Fabrication and Application of Thermoresponsively Patterned Microvasculature

Abstract

Hydrogels are a potent platform for developing medical technologies: their biocompatibility, viscoelastic structure and high-water content make them ideal for applications ranging from artificial tissue scaffolds to medicated wound dressings. Critically, they act as a medium in which water-soluble molecules, including nutrients, growth factors and cellular waste products, may move via diffusion or advection. These mass transport properties can be directly affected, without significantly compromising the mechanical or chemical properties of the polymer network itself, by creating micrometer scale cavities throughout the hydrogel. Modern methods of fabricating such features are limited by any combination of feature size, lumen geometry, scalability, interconnectivity or 3D complexity. Such limitations restrict the potential for hydrogel-based technologies, especially with regards to patterning microvasculature in engineered tissues. Using microfibers made with a nontoxic, thermoresponsive polymer, I patterned complex, tortuous, microscale channel networks in hydrogels that enable fluidic access to the full gel volume. Central to my research has been the application of 3D microchannel networks as exchange vessels, a necessary advancement on the path to artificial tissues that are not limited by diffusive transport. I patterned hydrogels using sacrificial, thermoresponsive templates to form channel networks whose size and architecture approached those of natural capillaries. Within these microchannels, I cultured endothelial monolayers that remained viable for over three weeks and exhibited functional barrier properties. Endothelialized microchannels were also cultured within hydrogels containing suspended fibroblasts, which remained viable at 14 days post-seeding, thereby demonstrating their potential for integration into more complicated artificial tissue systems. The highly anisotropic geometry of the microchannels is also advantageous for designing drug delivery vehicles, as it creates fluidic connections throughout the gel volume which can tune its transport properties while sacrificing very little solid material. By patterning interpenetrating polymer hydrogels with full-thickness microchannel networks, I created devices with accelerated drug-release times without sacrificing payload. Initial data suggests that patterned interpenetrating hydrogels loaded with therapeutics can be used to effectively treat partial-to-full thickness burn wounds. This work represents early steps in overcoming the mass transport barriers preventing the development of thick artificial tissues and the advancement of hydrogels as regenerative technologies.