determined clinically using patient-reported outcome measures (Knee Injury and Osteoarthritis Outcome Score, EuroQol-5 Dimensions-3 Levels, EuroQol-Visual Analog Scale, and Tegner Activity Scale) and by assessing the occurrence of serious adverse events and graft failure. Multivariable regression analysis was performed to identify significant predictors of the treatment outcomes. RESULTS: At a mean follow-up of 54.2 ± 19.4 months, 78 (87%) patients completed the questionnaires with significant improvements toward the baseline (P < .00625): KOOS Pain subscale from 62 ± 17 to 79 ± 18, KOOS Total score from 57 ± 16 to 70 ± 20, EuroQol-Visual Analog Scale from 61 ± 21 to 76 ± 16, EuroQol-5 Dimensions-3 Levels from 0.57 ± 0.20 to 0.80 ± 0.21, and Tegner Activity Scale from 2.8 ± 1.5 to 3.9 ± 1.9. The graft failure rate was 4%. A longer duration of preoperative symptoms, previous surgery, larger lesions, older age, and female sex were the main negative predictors for the treatment outcomes. The Chondropenia Severity Score and the number of fibroblast colony-forming units in fBMA positively influenced some of the clinical results and safety. CONCLUSION: A CHAS augmented with fBMA proved to be an adequate and safe approach for the treatment of KJSLs up to midterm follow-up. Based on the subanalysis of predictive factors, the surgical intervention should be performed in a timely and precise manner to prevent lesion enlargement, deterioration of the general knee cartilage status, and recurrent surgical procedures, especially in older and female patients. When a CHAS is used, the quantity of MSCs seems to play a role in augmentation. REGISTRATION: NCT06078072 (ClinicalTrials.gov identifier).

Biomaterials augmented with filtered bone marrow aspirate for the treatment of talar osteochondral lesions. A comparison of clinical and cellular parameters.

BACKGROUND: 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. PURPOSE: (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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 OF EVIDENCE: Level IV.

Partial Ankle Arthroplasty: Talus Resurfacing for Mild to Moderate Osteoarthritis and Talus Hemiarthroplasty for Complex Osteochondral Lesions.

BACKGROUND: To present prospective short-term results of a limited patient series treated with two innovative partial ankle arthroplasties: talar dome resurfacing for mild-to-moderate ankle osteoarthritis (OA) and talar shoulder hemiarthroplasty for chronic medial osteochondral lesions of the talus (OLT). METHODS: Eleven subjects underwent talus resurfacing, and six subjects were enrolled for talar hemiarthroplasty. The outcome was followed by patient-reported measures and by pursuing serious adverse events or implant failures over a 2-year period. Progression of ankle osteoarthritis, peri-implant bone changes, and implant migration were followed radiographically. RESULTS: Active dorsiflexion increased from 3° to 10° in resurfacing and from 15° to 22° in hemiarthroplasty. Patient-reported ankle function, quality of life, and activity level tended to improve only slightly after resurfacing (FAOS cumulative = 41 to 42; FAAM-ADL = 43 to 46; EQ-5D 3L = 0.38 to 0.39, Tegner activity scale = 1.6 to 2.0), but moderately after hemiarthroplasty (FAOS cumulative = 58 to 68, FAAM-ADL = 37 to 71, EQ-5D 3L = 0.53 to 0.72, Tegner activity scale = 3.1 to 3.1). No implant-related radiographic changes, implant failures, or implant-related revision surgeries were recorded. CONCLUSIONS: Based on a small and heterogeneous prospective case series, both partial ankle implants investigated were safe and stable over a 2-year follow-up period, without any radiographic OA progression of the remaining joint. However, patient-reported ankle function, quality of life, and activity level showed a tendency of only minor improvement after resurfacing but a moderate increase after hemiarthroplasty.

Multilayered biomimetic scaffolds for cartilage repair of the talus. A systematic review of the literature.

OBJECTIVE: The aim of the present review was to analyze the available evidence in the literature on the clinical and radiological outcomes of multilayered biomimetic scaffolds in the treatment of osteochondral lesions of the talus (OLTs). DESIGN: A systematic search was performed in three databases to identify clinical trials, where the multilayered biomimetic scaffolds were used for the treatment of OLTs. The PRISMA guidelines were followed. Qualitative analysis of the relevant data of the included studies was executed. The methodological quality of the analyzed studies was assessed with a modified Coleman Methodology Score (CMS). RESULTS: A total of 10 studies with 87 patients were included in the analysis. Only three multilayered biomimetic scaffolds have been investigated in clinical trials for the treatment of OLTs. The worst clinical and radiological outcomes, as well as safety profile were observed for the TruFit scaffold (Smith & Nephew, Andover, MA, USA), which had already been withdrawn from the market. The other two scaffolds (MaioRegen, Finceramica, Italy; Agili-C, Cartiheal, Israel) performed significantly better in the majority of the reviewed studies, especially in the clinical aspect. The radiological findings, the improvements of MOCART scores, the completeness of lesions' fill, and the structure of regenerated tissue were much more inconsistent. CONCLUSIONS: Two of the multilayered biomimetic scaffolds demonstrated an adequate potential in the treatment of complex OLTs. However, limited studies availability and their low level of medical evidence request further high-level investigations before the clinical decision making for such scaffolds in the treatment of OLTs can be defined.

A prospective, single-center study following operative treatment for osteochondral lesions of the talus.

