Hyaline articular cartilage has been known to be a troublesome tissue to repair once damaged. Since the introduction of autologous chondrocyte implantation (ACI) in 1994, a renewed interest in the field of cartilage repair with new repair techniques and the hope for products that are regenerative have blossomed. This article reviews the basic science structure and function of articular cartilage, and techniques that are presently available to effect repair and their expected outcomes

Although cartilage repair has been around since the time of open Pridie drilling, clinical outcomes for newer techniques such as arthroscopic debridement, microfracture (MFX), osteochondral autograft transfers (OATS), osteochondral allograft transplantation and Autologous Chondrocyte Implantation (ACI) are still finding their place in treating injured knees. Early mechanical symptoms are best managed by a gentle arthroscopic debridement of loose articular flaps. This allows the surgeon to assess the defect size, location in the tibio-femoral or patellofemoral joint, status of the cartilage overall and patients response to the intervention. If the symptom improvement is not satisfactory to the patient, after assessing background factors that will influence the results of a cartilage repair procedure, (alignment of the patellofemoral joint or axial alignment, ligament stability and status of the meniscus), the surgeon can choose the best procedure for that individual based on the expected outcomes of the various cartilage repair techniques while addressing the background factors. As all the techniques have failures and informed discussion with the patient prior to performing the procedure is critical in avoiding disappointment for the patient and the surgeon. The repair technique used should incorporate considerations of the defect size, location, and the patient age, activity level, expectations and ability to comply with the longer rehabilitation needed for biological procedures as compared to prosthetic implants

The parameters to be considered in the selection of a cartilage repair strategy are: the diameter of the chondral defect; the depth of the bone defect; the location of the defect (weight bearing); alignment. A chondral defect less than 3 cm in diameter can be managed by surface treatment such as microfracture, autologous chondrocyte transplantation, mosaicplasty, or periosteal grafting. An osteochondral defect less than 3 cm in diameter and less than 1 cm in depth can be managed by autologous chondrocyte transplantation, mosaicplasty or periosteal grafting. An osteochondral defect greater than 3 cm in diameter and 1 cm in depth is best managed by an osteochondral allograft. If there is an associated knee deformity, then an osteotomy should also be performed with all of the aforementioned procedures. In our series of osteochondral allografts for large post-traumatic knee defects realignment osteotomy is performed about 60% of the time in order to off load the transplant. To correct varus we realign the proximal tibia with an opening wedge osteotomy. To correct valgus, we realign the distal femur with a closing wedge osteotomy. Our results with osteochondral allografts for the large osteochondral defects of the knee have been excellent in 85% of patients at an average follow-up of 10 years. The Kaplan-Meier survivorship at 15 years is 72%. At an average follow-up of 22 years in 58 patients with distal femoral osteochondral allograft, 13 have been revised (22%). The 15-year survivorship was 84%. The results for the hip are early. To date we have performed this procedure on 16 patients. Surgical dislocation of the hip is carried out via a trochanteric osteotomy and the defect defined and trephined out. A press-fit fresh osteochondral allograft is inserted using the trephine technique. We have published our early results on a series of 8 patients with 5 good to excellent results, 1 fair result and 2 failures

PURPOSE. Recently, in tissue engineering several methods using stem cells have been developed to repair chondral and osteochondral defects. Most of these methods rely on the use of scaffolds. Studies in the literature have demonstrated, first in animals and then in humans, that the use of mesenchymal stem cells withdrawn by several methods from adipose tissue allows to regenerate hyaline articular cartilage. In fact, it has been cleared that adipose-derived cells have multipotentiality equivalent to bone marrow-derived stem cells and that they can very easily and very quickly be isolated in large amounts enabling their immediate use in operating room for one-step cartilage repair techniques. The purpose of this study is to evaluate the therapeutic effect of adipose-derived stem cells on cartilage repair and present our experience in the treatment of knee cartilage defects by the novel AMIC REPAIR TECHNIQUE AUGMENTED by immersing the collagen scaffold with mesenchymal stem cells withdrawn from adipose tissue of the abdomen. MATERIALS AND METHODS. Fat tissue processing involves mechanical forces and does not mandatorily require any enzymatic or chemical treatment in order to obtain the regenerative cells from the lipoaspirate. In our study, mesenchymal adipose stem cells were obtained by non-enzymatic filtration or microfragmentation of lipoaspirates of the abdomen adipose tissue that enabled the separation of the stromal vascular fraction and were used in one-step reconstruction of knee cartilage defects by means of this new AUGMENTED AMIC TECHNIQUE. The focal defects underwent bone marrow stimulation microfractures, followed by coverage with collagen double layer resorbable membrane (Chondro-gide. TM. -Geistlich Pharma AG, Wolhusen, Switzerland) soaked in the cells obtained from fat in 18 patients, aged between 31 and 58 years, at the level of the left knee in 10 cases and in the right in eight, with follow-up ranging between 12 and 36 months. RESULTS: Surgical procedures have been completed without technical problems neither intraoperative or early postoperative complications. The evaluation scores (IKDC, KOOS and VAS) showed a significant improvement, more than 30%, at the initial 6 months follow-up and furtherly improved in the subsequent follow-ups. Also the control MRIs showed a progressive filling and maturation of the repair tissue of the defects. CONCLUSIONS. Since we are reporting a short and medium-term experience, it is not, of course, possible to provide conclusive assessment considerations on this technique, as the experience has to mature along with the progression of follow-ups. The simplicity together with the absence of intraoperative difficulties or immediate complications and the experience gained by other authors, first in animals and then in early clinical cases, makes it, however, possible to say that this can be considered one of the techniques to which resort for one-step treatment of cartilage defects in the knee because it improves patient's conditions and has the potential to regenerate hyaline-like cartilage. Future follow-up works will confirm the results

