Showing papers on "Cartilage published in 2022"

Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits

Abstract: Description A biodegradable piezoelectric scaffold excited by exercise promotes chondrogenesis and cartilage regeneration in rabbit osteochondral defects. Exciting scaffolds regenerate cartilage Osteoarthritis is a common condition, but curative therapies are limited. Here, Liu and colleagues developed a biodegradable scaffold using PLLA [poly(l-lactic acid)] nanofibers that when placed under applied force generated a piezoelectric charge, leading to improved chondrogenesis in vitro. Rabbits with osteochondral defects in the medial femoral condyle that were treated with the PLLA scaffold demonstrated improved cartilage regeneration and subchondral bone regeneration after 1 or 2 months of exercise to generate piezoelectric charge from the joint loads. Although further work is needed to optimize the scaffold microstructure and components, this study provides evidence that biodegradable piezoelectric scaffolds can use joint-loading exercise to treat osteoarthritis. More than 32.5 million American adults suffer from osteoarthritis, and current treatments including pain medicines and anti-inflammatory drugs only alleviate symptoms but do not cure the disease. Here, we have demonstrated that a biodegradable piezoelectric poly(l-lactic acid) (PLLA) nanofiber scaffold under applied force or joint load could act as a battery-less electrical stimulator to promote chondrogenesis and cartilage regeneration. The PLLA scaffold under applied force or joint load generated a controllable piezoelectric charge, which promoted extracellular protein adsorption, facilitated cell migration or recruitment, induced endogenous TGF-β via calcium signaling pathway, and improved chondrogenesis and cartilage regeneration both in vitro and in vivo. Rabbits with critical-sized osteochondral defects receiving the piezoelectric scaffold and exercise treatment experienced hyaline-cartilage regeneration and completely healed cartilage with abundant chondrocytes and type II collagen after 1 to 2 months of exercise (2 to 3 months after surgery including 1 month of recovery before exercise), whereas rabbits treated with nonpiezoelectric scaffold and exercise treatment had unfilled defect and limited healing. The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.

Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7

Abstract: Objectives To investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression. Methods F-box and WD repeat domain containing 7 (FBXW7) ubiquitin ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA sequencing was performed in articular cartilage from Fbxw7 knockout and control mice. Results Mechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degeneration Conclusions FBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.

Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis

Abstract: Osteoarthritis, as a degenerative disease, is a common problem and results in high socioeconomic costs and rates of disability. The most commonly affected joint is the knee and characterized by progressive destruction of articular cartilage, loss of extracellular matrix, and progressive inflammation. Mesenchymal stromal cell (MSC)-based therapy has been explored as a new regenerative treatment for knee osteoarthritis in recent years. However, the detailed functions of MSC-based therapy and related mechanism, especially of cartilage regeneration, have not been explained. Hence, this review summarized how to choose, authenticate, and culture different origins of MSCs and derived exosomes. Moreover, clinical application and the latest mechanistical findings of MSC-based therapy in cartilage regeneration were also demonstrated.

Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage

Abstract: Abstract Osteoarthritis (OA) is a progressive chronic inflammation that leads to cartilage degeneration. OA Patients are commonly given pharmacological treatment, but the available treatments are not sufficiently effective. The development of sustained-release drug delivery systems (DDSs) for OA may be an attractive strategy to prevent rapid drug clearance and improve the half-life of a drug at the joint cavity. Such delivery systems will improve the therapeutic effects of anti-inflammatory effects in the joint cavity. Whereas, for disease-modifying OA drugs (DMOADs) which target chondrocytes or act on mesenchymal stem cells (MSCs), the cartilage-permeable DDSs are required to maximize their efficacy. This review provides an overview of joint structure in healthy and pathological conditions, introduces the advances of the sustained-release DDSs and the permeable DDSs, and discusses the rational design of the permeable DDSs for OA treatment. We hope that the ideas generated in this review will promote the development of effective OA drugs in the future.

