Developing Programmable Materials for Bioprinting

为什么和对谁来说这项研究是重要的：许多推动器官发生、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环路中。由于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是具有挑战性的。3D生物打印模型能够控制具有特定化学、生化和机械特性的不同细胞类型和水凝胶生物墨水的初始放置。该DG计划专注于设计能够被生物打印的软生物活性材料，以开发细胞加载的三维体外模型，补充现有方法，同时使研究人员能够在更长的时间内实时探测样品的生物化学和生物物理性质。预期结果：这项研究计划预计将通过评估材料的内在机械性能与其生物活性有关，为生物墨水的先验选择产生新的知识。一种生物墨水可以通过控制含有生物活性细胞外基质分子的配方中生物惰性多糖海藻酸盐的交联密度或浓度来进行机械调节，有望产生新的体外模型，在这种模型中可以调节细胞的生长、存活和增殖。最后，这些生物墨水将被设计成含有外部可寻址的刺激释放材料，这些材料可以引发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所起的作用。我的研究计划的长期目标是开发新的软生物材料配方，能够通过挤压生物打印来模拟自然组织的物理和生物特征。为了在未来五年中推进这一目标，将探索以下具体目标：(1)定量了解材料的内在特性如何影响印刷和印刷后结构的稳定性；(2)开发将生物活性成分纳入机械可调生物墨水的方法；以及(3)设计可编程材料，这种材料可以在外部刺激下经历机械变化，以模拟上皮向间充质(EMT)转变过程中的生物物理环境。预期好处：开发一种替代传统细胞培养和动物模型来探索基础生物学的新工具，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，以调查目前难以评估的问题。在这项研究计划中培训的HQP将成为生物印刷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.