Premature Rupture of the Fetal Membrane
Preterm labor is one of the leading and rising causes of infant mortality, and nearly 40% of these cases are linked with preterm premature rupture of membrane (pPROM). This is a debilitating condition that can sometimes be reversed by spontaneous sealing of the membrane which has been shown to be mediated by fetal macrophage recruitment and polarization. However, the role of mesenchymal cells in the recruitment and polarization of macrophages is not well understood, nor are the mechanical property changes the fetal membrane undergoes that may make it susceptible to rupture. Amnion-derived mesenchymal stem cells (MSCs) are a major constituent of the most loadbearing part of the fetal membrane, and understanding their differentiation, migration, and the soluble factors they release in response to the viscoplastic properties of their niche could be key to therapeutically addressing and perhaps preventing pPROM. Recent advances in biomaterial science have shown that specific mechanical properties of the extracellular matrix (ECM) can drive stem cell differentiation, signaling pathways, and remodeling of their environment. It has also been shown that the mechanical properties of the ECM change significantly in diseased versus normal states, independent of soluble signaling factors. The overarching hypothesis is that the viscoplastic properties of the ECM drive secretion of proteins from MSCs, which in turn affect recruitment of macrophages and in turn affects pPROM healing. Therefore, the specific aims of this project are to (1) investigate the viscoplastic property changes in the fetal membrane, (2) mimic those properties in RGD-functionalized alginate hydrogels to optimize wound healing, and then (3) assess the therapeutic effect of encapsulated MSCs on fetal membrane healing in vivo.
Measuring Dynamic Nanoscale Forces in the Cellular Environment
Cellular mechanics play a major role in countless biological processes such as cell differentiation, cell migration, and immune cell programming, and yet, the techniques currently available to measure force vectors in biological materials and timescales are inadequate. Current methods rely on 2D-limited measurements such as atomic force microscopy (AFM) and nanoindentation, or measurements in 3D that incorrectly assume perfect material elasticity such as microrheology or traction force microscopy (TFM). However, for live cell imaging in 3D, these restrictions may obfuscate results as the environments are either biologically irrelevant or they do not directly measure the material mechanics in a quantitative manner. Most biological materials exhibit dissipation and rearrangement of polymeric architecture in response to forces in a time-dependent manner, and precise measurement of this process is of key importance as the degree of a tissue remodelability has been linked to various diseases, including migratory metastatic cancers as well as those originating from the bone marrrow. If we can precisely measure mechanical forces and quantify the remodeling, the complex interplay between cell phenotype and tissue mechanics will allow the development of methods for detection and treatment of disease.
Immunogenic effects of microplastic pollution
As we are consuming more and more microplastic particles in our everyday lives, the deposition and incorporation of the particles in our tissues becomes a bigger issue. What effects do they have on our innate immune system? We aim to address these questions by determining both the micro and macro effects such particles have on the ECM and what changes they may stimulate on the innate immune system such as resident macrophages. Using a combination of rheology and nanoindentation to probe the mechanical effects, we also model their behavior using artificial ECM-mimicking hydrogels to tease out the relationship between tissue mechanics and immunogenic nature.