Nano-hydroxyapatite/chitosan scaffold incorporating bamboo, ginseng and saponin for bone repair against chondroid injury in osteoarthritis

Engineered dECM-based microsystem promotes cartilage regeneration in osteoarthritis by synergistically enhancing chondrogenesis of BMSCs and anti-inflammatory effect

Low-intensity pulsed ultrasound promotes osteoarthritic cartilage regeneration by BMSC-derived exosomes via modulating the NF-κB signaling pathway

Osteoarthritis (OA) is a common and serious joint disease characterized by synovitis and articular cartilage degeneration. Effective nonsurgical treatments for OA are still lacking. In this study, we designed an injectable temperature-sensitive hydrogel system delivering engineered extracellular vesicles for the treatment of OA. We increased the yield and efficacy of extracellular vesicles by three-dimensional(3D) culture of adipose mesenchymal stem cells. The anti-inflammatory drug celecoxib was then loaded into the extracellular vesicles via electroporation, resulting in the construction of engineered extracellular vesicles (CEVs) with both anti-inflammatory and cartilage regeneration functions. An injectable thermosensitive hydrogel was prepared with Pluronic F127 (F127) and hyaluronic acid (HA) for the delivery of CEVs, thereby forming a composite treatment system (CEVs@F127-HA). CEVs@F127-HA could inhibit M1-type macrophage polarization, protect the metabolic homeostasis of chondrocytes, and promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes in vitro. CEVs@F127-HA also prolonged the retention time of CEVs in the joint cavity and provided long-term synergistic therapeutic benefits. In vivo experiments utilizing a sodium iodoacetate-induced OA mouse model also demonstrated that CEVs@F127-HA could effectively reduce joint inflammation and promote cartilage repair and regeneration, thereby inhibiting OA progression. Thus, the two-in-one synergistic therapy of CEVs@F127-HA centrally addresses both pathological features of OA and is a potential and effective strategy for OA treatment.

Biomaterial-based scaffolds in promotion of cartilage regeneration: Recent advances and emerging applications

Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degradation, synovial inflammation, and limited regenerative capacity. Adipose-derived stem cell exosomes (ADSC-Exo) represent a promising cell-free therapeutic approach due to their immunomodulatory properties. Gluteal ADSC-Exo were isolated and characterized by nanoparticle tracking analysis and Western blotting. Their effects were evaluated in vitro in human chondrocytes, fibroblast-like synoviocytes, and THP-1-derived macrophages using proliferation, migration, immunofluorescence, Seahorse metabolic analysis, and RNA sequencing. In vivo, OA was induced in mice by destabilization of the medial meniscus (DMM) and treated with ADSC-Exo, a protein tyrosine phosphatase receptor type C (PTPRC/CD45) inhibitor alone, or in combination. Cartilage pathology and inflammation were assessed by histology, Osteoarthritis Research Society International (OARSI) scoring, immunohistochemistry, and enzyme-linked immunosorbent assays. CRISPR/Cas9-mediated deletion of PTPRC was performed in M1-polarized macrophages to validate mechanistic involvement. ADSC-Exo enhanced cell proliferation, migration, and extracellular matrix gene expression while suppressing catabolic markers under inflammatory conditions. ADSC-Exo promoted macrophage polarization toward an anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine production, and shifted macrophage metabolism toward oxidative phosphorylation. Transcriptomic analysis identified PTPRC as a consistently downregulated target. Genetic deletion of PTPRC attenuated inflammatory and glycolytic gene expression and reduced chondrocyte catabolic responses. In the DMM model, ADSC-Exo preserved cartilage structure, reduced OARSI scores, and suppressed synovial PTPRC expression and inflammatory mediators; these effects were selectively attenuated by PTPRC inhibition. Gluteal ADSC-Exo exert potent anti-inflammatory and chondroprotective effects through immunometabolic reprogramming of macrophages, with PTPRC identified as a key mediator, supporting their translational potential for OA therapy.

Numerous clinical studies have reported cell-based treatments for cartilage regeneration in knee joint osteoarthritis using mesenchymal stem cells (MSCs). However, the post-surgery rehabilitation and weight-bearing times remain unclear. Phenomenological computational models of cartilage regeneration have been only partially successful in predicting experimental results and this may be due to simplistic modeling assumptions and loading conditions of cellular activity. In the present study, we developed a knee joint model of cell and tissue differentiation based on a more mechanistic approach, which was applied to cartilage regeneration in osteoarthritis. First, a phenomenological biphasic poroelastic finite element model was developed and validated according to a previous study. Second, this method was applied to a real knee joint model with a cartilage defect created to simulate the tissue regeneration process. The knee joint model was able to accurately predict several aspects of cartilage regeneration, such as the cell and tissue distributions in the cartilage defect. Additionally, our results indicated that gait cycle loading with flexion was helpful for cartilage regeneration compared to the use of simple weight-bearing loading.

