Developing Programmable Materials for Bioprinting

为什么以及对谁来说这项研究是重要的：许多驱动器官发生、纤维化和癌症转移的事件发生在跨越组织、细胞和生物分子尺度的生化和生物物理介导的反馈回路中。由于能够在体外培养的细胞数量或动物模型相对于人体组织的生理相关性的限制，使用传统的细胞培养方法或小动物模型来研究这些尺度上的生物现象的传统工具具有挑战性。3D生物打印模型能够控制不同细胞类型和具有特定化学，生化和机械特性的水凝胶生物墨水的初始位置。该DG项目专注于能够进行生物打印的工程软生物活性材料，以开发充满细胞的三维体外模型，补充现有方法，同时使研究人员能够长时间实时探测样品的生物化学和生物物理特性。预期结果：该研究计划预计将通过评估与生物活性相关的材料的内在机械特性，为生物墨水的先验选择产生新的知识。一类可以通过控制生物惰性海藻酸多糖的交联密度或浓度来机械调节的生物墨水，其配方中含有生物活性的细胞外基质分子，有望产生新的体外模型，其中细胞生长、活力和增殖可以调节。最后，这些生物墨水将被设计成包含外部可定位的刺激释放材料，这些材料可以启动水凝胶支架的局部硬化或软化，以研究机械异质性在疾病进展、纤维化或细胞迁移中的作用。我的研究计划的长期目标是开发新型的软体生物材料配方，能够利用挤压生物打印技术模拟天然组织的物理和生物特性。为了在未来五年内推进这一目标，将探索以下具体目标：(1)定量了解材料固有特性如何影响印刷和印刷后结构稳定性；(2)开发将生物活性成分纳入机械可调生物墨水的方法；(3)设计可编程材料，这些材料可以在外部刺激下经历机械变化，以模拟上皮细胞到间质细胞（EMT）转变过程中的生物物理环境。预期收益：开发一种新的替代传统细胞培养和动物模型的工具来探索基础生物学，将对加拿大人的福祉产生重大影响，并为该领域的研究人员提供新的工具来研究目前难以评估的问题。在这个研究项目中训练的HQP将成为生物打印和组织工程跨学科领域的领导者。

Why and to whom the research is important: A multitude of events driving organogenesis, fibrosis, and cancer metastasis occurs in biochemical and biophysical mediated feedback loops that span the tissue, cellular, and biomolecular scale. Conventional tools to study biological phenomenon across these scales is challenging using conventional cell culture methods or small animal models due to limitations in the number of cells capable of being cultured in vitro or the physiological relevance of animal models relative to human tissues. 3D bioprinted models enable control of the initial placement of distinct cell types and hydrogel bioinks with specific chemical, biochemical, and mechanical characteristics. This DG program focuses on engineering soft bioactive materials capable of being bioprinted to develop cell-laden three-dimensional in vitro models that complement the existing methods while enabling researchers to probe the samples biochemistry and biophysical properties in real-time for extended periods. Expected outcomes: This research program is anticipated to generate new knowledge into the a priori selection of bioinks by evaluating the intrinsic mechanical properties of the materials in relation to their bioactivity. A class of bioinks that can be mechanically tuned by controlling the crosslinking density, or concentration, of a bioinert polysaccharide alginate in a formula that contains bioactive extracellular matrix molecules is expected to result in new in vitro models where cell growth, viability, and proliferation can be tuned. Finally, these bioinks will be engineered to contain externally addressable stimuli releasing materials that can initiate local stiffening or softening of the hydrogel scaffold to investigate the role mechanical heterogeneity plays in disease progression, fibrosis, or cell migration. The Long-term goal of my research program is to develop novel formulations of soft biomaterials capable of mimicking the physical and biological characteristics of native tissues using extrusion bioprinting. To advance this goal during the next five years the following specific objectives will be explored: (1) Quantitatively understand how intrinsic material properties impact printing and post-printing structural stability; (2) Develop methods to incorporate bioactive components into mechanically tunable bioinks; and (3) Engineer programmable materials that can be externally stimulated to undergo mechanical changes to mimic the biophysical environment during the epithelial-to-mesenchymal (EMT) transition. Expected Benefits: Developing a new alternative tool to conventional cell culture and animal models to probe fundamental biology will have a significant impact on the well-being of Canadians and provide researchers in the field with new tools to investigate problems that are currently difficult to assess. HQP trained in this research program will be leaders in the interdisciplinary field of bioprinting and tissue engineering.