BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown...BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown that decellularized extracellular matrix(ECM)derived from autologous,allogenic,or xenogeneic mesenchymal stromal cells(MSCs)can effectively restore osteochondral integrity.AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells(RMCs),a xenogeneic material from antler stem cells,is superior to the currently available treatments for osteochondral defects.METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70%confluence;50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition.Decellularized sheets of adipocyte-derived MSCs(aMSCs)and antlerogenic periosteal cells(another type of antler stem cells)were used as the controls.Three weeks after ascorbic acid stimulation,the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints.RESULTS The defects were successfully repaired by applying the ECM-sheets.The highest quality of repair was achieved in the RMC-ECM group both in vitro(including cell attachment and proliferation),and in vivo(including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues).Notably,the antler-stem-cell-derived ECM(xenogeneic)performed better than the aMSC-ECM(allogenic),while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells.CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell,particularly the active form(RMC-ECM),can achieve high quality repair/reconstruction of osteochondral defects,suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.展开更多
In clinical practice,repairing osteochondral defects(OCDs)is challenging because of the complex cartilage/subchondral bone structure and intricate immunological microenvironment.Here,we identify the crucial role of ad...In clinical practice,repairing osteochondral defects(OCDs)is challenging because of the complex cartilage/subchondral bone structure and intricate immunological microenvironment.Here,we identify the crucial role of adaptive immunity dysfunction by revealing that an increase of T helper 17(Th17)cells exacerbated osteochondral tissue degradation via its pro-inflammatory cytokine interleukin-17(IL-17)in the early-stage OCDs.Next,we leveraged this adaptive immunity mechanism and combined it with regenerative signals to develop a multifunctional hydrogel system capable of simultaneously tackling immune dysfunction and regenerative deficiency.Rapid IL-4 release from the methacrylated hyaluronic acid(HAMA)hydrogel exerts a potent immunomodulatory effect by inhibiting the differentiation and function of Th17 cells.Moreover,transforming growth factor-beta1 anchored on methacrylated hyaluronic acid and heparin(HAMA@HepMA)microparticles provides sustained regenerative signals,which synergistically transform the pro-inflammatory microenvironment into a pro-regenerative niche for enhanced OCDs healing.Our study suggests that targeting specific immune pathways can significantly enhance the efficacy of regenerative strategies,paving the way for innovative treatments in orthopedic medicine.展开更多
Osteochondral defects are caused by injury to both the articular cartilage and subchondral bone within skeletal joints. They can lead to irreversible joint damage and increase the risk of progression to osteoarthritis...Osteochondral defects are caused by injury to both the articular cartilage and subchondral bone within skeletal joints. They can lead to irreversible joint damage and increase the risk of progression to osteoarthritis. Current treatments for osteochondral injuries are not curative and only target symptoms, highlighting the need for a tissue engineering solution. Scaffold-based approaches can be used to assist osteochondral tissue regeneration, where biomaterials tailored to the properties of cartilage and bone are used to restore the defect and minimise the risk of further joint degeneration. This review captures original research studies published since 2015, on multiphasic scaffolds used to treat osteochondral defects in animal models. These studies used an extensive range of biomaterials for scaffold fabrication, consisting mainly of natural and synthetic polymers. Different methods were used to create multiphasic scaffold designs, including by integrating or fabricating multiple layers, creating gradients, or through the addition of factors such as minerals, growth factors, and cells. The studies used a variety of animals to model osteochondral defects, where rabbits were the most commonly chosen and the vast majority of studies reported small rather than large animal models. The few available clinical studies reporting cell-free scaffolds have shown promising early-stage results in osteochondral repair, but long-term follow-up is necessary to demonstrate consistency in defect restoration. Overall, preclinical studies of multiphasic scaffolds show favourable results in simultaneously regenerating cartilage and bone in animal models of osteochondral defects, suggesting that biomaterials-based tissue engineering strategies may be a promising solution.展开更多
