Biodegradable Synthetic Vascular Graft

 描述(由申请人提供)：原位组织工程消除了细胞采集手术，并大大降低了制造成本。绕过细胞接种和细胞培养步骤，提高了临床可译性。我们以前的研究证实了这种方法，即由弹性聚己内酯(PCL)鞘和弹性聚己二酸甘油(PGS)管芯组成的双层无细胞血管移植物在大鼠腹主动脉中经历了建设性的宿主重建成新生动脉。在临床环境中，老年人类患者的再生能力将低于这项研究和大多数其他生物医学研究中使用的年轻健康动物。越来越多的证据支持，衰老是慢性血管疾病的主要危险因素，并与新生血管受损和祖细胞功能和流动性降低有关。因此，我们预计，在人类患者中，通过原位方法进行动脉再生将更具挑战性。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建；2，评估使用从血管移植物中释放的基质细胞衍生因子-1α来招募祖细胞以补偿老年人祖细胞活力降低的有效性。这项补充研究的目的是设计无细胞血管移植物，以提高宿主祖细胞的原位募集，并评估其在老年动物中向动脉样组织的转化。SDF-1α是一种有效的趋化诱导剂，可诱导祖细胞植入。它将以持续的方式从凝聚(一种乳剂)输送系统中释放。我们的初步结果表明，凝聚酸保持了SDF-1α的生物活性，支持其长期缓释，并促进了人祖细胞在体外的迁移和募集。我们假设，活跃的细胞募集将促进原位建设性宿主重塑，导致快速转化为新生动脉。在研究的早期阶段，大型动物的成本是不合理的，然而，老年大鼠将被用来最好地反映人类患者的数量。为了验证我们的假设，我们将通过控制释放sdf-1α来加速宿主细胞的募集和内皮化。我们将使用18个月龄的雄性和雌性大鼠来反映50到65岁的人类患者，并在长达6个月的颈总动脉植入裸(对照)和sdf-1α凝集负载血管移植物。我们将检查早期宿主反应，包括炎症和细胞渗透，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对血管内皮化率和细胞外基质产生的影响。这项研究的成功完成将增强亲本R01的目标，并提供一个合适的动物模型来解决衰老对原位组织工程动脉再生的影响。

 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.