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
Cancer remains one of the leading causes of death worldwide,and tumour metastasis is responsible for more than 90%of cancer deaths.1,2 Bone is recognised as the most common site for metastasis of numerous malignancies...Cancer remains one of the leading causes of death worldwide,and tumour metastasis is responsible for more than 90%of cancer deaths.1,2 Bone is recognised as the most common site for metastasis of numerous malignancies,especially breast and prostate cancer.3,4 As a highly dynamic compartment,the bone microenvironment not only facilitates primary metastasis but also enhances secondary metastasis to organs,such as the brain,liver,and lung,liver,and brain.5-7 Therefore,effectively preventing critical bone metastasis is pivotal for impeding systemic tumour spread.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
Stenting is currently the major therapeutic treatment for cardiovascular diseases.However,the nonbiogenic metal stents are inclined to trigger a cascade of cellular and molecular events including inflammatory response...Stenting is currently the major therapeutic treatment for cardiovascular diseases.However,the nonbiogenic metal stents are inclined to trigger a cascade of cellular and molecular events including inflammatory response,thrombogenic reactions,smooth muscle cell hyperproliferation accompanied by the delayed arterial healing,and poor reendothelialization,thus leading to restenosis along with late stent thrombosis.To address prevalence critical problems,we present an endothelium-mimicking coating capable of rapid regeneration of a competently functioning new endothelial layer on stents through a stepwise metal(copper)-catechol-(amine)(MCA)surface chemistry strategy,leading to combinatorial endothelium-like functions with glutathione peroxidase-like catalytic activity and surface heparinization.Apart from the stable nitric oxide(NO)generating rate at the physiological level(2:2×10^(-10) mol/cm^(2)/min lasting for 60 days),this proposed strategy could also generate abundant amine groups for allowing a high heparin conjugation efficacy up to∼1μg/cm^(2),which is considerably higher than most of the conventional heparinized surfaces.The resultant coating could create an ideal microenvironment for bringing in enhanced antithrombogenicity,anti-inflammation,anti-proliferation of smooth muscle cells,re-endothelialization by regulating relevant gene expressions,hence preventing restenosis in vivo.We envision that the stepwise MCA coating strategy would facilitate the surface endothelium-mimicking engineering of vascular stents and be therefore helpful in the clinic to reduce complications associated with stenosis.展开更多
Integration of two or more biomolecules with synergetic and complementary effects on a material surface can help to obtain multi-functions for various biomedical applications.However,the amounts of biomolecules integr...Integration of two or more biomolecules with synergetic and complementary effects on a material surface can help to obtain multi-functions for various biomedical applications.However,the amounts of biomolecules integrated and their physiological functions are compromised due to the limited surface anchoring sites.Herein,we propose a novel concept of film engineering strategy“from surface to bulk synergetic modification”.This new concept is realized by employing the surface amine groups of plasma polymerized allylamine(PPAm)film for grafting a molecule e.g.,thrombin inhibitor,bivalirudin(BVLD),meanwhile its bulk amine groups is used as a universal depot for storing and releasing therapeutic nitric oxide(NO)gas as supplement to the functions of BVLD.It is demonstrated that such a“from surface to bulk synergetic modification”film engineering can impart the modified-substrates with anti-platelet and anti-coagulant dual functions,giving rise to a highly endotheliummimetic thromboresistant property.We believe that our research provides a very promising strategy to deliver multifunctional surface versatilely that require NO release in combination with other properties,which will find broad biomedical applications in blood-contacting devices,and et al.Moreover,it also provides a brand-new film engineering strategy for tailoring surface multi-functionalities of a wide range of materials.展开更多
