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Bioactive extracellular matrix scaffolds engineered with proangiogenic proteoglycan mimetics and loaded with endothelial progenitor cells promote neovascularization and diabetic wound healing

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Bioactive Materials 2022年第4期7卷 460-473页

作者： Siqi He Tanaya Walimbe Hongyuan Chen Kewa Gao Priyadarsini Kumar Yifan Wei Dake Hao Ruiwu Liu Diana L.Farmer Kit S.Lam Jianda Zhou alyssa panitch Aijun Wang Department of Burns and Plastic Surgery The Third Xiangya Hospital of Central South UniversityChina Department of Surgery UC DavisUnited States Department of Biomedical Engineering UC DavisUnited States Department of Biochemistry and Molecular Medicine UC DavisUnited States Institute for Pediatric Regenerative Medicine Shriners Hospitals for Children Northern CaliforniaUnited States

Diabetic ischemic wound treatment remains a critical clinical *** plays a significant role in wound healing during all stages of the tissue repair *** that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds,particularly diabetic wounds in highly ischemic *** 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 *** 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)*** 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 *** 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 ***,this study provides a promising novel treatment to accelerate diabetic ischemic wound healing,thereby reducing limb amputation and mortality of diabetic patients.

关键词： Diabetic ischemic wound ECM scaffold Endothelial progenitor cells Neovascularization Wound healing

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A bio-instructive parylene-based conformal coating suppresses thrombosis and intimal hyperplasia of implantable vascular devices

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Bioactive Materials 2023年第10期28卷 467-479页

作者： Dake Hao Jonathan Lin Ruiwu Liu Christopher Pivetti Kaeli Yamashiro Linda M.Schutzman Junichiro Sageshima Mimmie Kwong Nataliya Bahatyrevich Diana L.Farmer Misty D.Humphries Kit S.Lam alyssa panitch Aijun Wang Department of Surgery School of MedicineUniversity of California DavisSacramentoCA95817United States Institute for Pediatric Regenerative Medicine Shriners Hospitals for ChildrenSacramentoCA95817United States Department of Biochemistry and Molecular Medicine School of MedicineUniversity of California DavisSacramentoCA95817United States Wallace H.Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory UniversityAtlant1GA30332United States Department of Biomedical Engineering University of California DavisDavisCA95616United States

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.

关键词： Parylene coating Integrin ligand Thrombosis Intimal hyperplasia Implantable vascular devices

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A bioactive material with dual integrin-targeting ligands regulates specific endogenous cell adhesion and promotes vascularized bone regeneration in adult and fetal bone defects

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Bioactive Materials 2023年第2期20卷 179-193页

作者： Dake Hao Ruiwu Liu Tomas Gonzalez Fernandez Christopher Pivetti Jordan Elizabeth Jackson Edwin Samuel Kulubya Hong-Jiang Jiang Hai-Yang Ju Wen-Liang Liu alyssa panitch Kit S.Lam JKent Leach Diana L.Farmer Aijun Wang Department of Surgery School of MedicineUniversity of California DavisSacramentoCA95817United States Institute for Pediatric Regenerative Medicine Shriners Hospitals for ChildrenSacramentoCA95817United States Department of Biochemistry and Molecular Medicine School of MedicineUniversity of California DavisSacramentoCA95817United States Department of Biomedical Engineering University of California DavisDavisCA95616United States Wendeng Orthopaedic Hospital No.1 Fengshan RoadWendeng264400ShandongChina Department of Orthopaedic Surgery School of MedicineUniversity of California DavisSacramentoCA95817United States

Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone ***,current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration,thus leading to adverse tissue formation and decreased regenerative ***,we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone *** 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,*** 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^(+)*** a fetal sheep spinal bone defect model,the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse *** 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.

关键词： Integrin-based ligands Endogenous stem cells Bone formation Vascularization Adult and fetal bone defects

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A Cell-Penetrating Peptide for Inhibiting MAPKAP Kinase 2-Mediated Inflammatory Cytokine Release Following Glial Cell Activation

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World Journal of Neuroscience 2015年第2期5卷 115-130页

作者： James R. Wodicka Nnadozie I. Onunkwo Andrew J. Woolley alyssa panitch Kevin J. Otto Weldon School of Biomedical Engineering Purdue University West Lafayette USA Indiana University School of Medicine Indianapolis USA Department of Biological Sciences Purdue University West Lafayette USA Department of Biomedical Engineering University of Florida Gainesville USA

Central nervous system (CNS) injury initializes a reactive tissue response, which is characterized by a cascade of signals that result in inflammatory cytokine release and neuroinflammation. These signals are induced in part by activated microglia that migrates to the injury site in an attempt to remove dead tissue and promote healing. The ability to control the reactive tissue response is of significant importance to a variety of applications, such as neuroprostheses, whose functional lifespan is limited by glial cell activation. A possible strategy to mitigate glial cell activation is to reduce the release of inflammatory cytokines following a brain injury. One pathway that facilitates inflammatory cytokine release is the mitogen-activated protein kinase-activated protein kinase 2 (MK2) pathway, which increases cytokine mRNA synthesis, stability and translation following activation. Therefore, inhibiting MK2-mediated cytokine release can reduce microglial activationfollowing CNS injury. Through?in vitro?studies, we demonstrate the ability of a cell-penetrating peptide inhibitor of MK2 (MK2i) to reduce MK2-mediated cytokine release in mixed cortical cultures.?Immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and cytotoxicity assays in 7- -10-day-old E17 Sprague-Dawley rat mixed cortical cultures showed that MK2i treatment significantly lowered inflammatory cytokine production and increased cortical cell viability following?glial cell activation with tumor necrosis factor-α(TNF-α) and lipopolysaccharide (LPS). Results suggest that MK2i may reduce damage caused by activated glia in the inflamed CNS.

关键词： Injury Mitigation Treatment Drug MK2i

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