Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the...Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the lack of suitable tissue-engineered artificial matrices,current therapies for AC defects,espe-cially full-thickness AC defects and osteochondral interfaces,fail to replace or regenerate damaged carti-lage adequately.With rapid research and development advancements in AC tissue engineering(ACTE),functionalized hydrogels have emerged as promising cartilage matrix substitutes because of their favor-able biomechanical properties,water content,swelling ability,cytocompatibility,biodegradability,and lubricating behaviors.They can be rationally designed and conveniently tuned to simulate the extracel-lular matrix of cartilage.This article briefly introduces the composition,structure,and function of AC and its defects,followed by a comprehensive review of the exquisite(bio)design and(bio)fabrication of func-tionalized hydrogels for AC repair.Finally,we summarize the challenges encountered in functionalized hydrogel-based strategies for ACTE both in vivo and in vitro and the future directions for clinical translation.展开更多
Articular cartilage is a layer of low-friction,load-bearing soft hydrated tissue covering bone-ends in diarthrosis,which plays an important role in spreading the load,reducing the joint contact stress,joint friction a...Articular cartilage is a layer of low-friction,load-bearing soft hydrated tissue covering bone-ends in diarthrosis,which plays an important role in spreading the load,reducing the joint contact stress,joint friction and wear during exercise.The vital mechanical function展开更多
Cartilage regeneration and repair are considered clinical challenges since cartilage has limited capability for reconstruction.Although tissue-engineered materials have the ability to repair cartilage,they have weak m...Cartilage regeneration and repair are considered clinical challenges since cartilage has limited capability for reconstruction.Although tissue-engineered materials have the ability to repair cartilage,they have weak mechanical characteristics and cannot resist long-term overload.On the other hand,surgery to replace the joint is frequently done to treat significant cartilage deterioration these days.However,the materials that are being used for replacement have high friction coefficients,lack shock absorption functions,and lack cushioning.Further research on natural articular cartilage structure and function may lead to bionic hydrogels,which have suitable physicochemical and biological characteristics(e.g.,tribological and mechanical properties and the ability to support loadbearing capability),but need improvements.Based on their tribological and mechanical characteristics,the current review highlights the most recent advancements of bionic hydrogels used for articular cartilage,highlighting both the field's recent progress and its potential for future research.For this reason,firstly,some important property improvement methods of bionic hydrogels are discussed and then,the recent findings of various research on the making of those bionic materials are provided and compared.It seems that by using some modifications such as product design,surface treatments,animal tests,controlling the isoelectric point of hydrogels,and computer simulation,the intended mechanical and tribological characteristics of natural articular cartilage may be attained by the bionic hydrogels.展开更多
The boundary lubrication mechanism at the articulating surface of natural synovial joints has been the subject of much discussion in tribology.In this study,to elucidate the lubricating function of the superficial are...The boundary lubrication mechanism at the articulating surface of natural synovial joints has been the subject of much discussion in tribology.In this study,to elucidate the lubricating function of the superficial area of articular cartilage and synovial fluid(SF),cartilage specimens were processed with four different treatments:gentle and severe washing with detergent,incubation in NaCl solution,and trypsin digestion to selectively remove certain constituents from the cartilage surface.Subsequently,the frictional characteristics were examined in phosphate-buffered saline(PBS)and SF against glass.Angularly reciprocating sliding tests with a spherical glass probe and square articular cartilage specimens were performed at low contact loads in the mN range to extract the frictional behavior in the superficial area of the cartilage specimens.Meanwhile,the cartilage surface was observed to confirm the effects of treatments on the morphology of the cartilage surface using a fluorescence microscope and water-immersion methods.The coefficient of friction(COF)of the prepared cartilage specimens was varied from 0.05 to over 0.3 in PBS.However,a certain group of cartilage specimens exhibited a low COF of less than 0.1 with limited variation.For the low COF group of specimens,all four treatments increased the COF in PBS to different extents,and fluorescence microscopy revealed that the integrity of the cartilage surface was deteriorated by treatments.This means that the intact cartilage surface had lubricating constituents to maintain low friction,and the removal of such constituents resulted in the loss of the intrinsic boundary lubricity of the cartilage surface.The variation in the COF of the cartilage specimens was suppressed in SF because it had a clear boundary lubrication effect on the cartilage surface.The lubricating effect of SF could be confirmed even after degenerative treatment.展开更多