Inflammatory responses of nucleus pulposus(NP)can induce imbalanced anabolism and catabolism of extracellular matrix,and the cytosolic dsDNA accumulation and STING-NF-κB pathway activation found in NP inflammation ar...Inflammatory responses of nucleus pulposus(NP)can induce imbalanced anabolism and catabolism of extracellular matrix,and the cytosolic dsDNA accumulation and STING-NF-κB pathway activation found in NP inflammation are considered as fairly important cause of intervertebral disc(IVD)degeneration.Herein,we constructed a siSTING delivery hydrogel of aldehyde hyaluronic acid(HA-CHO)and poly(amidoamine)PAMAM/siRNA complex to intervene the abnormal STING signal for IVD degeneration treatment,where the formation of dynamic Schiff base bonds in the system(siSTING@HPgel)was able to overcome the shortcomings such as low cellular uptake,short half-life,and rapid degradation of siRNA-based strategy.PAMAM not only formed complexes with siRNA to promote siRNA transfection,but also served as dynamic crosslinker to construct hydrogel,and the injectable and self-healing hydrogel efficiently and steadily silenced STING expression in NP cells.Finally,the siSTING@HPgel significantly eased IVD inflammation and slowed IVD degeneration by prolonging STING knockdown in puncture-induced IVD degeneration rat model,revealing that STING pathway was a therapeutic target for IVD degeneration and such novel hydrogel had great potential for being applied to many other diseases for gene delivery.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
Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial a...Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial activity make the clinical applications in a dilemma.Inspired by the mussel adhesion mechanism,here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins(Mfps)-mimic peptide with clickable azido terminal.The peptide enables mussel-like adhesion on PEEK biomaterial surfaces,leaving azido groups for the further steps of biofunctionalizations.In this study,antimicrobial peptide(AMP)and osteogenic growth peptide(OGP)were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair.Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios,an optimal PEEK surface was finally obtained in this research,which could long-term inhibit bacterial growth,stabilize bone homeostasis and facilitate interfacial bone regeneration.In a word,this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants,in particular,achieving rational integration of multiple biofunctions to match clinical requirements.展开更多
3-CF3 S substituted thioflavones and benzothiophenes were achieved via the reactions of AgSCF3 with methylthiolated alkynones and alkynylthioanisoles,respectively,promoted by persulfate.This protocol possesses good fu...3-CF3 S substituted thioflavones and benzothiophenes were achieved via the reactions of AgSCF3 with methylthiolated alkynones and alkynylthioanisoles,respectively,promoted by persulfate.This protocol possesses good functional group tolerance and high yields.Mechanistic studies suggested that a classic two-step radical process was involved,which includes addition of CF3 S radical to triple bond and cyclization with SMe moiety.展开更多
Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy.Combination of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor bene...Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy.Combination of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor benefit.Herein,we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer(TNBC)treatment via synergism of PTT,vessel normalization,and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β(TGF-β)pathway.The nanomodulator,namely Vac@Apt@BPs,is developed by conjugation of TGF-βinhibitor Vactosertib(Vac)and nucleolin-recognizing aptamer(Apt)on the surface of black phosphorus nanoparticles(BPs).Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of TNBC.Via the blockade of TGF-βsignaling,Vac@Apt@BPs effectively inhibit the formation of tumor neovascular,and normalize the vessels to recover vascular integrity and alleviate the hypoxia stress.Together with the tumor eradication and immunogenic cell death via PTT,robust immune response was boosted by promoted maturation of dendritic cells,suppression of regulatory T cells,and stimulation of effective T cells.This synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.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
Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies a...Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies are still associated with some undesirable problems.Fortunately,recent advances in nanomaterials have provided unprecedented opportunities for diagnosis and therapy of bone-related diseases.This review provides a comprehensive and up-to-date overview of current advanced theranostic nanomaterials in bone-related diseases.First,the potential utility of nanomaterials for biological imaging and biomarker detection is illustrated.Second,nanomaterials serve as therapeutic delivery platforms with special functions for bone homeostasis regulation and cellular modulation are highlighted.Finally,perspectives in this field are offered,including current key bottlenecks and future directions,which may be helpful for exploiting nanomaterials with novel properties and unique functions.This review will provide scientific guidance to enhance the development of advanced nanomaterials for the diagnosis and therapy of bone-related diseases.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
The power generated by flexible wearable devices(FWDs)is normally insufficient to eradicate bacteria,and many conventional antibacterial strategies are also not suitable for flexible and wearable applications because ...The power generated by flexible wearable devices(FWDs)is normally insufficient to eradicate bacteria,and many conventional antibacterial strategies are also not suitable for flexible and wearable applications because of the strict mechanical and electrical requirements.Here,polypyrrole(PPy),a conductive polymer with a high mass density,is used to form a nanostructured surface on FWDs for antibacterial purposes.The conductive films with PPy nanorods(PNRs)are found to sterilize 98.2±1.6%of Staphylococcus aureus and 99.6±0.2%of Escherichia coli upon mild electrification(1 V).Bacteria killing stems from membrane stress produced by the PNRs and membrane depolarization caused by electrical neutralization.Additionally,the PNR films exhibit excellent biosafety and electrical stability.The results represent pioneering work in fabricating antibacterial components for FWDs by comprehensively taking into consideration the required conductivity,mechanical properties,and biosafety.展开更多
Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone ero...Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone erosion.Therefore,substantial efforts have been made to remedy these issues,with the aid of bioactive molecules,herbs and materials.Following recent insights,the importance of epigenetic gene regulation is increasingly evident,especially microRNAs.MicroRNAs can silence target genes by inhibiting mRNA translation or degrading mRNA molecules by binding to their 3′-untranslated region.There is accumulating evidence indicating that the miRNAs significantly involved in osteogenic gene expression,signaling pathway intervention and programmed cell death.Besides,numerous new target drugs(microRNA inhibitors or agonists)have been proposed to exploit its value in skeletal physiology and pathology.In this review,we mainly discuss the role of microRNAs in the context of skeletal disease-associated osteoblast differentiation,the applications of microRNA polymorphisms as biomarkers for diagnostic and therapeutic targets,and the challenges to meet this goal.Our summary provides novel horizon for improving the therapeutic effect of microRNAs,which may be beneficial to the further clinical translation of microRNAs in the treatments of skeletal diseases.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 Natural Science Foundation of China(No.82001965).
文摘Cancer remains one of the leading causes of death worldwide,and tumour metastasis is responsible for more than 90%of cancer deaths.1,2 Bone is recognised as the most common site for metastasis of numerous malignancies,especially breast and prostate cancer.3,4 As a highly dynamic compartment,the bone microenvironment not only facilitates primary metastasis but also enhances secondary metastasis to organs,such as the brain,liver,and lung,liver,and brain.5-7 Therefore,effectively preventing critical bone metastasis is pivotal for impeding systemic tumour spread.
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.
基金This work was supported by the National Natural Science Foundation of China(31570957)International Cooperation Project by the Science and Technology Department of Sichuan Province(2019YFH0103)+1 种基金Early Career Researcher Development Scheme 2017 of Institute of Health and Biomedical Innovation,Queensland University of Technology and International Team for Implantology Research Grant(1260_2017)Applied Basic Research Project funded by Sichuan Provincial Science and Technology Department(2017JY0296).
