Engineered Mineral Nanoparticles and Nanocomposites: A Versatile Multifunctional Platform for 3D Bioprinting and Tissue Engineering

这项提议的主要目标是开发一类新的生物材料，使用工程矿物纳米颗粒，利用生物打印技术获得由细胞和基质组成的三维(3D)复杂结构。从长远来看，我打算利用基于矿物的生物材料作为平台技术，制造具有用户定义结构的细胞指导支架，用于先进的组织工程。然而，如果不了解不同的矿物质(如钙、镁、硅、锌、铜)是如何调节细胞活动的，就不可能开发出有效的矿物基生物材料。对细胞-细胞、细胞-纳米颗粒、细胞-基质之间的相互作用进行系统的研究将把我们引向首要目标。在短期内(未来5年)，我提出了以下三个符合长期目标的目标：1)设计基于矿物的纳米颗粒，并通过组合筛选阐明它们对细胞行为的单独和协同作用。这将为破译矿物纳米颗粒与细胞(男性和女性来源)相互作用的机制提供新的见解。我们将确定新的生物活性纳米颗粒配方，可以有效地控制细胞行为，而不使用任何其他刺激剂。据我们所知，没有其他研究定制纳米颗粒组合物来设计细胞命运。2)开发使用具有细胞教育特性的矿物纳米颗粒的3D可打印水凝胶。这一目标将揭示矿物纳米颗粒、聚合物水凝胶和人体细胞之间的相互作用类型，并创造出机械弹性、3D可打印、生物响应的水凝胶。这一目标还将促进该领域对如何利用非共价相互作用来机械增强弱聚合物网络并形成坚韧的、可注射的自愈水凝胶的理解。3)测定可打印水凝胶生物打印复杂组织结构和指导细胞行为的能力。传统的水凝胶生物墨水在打印功能组织和控制细胞命运方面的应用受到其次优机械性能和有限生物活性的严重限制。为了克服这些挑战，具有可调生物和机械性能的矿物基水凝胶生物墨水将被用于设计具有高结构稳定性和精确时空控制细胞命运的组织结构。完成后，这项研究将对最终用户(如生物制造和生物制造行业)产生广泛的科学、工程和技术影响，并有可能改变生物活性材料开发、3D打印和组织工程。由这笔赠款支持的HQP将接受最先进的纳米材料、聚合物科学、干细胞生物学和生物打印技术方面的经验培训。受过这些跨学科技术培训的HQP在加拿大各地的学术和工业研发部门都很受欢迎。

The primary goal of this proposal is to develop a new class of biomaterials using engineered mineral nanoparticles to obtain three-dimensional (3D) complex structures consisting of cells and matrices using bioprinting technology. In the long-term, I intend to utilize mineral-based biomaterials as a platform technology to fabricate cell-instructive scaffolds with user-defined structures for advanced tissue engineering. However, without understanding how different minerals (e.g. calcium, magnesium, silicon, zinc, copper) regulate cellular activities, it is impossible to develop effective mineral-based biomaterials. A systematic investigation of the interactions between cell-cell, cell-nanoparticles, cell-matrix will lead us to the overarching goal. In the short term (next 5 years), I propose following three objectives that fit into the long-term goal: 1) To design mineral-based nanoparticles and elucidate their individual and synergistic effects on cellular behavior via combinatorial screening. This will provide new insight in deciphering the mechanisms by which mineral nanoparticles interact with the cells (male and female origin). We will identify new bioactive nanoparticle formulations that can effectively control cell behavior, without using any other stimulants. To our knowledge no other investigation has tailored nanoparticle compositions to engineer cell fate. 2) To develop 3D printable hydrogels using mineral nanoparticles with tailored cell-instructive properties. This objective will reveal the type of interactions between mineral nanoparticles, polymeric hydrogels and human cells, and create mechanically resilient, 3D-printable, bioresponsive hydrogels. This objective will also promote the field's understanding on how to leverage non-covalent interactions to mechanically reinforce weak polymeric networks and form tough, injectable, self-healing hydrogels. 3) To determine the ability of the printable hydrogels to bioprint complex tissue structures and direct cellular behavior. Utility of conventional hydrogel bioinks to print functional tissues and control cell fate is severely constrained by their suboptimal mechanical properties and limited bioactivity. To overcome these challenges, mineral-based hydrogel bioinks with tunable biological and mechanical properties will be used to engineer tissue constructs with high structural stability and precise spatio-temporal control over cell fate. Upon completion, this research will have broad scientific, engineering and technological impacts on the end-users (e.g. biofabrication and biomanufacturing industries) with potential to transform bioactive materials development, 3D printing and tissue engineering. HQP supported by this grant will receive state-of-the-art experiential training in nanomaterials, polymer science, stem cell biology and bioprinting technologies. HQP trained in these interdisciplinary technologies are highly sought in academic and industrial R&D sectors across Canada.