Are pro-regenerative therapies the future of osteoarthritis disease modification?

Au@CeO2 yolk-shell nanozymes restore mitochondrial dynamics and enhance chondrogenic drug response for cartilage regeneration in osteoarthritis

To investigate the effect of arthroscopy combined with high tibial osteotomy (HTO) on cartilage regeneration in patients with knee osteoarthritis. A retrospective analysis of 50 patients with varus and medial compartment osteoarthritis of the knee treated by arthroscopy combined with HTO. One year after the operation, a second-look arthroscopy was performed to observe the cartilage regeneration. The regeneration of cartilage was evaluated by different pathological staining of some of the new cartilage. Finally, part of the new cartilages (n = 6) were taken for quantitative real-time PCR and western blotting experiments to display the mechanism of cartilage regeneration. One year after arthroscopy combined with HTO, the results of arthroscopy revealed the formation of new tissue in the defect area of the medial compartment's cartilage in the knee joint. In addition, different pathological staining results indicated that the new tissue was cartilage-like tissue. Furthermore, HTO potently up-regulated the expression of p-ERK1/2 at the protein level in knee osteoarthritis patients compared with control group. However, there was no significant difference in the relative expression of collagen II at mRNA and protein level between control group and knee osteoarthritis patients. Arthroscopy combined with HTO can promote cartilage regeneration in patients with knee osteoarthritis.

Selenium nanozyme-crosslinked composite hydrogel for promoting cartilage regeneration in osteoarthritis via an integrated 'outside-in' and 'inside-out' strategy.

Adult skeletal stem cells (SSCs) that give rise to chondrocytes, osteocytes, and stromal cells as progeny have been shown to contribute to cartilage regeneration in osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase Tet1 regulates SSC function in OA. We investigated the differences in the SSC lineage tree and differentiation potential in neonatal and adult Tet1+/+ and Tet1-/- mice with and without injury and upon OA induction and progression. Using RNA sequencing, the transcriptomic differences between SSCs and bone cartilage stroma progenitor cells (BCSPs) were identified in Tet1+/+ mice and Tet1-/- mice. Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSCs and BCSPs. Tet1 inhibition led to enhanced chondrogenesis in human SSCs and chondroprogenitors isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of OA led to increased cartilage regeneration. Transcriptomic analyses of SSCs and BCSPs lacking Tet1 revealed pathway alterations in transforming growth factor β signaling, melatonin degradation, and cartilage development-associated genes. Lastly, we report that use of the hormone melatonin can dampen inflammation and improve cartilage health. Although Tet1 is a broad epigenetic regulator, melatonin can mimic the inhibition ability of TET1 to enhance the chondrogenic ability of SSCs. Melatonin administration has the potential to be an attractive stem cell-based therapy for cartilage regeneration.

The lack of effective treatment options for osteoarthritis (OA) is mostly due to the very limited regenerative capacity of articular cartilage. Mesenchymal stem cells (MSCs) have been most extensively explored for cell-based therapy to induce cartilage regeneration for OA. However, current in vitro expanded MSC-based approaches have significant drawbacks. On the other hand, osteoarthritic joints contain chondrocyte progenitors and MSCs in several niches which have the potential yet fail to differentiate into chondrocytes for cartilage regeneration. One of the underlying mechanisms of the failure is that these chondrocyte progenitors and MSCs in OA joints are deficient in the activity of chondrogenic transcription factor SOX9 (SRY-type high-mobility group box-9). Thereby, replenishing with exogenous SOX9 would reactivate the potential of these stem cells to differentiate into chondrocytes. Cell-permeable, super-positively charged SOX9 (scSOX9) protein is able to promote hyaline-like cartilage regeneration by inducing chondrogenic differentiation of bone marrow derived MSCs in vivo. This scSOX9 protein can be administered into osteoarthritic joints by intra-articular injection. This one-step, cell-free supplement of exogenous SOX9 may harness the regenerative potential of the intrinsic MSCs within the joint cavity to stimulate cartilage regeneration in OA.

