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Mid-term outcomes of microfragmented adipose tissue plus arthroscopic surgery for knee osteoarthritis:A randomized,activecontrol,multicenter clinical trial

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World Journal of Stem Cells 2023年第12期15卷 1063-1076页

作者： Cong-Zi Wu Zhen-Yu Shi Zhen Wu Wen-Jun Lin Wei-Bo Chen Xue-Wen Jia Si-Cheng Xiang Hui-Hui Xu Qin-Wen Ge Kai-Ao Zou Xu Wang Jia-Li Chen Ping-Er Wang Wen-Hua Yuan Hong-Ting Jin Pei-Jian Tong Institute of Orthopaedics and Traumatology of Zhejiang Province The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310053Zhejiang ProvinceChina epartment of Orthopedic Surgery The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou 310006Zhejiang ProvinceChina Department of Orthopaedic Surgery Tongde Hospital of Zhejiang ProvinceHangzhou 310012China Department of Orthopaedic Surgery The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325015Zhejiang ProvinceChina Department of Orthopaedic Surgery Ruian Hospital of Traditional Chinese MedicineWenzhou 325299Zhejiang ProvinceChina Department of Orthopaedics Ningbo First HospitalNingbo 315010Zhejiang ProvinceChina The First College of Clinical Medicine Zhejiang Chinese Medical UniversityHangzhou 310053Zhejiang ProvinceChina

BACKGROUND osteoarthritis(OA)is the most prevalent form of degenerative whole-joint disease.Before the final option of knee replacement,arthroscopic surgery was the most widely used joint-preserving surgical treatment.Emerging regenerative therapies,such as those involving platelet-rich plasma,mesenchymal stem cells,and microfragmented adipose tissue(MFAT),have been pushed to the forefront of treatment to prevent the progression of OA.Currently,MFAT has been successfully applied to treat different types of orthopedic diseases.AIM To assess the efficacy and safety of MFAT with arthroscopic surgery in patients with knee OA(KOA).METHODS A randomized,multicenter study was conducted between June 2017 and November 2022 in 10 hospitals in Zhejiang,China.Overall,302 patients diagnosed with KOA(Kellgren-Lawrence grades 2-3)were randomized to the MFAT group(n=151,were administered MFAT following arthroscopic surgery),or the control group(n=151,were administered hyaluronic acid following arthroscopic surgery).The study outcomes were changes in the Western Ontario and McMaster Universities osteoarthritis Index(WOMAC)score,the visual analog scale(VAS)score,the Lequesne index score,the Whole-Organ Magnetic Resonance Imaging Score(WORMS),and safety over a 24-mo period from baseline.RESULTS The changes in the WOMAC score(including the three subscale scores),VAS pain score,and Lequesne index score at the 24-mo mark were significantly different in the MFAT and control groups,as well as when comparing values at the posttreatment visit and those at baseline(P<0.001).The MFAT group consistently demonstrated significant decreases in the WOMAC pain scores and VAS scores at all follow-ups compared to the control group(P<0.05).Furthermore,the WOMAC stiffness score,WOMAC function score,and Lequesne index score differed significantly between the groups at 12 and 24 mo(P<0.05).However,no signicant between-group differences were observed in the WORMS at 24 mo(P=0.367).No serious adverse events occurred in both groups.CONCLUSION The MFAT inj

关键词： osteoarthritis Microfragmented adipose tissue Lipogems Arthroscopic surgery Knee

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Regulatory role of NFAT1 signaling in articular chondrocyteactivities and osteoarthritis pathogenesis

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BIOCELL 2023年第10期47卷 2125-2132页

作者： MINGCAI ZHANG TANNER CAMPBELL SPENCER FALCON JINXI WANG Harrington Laboratory for Molecular Orthopedics Department of Orthopedic SurgeryUniversity of Kansas Medical CenterKansas CityUSA

osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartilage remains themajor hallmark of the disease. Current treatments targeting OA symptoms have a limited impact on impeding orreversing the OA progression. Understanding the molecular and cellular mechanisms underlying OA development isa critical barrier to progress in OA therapy. Recent studies by the current authors’ group and others have revealedthat the nuclear factor of activated T cell 1 (NFAT1), a member of the NFAT family of transcription factors, regulatesthe expression of many anabolic and catabolic genes in articular chondrocytes of adult mice. Mice lacking NFAT1exhibit normal skeletal development but display OA in both appendicular and spinal facet joints as adults. Thisreview mainly focuses on the recent advances in the regulatory role of NFAT1 transcription factor in the activities ofarticular chondrocytes and its implication in the pathogenesis of OA.