Cartilage is known to have limited intrinsic repair capabilities and cartilage defects can progress to osteoarthritis (OA). OA is a major economic burden of the 21st century, being among the leading causes of disability. The risk of disability from knee OA is as great as that derived from cardiovascular disease; a fact that becomes even more concerning when considering that even isolated cartilage defects can cause pain and disability comparable to that of severe OA. Several cartilage repair procedures are in current clinical application, including microfracture, osteochondral autograft transfer, osteochondral allograft transplantation, and autologous chondrocyte implantation (ACI). Given the economic challenges facing our health care system, it appears prudent to choose procedures that provide the most durable long-term outcome. Comparatively few studies have examined long-term outcomes, an important factor when considering the substantial differences in cost and morbidity among the various treatment options. This study reviews the clinical outcomes of autologous chondrocyte implantation at a minimum of 10 years after treatment of chondral defects of the knee. Mean age at surgery was 36 ± 9 years; mean defect size measured 8.4 ± 5.5cm2. Outcome scores were prospectively collected pre- and postoperatively at the last follow up. We further analyzed potential factors contributing to failure in hopes of refining the indications for this procedure. Conclusions: ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery. A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure

Introduction. Bone marrow stimulation has been a successful treatment option in cartilage repair and microfracture was the procedure of choice since the late 1980s. Despite its success in young and active patients, microfracture has inherent shortcomings such as shallow channels, wall compression, and non-standardized depth and diameter. This in vitro study assessed bone marrow access comparing microfracture, 1 and 2mm K-Wires, 1mm drill, and a recently introduced standardized subchondral bone needling procedure (Nanofracture) that creates 9mm deep and 1mm wide channels. Methods. An adult ovine model was used to assess access to bone the marrow spaces as well as effects on bone following microfracture, nanofracture, K-wire, and drilling following ethical clearance. All bone marrow stimulation techniques were conducted on a full thickness articular cartilage defect on the medial femoral condyles by the same surgeon. The same groups were repeated in vitro in 4 paired ovine distal femurs. MicroCT (Inveon Scanner, Siemens, Germany) was performed using 3D reconstruction and 25 micron slice analysis (MIMICS, Materialise, Belgium). Results. Microfracture elicited shallow depth with bone compression surrounding the channels. Trabecular channel access was limited; the channel depth and diameter were non-standardized and highly user and instrument dependent. Nanofracture demonstrated deep cancellous bone perforation with a high number of open trabecular channels. K-Wire drilling with both diameters resulted in well-defined channel walls, outlined by fine osseous deposits. Trabecular channel access was limited. The diameter of bone perforation is standardized, but depth is defined by visual controls. 1mm drill bit reaming demonstrated better osseous evacuation, but still limited trabecular marrow access. Discussion and Conclusion. Nanofracture resulted in thin, fragmented cancellous bone channels without rotational heat generation. Compared to microfracture, drilling and K-Wire stimulation, nanofracture showed superior bone marrow access with multiple trabecular access channels extending 9mm into subchondral bone

An osteochondral defect greater than 3cm in diameter and 1cm in depth is best managed by an osteochondral allograft.

If there is an associated knee deformity, then an osteotomy is performed. In our series of osteochondral allografts for large post-traumatic knee defects realignment osteotomy is performed about 60% of the time in order to off-load the transplant. To correct varus we realign the proximal tibia with an opening wedge osteotomy. To correct valgus, we realign the distal femur with a closing wedge osteotomy.

Our results with osteochondral allografts for the large osteochondral defects of the knee both femur and tibia, have been excellent in 85% of patients at an average follow-up of 10 years. The Kaplan-Meier survivorship at 15 years is 72%. At an average follow-up of 22 years in 58 patients with distal femoral osteochondral allograft, 13 have been revised (22%). The 15-year survivorship was 84%.

Retrieval studies of 24 fresh osteochondral grafts obtained at graft revision or conversion total knee replacement at an average of 12 years (5 – 25) revealed the following. In the areas where the graft was still intact, the cartilage was of normal thickness and architecture. Matrix staining was normal except in the superficial and upper mid zones. Chondrocytes were mostly viable but there was chondrocyte clusters and loss of chondrocyte polarity. Host bone had extended to the calcified cartilage but variable remnants of dead bone surrounded by live bone persisted. With a stable osseous base the hyaline cartilage portion of the graft can survive for up to 25 years.

