High tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells implantation for knee cartilage regeneration

BACKGROUND High tibial osteotomy(HTO)is a well-established method for the treatment of medial compartment osteoarthritis of the knee with varus deformity.However,HTO alone cannot adequately repair the arthritic joint,necessitating cartilage regeneration therapy.Cartilage regeneration procedures with concomitant HTO are used to improve the clinical outcome in patients with varus deformity.AIM To evaluate cartilage regeneration after implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells(hUCB-MSCs)with concomitant HTO.METHODS Data for patients who underwent implantation of hUCB-MSCs with concomitant HTO were evaluated.The patients included in this study were over 40 years old,had a varus deformity of more than 5°,and a full-thickness International Cartilage Repair Society(ICRS)grade IV articular cartilage lesion of more than 4 cm2 in the medial compartment of the knee.All patients underwent second-look arthroscopy during hardware removal.Cartilage regeneration was evaluated macroscopically using the ICRS grading system in second-look arthroscopy.We also assessed the effects of patient characteristics,such as trochlear lesions,age,and lesion size,using patient medical records.RESULTS A total of 125 patients were included in the study,with an average age of 58.3±6.8 years(range:43-74 years old);95(76%)were female and 30(24%)were male.The average hip-knee-ankle(HKA)angle for measuring varus deformity was 7.6°±2.4°(range:5.0-14.2°).In second-look arthroscopy,the status of medial femoral condyle(MFC)cartilage was as follows:73(58.4%)patients with ICRS grade I,37(29.6%)with ICRS grade II,and 15(12%)with ICRS grade III.No patients were staged with ICRS grade IV.Additionally,the scores[except International Knee Documentation Committee(IKDC)at 1 year]of the ICRS grade I group improved more significantly than those of the ICRS grade II and III groups.CONCLUSION Implantation of hUCB-MSCs with concomitant HTO is an effective treatment for patients with medial compartment osteoarthritis and varus deformity.Regeneration of cartilage improves the clinical outcomes for the patients.

Enhancing cartilage regeneration and repair through bioactive and biomechanical modification of 3D acellular dermal matrix

Acellular dermal matrix(ADM)shows promise for cartilage regeneration and repair.However,an effective decellularization technique that removes cellular components while preserving the extracellular matrix,the transformation of 2D-ADM into a suitable 3D scaffold with porosity and the enhancement of bioactive and biomechanical properties in the 3D-ADM scaffold are yet to be fully addressed.In this study,we present an innovative decellularization method involving 0.125%trypsin and 0.5%SDS and a 1%Triton X-100 solution for preparing ADM and converting 2D-ADM into 3D-ADM scaffolds.These scaffolds exhibit favorable physicochemical properties,exceptional biocompatibility and significant potential for driving cartilage regeneration in vitro and in vivo.To further enhance the cartilage regeneration potential of 3D-ADM scaffolds.we incorporated porcine-derived small intestinal submucosa(SIS)for bioactivity and calcium sulfate hemihydrate(CSH)for biomechanical reinforcement.The resulting 3D-ADM+SIS scaffolds displayed heightened biological activity,while the 3D-ADM+CSH scaffolds notably bolstered biomechanical strength.Both scaffold types showed promise for cartilage regeneration and repair in vitro and in vivo,with considerable improvements observed in repairing cartilage defects within a rabbit articular cartilage model.In summary,this research introduces a versatile 3D-ADM scaffold with customizable bioactive and biomechanical properties,poised to revolutionize the field of cartilageregeneration.

Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration

Despite numerous studies on chondrogenesis,the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited.In this study,we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals,enabling sequential immunomodulation and endogenous articular cartilage regeneration.We first integrated the chondrogenic growth factor transforming growth factor-β3(TGF-β3)into mesoporous silica nanoparticles(MSNs).Then,TGF-β3@MSNs and insulin-like growth factor 1(IGF-1)were encapsulated within microspheres made of polydopamine(pDA).In the final step,growth factor-loaded MSN@pDA and a chitosan(CS)hydrogel containing platelet-derived growth factor-BB(PDGF-BB)were blended to produce growth factors loaded composite microspheres(GFs@μS)using microfluidic technology.The presence of pDA reduced the initial acute inflammatory response,and the early,robust release of PDGF-BB aided in attracting endogenous stem cells.Over the subsequent weeks,the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation.μS were incorporated into an acellular cartilage extracellular matrix(ACECM)and combined with a polydopamine-modified polycaprolactone(PCL)structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix,resulting in enhanced cartilage repair and patellar cartilage protection.This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling,leading to efficient articular cartilage regeneration.

