CAREER: Tissue Engineering Better Cell Therapies for Wound Healing.

职业：组织工程更好的细胞疗法促进伤口愈合。

• 批准号: 2040657
• 负责人: Ronke Olabisi
• 金额: $ 50万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2040657&HistoricalAwards=false
• 关键词: CAREER; Tissue; Engineering; Better; Cell

Chronic wounds are skin injuries that recur or fail to heal by 6 weeks. These wounds affect 6.5 million patients in the US and this number is growing rapidly due to a drastic increase in the number of diabetics, the obese, and the elderly--all populations in which wound healing is impaired. Mesenchymal stem cells (commonly known as adult stem cells) and insulin applied to wound surfaces have each shown promise in healing otherwise unhealable wounds. Mesenchymal stem cells assist wound healing by secreting factors that promote actions critical to wound healing, such as new blood vessel formation, increases in the production of skin components, and recruitment of cells that clean wounds and form scar tissue. Insulin assists wound healing by recruiting mesenchymal stem cells and skin cells to the wound area. Motivated by the recent observation that wounds treated with a combination of mesenchymal stem cells and insulin-producing cells healed faster than normal and without scarring, the objective of this project is to identify the type of insulin needed to achieve the observed accelerated healing and reduced scarring and to uncover the wound healing pathways that are recruited. Research results have the potential to transform wound care by enabling rapid healing that would avert the morbidity and mortality associated with chronic wounds and to enhance reconstructive and plastic surgery outcomes by reducing or eliminating scar formation. The project's long-term educational goal is to present future engineers with tissue engineering research in unfamiliar contexts, like aviation, to inspire innovative thinking for future careers in biomedical engineering. In pursuit of this goal, this project's educational objective is to apply research principles to teaching and to develop tissue engineering research modules that integrate research, teaching, mentorship, and learning for use in biomedical engineering course-based undergraduate research experiences (CUREs). The educational and outreach approach is to recruit female students, group them in teams and provide hands-on research activities with wound healing models that will enable them to formulate hypotheses and models, and to propose, conduct, and present experiments that will further their understanding of research. The women will be required to present their research in scientific meetings and to K-12 graders in an aviation science club.The project's research focus is on investigating the impact of mesynchymal stem cells (MSCs) and insulin producing cells (IPCs), both individually and coencapsulated, on wound healing and its pathways, and on identifying how cell-cell vs. cell-wound interactions govern the secretome of encapsulated cells. The project is motivated by recent studies from the PI's lab that achieved dramatically accelerated (14 vs 40 days), scar-free wound healing after combining these cells. The research plan has four specific aims. Aim 1 is to dissect, via in vitro studies, the role of IPCs vs insulin in survival and function of the coencapsulated cells, i.e., whether it is insulin itself, the presence of the IPCs or the hormone release that improves survival and function. Aim 2 is to dissect, via in vivo studies in mice, the role of IPCs vs insulin in the accelerated wound healing, i. e, whether insulin-producing fibroblasts have the same effect as commercially available IPCs (RIN-5F and RIN-14B) that secrete additional products. Aim 3 is to determine the extent, via in vitro studies, that coencapsulation promotes MSC factor release in comparison to MSC factor release elicited by wound environments, i.e., whether the Akt signaling pathway, which is critical to MSC survival, is activated more strongly in MSCs coencapsulated with IPCs or in MSCs delivered singly to wounds. Aim 4 is to determine the extent that IPCs+MSCs reduce scar formation, i.e., to extend the work to a limited study in pigs, which have an epidermis and dermis similar to human skin and heal at a comparable rate. In summary, this project will examine the metabolic pathways involved in IPC+MSC wound healing, the interplay between the two cells and the wound environment, and whether lessons learned can be applied to other cell therapies.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.

慢性伤口是皮肤损伤，复发或未能愈合6周。这些伤口影响了美国650万患者，并且由于糖尿病患者、肥胖患者和老年人的数量急剧增加，这一数字正在迅速增长-所有人群的伤口愈合都受到损害。间充质干细胞（通常称为成体干细胞）和应用于伤口表面的胰岛素均显示出治愈否则无法愈合的伤口的前景。间充质干细胞通过分泌促进对伤口愈合至关重要的作用的因子来辅助伤口愈合，所述作用例如新血管形成、皮肤成分的产生的增加以及清洁伤口和形成疤痕组织的细胞的募集。胰岛素通过将间充质干细胞和皮肤细胞募集到伤口区域来帮助伤口愈合。 最近观察到，用间充质干细胞和胰岛素产生细胞的组合治疗的伤口愈合速度比正常情况下更快，并且没有疤痕，因此该项目的目的是确定实现观察到的加速愈合和减少疤痕所需的胰岛素类型，并揭示招募的伤口愈合途径。 研究结果有可能通过实现快速愈合来改变伤口护理，从而避免与慢性伤口相关的发病率和死亡率，并通过减少或消除疤痕形成来提高重建和整形手术的结果。 该项目的长期教育目标是向未来的工程师提供在不熟悉的环境中（如航空）进行组织工程研究的机会，以激发未来生物医学工程职业的创新思维。为了实现这一目标，该项目的教育目标是将研究原则应用于教学，并开发组织工程研究模块，将研究，教学，指导和学习集成在生物医学工程课程中使用的本科生研究经验（CURES）。教育和推广方法是招募女学生，将她们分组，并提供带有伤口愈合模型的实践研究活动，使她们能够提出假设和模型，并提出、进行和展示实验，以加深她们对研究的理解。这些妇女将被要求在科学会议上和航空科学俱乐部的K-12年级学生面前展示她们的研究成果。该项目的研究重点是调查间充质干细胞（MSC）和胰岛素产生细胞（IPC）单独和共同封装对伤口愈合及其途径的影响，并确定细胞与细胞之间的相互作用与细胞与伤口之间的相互作用如何控制封装细胞的分泌组。 该项目的动机是PI实验室最近的研究，这些研究在结合这些细胞后实现了显着加速（14天vs 40天），无疤痕伤口愈合。 该研究计划有四个具体目标。 目的1是通过体外研究剖析IPC与胰岛素在共囊化细胞的存活和功能中的作用，即，无论是胰岛素本身、IPC的存在还是激素的释放都能提高生存率和功能。 目的2是通过小鼠体内研究，剖析IPC与胰岛素在加速伤口愈合中的作用，即：即，产生胰岛素的成纤维细胞是否具有与分泌额外产物的市售IPC（RIN-5 F和RIN-14 B）相同的作用。目的3是通过体外研究确定与伤口环境引起的MSC因子释放相比，共包封促进MSC因子释放的程度，即，Akt信号通路对MSC存活至关重要，在与IPC共包封的MSC中或在单独递送至伤口的MSC中是否被更强烈地激活。 目的4是确定IPC + MSC减少瘢痕形成的程度，即，将这项工作扩展到对猪的有限研究，猪的表皮和真皮与人类皮肤相似，愈合速度也相当。 总之，该项目将研究IPC+MSC伤口愈合中涉及的代谢途径，两种细胞和伤口环境之间的相互作用，以及所吸取的经验教训是否可以应用于其他细胞疗法。该奖项反映了NSF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。