An osteochondral defect greater than 3cm in diameter and 1cm in depth is best managed by an osteochondral allograft.

If there is an associated knee deformity, then an osteotomy was performed. In our series of osteochondral allografts for large post-traumatic knee defects, realignment osteotomy is performed about 60% of the time in order to off load the transplant. To correct varus we realign the proximal tibia with an opening wedge osteotomy. To correct valgus, we realign the distal femur with a closing wedge osteotomy.

Our results with osteochondral allografts for the large osteochondral defects of the knee both femur and tibia, have been excellent in 85% of patients at an average follow-up of 10 years. The Kaplan-Meier survivorship at 15 years is 72%. At an average follow-up of 22 years in 58 patients with distal femoral osteochondral allograft, 13 have been revised (22%). The 15-year survivorship was 84%.

Retrieval studies of 24 fresh osteochondral grafts obtained at graft revision or conversion to total knee replacement at an average of 12 years (5 – 25) revealed the following. In the areas where the graft was still intact, the cartilage was of normal thickness and architecture. Matrix staining was normal except in the superficial and upper mid-zones. Chondrocytes were mostly viable but there was chondrocyte clusters and loss of chondrocyte polarity. Host bone had extended to the calcified cartilage but variable remnants of dead bone surrounded by live bone persisted. With a stable osseous base the hyaline cartilage portion of the graft can survive for up to 25 years.

Gel-based autologous chondrocyte implantation (ACI) over the years have shown encouraging results in repairing the articular cartilage. More recently, the use of cultured mesenchymal stem cells (MSC) has represented a promising treatment option with the potential to differentiate and restore the hyaline cartilage in a more efficient way. This study aims to compare the clinical and radiological outcome obtained in these two groups.

Twenty-eight consecutive symptomatic patients diagnosed with full-thickness cartilage defects were assigned to two treatment groups (16 patients cultured bone marrow-derived MSC and 12 patients with gel-type ACI). The MSC group patients underwent microfracture and bone marrow aspiration in the first stage and injection of cultured MSC into the knee in the second stage. Clinical and radiological results were compared at a minimum follow up of five years

There was excellent clinical outcome noted with no statistically significant difference between the two groups. Both ACI and MSC group showed significant improvement of the KOOS, Lysholm and IKDC scores as compared to their preoperative values and this was maintained at 5 years follow up. The average MOCART score for all lesions was also nearly similar in the two groups. The mean T2* relaxation-times for the repair tissue and native cartilage were 27.8 and 30.6 respectively in the ACI group and 28 and 29.6 respectively in the MSC group.

Use of cultured MSC is less invasive, technically simpler and also avoids the need for a second surgery as compared to an ACI technique. With similar encouraging clinical results seen and the proven ability to restore true hyaline cartilage, cultured MSC represent a favorable treatment option in articular cartilage repair.

Recurrent patellar instability is a common problem and there are multiple demographic and pathoanatomic risk factors that predispose patients to dislocating their patella. The most common of these is trochlear dysplasia. In cases of severe trochlear dysplasia associated with patellar instability, a sulcus deepening trochleoplasty combined with a medial patellofemoral ligament reconstruction (MPFLR) may be indicated. Unaddressed trochlear pathology has been associated with failure and poor post-operative outcomes after stabilization. The purpose of this study is to report the clinical outcome of patients having undergone a trochleoplasty and MPFLR for recurrent lateral patellofemoral instability in the setting of high-grade trochlear dysplasia at a mean of 2 years follow-up. A prospectively collected database was used to identify 46 patients (14 bilateral) who underwent a combined primary MPFLR and trochleoplasty for recurrent patellar instability with high-grade trochlear dysplasia between August 2013 and July 2021. A single surgeon performed a thin flap trochleoplasty using a lateral para-patellar approach with lateral retinaculum lengthening in all 60 cases. A tibial tubercle osteotomy (TTO) was performed concomitantly in seven knees (11.7%) and the MPFLR was performed with a gracilis tendon autograft in 22%, an allograft tendon in 27% and a quadriceps tendon autograft in 57% of cases. Patients were assessed post-operatively at three weeks and three, six, 12 and 24 months. The primary outcome was the Banff Patellar Instability Instrument 2.0 (BPII 2.0) and secondary outcomes were incidence of recurrent instability, complications and reoperations. The mean age was 22.2 years (range, 13 to 45), 76.7% of patients were female, the mean BMI was 25.03 and the prevalence of a positive Beighton score (>4/9) was 40%. The mean follow-up was 24.3 (range, 6 to 67.7) months and only one patient was lost to follow-up before one year post-operatively. The BPII 2.0 improved significantly from a mean of 27.3 pre-operatively to 61.1 at six months (p < 0 .01) and further slight improvement to a mean of 62.1 at 12 months and 65.6 at 24 months post-operatively. Only one patient (1.6%) experienced a single event of subluxation without frank dislocation at nine months. There were three reoperations (5%): one for removal of the TTO screws and prominent chondral nail, one for second-look arthroscopy for persistent J-sign and one for mechanical symptoms associated with overgrowth of a lateral condyle cartilage repair with a bioscaffold. There were no other complications. In this patient cohort, combined MPFLR and trochleoplasty for recurrent patellar instability with severe trochlear dysplasia led to significant improvement of patient reported outcome scores and no recurrence of patellar dislocation at a mean of 2 years. Furthermore, in this series the procedure demonstrated a low rate (5%) of complications and reoperations

