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Stanford Cornea Project

Stanford Cornea Project. Laura Hartman, Dale Waters, Rachel Parke-Houben, Curtis W. Frank Stayce Beck, Luo Luo Zheng, Yuhua Hu Jennifer Cochran Resmi Charalel, Phil Huie, Vijay Vanchinathan Roopa Dalal, Michael Carrasco, Jaan Noolandi Christopher N. Ta. Who needs an artificial cornea?.

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Stanford Cornea Project

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  1. Stanford Cornea Project

  2. Laura Hartman, Dale Waters, Rachel Parke-Houben, Curtis W. Frank Stayce Beck, Luo Luo Zheng, Yuhua Hu Jennifer Cochran Resmi Charalel, Phil Huie, Vijay Vanchinathan Roopa Dalal, Michael Carrasco, Jaan Noolandi Christopher N. Ta

  3. Who needs an artificial cornea? • In the United States, over 33,000 corneal transplants are performed each year • Worldwide, 10 million people are blind due to corneal disease. Most of these people do not have access to corneal transplants and remain blind due to a lack of donor tissue supply and distribution. trachoma trachoma corneal ulcer corneal ulcer

  4. Current available keratoprosthesis Boston keratoprosthesis (PMMA) Osteo-odonto keratoprosthesis ≈1,200 devices implanted to date (still requires donor corneas) AlphaCor device (PHEMA) • 224 devices implanted with surprisingly high success rates. • requires complex surgery and is only performed by a select few surgeons throughout the world ≈ 300 devices implanted to date; limited use Falcinelli, G., et al. Arch Ophthalmol, 2005. 123(10): p. 1319-29.

  5. Properties of an Artificial Cornea • Biocompatible • Optically clear centrally • Nutrient permeable • Mechanically strong • Surface epithelialization • Peripheral tissue integration CAD model acknowledgement: L. Kourtis, Stanford Dept. of Mechanical Engineering

  6. The Stanford Approach protein modification (Collagen and EGF)  Epithelium grows back high diffusion + stable, optically clear hydrogel  “invisible” material 1. 2. Epithelium Stroma hydrogel hydrogel Stroma

  7. no chemical linkage • two interpenetrating networks (IPNs) • highly improved mechanical properties Single Network Double Network Material Single Network Double Network polymerization of 2nd network 1st network swollen in monomeric building blocks of 2nd network J.P. Gong, et al., Advanced Materials 2003

  8. Mechanical Stability 1st network: Poly(ethylene glycol) (PEG) ‏ 2nd network: Poly(acrylic acid) (PAA)‏ water content: ~90% IPN 8 • tunable material • mechanical stability • (contact lens vs. inlay) • pore size: diffusion • (nutrient vs. drug delivery) • longterm stability • (implant vs. tissue scaffold) 7 IPN 6 5 IPN Maximum Tensile Stress [MPa] PEG (4.6kDa)‏ 4 PEG (8kDa)‏ PEG (14kDa)‏ 3 2 PAA PAA PAA 1 0

  9. urea lactic acid amino acids sodium bicarbonate ascorbic acid Diffusion • A high rate of small molecule diffusion through the hydrogel is required to maintain a healthy epithelium glucose Epithelium Hydrogel (~100 μm) Flap edge Stroma

  10. Protein Tethering: Cell Re-Growth • no de-swelling of the gel • washing in buffer possible • no denaturation of proteins

  11. Protein Tethering: Qualitative BINDING OF COLLAGEN • Using fluorescently-labeled collagen, we have shown that this tethering method supports a stable binding of ECM protein. Control (adsorption) NHS/EDC (covalent linkage) PEG Diacrylamide Hydrogel PEG Diacrylamide Hydrogel

  12. Protein Tethering: Cell Re-Growth Corneal Fibroblast Cells Attach to ECM-Tethered Hydrogels A) control B D C D E Phalloidin (red) and Nuclear (DAPI(blue)) staining of primary rabbit corneal fibroblast cells grown on PEGacrylate/PAA Hydrogel tethered with A)Control, B) Collagen, C)Fibronectin, D)Laminin and E) 1:1 mixture of collagen and Fibronectin.

  13. In vivo experiments rabbit # 2 - post-op 50 days

  14. Future Work MATERIAL • Determine diffusion coefficients for other proteins through human cornea • Apply principles to development of artificial cornea • Modify refractive index for inlay application (presbyopia) DEVICE Protein tethering • Optimize the ECM content tethered to the hydrogel • Use time-lapse microscopy to study cell migration on the hydrogel • Addition of enhanced growth factor (EGF) to the protein layer Tissue Integration • Fine-tuning is still needed to reduce the pore diameter to 50 – 100 μm • Confocal fluorescence microscopy will be used to demonstrate that the channels are interconnected • Tether proteins to the channel walls and test for fibroblast growth IN VIVO EXPERIMENTS • Implant hydrogel-onlays/inlays • Implant artificial cornea

  15. Funding • National Institutes of Health / National Eye Institute • R01 EY016987 • NIH Grant 5T90 DK070103-03. • Singapore Eye Research Institute (SERI) • BioX • Stanford Office of Technology Licensing • Stanford MedScholar Program • Fight for Sight • Visx

  16. Thank you

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