Restoring the Mechanosensation in Engineered Skin using Controllable Cellular and Extracellular Cues

使用可控细胞和细胞外线索恢复工程皮肤的机械感觉

• 批准号: 2227383
• 负责人: Hasan Abaci
• 金额: $ 50.4万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2227383&HistoricalAwards=false
• 关键词: Restoring; Mechanosensation; Engineered; Skin; using

Mechanosensation is essential for perceiving the external world and social exchange. The skin is our largest sensory organ and is densely populated with nerve endings responsible for senses, such as touch, pain, pressure, and vibration. The long-term goal of this project is to integrate sensory neurons into bioengineered 3D skin constructs (BESCs) to enable studying skin mechanosensation and regeneration using human cells. The growth, location, and type of sensory neurons in BESCs will be controlled by locally providing specialized proteins secreted by specific cell types of the skin, as well as through localized electrical stimulation. This project will make a positive societal impact in the long term by 1) providing a physiologically-relevant in vitro model to a broader research community to study the innervation dynamics of sensory neurons during development and wound healing; and 2) evaluating the efficacy/toxicity of drug candidates using human cells. In addition, this project will contribute to STEM education and workforce development by providing research training and professional opportunities for students at all levels and will significantly benefit students pursuing a career in the fields of biomaterials, tissue engineering, and neuroscience. Training activities include: a 4-week summer boot camp for graduate student training; a graduate-level course; a Vertically Integrated Program (VIP) to integrate undergraduate research; a 2-week summer research experience involving K-12 students; and a 2-day-long virtual summer symposium for training young researchers.The molecular and cellular mechanisms underlying the specific types of mechanosensation are well-characterized. Yet, there is limited knowledge about what determines and instructs the branching patterns and proper innervation of somatosensory neurons (SSN) and sensory end-organs in the skin to mediate mechanosensation. The goal of this project is to induce and control the level of innervation in engineered skin through spatially-controlled microenvironmental cues, including 3D-patterned dermal extracellular matrix (ECM) conduits, follicular epidermal signals (e.g., hair follicles), and Schwann cells (SCs) differentiated via wireless electrical stimulation in defined patterns. Studies in Goal 1 will identify the ECM molecules that promote or prevent SSN outgrowth and employ the identified attractive/repulsive ECM cues in BESCs to guide the nerve endings to their final destination. Studies in Goal 2 will use a hair-bearing BESC model and determine the preferential innervation of the follicular (hairy) and interfollicular (non-hairy) epidermis by different subtypes of SSNs. Studies in Goal 3 will leverage electrical differentiation approaches to spatially control the Schwann cell fate commitment in the 3D dermis to regulate local myelination and function of SSNs. The key intellectual merit of this project for biomedical sciences is to decipher the individual effects of cellular and extracellular cues on the innervation and pattern formation of sensory neurons in the context of a 3D skin microenvironment using human cells. This study will also contribute to engineering by addressing a prevailing tissue engineering challenge of controlling innervation in 3D skin models. The cue-driven strategy involving environmental guidance signals and integrated wireless electrical biointerfaces can further be adapted for spatially-controlled innervation and engineering of other organs.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.

机械感觉对于感知外部世界和社会交换至关重要。皮肤是我们最大的感觉器官，密集分布着负责感觉的神经末梢，如触觉、疼痛、压力和振动。该项目的长期目标是将感觉神经元整合到生物工程3D皮肤结构（BESC）中，以便使用人类细胞研究皮肤机械感觉和再生。BESC中感觉神经元的生长、位置和类型将通过局部提供由皮肤的特定细胞类型分泌的专门蛋白以及通过局部电刺激来控制。该项目将通过以下方式长期产生积极的社会影响：1）为更广泛的研究社区提供生理相关的体外模型，以研究感觉神经元在发育和伤口愈合过程中的神经支配动力学; 2）使用人类细胞评估候选药物的疗效/毒性。此外，该项目将通过为各级学生提供研究培训和专业机会，为STEM教育和劳动力发展做出贡献，并将使在生物材料，组织工程和神经科学领域从事职业的学生受益匪浅。 培训活动包括：为期4周的研究生靴子营;研究生课程;整合本科研究的垂直整合计划（VIP）;涉及K-12学生的为期2周的夏季研究体验;以及为期2天的虚拟夏季研讨会，用于培训年轻研究人员。然而，有有限的知识是什么决定和指导的分支模式和适当的神经支配的躯体感觉神经元（SSN）和感觉终末器官在皮肤中介导机械感觉。该项目的目标是通过空间控制的微环境线索诱导和控制工程皮肤中的神经支配水平，包括3D图案化的真皮细胞外基质（ECM）导管、毛囊表皮信号（例如，毛囊），以及通过无线电刺激以限定的模式分化的雪旺细胞（SC）。目标1中的研究将确定促进或阻止SSN生长的ECM分子，并在BESC中使用已确定的吸引/排斥ECM线索来引导神经末梢到达其最终目的地。目标2中的研究将使用毛发BESC模型，并确定不同SSN亚型对毛囊（有毛）和毛囊间（无毛）表皮的优先神经支配。目标3中的研究将利用电分化方法在空间上控制3D真皮中的许旺细胞命运定型，以调节SSN的局部髓鞘形成和功能。该项目对生物医学科学的关键智力价值是在使用人体细胞的3D皮肤微环境中破译细胞和细胞外线索对感觉神经元的神经支配和模式形成的个体影响。这项研究也将有助于工程解决一个普遍的组织工程的挑战，控制神经支配的3D皮肤模型。线索驱动的策略，包括环境指导信号和集成无线电生物界面，可以进一步适应空间控制的神经支配和工程的其他organs.This奖项反映了NSF的法定使命，并已被认为是值得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的支持。