Articular cartilage damage caused by trauma or degenerative pathologies such as osteoarthritis can result in significant pain,mobility issues,and disability.Current surgical treatments have a limited capacity for effi...Articular cartilage damage caused by trauma or degenerative pathologies such as osteoarthritis can result in significant pain,mobility issues,and disability.Current surgical treatments have a limited capacity for efficacious cartilage repair,and long-term patient outcomes are not satisfying.Three-dimensional bioprinting has been used to fabricate biochemical and biophysical environments that aim to recapitulate the native microenvironment and promote tissue regeneration.However,conventional in vitro bioprinting has limitations due to the challenges associated with the fabrication and implantation of bioprinted constructs and their integration with the native cartilage tissue.In situ bioprinting is a novel strategy to directly deliver bioinks to the desired anatomical site and has the potential to overcome major shortcomings associated with conventional bioprinting.In this review,we focus on the new frontier of robotic-assisted in situ bioprinting surgical systems for cartilage regeneration.We outline existing clinical approaches and the utilization of robotic-assisted surgical systems.Handheld and robotic-assisted in situ bioprinting techniques including minimally invasive and non-invasive approaches are defined and presented.Finally,we discuss the challenges and potential future perspectives of in situ bioprinting for cartilage applications.展开更多
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
Due to the limited self healing capacity of human cartilage,the repair of defects gives rise to a challenging clinical problem.Cartilage tissue engineering provides a new method to solve cartilage repair.However,the s...Due to the limited self healing capacity of human cartilage,the repair of defects gives rise to a challenging clinical problem.Cartilage tissue engineering provides a new method to solve cartilage repair.However,the search for a suitable biological vector material has long been the focus of research interest in this regard.In this paper,the present situation of cartilage tissue engineering vector materials is reviewed.展开更多
Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage.Hydrogel is widely used because it could provide rapid defect filling and proper structure supp...Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage.Hydrogel is widely used because it could provide rapid defect filling and proper structure support,and is biocompatible for cell aggregation and matrix deposition.Efforts have been made to seek suitable scaffolds for cartilage tissue engineering.Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties.Gelation time,swelling ratio,biodegradability and biocompatibility of the hydrogels were systematically characterized,and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair.Furthermore,the new hydrogel design introduces a pre-gel state before photo-crosslinking,where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition.This granted multiple administration routes to the hydrogels,which brings hydrogels the ability to adapt to complex clinical situations.Pulsed electromagnetic fields(PEMF)have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials.PEMF treatment offers a better clinical outcome with fewer,if any,side effects,and wildly used in musculoskeletal tissue repair.Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering.In this study,the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model,and the potential application of PEMF in cartilage tissue engineering were investigated.PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro,and facilitate chondrogenesis and cartilage repair in vivo.All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment,this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.展开更多
Cartilage Decellularized ExtraCellular Matrix(dECM)materials have shown promising cartilage regenera-tion capacity due to their chondrogenic bioactivity.However,the limited retention of ECM components and the reduced ...Cartilage Decellularized ExtraCellular Matrix(dECM)materials have shown promising cartilage regenera-tion capacity due to their chondrogenic bioactivity.However,the limited retention of ECM components and the reduced integrity of functional ECM molecules during traditional decellularization processes im-pair the biomimicry of these materials.The current study aims to fabricate biomimetic materials con-taining decellularized cartilage particles that have an intact molecular structure and native composition as biomaterial inks and hydrogels for cartilage repair.For this,we established a novel two-fraction de-cellularization strategy for the preparation of reconstituted dECM(rdECM)particles by mixing the two-fraction components,as well as a one-fraction decellularization strategy for the preparation of biomimetic dECM(bdECM)particles.Hyaluronic acid-tyramine(THA)hydrogels containing rdECM or bdECM particles were produced and characterized via rheological test,swelling and stability evaluation,and compression test.The results showed that our novel decellularization strategies preserved intact proteoglycans and collagen at a higher retention rate with adequate DNA removal compared to traditional methods of de-cellularization.The addition of rdECM or bdECM particles significantly increased the shear moduli of the THA bioinks while preserving their shear-thinning properties.bdECM particle-embedded THA hydrogels also achieved long-term stability with a swelling ratio of 70%and high retention of glycosaminoglycans and collagen after long-term incubation,while rdECM particle-embedded THA hydrogels showed unsat-isfactory stability as self-standing biomaterials.Compared to pure THA hydrogels,the addition of bdECM particles significantly enhanced the compression moduli.In summary,our decellularization methods are successful in the retention of functional and intact cartilage components with high yield.Both rdECM and bdECM particles can be supplemented in THA bioinks for biomimetic cartilage 3D printing.Hydro-gels with cartilage bdECM particles possess the functional structure and the natural composition of car-tilage ECM,long-term stability,and enhanced mechanical properties,and are promising biomaterials for cartilage repair.展开更多
