CAREER: Dynamic Microgels that Mimic Platelet Behavior to Promote Healing

事业：模仿血小板行为以促进愈合的动态微凝胶

• 批准号: 1847488
• 负责人: Ashley Brown
• 金额: $ 50万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1847488&HistoricalAwards=false
• 关键词: CAREER; Dynamic; Microgels; Mimic; Platelet

Nontechnical AbstractPlatelets are blood cells that play an important role in stopping bleeding after injury. After bleeding stops, platelets also help the injured tissue heal. Before injury, platelets circulate in the blood stream and have a compact and round shape. This shape ensures that platelets are able to effectively interact with the blood vessel wall if injury occurs. Once injury occurs, signals at the injury site cause the platelet to change shape, going from small and round to spread and star-shaped. This shape change in response to injury is critical for platelets to both stop bleeding and then help to repair the damage tissue after a clot forms. The research component of this project focuses on the development of a new material that mimics the ability of platelets to change shape in response to injury. The developed materials will be tested for their ability to change shape in response to injury signals and for their ability to stop bleeding and improve healing. This proposal will also focus on community outreach in the state of North Carolina. The goals of the outreach component of this project are to increase awareness and support for biomimetic materials engineering. Biomimetic materials are materials that mimic certain aspects of natural systems, such as the materials described in this proposal that mimic platelet function. The outreach goals will be achieved by designing new materials for K-12 summer camps and day camps and by giving talks at local museum events. Technical AbstractNatural platelets are pivotal to hemostasis and tissue repair, and platelet shape change in response to thrombin at the wound site is critical for these functions. Prior to injury, platelets display a small, round morphology that enhances margination to the vessel wall; effective margination is essential for rapid clot formation. At the injury site, thrombin activates platelets and induces a significant platelet shape change. This shape change is required for platelet-mediated clot retraction, which contributes to long-term healing. However, the relationship between wound-triggered shape change of platelet-mimetic materials and hemostatic and wound healing outcomes has not been defined. To that end, the over-arching goal of this research project is to develop a wound-triggered, platelet-mimetic microgel that, like native platelets, activates and changes shape in response to thrombin. The research objectives are: 1) Design platelet-mimetic particles that activate and change shape in response to thrombin at the wound site and define the relationship between thrombin concentrations and shape change dynamics; 2) Determine the effect of shape change on particle margination and clotting kinetics; 3) Determine the effect of shape change on clot retraction and wound healing dynamics. The outreach component of this proposal will utilize a two-pronged approach to increase awareness and support for biomimetic materials engineering in the state of NC through 1) the development of educational experiences for K-12 students and 2) participation in museum-based community outreach events. The educational component will integrate with the research component by providing students with hands-on experience with biomimetic materials engineering.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.

血小板是在受伤后止血中起重要作用的血细胞。 出血停止后，血小板也有助于受伤组织愈合。在受伤之前，血小板在血流中循环，并且具有紧凑和圆形的形状。这种形状确保了血小板能够有效地与血管壁相互作用，如果发生损伤。一旦发生损伤，损伤部位的信号会导致血小板改变形状，从小而圆的形状变成扩散的星形。这种响应损伤的形状变化对于血小板来说至关重要，既可以止血，又可以在凝块形成后帮助修复受损组织。该项目的研究部分侧重于开发一种新材料，该材料模仿血小板在受伤时改变形状的能力。开发的材料将测试其响应损伤信号改变形状的能力，以及止血和改善愈合的能力。该提案还将侧重于北卡罗来纳州的社区外展。该项目外展部分的目标是提高人们对仿生材料工程的认识和支持。仿生材料是模仿自然系统的某些方面的材料，例如本提案中描述的模仿血小板功能的材料。将通过为K-12夏令营和日营设计新材料以及在当地博物馆活动中发表演讲来实现外联目标。 技术摘要天然血小板对止血和组织修复至关重要，血小板在伤口部位对凝血酶的形状变化对这些功能至关重要。在损伤之前，血小板显示出小而圆的形态，这增强了与血管壁的边缘化;有效的边缘化对于快速凝块形成至关重要。在损伤部位，凝血酶激活血小板并诱导显著的血小板形状变化。这种形状变化是血小板介导的凝块收缩所必需的，这有助于长期愈合。然而，尚未确定伤口触发的血小板模拟材料的形状变化与止血和伤口愈合结果之间的关系。为此，该研究项目的首要目标是开发一种伤口触发的血小板模拟微凝胶，像天然血小板一样，激活并改变形状以响应凝血酶。研究目标是：1）设计响应于伤口部位的凝血酶而激活和改变形状的血小板模拟颗粒，并定义凝血酶浓度和形状变化动力学之间的关系; 2）确定形状变化对颗粒边集和凝血动力学的影响; 3）确定形状变化对凝块收缩和伤口愈合动力学的影响。该提案的外展部分将采用双管齐下的方法，通过1）为K-12学生开发教育经验和2）参与博物馆为基础的社区外展活动，提高对NC州仿生材料工程的认识和支持。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。

项目成果

Fibrin‐based biomaterial systems to enhance anterior cruciate ligament healing

基于纤维蛋白的生物材料系统可增强前十字韧带愈合

• DOI: 10.1002/mds3.10147
• 发表时间: 2020
• 期刊: MEDICAL DEVICES & SENSORS
• 作者: Scull, Grant;Fisher, Matthew B.;Brown, Ashley C.
• 通讯作者: Brown, Ashley C.

Neonatal Fibrin Scaffolds Promote Enhanced Cell Adhesion, Migration, and Wound Healing In Vivo Compared to Adult Fibrin Scaffolds

• DOI: 10.1007/s12195-020-00620-5
• 发表时间: 2020-05-27
• 期刊: CELLULAR AND MOLECULAR BIOENGINEERING
• 影响因子: 2.8
• 作者: Nellenbach, Kimberly;Nandi, Seema;Brown, Ashley C.
• 通讯作者: Brown, Ashley C.

Development of Novel Microenvironments for Promoting Enhanced Wound Healing

• DOI: 10.1007/s43152-020-00009-6
• 发表时间: 2020-07
• 期刊: Current Tissue Microenvironment Reports
• 作者: G. Scull;Ashley C. Brown

Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses

• DOI: 10.1002/adtp.202100010
• 发表时间: 2021-03
• 期刊: Advanced Therapeutics
• 影响因子: 4.6
• 作者: Seema Nandi;Emily P. Mihalko;K. Nellenbach;Mario Castaneda;John D Schneible;Mary G Harp;Halston Deal;M. Daniele;S. Menegatti;T. Barker;Ashley C. Brown

Platelet-like particles improve fibrin network properties in a hemophilic model of provisional matrix structural defects

• DOI: 10.1016/j.jcis.2020.05.088
• 发表时间: 2020-10-01
• 期刊: JOURNAL OF COLLOID AND INTERFACE SCIENCE
• 影响因子: 9.9
• 作者: Nandi, Seema;Sommerville, Laura;Brown, Ashley C.
• 通讯作者: Brown, Ashley C.