As a highly specialized shock-absorbing connective tissue,articular cartilage(AC)has very limited self-repair capacity after traumatic injuries,posing a heavy socioeconomic burden.Common clinical therapies for small-t...As a highly specialized shock-absorbing connective tissue,articular cartilage(AC)has very limited self-repair capacity after traumatic injuries,posing a heavy socioeconomic burden.Common clinical therapies for small-to medium-size focal AC defects are well-developed endogenous repair and cell-based strategies,including microfracture,mosaicplasty,autologous chondrocyte implantation(ACI),and matrix-induced ACI(MACI).However,these treatments frequently result in mechanically inferior fibrocartilage,low cost-effectiveness,donor site morbidity,and short-term durability.It prompts an urgent need for innovative approaches to pattern a pro-regenerative microenvironment and yield hyaline-like cartilage with similar biomechanical and biochemical properties as healthy native AC.Acellular regenerative biomaterials can create a favorable local environment for AC repair without causing relevant regulatory and scientific concerns from cell-based treatments.A deeper understanding of the mechanism of endogenous cartilage healing is furthering the(bio)design and application of these scaffolds.Currently,the utilization of regenerative biomaterials to magnify the repairing effect of joint-resident endogenous stem/progenitor cells(ESPCs)presents an evolving improvement for cartilage repair.This review starts by briefly summarizing the current understanding of endogenous AC repair and the vital roles of ESPCs and chemoattractants for cartilage regeneration.Then several intrinsic hurdles for regenerative biomaterials-based AC repair are discussed.The recent advances in novel(bio)design and application regarding regenerative biomaterials with favorable biochemical cues to provide an instructive extracellular microenvironment and to guide the ESPCs(e.g.adhesion,migration,proliferation,differentiation,matrix production,and remodeling)for cartilage repair are summarized.Finally,this review outlines the future directions of engineering the next-generation regenerative biomaterials toward ultimate clinical translation.展开更多
Articular cartilage(AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis(OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying...Articular cartilage(AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis(OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intraarticular drug delivery systems(DDSs) in the future.展开更多
The extremely low friction and minimal wear in natural synovial joints appear to be established by effective lubrication mechanisms based on appropriate combination of articular cartilage and synovial fluid.The comple...The extremely low friction and minimal wear in natural synovial joints appear to be established by effective lubrication mechanisms based on appropriate combination of articular cartilage and synovial fluid.The complex structure of cartilage composed of collagen and proteoglycan with high water content contributes to high load-carrying capacity as biphasic materials and the various constituents of synovial fluid play important roles in various lubrication mechanisms.However,the detailed differences in functions of the intact and damaged cartilage tissues,and the interaction or synergistic action of synovia constituents with articular cartilage have not yet been clarified.In this study,to examine the roles of synovia constituents and the importance of cartilage surface conditions,the changes in friction were observed in the reciprocating tests of intact and damaged articular cartilage specimens against glass plate lubricated with lubricants containing phospholipid,protein and/or hyaluronic acid as main constituents in synovial fluid.The effectiveness of lubricant constituents and the influence of cartilage surface conditions on friction are discussed.In addition,the protectiveness by synovia constituents for intact articular cartilage surfaces is evaluated.展开更多
Osteoarthritis is the most prevalent chronic and debilitating joint disease,resulting in huge medical and socioeconomic burdens.Intra-articular administration of agents is clinically used for pain management.However,t...Osteoarthritis is the most prevalent chronic and debilitating joint disease,resulting in huge medical and socioeconomic burdens.Intra-articular administration of agents is clinically used for pain management.However,the effectiveness is inapparent caused by the rapid clearance of agents.To overcome this issue,nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents.Given the therapeutic programs are inseparable from pathological progress of osteoarthritis,an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders.In this review,we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release.Then,we review the interactions of nanoparticles with cartilage microenvironment and the rational design.Furthermore,we highlight advances in the therapeutic schemes according to the pathology signals.Finally,armed with an updated understanding of the pathological mechanisms,we place an emphasis on the development of“smart”bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals.We anticipate that the exploration of nanoparticles by balancing the efficacy,safety,and complexity will lay down a solid foundation tangible for clinical translation.展开更多
