Guided Tissue Engineering of 3D Vascularized Tissues

描述(由申请人提供)： 要成功地将组织工程疗法转化为临床应用，使退伍军人受益，需要克服一些技术、生物和外科挑战。可以工程化的组织的体积受到刺激形成稳定血管的程度的限制。需要广泛、稳定的血液供应来满足新组织的质量传输需求，并且大多数方法都是针对小体积临床前模型中的工程组织进行优化的。我们已经证明，在骨膜上植入含有模型组织工程疗法的骨腔可以产生临床上合适的形状和体积的三维血管化骨。4这项技术已经转化为临床应用，但需要骨腔组件的自体骨源。这种方法的广泛应用需要确定替代的、非自体组织来源。组织工程有可能为腔室组件提供替代来源。在我们之前的优秀奖中，我们调查并优化了用于血管组织形成的多孔水凝胶支架的设计。在前一个周期中，我们开发了聚合物合成和设计技术，在体外、体内和硅胶中评估了这些生物材料支架的血管形成和细胞响应，并研究了用于评估组织工程策略的新的成像技术。这些研究表明，我们有能力促进和影响血管在工程组织中的生长。在实现足够的血管内长入以工程大量的骨、协调血管形成和骨形成以及适合临床应用的工程复杂结构方面仍然存在挑战。这项建议的主要目标是：1)研究和优化生物信号包埋聚乙二醇基水凝胶的设计，用于工程化血管化骨；2)将这些材料应用于修复大型复杂颅面缺损的工程化血管化骨。为了实现我们的目标，我们将完成以下具体目标：目标1：研究和优化用于刺激血管组织侵入多孔水凝胶的梯度支架的生成。目的：研究多孔水凝胶在体内外对血管形成和骨形成的协调作用。目的：建立拓扑优化方法，为临床可移植大动物模型构建具有合适体积和结构的带血供骨组织工程奠定基础。这是一项雄心勃勃的提案，重点是优化技术，使新的重建技术更接近临床。

DESCRIPTION (provided by applicant): The successful translation of tissue engineering therapies into clinical application that will benefit veterans requires overcoming a number of technical, biological and surgical challenges. The volume of tissue that can be engineered is limited by the extent to which stable blood vessels can be stimulated to form. An extensive, stable blood supply is required to meet mass transport demands in the new tissues and most methods are optimized for engineering tissues in small volume pre-clinical models. We have shown that implantation of a chamber containing model tissue engineering therapies against the periosteum can lead to the generation of three-dimensional vascularized bone of clinically appropriate shape and volume.4 This technique has been translated into clinical application but required an autologous source of bone for the chamber components. Broad application of this approach requires the identification of alternative, non- autologous tissue sources. Tissue engineering has the potential to provide alternative sources for chamber components. In our previous MERIT grant we investigated and optimized the design of porous hydrogel scaffolds for vascularized tissue formation. In the previous cycle we developed techniques for polymer synthesis and design, evaluated vascularization and cellular response to these biomaterial scaffolds in vitro, in vivo, and in silio, and investigated new imaging techniques for the evaluation of tissue engineering strategies. These studies illustrate our ability to promote and influence vascular ingrowth into engineered tissues. Challenges remain in regards to achieving vascular ingrowth sufficient for engineering large volumes of bone, coordinating vascularization and bone formation and engineering complex structures suitable for clinical application. The broad goals of this proposal are to 1) investigate and optimize the design of biosignal-embedded poly(ethylene glycol)-based hydrogels for engineering vascularized bone and 2) apply these materials for engineering vascularized bone for reconstruction of large, complex craniofacial defects. In order to achieve our goals we will complete the following specific aims: Objective 1: Investigate and optimize the generation of gradients scaffolds for stimulating vascularized tissue invasion into porous hydrogels. Objective 2: Investigate porous hydrogel systems for coordination of vascularization and bone formation in porous hydrogels in vitro and in vivo. Objective 3: Develop topological optimization methods for applying the clinically-translatable large animal model to engineer vascularized bone of appropriate volume and structure for clinical application. This is an ambitious proposal focused on the optimization of techniques that will bring new reconstructive techniques closer to the clinic.