Entire Osteochondral Unit Research Articles

Subchondral bone: An emerging target for the treatment of articular surface lesions of the knee.

When dealing with the health status of the knee articular surface, the entire osteochondral unit has gained increasing attention, and in particular the subchondral bone, which plays a key role in the integrity of the osteochondral unit. The aim of this article was to discuss the current evidence on the role of the subchondral bone. Experts from different geographical regions were involved in performinga review on highly discussed topics about the subchondral bone, ranging from its etiopathogenetic role injoint degeneration processes to its prognostic role in chondral and osteochondral defects, upto treatment strategies to address both the subchondral bone and the articular surface. Subchondral bone has a central role both from an aetiologic point of view and as a diagnostic tool, and its status was found to be relevant also as a prognostic factor in the follow-up of chondral treatment. Finally, the recognition of its importance in the natural history of these lesions led to consider subchondral bone as a treatment target, with the development of osteochondral scaffolds and procedures to specifically address osteochondral lesions. Subchondral bone plays a central role in articular surface lesions from different points of view. Several aspects still need to be understood, but a growing interest in subchondral bone is to be expected in the upcoming future towards the optimization of joint preservation strategies. Level V, expert opinion.

Functionally graded hydrogels with opposing biochemical cues for osteochondral tissue engineering.

Osteochondral tissue (OC) repair remains a significant challenge in the field of musculoskeletal tissue engineering. OC tissue displays a gradient structure characterized by variations in both cell types and extracellular matrix components, from cartilage to the subchondral bone. These functional gradients observed in the native tissue have been replicated to engineer OC tissuein vitro. While diverse fabrication methods have been employed to create these microenvironments, emulating the natural gradients and effective regeneration of the tissue continues to present a significant challenge. In this study, we present the design and development of CMC-silk interpenetrating (IPN) hydrogel with opposing dual biochemical gradients similar to native tissue with the aim to regenerate the complete OC unit. The gradients of biochemical cues were generated using an in-house-built extrusion system. Firstly, we fabricated a hydrogel that exhibits a smooth transition of sulfated carboxymethyl cellulose (sCMC) and TGF-β1 (SCT gradient hydrogel) from the upper to the lower region of the IPN hydrogel to regenerate the cartilage layer. Secondly, a hydrogel with a hydroxyapatite (HAp) gradient (HAp gradient hydrogel) from the lower to the upper region was fabricated to facilitate the regeneration of the subchondral bone layer. Subsequently, we developed a dual biochemical gradient hydrogel with a smooth transition of sCMC + TGF-β1 and HAp gradients in opposing directions, along with a blend of both biochemical cues in the middle. The results showed that the dual biochemical gradient hydrogels with biochemical cues corresponding to the three zones (i.e. cartilage, interface and bone) of the OC tissue led to differentiation of bone-marrow-derived mesenchymal stem cells to zone-specific lineages, thereby demonstrating their efficacy in directing the fate of progenitor cells. In summary, our study provided a simple and innovative method for incorporating gradients of biochemical cues into hydrogels. The gradients of biochemical cues spatially guided the differentiation of stem cells and facilitated tissue growth, which would eventually lead to the regeneration of the entire OC tissue with a smooth transition from cartilage (soft) to bone (hard) tissues. This promising approach is translatable and has the potential to generate numerous biochemical and biophysical gradients for regeneration of other interface tissues, such as tendon-to-muscle and ligament-to-bone.

The Osteoarthritis Natural Progress and Changes in Intraosseous Pressure of the Guinea Pig Model in Different Degeneration Stages.

