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.

非技术抽象绘图集是血细胞，在损伤后停止出血方面起着重要作用。 出血停止后，血小板还有助于受伤的组织愈合。受伤之前，血小板在血液中循环，具有紧凑而圆形。这种形状可确保如果发生受伤，血小板能够有效与血管壁相互作用。一旦发生受伤，受伤部位的信号会导致血小板改变形状，从小和圆形到散布和星形。响应损伤的这种形状变化对于血小板既要停止出血，又有帮助在形成凝块后修复损伤组织。该项目的研究组成部分着重于开发一种新材料，该材料模仿了血小板因损害而改变形状的能力。开发的材料将经过测试，以响应伤害信号以及停止流血和改善愈合的能力而改变形状的能力。该提案还将集中于北卡罗来纳州的社区宣传。该项目的外展部分的目标是提高对仿生材料工程的认识和支持。仿生材料是模仿天然系统某些方面的材料，例如该提案中所描述的模仿血小板功能的材料。通过为K-12夏令营和一日营的新材料设计新材料以及在当地博物馆活动进行会谈，可以实现外展目标。 技术摘要的自然血小板对止血和组织修复至关重要，并且在伤口部位响应凝血酶的血小板形状变化对于这些功能至关重要。受伤之前，血小板显示出小的圆形形态，可增强对血管壁的边缘。有效边缘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明显的血小板形状变化。血小板介导的凝块回收需要这种形状变化，这有助于长期愈合。然而，尚未定义受伤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，该研究项目的整个目标是开发一个受伤的，可触发的血小板模拟微凝胶，与天然血小板一样，它会激活并改变形状，以响应凝血酶。研究目标是：1）设计血小板模拟颗粒，这些颗粒在伤口部位激活和改变形状，并定义凝血酶浓度与形状变化动态之间的关系； 2）确定形状变化对颗粒边缘和凝结动力学的影响； 3）确定形状变化对凝块回缩和伤口愈合动力学的影响。该提案的外展部分将利用两种方便的方法来提高NC状态的仿生材料工程的认识和支持，直到1）为K-12学生的教育经验发展，2）参与基于博物馆的社区外展活动。该教育部分将通过为学生提供仿生材料工程的动手经验来与研究组成部分融合。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响审查标准，认为值得通过评估来获得支持。

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.

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.

Maintaining Hemostatic Balance in Treating Disseminated Intravascular Coagulation

治疗弥散性血管内凝血时保持止血平衡

• DOI: 10.1097/aln.0000000000002862
• 发表时间: 2019
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Brown, Ashley C.;Levy, Jerrold H.
• 通讯作者: Levy, Jerrold H.