BACKGROUND: (1) To evaluate patient-reported outcomes and revision surgeries after various operative interventions for osteochondral lesions of the talus (OLT) in a prospective single center series over 10 years, and (2) to identify predicting factors related to subjective ankle status and quality of life pre- and postoperatively. METHODS: Ninety-nine patients underwent operative treatment due to primary or recurrent OLT, with an average follow up 3.5 (1.8) years. Treatment outcome was followed clinically (FAOS, EQ-5D, Tegner activity scale) and by pursuing any serious adverse events or graft failures. RESULTS: There were 80 responding patients (81%) for the study. The mean lesion size was 2.0 (1.1) cm2. All FAOS values increased from preoperative to final follow-up values (Symptoms 60-68, Pain 58-69, ADL 71-80, Sport 36-54, QoL 30-45). EQ-5D increased from 0.49 to 0.62, while Tegner activity scale change from 3.2 to 3.4. There were 19 (24%) serious adverse events recorded; 13 (16%) of them were graft-related. Graft survival rates were 100% at 1 year, 94% (males)/93% (females) at 2 years, and 77% (males)/47% (females) at 5 years. Female gender, higher BMI, and higher Kellgren-Lawrence ankle OA score were negative predictors for preoperative patient-reported ankle joint status. The foremost improvement after operative intervention was observed in patients with large osteochondral lesions without postoperative adverse events. CONCLUSION: Various operative interventions for OLT significantly improved patients' ankle status and quality of life. High graft survival rates were demonstrated over first two years, but notable decline was confirmed thereafter, especially in female patients.

Patient-reported joint status and quality of life in sports-related ankle disorders and osteoarthritis.

PURPOSE: To compare self-reported joint status, quality of life, level of activity and pain management in patients scheduled for surgical treatment of seven common ankle disorders: osteoarthritis (OA), primary osteochondral lesion of talus (P-OLT), recurrent osteochondral lesion of talus (R-OLT), lateral ankle instability (INST) and anterior (ANT-IMP), posterior (POST-IMP) and combined (COMB-IMP) ankle impingements. METHODS: The cross-sectional study design was implemented. Hospital records of 610 patients that were admitted for surgical intervention on the ankle joint over a seven year period were reviewed. Patient selection (over 18 years, no systemic musculoskeletal illnesses, only one isolated ankle pathology) resulted in 123 eligible patients for current study (OA 22, P-OLT 19, R-OLT 18, INST 15, ANT-IMP 20, POST-IMP 13, COMB-IMP 16). Foot and Ankle Outcome Score (FAOS), European quality of life in a visual analogue and in five dimensions (EQ-VAS, EQ-5D-3L), Tegner activity scale (TAS) and pain medication usage were recorded at the admission and compared across these seven groups. RESULTS: All evaluated ankle disorders induced the following: (a) subjective joint-specific dysfunction - FAOS cumulative: 42 (OA), 50 (R-OLT), 65 (P-OLT), 65 (INST), 63 (ANT-IMP), 61 (POST-IMP), 60 (COMB-IMP); (b) decreased quality of life - EQ-5D-3L: 0.41 (OA), 0.44 (R-OLT), 0.56 (P-OLT), 0.62 (INST), 0.64 (ANT-IMP), 0.56 (POST-IMP), 0.60 (COMB-IMP) and (c) decreased activity level - TAS: 2.1 (OA), 2.7 (R-OLT), 3.7 (P-OLT), 4.0 (INST), 4.7 (ANT-IMP), 4.4 (POST-IMP), 5.1 (COMB-IMP). FAOS subscales, EQ-5D-3L and TAS were significantly lower in OA and R-OLT patients. Between 31% (POST-IMP) and 68% (OA and R-OLT) of patients required pain medication over one month prior to the assessment. CONCLUSION: All analysed ankle disorders in patients amenable for surgical treatment induced a considerable decline in patients` perceived ankle function, quality of life and activity level. The worst subjective ankle status was reported equally by OA and R-OLT patients, while patients with the other five disorders reported comparable values.

Complex Osteochondral Lesions of the Talus Treated With a Novel Bi-Phasic Aragonite-based Implant.

To present initial results of a novel, bi-phasic, porous, biodegrade, and cell-free aragonite-based scaffold for treating complex osteochondral lesions of the talus (OLT). Four subjects (2 males and 2 females; 34-61 years old) were operated on their ankles due to chronic and deep OLT-Hepple grades 4 or 5 (1.8-2.2 cm2). Three subjects had OLT on the medial central trochlea, and 1 had a combined medial and lateral lesions. OLT were exposed through medial malleolus osteotomy, with an additional lateral arthrotomy in the combined lesions. Bi-phasic porous osteochondral scaffolds (single implant or 2 implants) were implanted in a press-fit manner using a designated surgical toolset. Treatment outcome was followed clinically (Foot and Ankle Outcome Score, EQ-5D 3L, Tegner activity scale) and by medical imaging (radiographs, magnetic resonance imaging) from 18 to 32 months. All Foot and Ankle Outcome Score values increased from preoperative to final follow-up values (Symptoms 62 to 71, Pain 53 to 84, ADL 60 to 89, Sport 19 to 65, and QoL 18 to 47). EQ-5D 3L increased from 0.59 to 0.76, and Tegner activity values increased from 1.5 to 3. Kellgren-Lawrence ankle radiographic scores remained stable (2 to 2). Postoperative MR evaluation demonstrated cartilage defect fill of 75% to 100% respect to the native cartilage in 3 subjects (4 OLTs), while 1 lesion was filled 25% to 50%. No graft related serious adverse events or graft failures were reported. The use of a bi-phasic osteochondral biodegradable aragonite-based scaffold in the treatment of complex OLT during the reported period presented positive and promising clinical and radiologic outcome, without serious adverse events or graft failures.