Articular cartilage and subchondral bone changes during the pathological progress of knee osteoarthritis (KOA) is a key event marking the development of the disease. The age varying alteration patterns within entire osteochondral unit remains poorly understood. The purpose of this study was to find a reasonable age range of the Dunkin-Hartley guinea pig model for the studying of KOA pathological process, and to investigate Intraosseous pressure (IOP) in the process during different degeneration stages of KOA. Male Dunkin-Hartley guinea pigs were selected and divided into groups of 3, 6, 9, 12, 18months old by age, 10 in each group. All knees underwent imaging examination including X-ray, Micro-CT and MRI. Observed the imaging findings with the use of Kellgren-Lawrence (K-L) classification and knee osteoarthritis MRI scores. Measured the IOP of distal femur (DF) and proximal tibia (PT) in each group, and observed the differences of bilateral tibiofemoral articular cartilage in histological and immunohistochemistry, staining results were evaluated by using Mankin's score. Analysis of variance (ANOVA) and t-tests were used to compare the differences indicators between groups. With the increase of age, changes in X-ray, Micro-CT and MRI imaging findings and pathological staining results of articular cartilage in all stages were consistent with the changing of degenerative KOA process. The IOP of DF and PT increased gradually with age, and reached its peak in 12-month age group, and then gradually decreased, there was a statistically significant difference of IOP between each group. The IOP of DF was slightly higher than that of PT, but the difference was not statistically significant. Dunkin-Hartley guinea pigs can be used as an animal model to study different pathological stages of KOA. There might be a correlation between the changes of IOP and the pathological progress of articular cartilage and subchondral bone in DF and PT.

Radiocapitellar Contact Characteristics After Osteochondral Defect Repair Using a Novel Hybrid Reconstructive Procedure

Background:Many procedures to reconstruct osteochondral defects of the elbow radiocapitellar (RC) joint lack versatility or durability or do not directly address the subchondral bone structure and function.Purpose/Hypothesis:To biomechanically characterize the RC joint contact area, force, pressure, and peak pressure before and after reconstruction of osteochondral defects using a novel hybrid reconstructive procedure. It was hypothesized that the procedure would restore the contact characteristics to the intact condition.Study Design:Controlled laboratory study.Methods:A total of 10 cadaveric elbows (mean age 67 ± 2.7 years) were dissected to isolate the humerus and radial head. RC contact area, contact force, mean contact pressure, and peak contact pressure were measured with the elbow at 45° of flexion and neutral forearm rotation at compressive loads of 25, 50, and 75 N. Osteochondral defects 8 and 11 mm in diameter were created at the center of the capitellum; the defects were then reconstructed with a titanium fenestrated threaded implant, countersunk in the subchondral bone, with an acellular dermal matrix allograft sutured in place on top of the implant. Five conditions (intact, 8-mm defect, 8-mm repair, 11-mm defect, and 11-mm repair) were tested and results were compared using repeated-measures analysis of variance.Results:Both 8- and 11-mm defects significantly increased RC mean contact pressure at all compressive loads (P ≤ .008) and significantly increased peak contact pressure at compressive loads of 50 and 75 N (P < .002) compared with the intact condition. Repair of the 8-mm defect significantly decreased RC mean contact pressure at 25- and 50-N loads (P ≤ .009) and significantly decreased peak contact pressure at 50- and 75-N loads (P ≤ .035) compared with the defect condition. Repair of the 11-mm defect decreased mean contact pressure significantly at all compressive loads (P ≤ .001) and peak contact pressure at 50- and 75-N loads (P < .044) compared with the defect condition.Conclusion:RC joint contact pressure was restored to intact conditions while avoiding increased peak contact pressure or edge loading after repairing osteochondral defects related to osteochondrosis with a novel hybrid reconstruction technique.Clinical Relevance:This hybrid procedure that addresses the entire osteochondral unit may provide a new treatment option for osteochondral defects.

Axial alignment is a critical regulator of knee osteoarthritis.

Although osteoarthritis (OA), a leading cause of disability, has been associated with joint malalignment, scientific translational evidence for this link is lacking. In a clinical case study, we provide evidence of osteochondral recovery upon unloading symptomatic isolated medial tibiofemoral knee OA associated with varus malalignment. By mapping response correlations at high resolution, we identify spatially complex degenerative changes in cartilage after overloading in a clinically relevant ovine model. We further report that unloading diminishes OA cartilage degeneration and alterations of critical parameters of the subchondral bone plate in a similar topographic fashion. Last, therapeutic unloading shifted the articular cartilage and subchondral bone phenotype to normal and restored several physiological correlations disturbed in neutral and varus OA, suggesting a protective effect on the integrity of the entire osteochondral unit. Collectively, these findings identify modifiable trajectories with considerable translational potential to reduce the burden of human OA.

