Approaches to corneal tissue engineering: top-down or bottom-up?

Abstract Tissue engineering creates biological tissues that aim to improve the function of diseased or damaged tissues such as the cornea (the main refractive component of the eye). Traditional tissue engineering strategies employ a “top-down” approach, in which cells are seeded on a polymeric scaffold that they then populate and create the appropriate extracellular matrix (ECM) often with the aid of perfusion, growth factors and/or mechanical stimulation. However, in highly organised tissues, such as the cornea, top-down approaches have difficulty recreating intricate but necessary microstructural features. With the desire to create more complex corneal tissues with features such as anisotropic hierarchical molecular assemblies, appropriate mechanical properties, cell binding motifs and corneal specific morphology, we are developing tissue engineering techniques that are moving away from the traditional top-down approach and instead focusing on building modular micro-tissues with repeated functional units which facilitate a bottom-up approach. Here we report on the success and shortcomings of both top-down and bottom-up approaches to creating engineered corneal tissues. Specifically, we will discuss recent work demonstrating the importance of engineering corneal ECM with appropriate levels of tissue compliance using a top-down approach. We will then highlight a bottom-up approach, which focuses on fabricating discreet bio-prosthetic ECM building blocks (corneal lamellae) with specific micro-architectural features derived solely from human corneal keratocytes under serum free conditions using enzyme responsive templates. These building blocks will then be used to generate a whole cornea whilst maintaining the intricate architecture and complexity of native corneal ECM.