Autonomous self-healing hydrogels were achieved through a dynamic combination of hydrogen bonding and ferric ion(Fe^(3+))migration.N,N′-methylenebis(acrylamide)(MBA),a cross-linking agent,was added in this study.Poly...Autonomous self-healing hydrogels were achieved through a dynamic combination of hydrogen bonding and ferric ion(Fe^(3+))migration.N,N′-methylenebis(acrylamide)(MBA),a cross-linking agent,was added in this study.Poly(acrylic acid)(PAA)/Fe^(3+)and PAA–MBA/Fe^(3+)hydrogels were prepared by introducing Fe^(3+)into the PAA hydrogel network.The ionic bonds were formed between Fe^(3+)ions and carboxyl groups.The microstructure,mechanical properties,and composition of hydrogels were characterized by field emission scanning electron microscopy and Fourier transform infrared spectroscopy.The experimental results showed that PAA/Fe^(3+)and PAA–MBA/Fe^(3+)hydrogels healed themselves without external stimuli.The PAA/Fe^(3+)hydrogel exhibited good mechanical properties,i.e.,the tensile strength of 50 kPa,the breaking elongation of 750%,and the self-healing efficiency of 82%.Meanwhile,the PAA–MBA/Fe^(3+)hydrogel had a tensile strength of 120 kPa.These fabricated hydrogels are biocompatible,which may have promising applications in cartilage tissue engineering.展开更多
To overcome cartilage injury, strategies have been developed in the last few years based on tissue engineering to rebuild the defects. Cartilage engineering is principally based on three main biological factors: cells...To overcome cartilage injury, strategies have been developed in the last few years based on tissue engineering to rebuild the defects. Cartilage engineering is principally based on three main biological factors: cells (native cells (chondrocytes) or a more primitive ones as mesenchymal stem cells), scaffolds and functionalization factors (growth factors, mechanical stimulation and/or hypoxia). Cartilage tissue engineering strategies generally result in homogeneous tissue structures with little resemblance to native zonal organization of articular cartilage. The main objective of our work concerns the buildup of complex biomaterials aimed at reconstructing biological tissue with three dimensional cells construction for mimicking cartilage architecture. Our strategy is based on structures formation by simple and progressive spraying of mixed alginate hydrogel and human mesenchymal stem cells (hMSC). In this work, the comportment of cells and more precisely their chondrogenic differentiation potential is compared to a traditional making process: the mold. We report here that spraying method allowed to product a scaffold with hMSC that confer a favorable environment for neocartilage construction.展开更多
Hyaline cartilage plays a critical role in maintaining joint function and pain.However,the lack of blood supply,nerves,and lymphatic vessels greatly limited the self-repair and regeneration of damaged cartilage,giving...Hyaline cartilage plays a critical role in maintaining joint function and pain.However,the lack of blood supply,nerves,and lymphatic vessels greatly limited the self-repair and regeneration of damaged cartilage,giving rise to various tricky issues in medicine.In the past 30 years,numerous treatment techniques and commercial products have been developed and practiced in the clinic for promoting defected cartilage repair and regeneration.Here,the current therapies and their relevant advantages and disadvantages will be summarized,particularly the tissue engineering strategies.Furthermore,the fabrication of tissue-engineered cartilage under research or in the clinic was discussed based on the traid of tissue engineering,that is the materials,seed cells,and bioactive factors.Finally,the commercialized cartilage repair products were listed and the regulatory issues and challenges of tissue-engineered cartilage repair products and clinical application would be reviewed.展开更多
Mechanobiological study of chondrogenic cells and multipotent stem cells for articular cartilage tissue engineering(CTE)has been widely explored.The mechanical stimulation in terms of wall shear stress,hydrostatic pre...Mechanobiological study of chondrogenic cells and multipotent stem cells for articular cartilage tissue engineering(CTE)has been widely explored.The mechanical stimulation in terms of wall shear stress,hydrostatic pressure and mechanical strain has been applied in CTE in vitro.It has been found that the mechanical stimulation at a certain range can accelerate the chondrogenesis and articular cartilage tissue regeneration.This review explicitly focuses on the study of the influence of the mechanical environment on proliferation and extracellular matrix production of chondrocytes in vitro for CTE.The multidisciplinary approaches used in previous studies and the need for in silico methods to be used in parallel with in vitro methods are also discussed.The information from this review is expected to direct facial CTE research,in which mechanobiology has not been widely explored yet.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
