Biocompatibility

Blood, Sweat, and Tears

How biomimicry and knowledge of blood-biomaterial interactions can lead to better contact lens materials.

By Roderick W.J. Bowers, PhD

Significant advances have been made over the years in contact lens design—particularly in the transmission of oxygen through the lens to the cornea, with the goal of improving safety (Sweeney, 2000). However, significant clinical limitations with current lenses remain.

For example, problems seen with older generations of hydrogels have reappeared with newer generations of silicone-based materials (Mirejovsky, 1993; Fonn, 2007; Tighe, 2001; Bowers, 1987). In fact, many contact lens wearers fall short of all-day comfortable wear. Studies suggest that 22 percent to 24 percent of patients permanently discontinue wear as a result of discomfort (Pritchard, 2002; Richdale, 2007). A significant opportunity exists for the development of a new class of contact lens materials capable of delivering a high quality, whole-day lens wearing experience, while at the same time meeting the physiological needs of the eye.

Recent articles have explored the relationship between material properties, lens comfort, and ocular health (Young, 2007; Jones, 2010). A key lens property is the ocular biocompatibility of the polymer with the eye. Although progress has been made, true biocompatibility remains an elusive goal (Young, 2007; Ratner, 2007). This article reviews the nature of biocompatibility and considers why an understanding of blood-biomaterial biocompatibility can be of significant value to lens polymer design. New research such as biomimicry, which uses these principles, and poly (ethylene glycol) hydrogels, are also considered.

Biocompatibility

Biocompatibility is a complex issue that, despite more than 50 years of study, is not fully understood (Ratner, 2007). In essence, it can be defined as a synthetic material that does not adversely affect the physiological environment in which the device is designed to operate, and the physiological environment does not adversely affect the material. More recently, this definition has been refined to a material that can elicit an appropriate host response (Williams, 1989).

A contact lens is a foreign body (FB) which, when placed on the eye, triggers a rapid FB response in which biomolecules such as protein, lipids, immunoglobulins, and complement proteins bind at the surface of the lens. This FB response is not a unique problem to soft contact lenses and is triggered by other synthetic polymers that come into contact with biological tissues and fluid (Bowers, 1985; Limber, 1975). Blood clotting on stents, biofilm formation on urinary catheters, and contact lens spoilation are all part of the same phenomenon. Therefore, an understanding of the mechanisms of one of these FB responses can help researchers design more comfortable lenses with a higher level of biocompatibility.

Protein Adsorption: Relevance of Blood to Tears

There are several reasons why studying blood-contacting surfaces is relevant to the design of new contact lens materials. Blood and tears are similar in composition, and the behavior and principles of protein adsorption at the interface of synthetic materials in blood and tears are similar (Mao, 2004; Gachon, 1979). In the case of thrombogenesis, or blood clotting, proteins bind and interact with a surface within milliseconds of contact with it. As time continues, other proteins and cells interact with these modified surfaces, leading to further changes and, ultimately, to the formation of emboli or blood clots.

Recent studies, for example, have shown that wearing a contact lens can increase albumin and immunoglobulin concentrations in tears (Luensmann, 2008). The exact role of these elevated protein concentrations is not fully understood. However, it is reasonable to assume that they have a similar role in blood, which is related to the inflammation and FB responses. Rejection and inflammation do not occur with most contact lens patients, but a hypothesis that links contact lens discomfort, especially at the end of the day, with subtle sub-clinical responses triggered by the binding of these proteins and subsequent activation of biological pathways, is plausible.

The classic signs of inflammation—redness, swelling, heat, and pain—are triggered in the body by the presence of an FB. Several inflammatory mediators are found in tears. These include immunoglobulins, plasmins, complement proteins, sticky proteins, and cytokines. Some of these come from leaky capillaries, while the lacrimal gland produces others. In the eye, the inflammatory response may be triggered directly by a contact lens or by various other stimuli such as mechanical trauma, tear components adsorbed on the lens surface, or the presence of bacteria. Because the mechanisms that transform synthetic materials in contact with tears and blood are similar, it seems reasonable that the solution to designing better lens materials is similar.

