Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug deliv...Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.展开更多
Supramolecular peptide nanofiber hydrogels are emerging biomaterials for tissue engineering,but it is difficult to fabricate multi-functional systems by simply mixing several short-motif-modified supramolecular peptid...Supramolecular peptide nanofiber hydrogels are emerging biomaterials for tissue engineering,but it is difficult to fabricate multi-functional systems by simply mixing several short-motif-modified supramolecular peptides because relatively abundant motifs generally hinder nanofiber cross-linking or the formation of long nanofiber.Coupling bioactive factors to the assembling backbone is an ideal strategy to design multi-functional supramolecular peptides in spite of challenging synthesis and purification.Herein,a multi-functional supramolecular peptide,P1R16,is developed by coupling a bioactive factor,parathyroid hormone related peptide 1(PTHrP-1),to the basic supramolecular peptide RADA16-I via solid-phase synthesis.It is found that P1R16 self-assembles into long nanofibers and co-assembles with RADA16-I to form nanofiber hydrogels,thus coupling PTHrP-1 to hydrogel matrix.P1R16 nanofiber retains osteoinductive activity in a dose-dependent manner,and P1R16/RADA16-I nanofiber hydrogels promote osteogenesis,angiogenesis and osteoclastogenesis in vitro and induce multi-functionalized osteoregeneration by intramembranous ossification and bone remodeling in vivo when loaded to collagen(Col)scaffolds.Abundant red blood marrow formation,ideal osteointegration and adapted degradation are observed in the 50%P1R16/Col scaffold group.Therefore,this study provides a promising strategy to develop multi-functional supramolecular peptides and a new method to topically administrate parathyroid hormone or parathyroid hormone related peptides for non-healing bone defects.展开更多
The coordination between neurogenesis and angiogenesis plays an important role in nerve tissue development and regeneration.Recently,using bioactive materials to drive neurogenic and angiogenic responses has gained in...The coordination between neurogenesis and angiogenesis plays an important role in nerve tissue development and regeneration.Recently,using bioactive materials to drive neurogenic and angiogenic responses has gained increasing attention.Understanding the neurovascular link between regulatory cues offers valuable insight into the mechanisms underlying nerve regeneration and the design of new bioactive materials.In this study,we utilized a dual-functionalized peptide nanofiber hydrogel presenting the brain-derived neurotrophic factor and vascular endothelial growth factor mimetic peptides RGIDKRHWNSQ(RGI)and KLTWQELYQLKYKGI(KLT)to construct an artificial neurovascular microenvironment.The dual-functionalized peptide nanofiber hydrogel enhanced the neurite outgrowth of pheochromocytoma(PC12)cells and tube-like structures formation of human umbilical vein endothelial cells(HUVECs)in vitro,and promoted rapid lesion infiltration of neural and vascular cells in a rat brain injury model.Using indirect co-culture models,we found that the dual-functionalized peptide hydrogel effectively mediated neurovascular crosstalk by regulating secretion of paracrine factors from PC12 cells and HUVECs.When the two cells types were directly co-cultured on the dua卜functionalized peptide hydrogel,the efficiency of cell-cell communication was enhanced,which further accelerated the differentiation and maturation of PC12 cells with an increased number of pseudopodia and spread morphology,and HUVECs tube-like structure formation.In summary,the dual-functionalized peptide nanofiber hydrogel successfully formed an artificial neurovascular niche to directly regulate the behaviors of neural and vascular cells and promote their neurovascular crosstalk through paracrine signaling and direct cell-cell contact.展开更多
Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closur...Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closure.This work presents a self-assembling hydrogel dressing that can assist the wound repair process mimicking the hierarchical structure of skin extracellular matrix.To this aim,the co-assembly behaviour of a carboxylated variant of xyloglucan(CXG)with a peptide amphiphile(PA-H3)has been investigated to generate hierarchical constructs with tuneable molecular composition,structure,and properties.Transmission electron microscopy and circular dichroism at a low concentration shows that CXG and PA-H3 co-assemble into nanofibres by hydrophobic and electrostatic interactions and further aggregate into nanofibre bundles and networks.At a higher concentration,CXG and PA-H3 yield hydrogels that have been characterized for their morphology by scanning electron microscopy and for the mechanical properties by smallamplitude oscillatory shear rheological measurements and compression tests at different CXG/PAH3 ratios.A preliminary biological evaluation has been carried out both in vitro with HaCat cells and in vivo in a mouse model.展开更多
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2023MC168the National Natural Science Foundation of China,No.31670989the Key R&D Program of Shandong Province,No.2019GSF107037(all to CS).
文摘Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
基金supported by the National Natural Science Foundation of China(No.82372405,No.81871752)the Fundamental Research Funds for the Central Universities(NO.2042023kf0199)+2 种基金the Key Research and Development Program of Hubei Province(No:2022BCA052)the Key Research and Development Program of Wuhan City(No.2023020402010591)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(No.ZNJC202014).
