Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous di...Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.展开更多
Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities an...Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA,particularly in younger individuals.Metabolic abnormalities,such as obesity and typeⅡdiabetes,are strongly linked to OA,and they affect both weightbearing and non-weight-bearing joints,thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight.This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk,including the impact of abnormal glucose and lipid metabolism,the potential pathogenesis and targeted therapeutic strategies.展开更多
Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined ...Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined the role ofβ-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit(FSU),which includes the intervertebral disc,vertebra and facet joint and is the smallest physiological motion unit of the spine.We showed that pain sensitivity in patients with spinal degeneration is highly correlated withβ-catenin protein levels.We then generated a mouse model of spinal degeneration by transgenic expression of constitutively activeβ-catenin in Col2^(+) cells.We found thatβ-catenin-TCF7 activated the transcription of CCL2,a known critical factor in osteoarthritic pain.Using a lumbar spine instability model,we showed that aβ-catenin inhibitor relieved low back pain.Our study indicates thatβ-catenin plays a critical role in maintaining spine tissue homeostasis,its abnormal upregulation leads to severe spinal degeneration,and its targeting could be an avenue to treat this condition.展开更多
Individual behaviors, such as drinking, smoking, screen time, and physical activity, can be strongly influenced by the behavior of friends. At the same time, the choice of friends can be influenced by shared behaviora...Individual behaviors, such as drinking, smoking, screen time, and physical activity, can be strongly influenced by the behavior of friends. At the same time, the choice of friends can be influenced by shared behavioral preferences. The actor-based stochastic models (ABSM) are developed to study the interdependence of social networks and behavior. These methods are efficient and useful for analysis of discrete behaviors, such as drinking and smoking;however, since the behavior evolution function is in an exponential format, the ABSM can generate inconsistent and unrealistic results when the behavior variable is continuous or has a large range, such as hours of television watched or body mass index. To more realistically model continuous behavior variables, we propose a co-evolution process based on a linear model which is consistent over time and has an intuitive interpretation. In the simulation study, we applied the expectation maximization (EM) and Markov chain Monte Carlo (MCMC) algorithms to find the maximum likelihood estimate (MLE) of parameter values. Additionally, we show that our assumptions are reasonable using data from the National Longitudinal Study of Adolescent Health (Add Health).展开更多
Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved ...Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved in OA development. Among these risk factors, alterations of mechanical loading in the joint leading to changes in biological signaling pathways have been known as a key event in OA development. The importance of AMPK-β-catenin-Runx2 signaling in the initiation and progression of OA has been recognized in recent years. In this review, we discuss the recent progress in understanding the role of this signaling pathway and the underlying interaction mechanisms during OA development. We also discuss the drug development aiming to target this signaling pathway for OA treatment.展开更多
Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing ...Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.展开更多
This open-label,single-arm,phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy,followed by adjuvant sintilimab,for resectable NSCLC.Forty-five patients re...This open-label,single-arm,phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy,followed by adjuvant sintilimab,for resectable NSCLC.Forty-five patients received anlotinib(10 mg,QD,PO,days 1-14),sintilimab(200 mg,day 1),and platinum-based chemotherapy of each three-week cycle for 3 cycles,followed by surgery within 4-6 weeks.Adjuvant sintilimab(200 mg)was administered every 3 weeks.The primary endpoint was achieving a pathological complete response(pCR).From June 10,2021 through October 10,2023,45 patients were enrolled and composed the intention-to-treat population.Twenty-six patients(57.8%)achieved pCR,and 30(66.7%)achieved major pathological response(MPR).Forty-one patients underwent surgery.In the per-protocol set(PP set),63.4%(26/41)achieved pCR,and 73.2%achieved MPR.The median event-free survival was not attained(95%CI,25.1-NE).During the neoadjuvant treatment phase,grade 3 or 4 treatment-related adverse events were observed in 25 patients(55.6%),while immune-related adverse events were reported in 7 patients(15.6%).We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC.Significant tumor microenvironment changes were observed in pCR patients,including reduced VEGF+cells and CD4+Foxp3+Treg cells,and increased perivascular CD4+T cells,CD39+CD8+T cells,and M1 macrophages.In conclusion,perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment(ClinicalTrials.gov NCT05400070).展开更多