Due to the sophisticated hierarchical structure and limited reparability of articular cartilage(AC),the ideal regeneration of AC defects has been a major challenge in the field of regenerative medicine.As defects prog...Due to the sophisticated hierarchical structure and limited reparability of articular cartilage(AC),the ideal regeneration of AC defects has been a major challenge in the field of regenerative medicine.As defects progress,they often extend from the cartilage layer to the subchondral bone and ultimately lead to osteoarthritis.Tissue engineering techniques bring new hope for AC regeneration.To meet the regenerative requirements of the heterogeneous and layered structure of native AC tissue,a substantial number of multilayered biomimetic scaffolds have been studied.Ideal multilayered scaffolds should generate zone-specific functional tissue similar to native AC tissue.This review focuses on the current status of multilayered scaffolds developed for AC defect repair,including design strategies based on the degree of defect severity and the zone-specific characteristics of AC tissue,the selection and composition of biomaterials,and techniques for design and manufacturing.The challenges and future perspectives of biomimetic multilayered scaffold strategies for AC regeneration are also discussed.展开更多
As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount...As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount of research on the topic,the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored,though many aspects still remain unclear.In this review,we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin,bone and articular cartilage repair.In addition to the identification procedure of USCs,we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs.Potential concerns and perspectives have also been summarized.展开更多
Tissue engineering provides a promising avenue for treating cartilage defects.However,great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regenerati...Tissue engineering provides a promising avenue for treating cartilage defects.However,great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration.In this study,decellularized cartilage extracellular matrix(ECM)and waterborne polyurethane(WPU)were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing(LDM)system,which combines rapid deposition manufacturing with phase separation techniques.The scaffolds successfully achieved hierarchical macro-microporous structures.After adding ECM,WPU scaffolds were markedly optimized in terms of porosity,hydrophilia and bioactive components.Moreover,the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution,adhesion,and proliferation than the WPU scaffolds.Most importantly,the WPU-ECM scaffold could facilitate the production of glycosaminoglycan(GAG)and collagen and the upregulation of cartilage-specific genes.These results indicated that the WPU-ECM scaffold with hierarchical macro-microporous structures could recreate a favorable microenvironment for cell adhesion,proliferation,differentiation,and ECM production.In vivo studies further revealed that the hierarchical macro-microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model.Six months after implantation,the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage.In conclusion,the hierarchical macro-microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.展开更多
Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic ...Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic differentiation potential,may be the main driver of cartilage repair.However,both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC.Tetrahedral framework nucleic acids(tFNAs),notable novel nanomaterials,are considered prospective biological regulators in biomedical engineering.Here,we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism.The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs.In addition,tFNAs,which were added to chondrogenic induction medium,were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3.In animal models,the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs.In conclusion,this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo,indicating that tFNAs may become a promising therapeutic for AC regeneration.展开更多
The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes.However,its role in articular cart...The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes.However,its role in articular cartilage remains obscure.Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes,the distribution of Twist1 proteins in normal versus OA human articular cartilage,and its role in modulating OA development in mice.High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features.The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro.In normal human articular cartilage,Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones.However,our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage.Moreover,Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples.To assess the role of Twist1 in OA pathophysiology,we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus.At 12 weeks post-surgery,micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice.Collectively,the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration.展开更多