文摘Stenting is currently the major therapeutic treatment for cardiovascular diseases.However,the nonbiogenic metal stents are inclined to trigger a cascade of cellular and molecular events including inflammatory response,thrombogenic reactions,smooth muscle cell hyperproliferation accompanied by the delayed arterial healing,and poor reendothelialization,thus leading to restenosis along with late stent thrombosis.To address prevalence critical problems,we present an endothelium-mimicking coating capable of rapid regeneration of a competently functioning new endothelial layer on stents through a stepwise metal(copper)-catechol-(amine)(MCA)surface chemistry strategy,leading to combinatorial endothelium-like functions with glutathione peroxidase-like catalytic activity and surface heparinization.Apart from the stable nitric oxide(NO)generating rate at the physiological level(2:2×10^(-10) mol/cm^(2)/min lasting for 60 days),this proposed strategy could also generate abundant amine groups for allowing a high heparin conjugation efficacy up to∼1μg/cm^(2),which is considerably higher than most of the conventional heparinized surfaces.The resultant coating could create an ideal microenvironment for bringing in enhanced antithrombogenicity,anti-inflammation,anti-proliferation of smooth muscle cells,re-endothelialization by regulating relevant gene expressions,hence preventing restenosis in vivo.We envision that the stepwise MCA coating strategy would facilitate the surface endothelium-mimicking engineering of vascular stents and be therefore helpful in the clinic to reduce complications associated with stenosis.
基金This work was supported by the National Natural Science Foundation of China(Project 31570957)the National Key Research and Development Program of China(2017YFB0702504)+1 种基金International Cooperation Project by Science and Technology Department of Sichuan Province(2019YFH0103)Applied Basic Research Project funded by Sichuan Provincial Science and Technology Department(2017JY0296).
文摘Integration of two or more biomolecules with synergetic and complementary effects on a material surface can help to obtain multi-functions for various biomedical applications.However,the amounts of biomolecules integrated and their physiological functions are compromised due to the limited surface anchoring sites.Herein,we propose a novel concept of film engineering strategy“from surface to bulk synergetic modification”.This new concept is realized by employing the surface amine groups of plasma polymerized allylamine(PPAm)film for grafting a molecule e.g.,thrombin inhibitor,bivalirudin(BVLD),meanwhile its bulk amine groups is used as a universal depot for storing and releasing therapeutic nitric oxide(NO)gas as supplement to the functions of BVLD.It is demonstrated that such a“from surface to bulk synergetic modification”film engineering can impart the modified-substrates with anti-platelet and anti-coagulant dual functions,giving rise to a highly endotheliummimetic thromboresistant property.We believe that our research provides a very promising strategy to deliver multifunctional surface versatilely that require NO release in combination with other properties,which will find broad biomedical applications in blood-contacting devices,and et al.Moreover,it also provides a brand-new film engineering strategy for tailoring surface multi-functionalities of a wide range of materials.
基金The study was sponsored by National Natural Science Foundation of China(81672150,51903050)Zhejiang medical and health science and technology project(2018KY117,2019ZD041)+1 种基金Natural Science Foundation of Zhejiang Province of China(LQ20H160053)New talent in medical field of Zhejiang Province,and the fundamental research funds for the central universities(2019QNA7027).
文摘Inflammatory responses of nucleus pulposus(NP)can induce imbalanced anabolism and catabolism of extracellular matrix,and the cytosolic dsDNA accumulation and STING-NF-κB pathway activation found in NP inflammation are considered as fairly important cause of intervertebral disc(IVD)degeneration.Herein,we constructed a siSTING delivery hydrogel of aldehyde hyaluronic acid(HA-CHO)and poly(amidoamine)PAMAM/siRNA complex to intervene the abnormal STING signal for IVD degeneration treatment,where the formation of dynamic Schiff base bonds in the system(siSTING@HPgel)was able to overcome the shortcomings such as low cellular uptake,short half-life,and rapid degradation of siRNA-based strategy.PAMAM not only formed complexes with siRNA to promote siRNA transfection,but also served as dynamic crosslinker to construct hydrogel,and the injectable and self-healing hydrogel efficiently and steadily silenced STING expression in NP cells.Finally,the siSTING@HPgel significantly eased IVD inflammation and slowed IVD degeneration by prolonging STING knockdown in puncture-induced IVD degeneration rat model,revealing that STING pathway was a therapeutic target for IVD degeneration and such novel hydrogel had great potential for being applied to many other diseases for gene delivery.
