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Purpose Cartilage cap resurfacing is a method to seal a superior semicircular canal dehiscence. The purpose of this study was to evaluate the detection of new bone formation after surgical placement of a cartilage cap over a dehiscent semicircular canal. Methods In this retrospective review, two neuroradiologists blinded to each other’s interpretation reviewed the temporal bones of 20 patients, five of which had a pre-operative computed tomography (CT) exam which was interpreted as unilateral superior semicircular canal dehiscence and with new bone formation following repair on follow-up CT. There were also 15 control subjects. Each neuroradiologist was blinded to history, including post-operative changes, and asked to determine if there was a dehiscence or no dehiscence. Results Out of the 15 controls, there was 100% inter-observer agreement. On the five post-operative patients, there was agreement in 4/5 that there was no dehiscence post-operatively and 1/5 agreement of dehiscence post-operatively, but ectopic bone adjacent to the dehiscence. Conclusion Our results indicate that new bone formation can be seen at the site of cartilage cap placement over the dehiscence and be interpreted as bony closure of the dehiscence.

Extracellular vesicles (EVs) are a population of small vesicles secreted by essentially all cell types, containing a wide variety of biological macromolecules. Due to their intrinsic capabilities for efficient intercellular communication, they are involved in various aspects of cellular functioning. In the past decade, EVs derived from stem cells attracted interest in the field of regenerative medicine. Owing to their regenerative properties, they have great potential for use in tissue repair, in particular for tissues with limited regenerative capabilities such as cartilage. The maintenance of articular cartilage is dependent on a precarious balance of many different components that can be disrupted by the onset of prevalent rheumatic diseases. However, while cartilage is a tissue with strong mechanical properties that can withstand movement and heavy loads for years, it is virtually incapable of repairing itself after damage has occurred. Stem cell-derived EVs (SC-EVs) transport regenerative components such as proteins and nucleic acids from their parental cells to recipient cells, thereby promoting cartilage healing. Many possible pathways through which SC-EVs execute their regenerative function have been reported, but likely there are still numerous other pathways that are still unknown. This review discusses various preclinical studies investigating intra-articular injections of free SC-EVs, which, while often promoting chondrogenesis and cartilage repair in vivo, showed a recurring limitation of the need for multiple administrations to achieve sufficient tissue regeneration. Potentially, this drawback can be overcome by making use of an EV delivery platform that is capable of sustainably releasing EVs over time. With their remarkable versatility and favourable chemical, biological and mechanical properties, hydrogels can facilitate this release profile by encapsulating EVs in their porous structure. Ideally, the optimal delivery platform can be formed in-situ, by means of an injectable hydrogel that can be administered directly into the affected joint. Relevant research fulfilling these criteria is discussed in detail, including the steps that still need to be taken before injectable hydrogels for sustained delivery of EVs can be applied in the context of cartilage regeneration in the clinic.

Compositional changes in the chemical makeup of hydrogels offer a powerful strategy for fine tuning of mechanical properties, enabling specific targeting for different applications. The chemical versatility exhibited by the tunable system introduced here can be leveraged to address a broad range of characteristics across the field of tissue engineering-from blood vessels to cartilage, for example-which demands materials with very different mechanical profiles. Furthermore, we rely exclusively on dynamic, non-covalent cross-linking to provide opportunities for 3D printing and injectability. This work describes a highly tunable system based on hydrogen bonding and ionic interactions. Single network hydrogels were made by exploiting various acrylic monomers including N-acryloyl glycinamide (NAGA) and acrylic acid (AAc). Additionally, hybrid hydrogels were explored by combining these acrylic networks with an ionically cross-linked alginate network. By combining orthogonal cross-linking strategies and altering the ratio between different components in these hybrid gels, a broad range of mechanical properties is demonstrated. The characteristics were extensively investigated using tensile testing, compression testing, and rheological measurements. The final scaffolds were also shown to be non-cytotoxic in preliminary cell viability studies for human dermal fibroblasts.

This short review focuses on developments in the field of bioprinting for cartilage tissue engineering, along with discussion on the various approaches for cartilage fabrication. The methods (cell-laden, cell-free and a combination of both) involved intended to obtain microenvironment to cells for better development and cell growth using the said methods. The controlled dimension of the scaffold can be decided with great precision. The hybrid bioprinting of cell laden and cell-free materials gives the most promising results for cartilage tissue engineering with multiple materials bio-print including high strength polymers. Although hybrid technology is new but currently 3D-printing for cartilage applications is in high demand, and complete conversation on the current and future viewpoints is presented in this review.

Autologous costal cartilage is used extensively in reconstructive surgery because of its stability, durability, and biocompatibility. The current preoperative evaluation of costal cartilage often only consists of a physical examination. Several studies have highlighted the benefits of preoperative imaging as a tool to ensure optimal graft harvest. This systematic review aims to synthesize the current evidence and establish the efficacy of the various imaging modalities for the assessment of costal cartilage.The data sources were explored using a search strategy based on the terms ("costal cartilage" OR "ribs" AND "imaging*") combined with Boolean operators. The primary outcome measures were the ability to measure the dimensions of costal cartilages and to detect the presence of calcifications.A total of 28 publications were included in the final review, with 12 case series, 7 case control studies, and 9 cohort studies. Twenty-two studies used computed tomography (CT); 4 studies used x-ray and 2 studies used ultrasonography, whereas no studies used magnetic resonance imaging. Meta-analysis of the data from these studies was not deemed possible.Our findings suggest that CT is the modality with the strongest evidence base that provides the greatest degree of information. The major benefits of CT are its ability to provide 3-dimensional image reconstruction for surgical planning, ability to detect synchondroses, and assess cartilage quality. Where radiation exposure is less preferable, x-ray and ultrasound (US) may play an important role. X-ray appears to be particularly useful when the main concern is the presence of calcification. The limited studies available indicate that US can provide useful and accurate information on cartilage quality and morphology. Further studies are warranted in exploring the use of US in preoperative planning, particularly in the pediatric population.

Estrogen is a steroid hormone that induces skeletal growth and affects endochondral ossification of the long tubular bone growth plate during the growth period. However, the effects of estrogen on endochondral ossification of the mandibular condylar cartilage are unclear. In this study, ovariectomized Wistar/ST rats were used to investigate the longitudinal effects of estrogen on mandibular growth. The rats were administered different doses of estrogen. Longitudinal micro-computed tomographic scanning, histological staining and ELISA on plasma growth hormone were performed to examine the effects of estrogen on mandibular growth. The results showed that mandibular growth was suppressed throughout the growth period by estrogen in a dose-dependent manner. In addition, long-term administration of a high dose of estrogen to the rats resulted in significant increase in growth hormone throughout the growth period, significant circularization of cell nuclei in the proliferative layer, intensely staining cartilage matrix in the subchondral bone, and significant suppression of estrogen receptor (ER) alpha and beta expression in the mandibular cartilage. However, regardless of estrogen concentration, in the posterior part of the mandibular cartilage, ER expression extended to both the hypertrophic and proliferative layers. These results indicate that estrogen suppresses mandibular growth throughout the growth period. Additionally, it influences endochondral ossification via its effect on ERs.

Organoids offer a promising strategy for articular tissue regeneration, joint disease modeling, and development of precision medicine. In this study, two types of human stem cells—primary mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs)—were employed to engineer organoids that mimicked bone, cartilage and adipose tissue, three key tissue components in articular joints. Prior to organoidogenesis, the iPSCs were first induced into mesenchymal progenitor cells (iMPCs). After characterizing the MSCs and iMPCs, they were used to generate cell-embedded extracellular matrix (ECM) constructs, which then underwent self-aggregation and lineage-specific differentiation in different induction media. Hydroxyapatite nanorods, an osteoinductive bioceramic, were leveraged to generate bone and osteochondral organoids, which effectively enhanced mineralization. The phenotypes of the generated organoids were confirmed on the basis of gene expression profiling and histology. Our findings demonstrate the feasibility and potential of generating articular tissue-recapitulating organoids from MSCs and iPSCs.