A novel mesenchymal stem cell-targeting dual-miRNA delivery system based on aptamer-functionalized tetrahedral framework nucleic acids:Application to endogenous regeneration of articular cartilage

Articular cartilage injury(ACI)remains one of the key challenges in regenerative medicine,as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage.Enhancing endogenous repair via micro-RNAs(miRNAs)shows promise as a regenerative therapy.miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells(MSCs).In this study,we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid(tFNA)-based targeting miRNA codelivery system,named A-T-M,was used.With tFNAs as vehicles,miR-140 and miR-455 were connected to and modified on tFNAs,while Apt19S(a DNA aptamer targeting MSCs)was directly integrated into the nanocomplex.The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms.Interestingly,a synergistic effect between miR-140 and miR-455 was revealed.Furthermore,A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation.A-T-M provides a new perspective and strategy for the regeneration of articular cartilage,showing strong clinical application value in the future treatment of ACI.

Nanoengineered hydrogels as 3D biomimetic extracellular matrix with injectable and sustained delivery capability for cartilage regeneration

The regeneration of articular cartilage remains a great challenge due to the difficulty in effectively enhancing spontaneous healing.Recently,the combination of implanted stem cells,suitable biomaterials and bioactive molecules has attracted attention for tissue regeneration.In this study,a novel injectable nanocomposite was rationally designed as a sustained release platform for enhanced cartilage regeneration through integration of a chitosan-based hydrogel,articular cartilage stem cells(ACSCs)and mesoporous SiO_(2)nanoparticles loaded with anhydroicaritin(AHI).The biocompatible engineered nanocomposite acting as a novel 3D biomimetic extracellular matrix exhibited a remarkable sustained release effect due to the synergistic regulation of the organic hydrogel framework and mesopore channels of inorganic mSiO_(2)nanoparticles(mSiO_(2)NPs).Histological assessment and biomechanical tests showed that the nanocomposites exhibited superior performance in inducing ACSCs proliferation and differentiation in vitro and promoting extracellular matrix(ECM)production and cartilage regeneration in vivo.Such a novel multifunctional biocompatible platform was demonstrated to significantly enhance cartilage regeneration based on the sustained release of AHI,an efficient bioactive natural small molecule for ACSCs chondrogenesis,within the hybrid matrix of hydrogel and mSiO_(2)NPs.Hence,the injectable nanocomposite holds great promise for use as a 3D biomimetic extracellular matrix for tissue regeneration in clinical diagnostics.

Secretive derived from hypoxia preconditioned mesenchymal stem cells promote cartilage regeneration and mitigate joint inflammation via extracellular vesicles

Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.

Elastic Fiber‑Reinforced Silk Fibroin Scaffold with A Double‑Crosslinking Network for Human Ear‑Shaped Cartilage Regeneration

Tissue engineering provides a promising approach for regenerative medicine.The ideal engineered tissue should have the desired structure and functional properties suitable for uniform cell distribution and stable shape fidelity in the full period of in vitro culture and in vivo implantation.However,due to insufficient cell infiltration and inadequate mechanical properties,engineered tissue made from porous scaffolds may have an inconsistent cellular composition and a poor shape retainability,which seriously hinders their further clinical application.In this study,silk fibroin was integrated with silk short fibers with a physical and chemical double-crosslinking network to fabricate fiber-reinforced silk fibroin super elastic absorbent sponges(Fr-SF-SEAs).The Fr-SF-SEAs exhibited the desirable synergistic properties of a honeycomb structure,hygroscopicity and elasticity,which allowed them to undergo an unconventional cyclic compression inoculation method to significantly promote cell diffusion and achieve a uniform cell distribution at a high-density.Furthermore,the regenerated cartilage of the Fr-SF-SEAs scaffold withstood a dynamic pressure environment after subcutaneous implantation and maintained its precise original structure,ultimately achieving human-scale ear-shaped cartilage regeneration.Importantly,the SF-SEAs prepara-tion showed valuable universality in combining chemicals with other bioactive materials or drugs with reactive groups to construct microenvironment bionic scaffolds.The established novel cell inoculation method is highly versatile and can be readily applied to various cells.Based on the design concept of dual-network Fr-SF-SEAs scaffolds,homogenous and mature cartilage was successfully regenerated with precise and complicated shapes,which hopefully provides a platform strategy for tissue engineering for various cartilage defect repairs.

