Every year in the United States, over 45,000 corneal transplants are performed. The success rate for this procedure is fairly high (90% after two years) and although current access to donor tissue is adequate, the quality of tissue varies significantly which influences surgical outcomes. In addition, the proliferation of LASIK procedures, which disqualifies a cornea for transplantation, threatens to reduce the availability of donor corneas in the near future. In recent years, laudable attempts have been made to produce corneal equivalents by tissue engineering. These constructs have proven the concept that three layers of cells, resembling the epithelium, keratocytes and endothelium may be cultured into a collagen matrix. However, such constructs have only met with limited success because the stromal matrix, which provides the cornea with its unique (and critically important) mechanical and optical properties, has not been reproduced. Randomly oriented collagen gels, which represent the typical starting point for tissue-engineered corneas, are not likely to be strong enough or clear enough for clinical use. In addition, expecting a significant in vivo ? remodeling response to integrate a partially functioning artificial cornea is not acceptable. The artificial ? construct should be functional at the time of implantation. For these reasons, we propose a stromal-centric approach toward the generation of an artificial cornea. By combining engineering, biology, biomechanics and biochemistry, two different routes, both designed to produce biomimetic stromal lamellae (the building blocks for an artificial cornea) will be attempted. The first method employs microfluidics to influence the self-assembly of thin, aligned lamellar sheets comprising collagen and proteoglycans. This approach is acellular and is designed to produce a biomimetic stromal scaffold de novo. The second approach utilizes mechanical cues such as contact guidance (provided by the ? de novo lamellae) and strain to """"""""direct"""""""" the synthesis of matrix by ascorbic acid stimulated human corneal fibroblasts. An extensive characterization of the synthetic response to the imposed stimuli will be conducted to gain a fundamental understanding of synthesis, remodeling and homoeostasis of highly structured matrix. Completion of both parts of this proposal will provide insight critical to achieving our ultimate goal, which is the ex vivo generation of a functional, biomimetic artificial cornea from natural components. ? ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (02))
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northeastern University
Engineering (All Types)
Schools of Engineering
United States
Zip Code
Paten, Jeffrey A; Siadat, Seyed Mohammad; Susilo, Monica E et al. (2016) Flow-Induced Crystallization of Collagen: A Potentially Critical Mechanism in Early Tissue Formation. ACS Nano 10:5027-40
Tonge, Theresa K; Ruberti, Jeffrey W; Nguyen, Thao D (2015) Micromechanical Modeling Study of Mechanical Inhibition of Enzymatic Degradation of Collagen Tissues. Biophys J 109:2689-2700
Paten, Jeffrey A; Tilburey, Graham E; Molloy, Eileen A et al. (2013) Utility of an optically-based, micromechanical system for printing collagen fibers. Biomaterials 34:2577-87
Flynn, Brendan P; Tilburey, Graham E; Ruberti, Jeffrey W (2013) Highly sensitive single-fibril erosion assay demonstrates mechanochemical switch in native collagen fibrils. Biomech Model Mechanobiol 12:291-300
Flynn, Brendan P; Tilburey, Graham E; Ruberti, Jeffrey W (2013) Erratum to: Highly sensitive single-fibril erosion assay demonstrates mechanochemical switch in native collagen fibrils. Biomech Model Mechanobiol 12:847
Wang, Lina; Johnson, Joshua A; Chang, David W et al. (2013) Decellularized musculofascial extracellular matrix for tissue engineering. Biomaterials 34:2641-54
Saeidi, Nima; Guo, Xiaoqing; Hutcheon, Audrey E K et al. (2012) Disorganized collagen scaffold interferes with fibroblast mediated deposition of organized extracellular matrix in vitro. Biotechnol Bioeng 109:2683-98
Mega, Yair; Robitaille, Mike; Zareian, Ramin et al. (2012) Quantification of lamellar orientation in corneal collagen using second harmonic generation images. Opt Lett 37:3312-4
Saeidi, Nima; Karmelek, Kathryn P; Paten, Jeffrey A et al. (2012) Molecular crowding of collagen: a pathway to produce highly-organized collagenous structures. Biomaterials 33:7366-74
Chang, Shu-Wei; Flynn, Brendan P; Ruberti, Jeffrey W et al. (2012) Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown. Biomaterials 33:3852-9

Showing the most recent 10 out of 17 publications