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Osteochondral (OC) defects cannot adequately repair themselves due to their sophisticated layered structure and lack of blood supply in cartilage. Although therapeutic interventions are reaching an advanced stage, current clinical therapies to repair defects are in their infancy. Among the possible therapies, OC tissue engineering has shown considerable promise, and multiple approaches utilizing scaffolds, cells, and bioactive factors have been pursued. The most recent trend in OC tissue engineering has been to design gradient scaffolds using different materials and construction strategies (such as bi-layered, multi-layered, and continuous gradient structures) to mimic the physiological and mechanical properties of OC tissues while further enabling OC repair. This review focuses specifically on design and construction strategies for gradient scaffolds and their role in the successful engineering of OC tissues. The current dilemmas in the field of OC defect repair and the efforts of tissue engineering to address these challenges were reviewed. In addition, the advantages and limitations of the typical fabrication techniques for gradient scaffolds were discussed, with examples of recent studies summarizing the future prospects for integrated gradient scaffold construction. This updated and enlightening review could provide insights into our current understanding of gradient scaffolds in OC tissue engineering. [ABSTRACT FROM AUTHOR]

Because of limited self-healing ability, the treatment of articular cartilage defects is still an important clinical challenge. Hydrogel-based biomaterials have broad application prospects in articular cartilage repair. In this study, gelatin methacrylate (GelMA)and silk fibroin (SF) were combined to form a composite hydrogel with an interpenetrating network (IPN) structure under ultraviolet irradiation and ethanol treatment. Introducing silk fibroin into GelMA hydrogel significantly increased mechanical strength as compressive modulus reached 300 kPa in a GelMA/SF-5 (50 mg/mL silk fibroin) group. Moreover, composite IPN hydrogels demonstrated reduced swelling ratios and favorable biocompatibility and supported chondrogenesis of bone mesenchymal stem cells (BMSCs) at day 7 and day 14. Additionally, significantly higher gene expressions of Col-2, Acan, and Sox-9 (p < 0.01) were found in IPN hydrogel groups when compared with the GelMA group. An in vivo study was performed to confirm that the GelMA-SF IPN hydrogel could promote cartilage regeneration. The results showed partial regeneration of cartilage in groups treated with hydrogels only and satisfactory cartilage repair in groups of cell-seeded hydrogels, indicating the necessity of additional seeding cells in hydro-gel-based cartilage treatment. Therefore, our results suggest that the GelMA/SF IPN hydrogels may be a potential functional material in cartilage repair and regeneration. [ABSTRACT FROM AUTHOR]

The regeneration of cartilage and osteochondral defects remains one of the most challenging clinical problems in orthopedic surgery. Currently, tissue-engineering techniques based on the delivery of appropriate growth factors and mesenchymal stem cells (MSCs) in hydrogel scaffolds are considered as the most promising therapeutic strategy for osteochondral defects regeneration. In this study, we fabricated a heparin-conjugated fibrin (HCF) hydrogel with synovium-derived mesenchymal stem cells (SDMSCs), transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-4 (BMP-4) to repair osteochondral defects in a rabbit model. An in vitro study showed that HCF hydrogel exhibited good biocompatibility, a slow degradation rate and sustained release of TGF-β1 and BMP-4 over 4 weeks. Macroscopic and histological evaluations revealed that implantation of HCF hydrogel with SDMSCs, TGF-β1 and BMP-4 significantly enhanced the regeneration of hyaline cartilage and the subchondral bone plate in osteochondral defects within 12 weeks compared to hydrogels with SDMSCs or growth factors alone. Thus, these data suggest that combined delivery of SDMSCs with TGF-β1 and BMP-4 in HCF hydrogel may synergistically enhance the therapeutic efficacy of osteochondral defect repair of the knee joints. [ABSTRACT FROM AUTHOR]

With the increase in population aging, the tendency of osteochondral injury will be accelerated, and repairing materials are increasingly needed for the optimization of the regenerative processes in bone and cartilage recovery. The local environment of the injury sites and the deficiency of Mg2+ retards the repairing period via inhibiting the progenitor osteogenesis and chondrogenesis cells' recruitment, proliferation, and differentiation, which results in the sluggish progress in the osteochondral repairing materials design. In this article, we elucidate the Mg2+-concentration specified effect on the cell proliferation, osteochondral gene expression, and differentiation of modeling chondrocytes (extracted from New Zealand white rabbit) and osteoblasts (MC3T3-E1). The concentration of Mg2+ in the culture medium affects the proliferation, chondrogenesis, and osteogenesis: (i) Appropriate concentrations of Mg2+ promote the proliferation of chondrocytes (1.25–10.0 mM) and MC3T3-E1 cells (2.5–30.0 mM); (ii) the optimal concentration of Mg2+ that promotes the gene expression of noncalcified cartilage is 15 mM, calcified cartilage 10 mM, and subchondral bone 5 mM, respectively; (iii) overdosed Mg2+ leads to the inhibition of cell activity for either chondrocytes (>20 mM) or osteoblasts (>30 mM). The biomimetic elucidation for orchestrating the allocation of gradient concentration of Mg2+ in accordance of the physiological condition is crucial for designing the accurate microenvironment in osteochondral injury defects for optimization of bone and cartilage repairing materials in the future. [ABSTRACT FROM AUTHOR]

