Psoriasis,an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course,continues to be primarily managed through topical therapy.While oral administration of tyrosine kinase ...Psoriasis,an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course,continues to be primarily managed through topical therapy.While oral administration of tyrosine kinase 2 inhibitors(TYK2i)stands as an effective approach for psoriasis treatment,the potential efficacy of topical application of TYK2i remains unexplored.Herein,the carbomer/alginic acid hydrogel is embedded with borneol(BO)as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy.The hydrogel system,i.e.,TYK2i-BO-gel,exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis,as evidenced by phenotypical images,psoriasis severity score index(PSI),histology,immunohistochemical staining,and PCR analysis.Remarkably,TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50%reduction in ear thickness changes(p<0.0001),PSI(p<0.0001)and epidermal thickness(p<0.05).Moreover,a strengthened anti-inflammatory effect caused by TYK2i-BO-gel is seen in a human skin explant model,implying its potential application for human patients.With the addition of BO,the TYK2i-BO-gel not only increases skin permeability but also inhibits the expression of antimicrobial peptides in keratinocytes and facilitates the anti-Th17 response of TYK2i with suppressed activation of STAT3.Therefore,this work represents the accessibility and effectiveness of TYK2i-BO-hydrogel as a new topical formulation for anti-psoriasis management and shows great potential for clinical application.展开更多
Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transduc...Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transducing key signals to cells.The main approach aimed at repairing injury to ischemic tissues is restoration of vascular function.Due to their potential to form capillary niches,endothelial cells(ECs)are of greatest interest for vascular regeneration.Integrin binding to ECM is crucial for cell anchorage to the surrounding matrix,spreading,migration,and further activation of intracellular signaling pathways.In this study,we proposed to establish an in-situ engineering strategy to remodel the ECM at the ischemic site to guide EC endogenous binding and establish effective EC/ECM interactions to promote revascularization.We designed and constructed a dual-function molecule(LXW7)2-SILY,which is comprised of two functional domains:the first one(LXW7)binds to integrinαvβ3 expressed on ECs,and the second one(SILY)binds to collagen.In vitro,we confirmed(LXW7)2-SILY improved EC adhesion and survival.After in situ injection,(LXW7)2-SILY showed stable retention at the injured area and promoted revascularization,blood perfusion,and tissue regeneration in a mouse hindlimb ischemia model.展开更多
Diabetic ischemic wound treatment remains a critical clinical challenge.Neovascularization plays a significant role in wound healing during all stages of the tissue repair process.Strategies that enhance angiogenesis ...Diabetic ischemic wound treatment remains a critical clinical challenge.Neovascularization plays a significant role in wound healing during all stages of the tissue repair process.Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds,particularly diabetic wounds in highly ischemic conditions.We previously identified a cyclic peptide LXW7 that specifically binds to integrinαvβ3 on endothelial progenitor cells(EPCs)and endothelial cells(ECs),activates vascular endothelial growth factor(VEGF)receptors,and promotes EC growth and maturation.In this study,we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides(SILY)to a dermatan sulfate(DS)glycosaminoglycan backbone,named LXW7-DS-SILY,and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix(ECM)scaffolds.We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment.When applied in an established Zucker Diabetic Fatty(ZDF)rat ischemic skin flap model,LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing,enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment.Altogether,this study provides a promising novel treatment to accelerate diabetic ischemic wound healing,thereby reducing limb amputation and mortality of diabetic patients.展开更多
Implantable vascular devices are widely used in clinical treatments for various vascular diseases. However, current approved clinical implantable vascular devices generally have high failure rates primarily due to the...Implantable vascular devices are widely used in clinical treatments for various vascular diseases. However, current approved clinical implantable vascular devices generally have high failure rates primarily due to their surface lacking inherent functional endothelium. Here, inspired by the pathological mechanisms of vascular device failure and physiological functions of native endothelium, we developed a new generation of bioactive parylene (poly(p-xylylene))-based conformal coating to address these challenges of the vascular devices. This coating used a polyethylene glycol (PEG) linker to introduce an endothelial progenitor cell (EPC) specific binding ligand LXW7 (cGRGDdvc) onto the vascular devices for preventing platelet adhesion and selectively capturing endogenous EPCs. Also, we confirmed the long-term stability and function of this coating in human serum. Using two vascular disease-related large animal models, a porcine carotid artery interposition model and a porcine carotid artery-jugular vein arteriovenous graft model, we demonstrated that this coating enabled rapid generation of self-renewable “living” endothelium on the blood contacting surface of the expanded polytetrafluoroethylene (ePTFE) grafts after implantation. We expect this easy-to-apply conformal coating will present a promising avenue to engineer surface properties of “off-the-shelf” implantable vascular devices for long-lasting performance in the clinical settings.展开更多
Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration.However,current strategies lack regulation of the specific endogenous cell...Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration.However,current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration,thus leading to adverse tissue formation and decreased regenerative efficiency.Here,we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone regeneration.The biomaterial works by presenting two synthetic ligands,LLP2A and LXW7,explicitly targeting integrinsα4β1 andαvβ3,respectively,expressed on the surfaces of the cells related to bone formation and vascularization,such as mesenchymal stem cells(MSCs),osteoblasts,endothelial progenitor cells(EPCs),and endothelial cells(ECs).In vitro,the LLP2A/LXW7 modified biomaterial improved the adhesion of MSCs,osteoblasts,EPCs,and ECs via integrinα4β1 andαvβ3,respectively.In an adult rat calvarial bone defect model,the LLP2A/LXW7 modified biomaterial enhanced bone formation and vascularization by synergistically regulating endogenous cells with osteogenic and angiogenic potentials,such as DLX5^(+)cells,osteocalcin^(+)cells,CD34^(+)/CD45-cells and CD31^(+)cells.In a fetal sheep spinal bone defect model,the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse effects.This innovative biomaterial offers an off-the-shelf,easy-to-use,and biologically safe product suitable for vascularized bone regeneration in both fetal and adult disease environments.展开更多
基金National Natural Science Foundation of China[grant number 82203906]Guangdong Basic and Applied Basic Research Foundation[grant number 2022A1515012020]Project of Guangzhou Science and Technology[grant number 202201020355].
文摘Psoriasis,an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course,continues to be primarily managed through topical therapy.While oral administration of tyrosine kinase 2 inhibitors(TYK2i)stands as an effective approach for psoriasis treatment,the potential efficacy of topical application of TYK2i remains unexplored.Herein,the carbomer/alginic acid hydrogel is embedded with borneol(BO)as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy.The hydrogel system,i.e.,TYK2i-BO-gel,exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis,as evidenced by phenotypical images,psoriasis severity score index(PSI),histology,immunohistochemical staining,and PCR analysis.Remarkably,TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50%reduction in ear thickness changes(p<0.0001),PSI(p<0.0001)and epidermal thickness(p<0.05).Moreover,a strengthened anti-inflammatory effect caused by TYK2i-BO-gel is seen in a human skin explant model,implying its potential application for human patients.With the addition of BO,the TYK2i-BO-gel not only increases skin permeability but also inhibits the expression of antimicrobial peptides in keratinocytes and facilitates the anti-Th17 response of TYK2i with suppressed activation of STAT3.Therefore,this work represents the accessibility and effectiveness of TYK2i-BO-hydrogel as a new topical formulation for anti-psoriasis management and shows great potential for clinical application.
基金supported by NIH grants(R01NS100761,R01NS115860 and R21HD107324)Department of Defense’s Congressionally Directed Medical Research Program(PR221734P1)+2 种基金Shriners Children’s grants(87300-NCA-24,85220-NCA-24,85400-NCA-24)American Heart Association grant(24TPA1288860)California Institute for Regenerative Medicine(CIRM)grant(TRAN3-13332).Utilization of the Combinatorial Chemistry and Chemical Biology Shared Resource was supported by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute(P30CA093373).
文摘Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transducing key signals to cells.The main approach aimed at repairing injury to ischemic tissues is restoration of vascular function.Due to their potential to form capillary niches,endothelial cells(ECs)are of greatest interest for vascular regeneration.Integrin binding to ECM is crucial for cell anchorage to the surrounding matrix,spreading,migration,and further activation of intracellular signaling pathways.In this study,we proposed to establish an in-situ engineering strategy to remodel the ECM at the ischemic site to guide EC endogenous binding and establish effective EC/ECM interactions to promote revascularization.We designed and constructed a dual-function molecule(LXW7)2-SILY,which is comprised of two functional domains:the first one(LXW7)binds to integrinαvβ3 expressed on ECs,and the second one(SILY)binds to collagen.In vitro,we confirmed(LXW7)2-SILY improved EC adhesion and survival.After in situ injection,(LXW7)2-SILY showed stable retention at the injured area and promoted revascularization,blood perfusion,and tissue regeneration in a mouse hindlimb ischemia model.