关键词： osteoarthritis Chondrocyte NFAT1 Transcription factor Regulation of gene expression

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Wharton’s jelly MSC-derived extracellular vehicles-loaded hyaluronic acid-alginate adhesives for treatment of osteoarthritis

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Journal of Materials Science & Technology 2023年第11期142卷 240-252页

作者： Yanhong Zhao Xige Zhao Hainan Xu Yi Xing Tengling Wu Xun Sun Mingjie Kuang Xinlong Ma Wenguang Liu Qiang Yang School and Hospital of Stomatology Tianjin Medical UniversityTianjin 300070China School of Materials Science and Engineering Tianjin Key Laboratory of Composite and Functional MaterialsTianjin UniversityTianjin 300350China Department of Spine Surgery Tianjin HospitalTianjin UniversityTianjin 300211China Laboratory of Molecular Signaling and Stem Cells Therapy Molecular Laboratory for Gene Therapy and Tooth RegenerationBeijing Key Laboratory of Tooth Regeneration and Function ReconstructionCapital Medical University School of StomatologyBeijing 100050China Department of Orthopedics the Provincial Hospital Affiliated to Shandong UniversityShandong 250014China

The repair of cartilage injury caused by osteoarthritis(OA)has long plagued clinicians.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(sEVs)show great potential in cartilage regeneration and immunoregulation to realise cell-free therapy.However,unprotected sEVs are prone to be washed away by the flow of fluids and degraded in vivo.In this work,we successfully revealed that human Wharton’s jelly of umbilical cord-derived MSC(hWJMSC)sEVs promote proliferation,inhibit apoptosis,and attenuate the inflammation of chondrocytes in vitro.In light of the long period required for cartilage regeneration,we synthesised an injectable and adhesive aldehyded sodium alginate crosslinked acylhydrazide-modified hyaluronic acid(ALG-CHO/HHA)hydrogel loaded with sEVs to boost the reparative effect of the sEVs.The hydrogel-bearing sEVs was injected into cartilage defects where they adhered to the cartilage surface.In this configuration,the sEVs were delivered in a sustainable manner with the degradation of the hydrogel at the injury sites,thus contributing to highly efficient cartilage repair by regulating the regenerative and immune microenvironment.The ALG-CHO/HHA-sEV platform meets the clinical demand for long-lasting repair with a single injection.Thus,this work provides a new idea and theoretical basis for the clinical application of sEVs in the treatment of OA.

关键词： Extracellular vesicles Hydrogel osteoarthritis Cartilage regeneration

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Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain

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World Journal of Stem Cells 2023年第4期15卷 196-208页

作者： Fatimah Almahasneh Ejlal Abu-El-Rub Ramada R Khasawneh Basic Medical Sciences Faculty of Medicine-Yarmouk UniversityIrbid 21163Jordan

osteoarthritis(OA)is the most common musculoskeletal disease,and it is a major cause of pain,disability and health burden.Pain is the most common and bothersome presentation of OA,but its treatment is still suboptimal,due to the short-term action of employed analgesics and their poor adverse effect profile.Due to their regenerative and anti-inflammatory properties,mesenchymal stem cells(MSCs)have been extensively investigated as a potential therapy for OA,and numerous preclinical and clinical studies found a significant improvement in joint pathology and function,pain scores and/or quality of life after administration of MSCs.Only a limited number of studies,however,addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs.In this paper,we review the evidence reported in literature that support the analgesic action of MSCs in OA,and we summarize the potential mechanisms of these antinociceptive effects.

关键词： osteoarthritis Pain Inflammation Mesenchymal stem cells Regeneration Analgesic mechanisms

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Usefulness of the acromioclavicular joint cross-sectional area as a diagnostic image parameter of acromioclavicular osteoarthritis

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World Journal of Clinical Cases 2022年第7期10卷 2087-2094页

作者： Young Joo Jee Youn Moon Jung Youn Han Yun-Sic Bang Keum Nae Kang Young Su Lim Young-SoonChoi Young-Uk Kim Department of Anesthesiology and Pain Medicine CHA Ilsan Medical CenterSchool of MedicineCHA UniversityIlsanGyeonggi-do 10414South Korea Department of Anesthesiology and Pain Medicine Seoul National University Hospital College of MedicineSeoul 03080South Korea Department of Anesthesiology and Pain Medicine CHA Bundang Medical CenterSchool of MedicineSeongnamGyeonggi-do 13496South Korea Department of Anesthesiology and Pain Medicine National Police HospitalSeoul 05715South Korea Department of Anesthesiology and Pain Medicine Catholic Kwandong UniversityCollege of MedicineInternational St.Mary’s HospitalIncheon 22711South Korea