Adult articular cartilage mechanical functionality is dependent on the unique zonal organization of its tissue. Current mesenchymal stem cell (MSC)-based treatment has resulted in sub-optimal cartilage repair, with inferior quality of cartilage generated from MSCs in terms of the biochemical content, zonal architecture and mechanical strength when compared to normal cartilage. The phenotype of cartilage derived from MSCs has been reported to be influenced by the microenvironmental biophysical cues, such as the surface topography and substrate stiffness. In this study, the effect of nano-topographic surfaces to direct MSC chondrogenic differentiation to chondrocytes of different phenotypes was investigated, and the application of these pre-differentiated cells for cartilage repair was explored. Specific nano-topographic patterns on the polymeric substrate were generated by nano-thermal imprinting on the PCL, PGA and PLA surfaces respectively. Human bone marrow MSCs seeded on these surfaces were subjected to chondrogenic differentiation and the phenotypic outcome of the differentiated cells was analyzed by real time PCR, matrix quantification and immunohistological staining. The influence of substrate stiffness of the nano-topographic patterns on MSC chondrogenesis was further evaluated. The ability of these pre-differentiated MSCs on different nano-topographic surfaces to form zonal cartilage was verified in in vitro 3D hydrogel culture. These pre-differentiated cells were then implanted as bilayered hydrogel constructs composed of superficial zone-like chondro-progenitors overlaying the middle/deep zone-like chondro-progenitors, was compared to undifferentiated MSCs and non-specifically pre-differentiated MSCs in a osteochondral defect rabbit model. Nano-topographical patterns triggered MSC morphology and cytoskeletal structure changes, and cellular aggregation resulting in specific chondrogenic differentiation outcomes. MSC chondrogenesis on nano-pillar topography facilitated robust hyaline-like cartilage formation, while MSCs on nano-grill topography were induced to form fibro/superficial zone cartilage-like tissue. These phenotypic outcomes were further diversified and controlled by manipulation of the material stiffness. Hyaline cartilage with middle/deep zone cartilage characteristics was derived on softer nano-pillar surfaces, and superficial zone-like cartilage resulted on softer nano-grill surfaces. MSCs on stiffer nano-pillar and stiffer nano-grill resulted in mixed fibro/hyaline/hypertrophic cartilage and non-cartilage tissue, respectively. Further, the nano-topography pre-differentiated cells possessed phenotypic memory, forming phenotypically distinct cartilage in subsequent 3D hydrogel culture. Lastly, implantation of the bilayered hydrogel construct of superficial zone-like chondro-progenitors and middle/deep zone-like chondro-progenitors resulted in regeneration of phenotypically better cartilage tissue with higher mechanical function. Our results demonstrate the potential of nano-topographic cues, coupled with substrate stiffness, in guiding the differentiation of MSCs to chondrocytes of a specific phenotype. Implantation of these chondrocytes in a bilayered hydrogel construct yielded cartilage with more normal architecture and mechanical function. Our approach provides a potential translatable strategy for improved articular cartilage regeneration using MSCs

Aims. To investigate (1) The relationship between macroscopic grading and durability of cartilage repair following collagen-covered autologous chondrocyte implantation (ACI-C) in the knee; (2) The influence of histology on durability of cartilage repair; (3) The relationship between macroscopic appearance and histology of repair tissue. Patients and methods. The modified Cincinnati scores (MCRS) of eighty-six patients were evaluated prospectively at one year and at the latest follow-up (mean follow-up = 4.7yrs. Range = 4 to 7 years). Needle biopsies of their cartilage repair site were stained with Haematoxylin and Eosin and some with Safranin O and the neo-cartilage was graded as hyaline-like (n=32, 37.2%), mixed fibro-hyaline (n=19, 22%) and fibro-cartilagenous tissue (n=35, 40.7%). Macroscopic grading of the repair tissue using the international cartilage repair society grading system (ICRS) was available for fifty-six patients in the study cohort. Statistical analyses were performed to investigate the significance of histology and ICRS grading on MCRS at 1 year and at the latest follow-up. Results. The MCRS of all three histology groups were comparable at one year evaluation (p=0.34). However, their clinical scores at the latest follow-up (mean = 4.7years) showed a significantly superior result for those with hyaline-like repair tissue when compared to those with mixed fibro-hyaline and fibro-cartilagenous repair (p=0.05). There was no correlation between the ICRS macroscopic grading and MCRS (clinical) grading either at one year (p=0.12) or at the latest follow-up (p=0.16). Also, the ICRS grading of the repair tissue did not correlate with its histological type (p=0.12). Conclusion. We conclude that any form of cartilage repair gave a good clinical outcome at one year. At four years and beyond, hyaline-like repair tissue was associated with a more favourable clinical outcome. Macroscopic evaluation using the ICRS grading system does not reflect the clinical outcome or its durability or the histological type of repair tissue