The role of mechanobiology in bone and cartilage model systems in characterizing initiation and progression of osteoarthritis

Multifaceted changes in the mechanobiological environment of skeletal joints, at multiple length scales, are central to the development of diseases-like osteoarthritis (OA). Recent evidence demonstrates related mechanical alterations in both bone and cartilage tissues, with crosstalk between the tissues being an important factor in acute and chronic degenerative processes. However, recapitulating multicellular tissue systems in the laboratory to study the entire osteochondral unit remains challenging. Thus, the development of accurate and reproducible OA model systems and the selection of the most suitable model for individual experimental approaches are critical. This review first discusses recent progress in understanding mechanosensory processes in healthy and osteoarthritic joints. Subsequently, we review advancements in the development of in vitro and ex vivo model systems ranging from 2D monocultures through to joint organ-on-a-chip models. Use of these systems allows for the study of multiple cell types in controlled, reproducible, and dynamic environments, which can incorporate precisely controlled mechanical and biochemical stimuli, and biophysical cues. The way in which these models have, and will continue to, improve our ability to recapitulate complex mechanical/paracrine signaling pathways in osteochondral tissues is then discussed. As the accuracy of model systems advances, they will have a significant impact on both our understanding of the pathobiology of OA and in identifying and screening therapeutic targets to improve treatment of this complex disease.

Treatment of hallux rigidus by a novel bi-phasic aragonite-based implant: results of a twoyear multi-centre clinical trial.

The twoyear results of a multi-centre clinical trial were examined to evaluate surgical treatment of hallux rigidus using a novel, bi-phasic, biodegradable, and cell-free aragonite-based scaffold (Agili-C™, CartiHeal Ltd, Israel). Twenty patients with moderate-to-severe hallux rigidus were recruited. After thorough metatarsophalangeal joint (MTPJ-1) debridement, the scaffolds were implanted into the defect centre. Eight patients received concomitant osteotomy. Treatment outcome was followed clinically (Pain VAS, FAAM-ADL, FAAM-Sport, AOFAS-HMIS, maximum active range of extension ROM-EXT, and flexion ROM-FLEX), and by medical imaging, at sixmonth intervals for two years. Adverse events were recorded throughout the study follow-up period. Significant clinical improvement over time was observed in all evaluated parameters (screening to final evaluation averages: Pain VAS 59 to 26, FAAM-ADL 57 to 77, FAAM-Sport 39 to 66, AOFAS-HMIS 51 to 81, ROM-EXT 18° to 36°), except for ROM-FLEX. Radiographs showed stable MTPJ-1 width over the two years in 17/18 cases (94%). MRI demonstrated progressive implant biodegradation, coupled with articular cartilage and subchondral bone regeneration, with a repair tissue defect fill of 75-100% in 14/17 (82%) subjects at their final visit. Revision surgery with implant removal was performed in two patients. Bi-phasic, osteochondral, biodegradable, aragonite-based scaffold demonstrated positive clinical outcome and a good safety profile in the treatment of medium-to-advanced hallux rigidus. According to the medical imaging, this implant has the potential to restore the entire osteochondral unit of metatarsal head.

Long-term Results of Matrix-assisted Autologous Chondrocyte Transplantation Combined With Autologous Bone Grafting for the Treatment of Juvenile Osteochondritis Dissecans.

