Hyun Joon Kong: Revascularization in Service of Tissue Regeneration

A Civil Engineer Takes on Biological Systems

Civil engineering is not the most traditional route to tissue regeneration research, but that is how chemical and biomolecular engineering professor and IGB researcher Hyun Joon Kong began his journey.

Kong's original interest was colloidal rheology, the study of the effect of colloidal interaction on the deformation and flow of colloidal suspension. As a University of Michigan doctoral student in the interdisciplinary program Macromolecular Science and Engineering, Kong studied the colloidal properties of cement particles and their roles in both the flow properties of cement paste and the mechanical properties of the cured cement.

However, in the course of this research, Kong began to realize that many of the processes he studied, including fluid flow and material mechanics, also occur in the human body.

"I thought if I studied biological systems, eventually I might find a good idea that would help me create a novel material that could have a wide range of applications," Kong says.

Instead Kong began to appreciate how his expertise in rheology and material chemistry could help with many biological problems. Kong, who is a member of the Regenerative Biology and Tissue Engineering Research Theme, became so interested in biomaterials and biotherapies that he now applies what he learned in industrial systems to biomedical challenges, especially issues related to structure, transport phenomena and tissue regeneration.

He has become particularly interested in ways to promote revascularization of tissue with constricted vascular systems, ischemic tissue, using bioactive molecules and cells. Any time tissue, be it heart or bone, needs to be repaired, revascularization is critical. Ischemic disease is a major cause of heart failure and limb amputation. But there are difficulties:
# Cells to help regeneration that are placed at the site, for example, the heart, disperse instead of staying where they are put.

# If cells do stay put, they are attacked by enzymes and by the body's immune system.

# Little is known about how to stimulate activities of these new cells to create new vascular networks

Kong's approach has been to create a provisional matrix, "a kind of factory to stimulate cells to make new tissue."

The coagulation of blood is a good model of a provisional matrix. That plaque of coagulated blood works as a temporary matrix or scaffold to help stem cells and protein molecules develop new tissues and capillaries. Once the work is done, the matrix disperses. Kong's work would likewise create a provisional matrix, but one that has greater mechanical strength and biotransport abilities than the natural matrix, which would be particularly useful in cases of an especially large wound or defect.

Kong has focused on developing a class of biomaterial called hydrogels, which are formed from the cross-linking of water-soluble polymers. Hydrogels, which serve as a "nano- or microporous scaffold," mimic and further improve the physical properties and permeability of the provisional matrix naturally formed at the injury. Hydrogels are composed of varying blends of water and bioactive polymers, which promote cell growth, migration, and differentiation essential to develop new vasculature.

"We are interested in designing and characterizing hydrogels and determining how cells interact with those hydrogels, so together they can ultimately develop a nicely interconnected vascular system," Kong says.

Making a hydrogel is a bit like baking a cake; varying the percentage of each ingredient gives different results. Different recipes result in differing mechanical properties like stiffness, toughness and degradability, as well as differing abilities to deliver chemical cues and perform other transport functions. These properties influence how well cells will function in the hydrogel. That, ultimately, is the challenge: to make hydrogels sturdy and yet hospitable to regenerative cells.

If a hydrogel is to be implanted in a limb for revascularization, for example, it should be fairly stiff and should gradually degrade to provide space for new blood vessel formation. Stiffening the hydrogel means reducing the amount of water in the environment. Less water, however, means less water transport and cell viability declines. Less water also slows the degradation rate, limiting vasculature development. Adding water to make the cells happier and boosting vasculature development decreases the hydrogel's durability.

"How can we de-couple structure, transport and degradation rate?" asks Kong.

In a recent paper, published in Advanced Functional Materials, Kong demonstrates success with a polymer that can crosslink parts of the hydrogel, making it stiff while being able to control the degradation rate of the hydrogel and allow or help regulate the protein release rate and subsequent revascularization without altering desired mechanical properties. Moving from in vitro to in vivo is another very big hurdle.

"That's a significant challenge," says Kong. "If we can't do that, these hydrogels won't be helpful."

Kong runs two labs, one in the Department of Chemical and Biomolecular Engineering (ChBE) and one in the IGB.

"The ChBE lab is the source to create new materials and IGB is where we launch the translational work," says Kong.

Theme members Larry Schook, Marie-Claude Hofmann and Matthew Wheeler are experts at isolating cells, analyzing cell activity and testing the hydrogels in various animal models. This IGB collaboration is an enormous boost for Kong's work: with a short walk he can meet with colleagues who help determine whether the hydrogels are viable for key cells and then test them in vivo.

While Kong is focusing on this revascularization project, he also has several other ongoing projects, including a US Army-funded project with Rashid Bashir in the College of Engineering to facilitate the regeneration of heart tissue, and an NSF-funded CAREER project looking to control stem cell differentiation in a 3D matrix. A third, small project, funded by a cosmetic company, looks at wrinkle formation, again using hydrogels.

So engineering's loss is biology's gain: Kong's hydrogel expertise will improve the quality of people's lives, from their hearts to their faces.