Universal coatings with versatile surface adhesion,good mechanochemical robustness,and the capacity for secondary modification are of great scientific interest.However,incorporating these advantages into a system is s...Universal coatings with versatile surface adhesion,good mechanochemical robustness,and the capacity for secondary modification are of great scientific interest.However,incorporating these advantages into a system is still a great challenge.Here,we report a series of catechol-decorated polyallylamines(CPAs),denoted as pseudo-Mytilus edulis foot protein 5(pseudoMefp-5),that mimic not only the catechol and amine groups but also the backbone of Mefp-5.CPAs can fabricate highly adhesive,robust,multifunctional polyCPA(PCPA)coatings based on synergetic catechol-polyamine chemistry as universal building blocks.Due to the interpenetrating entangled network architectures,these coatings exhibit high chemical robustness against harsh conditions(HCl,pH 1;NaOH,pH 14;H2O2,30%),good mechanical robustness,and wear resistance.In addition,PCPA coatings provide abundant grafting sites,enabling the fabrication of various functional surfaces through secondary modification.Furthermore,the versatility,multifaceted robustness,and scalability of PCPA coatings indicate their great potential for surface engineering,especially for withstanding harsh conditions in multipurpose biomedical applications.展开更多
Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment ...Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment is to relieve the pain.During OA progression,nerve ingrowth was observed in synovial tissue and articular cartilage.These abnormal neonatal nerves act as nociceptors to detect OA pain signals.The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system(CNS)is currently unknown.MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis.However,the role of miR-204 in OA pain has not been determined.In this study,we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model.Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1-LDL Receptor Related Protein 1(LRP1)signaling and blocking neuro-cartilage interaction in the joint.Our studies defined novel molecular targets for the treatment of OA pain.展开更多
Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferi...Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.展开更多
Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk facto...Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk factors,such as aging,mechanical overloading,trauma,overuse,etc.are involved in OA development.Several approaches have been utilized to repair cartilage defects.Among them,biomaterials-based mes-enchymal stromal cell(MSCs)therapy is considered as the most promising modality.The burgeoning material science and manufacturing technologies,such as 3D printing,allow us to mimic native articu-lar cartilage and regulate the artificial cartilage development,regeneration and functional restoration.In this review article,we will summarize the recent progress of biomaterials combined with MSCs or chon-drocytes in repairing cartilage damage induced by OA.Several typical natural and synthetic biomaterials,such as collagen,alginate,hyaluronic acid and poly(ethylene glycol),polylactide acid,polyurethane,etc.for cartilage repairing will be introduced.Moreover,critical signaling pathways associated with the pro-gression of OA,as well as the targeted pharmacologic,genetic therapies and tissue engineering scaffolds for OA and cartilage repairing are presented.We will also provide our prospects for future directions in this active research area.展开更多
The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix(ECM)-mimicking biomaterials.However,designing control...The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix(ECM)-mimicking biomaterials.However,designing controllable multivalency construction strategies is still challenging.Herein,we synthesized a series of well-defined multivalent antimicrobial peptide polymers(mAMPs)by clicking ligand molecules onto polymers prepared by reversible addition-fragmentation chain transfer polymerization.The multiple cationic ligands in the mAMPs could enhance the local disturbance of the anionic phospholipid layer of the bacterial membrane through multivalent binding,leading to amplification of the bactericidal effect.In addition to multivalency-enhanced antibacterial activity,mAMPs also enable multivalency-assisted hydrogel fabrication with an ECM-like dynamic structure.The resultant hydrogel with self-healing and injectable properties could be successfully employed as an antibacterial biomaterial scaffold to treat infected skin wounds.The multivalency construction strategy presented in this work provides new ideas for the biomimetic design of highly active and dynamic biomaterials for tissue repair and regeneration.展开更多
The immune responses are involved in every stage after implantation but the reported immune-regulated materials only work at the beginning without fully considering the different phases of bone healing.Here,poly(aryl-...The immune responses are involved in every stage after implantation but the reported immune-regulated materials only work at the beginning without fully considering the different phases of bone healing.Here,poly(aryl-ether-ether-ketone)(PEEK)is coated with a programmed surface,which rapidly releases interleukin-10(IL-10)in the first week and slowly delivers dexamethasone(DEX)up to 4 weeks.Owing to the synergistic effects of IL-10 and DEX,an aptly weak inflammation is triggered within the first week,followed by significant M2 polarization of macrophages and upregulation of the autophagy-related factors.The suitable immunomodulatory activities pave the way for osteogenesis and the steady release of DEX facilitates bone regeneration thereafter.The sequential immune-mediated process is also validated by an 8-week implementation on a rat model.This is the first attempt to construct implants by taking advantage of both immune-mediated modulation and sequential regulation spanning all bone regeneration phases,which provides insights into the fabrication of advanced biomaterials for tissue engineering and immunological therapeutics.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342,and 82172397)to D.C.and L.T.a grant from the Youth Innovation Promotion Association of the Chinese Academy of Sciences(2020353)to L.T.+1 种基金supported by the National Key Research and Development Program of China(2021YFB3800800 to L.T.and D.C)supported by the research grant NIH AG0599775.
