CAREER: Epithelial Organization in Thin Bioprinted Hydrogels

薄上皮在整个人体中形成坚固的屏障，作为内部和外部环境之间的保护界面。上皮也以更高的复杂性组织形成腺体，如胰腺、汗腺和唾液腺。腺上皮依赖于具有方向性组织的柔软层状细胞外基质来使这些细胞极化并使其具有分泌功能。如果受到严重伤害或疾病的损害，像唾液腺这样的脆弱的分支组织通常会做出修复（而不是再生）的反应，产生永久性的功能失调，紊乱的疤痕组织。由此导致的唾液功能丧失会对口腔健康和生活质量产生巨大影响。研究人员继续寻找再生这些疤痕组织的方法，三维（3D）生物打印是一种可能有潜在应用于这一需求的方法。本次CAREER奖的研究活动将侧重于将一种新的生物打印方法应用于上皮再生，目的是在3D支持水凝胶中提供更精确的细胞沉积。在教育和推广活动中，由牙科学生、研究生和本科生组成的多学科团队将合作实施独特的、低成本的生物打印机来解决同样的问题。更多的学生将被介绍到休斯敦日益增长的创业和创新文化中，为他们未来的职业生涯获得创造性的灵感。该项目的目标是招募、培训和留住具有不同背景的学生，以促进未来口腔健康领域多学科科学家的骨干队伍。研究者的实验室设计，合成和表征用于临床的聚合物和超分子生物材料，在组织再生，药物输送和临床前药物筛选方面的应用。这项CAREER提案的目标是利用生物材料和同轴微流体生物打印的最新进展来打印超薄水凝胶层，在生化组成和机械性能上具有可控的梯度，从而驱动共包膜上皮和周围间质的细胞组织和表型显示。具体的研究目标是：(1)定制水凝胶成分以支持同心上皮/间充质细胞相互作用；(2)量化不同尺寸、成分、孔隙度和细胞伴侣的生物打印水凝胶结构中上皮细胞的迁移和组织行为；(3)评估这些相同打印参数的分化和组织功能。与此同时，该项目的综合教育目标是在牙科学校环境下，培养一批跨越多个教育层次的口腔生物学和生物材料领域的专家。具体的教育目标是：(1)在暑期研究项目中为牙科专业的学生、生物科学专业的研究生和生物工程专业的本科生实施跨学科的生物打印教育；(2)增加历史上代表性不足或被排斥背景的学生的参与度；(3)利用休斯顿的创业生态系统，让学生接触STEM翻译和创业，同时进行创新方法的教学培训。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Thin epithelia form robust barriers throughout the human body, aligning as protective interfaces between interior and exterior environments. Epithelia also organize with even higher complexity to form glands, like the pancreas, sweat glands, and salivary glands. Glandular epithelia rely on a soft, layered extracellular matrix with a directional organization to polarize these cells and enable their secretory function. If damaged by severe injury or disease, delicate branched tissues like the salivary gland often respond with a repair (rather than regenerative) response, yielding a permanently dysfunctional, disorganized array of scar tissue. The resulting loss of salivary function can have dramatic impacts on oral health and quality of life. Researchers continue to search for ways to regenerate these scarred tissues, and three-dimensional (3D) bioprinting is one method that could have potential application to this need. The research activities of this CAREER award will focus on applying a new method of bioprinting to epithelial regeneration, with the intent of delivering more precise deposition of cells, within supportive hydrogels, in 3D. In the educational and outreach activities, multidisciplinary teams of dental students, graduate students, and undergraduates will partner together to implement unique, low-cost bioprinters toward these same problems. Larger groups of students will be introduced to Houston’s growing culture of entrepreneurship and innovation, gaining creative inspiration for their future careers. The program’s goal is to recruit, train, and retain students with diverse backgrounds, to advance a future cadre of multidisciplinary scientists in oral health. The investigator’s laboratory designs, synthesizes, and characterizes polymeric and supramolecular biomaterials for clinical use, across applications in tissue regeneration, drug delivery, and preclinical drug screening. The goal of this CAREER proposal is to leverage recent advances in biomaterials and coaxial microfluidic bioprinting to print ultrathin hydrogel layers, with controlled gradients in biochemical composition and mechanical properties, that drive cellular organization and phenotype display of co-encapsulated epithelia and surrounding mesenchyme. The specific research objectives are to: (1) tailor hydrogel composition to support concentric epithelial/mesenchymal cell interaction, (2) quantify epithelial cell migration and organization behavior within bioprinted hydrogel structures of varying dimension, composition, porosity, and cellular partners, and (3) assess differentiation and organization as a function of these same print parameters. In tandem, the integrated education goal of this project is to develop a cohort of experts at the interface of oral biology and biomaterials, across multiple education levels, within a dental school setting. Specific education objectives are to: (1) implement interdisciplinary bioprinting education for dental students, graduate students in biosciences, and undergraduates in bioengineering within a summer research program, (2) increase engagement for students from historically underrepresented or excluded backgrounds, and (3) leverage Houston’s startup ecosystem to expose students to STEM translation and entrepreneurship, alongside didactic training in methods of innovation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.