Chondrogenic medium in combination with a c-Jun N-terminal kinase inhibitor mediates engineered cartilage regeneration by regulating matrix metabolism and cell proliferation

Cartilage tissue engineering is a promising strategy for repairing cartilage defects.However,achieving satisfactory cartilage regeneration in vitro and maintaining its stability in vivo remains a challenge.The key to achieving this goal is establishing an efficient cartilage regeneration culture system to retain sufficient active cells with physiological functions,generate abundant cartilage extracellular matrix(ECM)and maintain a low level of cartilage ECM degradation.The current chondrogenic medium(CM)can effectively promote cartilage ECM production;however,it has a negative effect on cell proliferation.Meanwhile,the specific c-Jun N-terminal kinase pathway inhibitor SP600125 promotes chondrocyte proliferation but inhibits ECM synthesis.Here,we aimed to construct a three-dimensional cartilage regeneration model using a polyglycolic acid/polylactic acid scaffold in combination with chondrocytes to investigate the effect of different culture modes with CM and SP600125 on in vitro cartilage regeneration and their long-term outcomes in vivo systematically.Our results demonstrate that the long-term combination of CM and SP600125 made up for each other and maximized their respective advantages to obtain optimal cartilage regeneration in vitro.Moreover,the long-term combination achieved stable cartilage regeneration after implantation in vivo with a relatively low initial cell-seeding concentration.Therefore,the long-term combination of CM and SP600125 enhanced in vitro and in vivo cartilage regeneration stability with fewer initial seeding cells and thus optimized the cartilage regeneration culture system.

Modified hyaluronic acid hydrogels with chemical groups that facilitate adhesion to host tissues enhance cartilage regeneration

Stable integration of hydrogel implants with host tissues is of critical importance to cartilage tissue engineering.Designing and fabricating hydrogels with high adhesive strength,stability and regeneration potential are major challenges to be overcome.This study fabricated injectable adhesive hyaluronic acid(HA)hydrogel modified by aldehyde groups and methacrylate(AHAMA)on the polysaccharide backbone with multiple anchoring mechanisms(amide bond through the dynamic Schiff base reaction,hydrogen bond and physical interpenetration).AHAMA hydrogel exhibited significantly improved durability and stability within a humid environment(at least 7 days),together with higher adhesive strength(43 KPa to skin and 52 KPa to glass),as compared to commercial fibrin glue(nearly 10 KPa)and HAMA hydrogel(nearly 20 KPa).The results showed that AHAMA hydrogel was biocompatible and could be easily and rapidly prepared in situ.In vitro cell culture experiments showed that AHAMA hydrogel could enhance proliferation(1.2-folds after 3 days)and migration(1.5-folds after 12 h)of bone marrow stem cells(BMSCs),as compared to cells cultured in a culture dish.Furthermore,in a rat osteochondral defect model,implanted AHAMA hydrogel significantly promoted integration between neo-cartilage and host tissues,and significantly improved cartilage regeneration(modified O’Driscoll histological scores of 16.0±4.1 and 18.3±4.6 after 4 and 12-weeks of post-implantation in AHAMA groups respectively,12.0±2.7 and 12.2±2.8 respectively in HAMA groups,9.8±2.4 and 11.5±2.1 respectively in untreated groups).Hence,AHAMA hydrogel is a promising adhesive biomaterial for clinical cartilage regeneration and other biomedical applications.

