Over 550000 people in the U.S.require hemodialysis for management of end stage renal disease(ESRD).When anatomy restricts fistula creation,arteriovenous grafts(AVG)are implanted.AVGs have poor primary patency and high...Over 550000 people in the U.S.require hemodialysis for management of end stage renal disease(ESRD).When anatomy restricts fistula creation,arteriovenous grafts(AVG)are implanted.AVGs have poor primary patency and high risk of infection,highlighting a need for better alternatives.Previous AVG large animal models were limited by high complication rates and short-term follow-up.This study investigates the safety and durability of an ovine bilateral carotid-jugular AVG model.Eight female sheep underwent bilateral carotid-jugular AVG implantation via a single longitudinal incision overlying the trachea.Ringed PTFE grafts were anastomosed in a“lazy-S”configuration to provide the laxity needed to prevent avulsion and minimize kinking with neck movement.Post-operatively,sheep were evaluated daily to monitor for complications.Duplex ultrasonography of the grafts was performed at regular intervals out to 6 months to evaluate patency.At 6 months,angiography and duplex was performed followed by explant for gross and histologic analysis.Technical success was achieved in 16 of 16(100%)graft implants.No major complications,including stroke,anastomotic disruption,infection,wound breakdown,or death occurred.Primary patency of control PTFE grafts was 75%at 6 months,paralleling reported rates in humans.Bilateral carotid-jugular AVG implantation in sheep is a safe and durable model for self-controlled long-term evaluation of AVG conduit technology.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California Institute for Regenerative Medicine(CIRM),Grant/Award Number:TRAN3-13332。
文摘Over 550000 people in the U.S.require hemodialysis for management of end stage renal disease(ESRD).When anatomy restricts fistula creation,arteriovenous grafts(AVG)are implanted.AVGs have poor primary patency and high risk of infection,highlighting a need for better alternatives.Previous AVG large animal models were limited by high complication rates and short-term follow-up.This study investigates the safety and durability of an ovine bilateral carotid-jugular AVG model.Eight female sheep underwent bilateral carotid-jugular AVG implantation via a single longitudinal incision overlying the trachea.Ringed PTFE grafts were anastomosed in a“lazy-S”configuration to provide the laxity needed to prevent avulsion and minimize kinking with neck movement.Post-operatively,sheep were evaluated daily to monitor for complications.Duplex ultrasonography of the grafts was performed at regular intervals out to 6 months to evaluate patency.At 6 months,angiography and duplex was performed followed by explant for gross and histologic analysis.Technical success was achieved in 16 of 16(100%)graft implants.No major complications,including stroke,anastomotic disruption,infection,wound breakdown,or death occurred.Primary patency of control PTFE grafts was 75%at 6 months,paralleling reported rates in humans.Bilateral carotid-jugular AVG implantation in sheep is a safe and durable model for self-controlled long-term evaluation of AVG conduit technology.
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.