BACKGROUND: Cartilage tissue engineering is a promising way to repair cartilage defects. Different materials have been applied in the preparation of cartilage hydrogels, but all with various disadvantages. OBJECTIVE: The aim of this study was to prepare cartilage hydrogel using type II collagen, chondroitin sulfate and hyaluronic acid, to explore their gelation effect and compressive strength, and to analyze the feasibility of their application in cartilage tissue engineering. METHODS: Type II collagen (Col II), hyaluronic acid (HA) and chondroitin sulfate (CS) were mixed in a certain proportion to prepare gel scaffolds; changes in chemical groups were detected by Fourier transform infrared. After the hydrogel was prepared, its compressive strength was measured. Umbilical cord stem cells were co-cultured with hydrogel scaffolds to observe its cytocompatibility and analyze whether stem cells had cellular activity during co-culture; histological staining was applied to observe the hydrogel loaded with stem cells. RESULTS: Cartilage hydrogels were successfully prepared with good compressive strength, and Fourier transform infrared analysis showed that Schiff base reaction occurred during the preparation process and tight chemical cross-linking was formed. The results of umbilical cord stem cell co-culture showed that the hydrogel had good cytocompatibility and the stem cells had good activity in the hydrogel. CONCLUSIONS: Cartilage hydrogels with stable structures were successfully prepared and had good compressive strength. Hydrogel scaffold could provide a suitable living environment for umbilical cord stem cells, so that they maintain normal cell morphology and activity, and has a good application potential in cartilage tissue engineering.

The alteration of the extracellular matrix (ECM) homeostasis plays an important role in the development of osteoarthritis (OA). The pathological changes of OA are mainly manifested in the large reduction of components in ECM, like type II collagen and aggrecan, especially hyaluronic acid and chondroitin sulfate and often accompanied by inflammation. Rebuilding ECM and inhibiting inflammation may reverse OA progression. In this work, we developed new magnesium-containing glycosaminoglycans (Mg-GAGs), to create a positive ECM condition for promoting cartilage regeneration and alleviating OA. In vitro results suggested that the introduction of Mg-GAGs contributed to promoting chondrocyte proliferation and facilitated upregulating chondrogenic genes and suppressed inflammation-related factors. Moreover, Mg-GAGs exhibited positive effects on suppressing synovial inflammation, reducing chondrocyte apoptosis and preserving the subchondral bone in the ACLT-induced OA rabbit model. This study provides new insight into ECM-based therapeutic strategy and opens a new avenue for the development of novel OA treatment.

Objective To characterize the effects of parathyroid hormone (PTH) and alendronate (Alend) on the osteochondral tissue of temporomandibular joint (TMJ). Materials and Methods Ninety-six male and female transgenic reporter mice, 4 to 5 weeks old were divided into 6 groups: (1) Control group: Saline was injected daily for 14 days; (2) PTH: PTH was injected daily for 14 days; (3) Alend: Alend was injected every alternate days for 14 days; (4) Combined PTH and Alend: PTH was injected daily and Alend injected every alternate days for 14 days; (5) PTH then Alend: PTH was injected daily for 14 days followed by Alend injections in alternate days for 14 days; and (6) PTH wait Alend: PTH was injected daily for 14 days. There was a waiting period of 1 week before administration of Alend in alternate days for 14 days. Mice were injected with 5-ethnyl-2′-deoxyuridine (EdU), 48 and 24 hours prior to euthanization. Results There was significant increase in bone volume and decrease in osteoclastic activity in groups in which Alend was administered after PTH in both gender. There was significant increase in cartilage thickness with PTH or Alend alone in females, whereas in males, PTH alone led to increase in cartilage thickness. Chondrocyte apoptosis was significantly decreased with PTH or Alend alone in both male and female. Matrix metallopeptidase 13, and aggreganase-2 (ADAMTS5) expression were significantly decreased with PTH and Alend alone in both gender. Conclusion PTH and Alend administration causes anabolic effects in the osteochondral tissue of TMJ.

We and others have reported that low-magnitude high-frequency dynamic loading has an osteogenic effect on alveolar bone. Since chondrocytes and osteoblasts originate from the same progenitor cells, we reasoned that dynamic loading may stimulate a similar response in chondrocytes. A stimulating effect could be beneficial for patients with damaged condylar cartilage or mandibular deficiency.Studies were conducted on growing Sprague-Dawley rats divided into three groups: control, static load, and dynamic load. The dynamic load group received a dynamic load on the lower right molars 5 minutes per day with a 0.3 g acceleration and peak strain of 30 με registered by accelerometer and strain gauge. The static load group received an equivalent magnitude of static force (30 με). The control group did not receive any treatment. Samples were collected at days 0, 28, and 56 for reverse transcriptase polymerase chain reaction analysis, microcomputed tomography, and histology and fluorescent microscopy analysis.Our experiments showed that dynamic loading had a striking effect on condylar cartilage, increasing the proliferation and differentiation of mesenchymal cells into chondrocytes, and promoting chondrocyte maturation. This effect was accompanied by increased endochondral bone formation resulting in lengthening of the condylar process.Low-magnitude, high-frequency dynamic loading can have a positive effect on condylar cartilage and endochondral bone formation in vivo. This effect has the potential to be used as a treatment for regenerating condylar cartilage and to enhance the effect of orthopedic appliances on mandibular growth.

Transforming growth factor-beta (TGF-β) is an important regulator of joint homeostasis, of which dysregulation is closely associated with the development of osteoarthritis (OA). In normal conditions, its biological functions in a joint environment are joint protective, but it can be dramatically altered in different contexts, making its therapeutic application a challenge. However, with the deeper insights into the TGF-β functions, it has been proven that TGF-β augments cartilage regeneration by chondrocytes, and differentiates both the precursor cells of chondrocytes and stem cells into cartilage-generating chondrocytes. Following documentation of the therapeutic efficacy of chondrocytes augmented by TGF-β in the last decade, there is an ongoing phase III clinical trial examining the therapeutic efficacy of a mixture of allogeneic chondrocytes and TGF-β-overexpressing cells. To prepare cartilage-restoring chondrocytes from induced pluripotent stem cells (iPSCs), the stem cells are differentiated mainly using TGF-β with some other growth factors. Of note, clinical trials evaluating the therapeutic efficacy of iPSCs for OA are scheduled this year. Mesenchymal stromal stem cells (MSCs) have inherent limitations in that they differentiate into the osteochondral pathway, resulting in the production of poor-quality cartilage. Despite the established essential role of TGF-β in chondrogenic differentiation of MSCs, whether the coordinated use of TGF-β in MSC-based therapy for degenerated cartilage is effective is unknown. We herein reviewed the general characteristics and mechanism of action of TGF-β in a joint environment. Furthermore, we discussed the core interaction of TGF-β with principal cells of OA cell-based therapies, the chondrocytes, MSCs, and iPSCs. Impact Statement Transforming growth factor-beta (TGF-β) has been widely used as a core regulator to improve or formulate therapeutic regenerative cells for degenerative joints. It differentiates stem cells into chondrocytes and improves the chondrogenic potential of differentiated chondrocytes. Herein, we discussed the overall characteristics of TGF-β and reviewed the comprehension and utilization of TGF-β in cell-based therapy for degenerative joint disease.

Musculoskeletal disorders are the most common reason of chronic pain and disability representing worldwide an enormous socio-economic burden. In this review, new biomedical application fields for Raman spectroscopy (RS) technique related to skeletal tissues are discussed showing that it can provide a comprehensive profile of tissue composition in situ, in a rapid, label-free, and non-destructive manner. RS can be used as a tool to study tissue alterations associated to aging, pathologies, and disease treatments. The main advantage with respect to currently applied methods in clinics is its ability to provide specific information on molecular composition, which goes beyond other diagnostic tools. Being compatible with water, RS can be performed without pre-treatment on unfixed, hydrated tissue samples, without any labelling and chemical fixation used in histochemical methods. This review provides first the description of basic principles of RS as a biotechnology tool and introduces into the field of currently available RS based techniques, developed to enhance Raman signal. The main spectral processing statistical tools, fingerprint identification and available databases are mentioned. The recent literature has been analysed for such applications of RS as tendon and ligaments, cartilage, bone, and tissue engineered constructs for regenerative medicine. Several cases of proof-of-concept preclinical studies have been described. Finally, advantages, limitations, future perspectives, and challenges for translation of RS into clinical practice have been also discussed.

