Prevention of Hemodialysis Vascular Access Stenosis

预防血液透析血管通路狭窄

• 批准号: 7929596
• 负责人: Alfred K Cheung
• 金额: $ 111.42万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929596
• 关键词: 3-Dimensional; Address; Algorithms; Anastomosis - action; Animal Experiments; Animals; Area; Arteries; Biomedical Engineering; Blood Vessels; Canis familiaris; Cell Culture Techniques; Characteristics; Clinical; Clinical Medicine; Clinical Research; Clinical Trials; Computer Assisted; Computer Systems Development; Data; Development; Dialysis procedure; Diffusion; Dipyridamole; Discipline; Drug Delivery Systems; Drug Kinetics; Drug Transport; Drug usage; Elements; Failure; Family suidae; Funding; Future; Gel; Goals; Grant; Hemodialysis; Hyperplasia; Image; Imaging Techniques; In Vitro; Individual; Industry; Institutes; Lesion; Magnetic Resonance Angiography; Medical Device; Medicine; Methods; Microspheres; Modeling; Monitor; Morphology; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacy (field); Physiologic arteriovenous anastomosis; Polymers; Polytetrafluoroethylene; Postdoctoral Fellow; Preparation; Prevention; Property; Published Comment; Radiology Specialty; Research; Research Personnel; Safety; Sirolimus; Stenosis; Students; System; Testing; Therapeutic; Thrombosis; Tissue Model; Tissues; Training; Translating; United States National Institutes of Health; Utah; Validation; Vascular Graft; Veins; Venous; Work; X-Ray Computed Tomography; antiproliferative drugs; base; complex biological systems; copolymer; design; drug efficacy; imaging modality; in vivo; innovation; local drug delivery; mathematical model; meetings; multidisciplinary; novel; pharmacokinetic model; prevent; programs; reconstruction; scientific computing; success; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is "Clinical Medicine, Therapeutics and Drug Delivery". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to: (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug's physicochemical, pharmacokinetic and pharmacodynamic properties; (2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts; (3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems; (4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments: (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery); (2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing & Imaging Institute (pharmacokinetic modeling and validation in tissues); (3) D. Blumenthal, Dept. of Pharmacology & Toxicology (characterization of in vitro drug efficacy and mechanism of action); (4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager; (5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies.

描述(申请人提供)：新生内膜增生(NH)引起的狭窄通常发生在用于血液透析的动静脉(AV)移植物的吻合口，导致血栓形成和闭塞。这是一个竞争性更新提交的项目，该项目旨在开发可经皮注射的新型持续药物传递系统，并允许局部传递抗增殖药物以防止移植物狭窄。生物工程领域是“临床医学、治疗和药物输送”。使用一种独特的聚合物药库(Regel)将紫杉醇通过血管周围输送，我们已经在犬模型中证明了这种方法的可行性。我们现在已经完善了一个猪模型，并在几周内证明了双嘧达莫和雷帕霉素从血管周围储存库持续、可量化地输送到血管壁。这次更新的4个具体目标是：(1)根据每种药物的物理化学、药代动力学和药效学特性，优化局部给药的缓释聚合物凝胶系统；(2)开发和验证有限元模型，以预测在动静脉移植血管周围使用缓释系统给药的长期药代动力学；(3)确定使用缓释系统给药时，在移植物吻合口预防狭窄方面安全有效的药物；(4)调整和改进3D成像方法，包括磁共振血管成像(MRA)，以便更准确地量化猪模型中移植物吻合口的狭窄进展和药物疗效。有5个部门的6名主要调查人员：(1)R.Rathi，MacroMed，Inc.(开发用于药物输送的聚合物)；(2)S.Kern，Depts。(3)D.Blumenthal，D.Blumenthal，D.药理学与毒理学(体外药效及作用机制的表征)；(4)张安生，系。犹他大学医学系(动物实验和临床相关性)，兼任PI和项目经理；(5)D.Parker，系。放射学(MRA成像开发和NH形态的3D重建)。这个多学科团队，使用综合系统方法，对于开发创新方法来解决一个重要的临床问题至关重要。它还将为不同学科的学员提供极好的机会，以合作的方式相互交流。在这项为期5年的计划内，该项目的结果极有可能应用于试点临床研究。

项目成果

In-vitro Release of Rapamycin from a Thermosensitive Polymer for the Inhibition of Vascular Smooth Muscle Cell Proliferation.

从热敏聚合物中体外释放雷帕霉素以抑制血管平滑肌细胞增殖。

• DOI: 10.4172/jbb.1000002
• 发表时间: 2009
• 期刊: Journal of bioequivalence & bioavailability
• 作者: Zhu,Weiwei;Masaki,Takahisa;Cheung,AlfredK;Kern,StevenE
• 通讯作者: Kern,StevenE

PDGF-induced proliferation in human arterial and venous smooth muscle cells: molecular basis for differential effects of PDGF isoforms.

• DOI: 10.1002/jcb.22924
• 发表时间: 2011-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Li, Li;Blumenthal, Donald K.;Terry, Christi M.;He, Yuxia;Carlson, Mary L.;Cheung, Alfred K.
• 通讯作者: Cheung, Alfred K.

Investigating surface topology and cyclic-RGD peptide functionalization on vascular endothelialization.

• DOI: 10.1002/jbm.a.34700
• 发表时间: 2014-02
• 期刊: JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
• 影响因子: 4.9
• 作者: McNichols, Colton;Wilkins, Justin;Kubota, Atsutoshi;Shiu, Yan T.;Aouadi, Samir M.;Kohli, Punit
• 通讯作者: Kohli, Punit

Modelling ultrasound-induced mild hyperthermia of hyperplasia in vascular grafts.

模拟超声诱导的血管移植物增生的轻度高热。

• DOI: 10.1186/1742-4682-8-42
• 发表时间: 2011
• 期刊: Theoretical biology & medical modelling
• 作者: Brinton,MarkR;Stewart,RussellJ;Cheung,AlfredK;Christensen,DouglasA;Shiu,Yan-TingE
• 通讯作者: Shiu,Yan-TingE

In vitro pharmacological inhibition of human vascular smooth muscle cell proliferation for the prevention of hemodialysis vascular access stenosis.

体外药理抑制人血管平滑肌细胞增殖，用于预防血液透析血管通路狭窄。

• DOI: 10.1159/000078785
• 发表时间: 2004
• 期刊: Blood purification
• 影响因子: 3
• 作者: Masaki,Takahisa;Kamerath,CraigD;Kim,Seung-Jung;Leypoldt,JohnK;Mohammad,SyedF;Cheung,AlfredK
• 通讯作者: Cheung,AlfredK