Temporomandibular joint (TMJ) is sensitive to loading and mechanical stress that provokes morphological changes produced by the impact in the occlusal plane. Here, this impact is evaluated in TMJ articular disc and ar...Temporomandibular joint (TMJ) is sensitive to loading and mechanical stress that provokes morphological changes produced by the impact in the occlusal plane. Here, this impact is evaluated in TMJ articular disc and articular cartilage using an in vivo model of unilateral occlusal plane impact and by analysis of serial tissue sections stained with Hematoxylin-Eosin (H-E) or with Masson trichrome technique. Thus, six groups of 5 Wistar rats (200 - 250 g) are subjected to biomechanical dental stimulation by placing unilateral resin occlusal interference, or unilateral tooth wear made by upper left molars artificial mechanical devastation (1 control and 2 experimental groups for each treatment). Each treatment is evaluated two times at 1 and 15 days post-treatment. By H-E staining, control groups show chondrocytes arrangement as several cord cell groups in comparison with the experimental groups, which show an arrangement in one cord cell along of articular disc. However, this yields no significant difference (p < 0.05) in cell number between control and experimental groups. In contrast, in articular cartilage chondrocytes are random distributed along the superficial zone in control groups, while in experimental groups cell-free regions are observed in superficial zone. An image Blue hue analysis for trichrome stain is performed to quantify collagen;this shows a significant collagen decrease (p < 0.05) in almost all experimental groups compared with the controls. A degenerative process biomechanically induced by unilateral occlusal plane modification, causes cell and tissue changes on the TMJ structures that remain the degenerative changes observed in early osteoarthritis.展开更多
The effect of transforming growth factor β 1 (TGF β 1 ) gene transfection on the proliferation of bone marrow derived mesenchymal stem cells (MSC S ) and the mechanism was investigated to provide basis for accelerat...The effect of transforming growth factor β 1 (TGF β 1 ) gene transfection on the proliferation of bone marrow derived mesenchymal stem cells (MSC S ) and the mechanism was investigated to provide basis for accelerating articular cartilage repairing using molecular tissue engineering technology. TGF β 1 gene at different doses was transduced into the rat bone marrow derived MSCs to examine the effects of TGF β 1 gene transfection on MSCs DNA synthesis, cell cycle kinetics and the expression of proliferating cell nuclear antigen (PCNA). The results showed that 3 μl lipofectamine mediated 1 μg TGF β 1 gene transfection could effectively promote the proliferation of MSCs best; Under this condition (DNA/Lipofectamine=1μg/3μl), flow cytometry and immunohistochemical analyses revealed a significant increase in the 3 H incorporation, DNA content in S phase and the expression of PCNA. Transfection of gene encoding TGF β 1 could induce the cells at G0/G1 phase to S1 phase, modulate the replication of DNA through the enhancement of the PCNA expression, increase the content of DNA at S1 phase and promote the proliferation of MSCs. This new molecular tissue engineering approach could be of potential benefit to enhance the repair of damaged articular cartilage, especially those caused by degenerative joint diseases.展开更多
基金supported by grants from the AO Foundation (AOOCD Consortium TA1711481)Areas of Excellence Scheme from the University Grant Council of Hong Kong (Ao E/M-402/20)+1 种基金Theme-based Research Scheme from the University Grant Council of Hong Kong (T13-402/17-N)Key-Area Research and Development Program of Guangdong Province (2019B010941001)
文摘Articular cartilage(AC)is an avascular and flexible connective tissue located on the bone surface in the diarthrodial joints.AC defects are common in the knees of young and physically active individuals.Because of the lack of suitable tissue-engineered artificial matrices,current therapies for AC defects,espe-cially full-thickness AC defects and osteochondral interfaces,fail to replace or regenerate damaged carti-lage adequately.With rapid research and development advancements in AC tissue engineering(ACTE),functionalized hydrogels have emerged as promising cartilage matrix substitutes because of their favor-able biomechanical properties,water content,swelling ability,cytocompatibility,biodegradability,and lubricating behaviors.They can be rationally designed and conveniently tuned to simulate the extracel-lular matrix of cartilage.This article briefly introduces the composition,structure,and function of AC and its defects,followed by a comprehensive review of the exquisite(bio)design and(bio)fabrication of func-tionalized hydrogels for AC repair.Finally,we summarize the challenges encountered in functionalized hydrogel-based strategies for ACTE both in vivo and in vitro and the future directions for clinical translation.