3D printed silk-gelatin hydrogel scaffold with different porous structure and cell seeding strategy for cartilage regeneration

Hydrogel scaffolds are attractive for tissue defect repair and reorganization because of their human tissue-like characteristics.However,most hydrogels offer limited cell growth and tissue formation ability due to their submicron-or nano-sized gel networks,which restrict the supply of oxygen,nutrients and inhibit the proliferation and differentiation of encapsulated cells.In recent years,3D printed hydrogels have shown great potential to overcome this problem by introducing macro-pores within scaffolds.In this study,we fabricated a macroporous hydrogel scaffold through horseradish peroxidase(HRP)-mediated crosslinking of silk fibroin(SF)and tyramine-substituted gelatin(GT)by extrusion-based low-temperature 3D printing.Through physicochemical characterization,we found that this hydrogel has excellent structural stability,suitable mechanical properties,and an adjustable degradation rate,thus satisfying the requirements for cartilage reconstruction.Cell suspension and aggregate seeding methods were developed to assess the inoculation efficiency of the hydrogel.Moreover,the chondrogenic differentiation of stem cells was explored.Stem cells in the hydrogel differentiated into hyaline cartilage when the cell aggregate seeding method was used and into fibrocartilage when the cell suspension was used.Finally,the effect of the hydrogel and stem cells were investigated in a rabbit cartilage defect model.After implantation for 12 and 16 weeks,histological evaluation of the sections was performed.We found that the enzymatic cross-linked and methanol treatment SF5GT15 hydrogel combined with cell aggregates promoted articular cartilage regeneration.In summary,this 3D printed macroporous SF-GT hydrogel combined with stem cell aggregates possesses excellent potential for application in cartilage tissue repair and regeneration.

Advances of injectable hydrogel-based scaffolds for cartilage regeneration

Articular cartilage is an important load-bearing tissue distributed on the surface of diarthrodial joints.Due to its avascular,aneural and non-lymphatic features,cartilage has limited self-regenerative properties.To date,the utilization of biomaterials to aid in cartilage regeneration,especially through the use of injectable scaffolds,has attracted considerable attention.Various materials,therapeutics and fabrication approaches have emerged with a focus on manipulating the cartilage microenvironment to induce the formation of cartilaginous structures that have similar properties to the native tissues.In particular,the design and fabrication of injectable hydrogel-based scaffolds have advanced in recent years with the aim of enhancing its therapeutic efficacy and improving its ease of administration.This review summarizes recent progress in these efforts,including the structural improvement of scaffolds,network cross-linking techniques and strategies for controlled release,which present new opportunities for the development of injectable scaffolds for cartilage regeneration.

Tetrahedral framework nucleic acids promote the biological functions and related mechanism of synovium-derived mesenchymal stem cells and show improved articular cartilage regeneration activity in situ

Many recent studies have shown that joint-resident mesenchymal stem cells(MSCs)play a vital role in articular cartilage(AC)in situ regeneration.Specifically,synovium-derived MSCs(SMSCs),which have strong chondrogenic differentiation potential,may be the main driver of cartilage repair.However,both the insufficient number of MSCs and the lack of an ideal regenerative microenvironment in the defect area will seriously affect the regeneration of AC.Tetrahedral framework nucleic acids(tFNAs),notable novel nanomaterials,are considered prospective biological regulators in biomedical engineering.Here,we aimed to explore whether tFNAs have positive effects on AC in situ regeneration and to investigate the related mechanism.The results of in vitro experiments showed that the proliferation and migration of SMSCs were significantly enhanced by tFNAs.In addition,tFNAs,which were added to chondrogenic induction medium,were shown to promote the chondrogenic capacity of SMSCs by increasing the phosphorylation of Smad2/3.In animal models,the injection of tFNAs improved the therapeutic outcome of cartilage defects compared with that of the control treatments without tFNAs.In conclusion,this is the first report to demonstrate that tFNAs can promote the chondrogenic differentiation of SMSCs in vitro and enhance AC regeneration in vivo,indicating that tFNAs may become a promising therapeutic for AC regeneration.

Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions

The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration.However,cartilage defects are considerably more complicated in clinical conditions,especially when injuries occur at specific sites(e.g.,osteochondral tissue,growth plate,and weight-bearing area)or under inflammatory microenvironments(e.g.,osteoarthritis and rheumatoid arthritis).Therapeutic implantations,including advanced scaffolds,developed growth factors,and various cells alone or in combination currently used to treat cartilage lesions,address cartilage regeneration under abnormal conditions.This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.