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supported by the National Key Research and Development Program of China(2019YFA0112000)Research and Development of Biomedical Materials and Substitution of Tissue and Organ Repair under the National Key R&D Program(2016YFC1101505)+7 种基金the National Natural Science Foundation of China(82072425,82072498,81873991,81073990,21875092,31922040 and 81672238)the Young Medical Talents of Jiangsu Province(QNRC2016751)the Natural Science Foundation of Jiangsu Province(BK20180001)the Innovation and Entrepreneurship Program of Jiangsu Provincethe“Six Talent Peaks”program of Jiangsu Province(2018-XCL-013)the Basic Applied Research Program of Suzhou City(SYS2018032,KJXW2017009)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Special Project of Diagnosis and Treatment for Clinical Diseases of Suzhou(LCZX202003).
文摘Polyetheretherketone(PEEK)has been widely used as orthopedic and dental materials due to excellent mechanical and physicochemical tolerance.However,its biological inertness,poor osteoinduction,and weak antibacterial activity make the clinical applications in a dilemma.Inspired by the mussel adhesion mechanism,here we reported a biomimetic surface strategy for rational integration and optimization of anti-infectivity and osteo-inductivity onto PEEK surfaces using a mussel foot proteins(Mfps)-mimic peptide with clickable azido terminal.The peptide enables mussel-like adhesion on PEEK biomaterial surfaces,leaving azido groups for the further steps of biofunctionalizations.In this study,antimicrobial peptide(AMP)and osteogenic growth peptide(OGP)were bioorthogonally clicked on the azido-modified PEEK biomaterials to obtain a dual-effect of host defense and tissue repair.Since bioorthogonal clicking allows precise collocation between AMP and OGP through changing their feeding molar ratios,an optimal PEEK surface was finally obtained in this research,which could long-term inhibit bacterial growth,stabilize bone homeostasis and facilitate interfacial bone regeneration.In a word,this upgraded mussel surface strategy proposed in this study is promising for the surface bioengineering of inert medical implants,in particular,achieving rational integration of multiple biofunctions to match clinical requirements.
基金the National Natural Science Foundation of China(Nos.21991123,21677094)for financial support。
文摘3-CF3 S substituted thioflavones and benzothiophenes were achieved via the reactions of AgSCF3 with methylthiolated alkynones and alkynylthioanisoles,respectively,promoted by persulfate.This protocol possesses good functional group tolerance and high yields.Mechanistic studies suggested that a classic two-step radical process was involved,which includes addition of CF3 S radical to triple bond and cyclization with SMe moiety.
基金supported by grants from the National Natural Science Foundation of China(Nos.32000931,81672632,81972312,and 82103184)the Natural Science Foundation of Hunan Province for outstanding Young Scholars(No.2021JJ20083)+2 种基金Natural Science Foundation of Hunan Province of China(Nos.2021JJ30912,2021JJ40720 and 2021JJ30950)the science and technology innovation Program of Hunan Province(No.2022RC1165)the Open Sharing Fund for the Largescale Instruments and Equipment of Central South University,Changsha,China.
文摘Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy.Combination of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor benefit.Herein,we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer(TNBC)treatment via synergism of PTT,vessel normalization,and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β(TGF-β)pathway.The nanomodulator,namely Vac@Apt@BPs,is developed by conjugation of TGF-βinhibitor Vactosertib(Vac)and nucleolin-recognizing aptamer(Apt)on the surface of black phosphorus nanoparticles(BPs).Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of TNBC.Via the blockade of TGF-βsignaling,Vac@Apt@BPs effectively inhibit the formation of tumor neovascular,and normalize the vessels to recover vascular integrity and alleviate the hypoxia stress.Together with the tumor eradication and immunogenic cell death via PTT,robust immune response was boosted by promoted maturation of dendritic cells,suppression of regulatory T cells,and stimulation of effective T cells.This synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.