BACKGROUND Acromioclavicular joint(ACJ)space narrowing has been considered to be an important diagnostic image parameter of ACJ osteoarthritis(ACJO).However,the morphology of the ACJ space is irregular because of osteophyte formation,subchondral irregularity,capsular distention,sclerosis,and erosion.Therefore,we created the ACJ cross-sectional area(ACJCSA)as a new diagnostic image parameter to assess the irregular morphologic changes of the ACJ.AIM To hypothesize that the ACJCSA is a new diagnostic image parameter for ACJO.METHODS ACJ samples were obtained from 35 patients with ACJO and 30 healthy individuals who underwent shoulder magnetic resonance(S-MR)imaging that revealed no evidence of ACJO.Oblique coronal,T2-weighted,fat-suppressed SMR images were acquired at the ACJ level from the two groups.We measured the ACJCSA and the ACJ space width(ACJSW)at the ACJ on the S-MR images using our imaging analysis program.The ACJCSA was measured as the cross-sectional area of the ACJ.The ACJSW was measured as the narrowest point between the acromion and the clavicle.RESULTS The average ACJCSA was 39.88±10.60 mm;in the normal group and 18.80±5.13 mm;in the ACJO group.The mean ACJSW was 3.51±0.58 mm in the normal group and 2.02±0.48 mm in the ACJO group.ACJO individuals had significantly lower ACJCSA and ACJSW than the healthy individuals.Receiver operating characteristic curve analyses demonstrated that the most suitable ACJCSA cutoff score was 26.14 mm^(2),with 91.4%sensitivity and 90.0%specificity.CONCLUSION The optimal ACJSW cutoff score was 2.37 mm,with 88.6%sensitivity and 96.7%specificity.Even though both the ACJCSA and ACJSW were significantly associated with ACJO,the ACJCSA was a more sensitive diagnostic image parameter.

关键词： Acromioclavicular joint osteoarthritis Cross-sectional area Diagnosis

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Reactive oxygen species-scavenging nanoparticles coated with chondroitin sulfate protect cartilage against osteoarthritis in vivo

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Nano Research 2023年第2期16卷 2786-2797页

作者： Zhaoyi Wang Hao Xiong Zihe Zhai Yuejun Yao Tong Zhou Haolan Zhang Cunyi Fan Changyou Gao MOE Key Laboratory of Macromolecular Synthesis and Functionalization International Research Center for X PolymersDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou 310027China Department of Orthopedics Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai 200233China Center for Healthcare Materials Shaoxing InstituteZhejiang UniversityShaoxing 312035China Department of Orthopedics The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration Building 3Langu Science and Technology ParkLane 70Haiji 6th RoadShanghai 201306China

osteoarthritis(OA)is a prevalent chronic inflammatory disease in joints.Current interventions confront systemic toxicity and insufficient bioavailability.The unbalanced microenvironment of OA joints mainly fosters over-expressed reactive oxygen species(ROS),extracellular matrix disintegration,and apoptosis of chondrocytes.In this study,a kind of ROS-scavenging,biodegradable and drug-free nanoparticles(PP NPs)were constructed by the crosslinking of poly(propylene fumarate)(PPF)and ROS-scavenging poly(thioketal)(PTK).The high content of PTK and high crosslinking density of PPF and PTK innovatively endowed the NPs with slow degradation and prolonged ROS-elimination ability.The NPs were further surface-modified with chondroitin sulfate(CS),one of the dietary supplements for osteoarthritis.The intrinsic properties of resultant PP-CS NPs were excavated in vitro and in vivo.The PP-CS NPs could desirably consume 1,10-diphenyl-2-picrylhydrazyl(DPPH)radicals without toxicity to RAW264.7 cells in vitro.With an average diameter of~300 nm,the PP-CS NPs could be intra-articular administrated in OA rats and showed prolonged joint retention time,allowing only one injection per month.Moreover,the PP-CS NPs possessed a prolonged ROS depletion and M2 macrophage induction effect,down-regulated inflammatory cytokines,and reduced glycosaminoglycans loss.Consequently,the PP-CS NPs protected articular surface erosion,inhibited uneven cartilage matrix,and attenuated OA progression.