Background: Owing to the disappointing regenerative ability of osteochondral tissue, without treatment an osteochondral defect would progress to osteoarthritis. This situation motivates the need for new strategies to enhance the regeneration of osteochondral defects. Purpose: To develop a tissue-engineering scaffold by tethering bone morphogenetic protein 2 (BMP2) and transforming growth factor beta 3 (TGFβ3) in a layer-specific manner on a slotted decellularized osteochondral matrix (SDOM) and to evaluate the efficacy of this scaffold for osteochondral regeneration. Study Design: Controlled laboratory study. Methods: Normal osteochondral tissue from the rabbit patellofemoral groove was sectioned into a slot shape and decellularized for fabricating an SDOM. The collagen-binding domain (CBD) was fused into the N-terminus of BMP2 or TGFβ3 to synthesize 2 recombinant growth factors (GFs) (CBD-BMP2 or CBD-TGFβ3), which were tethered to the bone layer and cartilage layer, respectively, of the SDOM to prepare a tissue-engineering scaffold (namely, CBD-GFs/SDOM). After examining the influence of the CBD-GFs/SDOM on the viability and layer-specific differentiation of bone marrow mesenchymal stem cells in vitro, we determined the regeneration potential of the CBD-GFs/SDOM on osteochondral regeneration in a rabbit model. A total of 72 New Zealand White rabbits with a cylindrical osteochondral defect in the patellofemoral groove were randomly assigned to 3 groups: defect only (control [CTL] group), defect patched with an SDOM (SDOM group), and defect patched with the CBD-GFs/SDOM (CBD-GFs/SDOM group). At 6 or 12 weeks postoperatively, the rabbits were euthanized to harvest the knee joint, which was then evaluated via gross observation, micro–computed tomography, histological staining, and mechanical testing. Results: In vitro, the CBD-GFs/SDOM was noncytotoxic, showed high biomimetics with normal osteochondral tissue, was suitable for cell adhesion and growth, and had good layer-specific ability in inducing stem cell differentiation. Macroscopic images showed that the CBD-GFs/SDOM group had significantly better osteochondral regeneration than the CTL and SDOM groups had. Micro–computed tomography demonstrated that much more bony tissue was formed at the defect sites in the CBD-GFs/SDOM group compared with the defect sites in the CTL or SDOM group. Histological analysis showed that the CBD-GFs/SDOM group had a significant enhancement in osteochondral regeneration at 6 and 12 weeks postoperatively in comparison with the CTL or SDOM group. At 12 weeks postoperatively, the mechanical properties of reparative tissue were significantly better in the CBD-GFs/SDOM group than in the other groups. Conclusion: The CBD-GFs/SDOM is a promising scaffold for osteochondral regeneration. Clinical Relevance: The findings of this study indicated that the CBD-GFs/SDOM is an excellent candidate for reconstructing osteochondral defects, which may be translated for clinical use in the future.

Purpose To assess the ability of MRI-DTI to evaluate growth plate morphology and activity compared with that of histomorphometry and micro-CT in rabbits. Methods The hind limbs of female rabbits aged 16, 20, and 24 wk (n = 4 per age group) were studied using a 9.4T MRI scanner with a multi-gradient echo 3D sequence and DTI in 14 directions (b-value = 984 s/mm(2)). After MRI, the right and left hind limb were processed for histological analysis and micro-CT, respectively. The Wilcoxon signed-rank test was used to evaluate the height and volume of the growth plate. Intraclass correlation and Pearson correlation coefficient were used to evaluate the association between DTI metrics and age. Results The growth plate height and volume were similar for all modalities at each time point and age. Age was correlated with all tractography and DTI metrics in both the femur and tibia. A correlation was also observed between all the metrics at both sites. Tract number and volume declined with age; however, tract length did not show any changes. The fractional anisotropy color map showed lateral diffusion centrally in the growth plate and perpendicular diffusion in the hypertrophic zone, as verified by histology and micro-CT. Conclusion MRI-DTI may be useful for evaluating the growth plates. open access

Local-area cartilage segmentation (LACS) software was developed to segment medial femur (MF) cartilage on magnetic resonance imaging (MRI). Our objectives were 1) to extend LACS to the lateral femur (LF), medial tibia (MT), and lateral tibia (LT), 2) to compare LACS to an established manual segmentation method, and 3) to visualize cartilage responsiveness over each cartilage plate.Osteoarthritis Initiative participants with symptomatic knee osteoarthritis (OA) were selected, including knees selected at random (n = 40) and knees identified with loss of cartilage based on manual segmentation (Chondrometrics GmbH), an enriched sample of 126 knees. LACS was used to segment cartilage in the MF, LF, MT, and LT on sagittal 3D double-echo steady-state MRI scans at baseline and at 2-year follow-up. We compared LACS and Chondrometrics average thickness measures by estimating the correlation in each cartilage plate and estimating the standardized response mean (SRM) for 2-year cartilage change. We illustrated cartilage loss topographically with SRM heatmaps.The estimated correlation between LACS and Chondrometrics measures was r = 0.91 (95% confidence interval [95% CI] 0.86, 0.94) for LF, r = 0.93 (95% CI 0.89, 0.95) for MF, r = 0.97 (95% CI 0.96, 0.98) for LT, and r = 0.87 (95% CI 0.81, 0.91) for MT. Estimated SRMs for LACS and Chondrometrics measures were similar in the random sample, and SRM heatmaps identified subregions of LACS-measured cartilage loss.LACS cartilage thickness measurement in the MF and LF and tibia correlated well with established manual segmentation-based measurement, with similar responsiveness to change, among knees with symptomatic knee OA. LACS measurement of cartilage plate topography enables spatiotemporal analysis of cartilage loss in future knee OA studies.

One of the newest advances in 3D printing is the printing process of bio-scaffolds. The 3D printing of true materials for cartilage repairs accelerates cell growth and proliferation. In this study, a novel biomaterial was developed for the 3D printing of cartilage scaffolds composed of alginate, thymoquinone and halloysite nanotube. Calcium chloride was used as a cross-linker to form hydrogels. Experimental and numerical studies such as scanning electron microscopy, experimental tensile tests, and compression tests, chondrocyte cell seed, and MTT assay were also done. According to the results, alginate and halloysite nanotube increased the printing quality and mechanical performance of biomaterials. Tensile strength in bio-ink with the 30 mg/ml of alginate, 40 mg/ml of halloysite nanotube with 5% of thymoquinone increased up to 372 ± 42 kPa, while compressive stress reached 894 ± 39 kPa. Numerical results indicated that tensile and compressive properties of the scaffold structure depend on the space between printed rows. The best structure was obtained when the distance of rows was chosen at 0.4 mm, and the nozzle diameter was 0.3 mm. Finally, the biomaterial with the 30 mg/ml of alginate, 40 mg/ml of halloysite nanotube with 5% of thymoquinone showed a high mechanical and biological performance, compared to pure alginate bio-scaffolds. Biomaterials included alginic acid sodium salt/thymoquinone/halloysite nanotube mixed and 3D printed in high technology bioprinter, then mechanical and biological properties of printed bio-scaffolds obtained by different experimental tests.

Clinically, intra-articular administration can hardly achieve the truly targeted therapy, and the drugs are usually insufficient to show local and long-term therapeutic effects because of their rapid clearance. Herein, inspired by the phenomenon that bees track the scent of flowers to collect nectar, we developed cartilage-targeting hydrogel microspheres with reactive oxygen species (ROS)-responsive ability via combining the microfluidic method and photopolymerization processes to integrate cartilage-targeting peptides and ROS-responsive nanoparticles in the hydrogel matrix. The hydrogel microspheres with cartilage-targeting properties promoted better retention in the joint cavity and enhanced cellular uptake of the nanoparticles. Moreover, the ROS-responsive nanoparticles could react with osteoarthritis (OA)-induced intracellular ROS, resulting in the depolymerization of nanoparticles, which could not only eliminate excess ROS and reduce inflammation but also promote the release of dexamethasone (Dex) and kartogenin (KGN)