Osteochondral structure reconstruction by tissue engineering, a challenge in regenerative medicine, requires a scaffold that ensures both articular cartilage and subchondral bone remodeling. Functional hydrogels and scaffolds present a strategy for the controlled delivery of signaling molecules (growth factors and therapeutic drugs) and are considered a promising therapeutic approach. Icariin is a pharmacologically-active small molecule of prenylated flavonol glycoside and the main bioactive flavonoid isolated from Epimedium spp. The in vitro and in vivo testing of icariin showed chondrogenic and ostseoinductive effects, comparable to bone morphogenetic proteins, and suggested its use as an alternative to growth factors, representing a low-cost, promising approach for osteochondral regeneration. This paper reviews the complex structure of the osteochondral tissue, underlining the main aspects of osteochondral defects and those specifically occurring in osteoarthritis. The significance of icariin's structure and the extraction methods were emphasized. Studies revealing the valuable chondrogenic and osteogenic effects of icariin for osteochondral restoration were also reviewed. The review highlighted th recent state-of-the-art related to hydrogels and scaffolds enriched with icariin developed as biocompatible materials for osteochondral regeneration strategies. [ABSTRACT FROM AUTHOR]

Scaffolds are thought to be a key element needed for successful cartilage repair treatments, and this prospective extension study aimed to evaluate long-term structural and clinical outcomes following osteochondral defect treatment with a cell-free biphasic scaffold. Structural outcomes were assessed using quantitative 3-D magnetic resonance imaging (MRI) and morphological segmentation to determine the percentage of defect filling and repair cartilage T2 relaxation times, and clinical outcomes were determined with the modified Cincinnati Rating System, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Seventeen subjects with osteochondral defects in the knee were treated with ChondroMimetic scaffolds, from which 15 returned for long-term evaluation at a mean follow-up of 7.9 ± 0.3 years. The defects treated were trochlear donor sites for mosaicplasty in 13 subjects, and medial femoral condyle defects in 2 subjects. MRI analysis of scaffold-treated defects found a mean total defect filling of 95.2 ± 3.6%, and a tissue mean T2 relaxation time of 52.5 ± 4.8 ms, which was identical to the T2 of ipsilateral control cartilage (52.3 ± 9.2 ms). The overall modified Cincinnati Rating System score was statistically significant from baseline (p = 0.0065), and KOOS subscales were equivalent to other cartilage repair techniques. ChondroMimetic treatment resulted in a consistently high degree of osteochondral defect filling with durable, cartilage-like repair tissue at 7.9 years, potentially associated with clinical improvement. [ABSTRACT FROM AUTHOR]

Osteochondral defects of the ankle (OCD) are being increasingly identified as a clinically significant consequence of injury to the ankle, with the potential to lead to osteoarthritis if left untreated. The aim of this retrospective cohort study was to evaluate a single-stage treatment of OCD, based on bone marrow aspirate (BMA) centrifuged to produce bone marrow concentrate (BMC). In a dual syringe, the concentrate was mixed with thrombin in one syringe, whereas hyaluronan and fibrinogen were mixed in a second syringe. The two mixtures were then injected and combined into the prepared defect. Clinical outcome and quality of life scores (MOXFQ and EQ-5D) were collected at baseline and yearly thereafter. Multilevel models were used to analyse the pattern of scores over time. Ninety-four patients were treated between 2015 and 2020. The means of each of the three components of the MOXFQ significantly improved between baseline and 1 year (p < 0.001 for each component), with no further change from year 1 to year 3. The EQ-5D index also improved significantly from baseline to 1 year, with no evidence for further change. Our results strongly indicate that this BMC treatment is safe for, and well tolerated by, patients with OCD of the ankle as both primary treatment and those who have failed primary treatment. This technique provides a safe, efficacious alternative to currently employed cartilage repair techniques, with favourable outcomes and a low complication rate at 36 months. [ABSTRACT FROM AUTHOR]