Objectives:Osteoarthritis (OA) is a chronic disease of degenerative joints. Mesenchymal stem cells (MSCs) have been used for cartilage regeneration in OA. We investigated the therapeutic potential of human umbilical cord-derived MSCs (HUCMSCs) with hyaluronic acid (HA) hydrogel transplanted into a porcine OA preclinical model.Materials and Methods:The HUCMSCs were characterized with respect to morphology, surface markers, and differentiation capabilities. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to examine gene expressions in a HUCMSC–HA coculture. Two healthy female minipigs weighing 30–40 kg and aged approximately 4 months were used in this large animal study. A full-thickness chondral injury was created in the trochlear groove of each of the pig's rear knees. After 3 weeks, a second osteochondral defect was created. Then, 1.5 mL of a HUCMSC (5 × 106 cells) and HA composite (4%) was transplanted into the chondral-injured area in the right knee of each pig. Using the same surgical process, an osteochondral defect (untreated) was created in the left knee as a control. The pigs were sacrificed 12 weeks after transplantation. Macroscopic and microscopic histologies, qRT-PCR, and immunostaining evaluated the degree of chondral degradation.Results:The HUCMSCs exhibited typical MSC characteristics, including spindle morphology, expression of surface markers (positive for CD29, CD4, CD73, CD90, and human leukocyte antigen [HLA]-ABC; negative for CD34, CD45, and HLA-DR), and multipotent differentiation (adipogenesis, osteogenesis, and chondrogenesis). More extensive proliferation of HUCMSCs was noted with 4% and 25% of HA than without HA. Expression of COL2A1 and aggrecan in the HUCMSC-derived chondrocytes was increased when HA was included. The treated knees showed significant gross and histological improvements in hyaline cartilage regeneration when compared to the control knees. The International Cartilage Repair Society histological score was higher for the treated knees than the control knees.Conclusion:Our findings suggest that cartilage regeneration using a mixture of HUCMSCs and HA in a large animal model may be an effective treatment for OA, and this study is a stepping stone toward the future clinical trials.

Osteoarthritis (OA) is associated with articular cartilage abnormalities and affects people of older age: preventative or therapeutic treatment measures for OA and related articular cartilage disorders remain challenging. In this perspective review, we have integrated multiple biological, morphological, developmental, stem cell and homeostasis concepts of articular cartilage to develop a paradigm for cartilage regeneration. OA is conceptually defined as an injury of cartilage that initiates chondrocyte activation, expression of proteases and growth factor release from the matrix. This regenerative process results in the local activation of inflammatory response genes in cartilage without migration of inflammatory cells or angiogenesis. The end results are catabolic and anabolic responses, and it is the balance between these two outcomes that controls remodelling of the matrix and regeneration. A tantalizing clinical clue for cartilage regrowth in OA joints has been observed in surgically created joint distraction. We hypothesize that cartilage growth in these distracted joints may have a biological connection with the size of organs and regeneration. Therefore we propose a novel, practical and nonsurgical intervention to validate the role of distraction in cartilage regeneration in OA. The approach permits normal wake-up activity while during sleep; the index knee is subjected to distraction with a pull traction device. Comparison of follow-up magnetic resonance imaging (MRI) at 3 and 6 months of therapy to those taken before therapy will provide much-needed objective evidence for the use of this mode of therapy for OA. We suggest that the paradigm presented here merits investigation for treatment of OA in knee joints.

Osteoarthritis (OA) is a common disorder and the restoration of the diseased articular cartilage in patients with OA is still a challenge for researchers and clinicians. Currently, a variety of experimental strategies have investigated whether mesenchymal stem cells (MSCs) instead of chondrocytes can be used for the regeneration and maintenance of articular cartilage in OA. MSCs can modulate the immune response of individuals and positively influence the microenvironment of the stem cells already present in the diseased tissue. Through direct cell-cell interaction or the secretion of various factors, MSCs can initiate endogenous regenerative activities in the OA joint. Targeted gene-modified MSC-based therapy might further enhance the cartilage regeneration in OA. Conventionally, delivery of MSCs was attained by graft of engineered constructs derived from cell-seeded scaffolds. However, intra-articular MSCs transplantation without scaffolds is a more attractive option for OA treatment. This article briefly summarizes the current knowledge about MSC-based therapy for prevention or treatment of OA, discussing the direct intra-articular injection of MSCs for the treatment of OA in animal models and in clinical applications, as well as potential future strategies for OA treatment.