We investigated procedural safety, technical and clinical outcomes of the percutaneous image-guided radiofrequency ablation (PRFA) of intra-articular (IA), intra-articular close to cartilage (IACC), and extra-articular (EA) osteoid osteomas (OO). We proposed a new radiologic classification for osteoid osteoma depending on the degree and location of sclerosis which may correlate with technical failure and/or difficulties.According to the inclusion criteria, we enrolled consecutive patients who were referred to the investigation center from June 2018 to January 2022. After clinical and CT imaging features were suggestive for the diagnosis of OO, all the patients were treated by percutaneous CT-guided RFA with a standardized technique. Biopsy of the lesion was not performed in all patients. A retrospective analysis was conducted to assess the procedure's technical, primary clinical, and secondary clinical successes, recurrence rate, and complications. We classified all the OOs according to a new proposed classification of the site and the amount of sclerosis.A total number of 55 patients were enrolled in our study according to the inclusion criteria. The mean age of the enrolled patients was 24.07 ± 14.71 years (ranges from 7 to 57 years). The M/F ratio was roughly 2:1. The mean follow-up was 20.18 ± 12.60 months (ranges from 2 to 44 months). EA group included 36 patients, IA included 5 and IACC included 14 patients. Technical success was achieved in all cases of IA and IACC groups. Technical success in the EA group was 97.22% (1 technical failure). Primary clinical success was 100%, 92.85%, and 91.66% for IA, IACC, and EA groups, respectively. Accordingly, the recurrence rate was 5.88% in EA, and 7.14% in IACC, while no recurrence occurred in the IA group. No complications occurred. The secondary success rate of the 3 cases of recurrence was 100%.PRFA proved to be a safe procedure with a high rate of success for OO treatment even in intra-articular lesions in close contact with cartilage. This study showed that the results in terms of technical and clinical success are comparable for IA OO, IACC OO, and EA OO, even if the recurrence rate was higher in EA OO. Our proposed new classification of the degree and location of sclerosis may correlate to technical failure, but further studies with a larger number of patients are needed for validation.

This research study was designed to evaluate the aesthetic consequences of different dorsal augmentation techniques using diced cartilage on dorsal width and projection in rhinoplasty. Patients were assigned to three groups based on the dorsal augmentation technique used: diced cartilage wrapped in fascia (DCIF), free diced cartilage under fascia (DCUF), and free diced cartilage without fascia (FDC). Dorsal projection and dorsal aesthetic width were measured at two levels using pre- and postoperative photographs. A total of 98 patients were included in the study. DCIF was used in 51 patients, FDC in 27 patients, and DCUF in 20 patients. There was no significant difference in nasion projection, rhinion projection, or width of the dorsal aesthetic lines at the intercanthal and keystone levels among these groups. Significantly greater nasion and rhinion projection was observed with DCIF in thin-skinned patients followed-up for 6-12 months (nasion, P = 0.028; rhinion P = 0.039) but not at12 months. Two patients with a graft infection and one with graft malposition were encountered in the DCIF group. Experience from this study suggests that the application of FDC prevents such complications without sacrificing the dorsal augmentation and that DCIF is a better choice for more severe deformities.

To determine if the quantitative MRI techniques T2 and T1ρ mapping are sensitive to ischemic injury to epiphyseal cartilage in vivo in a piglet model of Legg-Calvé-Perthes disease using a clinical 3T MRI scanner. We hypothesized that T2 and T1ρ relaxation times would be increased in the epiphyseal cartilage of operated vs contralateral-control femoral heads 1 week following onset of ischemia.Unilateral femoral head ischemia was surgically induced in eight piglets. Piglets were imaged 1 week post-operatively in vivo at 3T MRI using a magnetization-prepared 3D fast spin echo sequence for T2 and T1ρ mapping and a 3D gradient echo sequence for cartilage segmentation. Ischemia was confirmed in all piglets using gadolinium contrast-enhanced MRI. Median T2 and T1ρ relaxation times were measured in the epiphyseal cartilage of the ischemic and control femoral heads and compared using paired t-tests. Histological assessment was performed on a subset of five piglets.T2 and T1ρ relaxation times were significantly increased in the epiphyseal cartilage of the operated vs control femoral heads (ΔT2 = 11.9 ± 3.7 ms, 95% CI = [8.8, 15.0] ms, P 0.0001; ΔT1ρ = 12.8 ± 4.1 ms, 95% CI = [9.4, 16.2] ms, P 0.0001). Histological assessment identified chondronecrosis in the hypertrophic and deep proliferative zones within ischemic epiphyseal cartilage.T2 and T1ρ mapping are sensitive to ischemic injury to the epiphyseal cartilage in vivo at clinical 3T MRI. These techniques may be clinically useful to assess injury and repair to the epiphyseal cartilage to better stage the extent of ischemic damage in Legg-Calvé-Perthes disease.

Wnt-1 inducible signaling pathway protein 2 (WISP-2/CCN5) is a recently identified adipokine that has been described as an important mediator of canonical Wnt activation in adipogenic precursor cells. In osteoarthritis (OA), the most common form of arthritis, chondrocytes exhibit aberrant and increased production of pro-inflammatory mediators and matrix degrading enzymes such as IL-1β and MMP-13. Although recent evidence suggests a role for Wnt signaling in OA physiopathology, little is known about the involvement of WISP-2 in cartilage degradation. In the present study, we determined the expression of WISP-2 in healthy and OA human chondrocytes. WISP-2 expression is modulated along chondrocyte differentiation and downregulated at the onset of hypertrophy by inflammatory mediators. We also investigated the effect of WISP-2 on cartilage catabolism and performed WISP-2 loss-of-function experiments using RNA interference technology in human T/C-28a2 immortalized chondrocytes. We demonstrated that recombinant human WISP-2 protein reduced IL-1β-mediated chondrocyte catabolism, that IL-1β and WNT/b-catenin signaling pathways are involved in rhWISP-2 protein and IL-1β effects in human chondrocytes, and that WISP-2 has a regulatory role in attenuating the catabolic effects of IL-1β in chondrocytes. Gene silencing of WISP-2 increased the induction of the catabolic markers MMP-13 and ADAMTS-5 and the inflammatory mediators IL-6 and IL-8 triggered by IL-1β in human primary OA chondrocytes in a Wnt/β-catenin dependent manner. In conclusion, here we have shown for the first time that WISP-2 may have relevant roles in modulating the turnover of extracellular matrix in the cartilage and that its downregulation may detrimentally alter the inflammatory environment in OA cartilage. We also proved the participation of Wnt/β-catenin signaling pathway in these processes. Thus, targeting WISP-2 might represent a potential therapeutical approach for degenerative and/or inflammatory diseases of musculoskeletal system, such as osteoarthritis.

Aims Staphylococcus aureus is a major cause of septic arthritis, and in vitro studies suggest α haemolysin (Hla) is responsible for chondrocyte death. We used an in vivo murine joint model to compare inoculation with wild type S. aureus 8325-4 with a Hla-deficient strain DU1090 on chondrocyte viability, tissue histology, and joint biomechanics. The aim was to compare the actions of S. aureus Hla alone with those of the animal’s immune response to infection. Methods Adult male C57Bl/6 mice (n = 75) were randomized into three groups to receive 1.0 to 1.4 × 107 colony-forming units (CFUs)/ml of 8325-4, DU1090, or saline into the right stifle joint. Chondrocyte death was assessed by confocal microscopy. Histological changes to inoculated joints were graded for inflammatory responses along with gait, weight changes, and limb swelling. Results Chondrocyte death was greater with 8325-4 (96.2% (SD 5.5%); p < 0.001) than DU1090 (28.9% (SD 16.0%); p = 0.009) and both were higher than controls (3.8% (SD 1.2%)). Histology revealed cartilage/bone damage with 8325-4 or DU1090 compared to controls (p = 0.010). Both infected groups lost weight (p = 0.006 for both) and experienced limb swelling (p = 0.043 and p = 0.018, respectively). Joints inoculated with bacteria showed significant alterations in gait cycle with a decreased stance phase, increased swing phase, and a corresponding decrease in swing speed. Conclusion Murine joints inoculated with Hla-producing 8325-4 experienced significantly more chondrocyte death than those with DU1090, which lack the toxin. This was despite similar immune responses, indicating that Hla was the major cause of chondrocyte death. Hla-deficient DU1090 also elevated chondrocyte death compared to controls, suggesting a smaller additional deleterious role of the immune system on cartilage. Cite this article: Bone Joint Res 2022;11(9):669–678.

