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A bioactive compliant vascular graft modulates macrophage polarization and maintains patency with robust vascular remodeling

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Bioactive Materials 2023年第1期19卷 167-178页

作者： Alexander Stahl dake hao Janos Barrera Dominic Henn Sien Lin Seyedsina Moeinzadeh Sungwoo Kim William Maloney Geoffrey Gurtner Aijun Wang Yunzhi Peter Yang Department of Orthopaedic Surgery Stanford University240 Pasteur DriveStanfordCA94304USA Department of Chemistry Stanford University121 Mudd BuildingStanfordCA94305USA Department of Surgery School of MedicineUniversity of California DavisSacramentoCA95817USA Institute for Pediatric Regenerative Medicine Shriners Hospitals for ChildrenSacramentoCA95817USA Department of Surgery Stanford University300 Pasteur DriveStanfordCA94305USA Department of Biomedical Engineering University of California DavisDavisCA95616USA Department of Materials Science and Engineering Stanford University496 Lomita MallStanfordCA94305USA Department of Bioengineering Stanford University443 Via OrtegaStanfordCA4305USA

Conventional synthetic vascular grafts are associated with significant failure rates due to their mismatched mechanical properties with the native vessel and poor regenerative potential.Though different tissue engineering approaches have been used to improve the biocompatibility of synthetic vascular grafts,it is still crucial to develop a new generation of synthetic grafts that can match the dynamics of native vessel and direct the host response to achieve robust vascular regeneration.The size of pores within implanted biomaterials has shown significant effects on macrophage polarization,which has been further confirmed as necessary for efficient vascular formation and remodeling.Here,we developed biodegradable,autoclavable synthetic vascular grafts from a new polyurethane elastomer and tailored the grafts’interconnected pore sizes to promote macrophage populations with a pro-regenerative phenotype and improve vascular regeneration and patency rate.The synthetic vascular grafts showed similar mechanical properties to native blood vessels,encouraged macrophage populations with varying M2 to M1 phenotypic expression,and maintained patency and vascular regeneration in a one-month rat carotid interposition model and in a four-month rat aortic interposition model.This innovative bioactive synthetic vascular graft holds promise to treat clinical vascular diseases.

关键词： Vascular graft Vascular compliance Pore size Macrophage polarization Vascular remodeling

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The functions and applications of A7R in anti-angiogenic therapy, imaging and drug delivery systems

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Asian Journal of Pharmaceutical Sciences 2019年第6期14卷 595-608页

作者： Lu Lu Hongyuan Chen dake hao Xinke Zhang Fengshan Wang Key Laboratory of Chemical Biology(Ministry of Education) Institute of Biochemical and Biotechnological DrugSchool of Pharmaceutical SciencesShandong UniversityJinan 250012China Department of General Surgery Shandong University Affiliated Shandong Provincial HospitalJinan 250021China Department of Surgery UC Davis Health Medical CenterSacramento 95817USA Key Laboratory of Chemical Biology(Ministry of Education) Department of PharmacologySchool of Pharmaceutical SciencesShandong UniversityJinan 250012China

Vascular endothelial growth factor receptor 2(VEGFR-2)and neuropilin-1(NRP-1)are two prominent antiangiogenic targets.They are highly expressed on vascular endothelial cells and some tumor cells.Therefore,targeting VEGFR-2 and NRP-1 may be a potential antiangiogenic and antitumor strategy.A7R,a peptide with sequence of Ala-Thr-Trp-Leu-Pro-Pro-Arg that was found by phage display of peptide libraries,can preferentially target VEGFR-2 and NRP-1 and destroy the binding between vascular endothelial growth factor 165(VEGF165)and VEGFR-2 or NRP-1.This peptide is a new potent inhibitor of tumor angiogenesis and a targeting ligand for cancer therapy.This review describes the discovery,function and mechanism of the action of A7R,and further introduces the applications of A7R in antitumor angiogenic treatments,tumor angiogenesis imaging and targeted drug delivery systems.In this review,strategies to deliver different drugs by A7R-modified liposomes and nanoparticles are highlighted.A7R,a new dual targeting ligand of VEGFR-2 and NRP-1,is expected to have efficient therapeutic or targeting roles in tumor drug delivery.

关键词： A7R Vascular endothelial growth factor receptor 2 Neuropilin-1 Antiangiogenesis Tumor angiogenesis imaging Drug delivery

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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 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.

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 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.

