"Blood Clotting: Engineering Healing Under Extreme Conditions"

Alfredo Alexander-Katz, PhD
Massachusetts Institute of Technology

The first stages of blood clotting in small arteries involve the combination of mechanical stimuli coupled to biochemical signals to unfold (activate) and stick a large biopolymer called von Willebrand Factor (vWF) at the site of injury. Once vWF is active (or unraveled), it also forms a physically cross linked network with platelets that is called a plug that serves as the first seal of the injured area, as well as the scaffold on which the fibrin clot will be polymerized in situ. In this talk we explore theoretically and experimentally the behavior of von Willebrand Factor starting from the single chain perspective and ending with large reversible aggregates that become the plug, which can be triggered by flow. In particular, vWF has three functions that depend crucially on the right combination of biochemistry and fluid mechanics: i) adhesion to the exposed collagen (or single molecule activation), ii) formation of the plug (self-healing aggregate assembly) , and iii) delivery of Factor VIII, which is a hydrophobic catalyst in the blood clotting cascade (targeted drug-delivery). We have uncovered multiple mechanisms of how vWF can have such a wide variety of functions by using an exquisite combination of self-interactions that compete with interactions with other proteins, as well as tuning the flow-induced unfolding of this extremely large protein by biological design of large repeating sequences. Furthermore, we will show that the aggregation process is universal. I will finalize by presenting a perspective on the biophysics vWF which is still a very rich area of mechanobiology from the fundamental and the practical point of view.

Biography
Alfredo Alexander-Katz is a Materials Science Professor at MIT working on the biophysics of blood clotting. He unraveled the mystery behind the process of blood clotting at high shear rates and opened new routes for the development of novel shear responsive materials. His current interests lie in the realm of self-assembly and dynamics of biological soft-materials using a combination of analytical theory and simulations. His group is particularly focused in designing novel polymer-like drug delivery carriers and understanding their response to chemical and physical stimuli. This work aims to enable a new generation of drug-delivery vectors that could target different areas of the body in a very specific manner, and to provide a much deeper understanding of the processes of adhesion and targeting in flow. The research in Alexander-Katz's group is highly interdisciplinary, and lies at the interface of materials, biology, physics, chemistry and medicine.