Interleukin-10 is a versatile adjuvant candidate to control the post-injurious environment in cartilage defects and promote chondrogenesis in ACI grafts.

Joint injury is a complex process involving specific mechanical effects on cartilage as well as induction of an inflammatory environment. IL-10 prevented crucial mechanisms of chondrodegeneration induced by an injurious single compression. IL-10 might be a multipurpose drug candidate for the treatment of cartilage-related sports injuries or osteoarthritis (OA).

Background: The treatment of osteochondral defects (OCDs) constitutes a major problem for orthopaedic surgeons. The altered mechanics and the cell types, with associated soluble factors derived from the exposed subchondral bone, are likely responsible for the mechanically and structurally inferior articular cartilage subsequently obtained as a repair tissue. There is therefore an unmet clinical need for bioresponsive biomaterials that allow cell delivery, reduce cell infiltration from the bone marrow, and support chondrogenesis in the presence of joint mechanical loading. Purpose: To develop a cell-laden injectable biomaterial, with bioadhesive properties, low cell invasion, and good mechanoresilience, in which simulated joint loading could induce tissue maturation through the production and activation of transforming growth factor beta 1 (TGF-β1). Study Design: Controlled laboratory study. Methods: Human bone marrow–derived mesenchymal stromal/stem cells were encapsulated in tyramine-modified hyaluronic acid (HA-Tyr) hydrogels, with crosslinking initiated by the addition of horseradish peroxidase (HRP) and various concentrations of hydrogen peroxide (H2O2; 0.3-2 mM). Cytocompatibility and biomechanical and adhesive properties were analyzed by live/dead staining, rheology, and push-out test, respectively. For multiaxial loading, cell-laden hydrogels were subjected to 10% compression superimposed onto a 0.5-N preload and shear loading (±25°) at 1 Hz for 1 hour per day and 5 times a week for 4 weeks. TGF-β1 production and activation were measured by enzyme-linked immunosorbent assay (ELISA). Results: The viscoelastic properties of the cell-laden HA-Tyr hydrogels, as crosslinked with different ratios of HRP and H2O2, were demonstrated for a range of cell densities and HRP/H2O2 concentrations. In the absence of serum supplementation, cell invasion into HA-Tyr hydrogels was minimal to absent. The bonding strength of HA-Tyr to articular cartilage compared favorably with clinically used fibrin gel. Conclusion: HA-Tyr hydrogels can be mechanically conditioned to induce activation of endogenous TGF-b1 produced by the embedded cells. HA-Tyr hydrogels function as cell carriers supporting biomechanically induced production and activation of TGF-β1 and as bioadhesive materials with low cell invasion, suggesting that they hold promise as a novel biomaterial for OCD repair strategies. Clinical Relevance: Leveraging physiological joint mechanics to support chondrogenic graft maturation in an optimized mechanosensitive hydrogel in the absence of exogenous growth factors is of highest interest for OCD repair.

Background: Both the superficial medial collateral ligament (sMCL) and the deep MCL (dMCL) contribute to the restraint of anteromedial (AM) rotatory instability (AMRI). Previous studies have not investigated how MCL reconstructions control AMRI. Purpose/Hypothesis: The purpose was to establish the optimal medial reconstruction for restoring normal knee kinematics in an sMCL- and dMCL-deficient knee. It was hypothesized that AMRI would be better controlled with the addition of an anatomically shaped (flat) sMCL reconstruction and with the addition of an AM reconstruction replicating the function of the dMCL. Study Design: Controlled laboratory study. Methods: A 6 degrees of freedom robotic system equipped with a force-torque sensor was used to test 8 unpaired knees in the intact, sMCL/dMCL sectioned, and reconstructed states. Four different reconstructions were assessed. The sMCL was reconstructed with either a single-bundle (SB) or a flattened hamstring graft aimed at better replicating the appearance of the native ligament. These reconstructions were tested with and without an additional AM reconstruction. Simulated laxity tests were performed at 0°, 30°, 60°, and 90° of flexion: 10 N·m valgus rotation, 5 N·m internal and external rotation (ER), and an AM drawer test (combined 134-N anterior tibial drawer in 5 N·m ER). The primary outcome measures of this force-controlled setup were anterior tibial translation (ATT; in mm) and axial tibial rotation (in degrees). Results: Sectioning the sMCL/dMCL increased valgus rotation, ER, and ATT with the simulated AM draw test at all flexion angles. SB sMCL reconstruction was unable to restore ATT, valgus rotation, and ER at 30°, 60°, and 90° of flexion to the intact state ( P < .05). Flat MCL reconstruction restored valgus rotation at all flexion angles to the intact state ( P > .05). ER was restored at all angles except at 90°, but ATT laxity in response to the AM drawer persisted. Addition of an AM reconstruction improved control of ATT relative to the intact state at all flexion angles ( P > .05). Combined flat MCL and AM reconstruction restored knee kinematics closest to the intact state. Conclusion: In a cadaveric model, AMRI resulting from an injured sMCL and dMCL complex could not be restored by an isolated SB sMCL reconstruction. A flat MCL reconstruction or an additional AM procedure, however, better restored medial knee stability. Clinical Relevance: In patients evaluated with a combined valgus and AM rotatory instability, a flat sMCL and an additional AM reconstruction may be superior to an isolated SB sMCL reconstruction.

