CAREER: Developing Spatially Organized Biomaterials to Engineer Complex Tissue Interfaces

第一部分： 非技术概述骨和软骨之间的组织界面称为骨软骨组织界面。骨软骨组织界面的损伤最终导致骨关节炎，这是一种以使人衰弱的疼痛和丧失活动能力为特征的疾病，影响了估计3100万美国人。因此，迫切需要修复或再生该界面以延迟或预防骨关节炎。不幸的是，骨软骨组织界面自身再生能力差，并且由于其复杂的组织而特别具有修复挑战性。该CAREER奖的研究部分侧重于开发一种促进骨软骨组织界面再生的生物材料。这种3D打印材料将为细胞提供信号，以形成与天然骨软骨组织相同的新组织。该CAREER奖的教育和推广活动将利用该项目的3D打印和健康相关性，吸引来自代表性不足和STEM成功率较低的背景的学生，并提高公众对生物材料的认识。PI将与现有的利哈伊计划合作，通过提供定制的本科研究项目来支持代表性不足和有风险的学生。本科研究人员还将与PI和研究生合作，为当地社区的初中和高中学生开发YouTube视频和动手3D打印活动。这些努力将招募，培训和授权不同的学生群体作为下一代科学家。 第二部分： 在肌肉骨骼组织界面中发现的结构-性质关系说明了细胞外基质（ECM）组织如何与组织性质和功能紧密相关。骨和软骨之间的骨软骨界面包含对正常关节功能至关重要的生物化学和物理性质的异质梯度。因此，用于骨软骨修复的生物材料必须提供适当的空间线索来指导有组织的ECM形成。该项目的重点是开发新的策略，以独立控制连续支架内的生化，机械和形态组织。中心假设是具有最佳空间特性的支架将驱动模仿天然骨软骨组织界面的ECM的形成。PI将联合收割机与新兴的3D打印技术相结合，以实现三个具体目标：1）证明生物活性肽可以在空间上组织而不影响支架形态和刚度; 2）证明支架刚度和形态可以独立修改;和3）证明肽、机械和形态梯度分别和一起影响干细胞分化和基质形成。该项目在健康和3D打印普及方面的应用为将研究部分与教育和推广活动相结合提供了一个绝佳的机会。教育目标的中心是吸引和留住来自STEM背景的学生。具体目标是：1）通过研究，指导和跨学科课程提高代表性不足和风险的本科生和研究生的成功; 2）通过动手3D打印活动向代表性不足的初中和高中学生推广STEM; 3）通过YouTube视频增加公众对3D打印和生物材料的了解。在PI的监督下，本科生和研究生将共同开发面向初中和高中生的外展活动，创建一个分层导师模式，以提高STEM保留率。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

PART 1: NON-TECHNICAL SUMMARYThe tissue interface between bone and cartilage is known as the osteochondral tissue interface. Damage to the osteochondral tissue interface eventually leads to osteoarthritis, a disease characterized by debilitating pain and loss of mobility that affects an estimated 31 million Americans. Thus, there is an urgent need to repair or regenerate this interface to delay or prevent osteoarthritis. Unfortunately, the osteochondral tissue interface has a poor ability to regenerate on its own and is particularly challenging to repair due to its complex organization. The research component of this CAREER award focuses on developing a biomaterial that promotes regeneration of the osteochondral tissue interface. This 3D-printed material will provide signals to cells to enable the formation of new tissue that is organized in the same way as natural osteochondral tissue. The education and outreach activities of this CAREER award will leverage the project’s 3D printing and health relevance to engage students from backgrounds underrepresented and at risk for lower success rates in STEM and increase awareness to the general public about biomaterials. The PI will partner with existing Lehigh programs that support underrepresented and at-risk students by providing customized undergraduate research projects. The undergraduate researchers will also collaborate with the PI and graduate students to develop YouTube videos and hands-on 3D printing activities for middle and high school students in the local community. These efforts will recruit, train, and empower a diverse group of students as next-generation scientists. PART 2: TECHNICAL SUMMARYThe structure-property relationships found in musculoskeletal tissue interfaces illustrate how extracellular matrix (ECM) organization is tightly linked to tissue properties and function. The osteochondral interface between bone and cartilage contains heterogenous gradients in biochemical and physical properties critical for normal joint function. Biomaterials for osteochondral repair must therefore present appropriate spatial cues to direct organized ECM formation. This project focuses on developing new strategies to independently control biochemical, mechanical, and morphological organization within a continuous scaffold. The central hypothesis is that scaffolds with optimal spatial properties will drive the formation of ECM that mimics the native osteochondral tissue interface. The PI will combine a peptide-polymer strategy with emerging 3D printing techniques to achieve three specific objectives: 1) demonstrate that bioactive peptides can be spatially organized without affecting scaffold morphology and stiffness; 2) show that scaffold stiffness and morphology can be modified independently; and 3) demonstrate that peptide, mechanical, and morphology gradients, separately and together, affect stem cell differentiation and matrix formation. This project’s application to health and popularity of 3D printing provides an excellent opportunity to integrate the research component with the education and outreach activities. The educational goal centers on engaging and retaining students from backgrounds underrepresented in STEM. The specific objectives are to: 1) enhance success of underrepresented and at-risk undergraduate and graduate students through research, mentoring, and interdisciplinary courses; 2) promote STEM to underrepresented middle and high school students through hands-on 3D printing activities; and 3) increase public knowledge about 3D printing and biomaterials through YouTube videos. Under the supervision of the PI, undergraduate and graduate students will co-develop outreach activities for middle and high school students, creating a hierarchical mentorship model to improve STEM retention.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.