Stem cell–homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model

Abstract: Osteoarthritis (OA) is a common joint disease characterized by progressive loss of cartilage and reduction in lubricating synovial fluid, which lacks effective treatments currently. Here, we propose a hydrogel-based miRNA delivery strategy to rejuvenate impaired cartilage by creating a regenerative microenvironment to mitigate chondrocyte senescence that mainly contributes to cartilage breakdown during OA development. An aging-related miRNA, miR-29b-5p, was first found to be markedly down-regulated in OA cartilage, and their up-regulation suppressed the expression of matrix metalloproteinases and senescence-associated genes (P16INK4a/P21) via ten-eleven-translocation enzyme 1 (TET1). An injectable bioactive self-assembling peptide nanofiber hydrogel was applied to deliver agomir-29b-5p, which was functionalized by conjugating a stem cell–homing peptide SKPPGTSS for endogenous synovial stem cell recruitment simultaneously. Sustained miR-29b-5p delivery and recruitment of synovial stem cells and their subsequent differentiation into chondrocytes led to successful cartilage repair and chondrocyte rejuvenation. This strategy enables miRNA-based therapeutic modality to become a viable alternative for surgery in OA treatment.

Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications

Abstract: The regeneration and repair of articular cartilage remains a major challenge for clinicians and scientists due to the poor intrinsic healing of this tissue. Since cartilage injuries are often clinically irregular, tissue-engineered scaffolds that can be easily molded to fill cartilage defects of any shape that fit tightly into the host cartilage are needed.In this study, bone marrow mesenchymal stem cell (BMSC) affinity peptide sequence PFSSTKT (PFS)-modified chondrocyte extracellular matrix (ECM) particles combined with GelMA hydrogel were constructed.In vitro experiments showed that the pore size and porosity of the solid-supported composite scaffolds were appropriate and that the scaffolds provided a three-dimensional microenvironment supporting cell adhesion, proliferation and chondrogenic differentiation. In vitro experiments also showed that GelMA/ECM-PFS could regulate the migration of rabbit BMSCs. Two weeks after implantation in vivo, the GelMA/ECM-PFS functional scaffold system promoted the recruitment of endogenous mesenchymal stem cells from the defect site. GelMA/ECM-PFS achieved successful hyaline cartilage repair in rabbits in vivo, while the control treatment mostly resulted in fibrous tissue repair.This combination of endogenous cell recruitment and chondrogenesis is an ideal strategy for repairing irregular cartilage defects.

Grafts

Abstract: *Department of Dermatology, Mayo Clinic Scottsdale, Scottsdale, Arizona †Phoenix Surgical Dermatology Group, Phoenix, Arizona; The authors have indicated no significant interest with commercial supporters.

Cartilage tissue engineering: From proinflammatory and anti-inflammatory cytokines to osteoarthritis treatments

Abstract: Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra-articular proinflammatory and anti-inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti-inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self-repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL-1β, TNF-α, IL-6, IL-15, IL-17 and IL-18, as well as the key anti-inflammatory factors reducing OA-related articular damage, including IL-4, insulin-like growth factor and TGF-β. The predominance of proinflammatory over anti-inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro- and anti-inflammatory factors.

3D printed hydrogel for articular cartilage regeneration

Abstract: Tissue engineering is a promising strategy for damaged cartilage tissue repair. Three-dimensional (3D) printed hydrogel exhibits great potential in cartilage tissue engineering for fabricating 3D cell culture scaffolds, owing to its similarity to the extracellular matrix (ECM). Numerous hydrogels have been tested for 3D printing in vitro articular cartilage tissues, including natural and synthetic hydrogels that mimic their in vivo counterparts. The advancement of materials science and 3D printing techniques enables a wide range of fabrication strategies that produce cartilage tissues with delicate structures and on multiple scales. Stimuli-responsive hydrogels, which rely on the external environment to transform to a desired structure or dimension, have likewise been widely studied in tissue engineering. This review summarizes the characteristics, functions, and research conducted on 3D printed hydrogels by categorizing cutting-edge hydrogel materials commonly used in cartilage tissue engineering and their complexes. The challenges and application prospects of hydrogels in cartilage tissue engineering are described. Novel composite hydrogels must be investigated to meet the requirements of native articular cartilage in the aspects of structure, scale, mechanical properties, among others. Combining stimuli-responsive hydrogels with biological scaffolds also shows great potential in various applications, including but not limited to articular cartilage, vascularization, and osteochondral repair.