Biomimicry and Hydrogel Design

Traditionally, the design of blood-contacting polymers and contact lens materials has focused on making synthetic alternatives to materials found in the body. The problem with this approach is that, unlike natural systems, synthetic materials lack the ability to integrate with biological systems such as blood and the tears.

In the natural environment, blood does not clot at the inner lumen of blood vessels and erythrocytes, and proteins and lipids do not excessively bind to the corneal surface. The obvious question to ask is why does it happen with synthetic polymers? One answer is that their surface properties differ from the natural tissues. Blood cells have an outer membrane that is composed of phospholipids such as phosphorylcholine (PC). Corneal epithelial cells are coated with a glycocalyx that is similar in composition to the vascular endothelial glycocalyx, which has surface properties to ensure that a stable and coherent mucin layer can form across the surface of the cells.

A promising solution to this problem is the science of biomimetics or biomimicry. These can be summarized as the examination of nature and its models, systems, and processes by designing synthetic polymers that mimic the properties of natural systems (Williams, 2009).

Coatings and bulk materials fabricated from PC-containing moieties are hemocompatible (Yianni, 1992). Contact lens materials, such as omafilcon A, have a superior resistance to protein and lipid binding as well as a higher resistance to dehydration (Young, 1997; Lemp, 1999).

It is postulated that the ability to bind water tightly to the PC head group under a range of pH conditions means that it is difficult for biomolecules to adhere. Polymers that are neutrally charged, highly hydrophilic, and that strongly bind water are attractive synthetic materials for the manufacture of devices such as contact lenses that provide improved levels of biocompatibility.

Another class of polymers that possess similar water binding properties to those found in natural systems such as PC are hydrogels based on poly (ethylene glycol) (PEG). PEGs are remarkable materials and have been prepared commercially for many decades and reviewed extensively in the scientific literature (Harris, 1992, Harris, 1997). PEGs continue to be investigated in the context of biomaterials science because of their ability to control the bioactivity of surfaces and bulk materials. They are also non-toxic and approved by the FDA for both oral and topical applications and consumption.

As with PC, PEGs are hydrophilic, neutral polymers that are capable of reacting strongly with water. The hydrophilic character of PEG is responsible for much of its usefulness in applications involving physiological systems. When exposed at the surface, PEGs significantly decrease the adsorption of blood cells and proteins.

It is not yet clear how PEG polymers achieve these effects. Several hypotheses have been proposed in the literature including: large exclusion volumes, osmotic repulsion, high molecular mobility, lack of protein binding sites, and hydrophilicity (Gombotz et al, 1991; Ostuni et al, 2001). Protein-resistant PEG-ylated surfaces are often described as near liquid assemblies of highly mobile chains that offer few binding sites to most proteins (Otsuka, 2010).

There is significant interest in designing PEG-based surfaces and materials for in vitro and in vivo biomedical applications such as drug delivery, tissue engineering, and ocular applications.

For example, one development group, Ocutec (United Kingdom), has overcome the problem of producing stable, transparent PEG materials and is working on contact lens applications.

Part of the attractiveness of PEG is that, because of its ability to hydrate and bind water, it exhibits many of the structural, physical, and chemical characteristics of the extra cellular matrix. It provides a powerful antifouling platform that can be further engineered to incorporate biomolecules that are designed to interact with physiological systems by governing the structure and functioning of cells (Graham, 1984; Otsuka, 2010).

Summary

A key property in contact lens comfort is the biocompatibility of the contact lens polymer with the pre-corneal environment. Although progress has been made, true biocompatibility continues to remain an elusive goal.

There are strong correlations between blood clotting and ocular compatibility. Therefore, the performance of biomaterials in blood may strongly depend on the development of new contact lens polymers. Biomimetic materials such as PC and PEG may hold real promise in designing contact lens polymers that offer superior comfort. CLS

For references, please visit www.clspectrum.com/references.asp and click on document #189.

Dr. Bowers is the managing director of InoSys, a technology business based in the United Kingdom offering technical consultancy services to the medical device industry with particular expertise in the contact lens sector. He is also a consultant to UK-based Ocutec, Ltd., a medical device company that is researching new materials and manufacturing contact lenses.