In spite of the considerable achievements in the field of regenerative medicine in the past several decades,osteochondral defect regeneration remains a challenging issue among diseases in the musculoskeletal system be...In spite of the considerable achievements in the field of regenerative medicine in the past several decades,osteochondral defect regeneration remains a challenging issue among diseases in the musculoskeletal system because of the spatial complexity of osteochondral units in composition,structure and functions.In order to repair the hierarchical tissue involving different layers of articular cartilage,cartilage-bone interface and subchondral bone,traditional clinical treatments including palliative and reparative methods have showed certain improvement in pain relief and defect filling.It is the development of tissue engineering that has provided more promising results in regenerating neo-tissues with comparable compositional,structural and functional characteristics to the native osteochondral tissues.Here in this review,some basic knowledge of the osteochondral units including the anatomical structure and composition,the defect classification and clinical treatments will be first introduced.Then we will highlight the recent progress in osteochondral tissue engineering from perspectives of scaffold design,cell encapsulation and signaling factor incorporation including bioreactor application.Clinical products for osteochondral defect repair will be analyzed and summarized later.Moreover,we will discuss the current obstacles and future directions to regenerate the damaged osteochondral tissues.展开更多
Due to a blood supply shortage,articular cartilage has a limited capacity for selfhealing once damaged.Articular chondrocytes,cartilage progenitor cells,embryonic stem cells,and mesenchymal stem cells are candidate ce...Due to a blood supply shortage,articular cartilage has a limited capacity for selfhealing once damaged.Articular chondrocytes,cartilage progenitor cells,embryonic stem cells,and mesenchymal stem cells are candidate cells for cartilage regeneration.Significant current attention is paid to improving chondrogenic differentiation capacity;unfortunately,the potential chondrogenic hypertrophy of differentiated cells is largely overlooked.Consequently,the engineered tissue is actually a transient cartilage rather than a permanent one.The development of hypertrophic cartilage ends with the onset of endochondral bone formation which has inferior mechanical properties.In this review,current strategies for inhibition of chondrogenic hypertrophy are comprehensively summarized;the impact of cell source options is discussed;and potential mechanisms underlying these strategies are also categorized.This paper aims to provide guidelines for the prevention of hypertrophy in the regeneration of cartilage tissue.This knowledge may also facilitate the retardation of osteophytes in the treatment of osteoarthritis.展开更多
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modif...Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.展开更多
Successful regeneration of cartilage tissue at a clinical scale has been a tremendous challenge in the past decades. Microcarriers (MCs), usually used for cell and drug delivery, have been studied broadly across a wid...Successful regeneration of cartilage tissue at a clinical scale has been a tremendous challenge in the past decades. Microcarriers (MCs), usually used for cell and drug delivery, have been studied broadly across a wide range of medical fields, especially the cartilage tissue engineering (TE). Notably, microcarrier systems provide an attractive method for regulating cell phenotype and microtissue maturations, they also serve as powerful injectable carriers and are combined with new technologies for cartilage regeneration. In this review, we introduced the typical methods to fabricate various types of microcarriers and discussed the appropriate ma-terials for microcarriers. Furthermore, we highlighted recent progress of applications and general design prin-ciple for microcarriers. Finally, we summarized the current challenges and promising prospects of microcarrier-based systems for medical applications. Overall, this review provides comprehensive and systematic guidelines for the rational design and applications of microcarriers in cartilage TE.展开更多
Cartilage has limited self-repair ability due to its avascular,alymphatic and aneural features.The combination of three-dimensional(3D)printing and tissue engineering provides an up-and-coming approach to address this...Cartilage has limited self-repair ability due to its avascular,alymphatic and aneural features.The combination of three-dimensional(3D)printing and tissue engineering provides an up-and-coming approach to address this issue.Here,we designed and fabricated a tri-layered(superficial layer(SL),middle layer(ML)and deep layer(DL))stratified scaffold,inspired by the architecture of collagen fibers in native cartilage tissue.The scaffold was composed of 3D printed depth-dependent gradient poly(e-caprolactone)(PCL)impregnated with methacrylated alginate(ALMA),and its morphological analysis and mechanical properties were tested.To prove the feasibility of the composite scaffolds for cartilage regeneration,the viability,proliferation,collagen deposition and chondrogenic differentiation of embedded rat bone marrow mesenchymal stem cells(BMSCs)in the scaffolds were assessed by Live/dead assay,CCK-8,DNA content,cell morphology,immunofluorescence and real-time reverse transcription polymerase chain reaction.BMSCs-loaded gradient PCL/ALMA scaffolds showed excellent cell survival,cell proliferation,cell morphology,collagen II deposition and hopeful chondrogenic differentiation compared with three individual-layer scaffolds.Hence,our study demonstrates the potential use of the gradient PCL/ALMA construct for enhanced cartilage tissue engineering.展开更多
