Understanding Mechano-Fibrinolysis: Fiber-Scale Multiphysics Experiments and Models

University Of Texas At Austin, Austin TX

Investigators

Abstract

Non-Technical Summary: Understanding naturally occurring, biological materials is a critical step toward designing new, better materials that can overcome many of today’s scientific and health challenges. One such biomaterial is fibrin, which is an important constituent of blood clot. To successfully and securely seal wounds, fibrin has evolved to be a highly stretchable and resilient material. At the same time, fibrin is easily removable as the wound is progressively healing. These diametrical functions are made possible by an intricate, mechanically-mediated interplay between fibrin’s structure and its chemistry. In this project, different microscopy techniques will be used in combination with computational models to better understand this interplay. The knowledge from this project will also have direct applicability to other prominent, fibrous biomaterials – such as collagen and elastin - and their mechanically-mediated structure-function relationships. Beyond its scientific scope, this project’s impact will be broadened as it contributes to the training of future scientists by creating research opportunities for undergraduate and graduate students. Through a collaboration with the non-profit Science Mill it will also integrate lessons about the role of fibrin - and other fibrous biomaterials - in human health and disease into the curriculum of the non-profit’s summer camps. As a result of this work, Kindergarten through grade 9 students from all walks of life including students with minoritized backgrounds will be better prepared for careers in health, science, technology, engineering, and mathematics. Technical Summary: Fibrin is a semi-flexible biopolymer with remarkable properties. For example, fibrin can undergo deformations of several hundred percent strain without failure. Its deformability and many other physical feats originate from its hierarchical architecture that spans many orders of magnitude. As such, it is a prototypical biopolymer whose study will enable fundamental understanding of other, nature-derived as well as synthetic biomaterials that can solve many of society’s most pressing problems. However, much remains unknown about fibrin. Among those unanswered questions about fibrin - and therefore about other biomaterials - is how fibrin’s state of mechanical deformation affects its rate of enzymatic digestion, i.e., its mechano-lysis. This question is a critical one to answer as enzymatic digestion is important in the regulation of many vital tissue functions such as tissue growth and remodeling as well as in tissue dysfunction such as in cancer. In this study, this question will be answered on the fiber scale, that is, on the 100s-of-nanometer-scale that a single fiber spans. To this end, a regiment of atomic force microscopy-based experiments was designed in which single fibrin fibers will be deformed, while their digestion under enzymatic loading will be microscopically quantified. These experiments will be combined with a detailed modeling approach that is integrated into the experimental design. Through this synergistic approach, it will be possible to delineate the effect of mechanical deformation on the multiple physical phenomena – such as enzyme transport, binding, and enzymatic activity – that determine fibrin’s response to enzymatic digestion. To ensure that this study reveals mechanistic insight rather than merely fitting observations, the computational model and understanding of mechano-fibrinolysis will be validated on the fiber network scale in which the degradation of an assembly of loaded fibers will be predicted and compared to experiments. 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.