文摘Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.
基金supported by the National Key Research and Development Program of China(2021YFB3800800)to L.T.and D.Csupported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to D.C.,grant 82360429 to Y.C and grant 82172397 to L.T+5 种基金supported by National Science Foundation of Guangxi(2022JJA141126)Advanced Innovation Teams and Xinghu Scholars Program of Guangxi Medical UniversityChina Postdoctoral Science Foundation(2019M650235)Key R&D Project of Qingxiu District,Nanning,Guangxi(2021003)to Y.C.the Hong Kong RGC grant HKU-17101821 to W.W.L.and D.C.SIAT Innovation Program for Excellent Young Researchers to K.L.
文摘Although aging has traditionally been viewed as the most important risk factor for osteoarthritis(OA),an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA,particularly in younger individuals.Metabolic abnormalities,such as obesity and typeⅡdiabetes,are strongly linked to OA,and they affect both weightbearing and non-weight-bearing joints,thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight.This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk,including the impact of abnormal glucose and lipid metabolism,the potential pathogenesis and targeted therapeutic strategies.
基金supported by the National Key Research and Development Program of China(2021YFB3800800)to L.T.and D.C.supported by the National Natural Science Foundation of China(NSFC)grants 82030067,82161160342,and 82250710174 to D.C.+1 种基金NSFC grant 82172397 to L.T.supported by the Chinese Postdoctoral Science Foundation(2022M710158)。
文摘Spine degeneration is an aging-related disease,but its molecular mechanisms remain unknown,although elevatedβ-catenin signaling has been reported to be involved in intervertebral disc degeneration.Here,we determined the role ofβ-catenin signaling in spinal degeneration and in the homeostasis of the functional spinal unit(FSU),which includes the intervertebral disc,vertebra and facet joint and is the smallest physiological motion unit of the spine.We showed that pain sensitivity in patients with spinal degeneration is highly correlated withβ-catenin protein levels.We then generated a mouse model of spinal degeneration by transgenic expression of constitutively activeβ-catenin in Col2^(+) cells.We found thatβ-catenin-TCF7 activated the transcription of CCL2,a known critical factor in osteoarthritic pain.Using a lumbar spine instability model,we showed that aβ-catenin inhibitor relieved low back pain.Our study indicates thatβ-catenin plays a critical role in maintaining spine tissue homeostasis,its abnormal upregulation leads to severe spinal degeneration,and its targeting could be an avenue to treat this condition.