Osteochondritis dissecans is a pathology affecting young patients that involves the entire osteochondral unit. In the case of unfixable fragments, regenerative cartilage treatments are a viable solution, but little is known about the use of these procedures for the treatment of juvenile osteochondritis dissecans (JOCD). The aim of this study was to evaluate the long-term results offered by matrix-assisted autologous chondrocyte transplantation combined with autologous bone grafting for the treatment of JOCD. Nineteen patients have been enrolled. The mean age at the time of treatment was 16.8±1.5 years, with a mean body mass index of 22.9±2.7. The average size of the defects was 2.8±1.2 cm. All patients were evaluated prospectively before surgery and at 12, 24, 60, and at a final follow-up of 120 months with International Knee Documentation Committee scores, EuroQol-Visual Analogue Scale, and the Tegner Score. A statistically significant improvement in all clinical scores was observed from baseline evaluation to 120 months of final follow-up. In particular, the International Knee Documentation Committee subjective score improved from the preoperative evaluation of 38.7±17.3 to 74.0±21.8 at 12 months (P<0.0005), with scores remaining stable for up to 120 months (83.8±20.7), with all follow-ups showing a statistically significant improvement compared with the basal value (P<0.0005). Three patients failed at 12 months, for a failure rate of 16% at 10 years of follow-up. Lesions >3.5 cm obtained worse subjective results. In addition, lesion size and female sex were significantly associated with failures. The matrix-assisted autologous chondrocyte transplantation technique with autologous bone grafting is a valid treatment option for JOCD in case of unfixable fragments. The clinical improvement obtained is significant and stable, with good results maintained for up to 10 years of follow-up and an overall low failure rate. Lesion size and sex could influence the clinical outcome and should be considered in the treatment choice. Level IV-case series.

Thermosensitive Hydrogel Based on PEO-PPO-PEO Poloxamers for a Controlled In Situ Release of Recombinant Adeno-Associated Viral Vectors for Effective Gene Therapy of Cartilage Defects.

Advanced biomaterial-guided delivery of gene vectors is an emerging and highly attractive therapeutic solution for targeted articular cartilage repair, allowing for a controlled and minimally invasive delivery of gene vectors in a spatiotemporally precise manner, reducing intra-articular vector spread and possible loss of the therapeutic gene product. As far as it is known, the very first successful in vivo application of such a biomaterial-guided delivery of a potent gene vector in an orthotopic large animal model of cartilage damage is reported here. In detail, an injectable and thermosensitive hydrogel based on poly(ethylene oxide) (PEO)-poly(propylene oxide) (PPO)-PEO poloxamers, capable of controlled release of a therapeutic recombinant adeno-associated virus (rAAV) vector overexpressing the chondrogenic sox9 transcription factor in full-thickness chondral defects, is applied in a clinically relevant minipig model in vivo. These comprehensive analyses of the entire osteochondral unit with multiple standardized evaluation methods indicate that rAAV-FLAG-hsox9/PEO-PPO-PEO hydrogel-augmented microfracture significantly improves cartilage repair with a collagen fiber orientation more similar to the normal cartilage and protects the subchondral bone plate from early bone loss.

Fresh Osteochondral Allograft Transplantation for Uncontained, Elongated Osteochondritis Dissecans Lesions of the Medial Femoral Condyle

Osteochondritis dissecans (OCD) lesions of the knee are a significant source of pain and disability. Although the pathologic process for this condition remains poorly understood, histologic studies suggest vascular insufficiency of the subchondral bone may be the underlying cause for focal necrosis and subsequent compromise of the overlying articular cartilage. These lesions most commonly affect the medial femoral condyle and can be found along the margins of the intercondylar notch. Because of significant bone involvement, osteochondral allograft (OCA) transplantation has emerged as a dominant treatment option for OCD lesions because it can accurately restore the entire osteochondral unit. Given the characteristic location and large, irregular shapes of these lesions, surgical management can be challenging. These lesions are often uncontained along the periphery of the condyle, which can compromise OCA graft fixation and healing. We describe our preferred technique for the treatment of large, uncontained OCD lesions of the medial femoral condyle using a unicompartmental OCA augmented with screw fixation.