Mcrs1 is a multifunctional protein that is critical for many cellular processes in a wide range of cell types. Previously, we showed that Mcrs1 binds to the Six1 transcription factor and reduces the ability of the Six1-Eya1 complex to upregulate transcription, and that Mcrs1 loss-of-function leads to the expansion of several neural plate genes, reduction of neural border and pre-placodal ectoderm (PPR) genes, and pleiotropic effects on various neural crest (NC) genes. Because the affected embryonic structures give rise to several of the cranial tissues affected in Branchio-otic/Branchio-oto-renal (BOR) syndrome, herein we tested whether these gene expression changes subsequently alter the development of the proximate precursors of BOR affected structures - the otic vesicles (OV) and branchial arches (BA). We found that Mcrs1 is required for the expression of several OV genes involved in inner ear formation, patterning and otic capsule cartilage formation. Mcrs1 knockdown also reduced the expression domains of many genes expressed in the larval BA, derived from either NC or PPR, except for emx2, which was expanded. Reduced Mcrs1 also diminished the length of the expression domain of tbx1 in BA1 and BA2 and interfered with cranial NC migration from the dorsal neural tube; this subsequently resulted in defects in the morphology of lower jaw cartilages derived from BA1 and BA2, including the infrarostral, Meckel's, and ceratohyal as well as the otic capsule. These results demonstrate that Mcrs1 plays an important role in processes that lead to the formation of craniofacial cartilages and its loss results in phenotypes consistent with reduced Six1 activity associated with BOR.

Studies have reported that megakaryocytic leukemia 1 (MKL1) is closely related to the pathological process of a variety of inflammatory diseases, but its role in osteoarthritis (OA) needs to be clarified. This study aimed to investigate the regulatory role of MKL1 in oxidative stress-induced chondrocyte apoptosis and cartilage matrix degeneration. The expressions of target mRNAs and proteins were measured by using reverse transcription-quantitative polymerase chain reaction and western blotting. ELISA assay was used to measure the levels of IL-6, IL-8, and TNF-α in chondrocytes. And commercial kits based on different spectrophotometry or colorimetry methods were performed to validate oxidative stress. CCK-8 and apoptosis kits were used to determine cell viability and apoptosis. Rat OA model was established by anterior cruciate ligament transection (ACLT), and the expression of MKL1 was interfered by injecting sh-MKL1 lentiviral vector into caudal vein. The results showed that the expression of MKL1was induced by H

Stable cartilage regeneration in immunocompetent animals remains a huge challenge, mainly ascribing to the

Background: Primary synovial chondromatosis (PSC) is a rare idiopathic pathology characterized by the formation of osseocartilaginous nodules within synovial joints, tendons, or bursae. The mineralization pattern of PSC nodules is poorly understood and has yet to be investigated using elemental analysis. Mapping this pattern could elucidate the progression of the disease. Materials and methods: PSC nodules discovered during dissection of a formalin fixed donor were analyzed. Scanning electron microscopy paired with energy dispersive X-ray spectroscopy (SEM-EDS) was used to quantify calcium and phosphorus levels to distinguish mineralized components from cartilage, indicated by increased carbon and oxygen concentrations. Results: Nine nodules with average dimensions 1.76cm x 1.25cm were identified in the semimembranosus bursa. SEM-EDS demonstrated increased calcium phosphate levels in nodular cores, while outer margins contained primarily carbon and oxygen. Quantification of these elements revealed nodular peripheries to contain 68.0% carbon, 30.2% oxygen, 0.8% calcium, and 1.0% phosphate, while cores were comprised of 38.1% carbon, 42.1% oxygen, 14.1% calcium, and 5.7% phosphate. Conclusions: Nodules were found to have mineralized cores embedded within a cartilaginous matrix. This pattern suggests disease progression is facilitated by endochondral ossification, opening the potential for new therapeutic techniques.

The clinical outcomes of surgical treatments for vocal cord paralysis and tracheal stenosis, such as medialization laryngoplasty and laryngotracheal reconstruction, vary owing to the complex anatomy and physiology of the human upper airway. However, advances in three-dimensional (3D) simulation and printing ushered its use on an office-based workstation to aid in several surgical areas.The preoperation neck computed tomography image was loaded into the InVesalius 3.0 software for manual segmentation of airway and nearby important anatomic landmarks including hyoid bone, thyroid cartilage, and cricoid cartilage. The 3D model of the desired anatomy structure was manufactured and used for presurgical planning and rehearsal of the surgery.We review cases of four patients: two cases of unilateral vocal palsy undergoing medialization laryngoplasty and two cases of tracheal stenosis patients who used the air-cartilage combined model.Preoperation planning of the medialization thyroplasty could be more precise by prevision of the paralyzed vocal cord plane. Tracheal surgery could benefit from a preoperative design of segmented length. The novel airway-cartilage combined model offers new insight into vocal cord and trachea surgery.

The high prevalence of temporomandibular joint osteoarthritis (TMJOA), which causes joint dysfunction, indicates the need for more effective methods for treatment and repair. Mandibular condylar cartilage (MCC), a typical fibrocartilage that experiences degenerative changes during the development of TMJOA, has become a research focus and therapeutic target in recent years. MCC is composed of four zones of cells at various stages of differentiation. The cell subsets in MCC exhibit different physiological and pathological characteristics during development and in TMJOA. Most studies of TMJOA are mainly concerned with gene regulation of pathological changes. The corresponding treatment targets with specific cell subsets in MCC may provide more accurate and reliable results for cartilage repair and TMJOA treatment. In this review, we summarized the current research progress on the cell subsets of MCC from the perspective of MCC development and degeneration. We hope to provide a reference for further exploration of the pathological process of TMJOA and improvement of TMJOA treatment.

Osteoarthritis (OA) is the most common joint disease worldwide, yet we continue to lack an understanding of disease etiology and pathology and effective treatment options. Essential to tissue homeostasis, disease pathogenesis, and therapeutic responses are the stratified organization of cartilage and cross talk at the osteochondral junction. Animal models may capture some of these features, but to establish clinically consistent therapeutics, there remains a need for high-fidelity models of OA that meet all the above requirements in a human patient-specific manner. In vitro bioengineered cartilage-bone tissue models could be developed to recapitulate physiological interactions with human cells and disease-initiating factors. In this study, we highlight human induced pluripotent stem cells (hiPSCs) as the advantageous cell source for these models and review approaches for chondrogenic fate specification from hiPSCs. To achieve native-like stratified cartilage organization with cartilage-bone interactions, spatiotemporal cues mimicking development can be delivered to engineered tissues by patterning of the cells, scaffold, and environment. Once healthy and native-like cartilage-bone tissues are established, an OA-like state can be induced through cytokine challenge or injurious loading. Bioengineered cartilage-bone tissues fall short of recapitulating the full complexity of native tissues, but have demonstrated utility in elucidating some mechanisms of OA progression and enabled screening of candidate therapeutics in patient-specific models. With rapid progress in stem cells, tissue engineering, imaging, and high-throughput omics research in recent years, we propose that advanced human tissue models will soon offer valuable contributions to our understanding and treatment of OA.

Inducing and maintaining a hyaline cartilage phenotype are the greatest challenge for cartilage regeneration. Synthetic chondroinductive biomaterials might be the answer to the unmet clinical need for a safe, stable, and cost-effective material capable of inducing true hyaline cartilage formation. The past decade witnessed an emergence of peptides to achieve chondrogenesis, as peptides have the advantages of versatility, high target specificity, minimized toxicity and immunogenicity, and ease of synthesis. In this study, we review peptides as the basis for creating promising synthetic chondroinductive biomaterials for in situ scaffold-based cartilage regeneration. We provide a thorough review of peptides evaluated for cartilage regeneration while distinguishing between peptides reported to induce chondrogenesis independently, and peptides reported to act in synergy with other growth factors to induce cartilage regeneration. In addition, we highlight that most peptide studies have been in vitro, and appropriate controls are not always present. A few rigorously performed in vitro studies have proceeded to in vivo studies, but the peptides in those in vivo studies were mainly introduced through systemic, subcutaneous, or intra-articular injections, with a paucity of studies employing in situ defects with appropriate controls. Clinical translation of peptides will require the evaluation of these peptides in well-controlled in vivo cartilage defect studies. In the decade ahead, we may be poised to leverage peptides to design devices that are safe, reproducible, cost-efficient, and scalable biomaterials, which are themselves chondroinductive to achieve true hyaline cartilage regeneration without the need for growth factors and other small molecules.