The socioeconomic impact of osteochondral (OC) damage has been increasing steadily over time in the global population, and the promise of tissue engineering in generating biomimetic tissues replicating the physiological OC environment and architecture has been falling short of its projected potential. The most recent advances in OC tissue engineering are summarised in this work, with a focus on electrospun and 3D printed biomaterials combined with stem cells and biochemical stimuli, to identify what is causing this pitfall between the bench and the patients' bedside. Even though significant progress has been achieved in electrospinning, 3D-(bio)printing, and induced pluripotent stem cell (iPSC) technologies, it is still challenging to artificially emulate the OC interface and achieve complete regeneration of bone and cartilage tissues. Their intricate architecture and the need for tight spatiotemporal control of cellular and biochemical cues hinder the attainment of long-term functional integration of tissue-engineered constructs. Moreover, this complexity and the high variability in experimental conditions used in different studies undermine the scalability and reproducibility of prospective regenerative medicine solutions. It is clear that further development of standardised, integrative, and economically viable methods regarding scaffold production, cell selection, and additional biochemical and biomechanical stimulation is likely to be the key to accelerate the clinical translation and fill the gap in OC treatment. [ABSTRACT FROM AUTHOR]

Large (>3 cm2), focal osteochondral lesions (OCL) may result in poor functional outcomes and early secondary osteoarthritis of the knee. The surgical management of these OCL remains challenging. The treatment strategy must be tailored to various aspects, including lesion-specific (e.g., size, location, chronicity), joint-specific (e.g., instability, limb alignment, meniscal status), and patient-specific factors (e.g., age, activity level, comorbidities). Simple chondroplasty and bone marrow stimulation (BMS) techniques should be reserved for smaller lesions, as they only realize midterm clinical benefits, related to inferior wear characteristics of the induced fibrocartilage (type I collagen). Therefore, much attention has been focused on surgical restoration with hyaline cartilage (type II collagen), based on chondrocyte transplantation and matrix-assisted autologous chondrocyte implantation (MACI). Limited graft availability, staged procedures (MACI), and high treatment costs are limitations of these techniques. However, acute traumatic OCL of the femoral condyles and patellofemoral joint may also be suitable for preservation by surgical fixation. Early detection of the fragment facilitates primary repair with internal fixation. The surgical repair of the articular surface may offer promising clinical and cost-effective benefits as a first-line therapy but remains under-investigated and potentially under-utilized. As a unique characteristic, the fixation technique allows the anatomic restoration of the hyaline articular surface with native cartilage and the repair of the subchondral bone. In this manuscript, we present a case series of large OCL around the knee that were preserved by surgical fixation. Furthermore, various implants and techniques reported for this procedure are reviewed. [ABSTRACT FROM AUTHOR]

Novel calcium phosphate cements containing a mixture of four amino acids, glycine, proline, hydroxyproline and either lysine or arginine (CAL, CAK) were characterized and used for treatment of artificial osteochondral defects in knee. It was hypothesized that an enhanced concentration of extracellular collagen amino acids (in complex mixture), in connection with bone cement in defect sites, would support the healing of osteochondral defects with successful formation of hyaline cartilage and subchondral bone. Calcium phosphate cement mixtures were prepared by in situ reaction in a planetary ball mill at aseptic conditions and characterized. It was verified that about 30–60% of amino acids remained adsorbed on hydroxyapatite particles in cements and the addition of amino acids caused around 60% reduction in compressive strength and refinement of hydroxyapatite particles in their microstructure. The significant over-expression of osteogenic genes after the culture of osteoblasts was demonstrated in the cement extracts containing lysine and compared with other cements. The cement pastes were inserted into artificial osteochondral defects in the medial femoral condyle of pigs and, after 3 months post-surgery, tissues were analyzed macroscopically, histologically, immunohistochemically using MRI and X-ray methods. Analysis clearly showed the excellent healing process of artificial osteochondral defects in pigs after treatment with CAL and CAK cements without any inflammation, as well as formation of subchondral bone and hyaline cartilage morphologically and structurally identical to the original tissues. Good integration of the hyaline neocartilage with the surrounding tissue, as well as perfect interconnection between the neocartilage and new subchondral bone tissue, was demonstrated. Tissues were stable after 12 months' healing. [ABSTRACT FROM AUTHOR]