An injectable continuous stratified structurally and functionally biomimetic construct for enhancing osteochondral regeneration

Osteochondral regeneration with the formation of hyaline cartilage and subchondral bone as well as the integration between the newly formed tissues with the host tissue still remains a great challenge. In this study, a construct containing an injectable continuous stratified scaffold and multiple cell systems was designed for enhancing osteochondral regeneration. Briefly, an injectable sodium alginate(SA)/bioglass (BG) composite hydrogel containing bone marrow stem cells (BMSCs) (SA/BG + BMSCs) was used for subchondral bone regeneration and an injectable thermosensitive SA/agarose (AG) composite hydrogel with co-culture of BMSCs and articular chondrocytes (ACs) (SA/AG + ACs/BMSCs) was applied for articular cartilage regeneration. The continuous SA phase and the stratified structure enable the scaffold to mimic the natural osteochondral structure. In addition, the SA/BG + BMSCs hydrogel could enhance the osteoblast differentiation of BMSCs by upregulating their alkaline phosphatase and collagen I gene expressions, and the SA/AG + ACs/BMSCs hydrogel could promote the chondrocyte differentiation of BMSCs by upregulating their Acan and collagen II gene expressions, which indicated that this stratified scaffold could mimic the natural osteochondral function. Furthermore, after the stratified construct was injected into a rat osteochondral defect model, obvious neonatal articular cartilage tissues and subchondral bone tissues with regular surface and highly integration with normal tissues could be observed. This structural and functional biomimetic construct, together with its proper swelling ratio, could not only stimulate the hyaline cartilage and subchondral bone regeneration in an entire osteochondral unit but also promote the integration between the newly formed tissues and the host tissue.

The effect of ageing and osteoarthritis on the mechanical properties of cartilage and bone in the human knee joint

Osteoarthritis is traditionally associated with cartilage degeneration although is now widely accepted as a whole-joint disease affecting the entire osteochondral unit; however site-specific cartilage and bone material properties during healthy ageing and disease are absent limiting our understanding. Cadaveric specimens (n = 12; 31–88 years) with grades 0–4 osteoarthritis, were dissected and spatially correlated cartilage, subchondral and trabecular bone samples (n = 8 per cadaver) were harvested from femoral and tibial localities. Nanoindentation was utilised to obtain cartilage shear modulus (G′) and bone elastic modulus (E). Cartilage G′ is strongly correlated to age (p = 0.003) and osteoarthritis grade (p = 0.007). Subchondral bone E is moderately correlated to age (p = 0.072) and strongly correlated to osteoarthritis grade (p = 0.013). Trabecular bone E showed no correlation to age (p = 0.372) or osteoarthritis grade (p = 0.778). Changes to cartilage G′ was significantly correlated to changes in subchondral bone E (p = 0.007). Results showed preferential medial osteoarthritis development and moderate correlations between cartilage G′ and sample location (p = 0.083). Also demonstrated for the first time was significant correlations between site-matched cartilage and subchondral bone material property changes during progressive ageing and osteoarthritis, supporting the role of bone in disease initiation and progression. This clinically relevant data indicates a causative link with osteoarthritis and medial habitual loading.

Treatment of Knee Osteochondritis Dissecans With a Cell-Free Biomimetic Osteochondral Scaffold: Clinical and Imaging Findings at Midterm Follow-up

Background: Osteochondritis dissecans (OCD) is a developmental condition of subchondral bone that may result in secondary separation and instability of the overlying articular cartilage, which in turn may lead to degeneration of the overall joint and early osteoarthritis. Biphasic scaffolds have been developed to address defects of the entire osteochondral unit by reproducing the different biological and functional requirements and guiding the growth of both bone and cartilage. Purpose: To evaluate midterm clinical and imaging results after cell-free osteochondral scaffold implantation for the treatment of knee OCD. Study Design: Case series; Level of evidence, 4. Methods: Twenty-seven patients (8 women, 19 men; mean age, 25.5 ± 7.7 years) were treated for knee OCD, with International Cartilage Repair Society (ICRS) grade 3 to 4 lesions with a mean size of 3.4 ± 2.2 cm2 (range, 1.5-12 cm2), and prospectively evaluated for up to 5 years using the ICRS classification system and the Tegner score. Eighteen patients underwent magnetic resonance imaging (MRI) at 24 and 60 months of follow-up, and the graft was evaluated using the magnetic resonance observation of cartilage repair tissue (MOCART) score for the cartilage layer, while a specific score was used for subchondral bone. Results: All patients significantly improved their clinical scores at each follow-up until their final evaluation. The mean International Knee Documentation Committee (IKDC) subjective score improved from 48.4 ± 17.8 to 82.2 ± 12.2 at 2 years (P < .0005), and it then remained stable for up to 5 years postoperatively (90.1 ± 12.0). The mean Tegner score increased from 2.4 ± 1.7 preoperatively to 4.4 ± 1.6 at 2 years (P = .001), with a further increase up to 5.0 ± 1.7 at 5 years of follow-up (P < .0005 vs preoperatively), reaching almost the preinjury level (5.7 ± 2.2). The MOCART score showed stable results between 24 and 60 months, whereas the subchondral bone status significantly improved over time. No correlation was found between MRI findings and clinical outcomes. Conclusion: This 1-step cell-free scaffold implantation procedure showed good and stable results for up to 60 months of follow-up for the treatment of knee OCD. MRI showed abnormalities, in particular at the subchondral bone level, but there was an overall improvement of features over time. No correlation was found between imaging and clinical findings.