To study the tissue size, calcification characteristics and the correlation between calcification, age, and on whether side of the 6th, 7th, and 8th costal cartilages in women, so as to provide reference for clinical application.A total of 70 cases of female costal cartilage applied with dual-source CT three-dimensional reconstruction were selected from the radiology storage center of Second Xiangya Hospital. The length, width, thickness, calcification rate, calcification degree, calcification type, calcification location, and the relation between calcification, age, and side of bilateral 6th, 7th, and 8th costal cartilages were observed and analyzed on volume reconstruction and maximum density projection images.(1) The respective length, width, and thickness of 6th, 7th, and 8th costal cartilages on both sides were measured. There were significant differences in length, width, and thickness between unilateral costal cartilages with different ordinal numbers. (2) Significant difference was confirmed in the total calcification types of the 6th, 7th, and 8th costal cartilages. (3) The higher the age, the higher the calcification rate was. The calcification degree of the 6th, 7th, and 8th costal cartilages was higher with the increase of age.Preoperative three-dimensional reconstruction and image post-processing of costal cartilage with dual-source CT can accurately measure the amount of cartilage tissue and define the characteristics of calcification, so as to guide the clinical selection of costal cartilage. In female patients of different ages, the calcification rate of costal cartilage increased with age, but no positive correlation was observed.

Knee articular cartilage defects can result in significant pain and loss of function in active patients. Osteochondral allograft (OCA) transplantation offers a single-stage solution to address large chondral and osteochondral defects by resurfacing focal cartilage defects with mature hyaline cartilage. To date, OCA transplantation of the knee has demonstrated excellent clinical outcomes and long-term survivorship. However, significant variability still exists among clinicians with regard to parameters for graft acceptance, surgical technique, and rehabilitation. Technologies to optimize graft viability during storage, improve osseous integration of the allograft, and shorten recovery timelines after surgery continue to evolve. The purpose of this review is to examine the latest evidence on treatment indications, graft storage and surgical technique, patient outcomes and survivorship, and rehabilitation after surgery.

Femoroacetabular impingement (FAI) has a strong clinical association with the development of hip osteoarthritis (OA); however, the pathobiological mechanisms underlying the transition from focal impingement to global joint degeneration remain poorly understood. The purpose of this study is to use whole-genome RNA sequencing to identify and subsequently validate differentially expressed genes (DEGs) in femoral head articular cartilage samples from patients with FAI and hip OA secondary to FAI. Thirty-seven patients were included in the study with whole-genome RNA sequencing performed on 10 gender-matched patients in the FAI and OA cohorts and the remaining specimens were used for validation analyses. We identified a total of 3531 DEGs between the FAI and OA cohorts with multiple targets for genes implicated in canonical OA pathways.Quantitative reverse transcription-polymerase chain reaction validation confirmed increased expression of FGF18 and WNT16 in the FAI samples, while there was increased expression of MMP13 and ADAMTS4 in the OA samples. Expression levels of FGF18 and WNT16 were also higher in FAI samples with mild cartilage damage compared to FAI samples with severe cartilage damage or OA cartilage. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. We independently validated the results of the sequencing analysis and found increased expression of anabolic markers in patients with FAI and minimal histologic cartilage damage, suggesting that anabolic signaling may be increased in early FAI with a transition to catabolic and inflammatory gene expression as FAI progresses towards more severe hip OA.Clinical significance:Cam-typeFAI has a strong clinical association with hip OA; however, the cellular pathophysiology of disease progression remains poorly understood. Several previous studies have demonstrated increased expression of inflammatory markers in FAI cartilage samples, suggesting the involvement of these inflammatory pathways in the disease progression. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. In addition to differences in inflammatory gene expression, we also identified differential expression in multiple pathways involved in hip OA progression.

A novel composite hydrogel was developed that shows remarkable similarities to load bearing biological tissues. The composite gel consisting of a poly(vinyl alcohol (PVA) matrix filled with poly(acrylic acid) (PAA) microgel particles exhibits osmotic and mechanical properties that are qualitatively different from regular gels. In the PVA/PAA system the swollen PAA particles “inflate” the PVA network. The swelling of the PAA is limited by the tensile stress P(el) developing in the PVA matrix. P(el) increases with increasing swelling degree, which is opposite to the decrease of the elastic pressure observed in regular gels. The maximum tensile stress P(el)(max) can be identified as a quantity that defines the load bearing ability of the composite gel. Systematic osmotic swelling pressure measurements have been made on PVA/PAA gels to determine the effects of PVA stiffness, PAA crosslink density, and Ca(2+) ion concentration on P(el)(max). It is found that P(el)(max) increases with the stiffness of the PVA matrix, and decreases with (i) increasing crosslink density of the PAA and (ii) increasing Ca(2+) ion concentration. Small angle neutron scattering (SANS) measurements indicate only a weak interaction between the PVA and PAA gels. It is demonstrated that the osmotic swelling pressure of PVA/PAA composite gels reproduces the osmotic behavior of healthy and osteoarthritic cartilage.

BACKGROUND: Facet joint (FJ) osteoarthritis (FJOA) is a widely prevalent spinal disorder, but its pathogenesis remains unclear largely due to the difficulties in conducting longitudinal human studies and lack of spontaneous FJOA animal models for mechanistic investigations. This study aimed to investigate whether spontaneous FJOA occurs in mice bearing mutant NFAT1 (nuclear factor of activated T cells 1) alleles. METHODS: The lumbar FJs of 50 NFAT1-mutant mice and of 50 wild-type control mice, both sexes, were examined by histopathology, quantitative gene expression analysis, semi-quantitative immunohistochemistry, and a novel FJOA scoring system for semi-quantitative assessments of the histopathologic changes at 2, 6, 12, and 18 months of age. Age-dependent and tissue-specific histopathologic and gene/protein expression changes were analyzed statistically. RESULTS: NFAT1-mutant FJs displayed significantly increased expression of specific catabolic genes (P < 0.05) and proteins (p < 0.001) in cartilage and synovium as early as 2 months of age, followed by early osteoarthritic structural changes such as articular surface fissuring and chondro-osteophyte formation at 6 months. More severe cartilage lesions, osteophytes, subchondral bone changes, synovitis, and tissue-specific molecular alterations in NFAT1-mutant FJs were observed at 12 and 18 months. Osteoarthritic structural changes were not detected in wild-type FJs at any ages, though age-related cartilage degeneration was observed at 18 months. The novel FJOA scoring system had high intra- and inter-observer reproducibility (correlation coefficients r > 0.97). Whole joint FJOA scoring showed significantly higher OA scores in NFAT1-mutant FJs than wild-type FJs at all timepoints (2-month: p = 0.0033, 6-month: p = 0.0001, 12-month: p < 0.0001, and 18-month: p < 0.0001). CONCLUSIONS: This study has identified the NFAT1-mutant mouse as a novel animal model of spontaneous FJOA with age-dependent and slow progressing osteoarthritic features, developed the first FJOA scoring system, and elucidated the molecular mechanisms of NFAT1 mutation-induced FJOA. CLINICAL RELEVANCE: This murine FJOA model resembles the features of human FJOA and may provide new insights into the pathogenesis and therapeutic strategies for FJOA in humans.

Abstract Magnetic resonance imaging (MRI) is widely regarded as the primary modality for the morphological assessment of cartilage and all other joint tissues involved in osteoarthritis. 2D fast spin echo fat-suppressed intermediate-weighted (FSE FS IW) sequences with a TE between 30 and 40ms have stood the test of time and are considered the cornerstone of MRI protocols for clinical practice and trials. These sequences offer a good balance between sensitivity and specificity and provide appropriate contrast and signal within the cartilage as well as between cartilage, articular fluid, and subchondral bone. Additionally, FS IW sequences enable the evaluation of menisci, ligaments, synovitis/effusion, and bone marrow edema-like signal changes. This review article provides a rationale for the use of FSE FS IW sequences in the morphological assessment of cartilage and osteoarthritis, along with a brief overview of other clinically available sequences for this indication. Additionally, the article highlights ongoing research efforts aimed at improving FSE FS IW sequences through 3D acquisitions with enhanced resolution, shortened examination times, and exploring the potential benefits of different magnetic field strengths. While most of the literature on cartilage imaging focuses on the knee, the concepts presented here are applicable to all joints. Key points 1. MRI is currently considered the modality of reference for a “whole-joint” morphological assessment of osteoarthritis. 2. Fat-suppressed intermediate-weighted sequences remain the keystone of MRI protocols for the assessment of cartilage morphology, as well as other structures involved in osteoarthritis. 3. Trends for further development in the field of cartilage and joint imaging include 3D FSE imaging, faster acquisition including AI-based acceleration, and synthetic imaging providing multi-contrast sequences.