文摘Individual behaviors, such as drinking, smoking, screen time, and physical activity, can be strongly influenced by the behavior of friends. At the same time, the choice of friends can be influenced by shared behavioral preferences. The actor-based stochastic models (ABSM) are developed to study the interdependence of social networks and behavior. These methods are efficient and useful for analysis of discrete behaviors, such as drinking and smoking;however, since the behavior evolution function is in an exponential format, the ABSM can generate inconsistent and unrealistic results when the behavior variable is continuous or has a large range, such as hours of television watched or body mass index. To more realistically model continuous behavior variables, we propose a co-evolution process based on a linear model which is consistent over time and has an intuitive interpretation. In the simulation study, we applied the expectation maximization (EM) and Markov chain Monte Carlo (MCMC) algorithms to find the maximum likelihood estimate (MLE) of parameter values. Additionally, we show that our assumptions are reasonable using data from the National Longitudinal Study of Adolescent Health (Add Health).
基金supported by National Key Research and Development Program of China(No.2021YFB3800800 to D.C.and L.T)the National Natural Science Foundation of China(No.82030067,82250710174,82161160342,82060406,82360429 and 82172397 to D.C.and L.T.and Y.C.)+2 种基金the Hong Kong RGC(China)(No.HKU-17101821 to W.W.L and D.C.)Shenzhen Science and Technology Program(Guangdong,China)(No.JSGGKQTD20210831174330015 to H.P.and D.C.)Natural Science Foundation of Guangxi(No.2022JJA141126 to Y.C.).
文摘Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved in OA development. Among these risk factors, alterations of mechanical loading in the joint leading to changes in biological signaling pathways have been known as a key event in OA development. The importance of AMPK-β-catenin-Runx2 signaling in the initiation and progression of OA has been recognized in recent years. In this review, we discuss the recent progress in understanding the role of this signaling pathway and the underlying interaction mechanisms during OA development. We also discuss the drug development aiming to target this signaling pathway for OA treatment.
基金supported by National Key Research and Development Program of China(2021YFB3800800)to Di Chen and Liping Tongsupported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to Di Chen+1 种基金grant(82302757)to Ke Lusupported by SIAT Innovation Program for Excellent Young Researchers.
文摘Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.
基金funded by the National Natural Science Foundation of China(Grant No.82173252)the Miaozi Talent Fund of Tangdu Hospital,Air Force Medical University.
文摘This open-label,single-arm,phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy,followed by adjuvant sintilimab,for resectable NSCLC.Forty-five patients received anlotinib(10 mg,QD,PO,days 1-14),sintilimab(200 mg,day 1),and platinum-based chemotherapy of each three-week cycle for 3 cycles,followed by surgery within 4-6 weeks.Adjuvant sintilimab(200 mg)was administered every 3 weeks.The primary endpoint was achieving a pathological complete response(pCR).From June 10,2021 through October 10,2023,45 patients were enrolled and composed the intention-to-treat population.Twenty-six patients(57.8%)achieved pCR,and 30(66.7%)achieved major pathological response(MPR).Forty-one patients underwent surgery.In the per-protocol set(PP set),63.4%(26/41)achieved pCR,and 73.2%achieved MPR.The median event-free survival was not attained(95%CI,25.1-NE).During the neoadjuvant treatment phase,grade 3 or 4 treatment-related adverse events were observed in 25 patients(55.6%),while immune-related adverse events were reported in 7 patients(15.6%).We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC.Significant tumor microenvironment changes were observed in pCR patients,including reduced VEGF+cells and CD4+Foxp3+Treg cells,and increased perivascular CD4+T cells,CD39+CD8+T cells,and M1 macrophages.In conclusion,perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment(ClinicalTrials.gov NCT05400070).
基金supported by the National Natural Science Foundation of China(projects 82072072,32171326,82272157,32261160372,and 82350710800)the Guangdong Basic and Applied Basic Research Foundation(2022B1515130010 and 2021A1515111035)+1 种基金the National Natural Science Foundation of China/Research Grants Council(NSFC/RGC)Joint Research Scheme(N_PolyU526/22)the Leading Talent Project of Guangzhou Development District(2020-L013)。
文摘Universal coatings with versatile surface adhesion,good mechanochemical robustness,and the capacity for secondary modification are of great scientific interest.However,incorporating these advantages into a system is still a great challenge.Here,we report a series of catechol-decorated polyallylamines(CPAs),denoted as pseudo-Mytilus edulis foot protein 5(pseudoMefp-5),that mimic not only the catechol and amine groups but also the backbone of Mefp-5.CPAs can fabricate highly adhesive,robust,multifunctional polyCPA(PCPA)coatings based on synergetic catechol-polyamine chemistry as universal building blocks.Due to the interpenetrating entangled network architectures,these coatings exhibit high chemical robustness against harsh conditions(HCl,pH 1;NaOH,pH 14;H2O2,30%),good mechanical robustness,and wear resistance.In addition,PCPA coatings provide abundant grafting sites,enabling the fabrication of various functional surfaces through secondary modification.Furthermore,the versatility,multifaceted robustness,and scalability of PCPA coatings indicate their great potential for surface engineering,especially for withstanding harsh conditions in multipurpose biomedical applications.