The treatment of osteochondral defects remains a challenge. Four scaffolds were produced using Food and Drug Administration (FDA)-approved polymers to investigate their therapeutic potential for the regeneration of the osteochondral unit. Polycaprolactone (PCL) and poly(vinyl-pyrrolidone) (PVP) scaffolds were made by electrohydrodynamic techniques. Hydroxyapatite (HAp) and/or sodium hyaluronate (HA) can be then loaded to PCL nanofibers and/or PVP particles. The purpose of adding hydroxyapatite and sodium hyaluronate into PCL/PVP scaffolds is to increase the regenerative ability for subchondral bone and joint cartilage, respectively. Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were seeded on these biomaterials. The biocompatibility of these biomaterials in vitro and in vivo, as well as their potential to support MSC differentiation under specific chondrogenic or osteogenic conditions, were evaluated. We show here that hBM-MSCs could proliferate and differentiate both in vitro and in vivo on these biomaterials. In addition, the PCL-HAp could effectively increase the mineralization and induce the differentiation of MSCs into osteoblasts in an osteogenic condition. These results indicate that PCL-HAp biomaterials combined with MSCs could be a beneficial candidate for subchondral bone regeneration. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the clinical and radiological efficacy of three-dimensional acellular scaffolds (MaioRegen) in restoring osteochondral knee defects. Methods: MEDLINE, Scopus, CINAHL, Embase, and Cochrane Databases were searched for articles in which patients were treated with MaioRegen for osteochondral knee defects. Results: A total of 471 patients were included in the study (mean age 34.07 ± 5.28 years). The treatment involved 500 lesions divided as follows: 202 (40.4%) medial femoral condyles, 107 (21.4%) lateral femoral condyles, 28 (5.6%) tibial plateaus, 46 (9.2%) trochleas, 74 (14.8%) patellas, and 43 (8.6%) unspecified femoral condyles. Mean lesion size was 3.6 ± 0.85 cm2. Only four studies reported a follow-up longer than 24 months. Significant clinical improvement has been reported in almost all studies with further improvement up to 5 years after surgery. A total of 59 complications were reported of which 52 (11.1%) experienced minor complications and 7 (1.48%) major complications. A total of 16 (3.39%) failures were reported. Conclusion: This systematic review describes the current available evidence for the treatment of osteochondral knee defects with MaioRegen Osteochondral substitute reporting promising satisfactory and reliable results at mid-term follow-up. A low rate of complications and failure was reported, confirming the safety of this scaffold. Considering the low level of evidence of the study included in the review, this data does not support the superiority of the Maioregen in terms of clinical improvement at follow-up compared to conservative treatment or other cartilage techniques. [ABSTRACT FROM AUTHOR]

Despite advances in cartilage repair strategies, treatment of focal chondral lesions remains an important challenge to prevent osteoarthritis. Articular cartilage is organized into several layers and lack of zonal organization of current grafts is held responsible for insufficient biomechanical and biochemical quality of repair-tissue. The aim was to develop a zonal approach for cartilage regeneration to determine whether the outcome can be improved compared to a non-zonal strategy. Hydrogel-filled polycaprolactone (PCL)-constructs with a chondrocyte-seeded upper-layer deemed to induce hyaline cartilage and a mesenchymal stromal cell (MSC)-containing bottom-layer deemed to induce calcified cartilage were compared to chondrocyte-based non-zonal grafts in a minipig model. Grafts showed comparable hardness at implantation and did not cause visible signs of inflammation. After 6 months, X-ray microtomography (µCT)-analysis revealed significant bone-loss in both treatment groups compared to empty controls. PCL-enforcement and some hydrogel-remnants were retained in all defects, but most implants were pressed into the subchondral bone. Despite important heterogeneities, both treatments reached a significantly lower modified O'Driscoll-score compared to empty controls. Thus, PCL may have induced bone-erosion during joint loading and misplacement of grafts in vivo precluding adequate permanent orientation of zones compared to surrounding native cartilage. [ABSTRACT FROM AUTHOR]

A rigid surface–volume registration scheme is presented in this study to register computed tomography (CT) and free-hand tracked ultrasound (US) images of the talocrural joint. Prior to registration, bone surfaces expected to be visible in US are extracted from the CT volume and bone contours in 2D US data are enhanced based on monogenic signal representation of 2D US images. A 3D monogenic signal data is reconstructed from the 2D data using the position of the US probe recorded with an optical tracking system. When registering the surface extracted from the CT scan to the monogenic signal feature volume, six transformation parameters are estimated so as to optimize the sum of monogenic signal features over the transformed surface. The robustness of the registration algorithm was tested on a dataset collected from 12 cadaveric ankles. The proposed method was used in a clinical case study to investigate the potential of US imaging for pre-operative planning of arthroscopic access to talar (osteo)chondral defects (OCDs). The results suggest that registrations with a registration error of 2 mm and less is achievable, and US has the potential to be used in assessment of an OCD’ arthroscopic accessibility, given the fact that 51% of the talar surface could be visualized. [ABSTRACT FROM AUTHOR]