Department of Chemical Engineering at the University of Michigan in Ann Arbor

 
 

Overall Objective
Particle Design
Dynamics in Blood Flow
Comparative In-Vivo Study
Mathematical Modeling
Plasma Protein Adsorption

Fabrication Techniques
Interactions with WBC

Instruments

Overall Lab Objective

Our research focuses on cell adhesion and drug delivery. Specifically, we are utilizing the physiological and cellular response to inflammation and corresponding blood hemodynamics to design bio-functionalized particles for targeted drug delivery and imaging.


Plasma Protein Adsorption
Daniel Sobczynski

Daniel’s current research is focused on the effect of plasma protein adsorption on adhesion of biodegradable vascular targeted carriers (VTCs) from human blood flow to inflamed endothelial cells. Plasma protein adsorption on intravenously injected drug carriers modulates their organ distribution and clearance from the bloodstream. However, the role of plasma protein in prescribing the adhesion of carriers to thevascular wall remains relatively unknown. Dan’s research looks at adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) particles in human blood flow and aims to understand the potential role that plasma proteins could play in this process. PLGA is a well-characterized and commonly proposed drug carrier and hence, FDA-approved. Overall, understanding how distinct plasma proteins modulate vascular-targeted carriers’ (such as PLGA) adhesion would allow for the design of highly functional delivery vehicles. Three main media Dan uses in his adhesion assays consist of buffer, plasma, and human blood and my results from these assays indicate that the effect of plasma proteins on adhesion of carriers is largely negative and a function of both particle material and human blood donor.


Physical Properties of Vascular-Targeted Particles
Margaret Fish

Margaret works on a wide variety of projects in the lab investigating how the physical properties of vascular-targeted particles prescribe their efficiency in vitro and in vivo. For instance, she has investigated dual particle ligand systems as a physical method for improving targeting in vitro and in vivo. She works on fabrication, characterization, and application of soft, polymer based particles for drug delivery. Margaret also investigates how altering the rigidity of red blood cells disrupts normal blood flow and the resulting behavior of particles and white blood cells.


Particle Interactions with White Cells
Dr. Cathy Fromen

Intravenously injected VTCs interact dynamically with cells in the complex fluid of blood. Cathy has translated groundwork investigating these particle-blood cell interactions laid by previous lab member, P. Onyskiw, to multiple in vivo models, including intravital microscopy of locally inflamed mesentery and a model of acute lung injury. This work investigates if intravenously (IV) administered particles can be designed to divert leukocyte accumulation from inflamed tissues, providing a novel anti-inflammatory therapy to regulate abnormal leukocyte recruitment.


Mathematical Modeling of Blood Flow
Dr. Cathy Fromen and Margaret Fish

One of the most important parameters in the design of vascular targeted carriers (VTCs) is the implementation of appropriate targeting ligands.  Using multiple leukocyte adhesion molecules (LAMs) on the surface of the particle to target inflamed endothelium can improve disease specificity and adhesion efficacy.  Margaret and Cathy have designed a range of particles with varied amounts of two LAMs, sLeA and anti-ICAM, and have studied the adhesion of these particles in human blood flows in vitro and in a model of inflamed mesentery in vivo. Their work has demonstrated that optimal particle ligand confirmations depend on the exact surface expression of the endothelium.

 

Diagram of five particle conditions. Particles designed with varied amounts of sLeA and aICAM ligand density at a constant total site density of 10,000 sites/µm2. Particle B represents 100% sLeA, particle I represents 75/25% sLeA/aICAM, particle F represents 50/50% sLeA/aICAM, particle J represents 25/75% sLeA/aICAM, and particle G represents 100% aICAM.

Representative adhesion of 500nm fluorescent polystyrene particles to a locally inflamed mesenteric vein following IV administration.


Fabrication of non-spherical biodegradable drug carriers
Hanieh Safari

In vitro and in vivo studies have demonstrated that shifting towards non-spherical elongated particles will increase their vascular targeting efficiency.  These particles benefit from increased circulation time, lower phagocytic uptake and increased binding towards the vascular wall. The current developed methods for fabricating non-spherical particles require complicated and expensive set up and are hard to scale up. Our lab has recently developed a simple method for fabricating non-spherical by stretching emulsion droplets with shear. Hanieh has been working on modification and optimization of this technique to fabricate elongated biodegradable particles in a range of sizes interesting for in vitro and in vivo targeting applications and studying the effect of shape on targeting efficiency of biodegradable drug carriers.


Investigating the role of rigidity in cellular dynamics
Mario Gutierrez and Margaret Fish

This work evaluates the impact of RBC geometry, rigidity, and RBC concentration on margination, i.e. localization to the vascular wall, of cells and particles in blood flow. The findings gained from investigating cellular and particle dynamics in blood flow will lead to profound advances in the understanding of physiology of many diseases, specifically sickle cell disease (SCD), polycythemia vera (PV), and for the development of sophisticated vascular-targeted drug carriers (VTCs) for applications in many human diseases.


Cellular Adhesion Molecule Expression
Alison Banka

The expression of cellular adhesion molecules (CAMs) by inflamed endothelial cells, an essential component of the body's inflammatory cascade, changes based on variables such as time and mechanical cues. Alison studies how together these different variables affect CAM expression in order to develop a more comprehensive in vitro model for certain inflammatory cardiovascular diseases.