文摘Osteoarthritis(OA)is a painful degenerative joint disease and is the leading cause of chronic disability among elderly individuals.To improve the quality of life for patients with OA,the primary goal for OA treatment is to relieve the pain.During OA progression,nerve ingrowth was observed in synovial tissue and articular cartilage.These abnormal neonatal nerves act as nociceptors to detect OA pain signals.The molecular mechanisms for transmitting OA pain in the joint tissues to the central nerve system(CNS)is currently unknown.MicroRNA miR-204 has been demonstrated to maintain the homeostasis of joint tissues and have chondro-protective effect on OA pathogenesis.However,the role of miR-204 in OA pain has not been determined.In this study,we investigated interactions between chondrocytes and neural cells and evaluated the effect and mechanism of miR-204 delivered by exosome in the treatment of OA pain in an experimental OA mouse model.Our findings demonstrated that miR-204 could protect OA pain by inhibition of SP1-LDL Receptor Related Protein 1(LRP1)signaling and blocking neuro-cartilage interaction in the joint.Our studies defined novel molecular targets for the treatment of OA pain.
基金financial support from the National Natural Science Foundation of China(Nos.31922040 and 82001965)Shenzhen Science and Technology Research Funding(Nos.SGLH20180625144002074,JCYJ20180507182637685,and JCYJ20190806165616542)+5 种基金Youth Innovation Promotion Association of Chinese Academy of Sciences(Nos.2017416 and 2020353)Guangdong Basic and Applied Basic Research Foundation(No.2020B1515120078)China Postdoctoral Science Foundation(2019M663190)SIAT Innovation Program for Excellent Young Researchers(E1G034)Nanchong Science and Technology Project(No.20SXQT0302)City University of Hong Kong Strategic Research Grant(SRG)(No.7005505).
文摘Polyetheretherketone(PEEK)is a desirable alternative to conventional biomedical metals for orthopedic implants due to the excellent mechanical properties.However,the inherent bioinertness of PEEK contributes to inferior osseointegration of PEEK implants,especially under pathological conditions of osteoporosis.Herein,a programmed surface is designed and fabricated on PEEK to dictate osteoimmunomodulation and bone regeneration sequentially.A degradable hybrid coating consisting of poly(lactide-co-glycolide)and alendronate(ALN)loaded nano-hydroxyapatite is deposited on PEEK and then interleukin-4(IL-4)is grafted onto the outer surface of the hybrid coating with the aid of N_(2) plasma immersion ion implantation and subsequent immersion in IL-4 solution.Dominant release of IL-4 together with ALN and Ca^(2+) during the first few days synergistically mitigates the early acute inflammatory reactions and creates an osteoimmunomodulatory microenvironment that facilitates bone regeneration.Afterwards,slow and sustained delivery of ALN and Ca^(2+) in the following weeks boosts osteogenesis and suppresses osteoclastogenesis simultaneously,consequently ameliorating bone-implant osseointegration even under osteoporotic conditions.By taking into account the different phases in bone repair,this strategy of constructing advanced bone implants with sequential functions provides customizable and clinically viable therapy to osteoporotic patients.
基金financially supported by the National Key Re-search and Development Program of China(No.2021YFB3800800)the National Natural Science Foundation of China(NSFC)(Nos.82030067,82161160342,82172397,82250710174 and 31922040)+1 种基金the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020353)the Shenzhen Science and Technol-ogy Research Funding(No.JCYJ20220818101414032).
