The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge.The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are im...The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge.The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are imperative for the regeneration of the infected wounds.Here,a novel and facile peptide containing injectable hydrogel with sustained antibacterial and angiogenic capabilities is developed.The antibacterial peptide that consists of 11 residues(CM11,WKLFKKILKVL)is loaded onto acrylate-modified gelatin through charge interactions.A vascular endothelial growth factor mimetic peptide KLT(KLTWQELYQLKYKGI)with a GCG(Gly-Cys-Gly)modification at the N-terminal is covalently coupled through a visible light-induced thiol-ene reaction.In this reaction,the acrylate gelatin undergoes cross-linkage within seconds.Based on the physical/chemical double crosslinking strategy,the bioactive peptides achieve sustained and sequential release.The results show that the hydrogel significantly inhibits methicillin-resistant Staphylococcus aureus(MRSA)growth through the rapid release of CM11 peptides at early stage;it forms obvious growth inhibition zones against pathogenic bacterial strains.Moreover,cell counting kit-8 assay and scratch test confirm that the CM11/KLT-functionalized hydrogels promote cell proliferation and migration through the later release of KLT peptides.In a mouse skin wound infected with self-luminous MRSA,the CM11/KLT-functionalized hydrogels enhance wound healing,with rapidly bacterial infection reduction,lower expression of inflammatory factors,and neovascularization promotion.These results suggest that the rationally designed,sustained and sequential release CM11/KLT-functionalized hydrogels have huge potential in promoting the healing of multi-drug resistant bacterial infected wounds.展开更多
Resorption and loss of alveolar bone leads to oral dysfunction and loss of natural or implant teeth. Biomimetic delivery of growth factors based on stem cell recruitment and osteogenic differentiation, as the key step...Resorption and loss of alveolar bone leads to oral dysfunction and loss of natural or implant teeth. Biomimetic delivery of growth factors based on stem cell recruitment and osteogenic differentiation, as the key steps in natural alveolar bone regenerative process, has been an area of intense research in recent years. A mesoporous self-healing hydrogel(DFH) with basic fibroblast growth factor(bFGF) entrapment and transforming growth factor β3(TGFβ3)-loaded chitosan microspheres(CMs) was developed. The formulation was optimized by multiple tests of self-healing, in-bottle inversion, SEM, rheological, swelling rate and in vitro degradation. In vitro tubule formation assays, cell migration assays, and osteogenic differentiation assays confirmed the ability of DFH to promote blood vessels, recruit stem cells, and promote osteogenic differentiation. The optimum DFH formula is 0.05 ml 4ArmPEG-DF(20%) added to 1 ml CsGlu(2%) containing bFGF(80 ng) and TGFβ3-microspheres(5 mg). The results of in vitro release studied by Elisa kit, indicated an 95% release of b FGF in7 d and long-term sustained release of TGFβ3. For alveolar defects rat models, the expression levels of CD29 and CD45, the bone volume fraction, trabecular number, and trabecular thickness of new bone monitored by Micro-CT in DFH treatment groups were significantly higher than others(*P < 0.05, vs Model). HE and Masson staining show the same results.In conclusion, DFH is a design of bionic alveolar remodelling microenvironment, that is in early time microvessels formed by b FGF provide nutritious to recruited endogenous stem cells, then TGFβ3 slowly released speed up the process of new bones formation to common facilitate rat alveolar defect repair. The DFH with higher regenerative efficiency dovetails nicely with great demand due to the requirement of complicated biological processes.展开更多
There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the dru...There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.展开更多
Microneedles have demonstrated value in targeted treatment of dermatosis.Current investigation aims to enhance the functions and optimize substance delivery to improve therapeutic effects.Here,we present innovative sh...Microneedles have demonstrated value in targeted treatment of dermatosis.Current investigation aims to enhance the functions and optimize substance delivery to improve therapeutic effects.Here,we present innovative shell-core microneedles with light-pH dual responsiveness for spatiotemporal sequential release of multiple Chinese herb drugs to treat scleroderma.By using a stepwise template-assisted method,we effectively prepare a hydrogel-based core layer containing polydopamine-MXene(P-MXene)loaded with triptolide(TP),and a shell layer composed of polyvinyl alcohol(PVA)encapsulating paeoniflorin(Pae).P-MXene can adsorb the sparingly soluble TP to ensure its encapsulation efficiency and contribute to the synergistic photothermal effect benefitting from its excellent photothermal conversion ability.Besides,PVA can rapidly dissolve upon microneedle piercing into the skin and quickly release the anti-inflammatory and detoxifying Pae,establishing a favorable low-acid subcutaneous environment.In response to pH changes and near-infrared effects,TP is sustainably released from P-MXene and delivered through the swollen pores of the hydrogel.On the basis of these characteristics,we demonstrate that these microneedles could effectively reduce profibrotic key cytokines interleukin-1βand transforming growth factor-β,thereby reducing collagen deposition and decreasing epidermal thickness,ameliorating skin fibrosis and capillary lesion in scleroderma mouse models.These findings highlight the important clinical potential of these microneedles in the treatment of skin diseases.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