High resolution MRI imaging at 9.4 Tesla of the osteochondral unit in a translational model of articular cartilage repair.

BackgroundNon-destructive structural evaluation of the osteochondral unit is challenging. Here, the capability of high-field magnetic resonance imaging (μMRI) at 9.4 Tesla (T) was explored to examine osteochondral repair ex vivo in a preclinical large animal model. A specific aim of this study was to detect recently described alterations of the subchondral bone associated with cartilage repair.MethodsOsteochondral samples of medial femoral condyles from adult ewes containing full-thickness articular cartilage defects treated with marrow stimulation were obtained after 6 month in vivo and scanned in a 9.4 T μMRI. Ex vivo imaging of small osteochondral samples (typical volume: 1–2 cm3) at μMRI was optimised by variation of repetition time (TR), time echo (TE), flip angle (FA), spatial resolution and number of excitations (NEX) from standard MultiSliceMultiEcho (MSME) and three-dimensional (3D) spoiled GradientEcho (SGE) sequences.ResultsA 3D SGE sequence with the parameters: TR = 10 ms, TE = 3 ms, FA = 10 °, voxel size = 120 × 120 × 120 μm3 and NEX = 10 resulted in the best fitting for sample size, image quality, scanning time and artifacts. An isovolumetric voxel shape allowed for multiplanar reconstructions. Within the osteochondral unit articular cartilage, cartilaginous repair tissue and bone marrow could clearly be distinguished from the subchondral bone plate and subarticular spongiosa. Specific alterations of the osteochondral unit associated with cartilage repair such as persistent drill holes, subchondral bone cysts, sclerosis of the subchondral bone plate and of the subarticular spongiosa and intralesional osteophytes were precisely detected.ConclusionsHigh resolution, non-destructive ex vivo analysis of the entire osteochondral unit in a preclinical large animal model that is sufficient for further analyses is possible using μMRI at 9.4 T. In particular, 9.4 T is capable of accurately depicting alterations of the subchondral bone that are associated with osteochondral repair.

Tibial plateau lesions. Surface reconstruction with a biomimetic osteochondral scaffold: Results at 2 years of follow-up

IntroductionTibial plateau articular pathology caused by post-traumatic or degenerative lesions is a challenge for the orthopaedic surgeon and can lead to early osteoarthritis. The aim of the present study was to evaluate the results of treatment of these complex defects with implantation of an osteochondral scaffold, which is designed to target the cartilage surface and to reconstruct joint anatomy by addressing the entire osteochondral unit. Materials and methodsEleven patients (5 female and 6 male) with a mean age of 37.3±11.0 years and osteochondral lesions of the tibial plateau (mean 5.1±2.7cm2; range 3.0–12.5cm2) were treated with the implantation of an osteochondral biomimetic collagen-hydroxyapatite scaffold (Maioregen®, Fin-Ceramica, Faenza, Italy). Comorbidities were addressed taking care to restore the correct limb alignment. Patients were evaluated pre-operatively and prospectively followed-up for 2 years using the International Knee Documentation Committee (IKDC) subjective and objective scores; activity level was documented using the Tegner score. ResultsThree patients experienced minor adverse events. No patients required further surgery for treatment failure during the study follow-up period, and 8 patients (72.7%) reported a marked improvement. The IKDC subjective score improved from 42.5±10.2 before treatment to 69.8±19.0 at 12 months (p<0.05), with stable results at 24 months. The IKDC objective score increased from 27.3% normal and nearly normal knees before treatment to 85.7% normal and nearly normal knees at 24 months of follow-up. The Tegner score increased from 2.3±2.1 before treatment to 4.8±2.4 at 12 months (p<0.05), and was stable at the final follow-up. ConclusionThe present study on the implantation of an osteochondral scaffold for the treatment of tibial plateau lesions showed a promising clinical outcome at short-term follow-up, which indicates that this procedure can be considered as a possible treatment option, even in these complex defects, when comorbidities are concomitantly addressed.