The bidirectional relationship between osteochondral defects(OCD)and osteoarthritis(OA),with each condition exacerbating the other,makes OCD regeneration in the presence of OA challenging.Type II collagen(Col2)is impo...The bidirectional relationship between osteochondral defects(OCD)and osteoarthritis(OA),with each condition exacerbating the other,makes OCD regeneration in the presence of OA challenging.Type II collagen(Col2)is important in OCD regeneration and the management of OA,but its potential applications in cartilage tissue engineering are significantly limited.This study investigated the regeneration capacity of Col2 scaffolds in critical-sized OCDs under surgically induced OA conditions and explored the underlying mechanisms that promoted OCD regeneration.Furthermore,the repair potential of Col2 scaffolds was validated in over critical-sized OCD models.After 90 days or 150 days since scaffold implantation,complete healing was observed histologically in critical-sized OCD,evidenced by the excellent integration with surrounding native tissues.The newly formed tissue biochemically resembled adjacent natural tissue and exhibited comparable biomechanical properties.The regenerated OA tissue demonstrated lower expression of genes associated with cartilage degradation than native OA tissue but comparable expression of genes related to osteochondral anabolism compared with normal tissue.Additionally,transcriptome and proteome analysis revealed the hindrance of TGF-β-Smad1/5/8 in regenerated OA tissue.In conclusion,the engrafting of Col2 scaffolds led to the successful regeneration of critical-sized OCDs under surgically induced OA conditions by inhibiting the TGF-β-Smad1/5/8 signaling pathway.展开更多
Due to tissue lineage variances and the anisotropic physiological character-istics,regenerating complex osteochondral tissues(cartilage and subchondral bone)remains a great challenge,which is primarily due to the dist...Due to tissue lineage variances and the anisotropic physiological character-istics,regenerating complex osteochondral tissues(cartilage and subchondral bone)remains a great challenge,which is primarily due to the distinct requirements for cartilage and subchondral bone regeneration.For cartilage regeneration,a significant amount of newly generated chondrocytes is required while maintaining their phenotype.Conversely,bone regeneration necessitates inducing stem cells to differentiate into osteoblasts.Additionally,the construction of the osteochondral interface is crucial.In this study,we fabricated a biphasic multicellular bioprinted scaffold mimicking natural osteochondral tissue employing three-dimensional(3D)bioprinting technol-ogy.Briefly,gelatin-methacryloyl(GelMA)loaded with articular chondrocytes and bone marrow mesenchymal stem cells(ACs/BMSCs),serving as the cartilage layer,preserved the phenotype of ACs and promoted the differentia-tion of BMSCs into chondrocytes through the interaction between ACs and BMSCs,thereby facilitating cartilage regeneration.GelMA/strontium-substituted xonotlite(Sr-CSH)loaded with BMSCs,serving as the subchondral bone layer,regulated the differentiation of BMSCs into osteoblasts and enhanced the secretion of cartilage matrix by ACs in the cartilage layer through the slow release of bioactive ions from Sr-CSH.Additionally,GelMA,serving as the matrix material,contributed to the reconstruction of the osteochondral interface.Ultimately,this biphasic multicellular bioprinted scaffold demonstrated satisfactory simultaneous regeneration of osteochondral defects.In this study,a promising strategy for the application of 3D bioprinting technology in complex tissue regeneration was proposed.展开更多
Osteochondral tissue is a highly specialized and complex tissue composed of articular cartilage and subchondral bone that are separated by a calcified cartilage interface.Multilayered or gradient scaffolds,often in co...Osteochondral tissue is a highly specialized and complex tissue composed of articular cartilage and subchondral bone that are separated by a calcified cartilage interface.Multilayered or gradient scaffolds,often in conjunction with stem cells and growth factors,have been developed to mimic the respective layers for osteochondral defect repair.In this study,we designed a hyaline cartilage-hypertrophic cartilage bilayer graft(RGD/RGDW)with chondrocytes.Previously,we demonstrated that RGD peptide-modified chondroitin sulfate cryogel(RGD group)is chondro-conductive and capable of hyaline cartilage formation.Here,we incorporated whitlockite(WH),a Mg^(2+)-containing calcium phosphate,into RGD cryogel(RGDW group)to induce chondrocyte hypertrophy and form collagen X-rich hypertrophic cartilage.This is the first study to use WH to produce hypertrophic cartilage.Chondrocytes-laden RGDW cryogel exhibited significantly upregulated expression of hypertrophy markers in vitro and formed ectopic hypertrophic cartilage in vivo,which mineralized into calcified cartilage in bone microenvironment.Subsequently,RGD cryogel and RGDW cryogel were combined into bilayer(RGD/RGDW group)and implanted into rabbit osteochondral defect,where RGD layer supports hyaline cartilage regeneration and bioceramic-containing RGDW layer promotes calcified cartilage formation.While the RGD group(monolayer)formed hyaline-like neotissue that extends into the subchondral bone,the RGD/RGDW group(bilayer)regenerated hyaline cartilage tissue confined to its respective layer and promoted osseointegration for integrative defect repair.展开更多
Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair ...Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro . Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo . These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD.展开更多
BACKGROUND Stress radiographs have demonstrated superior efficacy in the evaluation of ankle instability.AIM To determine if there is a degree of instability evidenced by stress radiographs that is associated with pat...BACKGROUND Stress radiographs have demonstrated superior efficacy in the evaluation of ankle instability.AIM To determine if there is a degree of instability evidenced by stress radiographs that is associated with pathology concomitant with ankle ligamentous instability.METHODS A retrospective review of 87 consecutive patients aged 18-74 who had stress radiographs performed at a single institution between 2014 and 2020 was performed.These manual radiographic stress views were then correlated with magnetic resonance imaging and operative findings.RESULTS A statistically significant association was determined for the mean and median stress radiographic values and the presence of peroneal pathology(P=0.008 for tendonitis and P=0.020 for peroneal tendon tears).A significant inverse relationship was found between the presence of an osteochondral defect and increasing degrees of instability(P=0.043).CONCLUSION Although valuable in the clinical evaluation of ankle instability,stress radiographs are not an independent predictor of conditions associated with ankle in-stability.展开更多
Osteochondral defects(OCDs)pose a significant clinical challenge due to their limited self-repair capacity.The complex structure and distinct biological properties of articular cartilage and subchondral bone further c...Osteochondral defects(OCDs)pose a significant clinical challenge due to their limited self-repair capacity.The complex structure and distinct biological properties of articular cartilage and subchondral bone further complicate regeneration.In this study,we introduce a novel osteochondral regeneration strategy leveraging single-cell RNA sequencing(ScRNA-seq)to identify a unique population of skeletal stem cells(SSCs)derived from the infrapatellar fat pad(IFP).These SSCs exhibit high differentiation potential and robust chondrogenic capacity.Using flow cytometry,we isolated SSCs and extracted their exosomes(Exos),which were subsequently combined with hydrogels to develop a novel bioink.Employing 3D printing technology,we fabricated an innovative hydrogel scaffold designed to adapted to the defective areas enhance OCD repair.In a rat OCD model,the 3D-printed hydrogel scaffold loaded with SSC-derived Exos(SSC-Exos)demonstrated exceptional osteo-chondral regeneration,facilitating synchronous repair of both cartilage and subchondral bone.In vitro experi-ments revealed that SSC-Exos significantly enhanced the chondrogenic differentiation of bone marrow mesenchymal stem cells(BMSCs).Importantly,SSC-Exos derived from the IFP exhibited superior cartilage regeneration capabilities compared to Exos from adipose-derived mesenchymal stem cells(ADSC-Exos).Highthroughput sequencing further elucidated the critical role of the microRNA-214-3p(miR-214-3p)/jagged ca-nonical Notch ligand 2(JAG2)axis in SSC-Exos-mediated cartilage regeneration.Collectively,the 3D-printed hydrogel scaffold loaded with SSC-Exos represents an innovative and effective strategy for OCD repair,with potential for clinical translation.展开更多
Poly(lactide-co-glycolide)-bilayered scaffolds with the same porosity or different ones on the two layers were fabricated,and the porosity effect on in vivo repairing of the osteochondral defect was examined in a comp...Poly(lactide-co-glycolide)-bilayered scaffolds with the same porosity or different ones on the two layers were fabricated,and the porosity effect on in vivo repairing of the osteochondral defect was examined in a comparative way for the first time.The constructs of scaffolds and bone marrow-derived mesenchymal stem cells were implanted into pre-created osteochondral defects in the femoral condyle of New Zealand white rabbits.After 12 weeks,all experimental groups exhibited good cartilage repairing according to macroscopic appearance,cross-section view,haematoxylin and eosin staining,toluidine blue staining,immunohistochemical staining and real-time polymerase chain reaction of characteristic genes.The group of 92%porosity in the cartilage layer and 77%porosity in the bone layer resulted in the best efficacy,which was understood by more biomechanical mimicking of the natural cartilage and subchondral bone.This study illustrates unambiguously that cartilage tissue engineering allows for a wide range of scaffold porosity,yet some porosity group is optimal.It is also revealed that the biomechanical matching with the natural composite tissue should be taken into consideration in the design of practical biomaterials,which is especially important for porosities of a multi-compartment scaffold concerning connected tissues.展开更多