ObjectivesTo investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.MethodsKnee articular cartilages from OA patients were analysed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module domain (Link_TSG6) on cytokine-induced glycosaminoglycan loss in OA cartilage explants were compared. Mesenchymal stem/stromal cell (MSC)-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β- or TNF-stimulated ADAMTS4, ADAMTS5 and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model and cartilage damage and tactile allodynia were assayed.ResultsTSG-6 is predominantly associated with chondrocytes in regions of cartilage damage and its expression is negatively correlated with MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at dose-dependently inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants; about 50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Similarly, Link_TSG6 displayed more potent effects in 3D pellet cultures, suppressing aggrecanase and collagenase gene expression. Link_TSG6 treatment reduced touch-evoked pain and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.ConclusionsNative TSG-6 is associated with a low catabolic chondrocyte phenotype in OA cartilage. Link_TSG6, which has enhanced chondroprotective activity compared to the full-length TSG-6 protein, demonstrates potential as a disease modifying OA drug (DMOAD) and warrants further investigation and development.KEY MESSAGESWhat is already known about this subject?TSG-6, a protein with anti-inflammatory and protective effects in other tissues, is expressed in joints affected by osteoarthritis – a condition for which there are no disease-modifying drugs.What does this study add?A novel protective mechanism has been identified, whereby TSG-6 inhibits inflammatory cytokine-induced catabolic pathways in cartilage.The Link module of TSG-6 (Link_TSG6) has been shown to have greater potency than TSG-6 as an inhibitor of cartilage damage and is efficacious in a rat model of osteoarthritis.Data from cartilage explants indicate that OA patients can be stratified for Link_TSG6 responsiveness.How might this impact on clinical practice or future developments?Link_TSG6 has been identified as potential disease-modifying OA drug that mimics an intrinsic protective process.

Objective Lubricin, a glycoprotein encoded by the proteoglycan 4 (PRG4) gene, is an essential boundary lubricant that reduces friction between articular cartilage surfaces. The loss of lubricin subsequent to joint injury plays a role in the pathogenesis of post-traumatic osteoarthritis (PTOA). Here we describe the development and evaluation of an adeno-associated virus (AAV)-based PRG4 gene therapy intended to restore lubricin in injured joints. The green fluorescent protein (GFP) gene was inserted the PRG4 gene to facilitate tracing the distribution of the transgene product (AAV-PRG4-GFP) in vivo. Methods Transduction efficiency of AAV-PRG4-GFP was evaluated in joint cells, and the conditioned medium containing secreted PRG4-GFP was used for shear loading/friction and viability tests. In vivo transduction of joint tissues following intra-articular injection of AAV-PRG4-GFP was confirmed in the mouse stifle joint in a surgical model of destabilization of the medial meniscus (DMM), and chondroprotective activity was tested in a rabbit anterior cruciate ligament transection (ACLT) model. Results In vitro studies showed that PRG4-GFP has lubricin-like cartilage binding and anti-friction properties. Significant cytoprotective effects were seen when cartilage was soaked in PRG4-GFP prior to cyclic shear loading (n = 3). Polymerase chain reaction and confocal microscopy confirmed the presence of PRG4-GFP DNA and protein, respectively, in a mouse DMM (n = 3 per group). In the rabbit ACLT model, AAV-PRG4-GFP gene therapy enhanced lubricin expression (p = 0.001 versus AAV-GFP: n = 7-14) and protected the cartilage from degeneration (p = 0.014 versus AAV-GFP: n = 9-10) when treatments were administered immediately post-operation, but efficacy was lost when treatment was delayed for 2 weeks. Conclusion AAV-PRG4-GFP gene therapy protected cartilage from degeneration in a rabbit ACLT model; however, data from the ACLT model suggest that early intervention is essential for efficacy.

Cartilage does not naturally heal, and cartilage lesions from trauma and wear-and-tear can lead to eventual osteoarthritis. To address long-term repair, tissue engineering of functional biologic implants to treat cartilage lesions is desirable, but the development of such implants is hindered by several limitations, including (1) donor tissue scarcity due to the presence of diseased tissues in joints, (2) dedifferentiation of chondrocytes during expansion, and (3) differences in functional output of cells dependent on donor age. Toward overcoming these challenges, (1) costal cartilage has been explored as a donor tissue, and (2) methods have been developed to rejuvenate the chondrogenic phenotype of passaged chondrocytes for generating self-assembled neocartilage. However, it remains unclear how the rejuvenation processes are influenced by donor age and, thus, how to develop strategies that specifically target age-related differences. Using histological, biochemical, proteomic, and mechanical assays, this study sought to determine the differences among neocartilage generated from neonatal, juvenile, and adult donors using the Yucatan minipig, a clinically relevant large animal model. Based on the literature, a relatively young adult population of animals was chosen due to a reduction in functional output of human articular chondrocytes after 40 years of age. After isolation, costal chondrocytes were expanded, rejuvenated, and self-assembled, and the neocartilages were assessed. The aggregate modulus values of neonatal constructs were at least 1.65-fold of those from the juvenile or adult constructs. Poisson's ratio also significantly differed among all groups, with neonatal constructs exhibiting values 49% higher than adult constructs. Surprisingly, other functional properties such as tensile modulus and glycosaminoglycan content did not significantly differ among groups. Total collagen content was slightly elevated in the adult constructs compared to neonatal and juvenile constructs. A more nuanced view using bottom-up mass spectrometry showed that Col2a1 protein was not significantly different among groups, but protein content of several other collagen subtypes (i.e., Col1a1, Col9a1, Col11a2, and Col12a1) was modulated by donor age. For example, Col12a1 protein content in adult constructs was found to be 102.9% higher than neonatal-derived constructs. Despite these differences, this study shows that different aged donors can be used to generate neocartilages of similar functional properties. IMPACT STATEMENT: Tissue-engineered neocartilage can be generated with functional properties that mimic native cartilage tissue. However, cell sourcing challenges hinder clinical translation of tissue-engineered cartilage. Chondrocytes can be expanded and rejuvenated for the generation of functional self-assembled cartilage, making an allogeneic approach feasible. However, it is currently unclear if donor age impacts functional properties. In this study, using the Yucatan minipig as a clinically relevant large animal model, we demonstrate that functional properties of self-assembled neocartilage are relatively consistent regardless of donor age, suggesting that a wider range of donor ages may be used for cartilage tissue engineering than previously expected.

As the volume of hip arthroscopy continues to rise, determining appropriate indications for the procedure is of paramount importance. Outcomes can be predicted based on well-powered studies focused on determining which patients meet thresholds for achieving the minimal clinically important difference, the patient acceptable symptomatic state, and substantial clinical benefit after treatment. Recent research has shown that acetabular cartilage damage predicts lesser outcomes, and the more advanced the damage, the worse the results. What is concerning is that even the smallest degree of chondromalacia with fibrillation is a negative predictor of achieving the patient acceptable symptomatic state. In contrast, greater than 3 mm of joint space, no cysts, no dysplasia, younger age, lower alpha angle, preoperative 12-item International Hip Outcome Tool score greater than 48.5, and proper version all predict significant improvement after hip arthroscopy.

Objective This study aimed to evaluate the efficacy of low intensity (0.1-0.8 Watt/cm(2)) pulsed ultrasound on chondrocyte cell proliferation and migration. Methods Low-intensity pulsed ultrasound (frequency 3 MHz, duty cycle 25%, and pulse repetition frequency 150 Hz) for 5 minutes at different spatial average intensities was applied on chondrocyte cells. First, the optimum dose with significantly increased proliferation was determined to be 0.5 W/cm(2) for 5 minutes of duration. Then, 0.5 W/cm(2) ultrasound intensity was applied for durations of 2.5, 5, 7.5, and 10 minutes, and healing was assessed by monitoring cell migration and proliferation. Results At the intensity of 0.5 W/cm(2) 48 hours after the application, a statistically significant increase in proliferation (p = .0089) was observed in chondrocyte cells compared to the control group. Proliferation was analyzed at 4, 8, 24, and 48 hours after applying 0.5 W/cm(2) ultrasound for durations of 2.5, 5, 7.5, and 10 minutes. Statistically significant increases were observed at 4 hours (p = .009), 8 hours (p = .032), 24 hours (p = .0084), and 48 hours (p = .00098) with 10 minutes of exposure. For 7.5 min of exposure duration, significant increases were observed at 48 hours (p = .045). In migration for all parameters, no statistically significant improvement (p > .05) was observed. Conclusion It was shown that low intensity pulsed ultrasound induces cartilage cell proliferation; therefore, it may have a disease-modifying effect in the treatment of osteoarthritis. However, no positive effect was observed on cartilage cell migration., Adnan Menderes University Scientific Research Projects Unit [TPF-17048], This work was supported by the Adnan Menderes University Scientific Research Projects Unit [TPF-17048].