Click chemistry-based pre-targeting cell delivery for cartilage regeneration

A fraction of the OA patient population is affected by post-traumatic osteoarthritis(PTOA)following acute joint injuries.Stopping or reversing the progression of PTOA following joint injury could improve long-term functional outcomes,reduced disability,and medical costs.To more effectively treat articular cartilage injury,we have developed a novel cell-based therapy that involves the pretargeting of apoptotic chondrocytes and the delivery of healthy,metabolically active chondrocytes using click chemistry.Specifically,a pre-targeting agent was prepared via conjugating apoptotic binding peptide(ApoPep-1)and trans-cyclooctene(TCO)onto polyethylene glycol(PEG)polymer carrier.The pre-targeting agent would be introduced to injured areas of articular cartilage,leading to the accumulation of TCO groups on the injured areas from actively binding to apoptotic chondrocytes.Subsequently,methyltetrazine(Tz)-bearing chondrocytes would be immobilized on the surface of TCO-coated injured cartilage via Tz-TCO click chemistry reaction.Using an ex vivo human cartilage explant PTOA model,the effectiveness of this new approach was evaluated.Our studies show that this novel approach(Tz-TCO click chemistry)significantly enhanced the immobilization of healthy and metabolically active chondrocytes to the areas of apoptotic chondrocytes.Histological analyses demonstrated that this treatment regimen would significantly reduce the area of cartilage degeneration and enhance ECM regeneration.The results support that Tz-TCO click chemistry-mediated cell delivery approach has great potential in clinical applications for targeting and treatment of cartilage injury.

Repair of articular cartilage defects in minipigs by microfracture surgery and BMSCs transplantation

Objective:To investigate the feasibility of minimal invasive repair of cartilage defect by arthroscope-aided microfracture surgery and autologous transplantation of mesenchymal stem cells. Methods: Bone marrow of minipigs was taken out and the bone marrow derived mesenchymal stem cells (BMSCs) were isolated and cultured to passage 3. Then 6 minipigs were randomly divided into 2 groups with 6 knees in each group. After the articular cartilage defect was induced in each knee, the left defect received microfracture surgery and was injected with 2.5 ml BMSCs cells at a concentration of 3×107 cells/ml into the articular cavity; while right knee got single microfracture or served as blank control group. The animals were killed at 8 or 16 weeks, and the repair tissue was histologically and immunohistochemically examined for the presence of type Ⅱ collagen and glycosaminoglycans (GAGs) at 8 and 16 weeks. Results: Eight weeks after the surgery, the overlying articular surface of the cartilage defect showed normal color and integrated to adjacent cartilage. And 16 weeks after surgery, hyaline cartilage was observed at the repairing tissues and immunostaining indicated the diffuse presence of this type Ⅱ collagen and GAGs throughout the repair cartilage in the treated defects. Single microfracture group had the repairing of fibrocartilage, while during the treatment, the defects of blank group were covered with fewer fiber tissues, and no blood capillary growth or any immunological rejection was observed. Conclusion: Microfracture technique and BMSCs transplantation to repair cartilage defect is characterized with minimal invasion and easy operation, and it will greatly promote the regeneration repair of articular cartilage defect.

Comparative effectiveness of adipose-derived mesenchymal stromal cells in the management of knee osteoarthritis:A meta-analysis

BACKGROUND Osteoarthritis(OA)is the most common joint disorder,is associated with an increasing socioeconomic impact owing to the ageing population.AIM To analyze and compare the efficacy and safety of bone-marrow-derived mesenchymal stromal cells(BM-MSCs)and adipose tissue-derived MSCs(AD-MSCs)in knee OA management from published randomized controlled trials(RCTs).METHODS Independent and duplicate electronic database searches were performed,including PubMed,EMBASE,Web of Science,and Cochrane Library,until August 2021 for RCTs that analyzed the efficacy and safety of AD-MSCs and BM-MSCs in the management of knee OA.The visual analog scale(VAS)score for pain,Western Ontario McMaster Universities Osteoarthritis Index(WOMAC),Lysholm score,Tegner score,magnetic resonance observation of cartilage repair tissue score,knee osteoarthritis outcome score(KOOS),and adverse events were analyzed.Analysis was performed on the R-platform using OpenMeta(Analyst)software.Twenty-one studies,involving 936 patients,were included.Only one study compared the two MSC sources without patient randomization;hence,the results of all included studies from both sources were pooled,and a comparative critical analysis was performed.RESULTS At six months,both AD-MSCs and BM-MSCs showed significant VAS improvement(P=0.015,P=0.012);this was inconsistent at 1 year for BM-MSCs(P<0.001,P=0.539),and AD-MSCs outperformed BM-MSCs compared to controls in measures such as WOMAC(P<0.001,P=0.541),Lysholm scores(P=0.006;P=0.933),and KOOS(P=0.002;P=0.012).BM-MSC-related procedures caused significant adverse events(P=0.003)compared to AD-MSCs(P=0.673).CONCLUSION Adipose tissue is superior to bone marrow because of its safety and consistent efficacy in improving pain and functional outcomes.Future trials are urgently warranted to validate our findings and reach a consensus on the ideal source of MSCs for managing knee OA.