Clinical therapeutics for the regeneration of osteochondral defects(OCD)in the early stages of osteoarthritis remain an enormous challenge in orthopaedics.For in-depth studies of tissue engineering and regenerative me...Clinical therapeutics for the regeneration of osteochondral defects(OCD)in the early stages of osteoarthritis remain an enormous challenge in orthopaedics.For in-depth studies of tissue engineering and regenerative medicine in terms of OCD treatment,the utility of an optimal OCD animal model is crucial for assessing the effects of implanted biomaterials on the repair of damaged osteochondral tissues.Currently,the most frequently used in vivo animal models for OCD regeneration include mice,rats,rabbits,dogs,pigs,goats,sheep,horses and nonhuman primates.However,there is no single“gold standard”animal model to accurately recapitulate human disease in all aspects,thus understanding the benefits and limitations of each animal model is critical for selecting the most suitable one.In this review,we aim to elaborate the complex pathological changes in osteoarthritic joints and to summarise the advantages and limitations of OCD animal models utilised for biomaterial testing along with the methodology of outcome assessment.Furthermore,we review the surgical procedures of OCD creation in different species,and the novel biomaterials that promote OCD regeneration.Above all,it provides a significant reference for selection of an appropriate animal model for use in preclinical in vivo studies of biomaterial-assisted osteochondral regeneration in osteoarthritic joints.展开更多
The regeneration of critical-sized osteochondral defects remains a significant challenge due to the limited self-healing capacity of cartilage.Traditional approaches,such as autologous chondrocyte implantation(ACI)and...The regeneration of critical-sized osteochondral defects remains a significant challenge due to the limited self-healing capacity of cartilage.Traditional approaches,such as autologous chondrocyte implantation(ACI)and matrix-induced autologous chondrocyte implantation(MACI),have shown promise but are limited by issues like insufficient cell availability,dedifferentiation of chondrocytes during expansion,and the formation of fibrocartilage rather than functional hyaline cartilage.This study presents a promising approach utilizing transcript-activated matrices(TAMs)with mRNA to enhance the therapeutic potential of bone marrow mesenchymal stem cells(BMSCs)in situ.Chemically modified mRNA(cmRNA)encoding transforming growth factor β3(TGF-β3)was encapsulated in a collagen hydrogel to provide localized,sustained delivery of chondrogenic signals.In a rat model of critical-sized osteochondral defects,this strategy significantly promoted cartilage regeneration,achieving structural and molecular restoration within six weeks.Histological and biochemical analyses revealed robust chondrogenesis,enhanced extracellular matrix deposition,and superior mechanical properties.Moreover,TAM therapy maintained subchondral bone integrity This work highlights the transformative potential of mRNA-activated matrices as a platform technology that not only addresses key limitations of existing cartilage repair strategies but also provides a biomimetic microenvironment that guides stem cell differentiation and tissue regeneration.展开更多
基金National Natural Science Foundation of China,No.U20A20403This study was conducted in accordance with the Animal Ethics Committee of the Institute of Antler Science and Product Technology,Changchun Sci-Tech University(AEC No:CKARI202309).
文摘BACKGROUND Cartilage defects are some of the most common causes of arthritis.Cartilage lesions caused by inflammation,trauma or degenerative disease normally result in osteochondral defects.Previous studies have shown that decellularized extracellular matrix(ECM)derived from autologous,allogenic,or xenogeneic mesenchymal stromal cells(MSCs)can effectively restore osteochondral integrity.AIM To determine whether the decellularized ECM of antler reserve mesenchymal cells(RMCs),a xenogeneic material from antler stem cells,is superior to the currently available treatments for osteochondral defects.METHODS We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70%confluence;50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition.Decellularized sheets of adipocyte-derived MSCs(aMSCs)and antlerogenic periosteal cells(another type of antler stem cells)were used as the controls.Three weeks after ascorbic acid stimulation,the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints.RESULTS The defects were successfully repaired by applying the ECM-sheets.The highest quality of repair was achieved in the RMC-ECM group both in vitro(including cell attachment and proliferation),and in vivo(including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues).Notably,the antler-stem-cell-derived ECM(xenogeneic)performed better than the aMSC-ECM(allogenic),while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells.CONCLUSION Decellularized xenogeneic ECM derived from the antler stem cell,particularly the active form(RMC-ECM),can achieve high quality repair/reconstruction of osteochondral defects,suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.