Clinical results of multilayered biomaterials for osteochondral regeneration.

Several techniques have been used during the years to treat chondral and osteochondral lesions. Among them, the emerging trend in the field of osteochondral regeneration is to treat the entire osteochondral unit by implanting cell-free scaffolds, which provide a three-dimensional support for the cell growth and may act themselves as stimuli for an “in situ” tissue regeneration. Various multi-layered products have been proposed that mimic both the subchondral bone and the cartilaginous layer. Among these, three have currently been reported in the literature. One has been widely investigated: it is a nanocomposite three-layered collagen-hydroxyapatite scaffold, which is showing promising results clinically and by MRI even at mid-term follow-up. The second is a PLGA-calcium-sulfate bilayer scaffold: however, the literature findings are still controversial and only short-term outcomes of limited case-series have been published. The most recent one is a solid aragonite-based scaffold, which seems to give promising clinical and MRI outcomes, even if the literature is still lacking more in-depth evaluations.Even though the Literature related to this topic is quickly increasing in number, the clinical evidence it is still limited to some case series, and high-level studies are needed to better demonstrate their real effectiveness.

Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo.

Direct therapeutic gene transfer is a promising tool to treat articular cartilage defects. Here, we tested the ability of an recombinant adeno-associated virus (rAAV) insulin-like growth factor I (IGF-I) vector to improve the early repair of cartilage lesions in vivo. The vector was administered for 3 weeks in osteochondral defects created in the knee joints of rabbits compared with control (lacZ) treatment and in cells that participate in the repair processes (mesenchymal stem cells, chondrocytes). Efficient IGF-I expression was observed in the treated lesions and in isolated cells in vitro. rAAV-mediated IGF-I overexpression was capable of stimulating the biologic activities (proliferation, matrix synthesis) both in vitro and in vivo. IGF-I treatment in vivo was well tolerated, revealing significant improvements of the repair capabilities of the entire osteochondral unit. IGF-I overexpression delayed terminal differentiation and hypertrophy in the newly formed cartilage, possibly due to contrasting effects upon the osteogenic expression of RUNX2 and β-catenin and to stimulating effects of this factor on the parathyroid hormone/parathyroid hormone-related protein pathway in this area. Production of IGF-I improved the reconstitution of the subchondral bone layer in the defects, showing increased RUNX2 expression levels in this zone. These findings show the potential of directly applying therapeutic rAAVs to treat cartilage lesions.

Clinical Results and MRI Evolution of a Nano-Composite Multilayered Biomaterial for Osteochondral Regeneration at 5 Years