Introduction. The degree of cartilage degeneration assessed intraoperatively may not be sufficient as a criterion for patellar resurfacing in total knee arthroplasty (TKA). However, single-photon emission tomography/computed tomography (SPECT/CT) is useful for detecting osteoarthritic involvement deeper in the subchondral bone. The purpose of the study was to determine whether SPECT/CT reflected the cartilage lesion underneath the patella in patients with end-stage osteoarthritis (OA) and whether clinical outcomes after TKA without patellar resurfacing differed according to the severity of patellofemoral (PF) OA determined by visual assessment and SPECT/CT findings. Methods. This study included 206 knees which underwent TKA. The degree of cartilage degeneration was graded intraoperatively according to the International Cartilage Repair Society grading system. Subjects were classified into four groups according to the degree of bone tracer uptake (BTU) on SPECT/CT in the PF joint. The Feller's patella score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were assessed preoperatively and postoperative 1 and 2 years. Results. The increased BTU in the PF joint was associated with more severe degenerative cartilage changes underneath the patella (P < 0.001). The risk for the presence of denudated cartilage was greater in the high uptake group (odds ratio = 5.89). There was no association between clinical outcomes and visual grading of patellar cartilage degeneration or the degree of BTU on SPECT/CT. Discussion and Conclusions. The visual assessment of the degree of cartilage degeneration underneath the patella and preoperative SPECT/CT evaluation of the PF joint were not predictive of clinical outcome after TKA with unresurfaced patella

Purpose. Platelet-derived growth factor-BB (PDGF-BB) is a well characterized wound healing protein known to be chemotactic and mitogenic for cells of mesenchymal origin, including osteoblasts and chondrocytes. Biocompatible scaffolds, combined with growth factors such as PDGF-BB, have potential to stimulate regeneration and repair of osseous and cartilaginous tissues. The purpose of this study was to determine the efficacy and safety of recombinant human PDGF-BB (rhPDGF-BB) combined with a collagen implant to augment healing of osteochondral defects. Method. A single osteochondral defect (8mm x 8mm) was created in the medial femoral condyle of 32 adult goats. Collagen implants(8.5mm x 8mm) hydrated with four doses of rhPDGF-BB (0g, 15g, 75g, 500g) were press-fit into the defect. Defects in four animals were left untreated. All goats were sacrificed 12 weeks postoperatively. Macroscopic evaluation and quantitative CT analyses were performed. Histologic sections were stained with Safranin O/Fast Green and assessed with a modified ODriscoll scoring scale for cartilage and bone repair. Significance was determined by One-Way ANOVA or nonparametric Kruskal-Wallis. Results. Macroscopic evaluation indicated significant improvement of the gross cartilage repair score for the rhPDGF-BB treatment groups compared to the 0g rhPDGF-BB control (500g;0g) and empty defect groups (500,75,15g; Empty). MicroCT analysis indicated a significant increase in trabecular number for the 500g group compared to 0g control, 75g, and Empty groups(p=0.004). Average bone volume reconstitution for the 500g group was increased (58.8%) compared to the 0g control. The total cartilage repair score was significantly improved (p=0.048) in the 500g treatment group (14.30.3) compared to the 0g control group (12.10.4). All rhPDGF-BB treatment groups exhibited increased Safranin-O staining of the matrix compared to the 0g control group, and a significantly decreased incidence(p=0.01) of subchondral cyst formation compared to the empty defect group. Conclusion. The results of this study indicate that rhPDGF-BB, combined with a collagen implant, is safe and improves repair of large osteochondral defects located in a high-load bearing region in a caprine model. Increases in gross scoring and histopathologic cartilage repair score for the rhPDGF-BB treatment groups, in addition to the presence of bony bridging, especially for the 500g rhPDGF-BB treatment group, indicate enhanced reconstitution of the subchondral bone and overlying repair tissue. The cartilage repair score was increased, on average, in the empty defect group relative to the 0g rhPDGF-BB group, however this score may be partially inflated due to collapse of the surrounding native tissue into the defect. Combined with a significant decrease in cyst formation in all rhPDGF-BB treatment groups, these results suggest that rhPDGF-BB, combined with a collagen implant, may have promise as a therapeutic agent for osteochondral defect repair