Cleft rhinoplasty is a challenging form of nasal correction of both esthetic and functional deformities. The septal cartilage in many Asian patients are not sufficient and weak. Does a combination of the septal cartilage and the bony septum have both esthetic and functional benefits to secondary unilateral cleft rhinoplasty?Thirty patients with a unilateral cleft lip palate underwent open rhinoplasty from October 2018 to January 2021. After preserving a 10 mm L-strut, the posterior cartilaginous and bony septum were harvested as an integrative unit. The osteocartilaginous graft was used as a caudal septal extension graft and an extended spreader graft. Correcting the asymmetry of the tip and tip projection followed. The intraoperative harvested composite graft was analyzed. Acoustic rhinometry and the 3-dimensional anthropometric measurements of the external nose were assessed before and after surgery.The osteocartilaginous unit was much larger than the cartilaginous part of this unit. The mean nasal tip height and the nasolabial angle increased significantly after surgery. The measurement of cross-sectional areas and volumes by acoustic rhinometry revealed that septorhinoplasty provided a significant increase in the function of both nasal cavities.This septal bony cartilaginous graft is effective for cleft lip nasal deformity when correcting the deviated septum, creating a supporting frame to correct the nasal tip asymmetry, improving function.

Patients with alveolar cleft unrepaired suffer from nasal deformities of different magnitude. Bone and cartilage grafts are harvested through several incisions. In this study, we present a method to simultaneously correct nasal deformities and repair alveolar cleft using grafts from the nasal septum.All 6 patients with unilateral cleft lip and palate have alveolar cleft unrepaired combined with nasal deformity. Computed tomography scans and 3-dimensional-printed models of vomer and ethmoid bone were used for the purpose of preoperative design and for assessing the magnitude of deformity. Grafts of bone and cartilage from deviated septum were harvested by septoplasty through which dorsum deviation was corrected. Bone grafts from vomer and ethmoid were then fixed to the prepared alveolar cleft to repair the defect and elevate the alar base. Septal cartilage was adjusted into different shapes of grafts and deformities of nasal tip, nostrils, and columella were then corrected by rhinoplasty to restore the symmetry of the nose.Symmetry of nostrils was improved. The height of alar base on the cleft side was elevated to the level close to the noncleft side. Deviation of the septum, nasal dorsum, and columella was corrected. Projection of the nasal tip was adjusted to facial midline. Midface aesthetics was generally improved.Application of septal grafts reduce the number of incisions. One-stage repair of alveolar cleft and nasal deformities, with the aid of digital design, improves the postoperative experience and the general outcome of the surgery.

In dorsal augmentation, costal cartilage can be used in a number of different ways: monobloc, fascia wrapped, or glued diced cartilage grafting (GDCG). The authors developed a mold to make the use of GDCG more convenient. This report describes their experience with GDCG using a novel mold for dorsal augmentation.The study involved 80 patients who underwent dorsal augmentation with the molded GDCG. Facial photographs and medical records were reviewed to assess patient satisfaction and postoperative complications. For the 23 patients who had three-dimensional scanned imaging, dorsal widths and dorsal heights at the radix and rhinion levels were measured to investigate changes in the implants over time. Resorption of the graft was assessed comparing the 3-month postoperative photograph with the latest photograph taken at the last follow-up (at least 1 year after the surgery). Serial changes of the dorsum were assessed with three-dimensional scanned images.A total of 66 patients (82.5 percent) were satisfied with their surgical outcomes. Complications were encountered in 19 patients (23.8 percent) and eight revision procedures (10 percent) were performed. One patient underwent revision surgery because of resorption of the GDCG. Analysis using a three-dimensional scanning device showed a significant increment of the dorsal height ( p0.05) without dorsal widening when comparing preoperative with 1-year postoperative follow-up data. There were no significant reductions in dorsal height between postoperative 3 months and 1 year.The use of a novel mold for shaping glued diced cartilage appears to be a useful technique for dorsal augmentation in rhinoplasty.Therapeutic, IV.

The multiple toothpick-shaped costal cartilage (MTCC) injection technique was introduced as an improvement based on the free diced costal cartilage (FDCC) injection technique for augmentation rhinoplasty. However, radix irregularities may occur when using the MTCC technique. Considering that the FDCC grafts are easier to shape at the nasal radix, we adopted a combination method of the 2 techniques to achieve natural and smooth contour.Four patients accepted this method for augmentation rhinoplasty. Through a unilateral marginal incision, the costal cartilage grafts were injected for nasal augmentation at the subperiosteal plane. The FDCC grafts and the MTCC grafts were used for nasal radix and dorsum augmentation, respectively. Nasal contour was adjusted by external shaping. The follow-up ranged from 24 to 43 months.All patients were satisfied with the surgical outcome. There were no major complications occurred during the follow-up. One patient underwent rasping revision due to her own beauty-appreciation changes.The combination method can take advantages of the FDCC and MTCC injection techniques. It can effectively lower the incidence of contour irregularities and graft displacement. Meanwhile, it is easy to perform without special procedure, and is time-saving and cartilage-saving.

Introduced over 50 years ago, the "tripod concept" has long been the foundation of our understanding of tip dynamics in rhinoplasty. Modern approaches to rhinoplasty have built on these principles and seen the evolution of several operative techniques to address tip aesthetics. This article and accompanying case video detail our algorithmic approach to tip shaping, based on the use of complete lower lateral cartilage reshaping and tensioning, clarified use of medial crural transection and overlap, with stabilization on a fixed-floating septal extension graft, and deliberate management of the soft-tissue envelope. The intraoperative sequencing, key technical considerations, relevant classification schemes, and global decision-making processes are reviewed. .

The periosteum, the outer layer of bone, is a major source of skeletal stem/progenitor cells (SSPCs) for bone repair. Here, we discuss recent findings on the characterization, role, and regulation of periosteal SSPCs (pSSPCs) during bone regeneration.Several markers have been described for pSSPCs but lack tissue specificity. In vivo lineage tracing and transcriptomic analyses have improved our understanding of pSSPC functions during bone regeneration. Bone injury activates pSSPCs that migrate, proliferate, and have the unique potential to form both bone and cartilage. The injury response of pSSPCs is controlled by many signaling pathways including BMP, FGF, Notch, and Wnt, their metabolic state, and their interactions with the blood clot, nerve fibers, blood vessels, and macrophages in the fracture environment. Periosteal SSPCs are essential for bone regeneration. Despite recent advances, further studies are required to elucidate pSSPC heterogeneity and plasticity that make them a central component of the fracture healing process and a prime target for clinical applications.

Articular cartilage defects have limited healing potential and, when left untreated, can lead to osteoarthritis. Tissue engineering focuses on regenerating the damaged joint surface, preferably in an early stage. Here, we investigate the regenerative potential of three-dimensional (3D) constructs consisting of human induced pluripotent stem cell (iPSC)-derived chondrocytes in gelatin methacryloyl (GelMA) hydrogel for stable hyaline cartilage production. iPSC-derived chondrocytes are encapsulated in GelMA hydrogel at low (1 × 107 ml-1 ) and high (2 × 107 ml-1 ) density. In a conventional medium, GelMA hydrogel supports the chondrocyte phenotype, as opposed to cells cultured in 3D in absence of hydrogel. Moreover, encapsulated iPSC-derived chondrocytes preserve their in vivo matrix formation capacity after 21 days in vitro. In differentiation medium, hyaline cartilage-like tissue forms after 21 days, demonstrated by highly sulfated glycosaminoglycans and collagen type II. Matrix deposition is delayed at low encapsulation density, corroborating with lower transcript levels of COL2A1. An ectopic assay in nude mice demonstrates further maturation of the matrix deposited in vitro. Direct ectopic implantation of iPSC-derived chondrocyte-laden GelMA, without in vitro priming, also generates hyaline cartilage-like tissue, albeit less mature. Since it is unclear what maturity upon implantation is desired for joint surface regeneration, this is an attractive technology to generate immature and more mature hyaline cartilage-like tissue. ispartof: BIOTECHNOLOGY AND BIOENGINEERING vol:119 issue:10 pages:2950-2963 ispartof: location:United States status: published