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

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Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection

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World Journal of Stem Cells 2021年第7期13卷 776-794页

作者： Aida Nasirishargh Priyadarsini Kumar Lalithasri Ramasubramanian Kaitlin Clark dake hao Sabrina V Lazar Aijun Wang Surgical Bioengineering Laboratory Department of SurgeryUniversity of CaliforniaDavis School of MedicineSacramentoCA 95817United States Institute for Pediatric Regenerative Medicine Shriners Hospitals for ChildrenSacramentoCA 95817United States Department of Biomedical Engineering University of California DavisDavisCA 95616United States

Mesenchymal stem/stromal cells(MSCs)are extensively studied as cell-therapy agents for neurological diseases.Recent studies consider exosomes secreted by MSCs as important mediators for MSCs’neuroprotective functions.Exosomes transfer functional molecules including proteins,lipids,metabolites,DNAs,and coding and non-coding RNAs from MSCs to their target cells.Emerging evidence shows that exosomal microRNAs(miRNAs)play a key role in the neuroprotective properties of these exosomes by targeting several genes and regulating various biological processes.Multiple exosomal miRNAs have been identified to have neuroprotective effects by promoting neurogenesis,neurite remodeling and survival,and neuroplasticity.Thus,exosomal miRNAs have significant therapeutic potential for neurological disorders such as stroke,traumatic brain injury,and neuroinflammatory or neurodegenerative diseases and disorders.This review discusses the neuroprotective effects of selected miRNAs(miR-21,miR-17-92,miR-133,miR-138,miR-124,miR-30,miR146a,and miR-29b)and explores their mechanisms of action and applications for the treatment of various neurological disease and disorders.It also provides an overview of state-of-the-art bioengineering approaches for isolating exosomes,optimizing their yield and manipulating the miRNA content of their cargo to improve their therapeutic potential.

关键词： Mesenchymal stromal cells Mesenchymal stromal cell-derived exosomes Exosomal microRNAs Neuroprotective effect

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Enhanced pitting corrosion resistance of CoCrFeMnNi high entropy alloy in the presence of Desulfovibrio vulgaris via nitrogen doping

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Journal of Materials Science & Technology 2023年第8期139卷 92-102页

作者： Chuntian Yang hao Feng Xiaobo Chen Yu Han Huabing Li dake Xu Fuhui Wang Shenyang National Laboratory for Materials Science Northeastern UniversityShenyang110819China Electrobiomaterials Institute Key Laboratory for Anisotropy and Texture of Materials(Ministry of Education)Northeastern UniversityShenyang110819China School of Engineering RMIT UniversityCarltonVIC 3053Australia School of Metallurgy Northeastern UniversityShenyang110819China

Corrosion-resistant high nitrogen high entropy alloys(HEAs)were manufactured by pressurized metal-lurgy.This work revealed the inhibitory effect of nitrogen on pitting corrosion of HEAs caused by sul-fate reducing bacterium Desulfovibrio vulgaris.Results indicated that HEA-0 N was susceptible to pitting corrosion and sulfidation under attack of D.vulgaris,whereas the addition of nitrogen significantly de-creased the pitting sensitivity.Pitting potentials of HEA-0.52 N and HEA-1.23 N increased by 133%and 171%,respectively compared to HEA-0 N in the presence of SRB.X-ray photoelectron spectroscopy results unveiled that nitrogen enriched in passive film and strengthened it by increasing fraction of Cr_(2)O_(3)and Fe^(3+)_(ox).Surface of the nitrogen-alloyed HEAs exhibited less defective passive films as revealed by Mott-Schottky results.Nitrogen doping provides a novel insight into the design of microbial corrosion resistant HEA.

关键词： High entropy alloy Microbiologically influenced corrosion Sulfate reducing bacteria Nitrogen doping Pitting corrosion

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Host defense peptide-mimickingβ-peptide polymer displaying strong antibacterial activity against cariogenic Streptococcus mutans

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Journal of Materials Science & Technology 2023年第2期133卷 77-88页

作者： Yi Yang Yuxin Qian Mingxing Zhang Shuang hao Hui Wang Yongqiang Fan Runhui Liu dake Xu Fuhui Wang Life and Health Sciences Northeastern UniversityShenyang 110819China Shenyang National Laboratory for Materials Science Northeastern UniversityShenyang 110819China Electrobiomaterials Institute Key Laboratory for Anisotropy and Texture of MaterialsMinistry of EducationNortheastern UniversityShenyang 110819China State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai 200237China School of Environmental and Safety Engineering Liaoning Petrochemical UniversityFushun 113001China Key Laboratory for Ultrafine Materials of Ministry of Education Frontiers Science Center for Materiobiology and Dynamic ChemistryResearch Center for Biomedical Materials of Ministry of EducationSchool of Materials Science and EngineeringEast China University of Science and TechnologyShanghai 200237China