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supported by the National Natural Science Foundation of China(82072425,82072498,81871788,21875092,31922040,82272157)the Natural Science Foundation of Jiangsu Province(BK2021650 and BK20220059)+5 种基金the“Jiangsu Specially-Appointed Professor”Programthe Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Jiangsu Medical Research Project(ZD2022021)Special Project of DiagnosisTreatment Technology for Key Clinical Diseases in Suzhou(LCZX202003)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_3217).
文摘Bone-related diseases refer to a group of skeletal disorders that are characterized by bone and cartilage destruction.Conventional approaches can regulate bone homeostasis to a certain extent.However,these therapies are still associated with some undesirable problems.Fortunately,recent advances in nanomaterials have provided unprecedented opportunities for diagnosis and therapy of bone-related diseases.This review provides a comprehensive and up-to-date overview of current advanced theranostic nanomaterials in bone-related diseases.First,the potential utility of nanomaterials for biological imaging and biomarker detection is illustrated.Second,nanomaterials serve as therapeutic delivery platforms with special functions for bone homeostasis regulation and cellular modulation are highlighted.Finally,perspectives in this field are offered,including current key bottlenecks and future directions,which may be helpful for exploiting nanomaterials with novel properties and unique functions.This review will provide scientific guidance to enhance the development of advanced nanomaterials for the diagnosis and therapy of bone-related diseases.
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.
基金The authors acknowledge the financial support from Hong Kong PDFS-RGC Postdoctoral Fellowship Scheme(PDFS2122-1S08 and CityU 9061014)Hong Kong HMRF(Health and Medical Research Fund)(2120972 and CityU 9211320)National Natural Science Foundation of China(81903057 and 31922040).
文摘The power generated by flexible wearable devices(FWDs)is normally insufficient to eradicate bacteria,and many conventional antibacterial strategies are also not suitable for flexible and wearable applications because of the strict mechanical and electrical requirements.Here,polypyrrole(PPy),a conductive polymer with a high mass density,is used to form a nanostructured surface on FWDs for antibacterial purposes.The conductive films with PPy nanorods(PNRs)are found to sterilize 98.2±1.6%of Staphylococcus aureus and 99.6±0.2%of Escherichia coli upon mild electrification(1 V).Bacteria killing stems from membrane stress produced by the PNRs and membrane depolarization caused by electrical neutralization.Additionally,the PNR films exhibit excellent biosafety and electrical stability.The results represent pioneering work in fabricating antibacterial components for FWDs by comprehensively taking into consideration the required conductivity,mechanical properties,and biosafety.
基金supported by grants from the National Natural Sci-ence Foundation of China(82072425,82072498,82074473,81873991,31922040 and 81873990)the Young Medical Talents of Jiangsu Province(QNRC2016751)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20200198,BE2021650)Special Project of Diagno-sis and Treatment Technology for Key Clinical Diseases in Suzhou(LCZX202003,LCZX201824).
文摘Skeletal diseases normally represents a grievous imbalance between osteoblasts for bone formation and osteoclasts for bone resorption.A lack of osteogenic function can make it difficult to repair pathological bone erosion.Therefore,substantial efforts have been made to remedy these issues,with the aid of bioactive molecules,herbs and materials.Following recent insights,the importance of epigenetic gene regulation is increasingly evident,especially microRNAs.MicroRNAs can silence target genes by inhibiting mRNA translation or degrading mRNA molecules by binding to their 3′-untranslated region.There is accumulating evidence indicating that the miRNAs significantly involved in osteogenic gene expression,signaling pathway intervention and programmed cell death.Besides,numerous new target drugs(microRNA inhibitors or agonists)have been proposed to exploit its value in skeletal physiology and pathology.In this review,we mainly discuss the role of microRNAs in the context of skeletal disease-associated osteoblast differentiation,the applications of microRNA polymorphisms as biomarkers for diagnostic and therapeutic targets,and the challenges to meet this goal.Our summary provides novel horizon for improving the therapeutic effect of microRNAs,which may be beneficial to the further clinical translation of microRNAs in the treatments of skeletal diseases.