Stem Cells in Temporomandibular Joint Engineering: State of Art and Future Persectives

Abstract: Temporomandibular joint (TMJ) osteoarthritis is a degenerative disease, characterized by gradual cartilage degradation, bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical therapy have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In last years, stem cell-based therapy has collected much attention as a possible approach toward tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will describe the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ, particularly focusing on the MSC-based therapy and tissue engineering.

Harnessing Tissue-derived Extracellular Vesicles for Osteoarthritis Theranostics

Abstract: Osteoarthritis (OA) is a prevalent chronic whole-joint disease characterized by low-grade systemic inflammation, degeneration of joint-related tissues such as articular cartilage, and alteration of bone structures that can eventually lead to disability. Emerging evidence has indicated that synovium or articular cartilage-secreted extracellular vesicles (EVs) contribute to OA pathogenesis and physiology, including transporting and enhancing the production of inflammatory mediators and cartilage degrading proteinases. Bioactive components of EVs are known to play a role in OA include microRNA, long non-coding RNA, and proteins. Thus, OA tissues-derived EVs can be used in combination with advanced nanomaterial-based biosensors for the diagnostic assessment of OA progression. Alternatively, mesenchymal stem cell- or platelet-rich plasma-derived EVs (MSC-EVs or PRP-EVs) have high therapeutic value for treating OA, such as suppressing the inflammatory immune microenvironment, which is often enriched by pro-inflammatory immune cells and cytokines that reduce chondrocytes apoptosis. Moreover, those EVs can be modified or incorporated into biomaterials for enhanced targeting and prolonged retention to treat OA effectively. In this review, we explore recently reported OA-related pathological biomarkers from OA joint tissue-derived EVs and discuss the possibility of current biosensors for detecting EVs and EV-related OA biomarkers. We summarize the applications of MSC-EVs and PRP-EVs and discuss their limitations for cartilage regeneration and alleviating OA symptoms. Additionally, we identify advanced therapeutic strategies, including engineered EVs and applying biomaterials to increase the efficacy of EV-based OA therapies. Finally, we provide our perspective on the future of EV-related diagnosis and therapeutic potential for OA treatment.

Silk fibroin-based biomaterials for cartilage/osteochondral repair

Abstract: Osteoarthritis (OA) is a common joint disease with a high disability rate. In addition, OA not only causes great physiological and psychological harm to patients, but also puts great pressure on the social healthcare system. Pathologically, the disintegration of cartilage and the lesions of subchondral bone are related to OA. Currently, tissue engineering, which is expected to overcome the defects of existing treatment methods, had a lot of research in the field of cartilage/osteochondral repair. Silk fibroin (SF), as a natural macromolecular material with good biocompatibility, unique mechanical properties, excellent processability and degradability, holds great potential in the field of tissue engineering. Nowadays, SF had been prepared into various materials to adapt to the demands of cartilage/osteochondral repair. SF-based biomaterials can also be functionally modified to enhance repair performance further. In this review, the preparation methods, types, structures, mechanical properties, and functional modifications of SF-based biomaterials used for cartilage/osteochondral repair are summarized and discussed. We hope that this review will provide a reference for the design and development of SF-based biomaterials in cartilage/osteochondral repair field.

3D Bioprinting of Heterogeneous Constructs Providing Tissue‐Specific Microenvironment Based on Host–Guest Modulated Dynamic Hydrogel Bioink for Osteochondral Regeneration

