Angiogenic growth factor delivery for vascular regeneration in critical limb ischemia using acoustically-responsive scaffolds

使用声响应支架输送血管生长因子以促进严重肢体缺血的血管再生

• 批准号: 10094233
• 负责人: Mario Leonardo Fabiilli
• 金额: $ 57.67万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094233
• 关键词: 3-Dimensional; Acoustics; Affect; Automobile Driving; Biocompatible Materials; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Consensus; Development; Dose; Emulsions; Encapsulated; FGF2 gene; Fibrin; Focused Ultrasound; Frequencies; Generations; Goals; Growth; Growth Factor; Implant; Injections; Intervention; Lead; Limb structure; Methods; Modeling; Mus; Natural regeneration; Outcome; Patients; Pattern; Penetration; Perfusion; Peripheral arterial disease; Platelet-Derived Growth Factor; Pre-Clinical Model; Property; Research; Risk; Route; Signal Transduction; Site; System; Testing; Therapeutic Index; Tissue Engineering; Tissues; Translating; Translations; Ultrasonography; Viscosity; active control; angiogenesis; base; blood vessel development; clinical translation; clinically translatable; critical limb Ischemia; high risk; improved; in vivo; limb amputation; limb ischemia; mortality; novel strategies; platelet-derived growth factor BB; pre-clinical; regenerative; release factor; response; restoration; scaffold; spatiotemporal; subcutaneous; success; therapeutic angiogenesis; therapeutically effective

ABSTRACT The clinical use of pro-angiogenic growth factors could greatly impact the treatment of critical limb ischemia (CLI), a condition characterized by arterial blockages in the extremities. With CLI, 40% of patients are ineligible for available therapies and even with intervention, the 6-month risk of limb amputation is 25-40% with an annual mortality of 20%. In preclinical models of CLI, collateral blood vessel formation and perfusion restoration are observed in the ischemic limb following the administration of angiogenic growth factors. However, attempts at clinically translating these promising preclinical results, via the use of at-site or systemic injections of angiogenic growth factors, has remained a challenge. The delivery of growth factors via injection or using conventional scaffold-based approaches does not afford active control of the dose, timing, or spatial localization at the intended site of collateral vessel formation. Furthermore, no consensus exists regarding what range of these parameters, including what combination of growth factors, are required for effective therapeutic angiogenesis. Thus, there is an urgent need to develop a safe and effective delivery system for multiple angiogenic growth factors that recapitulates critical aspects of endogenous growth factor signaling and facilitates identification of these crucial parameters. Our long-term goal is to develop implantable biomaterials for the delivery of regenerative molecules, where delivery can be manipulated spatiotemporally in an externally-regulated, on-demand manner. The modulating mechanism is megahertz-range ultrasound, which is clinically translatable since it can be applied non-invasively, focused with sub-millimeter precision, and delivered in a spatiotemporally defined manner to sites deep within the body. The objective of this proposal is to develop an implantable scaffold where the released dose, sequence, and localization of two growth factors involved in angiogenesis - basic fibroblast growth factor (bFGF) and platelet derived growth factor-BB (PDGF- BB) - are non-invasively controlled. The scaffold, termed an acoustically-responsive scaffold (ARS), is doped with two ultrasound-sensitive emulsions that each contain a growth factor. The central hypothesis driving this project is that ultrasound can spatiotemporally pattern angiogenesis in and around an ARS by controlling the sequential release of bFGF and PDGF-BB. The rationale for the proposed research is that an ARS enables the study of how various doses and spatiotemporal gradients of bFGF and PDGF-BB affect the development of blood vessels, which can be used in the translation of therapeutic angiogenesis for the treatment of CLI. The hypothesis will be tested via three specific aims: 1) enhance selective release of growth factors from the ARS; 2) use an ARS to demonstrate the impact of spatiotemporally-generated gradients of bFGF on angiogenesis; and 3) demonstrate restoration of perfusion in a murine hind limb ischemia model using an ARS. Successful completion of the proposed research is significant since it will elucidate how microenvironmental factors – such as growth factor doses, spatiotemporal profiles, and sequence – affect angiogenesis.

抽象的 促血管生成生长因子的临床使用可能极大地影响严重肢体缺血的治疗 (CLI)，一种以四肢动脉阻塞为特征的疾病。对于 CLI，40% 的患者不符合资格 对于现有的治疗方法，甚至进行干预，6 个月截肢的风险为 25-40% 年死亡率20%。在 CLI 临床前模型中，侧支血管形成和灌注 在施用血管生成生长因子后观察到缺血肢体的恢复。 然而，尝试通过使用现场或系统性方法将这些有希望的临床前结果临床转化 注射血管生成生长因子仍然是一个挑战。通过注射输送生长因子 或使用传统的基于支架的方法无法主动控制剂量、时间或空间 定位于侧支血管形成的预期部位。此外，关于 有效需要这些参数的范围，包括生长因子的组合 治疗性血管生成。因此，迫切需要开发一种安全、有效的给药系统。 多种血管生成生长因子，概括了内源性生长因子信号传导的关键方面， 有助于识别这些关键参数。我们的长期目标是开发可植入生物材料 用于再生分子的递送，其中可以在时空上操纵递送 外部调节、按需方式。调制机制是兆赫范围的超声波，即 临床可转化，因为它可以非侵入性地应用，以亚毫米精度聚焦，并且 以时空限定的方式输送到身体深处的部位。该提案的目标是 开发可植入支架，其中两种生长因子的释放剂量、序列和定位 参与血管生成——碱性成纤维细胞生长因子（bFGF）和血小板衍生生长因子-BB（PDGF- BB) - 非侵入性控制。该支架被称为声响应支架（ARS），经过掺杂 含有两种超声波敏感乳液，每种乳液都含有生长因子。驱动这一现象的中心假设 该项目的目的是，超声波可以通过控制 ARS 内部和周围的血管生成来形成时空模式的血管生成。 bFGF 和 PDGF-BB 的顺序释放。拟议研究的基本原理是 ARS 能够 研究bFGF和PDGF-BB的不同剂量和时空梯度如何影响发育 血管，可用于转化治疗性血管生成以治疗 CLI。这 该假设将通过三个具体目标进行检验：1）增强 ARS 中生长因子的选择性释放； 2) 使用ARS来证明bFGF时空生成的梯度对血管生成的影响； 3) 使用 ARS 证明小鼠后肢缺血模型中灌注的恢复。成功的 完成拟议的研究具有重要意义，因为它将阐明微环境因素（例如 生长因子的剂量、时空分布和序列会影响血管生成。