文摘Supramolecular peptide nanofiber hydrogels are emerging biomaterials for tissue engineering,but it is difficult to fabricate multi-functional systems by simply mixing several short-motif-modified supramolecular peptides because relatively abundant motifs generally hinder nanofiber cross-linking or the formation of long nanofiber.Coupling bioactive factors to the assembling backbone is an ideal strategy to design multi-functional supramolecular peptides in spite of challenging synthesis and purification.Herein,a multi-functional supramolecular peptide,P1R16,is developed by coupling a bioactive factor,parathyroid hormone related peptide 1(PTHrP-1),to the basic supramolecular peptide RADA16-I via solid-phase synthesis.It is found that P1R16 self-assembles into long nanofibers and co-assembles with RADA16-I to form nanofiber hydrogels,thus coupling PTHrP-1 to hydrogel matrix.P1R16 nanofiber retains osteoinductive activity in a dose-dependent manner,and P1R16/RADA16-I nanofiber hydrogels promote osteogenesis,angiogenesis and osteoclastogenesis in vitro and induce multi-functionalized osteoregeneration by intramembranous ossification and bone remodeling in vivo when loaded to collagen(Col)scaffolds.Abundant red blood marrow formation,ideal osteointegration and adapted degradation are observed in the 50%P1R16/Col scaffold group.Therefore,this study provides a promising strategy to develop multi-functional supramolecular peptides and a new method to topically administrate parathyroid hormone or parathyroid hormone related peptides for non-healing bone defects.
基金support from the National Key R&D Program of China(Nos.2020YFC1107600 and 2018YFB0704304)the National Natural Science Foundation of China(Nos.31771056 and 31771052)Shandong Province Key R&D Program of China(No.2019JZZY011106).
文摘The coordination between neurogenesis and angiogenesis plays an important role in nerve tissue development and regeneration.Recently,using bioactive materials to drive neurogenic and angiogenic responses has gained increasing attention.Understanding the neurovascular link between regulatory cues offers valuable insight into the mechanisms underlying nerve regeneration and the design of new bioactive materials.In this study,we utilized a dual-functionalized peptide nanofiber hydrogel presenting the brain-derived neurotrophic factor and vascular endothelial growth factor mimetic peptides RGIDKRHWNSQ(RGI)and KLTWQELYQLKYKGI(KLT)to construct an artificial neurovascular microenvironment.The dual-functionalized peptide nanofiber hydrogel enhanced the neurite outgrowth of pheochromocytoma(PC12)cells and tube-like structures formation of human umbilical vein endothelial cells(HUVECs)in vitro,and promoted rapid lesion infiltration of neural and vascular cells in a rat brain injury model.Using indirect co-culture models,we found that the dual-functionalized peptide hydrogel effectively mediated neurovascular crosstalk by regulating secretion of paracrine factors from PC12 cells and HUVECs.When the two cells types were directly co-cultured on the dua卜functionalized peptide hydrogel,the efficiency of cell-cell communication was enhanced,which further accelerated the differentiation and maturation of PC12 cells with an increased number of pseudopodia and spread morphology,and HUVECs tube-like structure formation.In summary,the dual-functionalized peptide nanofiber hydrogel successfully formed an artificial neurovascular niche to directly regulate the behaviors of neural and vascular cells and promote their neurovascular crosstalk through paracrine signaling and direct cell-cell contact.
基金support of the ERC Starting Grant(STROFUNSCAFF)the UK Regenerative Medicine Platform(UKRMP2)Acellular/Smart Materials.C.D.acknowledges the support of University of Palermo FFR 2018/2021.
文摘Hydrogel wound dressings can play critical roles in wound healing protecting the wound from trauma or contamination and providing an ideal environment to support the growth of endogenous cells and promote wound closure.This work presents a self-assembling hydrogel dressing that can assist the wound repair process mimicking the hierarchical structure of skin extracellular matrix.To this aim,the co-assembly behaviour of a carboxylated variant of xyloglucan(CXG)with a peptide amphiphile(PA-H3)has been investigated to generate hierarchical constructs with tuneable molecular composition,structure,and properties.Transmission electron microscopy and circular dichroism at a low concentration shows that CXG and PA-H3 co-assemble into nanofibres by hydrophobic and electrostatic interactions and further aggregate into nanofibre bundles and networks.At a higher concentration,CXG and PA-H3 yield hydrogels that have been characterized for their morphology by scanning electron microscopy and for the mechanical properties by smallamplitude oscillatory shear rheological measurements and compression tests at different CXG/PAH3 ratios.A preliminary biological evaluation has been carried out both in vitro with HaCat cells and in vivo in a mouse model.