基金supported by National Natural Science Foundation of China(82071567,82101646,82102598,82172459 and 82102597)Natural Science Foundation of Zhejiang Province(LQ21H060008).
文摘In clinical practice,repairing osteochondral defects(OCDs)is challenging because of the complex cartilage/subchondral bone structure and intricate immunological microenvironment.Here,we identify the crucial role of adaptive immunity dysfunction by revealing that an increase of T helper 17(Th17)cells exacerbated osteochondral tissue degradation via its pro-inflammatory cytokine interleukin-17(IL-17)in the early-stage OCDs.Next,we leveraged this adaptive immunity mechanism and combined it with regenerative signals to develop a multifunctional hydrogel system capable of simultaneously tackling immune dysfunction and regenerative deficiency.Rapid IL-4 release from the methacrylated hyaluronic acid(HAMA)hydrogel exerts a potent immunomodulatory effect by inhibiting the differentiation and function of Th17 cells.Moreover,transforming growth factor-beta1 anchored on methacrylated hyaluronic acid and heparin(HAMA@HepMA)microparticles provides sustained regenerative signals,which synergistically transform the pro-inflammatory microenvironment into a pro-regenerative niche for enhanced OCDs healing.Our study suggests that targeting specific immune pathways can significantly enhance the efficacy of regenerative strategies,paving the way for innovative treatments in orthopedic medicine.
基金support from the National Health and Medical Research Council(NHMRC)of Australia(GNT1120249).
文摘Osteochondral defects are caused by injury to both the articular cartilage and subchondral bone within skeletal joints. They can lead to irreversible joint damage and increase the risk of progression to osteoarthritis. Current treatments for osteochondral injuries are not curative and only target symptoms, highlighting the need for a tissue engineering solution. Scaffold-based approaches can be used to assist osteochondral tissue regeneration, where biomaterials tailored to the properties of cartilage and bone are used to restore the defect and minimise the risk of further joint degeneration. This review captures original research studies published since 2015, on multiphasic scaffolds used to treat osteochondral defects in animal models. These studies used an extensive range of biomaterials for scaffold fabrication, consisting mainly of natural and synthetic polymers. Different methods were used to create multiphasic scaffold designs, including by integrating or fabricating multiple layers, creating gradients, or through the addition of factors such as minerals, growth factors, and cells. The studies used a variety of animals to model osteochondral defects, where rabbits were the most commonly chosen and the vast majority of studies reported small rather than large animal models. The few available clinical studies reporting cell-free scaffolds have shown promising early-stage results in osteochondral repair, but long-term follow-up is necessary to demonstrate consistency in defect restoration. Overall, preclinical studies of multiphasic scaffolds show favourable results in simultaneously regenerating cartilage and bone in animal models of osteochondral defects, suggesting that biomaterials-based tissue engineering strategies may be a promising solution.
基金supported by General Research Fund,Research Grants Council,University Grants Committee,Hong Kong SAR(CityU 11205520 to Dong-An Wang)National Natural Science Foundation of China(NSFC51973180 to Dong-An Wang)+2 种基金Grant from Karolinska Institutet Ming Wai Lau Centre of Reparative Medicine (to Dong-An Wang)and, Grants from City University of Hong Kong (7020028, 7005949, 9231412, 9231486 to Dong-An Wang)Young scientists lifting project of Jiangsu Province, China (TJ-2022-072 to Hang Yao).