Cariogenic Streptococcus mutans(S.mutans)is a leading cause of bacterial-induced oral diseases.Current strategies to kill bacteria based on Host defense peptide(HDP)mimicking polymers hold promise to treat oral bacterial infection.Here,we explore the impact of hydrophobic subunit and chain length variation on the antibacterial and antibiofilm activity ofβ-peptide polymers.The physicochemical and biological prop-erties,such as the toxicity,the antibacterial activity,and the effect on bacterial transcription ofβ-peptide polymers,were systematically investigated with numerous techniques.The results exhibited that the op-timalβ-peptide polymer has low toxicity towards human periodontal ligament fibroblasts,andβ-peptide polymers(especially P3)have more excellent antibacterial activity against S.mutans than metronidazole.In addition,β-peptide polymers inhibited the reversible and irreversible bacterial adhesion during the formation of biofilms.The polymer can promote biofilm dispersion by decreasing the hydrophobicity of bacterial cells after adhering to cell surfaces.Analysis of the transcriptome for S.mutans treated withβ-peptide polymers demonstrated thatβ-peptide polymers could reduce the cariogenicity of S.mutans by impacting the transcription of the energy and acid metabolism-related genes.β-peptide polymers are promising antimicrobial agents in clinical dentistry due to their high antibacterial efficiency and low tox-icity.

关键词： β-peptide polymers Host defense peptide S.mutans RT-qPCR Transcriptome

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废弃活性污泥中产聚羟基脂肪酸酯菌株Bacillus sp. PB-3的发酵条件优化

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生物加工过程 2012年第5期10卷 28-33页

作者：郝大可李强韩省王佳佳罗琰宫恺山东省医学科学院济南250062 济南大学山东省医学科学院医学与生命科学学院济南250022 济南大学化学化工学院济南250022

通过尼罗红染色法结合荧光显微镜镜检,从废弃活性污泥中分离得到1株高产聚羟基脂肪酸酯(PHAs)的菌株Bacillus sp.PB-3,经气相色谱法鉴定该菌株胞内产物为聚β-羟基丁酸酯(PHB)。对培养基成分及发酵条件优化后,获得最佳培养方案:12 g/L... 详细信息

通过尼罗红染色法结合荧光显微镜镜检,从废弃活性污泥中分离得到1株高产聚羟基脂肪酸酯(PHAs)的菌株Bacillus sp.PB-3,经气相色谱法鉴定该菌株胞内产物为聚β-羟基丁酸酯(PHB)。对培养基成分及发酵条件优化后,获得最佳培养方案:12 g/L的葡萄糖为C源,2 g/L的牛肉膏为N源,初始pH 7.5,培养基装液量80 mL,转速为200 r/min,37℃培养48 h,PHB质量分数可达菌体干质量的32.09%,比优化前提高30%。

关键词：聚羟基脂肪酸酯聚羟基丁酸酯筛选发酵

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Genetic Flux Between H1 and H2 Haplotypes of the 17q21.31 Inversion in European Population

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Genomics, Proteomics & Bioinformatics 2011年第3期9卷 113-118页

作者： Libin Deng Xiaoli Tang Xiangwen hao Wei Chen Jiari Lin Yangyu Yu dake Zhang Changqing Zeng Faculty of Basic Medical Science Nanchang University Nanchang 330006 China Beijing Institute of Genomics Chinese Academy of Sciences Beijing 100029 China Institute of Translational Medicine Nanchang University Nanchang 330006 China

The chromosome 17q21.31 inversion is a 900-kb common structural polymorphism found primarily in European population. Although the genetic flux within inversion region was assumed to be considerable suppressed, it is still unclear about the details of genetic exchange between the H1 （non-inverted sequence） and H2 （inverted sequence） haplotypes of this inversion. Here we describe a refmed map of genetic exchanges between pairs of gene arrangements within the 17q21.31 region. Using HapMap phase II data of 1,546 single nucleotide polymorphisms, we successfully deduced 96 H1 and 24 H2 haplotypes in European samples by neighbor-joining tree reconstruction. Furthermore, we identified 15 and 26 candidate tracts with reciprocal and non-reciprocal genetic exchanges, respectively. In all 15 regions harboring reciprocal exchange, haplotypes reconstructed by clone sequencing did not support these exchange events, suggesting that such signals of exchange between two sister chromosomes in certain heterozygous individual were caused by phasing error regions. On the other hand, the finished clone sequencing across 4 of 26 tracts with non-reciprocal genetic flux confirmed that this kind of genetic exchange was caused by gene conversion. In summary, as crossover between pairs of gene arrangements had been considerably suppressed, gene conversion might be the most important mechanism for genetic exchange at 17q21.31.

关键词： genetic flux inversion haplotype polymorphism

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