基金National Natural Science Foundation of China,10872147Natural Science Foundation of Tianjin,09JCYBJC1400
文摘Articular cartilage is a layer of low-friction,load-bearing soft hydrated tissue covering bone-ends in diarthrosis,which plays an important role in spreading the load,reducing the joint contact stress,joint friction and wear during exercise.The vital mechanical function
基金supported by National Natural Science Foundation of China(Grant No.51975296).
文摘Cartilage regeneration and repair are considered clinical challenges since cartilage has limited capability for reconstruction.Although tissue-engineered materials have the ability to repair cartilage,they have weak mechanical characteristics and cannot resist long-term overload.On the other hand,surgery to replace the joint is frequently done to treat significant cartilage deterioration these days.However,the materials that are being used for replacement have high friction coefficients,lack shock absorption functions,and lack cushioning.Further research on natural articular cartilage structure and function may lead to bionic hydrogels,which have suitable physicochemical and biological characteristics(e.g.,tribological and mechanical properties and the ability to support loadbearing capability),but need improvements.Based on their tribological and mechanical characteristics,the current review highlights the most recent advancements of bionic hydrogels used for articular cartilage,highlighting both the field's recent progress and its potential for future research.For this reason,firstly,some important property improvement methods of bionic hydrogels are discussed and then,the recent findings of various research on the making of those bionic materials are provided and compared.It seems that by using some modifications such as product design,surface treatments,animal tests,controlling the isoelectric point of hydrogels,and computer simulation,the intended mechanical and tribological characteristics of natural articular cartilage may be attained by the bionic hydrogels.
基金support was given by the Grant-in Aid for Scientific Research(A)of Japan Society for the Promotion of Science(21H04535).
文摘The boundary lubrication mechanism at the articulating surface of natural synovial joints has been the subject of much discussion in tribology.In this study,to elucidate the lubricating function of the superficial area of articular cartilage and synovial fluid(SF),cartilage specimens were processed with four different treatments:gentle and severe washing with detergent,incubation in NaCl solution,and trypsin digestion to selectively remove certain constituents from the cartilage surface.Subsequently,the frictional characteristics were examined in phosphate-buffered saline(PBS)and SF against glass.Angularly reciprocating sliding tests with a spherical glass probe and square articular cartilage specimens were performed at low contact loads in the mN range to extract the frictional behavior in the superficial area of the cartilage specimens.Meanwhile,the cartilage surface was observed to confirm the effects of treatments on the morphology of the cartilage surface using a fluorescence microscope and water-immersion methods.The coefficient of friction(COF)of the prepared cartilage specimens was varied from 0.05 to over 0.3 in PBS.However,a certain group of cartilage specimens exhibited a low COF of less than 0.1 with limited variation.For the low COF group of specimens,all four treatments increased the COF in PBS to different extents,and fluorescence microscopy revealed that the integrity of the cartilage surface was deteriorated by treatments.This means that the intact cartilage surface had lubricating constituents to maintain low friction,and the removal of such constituents resulted in the loss of the intrinsic boundary lubricity of the cartilage surface.The variation in the COF of the cartilage specimens was suppressed in SF because it had a clear boundary lubrication effect on the cartilage surface.The lubricating effect of SF could be confirmed even after degenerative treatment.
