Department of Ultrasound, Second Affiliated Hospital of Army Medical University, Chongqing, China; Department of Radiology, University of Michigan, Ann Arbor, MI, United States.
Department of Radiology, University of Michigan, Ann Arbor, MI, United States.
Acta Biomater. 2021 Jul 15;129:73-83. doi: 10.1016/j.actbio.2021.04.048. Epub 2021 May 5.
Vascularization is a critical step following implantation of an engineered tissue construct in order to maintain its viability. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for anastomosis and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially- controlling regenerative processes using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). A therapeutic payload, which is initially contained within the PSDE, is released by an ultrasound-mediated process called acoustic droplet vaporization (ADV). During ADV, the perfluorocarbon (PFC) phase within the PSDE is vaporized into a gas bubble. In this study, we generated ex situ four different spatial patterns of ADV within ARSs containing basic fibroblast growth factor (bFGF), which were subcutaneously implanted in mice. The PFC species within the PSDE significantly affected the morphology of the ARS, based on the stability of the gas bubble generated by ADV, which impacted host cell migration. Irrespective of PFC, significantly greater cell proliferation (i.e., up to 2.9-fold) and angiogenesis (i.e., up to 3.7-fold) were observed adjacent to +ADV regions of the ARSs compared to -ADV regions. The morphology of the PSDE, macrophage infiltration, and perfusion in the implant region were also quantified. These results demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis. Overall, these finding can be applied to improve strategies for spatially-controlling vascularization. STATEMENT OF SIGNIFICANCE: Vascularization is a critical step following implantation of an engineered tissue. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for inosculation and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially-controlling angiogenesis using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). An ultrasound-mediated process called acoustic droplet vaporization (ADV) was used to release basic fibroblast growth factor (bFGF), which was initially contained within the PSDE. We demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis in vivo. Overall, these finding can improve strategies for spatially-controlling vascularization.
血管化是在植入工程组织构建体后维持其活力的关键步骤。空间模式化或定向血管化的能力可能对吻合和血管内生长具有治疗益处。然而，用于刺激血管生成的无细胞和基于细胞的策略通常无法提供这种控制。我们已经开发了一种基于超声的方法，使用称为响应性声纳支架 (ARS) 的无细胞复合水凝胶来空间控制再生过程。ARS 由掺入相移双乳液 (PSDE) 的纤维蛋白基质组成。最初包含在 PSDE 中的治疗有效载荷通过称为声空化的超声介导过程释放。在 ADV 期间，PSDE 中的全氟碳 (PFC) 相蒸发成气泡。在这项研究中，我们在含有碱性成纤维细胞生长因子 (bFGF) 的 ARS 中体外生成了四种不同的 ADV 空间模式，然后将其植入小鼠体内。基于 ADV 产生的气泡的稳定性，PSDE 内的 PFC 种类显著影响 ARS 的形态，这影响了宿主细胞的迁移。无论 PFC 如何，与 -ADV 区域相比，ARS 的 +ADV 区域附近观察到显著更高的细胞增殖（即高达 2.9 倍）和血管生成（即高达 3.7 倍）。还定量了植入区域的 PSDE 形态、巨噬细胞浸润和灌注。这些结果表明，ARS 内的空间定义的 ADV 模式可以引发空间定义的血管生成模式。总体而言，这些发现可应用于改善空间控制血管生成的策略。
血管化是工程组织植入后的关键步骤。空间模式化或定向血管化的能力可能对吻合和血管内生长具有治疗益处。然而，用于刺激血管生成的无细胞和基于细胞的策略通常无法提供这种控制。我们已经开发了一种基于超声的方法，使用称为响应性声纳支架 (ARS) 的无细胞复合水凝胶来空间控制血管生成。ARS 由掺入相移双乳液 (PSDE) 的纤维蛋白基质组成。一种称为声空化的超声介导过程用于释放最初包含在 PSDE 中的碱性成纤维细胞生长因子 (bFGF)。我们证明，ARS 内的空间定义的 ADV 模式可以在体内引发空间定义的血管生成模式。总体而言，这些发现可以改善空间控制血管化的策略。