文摘Osteoarthritis(OA)is a degenerative disease involving entire joint.It is often initiated from the low-grade inflammation in synovial tissue and then affects articular cartilage and subchondral bone.Multiple risk factors,such as aging,mechanical overloading,trauma,overuse,etc.are involved in OA development.Several approaches have been utilized to repair cartilage defects.Among them,biomaterials-based mes-enchymal stromal cell(MSCs)therapy is considered as the most promising modality.The burgeoning material science and manufacturing technologies,such as 3D printing,allow us to mimic native articu-lar cartilage and regulate the artificial cartilage development,regeneration and functional restoration.In this review article,we will summarize the recent progress of biomaterials combined with MSCs or chon-drocytes in repairing cartilage damage induced by OA.Several typical natural and synthetic biomaterials,such as collagen,alginate,hyaluronic acid and poly(ethylene glycol),polylactide acid,polyurethane,etc.for cartilage repairing will be introduced.Moreover,critical signaling pathways associated with the pro-gression of OA,as well as the targeted pharmacologic,genetic therapies and tissue engineering scaffolds for OA and cartilage repairing are presented.We will also provide our prospects for future directions in this active research area.
基金We acknowledge the National Natural Science Foundation of China(32222041,21875092 and 82272157)National Natural Science Foundation of Jiangsu Province(BK20220059)+1 种基金National Key Research and Development Program of China(2019YFA0112000)Innovation and Entrepreneurship Program of Jiangsu Province,and the“Jiangsu Specially-Appointed Professor”Program.
文摘The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix(ECM)-mimicking biomaterials.However,designing controllable multivalency construction strategies is still challenging.Herein,we synthesized a series of well-defined multivalent antimicrobial peptide polymers(mAMPs)by clicking ligand molecules onto polymers prepared by reversible addition-fragmentation chain transfer polymerization.The multiple cationic ligands in the mAMPs could enhance the local disturbance of the anionic phospholipid layer of the bacterial membrane through multivalent binding,leading to amplification of the bactericidal effect.In addition to multivalency-enhanced antibacterial activity,mAMPs also enable multivalency-assisted hydrogel fabrication with an ECM-like dynamic structure.The resultant hydrogel with self-healing and injectable properties could be successfully employed as an antibacterial biomaterial scaffold to treat infected skin wounds.The multivalency construction strategy presented in this work provides new ideas for the biomimetic design of highly active and dynamic biomaterials for tissue repair and regeneration.
基金The authors acknowledge the National Natural Science Foundation of China(nos.31922040 and 32000962)Shenzhen Science and Technology Research Funding(nos.SGLH20180625144002074 and JCYJ20180507182637685)+4 种基金Guangdong Basic and Applied Basic Research Foundation(no.2020B1515120078)Youth Innovation Promotion Association of the Chinese Academy of Sciences(nos.2017416 and 2020353)Shenzhen-Hong Kong Innovative Collaborative Research and Development Program(no.9240014)City University of Hong Kong Strategic Research Grant(SRG)(no.7005264)Hong Kong Research Grants Council(RGC)General Research Funds(GRF)(no.CityU 11205617).
文摘The immune responses are involved in every stage after implantation but the reported immune-regulated materials only work at the beginning without fully considering the different phases of bone healing.Here,poly(aryl-ether-ether-ketone)(PEEK)is coated with a programmed surface,which rapidly releases interleukin-10(IL-10)in the first week and slowly delivers dexamethasone(DEX)up to 4 weeks.Owing to the synergistic effects of IL-10 and DEX,an aptly weak inflammation is triggered within the first week,followed by significant M2 polarization of macrophages and upregulation of the autophagy-related factors.The suitable immunomodulatory activities pave the way for osteogenesis and the steady release of DEX facilitates bone regeneration thereafter.The sequential immune-mediated process is also validated by an 8-week implementation on a rat model.This is the first attempt to construct implants by taking advantage of both immune-mediated modulation and sequential regulation spanning all bone regeneration phases,which provides insights into the fabrication of advanced biomaterials for tissue engineering and immunological therapeutics.