Chemotherapy,as one of the most commonly used treatment modalities for cancer therapy,provides limited benefits to hepatoma patients,owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepat...Chemotherapy,as one of the most commonly used treatment modalities for cancer therapy,provides limited benefits to hepatoma patients,owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepatoma.Bioinformatic analysis identified the therapeutic role of a liver-specific microRNA-miR-122 for enhancing chemo-therapeutic efficacy in hepatoma.Herein,a cyclodextrin-cored star copolymer nanoparticle system(sCDP/DOX/miR-122)is constructed to co-deliver miR-122 with doxorubicin(DOX)for hepatoma therapy.In this nanosystem,miR-122 is condensed by the outer cationic poly(2-(dimethylamino)ethyl methacrylate)chains of sCDP while DOX is accommodated in the inner hydrophobic cyclodextrin cavities,endowing a sequential release manner of miR-122 and DOX.The preferentially released miR-122 not only directly induces cell apoptosis by down regulation of Bcl-w and enhanced p53 activity,but also increases DOX accumulation through inhibiting cytotoxic efflux transporter expression,which realizes synergistic performance on cell inhibition.Moreover,sCDP/DOX/miR-122 displays remarkably increased anti-tumor efficacy in vivo compared to free DOX and sCDP/DOX alone,indicating its great promising in hepatoma therapy.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
Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immun...Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy.However,instead of a straightforward combination of multiple therapeutics,it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies,which are based on a comprehensive understanding of the physiological and pathological features.In this case,the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes.Therefore,the concept of Sequential Drug Delivery System(SDDS)is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions,thus complying with the dynamic disease evolution and the human immunity.This review summarizes the recent advancements inbiomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy.Furthermore,the rationales behind various engineering strategies are discussed.Finally,an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.展开更多
Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with...Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.展开更多
基金support from the Research Foundation of Peking University School and Hospital of Stomatology(No.PKUSS20210113)the National Natural Science Foundation of China(Nos.51972003,and 52271127)+1 种基金the National Key Technologies R&D Program(No.2022YFC2403203-3)Intergovernmental International Cooperation Project of Beijing Municipal Science and Technology Commission(No.Z221100002722004).
文摘The effective management of bacterial infections that are resistant to multiple drugs remains a substantial clinical challenge.The eradication of drug-resistant bacteria and subsequent promotion of angiogenesis are imperative for the regeneration of the infected wounds.Here,a novel and facile peptide containing injectable hydrogel with sustained antibacterial and angiogenic capabilities is developed.The antibacterial peptide that consists of 11 residues(CM11,WKLFKKILKVL)is loaded onto acrylate-modified gelatin through charge interactions.A vascular endothelial growth factor mimetic peptide KLT(KLTWQELYQLKYKGI)with a GCG(Gly-Cys-Gly)modification at the N-terminal is covalently coupled through a visible light-induced thiol-ene reaction.In this reaction,the acrylate gelatin undergoes cross-linkage within seconds.Based on the physical/chemical double crosslinking strategy,the bioactive peptides achieve sustained and sequential release.The results show that the hydrogel significantly inhibits methicillin-resistant Staphylococcus aureus(MRSA)growth through the rapid release of CM11 peptides at early stage;it forms obvious growth inhibition zones against pathogenic bacterial strains.Moreover,cell counting kit-8 assay and scratch test confirm that the CM11/KLT-functionalized hydrogels promote cell proliferation and migration through the later release of KLT peptides.In a mouse skin wound infected with self-luminous MRSA,the CM11/KLT-functionalized hydrogels enhance wound healing,with rapidly bacterial infection reduction,lower expression of inflammatory factors,and neovascularization promotion.These results suggest that the rationally designed,sustained and sequential release CM11/KLT-functionalized hydrogels have huge potential in promoting the healing of multi-drug resistant bacterial infected wounds.