The repair of articular cartilage defects is still challenging in the fields of orthopedics and maxillofacial surgery due to the avascular structure of articular cartilage and the limited regenerative capacity of matu...The repair of articular cartilage defects is still challenging in the fields of orthopedics and maxillofacial surgery due to the avascular structure of articular cartilage and the limited regenerative capacity of mature chondrocytes.To provide viable treatment options,tremendous efforts have been made to develop various chondrogenically-functionalized biomaterials for cartilage tissue engineering.Peptides that are derived from and mimic the functions of chondroconductive cartilage extracellular matrix and chondroinductive growth factors,represent a unique group of bioactive agents for chondrogenic functionalization.Since they can be chemically synthesized,peptides bear better reproducibility,more stable efficacy,higher modifiability and yielding efficiency in comparison with naturally derived biomaterials and recombinant growth factors.In this review,we summarize the current knowledge in the designs of the chondroinductive/chondroconductive peptides,the underlying molecular mechanisms and their-functionalized biomaterials for cartilage tissue engineering.We also systematically compare their in-vitro and in-vivo efficacies in inducing chondrogenesis.Our vision is to stimulate the development of novel peptides and their-functionalized biomaterials for cartilage tissue engineering.展开更多
Osteoarthritis(OA)has been defined as a chronic inflammatory joint disease characterized by progressive articular cartilage degeneration.Recently growing interest in regenerative medicine,using cell therapy and tissue...Osteoarthritis(OA)has been defined as a chronic inflammatory joint disease characterized by progressive articular cartilage degeneration.Recently growing interest in regenerative medicine,using cell therapy and tissue engineering,where cellular components in combination with engineered scaffolds and bioactive materials were used to induce functional tissue regeneration.In the present study,nanofibrous scaffold based on chitosan(CS)/poly(vinyl alcohol)(PVA)were used to develop biologically functionalized biomaterial to mimic the extracellular matrix,allowing the human adipose tissue derived mesenchymal stem cells(ADSCs)to proliferate and differentiate to chondrogenic cells.The morphology of the nanofibrous mat was examined using field emission scanning electron microscope(FE/SEM).The characteristic functional groups and the nature of the chemical bonds between atoms were evaluated using Fourier transform infrared spectroscopy(FTIR)spectrum.Characterization of the seeded cells was morphologically evaluated by scanning electron microscopy and by flow cytometry for the expression of the stem cell surface markers.The differentiation potential was verified after chondrogenic induction by analyzing the expression of chondrogenic marker genes using real-time(RT PCR).Current study suggest significant potential for the use of ADSCs with the nanofibrous scaffolds in improving the osteoarthritis pathology.展开更多
Methacrylated gelatin(GelMA)/bacterial cellulose(BC)composite hydrogels have been successfully prepared by immersing BC particles in GelMA solution followed by photo-crosslinking.The morphology of GelMA/BC hydrogel wa...Methacrylated gelatin(GelMA)/bacterial cellulose(BC)composite hydrogels have been successfully prepared by immersing BC particles in GelMA solution followed by photo-crosslinking.The morphology of GelMA/BC hydrogel was examined by scanning electron microscopy and compared with pure GelMA.The hydrogels had very well interconnected porous network structure,and the pore size decreased from 200 to 10 mm with the increase of BC content.The composite hydrogels were also characterized by swelling experiment,X-ray diffraction,thermogravimetric analysis,rheology experiment and compressive test.The composite hydrogels showed significantly improved mechanical properties compared with pure GelMA.In addition,the biocompatility of composite hydrogels were preliminarily evaluated using human articular chondrocytes.The cells encapsulated within the composite hydrogels for 7 days proliferated and maintained the chondrocytic phenotype.Thus,the GelMA/BC composite hydrogels might be useful for cartilage tissue engineering.展开更多
基金the funding provided by the United Kingdom(UK)Engineering and Physical Sciences Research Council(EPSRC)Doctoral Prize Fellowship(EP/R513131/1)。
文摘Articular cartilage damage caused by trauma or degenerative pathologies such as osteoarthritis can result in significant pain,mobility issues,and disability.Current surgical treatments have a limited capacity for efficacious cartilage repair,and long-term patient outcomes are not satisfying.Three-dimensional bioprinting has been used to fabricate biochemical and biophysical environments that aim to recapitulate the native microenvironment and promote tissue regeneration.However,conventional in vitro bioprinting has limitations due to the challenges associated with the fabrication and implantation of bioprinted constructs and their integration with the native cartilage tissue.In situ bioprinting is a novel strategy to directly deliver bioinks to the desired anatomical site and has the potential to overcome major shortcomings associated with conventional bioprinting.In this review,we focus on the new frontier of robotic-assisted in situ bioprinting surgical systems for cartilage regeneration.We outline existing clinical approaches and the utilization of robotic-assisted surgical systems.Handheld and robotic-assisted in situ bioprinting techniques including minimally invasive and non-invasive approaches are defined and presented.Finally,we discuss the challenges and potential future perspectives of in situ bioprinting for cartilage applications.