基金supported by the Areas of Excellence Scheme from University Grant Council of Hong Kong(AoE/M-402/20)the AO Foundation,Switzerland(AO-OCD Consortium TA1711481)+1 种基金the Theme-based Research Scheme from University Grant Council of Hong Kong(T13-402/17-N)the Mainland-Hong Kong Joint Funding Scheme of Innovation and Technology Fund:ITF MHKJFS(MHP/011/20).
文摘As a highly specialized shock-absorbing connective tissue,articular cartilage(AC)has very limited self-repair capacity after traumatic injuries,posing a heavy socioeconomic burden.Common clinical therapies for small-to medium-size focal AC defects are well-developed endogenous repair and cell-based strategies,including microfracture,mosaicplasty,autologous chondrocyte implantation(ACI),and matrix-induced ACI(MACI).However,these treatments frequently result in mechanically inferior fibrocartilage,low cost-effectiveness,donor site morbidity,and short-term durability.It prompts an urgent need for innovative approaches to pattern a pro-regenerative microenvironment and yield hyaline-like cartilage with similar biomechanical and biochemical properties as healthy native AC.Acellular regenerative biomaterials can create a favorable local environment for AC repair without causing relevant regulatory and scientific concerns from cell-based treatments.A deeper understanding of the mechanism of endogenous cartilage healing is furthering the(bio)design and application of these scaffolds.Currently,the utilization of regenerative biomaterials to magnify the repairing effect of joint-resident endogenous stem/progenitor cells(ESPCs)presents an evolving improvement for cartilage repair.This review starts by briefly summarizing the current understanding of endogenous AC repair and the vital roles of ESPCs and chemoattractants for cartilage regeneration.Then several intrinsic hurdles for regenerative biomaterials-based AC repair are discussed.The recent advances in novel(bio)design and application regarding regenerative biomaterials with favorable biochemical cues to provide an instructive extracellular microenvironment and to guide the ESPCs(e.g.adhesion,migration,proliferation,differentiation,matrix production,and remodeling)for cartilage repair are summarized.Finally,this review outlines the future directions of engineering the next-generation regenerative biomaterials toward ultimate clinical translation.
基金supported by the National Key R&D Program of China (2019YFA0110600, China)Medical Research and Development Projects (BLB20J001, China)。
文摘Articular cartilage(AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis(OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intraarticular drug delivery systems(DDSs) in the future.
基金the Grant-in-Aid for Specially Promoted Research of Japan Society for the Promotion of Science(23000011).
文摘The extremely low friction and minimal wear in natural synovial joints appear to be established by effective lubrication mechanisms based on appropriate combination of articular cartilage and synovial fluid.The complex structure of cartilage composed of collagen and proteoglycan with high water content contributes to high load-carrying capacity as biphasic materials and the various constituents of synovial fluid play important roles in various lubrication mechanisms.However,the detailed differences in functions of the intact and damaged cartilage tissues,and the interaction or synergistic action of synovia constituents with articular cartilage have not yet been clarified.In this study,to examine the roles of synovia constituents and the importance of cartilage surface conditions,the changes in friction were observed in the reciprocating tests of intact and damaged articular cartilage specimens against glass plate lubricated with lubricants containing phospholipid,protein and/or hyaluronic acid as main constituents in synovial fluid.The effectiveness of lubricant constituents and the influence of cartilage surface conditions on friction are discussed.In addition,the protectiveness by synovia constituents for intact articular cartilage surfaces is evaluated.