关键词： reactive oxygen species polythioketal osteoarthritis nanoparticles chondroitin sulfate

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A low dose cell therapy system for treating osteoarthritis:In vivo study and in vitro mechanistic investigations

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Bioactive Materials 2022年第1期7卷 478-490页

作者： Bin Wang Wei Liu Jiao Jiao Li Senlin Chai Dan Xing Hongsheng Yu Yuanyuan Zhang Wenjin Yan Zhihong Xu Bin Zhao Yanan Du Qing Jiang Department of Sports Medicine and Adult Reconstruction Surgery Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing201180China Department of Orthopaedics Shanxi Medical University Second Affiliated HospitalTaiyuan030001China Beijing CytoNiche Biotechnology Co.Ltd Beijing10081China School of Biomedical Engineering Faculty of Engineering and ITUniversity of Technology SydneyUltimoNSW2007Australia Laboratory for Bone and Joint Disease Model Animal Research Center(MARC)Nanjing UniversityNanjing210093China Arthritis Clinic&Research Center Peking University People’s HospitalPeking UniversityBeijing100044China Department of Biomedical Engineering School of MedicineTsinghua-Peking Center for Life SciencesTsinghua UniversityBeijing100084China

Mesenchymal stem cells(MSCs)can be effective in alleviating the progression of osteoarthritis(OA).However,low MSC retention and survival at the injection site frequently require high doses of cells and/or repeated injections,which are not economically viable and create additional risks of complications.In this study,we produced MSC-laden microcarriers in spinner flask culture as cell delivery vehicles.These microcarriers containing a low initial dose of MSCs administered through a single injection in a rat anterior cruciate ligament(ACL)transection model of OA achieved similar reparative effects as repeated high doses of MSCs,as evaluated through imaging and histological analyses.Mechanistic investigations were conducted using a co-culture model involving human primary chondrocytes grown in monolayer,together with MSCs grown either within 3D constructs or as a monolayer.Co-culture supernatants subjected to secretome analysis showed significant decrease of inflammatory factors in the 3D group.RNA-seq of co-cultured MSCs and chondrocytes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis revealed processes relating to early chondrogenesis and increased extracellular matrix interactions in MSCs of the 3D group,as well as phenotypic maintenance in the co-cultured chondrocytes.The cell delivery platform we investigated may be effective in reducing the cell dose and injection frequency required for therapeutic applications.

关键词： osteoarthritis Mesenchymal stem cells Microcarriers Tissue engineering Transcriptome

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Tropoelastin improves adhesion and migration of intra-articular injected infrapatellar fat pad MSCs and reduces osteoarthritis progression

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Bioactive Materials 2022年第4期7卷 443-459页

作者： Junjun Yang Xin Wang Yahan Fan Xiongbo Song Jiangyi Wu Zhenlan Fu Tao Li Yang Huang ZheXiong Tang Shuo Meng Na Liu Jiajia Chen Pingju Liu Liu Yang Xiaoyuan Gong Cheng Chen Center for Joint Surgery Southwest HospitalArmy Medical University(Third Military Medical University)Chongqing400038China College of Medical Informatics Chongqing Medical UniversityChongqing400016China Blood Transfusion Department Southwest HospitalArmy Medical University(Third Military Medical University)Chongqing400038China Department of Sports Medicine Peking University Shenzhen HospitalPeking UniversityShenzhen518036China Key Laboratory of Freshwater Fish Reproduction and Development Ministry of EducationLaboratory of Molecular Developmental BiologySchool of Life SciencesSouthwest UniversityChongqing400038China Biomedical Analysis Center Army Medical University(Third Military Medical University)Chongqing400038China Department of Orthopedics Zunyi Traditional Chinese Medicine HospitalZunyi563099China

Intra-articular injection of mesenchymal stem cells(MSCs)is a promising strategy for osteoarthritis(OA)treatment.However,more and more studies reveal that the injected MSCs have poor adhesion,migration,and survival in the joint cavity.A recent study shows that tropoelastin(TE)regulates adhesion,proliferation and phenotypic maintenance of MSCs as a soluble additive,indicating that TE could promote MSCs-homing in regenerative medicine.In this study,we used TE as injection medium,and compared it with classic media in MSCs intra-articular injection such as normal saline(NS),hyaluronic acid(HA),and platelet-rich plasma(PRP).We found that TE could effectively improve adhesion,migration,chondrogenic differentiation of infrapatellar fat pad MSCs(IPFP-MSCs)and enhance matrix synthesis of osteoarthritic chondrocytes(OACs)in indirect-coculture system.Moreover,TE could significantly enhance IPFP-MSCs adhesion via activation of integrin β1,ERK1/2 and vinculin(VCL)in vitro.In addition,intra-articular injection of TE-IPFP MSCs suspension resulted in a short-term increase in survival rate of IPFP-MSCs and better histology scores of rat joint tissues.Inhibition of integrin β1 or ERK1/2 attenuated the protective effect of TE-IPFP MSCs suspension in vivo.In conclusion,TE promotes performance of IPFP-MSCs and protects knee cartilage from damage in OA through enhancement of cell adhesion and activation of integrin β1/ERK/VCL pathway.Our findings may provide new insights in MSCs intra-articular injection for OA treatment.