文摘The bidirectional relationship between osteochondral defects(OCD)and osteoarthritis(OA),with each condition exacerbating the other,makes OCD regeneration in the presence of OA challenging.Type II collagen(Col2)is important in OCD regeneration and the management of OA,but its potential applications in cartilage tissue engineering are significantly limited.This study investigated the regeneration capacity of Col2 scaffolds in critical-sized OCDs under surgically induced OA conditions and explored the underlying mechanisms that promoted OCD regeneration.Furthermore,the repair potential of Col2 scaffolds was validated in over critical-sized OCD models.After 90 days or 150 days since scaffold implantation,complete healing was observed histologically in critical-sized OCD,evidenced by the excellent integration with surrounding native tissues.The newly formed tissue biochemically resembled adjacent natural tissue and exhibited comparable biomechanical properties.The regenerated OA tissue demonstrated lower expression of genes associated with cartilage degradation than native OA tissue but comparable expression of genes related to osteochondral anabolism compared with normal tissue.Additionally,transcriptome and proteome analysis revealed the hindrance of TGF-β-Smad1/5/8 in regenerated OA tissue.In conclusion,the engrafting of Col2 scaffolds led to the successful regeneration of critical-sized OCDs under surgically induced OA conditions by inhibiting the TGF-β-Smad1/5/8 signaling pathway.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072396,32271379CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:CIFMS,2019-I2M-5-037+3 种基金Shanghai's Top Priority Research Center,Grant/Award Number:2022ZZ01017Interdisciplinary Program of Shanghai Jiao Tong University,Grant/Award Number:YG2021ZD12Science and Technology Commission of Shanghai Municipality,Grant/Award Number:21490711700Science and Technology Project of Xuzhou Health Commission,Grant/Award Number:XWKYHT20230077。
文摘Due to tissue lineage variances and the anisotropic physiological character-istics,regenerating complex osteochondral tissues(cartilage and subchondral bone)remains a great challenge,which is primarily due to the distinct requirements for cartilage and subchondral bone regeneration.For cartilage regeneration,a significant amount of newly generated chondrocytes is required while maintaining their phenotype.Conversely,bone regeneration necessitates inducing stem cells to differentiate into osteoblasts.Additionally,the construction of the osteochondral interface is crucial.In this study,we fabricated a biphasic multicellular bioprinted scaffold mimicking natural osteochondral tissue employing three-dimensional(3D)bioprinting technol-ogy.Briefly,gelatin-methacryloyl(GelMA)loaded with articular chondrocytes and bone marrow mesenchymal stem cells(ACs/BMSCs),serving as the cartilage layer,preserved the phenotype of ACs and promoted the differentia-tion of BMSCs into chondrocytes through the interaction between ACs and BMSCs,thereby facilitating cartilage regeneration.GelMA/strontium-substituted xonotlite(Sr-CSH)loaded with BMSCs,serving as the subchondral bone layer,regulated the differentiation of BMSCs into osteoblasts and enhanced the secretion of cartilage matrix by ACs in the cartilage layer through the slow release of bioactive ions from Sr-CSH.Additionally,GelMA,serving as the matrix material,contributed to the reconstruction of the osteochondral interface.Ultimately,this biphasic multicellular bioprinted scaffold demonstrated satisfactory simultaneous regeneration of osteochondral defects.In this study,a promising strategy for the application of 3D bioprinting technology in complex tissue regeneration was proposed.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(NRF-2021K1A3A1A57086407,NRF-2021R1A2C2008821,NRF-2022R1I1A1A01071991)Arun Kumar Rajendran was supported by the National Research Foundation of Korea(NRF)grant Brain Pool program funded by the Ministry of Science and ICT through the National Research Foundation of Korea(2020H1D3A1A04081286)The Institute of Engineering Research at Seoul National University provided research facilities,and additional support came from the SNU Engineering-Medicine Collaboration grant.
文摘Osteochondral tissue is a highly specialized and complex tissue composed of articular cartilage and subchondral bone that are separated by a calcified cartilage interface.Multilayered or gradient scaffolds,often in conjunction with stem cells and growth factors,have been developed to mimic the respective layers for osteochondral defect repair.In this study,we designed a hyaline cartilage-hypertrophic cartilage bilayer graft(RGD/RGDW)with chondrocytes.Previously,we demonstrated that RGD peptide-modified chondroitin sulfate cryogel(RGD group)is chondro-conductive and capable of hyaline cartilage formation.Here,we incorporated whitlockite(WH),a Mg^(2+)-containing calcium phosphate,into RGD cryogel(RGDW group)to induce chondrocyte hypertrophy and form collagen X-rich hypertrophic cartilage.This is the first study to use WH to produce hypertrophic cartilage.Chondrocytes-laden RGDW cryogel exhibited significantly upregulated expression of hypertrophy markers in vitro and formed ectopic hypertrophic cartilage in vivo,which mineralized into calcified cartilage in bone microenvironment.Subsequently,RGD cryogel and RGDW cryogel were combined into bilayer(RGD/RGDW group)and implanted into rabbit osteochondral defect,where RGD layer supports hyaline cartilage regeneration and bioceramic-containing RGDW layer promotes calcified cartilage formation.While the RGD group(monolayer)formed hyaline-like neotissue that extends into the subchondral bone,the RGD/RGDW group(bilayer)regenerated hyaline cartilage tissue confined to its respective layer and promoted osseointegration for integrative defect repair.