Objectives. Articular cartilage damage is a primary outcome of pre-clinical and clinical studies evaluating meniscal and cartilage repair or replacement techniques. Recent studies have quantitatively characterized India Ink stained cartilage damage through light reflectance and the application of local or global thresholds. We develop a method for the quantitative characterisation of inked cartilage damage with improved generalisation capability, and compare its performance to the threshold-based baseline approach against gold standard labels. Methods. The Trainable WEKA Segmentation (TWS) tool (Arganda-Carreras et al., 2017) available in Fiji (Rueden et al., 2017) was used to train two separate Random Forest classifiers to automatically segment cartilage damage on ink stained cadaveric ovine stifle joints. Gold standard labels were manually annotated for the training, validation and test datasets for each of the femoral and tibial classifiers. Each dataset included a sample of medial and lateral femoral condyles and tibial plateaus from various stifle joints, selected to ensure no overlap across datasets according to ovine identifier. Training was performed on the training data with the TWS tool using edge, texture and noise reduction filters selected for their suitability and performance. The two trained classifiers were then applied to the validation data to output damage probability maps, on which a threshold value was calibrated. Model predictions on the unseen test set were evaluated against the gold standard labels using the Dice Similarity Coefficient (DSC) – an overlap-based metric, and compared with results for the baseline global threshold approach applied in Fiji as shown in Figures 1 and 2. Results. Test set results for the global threshold approach against gold standard labels were 45.0% DSC for the femoral condyle and 32.0% DSC for the tibial plateau. Results for the developed TWS classifiers on the same unseen test data were 79.0% and 72.7% DSC, showing absolute gains of 34.0% and 40.7% DSC over the global threshold baseline for the femoral and tibial classifiers. The trained TWS classifiers were then applied to an external set of unlabelled images of ink stained femoral condyles and tibial plateaus. Model results on sample images shown in Figure 3 further highlight the generalisation capability of the developed models. The most prominent classification features were Hessian filters (32.9%), Entropy (19.4%), Gaussian blur (10.1%), Gabor filters (6.3%) and Sobel filters (6.0%), with all other features contributing less than 6%. Conclusions. Our findings show that the developed segmentation method more accurately quantifies cartilage damage and provides improved generalisation capability over a range of input variations such as inconsistent orientation and lighting conditions. The developed model enables the use of articular cartilage damage as a reliable and quantitative outcome measure in studies involving large datasets, with reduced requirements for complex pre-processing and specialised equipment. For any figures or tables, please contact the authors directly

Introduction. Autologous Chondrocyte Implantation (ACI) is an effective surgical treatment for chondral defects. ACI involves arthrotomy for cell implantation. We describe the development of an intra-articular injection of cultured MSC, progressing from in-vitro analysis, through animal model, clinical and radiological outcome at five years follow up. Materials and Methods. We prospectively investigated sixteen patients with symptomatic ICRS grade III and IV lesions. These patients underwent cartilage repair using cultured mesenchymal stem cell injections and are followed up for five years. Results. Statistically significant clinical improvement was noted by two years and was sustained for five years of the study. At five years, mean Lysholm score was 80, compared to 44 pre-operatively. Symptomatic KOOS improved to 88 from 55. Subjective IKD Calso showed improvement from 42 to 76. On morphological MRI MOCART score was 76 and qualitative MRI showed the mean T2relaxation-times were 28 and 31 for their pair tissue and native cartilage respectively. Discussion. Cultured MSC provides a good number of uncommitted stem cells to the previously prepared chondral defects of the knee by “homing on” phenomenon. Cultured cells, suspended in serum can be delivered by an intra-articular injection. Conclusion. Use of cultured MSC is less invasive, avoids complications associated with arthrotomy, compared to ACI technique. Good clinical results were found to be sustained at five years of follow-up with a regenerate that appears like surrounding native cartilage. The use of Cultured Mesenchymal Stem Cells (MSC) has represented a promising treatment to restore the articular cartilage

