Mechanisms and Application of Micropunctured Induced Angiogenesis for the Rapid Perfusion of Intraoperative Bioprinted Flaps

微刺诱导血管生成术中生物打印皮瓣快速灌注的机制及应用

• 批准号: 10179655
• 负责人: DINO J RAVNIC
• 金额: $ 69.38万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179655
• 关键词: Adipocytes; Adipose tissue; Aptitude; Area; Assimilations; Biology; Blood Vessels; Cellular Infiltration; Cellular biology; Collagen; Dependence; Deposition; Development; Endothelium; Engineering; Excision; Extravasation; Fostering; Foundations; Generations; Goals; Health; Hemorrhage; Hour; Hypoxia; Implant; In Situ; In Vitro; Knowledge; Malignant Neoplasms; Micropuncture; Modeling; National Research Service Awards; Needles; Operative Surgical Procedures; Outcome; Oxygen; Pattern; Perforation; Perfusion; Pharmacology; Procedures; Public Health; Rattus; Research; Resistance; Route; Saphenous Vein; Science; Surgical Flaps; Techniques; Testing; Thick; Thinness; Thrombosis; Tissue Engineering; Tissues; Training; Translations; Trauma; Traumatic injury; Ultrafine; United States National Institutes of Health; Vascularization; Work; angiogenesis; base; bioprinting; clinically relevant; combinatorial; endothelial stem cell; gain of function; improved; in vitro testing; in vivo; innovation; intravital microscopy; loss of function; macrophage; materials science; monocyte; neovascularization; novel; progenitor; reconstruction; scale up; soft tissue; success; tissue reconstruction

PROJECT SUMMARY/ABSTRACT Advances have allowed for the in vitro creation of thin vascularized replacement grafts but lack of a continuous and anastomosable vasculature limits translation and scale-up of size. There is little knowledge about the utility of surgical approaches in facilitating prompt inosculation of implanted engineered tissues. Our long-term goal is to develop surgical strategies which augment the vascular integration of thick engineered flaps; which would offer more clinical relevance. The objective of this proposal is to define the mechanisms and impact of a coordinated surgical and additive manufacturing approach for the rapid vascularization of an engineered adipose flap, which would be applicable for soft tissue reconstruction. We have developed an innovative microsurgical tactic, termed “vascular micropuncture”, which increases the angiogenic capabilities of the rat recipient vasculature in order to quickly perfuse an adjacently placed un-anastomosable thin engineered graft. This results in graft perfusion within 24 hours and a doubling of neovascularization. If combined with standard vascular interposition conduits (e.g. saphenous vein), which can be used to lengthen the recipient pedicle, it offers an easily translatable approach for thick flap engineering. Our central hypothesis is that vascular micropuncture and lengthening of the recipient vasculature can enable direct inosculation and rapid perfusion of a thick adipose flap that is intraoperatively bioprinted with adipocyte/endothelial progenitor cell spheroids. The rationale is that completion of these studies will reveal how to best optimize complementary tactics for the inosculation of concurrently engineered in situ flaps. Our central hypothesis will be tested by three specific aims: 1) Demonstrate that micropuncture induces angiogenesis by allowing for immediate monocyte/macrophage extravasation; 2) High-throughput bioprinting and in vitro testing of a hypoxia-resistant vascularized adipose graft; 3) Coordinated in situ thick flap generation and surgically induced rapid perfusion. We will pursue these aims using novel combinatorial techniques from both the surgical and engineering sciences, including recently developed microsurgical and aspiration assisted bioprinting approaches. This proposed research is significant because it will integrate these advances to intraoperatively assemble and rapidly perfuse a thick engineered flap; a noteworthy advance from the often-described thin engineered graft. The expected outcome is that mechanisms of micropunctured induced angiogenesis will be identified and experimental techniques for augmenting engineered tissue inosculation will be determined. These results will have a positive impact by laying the foundation in developing new and translatable reconstructive approaches for large volume soft tissue loss.

项目摘要/摘要 进展允许在体外创造薄的血管化的替代移植物，但缺乏连续的 而可吻合的血管结构限制了尺寸的平移和放大。人们对这一实用程序知之甚少 促进植入的工程化组织迅速融合的外科方法。我们的长期目标 是开发外科手术策略，以增强厚皮瓣的血管整合；这将 提供更多的临床相关性。这项提案的目标是界定一项 工程化脂肪快速血管化的手术配合和添加剂制造方法 可应用于软组织重建。我们开发了一种创新的显微外科手术 一种名为“血管微穿刺术”的方法，可增强受体大鼠的血管生成能力。 血管系统，以便快速灌流邻近放置的不能吻合的薄层工程移植物。这将导致 24小时内移植物灌注量增加一倍，新生血管增加一倍。如果与标准血管结合 插入导管(如隐静脉)，可用于延长受者的椎弓根，它提供了一种 易于翻译的厚襟翼工程方法。我们的中心假设是血管微穿刺术 而延长受者的血管系统可以使厚脂肪直接吻合和快速灌流 术中生物打印脂肪细胞/内皮祖细胞球体的皮瓣。理由是 这些研究的完成将揭示如何最佳地优化互补策略，以将 同时设计的原位皮瓣。我们的中心假设将通过三个具体目标进行检验：1)论证 微穿刺术通过允许单核/巨噬细胞立即渗出而诱导血管生成；2) 抗缺氧血管脂肪移植物的高通量生物打印和体外测试；3)协调 原位厚皮瓣生成和手术诱导快速灌流。我们将用小说来追求这些目标 来自外科和工程科学的组合技术，包括最近开发的 显微外科和抽吸辅助生物打印方法。这项拟议的研究具有重要意义，因为它 将整合这些先进技术，在术中组装并快速灌流一块厚厚的工程皮瓣； 从经常被描述的薄型工程移植物中取得了值得注意的进展。预期的结果是，机制 将确定微穿刺法诱导血管生成的可能性，并采用实验技术增强 工程化组织融合将被确定。这些结果将产生积极的影响，为 为开发新的、可翻译的大体积软组织缺失重建方法奠定了基础。