Manipulating the host-biomaterial interface for enhanced scaffold vascularization

操纵宿主-生物材料界面以增强支架血管化

• 批准号: 10644159
• 负责人: DINO J RAVNIC
• 金额: $ 80.11万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10644159
• 关键词: Address; Architecture; Biodegradation; Blood Vessels; Blood capillaries; Caliber; Cell Size; Cells; Cellular Infiltration; Collagen; Custom; Data; Development; Engineering; Extracellular Matrix; Extravasation; Failure; Fostering; Foundations; Gelatin; Generations; Goals; Health; Hemorrhage; Hydrogels; Immune; In Situ; In Vitro; Infiltration; Injury; Link; Micropuncture; Microsurgery; Needles; Operative Surgical Procedures; Outcome; Pattern; Perforation; Perfusion; Pilot Projects; Procedures; Public Health; Publishing; Rattus; Reconstructive Surgical Procedures; Research; Science; Site; Surgeon; Techniques; Testing; Thrombosis; Tissue Adhesives; Tissue Engineering; Tissues; Ultrafine; United States National Institutes of Health; Vascularization; angiogenesis; base; biomaterial compatibility; biomaterial interface; collagen scaffold; combinatorial; design; hydrogel scaffold; implantation; improved; in vivo; innovation; macrophage; mimetics; nanoscale; neovascularization; novel; particle; prevent; reconstruction; regenerative; scaffold; soft tissue

Abstract This research is significant as it will facilitate a new generation of regenerative scaffolds. Voluminous soft tissue loss is often encountered after injury, and reconstructive procedures are suboptimal. Over the past two decades, collagen-based scaffolds have become vital to surgeons by providing a platform for tissue revascularization and reconstruction. However, their slow random vascularization upon implantation often leads to failure and prevents true recapitulation of native tissue vascular hierarchy. Thus, scaffolds which could rapidly guide microvascular development would be exceedingly relevant to replacing ‘like tissue with like tissue’, a hallmark of reconstructive surgery. This proposal’s objective is to develop a coordinated engineering-surgical approach for rapid and guided scaffold vascularization. We have developed a novel microsurgical tactic, termed vascular “micropuncture” (MP), which increases the angiogenic capabilities of the rat recipient macrovasculature to quickly vascularize an adjacently placed bulk scaffold. We believe the resulting capillary outgrowth is induced by the instantaneous extravasation of immune cells, especially macrophages. While this partially expedites vascularization in an adjacently placed bulk collagen scaffold, the resulting neo-microvasculature has a random pattern. Currently used bulk scaffolds have nanoscale pores that are orders of magnitude smaller than cell size and lack interconnectivity. This does not permit for rapid and guided cell infiltration; hence vascularization is slow and random. To address this, we have pioneered the development of in situ forming extracellular matrix (ECM)- mimetic granular scaffolds with customizable microarchitectures and cell permeating capabilities. Our preliminary data suggests that our microporous granular scaffolds are well suited to guide MP-induced vascularization. Our central hypothesis is that customized microporous granular scaffolds can be used alongside MP to enhance and guide vascularization. The rationale is that completion of these studies will reveal how to best optimize complementary tactics for the multifaceted problem of guided engineered tissue vascularization. Our central hypothesis will be tested by three specific aims: 1) To develop ECM-mimetic in situ forming microporous granular hydrogel scaffolds that regulate cellular activities pertinent to accelerating angiogenesis in vitro and in vivo; 2) Controlling scaffold vascularization by varying recipient MP interval and diameter; and 3) Controlling macrophage infiltration and vascular architecture by scaffold design. We will pursue these aims using innovative combinatorial techniques from both the surgical and engineering sciences. The expected outcome is a rapidly vascularized scaffold having a controllable microvascular hierarchy while also creating experimental techniques at the engineering-microsurgery interface. These results will have a positive impact by laying the foundation in developing new and translatable reconstructive approaches for large volume tissue loss.

摘要 这项研究意义重大，因为它将促进新一代的再生支架。大量软组织 在受伤后常常会遇到损失，并且重建程序是次优的。在过去的二十年里， 基于胶原的支架通过提供组织血管再生的平台 重建然而，它们在植入时缓慢的随机血管化常常导致失败，并阻止了植入。 天然组织血管层次的真实再现。因此，可以快速引导微血管的支架 发展将是非常相关的取代“类似组织与类似组织”，一个标志性的重建 手术该提案的目标是开发一种协调的工程手术方法， 引导支架血管化。我们开发了一种新的显微外科手术策略，称为血管 “微穿刺”（MP），其增加大鼠受体大血管系统的血管生成能力， 使邻近放置的散装支架快速血管化。我们认为，由此产生的毛细血管生长是由 免疫细胞，特别是巨噬细胞的瞬时外渗。虽然这部分加快了 通过在相邻放置的散装胶原支架中进行血管化，所得的新微血管具有随机的微血管结构。 格局目前使用的散装支架具有比细胞尺寸小几个数量级的纳米级孔 缺乏互联性。这不允许快速和引导的细胞浸润;因此血管形成缓慢 随机的为了解决这个问题，我们率先开发了原位形成细胞外基质（ECM）- 具有可定制的微结构和细胞渗透能力的模拟颗粒支架。我们的初步 数据表明我们的微孔颗粒支架非常适合于引导MP诱导的血管形成。我们 中心假设是，定制的微孔颗粒支架可以与MP一起使用，以增强 并引导血管化。其理由是，完成这些研究将揭示如何最好地优化 引导工程组织血管化的多方面问题的互补策略。我们的中央 本论文将从以下三个方面对这一假设进行验证：1）开发一种原位形成微孔颗粒的ECM模拟物 调节与体外和体内加速血管生成有关的细胞活性的水凝胶支架; 2） 通过改变受体MP间隔和直径来控制支架血管化;以及3）控制巨噬细胞 通过支架设计实现渗透和血管结构。我们将利用创新的方法来实现这些目标。 外科和工程科学的组合技术。预期的结果是， 具有可控微血管层次的血管化支架，同时还创造了实验技术， 在工程显微外科接口。这些成果将产生积极的影响， 为大体积组织缺损开发新的和可平移的重建方法。

项目成果

Accelerating Patterned Vascularization Using Granular Hydrogel Scaffolds and Surgical Micropuncture.

• DOI: 10.1002/smll.202307928
• 发表时间: 2023-10
• 期刊: Small
• 影响因子: 13.3
• 作者: Zaman Ataie;S. Horchler;Arian Jaberi;Srinivas V Koduru;Jessica C El-Mallah;Mingjie Sun;Sina Kheirabadi;Alexander Kedzierski;Aneesh Risbud;Angelo Roncalli Alves E Silva;D. Ravnic;Amir Sheikhi