基金supported by grants from the Guangzhou Science and Technology Program Key Project(Grant No.201803010044)Guangdong Province College Characteristic Innovation Project(2019KTSCX011)+2 种基金Guangdong Province Natural Sciences Fund Project(2021A1515012480)the Key Areas Research and Development Program of Guangzhou(202103030003)Guangdong Province Special Fund Projects(Yueziranzihe,2021,No.50).
文摘Resorption and loss of alveolar bone leads to oral dysfunction and loss of natural or implant teeth. Biomimetic delivery of growth factors based on stem cell recruitment and osteogenic differentiation, as the key steps in natural alveolar bone regenerative process, has been an area of intense research in recent years. A mesoporous self-healing hydrogel(DFH) with basic fibroblast growth factor(bFGF) entrapment and transforming growth factor β3(TGFβ3)-loaded chitosan microspheres(CMs) was developed. The formulation was optimized by multiple tests of self-healing, in-bottle inversion, SEM, rheological, swelling rate and in vitro degradation. In vitro tubule formation assays, cell migration assays, and osteogenic differentiation assays confirmed the ability of DFH to promote blood vessels, recruit stem cells, and promote osteogenic differentiation. The optimum DFH formula is 0.05 ml 4ArmPEG-DF(20%) added to 1 ml CsGlu(2%) containing bFGF(80 ng) and TGFβ3-microspheres(5 mg). The results of in vitro release studied by Elisa kit, indicated an 95% release of b FGF in7 d and long-term sustained release of TGFβ3. For alveolar defects rat models, the expression levels of CD29 and CD45, the bone volume fraction, trabecular number, and trabecular thickness of new bone monitored by Micro-CT in DFH treatment groups were significantly higher than others(*P < 0.05, vs Model). HE and Masson staining show the same results.In conclusion, DFH is a design of bionic alveolar remodelling microenvironment, that is in early time microvessels formed by b FGF provide nutritious to recruited endogenous stem cells, then TGFβ3 slowly released speed up the process of new bones formation to common facilitate rat alveolar defect repair. The DFH with higher regenerative efficiency dovetails nicely with great demand due to the requirement of complicated biological processes.
基金supported by the National Basic Research Program of China(973 Program,No.2012CB933600)the National Natural Science Foundation of China(Nos.81771964 and 82072051)+4 种基金the Shanghai Municipal Natural Science Foundation(No.15ZR1408500)funded by the Special Project of Clinical Research of Health Industry of Shanghai Municipal Health Commission(No.201940178)the Scientific Research Project of Hongkou District Health Committee of Shanghai(No.2002-17)the Clinical Research Project of Wu Jieping Medical Foundation(No.320.6750.2020-18-2)the Research Project of Shanghai Fourth People’s Hospital(No.sykyqd 00701&00702).
文摘There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.
基金supported by National Key Research and Development Program of China(2020YFA0908200)National Natural Science Foundation of China(T2225003)+6 种基金National Natural Science Foundation of China(52073060)National Natural Science Foundation of China(61927805)Nanjing Medical Science and Technique Development Foundation(ZKX21019)Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01)Natural Science Foundation of Jiangsu Province(BK20180408)Guangdong Basic and Applied Basic Research Foundation(2021B1515120054)Shenzhen Science and Technology Program(JCYJ20210324133214038).
文摘Microneedles have demonstrated value in targeted treatment of dermatosis.Current investigation aims to enhance the functions and optimize substance delivery to improve therapeutic effects.Here,we present innovative shell-core microneedles with light-pH dual responsiveness for spatiotemporal sequential release of multiple Chinese herb drugs to treat scleroderma.By using a stepwise template-assisted method,we effectively prepare a hydrogel-based core layer containing polydopamine-MXene(P-MXene)loaded with triptolide(TP),and a shell layer composed of polyvinyl alcohol(PVA)encapsulating paeoniflorin(Pae).P-MXene can adsorb the sparingly soluble TP to ensure its encapsulation efficiency and contribute to the synergistic photothermal effect benefitting from its excellent photothermal conversion ability.Besides,PVA can rapidly dissolve upon microneedle piercing into the skin and quickly release the anti-inflammatory and detoxifying Pae,establishing a favorable low-acid subcutaneous environment.In response to pH changes and near-infrared effects,TP is sustainably released from P-MXene and delivered through the swollen pores of the hydrogel.On the basis of these characteristics,we demonstrate that these microneedles could effectively reduce profibrotic key cytokines interleukin-1βand transforming growth factor-β,thereby reducing collagen deposition and decreasing epidermal thickness,ameliorating skin fibrosis and capillary lesion in scleroderma mouse models.These findings highlight the important clinical potential of these microneedles in the treatment of skin diseases.