基金supported by RGC Themebased Research Scheme of Hong Kong (T13-402/17N)National Natural Science Foundation of China (81802152)+5 种基金Natural Science Foundation of Guangdong Province (2019A1515012224)RGC Areas of Excellence (AoE/M-402/20)RGC Collaborative Research Fund (C4026-17WF)General Research Fund (14121918 and 14173917)the Innovation and Technology Commission Funding (ITS/208/18FX)Key-Area Research and Development Program of Guangdong Province (2019B010941001)。
文摘Osteoarthritis is the most prevalent chronic and debilitating joint disease,resulting in huge medical and socioeconomic burdens.Intra-articular administration of agents is clinically used for pain management.However,the effectiveness is inapparent caused by the rapid clearance of agents.To overcome this issue,nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents.Given the therapeutic programs are inseparable from pathological progress of osteoarthritis,an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders.In this review,we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release.Then,we review the interactions of nanoparticles with cartilage microenvironment and the rational design.Furthermore,we highlight advances in the therapeutic schemes according to the pathology signals.Finally,armed with an updated understanding of the pathological mechanisms,we place an emphasis on the development of“smart”bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals.We anticipate that the exploration of nanoparticles by balancing the efficacy,safety,and complexity will lay down a solid foundation tangible for clinical translation.
基金supported by the National Key Research and Development Program of China(No.2019YFA0110600)the National Natural Science Foundation of China(No.81772319).
文摘Due to the sophisticated hierarchical structure and limited reparability of articular cartilage(AC),the ideal regeneration of AC defects has been a major challenge in the field of regenerative medicine.As defects progress,they often extend from the cartilage layer to the subchondral bone and ultimately lead to osteoarthritis.Tissue engineering techniques bring new hope for AC regeneration.To meet the regenerative requirements of the heterogeneous and layered structure of native AC tissue,a substantial number of multilayered biomimetic scaffolds have been studied.Ideal multilayered scaffolds should generate zone-specific functional tissue similar to native AC tissue.This review focuses on the current status of multilayered scaffolds developed for AC defect repair,including design strategies based on the degree of defect severity and the zone-specific characteristics of AC tissue,the selection and composition of biomaterials,and techniques for design and manufacturing.The challenges and future perspectives of biomimetic multilayered scaffold strategies for AC regeneration are also discussed.
基金supported by National Natural Science Foundation of China(Grant No.31771065)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Grant No.ZYJC18002).
文摘As an emerging type of adult stem cell featuring non-invasive acquisition,urine-derived stem cells(USCs)have shown great potential for applications in tissue engineering and regenerative medicine.With a growing amount of research on the topic,the effectiveness of USCs in various disease models has been shown and the underlying mechanisms have also been explored,though many aspects still remain unclear.In this review,we aim to provide an up-to-date overview of the biological characteristics of USCs and their applications in skin,bone and articular cartilage repair.In addition to the identification procedure of USCs,we also summarize current knowledge of the underlying repair mechanisms and application modes of USCs.Potential concerns and perspectives have also been summarized.
基金This work was supported by the National Key R&D Program of China(2018YFC1105900)the National Natural Science Foundation of China(81772319)+2 种基金the Natural Science Foundation of Beijing Municipality(7204270)the Beijing JST Research Funding(ZR-201908)the Innovation Fund for Outstanding Doctoral Candidates of Peking University Health Science Center(71013Y2029).
文摘Tissue engineering provides a promising avenue for treating cartilage defects.However,great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration.In this study,decellularized cartilage extracellular matrix(ECM)and waterborne polyurethane(WPU)were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing(LDM)system,which combines rapid deposition manufacturing with phase separation techniques.The scaffolds successfully achieved hierarchical macro-microporous structures.After adding ECM,WPU scaffolds were markedly optimized in terms of porosity,hydrophilia and bioactive components.Moreover,the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution,adhesion,and proliferation than the WPU scaffolds.Most importantly,the WPU-ECM scaffold could facilitate the production of glycosaminoglycan(GAG)and collagen and the upregulation of cartilage-specific genes.These results indicated that the WPU-ECM scaffold with hierarchical macro-microporous structures could recreate a favorable microenvironment for cell adhesion,proliferation,differentiation,and ECM production.In vivo studies further revealed that the hierarchical macro-microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model.Six months after implantation,the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage.In conclusion,the hierarchical macro-microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.