基金supported by the collaborative project from the National Key R&D Program of China and Innovation and Tech-nology Fund Mainland-Hong Kong Joint Funding Scheme(Nos.2021YFE0202300 and MHP/011/20)the Sino-Swiss collaborative project from the Ministry of Science and Technology and the Swiss National Science Foundation under the SSSTC program(Grant Nos.2015DFG32200 and 156362)+2 种基金Shenzhen Collaborative Innovation Plan-International Cooperation Project(Grant No.GJHZ20190821160803823)Development and Reform Commission of Shenzhen Municipality(2019)(No.561)Shenzhen Double Chain Project for Innovation and Development Industry supported by Bureau of Industry and Information Technology of Shenzhen(No.201908141541).
文摘Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro . Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo . These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD.
文摘BACKGROUND Stress radiographs have demonstrated superior efficacy in the evaluation of ankle instability.AIM To determine if there is a degree of instability evidenced by stress radiographs that is associated with pathology concomitant with ankle ligamentous instability.METHODS A retrospective review of 87 consecutive patients aged 18-74 who had stress radiographs performed at a single institution between 2014 and 2020 was performed.These manual radiographic stress views were then correlated with magnetic resonance imaging and operative findings.RESULTS A statistically significant association was determined for the mean and median stress radiographic values and the presence of peroneal pathology(P=0.008 for tendonitis and P=0.020 for peroneal tendon tears).A significant inverse relationship was found between the presence of an osteochondral defect and increasing degrees of instability(P=0.043).CONCLUSION Although valuable in the clinical evaluation of ankle instability,stress radiographs are not an independent predictor of conditions associated with ankle in-stability.
基金supported by the Key Program of the National Natural Science Foundation of China.(NO.82230085,NO.82272572 and NO.82272495)the Natural Science Foundation of Hunan Province.(NO.2022JJ30984).
文摘Osteochondral defects(OCDs)pose a significant clinical challenge due to their limited self-repair capacity.The complex structure and distinct biological properties of articular cartilage and subchondral bone further complicate regeneration.In this study,we introduce a novel osteochondral regeneration strategy leveraging single-cell RNA sequencing(ScRNA-seq)to identify a unique population of skeletal stem cells(SSCs)derived from the infrapatellar fat pad(IFP).These SSCs exhibit high differentiation potential and robust chondrogenic capacity.Using flow cytometry,we isolated SSCs and extracted their exosomes(Exos),which were subsequently combined with hydrogels to develop a novel bioink.Employing 3D printing technology,we fabricated an innovative hydrogel scaffold designed to adapted to the defective areas enhance OCD repair.In a rat OCD model,the 3D-printed hydrogel scaffold loaded with SSC-derived Exos(SSC-Exos)demonstrated exceptional osteo-chondral regeneration,facilitating synchronous repair of both cartilage and subchondral bone.In vitro experi-ments revealed that SSC-Exos significantly enhanced the chondrogenic differentiation of bone marrow mesenchymal stem cells(BMSCs).Importantly,SSC-Exos derived from the IFP exhibited superior cartilage regeneration capabilities compared to Exos from adipose-derived mesenchymal stem cells(ADSC-Exos).Highthroughput sequencing further elucidated the critical role of the microRNA-214-3p(miR-214-3p)/jagged ca-nonical Notch ligand 2(JAG2)axis in SSC-Exos-mediated cartilage regeneration.Collectively,the 3D-printed hydrogel scaffold loaded with SSC-Exos represents an innovative and effective strategy for OCD repair,with potential for clinical translation.
基金This work was supported by Chinese Ministry of Science and Technology(973 Programs No.2009CB930000 and No.2011CB606203)National Science Foundation of China(Grant No.21034002,31170925,and 51273046)+1 种基金Science and Technology Developing Foundation of Shanghai(Grant No.13XD1401000)Shanghai International Science and Technology Partnership Program(No.11540702700).