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.
文摘Due to the limited self healing capacity of human cartilage,the repair of defects gives rise to a challenging clinical problem.Cartilage tissue engineering provides a new method to solve cartilage repair.However,the search for a suitable biological vector material has long been the focus of research interest in this regard.In this paper,the present situation of cartilage tissue engineering vector materials is reviewed.
基金This work was partially supported by grants from University Grants Committee,Research Grants Council of the Hong Kong Special Administrative Region,China(14108720,14121721,14202920,T13-402/17-N and AoE/M-402/20).
文摘Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage.Hydrogel is widely used because it could provide rapid defect filling and proper structure support,and is biocompatible for cell aggregation and matrix deposition.Efforts have been made to seek suitable scaffolds for cartilage tissue engineering.Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties.Gelation time,swelling ratio,biodegradability and biocompatibility of the hydrogels were systematically characterized,and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair.Furthermore,the new hydrogel design introduces a pre-gel state before photo-crosslinking,where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition.This granted multiple administration routes to the hydrogels,which brings hydrogels the ability to adapt to complex clinical situations.Pulsed electromagnetic fields(PEMF)have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials.PEMF treatment offers a better clinical outcome with fewer,if any,side effects,and wildly used in musculoskeletal tissue repair.Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering.In this study,the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model,and the potential application of PEMF in cartilage tissue engineering were investigated.PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro,and facilitate chondrogenesis and cartilage repair in vivo.All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment,this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.
基金AO Foundation and AOSpine Inter-national.Peng Guo and Nan Jiang were funded by Sino Swiss Sci-ence and Technology Cooperation Program(Nos.EG-CN_01-032019 and EG-CN_04-042018)China Scholarship Council.MD and GM gratefully acknowledge funding from the Swiss National Sci-ence Foundation(SNSF,No.310030E_189310).
文摘Cartilage Decellularized ExtraCellular Matrix(dECM)materials have shown promising cartilage regenera-tion capacity due to their chondrogenic bioactivity.However,the limited retention of ECM components and the reduced integrity of functional ECM molecules during traditional decellularization processes im-pair the biomimicry of these materials.The current study aims to fabricate biomimetic materials con-taining decellularized cartilage particles that have an intact molecular structure and native composition as biomaterial inks and hydrogels for cartilage repair.For this,we established a novel two-fraction de-cellularization strategy for the preparation of reconstituted dECM(rdECM)particles by mixing the two-fraction components,as well as a one-fraction decellularization strategy for the preparation of biomimetic dECM(bdECM)particles.Hyaluronic acid-tyramine(THA)hydrogels containing rdECM or bdECM particles were produced and characterized via rheological test,swelling and stability evaluation,and compression test.The results showed that our novel decellularization strategies preserved intact proteoglycans and collagen at a higher retention rate with adequate DNA removal compared to traditional methods of de-cellularization.The addition of rdECM or bdECM particles significantly increased the shear moduli of the THA bioinks while preserving their shear-thinning properties.bdECM particle-embedded THA hydrogels also achieved long-term stability with a swelling ratio of 70%and high retention of glycosaminoglycans and collagen after long-term incubation,while rdECM particle-embedded THA hydrogels showed unsat-isfactory stability as self-standing biomaterials.Compared to pure THA hydrogels,the addition of bdECM particles significantly enhanced the compression moduli.In summary,our decellularization methods are successful in the retention of functional and intact cartilage components with high yield.Both rdECM and bdECM particles can be supplemented in THA bioinks for biomimetic cartilage 3D printing.Hydro-gels with cartilage bdECM particles possess the functional structure and the natural composition of car-tilage ECM,long-term stability,and enhanced mechanical properties,and are promising biomaterials for cartilage repair.
