New sphere-templated polymeric scaffolds for artificial cornea World Cornea Congress VI New sphere-templated polymeric scaffolds for artificial cornea Thank you very much, Dr. Slattery for your kind introduction. Good afternoon. I am honored to have this opportunity to talk to you about restoring vision, the topic that I feel passionate about. I would like to take this opportunity to explore with you the enormous challenges of the treatment of blindness in the world, not only from my personal experience as a surgeon, but also from a greater global perspective which defines the direction of my research. I hope this will serve as a window of opportunity to bring the awareness to global blindness and to stimulate your interests in our collective translational research efforts of many teams of researchers, both from the school of medicine and the school of engineering at UW. I am truly privileged to represent them. Like many medical specialties, Ophthalmology is an exemplary field that embrace rapid translation of cutting edge science and technology to benefit our patients. Science and technology has transformed our way to deliver care to our patients, even within my short career. Examples include the application of laser, ultrasound for new surgical treatments, as well as biomaterials as found in intraocular lens implants, contact lenses. For the next hour, I hope to provide you with a glimpse of these efforts, in the past as well as to the future. I understand that many people are sensitive to the images of eye pathology. I will give you warnings before these images emerge so you can close your eyes if you like. Tueng T. Shen, M.D., Ph.D. Shai Garty, PhD, Shintaro Kanayama, MD, PhD, Bryan Y Kim, BA Max Maginness, PhD, Buddy D. Ratner, PhD Financial Disclosure: The authors have no financial interest in the subject matter of this poster

Background Corneal blindness, affecting 12 million people, is the second leading cause of treatable blindness worldwide [1]. While corneal transplantation using high-quality human donor corneas has been successful in selected developed countries, majority of the people with corneal blindness today remain untreated because of the lack of donor cornea. Currently available artificial corneas for human use includes the Boston-Keratoprosthesis (Boston KPro) [2] and AlphaCor [3]. Both corneal substitutes have limited use worldwide because of the limited availability of donor cornea (Boston K-pro) and sub-optimal integration with host tissue (AlphaCor), leading to high risks for catastrophic infections and extrusions [4].

Limitations of current artificial cornea Tolerated but not integrated Still needs donor tissue High cost: $5,000 - $10,000 per device High risk of infection Require long term medication Require long term follow-up Treatment of the last resort in the developed countries Limited application in the developing world

Purpose We have developed novel polymeric materials and unique engineered design as complete replacement for human cornea. Our artificial cornea is made as a one piece consist a transparent polymeric optic-core inter-connected with a flexible, well defined porous polymer periphery. The composite polymer fabrication is made using an injection molding technique. Our device is designed and engineered to enhance the essential functions of the human cornea (refractive function and strong barrier) and eliminate its weaknesses (astigmatism, vulnerable to infections). The design has the potential to be adapted in the developing nations where resources are limited.

Methods Our design consists of a transparent polymeric optic core, fully integrated with a flexible, porous polymer periphery. The optic center is ensuring superb optic properties enable to restore vision and can be customized to refractive requirements of individual patients. The hybrid composite structure is made of collagen covalently attached to synthetic polymer. This rigid structure, is achieving improved biocompatibility. The well-defined porous periphery of the scaffold design based on the unique tissue integration properties of the spherically templated angiogenic regenerative (STAR) porous biomaterials. The STAR porous biomaterials are made by molding into a prefilled mold contains sintered uniform size PMMA beads. This engineered structure is maximizing the rapid tissue attachment and integration to the host. In addition, the surface properties of the device are readily customized for post-implantation healing when further facilitated by embedding bio-molecules to the porous peripheral scaffold.

Methods Healing and biointegration of implanted scaffold was encouraged by optimizing the porous structure and embedding biomolecules in the polymeric scaffold. The polymeric system properties were examined both in vitro using different analytical tools including rheological and morphological analysis, microscopy and bioassays in addition to in vivo rabbit models. The ex vivo implants were further analyzed using histology, immuno-histochemistry and high resolution scanning electron microscopy (HR-SEM).

Materials: Sphere-templated material We came to select a unique technique of making porous materials using sphere templated materials that was initially developed in Professor Ratner’s lab. This method polymerizes the polymer of choice with pmma beads of well defined size distribution. The beads are then removed leaving the porous material of desired size. It was found that at 30-40 um pore size, there was significant cellular integration. Effect of pore size on blood vessel density in sphere-templated polyHEMA implants Marshall, A.J. and B.D. Ratner, Quantitative characterization of sphere-templated porous biomaterials. AIChE Journal, 2005. 51(4): p. 1221-1232

In vitro 3T3 Fibroblasts culture on surface of STAR material Results (in vitro) In vitro 3T3 Fibroblasts culture on surface of STAR material HR-SEM of STAR Silicone material

Results: In vivo integration model In addition to in vitro cell culture studies, we established an in vivo rabbit model to evaluate the integration of the porous peripheral biomaterial in the similar setting to that of transplant. suturing test SEM In vivo implant Collagen staining

Conclusions Our preliminary findings suggest that the materials tested are well-tolerated in vitro using Fibroblast cells and corneal epithelial cells and in vivo as shown in the rabbits model. Those findings were supported by additional analyses including the immuno-histochemistry and morphological examinations. Those materials have the potential to be adapted as fully synthetic artificial cornea on a worldwide scale, especially in developing-nations with limited resources.

References Whitcher JP, Srinivasan M, Upadhyay MP. Bull World Health Organ. 2001;79(3):214-21.. Duan, D, Klenkler BJ, Sheardown H, Expert Review of Medical Devices, 2006. 3(1): p. 59-72. Chirila TV, Hicks CR, Dalton PD, Vijayasekaran S, Lou X, Hong Y, Clayton AB, Ziegelaar BW, Fitton JH, Platten S, Crawford GJ, Constable IJ, Progress in Polymer Science 1998; 23,3, 447-473. Dudenhoefer EJ, Nouri M, Gipson IK, Baratz KH, Tisdale AS, Dryja TP, Abad JC, Dohlman CH. Cornea. 2003; 22(5):424-8.

Acknowledgements UW collaborators: Shen lab: Professor Buddy Ratner, (BioE) Professor James D. Bryers, (BioE) Professor Brian Otis, (EE) Professor Karl Böhringer, (EE) Professor Babak Parvis, (EE) Shen lab: Shai Garty, PhD Shintaro Kanayama, MD, PhD Bryan Kim, BA Funding: Coulter Foundation, NEI, NSF, RPB I would like to thank all my collaborators, mentors and trainees who are essential part of this effort to deliver a viable solution for a treatable blindness. I hope I had a chance to share with you a fragment of exciting research opportunities in vision and shared a small moment of our dream for the future. It is my patients, the one who do not see yet, are the constant source of motivation that drive us to apply science and engineering, to medicine. As we look into the eyes of friends, family, I hope you can imagine the opportunities that we will have in the future when everyone can have the enjoy to see the beautiful world in front of us. Thank you for your attention. Author: Tueng T. Shen, M.D., Ph.D. Associate Professor University of Washington Eye Institute Adjunct, Bioengineering University of Washington School of Engineering