文摘Poly(lactide-co-glycolide)-bilayered scaffolds with the same porosity or different ones on the two layers were fabricated,and the porosity effect on in vivo repairing of the osteochondral defect was examined in a comparative way for the first time.The constructs of scaffolds and bone marrow-derived mesenchymal stem cells were implanted into pre-created osteochondral defects in the femoral condyle of New Zealand white rabbits.After 12 weeks,all experimental groups exhibited good cartilage repairing according to macroscopic appearance,cross-section view,haematoxylin and eosin staining,toluidine blue staining,immunohistochemical staining and real-time polymerase chain reaction of characteristic genes.The group of 92%porosity in the cartilage layer and 77%porosity in the bone layer resulted in the best efficacy,which was understood by more biomechanical mimicking of the natural cartilage and subchondral bone.This study illustrates unambiguously that cartilage tissue engineering allows for a wide range of scaffold porosity,yet some porosity group is optimal.It is also revealed that the biomechanical matching with the natural composite tissue should be taken into consideration in the design of practical biomaterials,which is especially important for porosities of a multi-compartment scaffold concerning connected tissues.
基金This work was supported by the National Key R&D Program of China(No.2021YFA1102600)the National Natural Science Foundation of China(No.82002315).
文摘Clinical therapeutics for the regeneration of osteochondral defects(OCD)in the early stages of osteoarthritis remain an enormous challenge in orthopaedics.For in-depth studies of tissue engineering and regenerative medicine in terms of OCD treatment,the utility of an optimal OCD animal model is crucial for assessing the effects of implanted biomaterials on the repair of damaged osteochondral tissues.Currently,the most frequently used in vivo animal models for OCD regeneration include mice,rats,rabbits,dogs,pigs,goats,sheep,horses and nonhuman primates.However,there is no single“gold standard”animal model to accurately recapitulate human disease in all aspects,thus understanding the benefits and limitations of each animal model is critical for selecting the most suitable one.In this review,we aim to elaborate the complex pathological changes in osteoarthritic joints and to summarise the advantages and limitations of OCD animal models utilised for biomaterial testing along with the methodology of outcome assessment.Furthermore,we review the surgical procedures of OCD creation in different species,and the novel biomaterials that promote OCD regeneration.Above all,it provides a significant reference for selection of an appropriate animal model for use in preclinical in vivo studies of biomaterial-assisted osteochondral regeneration in osteoarthritic joints.
基金the National Natural Science Foundation of China(82002355)for financial supportthe Shenzhen Science and Technology Major Project(KJZD20230923114302006)+3 种基金Shenzhen Science and Technology Program(ZDSYS20220606100606013)the National Natural Science Foundation of China(82372403)for financial supportthe National Natural Science Foundation of China(no.32071341)for financial supportSIAT-GeneHeal Medicine mRNA Regenerative Medicine Laboratory(E1Z124)for financial support.
文摘The regeneration of critical-sized osteochondral defects remains a significant challenge due to the limited self-healing capacity of cartilage.Traditional approaches,such as autologous chondrocyte implantation(ACI)and matrix-induced autologous chondrocyte implantation(MACI),have shown promise but are limited by issues like insufficient cell availability,dedifferentiation of chondrocytes during expansion,and the formation of fibrocartilage rather than functional hyaline cartilage.This study presents a promising approach utilizing transcript-activated matrices(TAMs)with mRNA to enhance the therapeutic potential of bone marrow mesenchymal stem cells(BMSCs)in situ.Chemically modified mRNA(cmRNA)encoding transforming growth factor β3(TGF-β3)was encapsulated in a collagen hydrogel to provide localized,sustained delivery of chondrogenic signals.In a rat model of critical-sized osteochondral defects,this strategy significantly promoted cartilage regeneration,achieving structural and molecular restoration within six weeks.Histological and biochemical analyses revealed robust chondrogenesis,enhanced extracellular matrix deposition,and superior mechanical properties.Moreover,TAM therapy maintained subchondral bone integrity This work highlights the transformative potential of mRNA-activated matrices as a platform technology that not only addresses key limitations of existing cartilage repair strategies but also provides a biomimetic microenvironment that guides stem cell differentiation and tissue regeneration.