基金supported by the General Project of Natural Science of Shanxi Provincial Basic Research Program(Grant No.202203021211125)the National Natural Science Foundation of China(Grant No.11802197).
文摘Autonomous self-healing hydrogels were achieved through a dynamic combination of hydrogen bonding and ferric ion(Fe^(3+))migration.N,N′-methylenebis(acrylamide)(MBA),a cross-linking agent,was added in this study.Poly(acrylic acid)(PAA)/Fe^(3+)and PAA–MBA/Fe^(3+)hydrogels were prepared by introducing Fe^(3+)into the PAA hydrogel network.The ionic bonds were formed between Fe^(3+)ions and carboxyl groups.The microstructure,mechanical properties,and composition of hydrogels were characterized by field emission scanning electron microscopy and Fourier transform infrared spectroscopy.The experimental results showed that PAA/Fe^(3+)and PAA–MBA/Fe^(3+)hydrogels healed themselves without external stimuli.The PAA/Fe^(3+)hydrogel exhibited good mechanical properties,i.e.,the tensile strength of 50 kPa,the breaking elongation of 750%,and the self-healing efficiency of 82%.Meanwhile,the PAA–MBA/Fe^(3+)hydrogel had a tensile strength of 120 kPa.These fabricated hydrogels are biocompatible,which may have promising applications in cartilage tissue engineering.
文摘To overcome cartilage injury, strategies have been developed in the last few years based on tissue engineering to rebuild the defects. Cartilage engineering is principally based on three main biological factors: cells (native cells (chondrocytes) or a more primitive ones as mesenchymal stem cells), scaffolds and functionalization factors (growth factors, mechanical stimulation and/or hypoxia). Cartilage tissue engineering strategies generally result in homogeneous tissue structures with little resemblance to native zonal organization of articular cartilage. The main objective of our work concerns the buildup of complex biomaterials aimed at reconstructing biological tissue with three dimensional cells construction for mimicking cartilage architecture. Our strategy is based on structures formation by simple and progressive spraying of mixed alginate hydrogel and human mesenchymal stem cells (hMSC). In this work, the comportment of cells and more precisely their chondrogenic differentiation potential is compared to a traditional making process: the mold. We report here that spraying method allowed to product a scaffold with hMSC that confer a favorable environment for neocartilage construction.
文摘Hyaline cartilage plays a critical role in maintaining joint function and pain.However,the lack of blood supply,nerves,and lymphatic vessels greatly limited the self-repair and regeneration of damaged cartilage,giving rise to various tricky issues in medicine.In the past 30 years,numerous treatment techniques and commercial products have been developed and practiced in the clinic for promoting defected cartilage repair and regeneration.Here,the current therapies and their relevant advantages and disadvantages will be summarized,particularly the tissue engineering strategies.Furthermore,the fabrication of tissue-engineered cartilage under research or in the clinic was discussed based on the traid of tissue engineering,that is the materials,seed cells,and bioactive factors.Finally,the commercialized cartilage repair products were listed and the regulatory issues and challenges of tissue-engineered cartilage repair products and clinical application would be reviewed.
基金EPSRC-IAA Research Impact Fund,(No.RIF202/RIR1035-109)Royal Society Research Grant(No.RGS\R2\212280).
文摘Mechanobiological study of chondrogenic cells and multipotent stem cells for articular cartilage tissue engineering(CTE)has been widely explored.The mechanical stimulation in terms of wall shear stress,hydrostatic pressure and mechanical strain has been applied in CTE in vitro.It has been found that the mechanical stimulation at a certain range can accelerate the chondrogenesis and articular cartilage tissue regeneration.This review explicitly focuses on the study of the influence of the mechanical environment on proliferation and extracellular matrix production of chondrocytes in vitro for CTE.The multidisciplinary approaches used in previous studies and the need for in silico methods to be used in parallel with in vitro methods are also discussed.The information from this review is expected to direct facial CTE research,in which mechanobiology has not been widely explored yet.