关键词： Tropoelastin osteoarthritis Infrapatellar fat pad MSCs

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Cartilage-targeting and inflammatory-responsive nanocarriers for effective osteoarthritis treatment via reactive oxygen species scavenging and anti-angiogenesis

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Journal of Materials Science & Technology 2023年第12期143卷 30-42页

作者： Sixiang Wang Yan Gao Lili Dong Peixing Chen Wanqian Liu Li Yang National Innovation and Attracting Talents“111”base Key Laboratory of Biorheological Science and TechnologyMinistry of EducationCollegeof BioengineeringChongqing UniversityChongqing 400030China Department of Orthopaedics The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400042China Chongqing Key Laboratory of Nano/Micro Composite Material and Device School of Metallurgy and Materials EngineeringChongqing University of Science and TechnologyChongqing 401331China

osteoarthritis(OA),a common disabling joint disease,is highly associated with microenvironmental changes in the cartilage and subchondral bone.Elevated reactive oxygen species(ROS)in the cartilage and subchondral bone angiogenesis accelerate articular cartilage erosion.New cartilage-targeting drug deliv-ery systems that are aimed at preventing ROS production and angiogenesis may be of clinical significance for OA treatment.Herein,an ROS scavenger and an inflammatory-responsive nanocarrier are designed by immobilizing the natural polyphenol(curcumin)in chitosan-catechol nanoformulations(Cur-CS-C NPs)via boronate ester.The robust cartilage-targeting effects and ROS scavenging capacities of Cur-CS-C NPs were respectively determined in cartilage explants and chondrocytes.Intra-articular injection of Cur-CS-C NPs in OA rat models efficiently suppressed angiogenesis and cartilage degradation partially via the ROS-mediated NF-κB/PI3K-Akt signaling pathway.The developed curcumin-functionalized nanocarriers can significantly delay OA progression and provide a promising therapeutic strategy for other inflamma-tory diseases that are characterized by oxidative stress and angiogenesis.

关键词： osteoarthritis Reactive oxygen species Angiogenesis Cartilage-targeting Drug delivery systems Chitosan-catechol nanocarriers

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LOXL3 Inhibits Autophagy of Chondrocytes by Activating Rheb in osteoarthritis

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Current Medical Science 2023年第6期43卷 1195-1200页

作者： Guang-ping ZHENG Chen LIU Liang ZHANG Qiang ZHONG Yun ZHANG Zhong-ming HUANG Ganzhou Municipal Key Laboratory of Bone and Joint Research The Affiliated Ganzhou Hospital of Nanchang UniversityGanzhou341000China Research Center of Translational Medicine Jinan Central Hospital Affiliated to Shandong First Medical UniversityJinan250013China

Objective This study aimed to investigate the potential mechanisms by which lysyl oxidase like 3(LOXL3)affects the autophagy in chondrocytes in osteoarthritis(OA),specifically through the activation of mammalian target of rapamycin complex 1(mTORC1).Methods To establish an OA model,rats underwent anterior cruciate ligament transection(ACLT).Chondrocytes were isolated from cartilage tissues and cultured.Western blotting was performed to assess the expression of LOXL3,Rheb,phosphorylation of p70S6K(p-p70S6K,a downstream marker of mTORC1),and autophagy markers.The autophagy of chondrocytes was observed using an immunofluorescence assay.Results The expression levels of both LOXL3 and Rheb proteins were upregulated in chondrocytes isolated from the OA model cartilage,in comparison to those from the normal cartilage.The silencing of LOXL3 resulted in a decrease in the protein levels of Rheb and p-p70S6K,as well as an increase in the expression of autophagy-related proteins.Additionally,the effect of LOXL3 could be reversed through the silencing of Rheb.The results of the immunofluorescence assay confirmed the impact of LOXL3 and Rheb on chondrocyte autophagy.Conclusion LOXL3 inhibits chondrocyte autophagy by activating the Rheb and mTORC1 signaling pathways.

关键词： osteoarthritis LOXL3 Rheb mTORC1 chondrocyte autophagy

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