Background: Several cartilage lesions involve the subchondral bone, and there is a need for biphasic scaffolds to treat the entire osteochondral unit to reproduce the different biological and functional requirements and guide the growth of the 2 tissues. Purpose: To evaluate the results of a cell-free collagen-hydroxyapatite osteochondral scaffold at midterm, and to use magnetic resonance imaging (MRI) analysis to document the imaging evolution of the tissue regeneration process through 5 years of follow-up. Study Design: Case series; Level of evidence, 4. Methods: Twenty-seven patients (9 women, 18 men; mean age, 34.9 ± 10.2 years) treated for knee chondral or osteochondral lesions (size, 1.5-6 cm2) were followed for 2 and 5 years and were clinically evaluated using the International Knee Documentation Committee (IKDC) and Tegner scores. An MRI evaluation was performed at both follow-ups in 23 lesions, and the magnetic resonance observation of cartilage repair tissue (MOCART) score and specific subchondral bone parameters (bone regeneration, bone signal quality, osteophytes or upcoming bone front, sclerotic areas, and edema) were analyzed. Results: A statistically significant improvement in all clinical scores was observed from the initial evaluation to the 2- and 5-year follow-ups, and the results were stable over time. The mean IKDC subjective score improved from 40.0 ± 15.0 to 76.5 ± 14.5 (2-year follow-up) and 77.1 ± 18.0 (5-year follow-up) and the mean Tegner score from 1.6 ± 1.1 to 4.0 ± 1.8 (2-year follow-up) and 4.1 ± 1.9 (5-year follow-up). The MRI evaluation showed a significant improvement in both the MOCART score and subchondral bone status from 2 to 5 years. At 5 years, complete filling of the cartilage was shown in 78.3% of the lesions, complete integration of the graft was detected in 69.6% of cases, the repair tissue surface was intact in 60.9%, and the structure of the repair tissue was homogeneous in 60.9% of the cases. No correlation was found between MRI findings and clinical outcome. Conclusion: This osteochondral scaffold was used for the treatment of chondral and osteochondral knee defects with a single-step procedure. The study results highlighted the safety and potential of this procedure, which offered a good clinical outcome with stable results at midterm follow-up. Although the MRI findings improved over time, some abnormalities persisted, but no correlation was found between the imaging and clinical results.

Osteochondral scaffold reconstruction for complex knee lesions: a comparative evaluation

BackgroundThe primary aim of the present study is to evaluate the results obtained in challenging knee lesions with the implant of an osteochondral scaffold and concomitant treatment of all comorbidities. The secondary aim is to compare the results obtained with those found when a chondral scaffold was applied. Materials and methodsPatients affected by complex lesions of the knee articular surface were included. “Complex cases” were defined according to the following criteria: previous clinical history of intra-articular fracture, lesion located at the tibial plateau, concurrent knee axial realignment procedure, concurrent meniscal scaffold or allograft implantation, and multiple articular surface lesions treated. Thirty-three patients were treated with the implantation of an osteochondral scaffold. The results of a homogeneous group of 23 patients previously treated and prospectively evaluated after implantation of a chondral scaffold were analyzed and compared. ResultsIKDC subjective score improved significantly from pre-operative (40.4±14.1) to 12months' follow-up (69.6±17.0; p<0.0005) with a further improvement at the final evaluation at 24months (75.5±15.0; p=0.038). The same positive trend was confirmed by the VAS and Tegner scores. At final follow-up the group treated with the osteochondral scaffold presented a better subjective IKDC score with respect to the group treated with the chondral scaffold (p=0.034). ConclusionsA regenerative procedure to address the entire osteochondral unit, together with the treatment of all comorbidities, might offer good results also in complex cases otherwise doomed to non-biological resurfacing. Level of evidence IIIComparative study.

Alterations of the subchondral bone in osteochondral repair – translational data and clinical evidence

Alterations of the subchondral bone are pathological features associated with spontaneous osteochondral repair following an acute injury and with articular cartilage repair procedures. The aim of this review is to discuss their incidence, extent and relevance, focusing on recent knowledge gained from both translational models and clinical studies of articular cartilage repair. Efforts to unravel the complexity of subchondral bone alterations have identified (1) the upward migration of the subchondral bone plate, (2) the formation of intralesional osteophytes, (3) the appearance of subchondral bone cysts, and (4) the impairment of the osseous microarchitecture as potential problems. Their incidence and extent varies among the different small and large animal models of cartilage repair, operative principles, and over time. When placed in the context of recent clinical investigations, these deteriorations of the subchondral bone likely are an additional, previously underestimated, factor that influences the long-term outcome of cartilage repair strategies. Understanding the role of the subchondral bone in both experimental and clinical articular cartilage repair thus holds great promise of being translated into further improved cell- or biomaterial-based techniques to preserve and restore the entire osteochondral unit.