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 grants from the National Natural Science Foundation of China(No.51772233)the National Key Research and Development Program of China(2018YFB1105500)+3 种基金the Major Special Projects of Technological Innovation of Hubei Province(No.2019ACA130)the Application Foundation and Front Research Program of Wuhan(No.2018010401011273)Foshan Xianhu Laboratory of the Advanced Energy Science and Technology Guangdong Laboratory(XHT2020-008)the Fundamental Research Funds for the Central Universities(2020-YB-015).
文摘In spite of the considerable achievements in the field of regenerative medicine in the past several decades,osteochondral defect regeneration remains a challenging issue among diseases in the musculoskeletal system because of the spatial complexity of osteochondral units in composition,structure and functions.In order to repair the hierarchical tissue involving different layers of articular cartilage,cartilage-bone interface and subchondral bone,traditional clinical treatments including palliative and reparative methods have showed certain improvement in pain relief and defect filling.It is the development of tissue engineering that has provided more promising results in regenerating neo-tissues with comparable compositional,structural and functional characteristics to the native osteochondral tissues.Here in this review,some basic knowledge of the osteochondral units including the anatomical structure and composition,the defect classification and clinical treatments will be first introduced.Then we will highlight the recent progress in osteochondral tissue engineering from perspectives of scaffold design,cell encapsulation and signaling factor incorporation including bioreactor application.Clinical products for osteochondral defect repair will be analyzed and summarized later.Moreover,we will discuss the current obstacles and future directions to regenerate the damaged osteochondral tissues.
基金supported by Research Grants from the AO Foundation(S-12-19P) and the National Institutes of Health(R03 AR062763-01A1)to M.P.and the National Science Foundation for Distinguished Young Scholars of China(81000798)the Science and Technology Commission of Shanghai Municipality,China(15ZR14140)to P.L.F.
文摘Due to a blood supply shortage,articular cartilage has a limited capacity for selfhealing once damaged.Articular chondrocytes,cartilage progenitor cells,embryonic stem cells,and mesenchymal stem cells are candidate cells for cartilage regeneration.Significant current attention is paid to improving chondrogenic differentiation capacity;unfortunately,the potential chondrogenic hypertrophy of differentiated cells is largely overlooked.Consequently,the engineered tissue is actually a transient cartilage rather than a permanent one.The development of hypertrophic cartilage ends with the onset of endochondral bone formation which has inferior mechanical properties.In this review,current strategies for inhibition of chondrogenic hypertrophy are comprehensively summarized;the impact of cell source options is discussed;and potential mechanisms underlying these strategies are also categorized.This paper aims to provide guidelines for the prevention of hypertrophy in the regeneration of cartilage tissue.This knowledge may also facilitate the retardation of osteophytes in the treatment of osteoarthritis.
文摘Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.
基金The authors thank Shuo Wang and Shen Ji for helpful discussion.This work was supported by the National Natural Science Foundation of China(Grant No.81773091)the Natural Science Foundation of Beijing Municipality(Grant No.7212020)+4 种基金Science and Technology Planning Project of Beijing Municipal Education Commission(Grant No.KM202110025013)the Beijing Municipal Excellent Talents Project(Grant No.2020A43)Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDA16020802)CAS Engineering Laboratory for Intelligent Organ Manufacturing(Grant No.KFJ-PTXM-039)the National Natural Science Foundation of China(Grant No.82001848).
文摘Successful regeneration of cartilage tissue at a clinical scale has been a tremendous challenge in the past decades. Microcarriers (MCs), usually used for cell and drug delivery, have been studied broadly across a wide range of medical fields, especially the cartilage tissue engineering (TE). Notably, microcarrier systems provide an attractive method for regulating cell phenotype and microtissue maturations, they also serve as powerful injectable carriers and are combined with new technologies for cartilage regeneration. In this review, we introduced the typical methods to fabricate various types of microcarriers and discussed the appropriate ma-terials for microcarriers. Furthermore, we highlighted recent progress of applications and general design prin-ciple for microcarriers. Finally, we summarized the current challenges and promising prospects of microcarrier-based systems for medical applications. Overall, this review provides comprehensive and systematic guidelines for the rational design and applications of microcarriers in cartilage TE.
基金This study was supported by the National Natural Science Foundation of China(Nos 51975400,61703298,61501316,51505324)National Key Research and Development Program(2019YFB1310200)+1 种基金Shanxi Provincial Key Research and Development Project(201803D421050)Beijing Natural Science Foundation(7202190).