基金partially supported by California Institute for Regenerative Medicine[grant number DISC1-10516-0]Shriners Hospitals for Children developmental research award[grant number 87200-NCA-19]supported by NCI P30CA093373 Cancer Center Support Grant.
文摘Diabetic ischemic wound treatment remains a critical clinical challenge.Neovascularization plays a significant role in wound healing during all stages of the tissue repair process.Strategies that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds,particularly diabetic wounds in highly ischemic conditions.We previously identified a cyclic peptide LXW7 that specifically binds to integrinαvβ3 on endothelial progenitor cells(EPCs)and endothelial cells(ECs),activates vascular endothelial growth factor(VEGF)receptors,and promotes EC growth and maturation.In this study,we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides(SILY)to a dermatan sulfate(DS)glycosaminoglycan backbone,named LXW7-DS-SILY,and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix(ECM)scaffolds.We confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic environment.When applied in an established Zucker Diabetic Fatty(ZDF)rat ischemic skin flap model,LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing,enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic environment.Altogether,this study provides a promising novel treatment to accelerate diabetic ischemic wound healing,thereby reducing limb amputation and mortality of diabetic patients.
基金supported by the UC Davis School of Medicine Dean’s Fellowship award,the Science Translation and Innovative Research(STAIR)grant offered by UC Davis Venture Catalyst,the National Heart,Lung,And Blood Institute under Award Number T32 HL086350 and U54HL 119893 through UC BRAID Center for Accelerated Innovation Technology Grant,and California Institute for Regenerative Medicine(CIRM)grant(TRAN3-13332).The authors would also like to thank the Combinatorial Chemistry Shared Resource at University of California Davis for assistance with design and synthesis of peptides and their derivativesUtilization of this Shared Resource was supported by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute(P30CA093373).
文摘Implantable vascular devices are widely used in clinical treatments for various vascular diseases. However, current approved clinical implantable vascular devices generally have high failure rates primarily due to their surface lacking inherent functional endothelium. Here, inspired by the pathological mechanisms of vascular device failure and physiological functions of native endothelium, we developed a new generation of bioactive parylene (poly(p-xylylene))-based conformal coating to address these challenges of the vascular devices. This coating used a polyethylene glycol (PEG) linker to introduce an endothelial progenitor cell (EPC) specific binding ligand LXW7 (cGRGDdvc) onto the vascular devices for preventing platelet adhesion and selectively capturing endogenous EPCs. Also, we confirmed the long-term stability and function of this coating in human serum. Using two vascular disease-related large animal models, a porcine carotid artery interposition model and a porcine carotid artery-jugular vein arteriovenous graft model, we demonstrated that this coating enabled rapid generation of self-renewable “living” endothelium on the blood contacting surface of the expanded polytetrafluoroethylene (ePTFE) grafts after implantation. We expect this easy-to-apply conformal coating will present a promising avenue to engineer surface properties of “off-the-shelf” implantable vascular devices for long-lasting performance in the clinical settings.
基金supported by the National Institutes of Health(NIH)grants(5R01NS100761,1R01NS115860)California Institute for Regenerative Medicine(CIRM)grants(CLIN1-11404,CLIN2-12129,TRAN3-13332)+2 种基金the Shriners Hospitals for Children Postdoctoral Fellowship(84705-NCA-19)research grants(85108-NCA-19,85135-NCA-21)Utilization of this Shared Resource was supported by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute(P30CA093373).
文摘Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration.However,current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration,thus leading to adverse tissue formation and decreased regenerative efficiency.Here,we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone regeneration.The biomaterial works by presenting two synthetic ligands,LLP2A and LXW7,explicitly targeting integrinsα4β1 andαvβ3,respectively,expressed on the surfaces of the cells related to bone formation and vascularization,such as mesenchymal stem cells(MSCs),osteoblasts,endothelial progenitor cells(EPCs),and endothelial cells(ECs).In vitro,the LLP2A/LXW7 modified biomaterial improved the adhesion of MSCs,osteoblasts,EPCs,and ECs via integrinα4β1 andαvβ3,respectively.In an adult rat calvarial bone defect model,the LLP2A/LXW7 modified biomaterial enhanced bone formation and vascularization by synergistically regulating endogenous cells with osteogenic and angiogenic potentials,such as DLX5^(+)cells,osteocalcin^(+)cells,CD34^(+)/CD45-cells and CD31^(+)cells.In a fetal sheep spinal bone defect model,the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse effects.This innovative biomaterial offers an off-the-shelf,easy-to-use,and biologically safe product suitable for vascularized bone regeneration in both fetal and adult disease environments.