基金This study was supported by the National Key R&D Program of China(2019YFA0110600).
文摘Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic differentiation potential,may be the main driver of cartilage repair.However,both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC.Tetrahedral framework nucleic acids(tFNAs),notable novel nanomaterials,are considered prospective biological regulators in biomedical engineering.Here,we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism.The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs.In addition,tFNAs,which were added to chondrogenic induction medium,were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3.In animal models,the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs.In conclusion,this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo,indicating that tFNAs may become a promising therapeutic for AC regeneration.
基金This work was funded by the State of Connecticut EstablishedInvestigator Stem Cell Grant (#11SCB08 to HD)Stem Cell Seed Grant (#13-SCA-UCHC-11 to RG).
文摘The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes.However,its role in articular cartilage remains obscure.Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes,the distribution of Twist1 proteins in normal versus OA human articular cartilage,and its role in modulating OA development in mice.High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features.The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro.In normal human articular cartilage,Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones.However,our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage.Moreover,Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples.To assess the role of Twist1 in OA pathophysiology,we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus.At 12 weeks post-surgery,micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice.Collectively,the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration.
文摘Temporomandibular joint (TMJ) is sensitive to loading and mechanical stress that provokes morphological changes produced by the impact in the occlusal plane. Here, this impact is evaluated in TMJ articular disc and articular cartilage using an in vivo model of unilateral occlusal plane impact and by analysis of serial tissue sections stained with Hematoxylin-Eosin (H-E) or with Masson trichrome technique. Thus, six groups of 5 Wistar rats (200 - 250 g) are subjected to biomechanical dental stimulation by placing unilateral resin occlusal interference, or unilateral tooth wear made by upper left molars artificial mechanical devastation (1 control and 2 experimental groups for each treatment). Each treatment is evaluated two times at 1 and 15 days post-treatment. By H-E staining, control groups show chondrocytes arrangement as several cord cell groups in comparison with the experimental groups, which show an arrangement in one cord cell along of articular disc. However, this yields no significant difference (p < 0.05) in cell number between control and experimental groups. In contrast, in articular cartilage chondrocytes are random distributed along the superficial zone in control groups, while in experimental groups cell-free regions are observed in superficial zone. An image Blue hue analysis for trichrome stain is performed to quantify collagen;this shows a significant collagen decrease (p < 0.05) in almost all experimental groups compared with the controls. A degenerative process biomechanically induced by unilateral occlusal plane modification, causes cell and tissue changes on the TMJ structures that remain the degenerative changes observed in early osteoarthritis.
基金This project was supported by a grant from NationalNatural Science Foundation of China (No. 30 170 2 70 )
文摘The effect of transforming growth factor β 1 (TGF β 1 ) gene transfection on the proliferation of bone marrow derived mesenchymal stem cells (MSC S ) and the mechanism was investigated to provide basis for accelerating articular cartilage repairing using molecular tissue engineering technology. TGF β 1 gene at different doses was transduced into the rat bone marrow derived MSCs to examine the effects of TGF β 1 gene transfection on MSCs DNA synthesis, cell cycle kinetics and the expression of proliferating cell nuclear antigen (PCNA). The results showed that 3 μl lipofectamine mediated 1 μg TGF β 1 gene transfection could effectively promote the proliferation of MSCs best; Under this condition (DNA/Lipofectamine=1μg/3μl), flow cytometry and immunohistochemical analyses revealed a significant increase in the 3 H incorporation, DNA content in S phase and the expression of PCNA. Transfection of gene encoding TGF β 1 could induce the cells at G0/G1 phase to S1 phase, modulate the replication of DNA through the enhancement of the PCNA expression, increase the content of DNA at S1 phase and promote the proliferation of MSCs. This new molecular tissue engineering approach could be of potential benefit to enhance the repair of damaged articular cartilage, especially those caused by degenerative joint diseases.