Osteoarthritis (OA) is the fastest growing global health problem, with a total joint replacement being the only effective treatment for patients with end stage OA. Many groups are examining the use of bone marrow or adipose derived mesenchymal stem cells (MSCs) to repair cartilage, or modulate inflammation to promote healing, however, little efficacy in promoting cartilage repair, or reducing patient symptoms over temporary treatments such as micro-fracture has been observed. There is a growing body of literature demonstrating that MSCs derived from the synovial lining of the joint are superior in terms of chondrogenic differentiation and while improvements in clinical outcome measures have been observed with synovial MSCs, results from clinical studies are still highly variable. Based on our results, we believe this variability in clinical studies with MSCs results in part from the isolation, expansion and re-injection of distinct MSCs subtypes in normal vs. OA tissues, each with differing regenerating potential. However, it remains unknown if this heterogeneity is natural (e.g. multiple MSC subtypes present) or if MSCs are influenced by factors in vivo (disease state/stage). Therefore, in this study, we undertook an ‘omics’ screening approach on MSCs from normal and OA knee synovial tissue. Specifically, we characterized their global proteome and genomic expression patterns to determine if multiple MSC from normal and OA joints are distinct at the protein/gene expression level and/if so, what proteins/genes are differentially expressed between MSCs derived from normal and OA synovial tissue. Synovium tissue was collected from OA patients undergoing joint replacement and normal cadaveric knees. The in vitro adipogenic, chondrogenic and osteogenic differentiation potential of the MSCs was analyzed via qPCR and histology. Fully characterized MSC populations where then analyzed through an unbiased shotgun proteomics, and microarray analysis. Synovial MSCs isolated from both OA and normal knees demonstrated similar multipotent differentiation capacity. Likewise, both OA and normal MSCs display the typical MSCs cell surface marker profile in vitro (CD90+, CD44+, CD73+, CD105+). Using shotgun proteomics, 7720 unique peptides corresponding to 2183 proteins were identified and quantified between normal and OA MSCs. Of these 2183 proteins, 994 were equally expressed in normal and OA, MSCs, 324 were upregulated in OA MSCs (with 50 proteins exclusively expressed in OA MSCs), 630 proteins were upregulated in normal MSCs (with 16 proteins exclusively expressed in normal MSCs). Microarray analysis of normal and OA MSCs demonstrated a similar result in where, 967 genes were differentially expressed between normal and OA MSCs, with 423 genes upregulated in OA, and 544 genes upregulated in normal MSCs. In this project, we have demonstrated that although normal and OA synovial derived MSCs demonstrate similar multipotent differentiation potential and cell surface markers expression, these cells demonstrated significant differences at the molecular level (protein and gene expression). Further research is required to determine if these differences influence functional differences in vitro and/or in vivo and what drives this dramatic change in the regulatory pathways within normal vs. OA synovial MSCs

Previous study reported that intra-articular injection of MgSO4 could alleviate pain related behaviors in a collagenase induced OA model in rats. It provided us a good description on the potential of Mg2+ in OA treatment. However, the specific efficiency of Mg2+ on OA needs to be further explored and confirmed. The underlying mechanisms should be elucidated as well. Increasing attention has been paid on existence of synovial fluid MSCs (SF-MSCs) (not culture expanded) which may participate in endogenous reparative capabilities of the joint. On the other hand, previous studies demonstrated that Mg2+ not only promoted the expression of integrins but also enhanced the strength of fibronectin-integrin bonds that indicated the promotive effect of Mg2+ on cell adhesion, moreover, Mg2+ was proved could enhance chondrogenic differentiation of synovial membrane derived MSCs by modulating integrins. Based on these evidence, we hypothesize herein intra-articular injection of Mg2+ can attenuate cartilage degeneration in OA rat through modulating the biological behavior of SF-MSCs. Human and rat SF-MSCs were collected after obtaining Experimental Ethics approval. The biological behaviors of both human and rat SF-MSCs including multiple differentiation, adhesion, colony forming, proliferation, etc. were determined in vitro in presence or absence of Mg2+ (10 mmol/L). Male SD rats (body weight: 450–500 g) were used to establish anterior cruciate ligament transection and partial medial meniscectomy (ACLT+PMM) OA models. The rats received ACLT+PMM were randomly divided into saline (control) group and MgCl2 (0.5 mol/L) group (n=6 per group). Intra-articular injection was performed on week 4 post-operation, twice per week for two weeks. Knee samples were harvested on week 2, 4, 8, 12 and 16 after injection for histological analysis for assessing the progression of OA. On week 2 and 4 after injection, the rat SF-MSCs were also isolated before the rats were sacrificed for assessing the abilities of chondrogenic differentiation, colony forming and adhesion in vitro. Statistical analysis was done using Graphpad Prism 6.01. Unpaired t test was used to compare the difference between groups. Significant difference was determined at P < 0 .05. The adhesion and chondrogenic differentiation ability of both human and rat SF-MSCs were significantly enhanced by Mg2+ (10 mmol/L) supplementation in vitro. However, no significant effects of Mg2+ (10 mmol/L) on the osteogenic and adipogenic differentiation as well as the colony forming and proliferation. In the animal study, histological analysis by Saffranin O and Toluidine Blue indicated the cartilage degeneration was significantly alleviated by intra-articular injection of Mg2+, in addition, the expression of Col2 in cartilage was also increased in MgCl2 group with respect to control group indicated by immunohistochemistry. Moreover, the OARSI scoring was decreased in MgCl2 group as well. Histological analysis and RT-qPCR indicated that the chondrogenic differentiation of SF-MSCs isolated from Mg2+ treated rats were significantly enhanced compare to control group. In the current study, we have provided direct evidence supporting that Mg2+ attenuated the progression of OA. Except for the effect of Mg2+ on preventing cartilage degeneration had been demonstrated in this study, for the first time, we demonstrated the promoting effect of Mg2+ on adhesion and chondrogenic differentiation of endogenous SF-MSCs within knee joint that may favorite cartilage repair. We have confirmed that the anti-osteoarthritic effect of Mg2+ involves the multiple actions which refer to prevent cartilage degeneration plus enhance the adhesion and chondrogenic differentiation of SF-MSCs in knee joint to attenuate the progression of OA. These multiple actions of Mg2+ may be more advantage than traditional products. Besides, this simple, widely available and inexpensive administration of Mg2+ has the potential on reducing the massive heath economic burden of OA. However, the current data just provided a very basic concept, the exact functions and underlying mechanisms of Mg2+ on attenuating OA progression still need to be further explored both in vitro and in vivo. Formula of Mg2+ containing solution also need to be optimized, for example, a sustained and controlled release delivery system need to be developed for improving the long-term efficacy

