Designing an Artificial Cornea Using Polymer Networks
by Andy Dow
While medicine currently lacks a synthetic substitute for a fully functional human eye, scientists at Stanford are making significant progress in engineering some of the eyeÕs most critical parts. Dr. Curtis Frank, Professor of Chemical Engineering, in collaboration with Dr. Christopher Ta, Professor of Ophthalmology at the School of Medicine, and a number of other researchers have developed a new hydrogel with biomimetic properties - those that mimic a biological substance - that is a prime candidate for use as an artificial cornea. Their research holds exciting promise for the millions of people worldwide affected by corneal disease who may lack access to transplant tissue.
Molecular Mechanics of Strength and Elasticity
One of the most important properties of the hydrogel, as its name implies, is its ability to swell in water. High water content facilitates the diffusion of glucose, an important molecule that aids in the growth of a healthy layer of cells over the cornea. The materialÕs ability to swell in water is related to its tensile strength Ð essentially a measure of the force required to pull the material apart. The optimal material would be stretchy, yet difficult to fracture. As an added benefit, the combination of elasticity and durability increases the ease of suturing in a surgical procedure for implanting the artificial cornea.
To achieve this strength and high swellability, FrankÕs research group used an interpenetrating polymer network. Network formation begins with what Frank describes as a Ò3-D fishnetÓ of one material Ð in this case, poly(ethylene glycol). When placed in water, this polymer (consisting of repeating ethylene glycol monomers) remains covalently connected and swells. To create the interpenetrating network, they imbibe the first network with a mixture of acrylic acid monomers and water. At this point, the water serves as a sort of Trojan horse for carrying the nascent polymer inside the poly(ethylene glycol). These poly(acrylic acid) chains weave in and out of the swollen poly(ethylene glycol) network so that the two networks interlock. Even though the two polymers do not covalently bond to one another, their complex entanglement gives the material considerable strength. ÒThey are co-continuous,Ó Frank remarks. ÒYou couldnÕt pull them apart.Ó
Thermodynamic Considerations
While the mechanical properties of the material contribute to its strength, Frank points out that thermodynamic factors play a role as well. Part of the tensile strength comes from favorable hydrogen bonding between the two polymers that render the hydrogel energetically stable. Hydrogen bonds are a type of strong intermolecular force between partially positive hydrogen atoms on one molecule and an electronegative atom on another. Although Frank initially worried that hydrogen bonding with water might overwhelm those between polymers, he believes that the strong intermolecular forces between the polymer networks do in fact lend extensive strength to the material.
In addition to strength, these hydrogen bonds play a significant role in another important engineering parameter for a cornea: transparency. Because the polymers undergo hydrogen bonding with both water and each other, they are soluble in water and miscible with one another. The thermodynamically favorable interactions among molecules of water and the two polymers lead to a well-integrated material with all three components in a single phase. This uniformity creates optical clarity.
Bio-Integration
To ensure that the hydrogel would provide a clear window for sight once implanted in an eye, the researchers had to prevent unwanted protein deposits from building up a clouding layer of cell debris on the surface. The team knew from empirical observations that both poly(ethylene glycol) and poly(acrylic acid) are resistant to non-specific protein adsorption. However, the full situation is more complicated. Some cellular growth on the hydrogels is necessary for healthy biological acceptance of the new material, and a layer of epithelial cells on the surface of the cornea provides an important natural barrier to bacterial infection.
After demonstrating that cells would not grow on the engineered material without surface modification, FrankÕs team developed a surface coupling technique to make the hydrogel controllably attractive to cells. While avoiding unwanted protein adsorption, they can pattern the materialÕs surface with bifunctional chemical linkers that bind to proteins at specific regions and promote epithelial cell growth at those areas. ÒYou start with a system that you want to remain relatively uncontaminated, and then you can control cell growth by virtue of the surface pattern,Ó Frank explains.
Seeing Ahead
This successful and controllable epithelial adhesion is one of a number of factors that set this material apart from previously designed commercial devices, none of which support such epithelial growth. ÒThis material is new for any kind of ocular application,Ó notes Frank. It appears to be heads above others in performance thanks to its mechanical, thermodynamic and biocompatible properties. ÒWe have a material right now that is very good,Ó he says, Òand we want to understand why itÕs good so that we can potentially make it better.Ó Frank acknowledges that the next steps in this research toward achieving applicability will be to develop what is now a highly qualitative knowledge of these properties into a quantitative understanding.
A synthetic material that not only emulates, but also successfully integrates with biological tissue could affect corrective ophthalmology worldwide. In fact, Ta notes that it would greatly impact countries outside the U.S., where smaller donor pools and large infrastructure costs for harvesting and transporting corneas create a shortage of tissue for traditional transplant surgery. Even in the U.S., an appropriately designed material might surpass donor tissue in visual recovery periods and biological acceptance after surgery. Some might caution that until full application of the material is realized, seeing is believing. For many future beneficiaries, seeing will be all the belief they need.
Sidebox: Interdisciplinary Success
Creating an artificial cornea involves many different engineering considerations, and its design therefore requires expertise in many areas. It should come as no surprise that the scientists tackled a project with biological, clinical and materials science dimensions through an interdisciplinary approach, pooling some of StanfordÕs best resources of knowledge. Development of the hydrogels was a collaborative effort between the Chemical Engineering Department and the School of Medicine. Professor Curtis Frank and other chemical engineers, including MD/PhD student David Myung, worked closely with Professor Christopher Ta of Ophthalmology, another principal investigator for the project. Ta clarified the clinical needs that the chemical engineers must meet in their design considerations, such as optical clarity and an epithelial cell layer to defend against infection. Jennifer Cochran, Assistant Professor in Bioengineering, also contributed to the research effort through her expertise in cell biology. ÒThe materials science needs to be developed in the context of what the interfacial and cell biology needs are, as well as what the clinical needs are,Ó comments Frank. ÒOne component alone couldnÕt solve the problem.Ó