Adhesive hydrogels in osteoarthritis:from design to application

Osteoarthritis(OA)is the most common type of degenerative joint disease which affects 7%of the global population and more than 500 million people worldwide.One research frontier is the development of hydrogels for OA treatment,which operate either as functional scaffolds of tissue engineering or as delivery vehicles of functional additives.Both approaches address the big challenge:establishing stable integration of such delivery systems or implants.Adhesive hydrogels provide possible solutions to this challenge.However,few studies have described the current advances in using adhesive hydrogel for OA treatment.This review summarizes the commonly used hydrogels with their adhesion mechanisms and components.Additionally,recognizing that OA is a complex disease involving different biological mechanisms,the bioactive therapeutic strategies are also presented.By presenting the adhesive hydrogels in an interdisciplinary way,including both the fields of chemistry and biology,this review will attempt to provide a comprehensive insight for designing novel bioadhesive systems for OA therapy.

Tissue adhesive,ROS scavenging and injectable PRP-based‘plasticine’for promoting cartilage repair

Platelet-rich plasma(PRP)that has various growth factors has been used clinically in cartilage repair.However,the short residence time and release time at the injury site limit its therapeutic effect.The present study fabricated a granular hydrogel that was assembled from gelatin microspheres and tannic acid through their abundant hydrogen bonding.Gelatin microspheres with the gelatin concentration of 10wt%and the diameter distribution of 1-10 lm were used to assemble by tannic acid to form the granular hydrogel,which exhibited elasticity under low shear strain,but flowability under higher shear strain.The viscosity decreased with the increase in shear rate.Meanwhile,the granular hydrogel exhibited self-healing feature during rheology test.Thus,granular hydrogel carrying PRP not only exhibited well-performed injectability but also performed like a‘plasticine’that possessed good plasticity.The granular hydrogel showed tissue adhesion ability and reactive oxygen species scavenging ability.Granular hydrogel carrying PRP transplanted to full-thickness articular cartilage defects could integrate well with native cartilage,resulting in newly formed cartilage articular fully filled in defects and well-integrated with the native cartilage and subchondral bone.The unique features of the present granular hydrogel,including injectability,plasticity,porous structure,tissue adhesion and reactive oxygen species scavenging provided an ideal PRP carrier toward cartilage tissue engineering.

Strategies to minimize hypertrophy in cartilage engineering and regeneration

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.

Bioprinting and regeneration of auricular cartilage using a bioactive bioink based on microporous photocrosslinkable acellular cartilage matrix

Tissue engineering provides a promising strategy for auricular reconstruction.Although the first international clinical breakthrough of tissue-engineered auricular reconstruction has been realized based on polymer scaffolds,this approach has not been recognized as a clinically available treatment because of its unsatisfactory clinical efficacy.This is mainly since reconstruction constructs easily cause inflammation and deformation.In this study,we present a novel strategy for the development of biological auricle equivalents with precise shapes,low immunogenicity,and excellent mechanics using auricular chondrocytes and a bioactive bioink based on biomimetic microporous methacrylate-modified acellular cartilage matrix(ACMMA)with the assistance of gelatin methacrylate(GelMA),poly(ethylene oxide)(PEO),and polycaprolactone(PCL)by integrating multi-nozzle bioprinting technology.Photocrosslinkable ACMMA is used to emulate the intricacy of the cartilage-specific microenvironment for active cellular behavior,while GelMA,PEO,and PCL are used to balance printability and physical properties for precise structural stability,form the microporous structure for unhindered nutrient exchange,and provide mechanical support for higher shape fidelity,respectively.Finally,mature auricular cartilage-like tissues with high morphological fidelity,excellent elasticity,abundant cartilage lacunae,and cartilage-specific ECM deposition are successfully regenerated in vivo,which provides new opportunities and novel strategies for the fabrication and regeneration of patient-specific auricular cartilage.