Biodegradable Synthetic Vascular Graft

可生物降解的合成血管移植物

• 批准号: 9103669
• 负责人: Yadong Wang
• 金额: $ 17.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-25 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103669
• 关键词: Address; Adult; Affect; Age; Aging; Animal Model; Animals; Arteries; Atherosclerosis; Biochemical; Biomechanics; Biomedical Research; Blood Vessels; Budgets; Bypass; Cardiovascular Diseases; Cell Culture Techniques; Cells; Charge; Chemotactic Factors; Childhood; Chronic; Clinic; Clinical; Common carotid artery; Complex; Cues; Data; Diglycerides; Elderly; Emulsions; Engineering; Ethylenes; Extracellular Matrix; Female; Goals; Harvest; Heparin; Heparin Binding; Homing; Human; Hypertension; Immune response; Implant; In Situ; In Vitro; Individual; Infiltration; Inflammation; Liquid substance; Literature; Natural regeneration; Operative Surgical Procedures; Parents; Patients; Phase; Phenotype; Polymers; Population; Procedures; Production; Progenitor Cell Engraftment; Property; Proteins; Rattus; Recruitment Activity; Research; Research Project Grants; Risk Factors; Signal Transduction; Stem cells; Stromal Cells; Surface; System; Technology; Testing; Tissue Engineering; Tissues; Translations; Tube; Tubular formation; Use Effectiveness; Vascular Diseases; Vascular Graft; abdominal aorta; age effect; aged; base; cell motility; cellular engineering; clinically relevant; controlled release; cost; cytokine; design; elastomeric; human old age (65+); improved; in vivo; insight; juvenile animal; male; manufacturing process; migration; neovascularization; patient population; poly(glycerol-sebacate); polycaprolactone; polycation; progenitor; public health relevance; regenerative; response; success

 DESCRIPTION (provided by applicant): In situ tissue engineering eliminates cell harvesting surgeries and reduces manufacturing costs substantially. Bypassing cell seeding and cell culture steps improve clinical translatability. This approach was proven by our previous study demonstrating that a bilayer cell-free vascular graft composed of an elastomeric poly(glycerol sebacate) (PGS) tubular core and a tough polycaprolactone (PCL) sheath undergoes constructive host remodeling into neo-arteries in rat abdominal aorta. In the clinical setting, elderly human patients will have lower regenerative capability than young healthy animals used in this and most other biomedical research. Accumulating evidences support that aging is a major risk factor of chronic vascular diseases, and is associated with impaired neovascularization and reduced functionality and mobility of progenitor cells. Thus, we anticipate that arterial regeneration via in situ approach will be more challenging in human patients. To narrow the gap of technology translation to the clinics, this project will: 1, use 18-month-old rats to better predict host remodeling in human patients, and 2, evaluate the effectiveness of using stromal cell-derived factor (SDF)-1α released from the vascular grafts to recruit progenitor cells to compensate for the reduced motility of progenitor cells in older individuals. The objective of this supplement research is to engineer cell-free vascular grafts that can enhance host progenitor cell recruitment in situ and evaluate their transformation into artery-like tissues in aged animals. SDF-1α is a potent chemoattractant for inducing progenitor cell engraftment. It will be released from a coacervate (a form of emulsion) delivery system in a sustained manner. Our preliminary results show that coacervate maintains bioactivity of SDF-1α, supports its long-term sustained release, and enhances migration and recruitment of human progenitor cells in vitro. We hypothesize that active cell recruitment will promote constructive host remodeling in situ, leading to rapid transformation to a neo-artery. The cost of large animals is not justified at this early phase of research, however aged rats will be used to best mirror human patient population. To test our hypothesis, we will accelerate host cell recruitment and endothelialization by controlled release of SDF-1α. We will use both male and female 18 month-old rats to reflect 50-to-65 year old human patients and implant both bare (control) and SDF-1α coacervate-loaded vascular grafts to common carotid arteries up to 6 months. We will examine early host responses including inflammation and cell infiltration, and correlation between the phenotypes and organization of the recruited cells. We will also investigate the impact of SDF-1α on the rate of endothelialization and ECM production. Successful completion of the proposed research will enhance the aims of the parent R01 and provide an appropriate animal model to address the effect of aging on in situ tissue engineering for arterial regeneration.

 描述（由申请人提供）：原位组织工程消除了细胞采集手术并显着降低了制造成本，绕过细胞接种和细胞培养步骤提高了临床可转化性，该方法证明了双层无细胞血管移植物的组成。弹性体聚癸二酸甘油酯（PGS）管状核心和坚韧聚己内酯（PCL）鞘的结构在大鼠腹部进行建设性宿主重塑为新动脉在临床环境中，老年患者的再生能力低于本研究和大多数其他生物医学研究中使用的年轻健康动物，越来越多的证据表明衰老是慢性血管疾病的主要危险因素，并且与新生血管受损有关。因此，我们预计通过原位方法进行动脉再生在人类患者中将更具挑战性，为了缩小技术转化到临床的差距，该项目将： 1、使用18 个月大的大鼠更好地预测人类患者的宿主重塑，2 评估使用血管移植物释放的基质细胞衍生因子 (SDF)-1α 募集祖细胞以补偿祖细胞运动性降低的有效性这项补充研究的目的是设计无细胞血管移植物，以增强宿主祖细胞的原位募集，并评估它们在老年动物中向动脉样组织的转化。用于诱导祖细胞植入的有效化学引诱剂，它将从凝聚层（乳液形式）递送系统中持续释放。我们的初步结果表明，凝聚层保持了 SDF-1α 的生物活性，支持其长期持续释放。增强人类祖细胞的体外迁移和募集，我们认为活跃的细胞募集将促进原位宿主的建设性重塑，从而导致大型动物快速转化为新动脉。在研究的早期阶段是不合理的，但是老年大鼠将被用来最好地反映人类患者群体，为了检验我们的假设，我们将通过控制 SDF-1α 的释放来加速宿主细胞的募集和内皮化。我们将使用 18 个月大的雌性大鼠来模拟 50 至 65 岁的人类患者，并将裸露（对照）和 SDF-1α 凝聚的血管移植物植入颈总动脉长达 6 个月。检查早期宿主反应，包括炎症和细胞浸润，以及招募细胞的表型和组织之间的相关性。我们还将研究 SDF-1α 对内皮化速率和 ECM 产生的影响。成功完成拟议的研究将增强。母体 R01 的目标，并提供适当的动物模型来解决衰老对动脉再生的原位组织工程的影响。