文摘Cartilage has limited self-repair ability due to its avascular,alymphatic and aneural features.The combination of three-dimensional(3D)printing and tissue engineering provides an up-and-coming approach to address this issue.Here,we designed and fabricated a tri-layered(superficial layer(SL),middle layer(ML)and deep layer(DL))stratified scaffold,inspired by the architecture of collagen fibers in native cartilage tissue.The scaffold was composed of 3D printed depth-dependent gradient poly(e-caprolactone)(PCL)impregnated with methacrylated alginate(ALMA),and its morphological analysis and mechanical properties were tested.To prove the feasibility of the composite scaffolds for cartilage regeneration,the viability,proliferation,collagen deposition and chondrogenic differentiation of embedded rat bone marrow mesenchymal stem cells(BMSCs)in the scaffolds were assessed by Live/dead assay,CCK-8,DNA content,cell morphology,immunofluorescence and real-time reverse transcription polymerase chain reaction.BMSCs-loaded gradient PCL/ALMA scaffolds showed excellent cell survival,cell proliferation,cell morphology,collagen II deposition and hopeful chondrogenic differentiation compared with three individual-layer scaffolds.Hence,our study demonstrates the potential use of the gradient PCL/ALMA construct for enhanced cartilage tissue engineering.
基金This study is supported by the grants from Key Research and Development Plan of Zhejiang Province(No.2021C04013).
文摘The repair of articular cartilage defects is still challenging in the fields of orthopedics and maxillofacial surgery due to the avascular structure of articular cartilage and the limited regenerative capacity of mature chondrocytes.To provide viable treatment options,tremendous efforts have been made to develop various chondrogenically-functionalized biomaterials for cartilage tissue engineering.Peptides that are derived from and mimic the functions of chondroconductive cartilage extracellular matrix and chondroinductive growth factors,represent a unique group of bioactive agents for chondrogenic functionalization.Since they can be chemically synthesized,peptides bear better reproducibility,more stable efficacy,higher modifiability and yielding efficiency in comparison with naturally derived biomaterials and recombinant growth factors.In this review,we summarize the current knowledge in the designs of the chondroinductive/chondroconductive peptides,the underlying molecular mechanisms and their-functionalized biomaterials for cartilage tissue engineering.We also systematically compare their in-vitro and in-vivo efficacies in inducing chondrogenesis.Our vision is to stimulate the development of novel peptides and their-functionalized biomaterials for cartilage tissue engineering.
基金This research was financially supported by National Research Centre,Cairo,Egypt(Project grant no.P11010170).
文摘Osteoarthritis(OA)has been defined as a chronic inflammatory joint disease characterized by progressive articular cartilage degeneration.Recently growing interest in regenerative medicine,using cell therapy and tissue engineering,where cellular components in combination with engineered scaffolds and bioactive materials were used to induce functional tissue regeneration.In the present study,nanofibrous scaffold based on chitosan(CS)/poly(vinyl alcohol)(PVA)were used to develop biologically functionalized biomaterial to mimic the extracellular matrix,allowing the human adipose tissue derived mesenchymal stem cells(ADSCs)to proliferate and differentiate to chondrogenic cells.The morphology of the nanofibrous mat was examined using field emission scanning electron microscope(FE/SEM).The characteristic functional groups and the nature of the chemical bonds between atoms were evaluated using Fourier transform infrared spectroscopy(FTIR)spectrum.Characterization of the seeded cells was morphologically evaluated by scanning electron microscopy and by flow cytometry for the expression of the stem cell surface markers.The differentiation potential was verified after chondrogenic induction by analyzing the expression of chondrogenic marker genes using real-time(RT PCR).Current study suggest significant potential for the use of ADSCs with the nanofibrous scaffolds in improving the osteoarthritis pathology.
基金supported by the Science Foundation of Guizhou Province([2019]1428 and[2019]1429).
文摘Methacrylated gelatin(GelMA)/bacterial cellulose(BC)composite hydrogels have been successfully prepared by immersing BC particles in GelMA solution followed by photo-crosslinking.The morphology of GelMA/BC hydrogel was examined by scanning electron microscopy and compared with pure GelMA.The hydrogels had very well interconnected porous network structure,and the pore size decreased from 200 to 10 mm with the increase of BC content.The composite hydrogels were also characterized by swelling experiment,X-ray diffraction,thermogravimetric analysis,rheology experiment and compressive test.The composite hydrogels showed significantly improved mechanical properties compared with pure GelMA.In addition,the biocompatility of composite hydrogels were preliminarily evaluated using human articular chondrocytes.The cells encapsulated within the composite hydrogels for 7 days proliferated and maintained the chondrocytic phenotype.Thus,the GelMA/BC composite hydrogels might be useful for cartilage tissue engineering.