Background. Autologous chondrocyte implantation (ACI) and mosaicplasty (MP) are two methods of repair of symptomatic articular cartilage defects in the adult knee. This study represents the only long-term comparative clinical trial of the two methods. Methods. A prospective, randomised comparison of the two modalities involving 100 patients with symptomatic articular cartilage lesions was undertaken. Patients were followed for ten years. Pain and function were assessed using the modified Cincinnati score, Bentley Stanmore Functional rating system and visual analogue scores. ‘Failure’ was determined by pain, a poor outcome score and arthroscopic evidence of graft disintegration. Results. Patients had a mean age at index operation of 31. There was a long mean pre-op duration of symptoms of seven years and the defects had an average of 1.5 operations (excluding arthroscopy) to the articular cartilage lesion prior to the cartilage repair surgery. The aetiology of the articular cartilage defects was mainly trauma; some patients had osteochondritis dissecans or chondromalacia patellae. Five patients were lost to follow-up. A total of 23 out of 42 mosaicplasty patients failed, 10 out of 58 ACI patients failed (p<0.001). Most patients did well for the first two years when there was a steep failure of mosaicplasty patients, after which the failure rate was more constant. There was a low steady failure rate of ACI over the 10 years. Older patients treated by ACI did worse than younger patients; age was less of a prognostic indicator in MP. Patients irrespective of gender or aetiology of the defect fared better with ACI than MP. Conclusion. At ten years, patients who underwent cartilage repair using ACI fared significantly better than those who underwent mosaicplasty

Introduction. Osteoarthritis (OA), a painful, debilitating joint disease, often caused by excessive joint stress, is a leading cause of disability (World Health Organisation, 2003) and increases with age and obesity. A 5° varus malalignment increases loading in the medial knee compartment from 70% to 90% (Tetsworth and Paley, 1994). Internal unloading implants, placed subcutaneously upon the medial aspect of the knee joint, are designed to offload the medial compartment of the knee without violating natural joint tissues. The aim of this study is to investigate the effect of an unloading implant, such as the Atlas™ knee system, on stress within the tibiofemoral joint with different grades of cartilage defects. Methods. To simulate surgical treatment of medial knee OA, a three-dimensional computer-aided design of an Atlas™ knee system was virtually fixed to the medial aspect of a validated finite element knee model (Mootanah, 2014), using CATIA v5 software (Dassault Systèmes, Velizy Villacoublay, France). The construct was meshed and assigned material properties and boundary conditions, using Abaqus finite element software (Dassault Systèmes, Velizy Villacoublay, France). A cartilage defect was simulated by removing elements corresponding to 4.7 mm. 2. The international cartilage repair society (ICRS) Grade II and III damage were simulated by normalized defect depth of 33% and 67%, respectively. The femur was mechanically grounded and the tibia was subjected to loading conditions corresponding to the stance phase of walking of a healthy 50-year-old 68-Kg male with anthropometrics that matched those of the cadaver. Finite element analyses were run for peak shear and von Mises stress in the medial and lateral tibiofemoral compartments. Results. Von Mises stress distribution in the tibial cartilage, with ICRS Grade II and III defects, without the unloading implant, at the end of weight acceptance (15% of the gait cycle) were analysed. The internal unloading implant reduces peak von Mises stress by 40% and 43% for Grade II and Grade III cartilage defects, respectively. The corresponding reductions in shear stress are 36% and 40%. Consistent reduction in peak von Mises stress values in the medial cartilage-cartilage and cartilage-meniscus contact areas were predicted throughout the stance phase of the gait cycle for ICRS Grade II defect. Similar results were obtained for Grade III defect and for peak shear stress values. There were no overall increases in peak von Mises stress values in the lateral tibial cartilage. Discussion and Conclusions. The internal unloading implant is capable of reducing von Mises and shear stress values in the medial tibial cartilage with ICRS Grade II and III defects at the cartilage-cartilage and cartilage-meniscus interfaces throughout the stance phase of the gait cycle. This did not result in increased stress values in the lateral tibial cartilage. Our model did not account for the viscoelastic effects of the cartilage and meniscus. Results of this study are based on only one knee specimen. The internal unloading implant may protect the cartilage in individuals with medial knee osteoarthritis, thereby delaying the need for knee replacements