Platelet-released growth factors (PRGF) and its related clinically used formulations (e.g., Vivostat Platelet-Rich Fibrin (PRF®)) contain a variety of chemokines, cytokines, and growth factors and are therefore used to support healing of chronic, hard-to-heal, or infected wounds. Human beta-defensin-3 (hBD-3) is an antimicrobial peptide inducibly expressed in human keratinocytes especially upon wounding. The potent antimicrobial activity of hBD-3 together with its wound closure-promoting activities suggests that hBD-3 may play a crucial role in wound healing. Therefore, we analyzed the influence of PRGF on hBD-3 expression in human primary keratinocytes in vitro. In addition, we investigated the influence of Vivostat PRF on hBD-3 expression in artificially generated human skin wounds in vivo. PRGF treatment of primary keratinocytes induced a significant, concentration- and time-dependent increase in hBD-3 gene expression which was partially mediated by the epidermal growth factor receptor (EGFR). In line with these cell culture data, in vivo experiments revealed an enhanced hBD-3 expression in experimentally produced human wounds after the treatment with Vivostat PRF. Thus, the induction of hBD-3 may contribute to the beneficial effects of thrombocyte concentrate lysates in the treatment of chronic or infected wounds.

Autologous thrombocyte concentrate lysates, for example, platelet-released growth factors, (PRGFs) or their clinically related formulations (e.g., Vivostat PRF®) came recently into the physicians' focus as they revealed promising effects in regenerative and reparative medicine such as the support of healing of chronic wounds. To elucidate the underlying mechanisms, we analyzed the influence of PRGF and Vivostat PRF on human keratinocyte differentiation in vitro and on epidermal differentiation status of skin wounds in vivo. Therefore, we investigated the expression of early (keratin 1 and keratin 10) and late (transglutaminase-1 and involucrin) differentiation markers. PRGF treatment of primary human keratinocytes decreased keratin 1 and keratin 10 gene expression but induced involucrin and transglutaminase-1 gene expression in an epidermal growth factor receptor- (EGFR-) dependent manner. In concordance with these results, microscopic analyses revealed that PRGF-treated human keratinocytes displayed morphological features typical of keratinocytes undergoing terminal differentiation. In vivo treatment of artificial human wounds with Vivostat PRF revealed a significant induction of involucrin and transglutaminase-1 gene expression. Together, our results indicate that PRGF and Vivostat PRF induce terminal differentiation of primary human keratinocytes. This potential mechanism may contribute to the observed beneficial effects in the treatment of hard-to-heal wounds with autologous thrombocyte concentrate lysates in vivo.

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Purpose This study aimed to identify and prevent preoperative factors that can be influenced in preoperative planning to reduce postoperative malcorrections. Methods The method used in this study was a retrospective two-centre analysis of 78 pre and postoperative fully weight-bearing radiographs of patients who underwent valgus osteotomy correction due to symptomatic medial compartment osteoarthritis. A computer software (TraumaCad®) was used to aim for an intersection point of the mechanical tibiofemoral axis (mTFA) with the tibia plateau at 55–60% (medial = 0%, lateral = 100%). Postoperative divergence ± 5% of this point was defined as over- and undercorrection. Preoperative joint geometry factors were correlated with postoperative malcorrection. Planning was conducted using the established method described by Miniaci (Group A) and with additional correction of the joint line convergence angle (JLCA) using the formula JLCA-2/2 (Group B). Additionally, in a small clinical case series, planning was conducted with JLCA correction. Statistical analysis was performed using (multiple) linear regression analysis and analysis of variance (ANOVA) with p < 0.05 considered significant. Results In 78 analysed cases, postoperative malcorrection was detected in 37.2% (5.1% undercorrection, 32.1% overcorrection). Linear regression analysis revealed preoperative body mass index (BMI, p = 0.04), JLCA (p = 0.0001), and osteotomy level divergence (p = 0.0005) as factors correlated with overcorrection. In a multiple regression analysis, JLCA and osteotomy level divergence remained significant factors. Preoperative JLCA correction reduced the planned osteotomy gap (A 9.7 ± 2.8 mm vs B 8.3 ± 2.4 mm; p > 0.05) and postoperative medial proximal tibial angle (MPTA: A 94.3 ± 2.1° vs B 92.3 ± 1.5°; p < .05) in patients with preoperative JLCA ≥ 4°. The results were validated using a virtual postoperative correction of cases with overcorrection. A case series (n = 8) with a preoperative JLCA > 4 revealed a postoperative accuracy using the JLCA correction of 3.4 ± 1.9%. Conclusion Preoperative JLCA ≥ 4° and tibial osteotomy level divergence were identified as risk factors for postoperative overcorrection. Preoperative JLCA correction using the formula JLCA-2/2 is proposed to better control ideal postoperative correction and reduce MPTA. The intraoperatively realised osteotomy level should be precisely in accordance with preoperative planning. Level of evidence III, cross-sectional study.