The need for human cornea equivalent tissues continues to grow with an estimated 10 million people worldwide suffering from corneal vision loss. There remain few clinical options today to meet these growing needs. In this renewal proposal we will build upon our progress in generating functional human cornea replacements. The hypothesis is that tissue engineered cornea systems based on mechanically robust, patterned, porous, thin optically clear silk protein films, in combination with appropriate cell types, can generate functional cornea tissue equivalents to meet these clinical needs. Our current data support the approaches planned and also allow for broader impact for these new cornea tissues systems for both in vivo clinical goals as well as for in vitro tissue equivalents fr drug screening. We plan to expand on our progress to date and generate multifunctional corneal tissue systems with tuned rates of tissue remodeling, innervation guidance, circumvention of suturing upon implantation and modulation of local infections and inflammation. Further, we plan to establish these corneal tissue systems to meet clinical needs as well as for in vitro substitute for drug screening.
The aims will address optimizing the structure and function of the lamellar biomaterial structures that form the basis of our cornea designs (focusing on remodeling rates, control of infections and inflammation, ad hoc cell substrate, and optimized co-culture methods to develop partial thickness equivalent tissues based on corneal stem cells, epithelial, and neuronal cells), in vitro studies for sustained tissue function to screen ocular drugs, as well as n vivo studies to asses clinical relevance in order to progress to full integration of the tissue equivalents, are planned. An interdisciplinary team of investigators that has been involved in the present proposal will pursue the new project goals in this renewal, including David Kaplan (silk biomaterials, tissue engineered cornea), James Funderburgh (corneal tissue biology, corneal stem cells), and Mark Rosenblatt (clinical, animal models).

Public Health Relevance

The answer to the growing need for corneal transplants is based mainly on two main approaches: allogenic and synthetic materials. Although allogenic materials originating from human donors are the preferred choice, there is a shortage in availability of quality-donor graft material, due to the increasing number of LASIK surgeries, which compromise the corneal stroma. In addition, tissue rejection limits the long-term success of this approach. Alternatively, synthetic keratoprostheses based on polymethylmethacrylate still require corneal tissue carriers and have myriad potential complications including corneal melting, uveitis, endophthamitis, and retinal detachment, resulting in high incidence of graft failure. Furthermore, increased interest in reducing animal testing for commercial products prompts the need for in vitro preclinical cornea tissue models.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mckie, George Ann
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Tufts University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Gosselin, Emily A; Torregrosa, Tess; Ghezzi, Chiara E et al. (2018) Multi-layered silk film coculture system for human corneal epithelial and stromal stem cells. J Tissue Eng Regen Med 12:285-295
Ghezzi, Chiara E; Marelli, Benedetto; Omenetto, Fiorenzo G et al. (2017) 3D Functional Corneal Stromal Tissue Equivalent Based on Corneal Stromal Stem Cells and Multi-Layered Silk Film Architecture. PLoS One 12:e0169504
Wang, Siran; Ghezzi, Chiara E; Gomes, Rachel et al. (2017) In vitro 3D corneal tissue model with epithelium, stroma, and innervation. Biomaterials 112:1-9
Jia, Liang; Ghezzi, Chiara E; Kaplan, David L (2016) Optimization of silk films as substrate for functional corneal epithelium growth. J Biomed Mater Res B Appl Biomater 104:431-41
He, Min; Storr-Paulsen, Thomas; Wang, Annie L et al. (2016) Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion. Invest Ophthalmol Vis Sci 57:6134-6146
Wang, Siran; Ghezzi, Chiara E; White, James D et al. (2015) Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds. J Biomed Mater Res A 103:3339-48
An, Bo; Tang-Schomer, Min; Huang, Wenwen et al. (2015) Physical and biological regulation of neuron regenerative growth and network formation on recombinant dragline silks. Biomaterials 48:137-146
Ghezzi, Chiara E; Rnjak-Kovacina, Jelena; Kaplan, David L (2015) Corneal tissue engineering: recent advances and future perspectives. Tissue Eng Part B Rev 21:278-87
Rnjak-Kovacina, Jelena; DesRochers, Teresa M; Burke, Kelly A et al. (2015) The effect of sterilization on silk fibroin biomaterial properties. Macromol Biosci 15:861-74
Thurber, Amy E; Omenetto, Fiorenzo G; Kaplan, David L (2015) In vivo bioresponses to silk proteins. Biomaterials 71:145-157

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