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the National Natural Science Foundation of China(Grant No.81501575 and 81802873)the National Science and Technology Major Project of China(Grant No.2018ZX10302205)+1 种基金Natural Science Foundation of Tianjin(Grant No.18JCQNJC81300)the Key Research Project of Tianjin Health Industry(Grant No.14KG142).
文摘Chemotherapy,as one of the most commonly used treatment modalities for cancer therapy,provides limited benefits to hepatoma patients,owing to its inefficient delivery as well as the intrinsic chemo-resistance of hepatoma.Bioinformatic analysis identified the therapeutic role of a liver-specific microRNA-miR-122 for enhancing chemo-therapeutic efficacy in hepatoma.Herein,a cyclodextrin-cored star copolymer nanoparticle system(sCDP/DOX/miR-122)is constructed to co-deliver miR-122 with doxorubicin(DOX)for hepatoma therapy.In this nanosystem,miR-122 is condensed by the outer cationic poly(2-(dimethylamino)ethyl methacrylate)chains of sCDP while DOX is accommodated in the inner hydrophobic cyclodextrin cavities,endowing a sequential release manner of miR-122 and DOX.The preferentially released miR-122 not only directly induces cell apoptosis by down regulation of Bcl-w and enhanced p53 activity,but also increases DOX accumulation through inhibiting cytotoxic efflux transporter expression,which realizes synergistic performance on cell inhibition.Moreover,sCDP/DOX/miR-122 displays remarkably increased anti-tumor efficacy in vivo compared to free DOX and sCDP/DOX alone,indicating its great promising in hepatoma therapy.
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supported by the National Natural Science Foundation of China(22478438,81972894,82303820,82273882,32401048 and 22278442)the Science Fund for Distinguished Young Scholars of Jiangsu Province(BK20240098,China)+4 种基金the Natural Science Foundation of Jiangsu Province(BK20231017,China)the China Postdoctoral Science Foundation(2023M733891)the Jiangsu Funding Program for Excellent Postdoctoral Talent(317717,China)the Fundamental Research Funds for the Central Universities(2632023GR11,China)the Special Research Fund from the State Key Laboratory of Natural Medicines at China Pharmaceutical University(SKLNMZZ2024JS19).
文摘Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy.However,instead of a straightforward combination of multiple therapeutics,it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies,which are based on a comprehensive understanding of the physiological and pathological features.In this case,the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes.Therefore,the concept of Sequential Drug Delivery System(SDDS)is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions,thus complying with the dynamic disease evolution and the human immunity.This review summarizes the recent advancements inbiomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy.Furthermore,the rationales behind various engineering strategies are discussed.Finally,an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.
基金The authors gratefully acknowledge the support for this work from the National Key research and Development Program(Grant No.2018YFA0703100)the National Natural Science Foundation of China(Grant Nos.82072082,31900959)+2 种基金the Youth Innovation Promotion Association of CAS(Grant No.2019350)the Guangdong Natural Science Foundation(Grant No.2019A1515011277)the Shenzhen Fundamental Research Foundation(Grant No.JCYJ20180507182237428).
文摘Low patency ratio of small-diameter vascular grafts remains a major challenge due to the occurrence of thrombosis formation and intimal hyperplasia after transplantation.Although developing the functional coating with release of bioactive molecules on the surface of small-diameter vascular grafts are reported as an effective strategy to improve their patency ratios,it is still difficult for current functional coatings cooperating with spatiotemporal control of bioactive molecules release to mimic the sequential requirements for antithrombogenicity and endothelialization.Herein,on basis of 3D-printed polyelectrolyte-based vascular grafts,a biologically inspired release system with sequential release in spatiotemporal coordination of dual molecules through an electrostatic self-assembly was first described.A series of tubes with tunable diameters were initially fabricated by a coaxial extrusion printing method with customized nozzles,in which a polyelectrolyte ink containing of ε-polylysine and sodium alginate was used.Further,dual bioactive molecules,heparin with negative charges and Tyr-Ile-Gly-Ser-Arg(YIGSR)peptide with positive charges were layer-by-layer assembled onto the surface of these 3D-printed tubes.Due to the electrostatic interaction,the sequential release of heparin and YIGSR was demonstrated and could construct a dynamic microenvironment that was thus conducive to the antithrombogenicity and endothelialization.This study opens a new avenue to fabricate a small-diameter vascular graft with a biologically inspired release system based on electrostatic interaction,revealing a huge potential for development of small-diameter artificial vascular grafts with good patency.
