CAREER: Harnessing Multiscale Biophysical Cues for Engineering Adult Heart Tissue

这一学院早期职业发展(CALEAR)奖将揭示如何使用多种长度尺度的生物物理信号来设计个性化的心脏组织。这些工程化的组织可以取代成年人受损的心肌。心脏病发作会导致永久性的心肌丧失，并可能导致心力衰竭。目前的治疗方法不能再生受损的心肌。诱导多能干细胞来自人自身的细胞，可以成为任何类型的细胞。因此，这些细胞为个性化的工程化心脏组织再生带来了新的希望。然而，到目前为止，由这些细胞制成的心脏组织缺乏成人组织的功能。这是因为由干细胞产生的心肌细胞在形状、大小和功能上都不成熟。目前迫切需要提高心肌细胞的成熟度来构建成人心脏组织工程。这项研究从心脏的多尺度结构中获得灵感，将探索如何使用三维生物物理信号来提高心肌细胞成熟度，以及如何利用这种知识来制造个性化的成人心脏组织。补充性教育计划将利用这一研究背景，通过课程改革促进工程教育的公平。这项工作还将为那些历史上被可扩展的K-12计划排除在外的人拓宽工程途径。这项研究计划的目标是发展对如何使用多尺度生物物理线索来影响工程心脏组织的结构和功能成熟度的基本机械理解。利用一种新的多尺度平台，允许对刚度、粘弹性和三维几何约束进行正交控制，本研究将确定这些微尺度和中尺度信号如何影响由细胞超微结构、收缩力和传导速度定义的心肌细胞成熟。通过生物信息学分析，这项工作将揭示这些线索单独和共同影响的机制。此外，这项工作将确定在单位生物制造过程中引入的生物物理介导的成熟是否持续存在于大规模工程心脏组织的分级形成中。这项包含设计的研究将确定生物物理刺激在工程成人心脏组织中与细胞性别相关的不同影响。综合教育计划将创建促进工程教育公平的系统，并扩大历史上被排除在外的种族和民族群体的参与。这一奖项将代表着将机械生物学的见解转化为生物制造过程的重要一步，从而能够创建个性化的、全功能的工程组织，并通过新的教师驱动的变革模式对公平、多样性和工程学中的包容性产生可衡量的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will reveal how biophysical signals at multiple length scales can be used to engineer personalized heart tissues. These engineered tissues could replace damaged heart muscle in adults. Heart attack causes permanent loss of heart muscle and can lead to heart failure. Current treatments cannot regenerate damaged heart muscle. Induced pluripotent stem cells, which come from a person’s own cells, can become any cell type. As such, these cells offer new hope for personalized engineered heart tissue regeneration. However, heart tissues made from these cells to date lack the functionality of adult tissues. This is because heart muscle cells generated from stem cells are immature in shape, size, and function. There is a critical need to improve heart muscle cell maturity for engineering adult heart tissue. Drawing inspiration from the heart’s multiscale structure, this research will explore how three-dimensional biophysical signals can be used to improve heart muscle cell maturity and how this knowledge can be leveraged to manufacture personalized adult heart tissues. The complementary education program will use this research context to promote equity in engineering education through curriculum innovation. This work will also broaden access to engineering for those who have been historically excluded through scalable K-12 programs.The goal of this research program is to develop fundamental mechanistic understanding of how multiscale biophysical cues can be used to influence the structural and functional maturity of engineered heart tissues. Using a novel multiscale platform that permits orthogonal control of stiffness, viscoelasticity, and three-dimensional geometric confinement, this research will determine how these microscale and mesoscale cues influence cardiomyocyte maturation defined by cellular ultrastructure, contractile force, and conduction velocity. Through bioinformatic analyses, this work will uncover mechanisms by which these cues have influence individually and collectively. Additionally, this work will determine if biophysically mediated maturation introduced in unit biomanufacturing processes persists in the hierarchical formation of large-scale engineered heart tissues. This inclusively designed research will identify differential effects of biophysical stimuli associated with cell sex in engineering adult heart tissues. The integrated education program will create systems to advance equity in engineering education and broaden participation of historically excluded racial and ethnic groups. This award will present a major step toward transforming mechanobiological insights into biomanufacturing processes enabling the creation of personalized, fully functional engineered tissues and to measurably impact equity, diversity, and inclusion in engineering with new faculty-driven change models.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.