Abstract: 3D bioprinting is a promising strategy to develop heterogeneous constructs that mimic osteochondral tissue. However, conventional bioprinted hydrogels suffer from intrinsically weak mechanical strength, limited cell adaptability, and no sustained release of biochemical drugs, restraining their use as bioinks to emulate native osteochondral extracellular matrix. Herein, a novel host–guest modulated dynamic hydrogel is developed for 3D bioprinting heterogeneous cell‐laden constructs for osteochondral regeneration. Apart from gelatin methacryloyl (GelMA), this bioink consists of dopamine‐functionalized GelMA and acrylate β‐cyclodextrin and is crosslinked by host–guest interaction to develop the dynamic network for obtaining promoted cell adaptability, enhanced cell adhesion, reinforced mechanical strength, and tunable modulus. Moreover, based on the sustained drug release provided by the cavity of β‐cyclodextrin, a heterogeneous construct is constructed by employing kartogenin (a chondrogenic factor) into the upper zone with lower Young's modulus and melatonin (an osteogenic factor) into the bottom zone with higher modulus to mimic the osteochondral microenvironment. With the favorable regeneration results in vitro and in vivo, a broad application of this bioink in 3D bioprinting for tissues engineering is expected.

Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis

Abstract: Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) "difficult-to-treat". Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA.

Exosomes derived from platelet-rich plasma administration in site mediate cartilage protection in subtalar osteoarthritis

Abstract: Subtalar osteoarthritis (STOA) is often secondary to chronic ankle sprains, which seriously affects the quality of life of patients. Due to its etiology and pathogenesis was not studied equivocally yet, there is currently a lack of effective conservative treatments. Although they have been used for tissue repair, platelet-rich plasma-derived exosomes (PRP-Exo) have the disadvantage of low retention and short-lived therapeutic effects. This study aimed to determine whether incorporation of PRP-Exo in thermosensitive hydrogel (Gel) increased their retention in the joint and thereby playing a therapeutic role on STOA due to chronic mechanical instability established by transecting lateral ligaments (anterior talofibular ligament (ATFL)/calcaneal fibular ligament (CFL)). PRP-Exo incorporated Gel (Exo-Gel) system, composed of Poloxamer-407 and 188 mixture-based thermoresponsive hydrogel matrix in an optimal ratio, was determined by its release ability of Exo and rheology of Gel response to different temperature. The biological activity of Exo-Gel was evaluated in vitro, and the therapeutic effect of Exo-Gel on STOA was evaluated in vivo. Exo released from Exo-Gel continuously for 28 days could promote the proliferation and migration of mouse bone mesenchymal stem cells (mBMSCs) and chondrocytes, at the same time enhance the chondrogenic differentiation of mBMSCs, and inhibit inflammation-induced chondrocyte degeneration. In vivo experiments confirmed that Exo-Gel increased the local retention of Exo, inhibited the apoptosis and hypertrophy of chondrocytes, enhanced their proliferation, and potentially played the role in stem cell recruitment to delay the development of STOA. Thus, Delivery of PRP-Exo incorporated in thermosensitive Gel provides a novel approach of cell-free therapy and has therapeutic effect on STOA.

Osteoarthritis endotype discovery via clustering of biochemical marker data

Abstract: Objectives Osteoarthritis (OA) patient stratification is an important challenge to design tailored treatments and drive drug development. Biochemical markers reflecting joint tissue turnover were measured in the IMI-APPROACH cohort at baseline and analysed using a machine learning approach in order to study OA-dominant phenotypes driven by the endotype-related clusters and discover the driving features and their disease-context meaning. Method Data quality assessment was performed to design appropriate data preprocessing techniques. The k-means clustering algorithm was used to find dominant subgroups of patients based on the biochemical markers data. Classification models were trained to predict cluster membership, and Explainable AI techniques were used to interpret these to reveal the driving factors behind each cluster and identify phenotypes. Statistical analysis was performed to compare differences between clusters with respect to other markers in the IMI-APPROACH cohort and the longitudinal disease progression. Results Three dominant endotypes were found, associated with three phenotypes: C1) low tissue turnover (low repair and articular cartilage/subchondral bone turnover), C2) structural damage (high bone formation/resorption, cartilage degradation) and C3) systemic inflammation (joint tissue degradation, inflammation, cartilage degradation). The method achieved consistent results in the FNIH/OAI cohort. C1 had the highest proportion of non-progressors. C2 was mostly linked to longitudinal structural progression, and C3 was linked to sustained or progressive pain. Conclusions This work supports the existence of differential phenotypes in OA. The biomarker approach could potentially drive stratification for OA clinical trials and contribute to precision medicine strategies for OA progression in the future. Trial registration number NCT03883568.