Modular injectable hydrogel designs based on mixed-shell polymeric micelles with thermosensitive patchy domains

NON-TECHNICAL SUMMARY: Hydrogels are three-dimensional networks that can hold large amounts of water. Thermogels are solutions at room temperature that become hydrogels at body temperature. This temperature triggered gelation is advantageous in biomedical applications since the hydrogel can be introduced in the human body by simple injection without the need for surgery. However, currently available thermogels lack design flexibility that enables the control over hydrogel properties, such as stiffness, degradability and biofunctionality. This challenge with current thermogels stems from the formation of poorly-defined network structures after injection. To overcome this problem, this project explores a novel thermogel design using polymeric nanoparticles that form “sticky” patches on their outside surface due to the change in temperature from room temperature to body temperature, which allows them to stick together to form well-defined hydrogel networks. The developed thermogels are expected to be applied for a wide range of human healthcare applications such as localized drug delivery, soft tissue fillers, chronic wound dressings and tissue engineering scaffolds to repair damaged tissue. The project also integrates educational activities with the research efforts by offering hands-on experience and research opportunities to first and second year undergraduate students in order to close the gap between science/engineering education and interdisciplinary biomaterials research and train the next generation of researchers. TECHNICAL SUMMARY: Despite the unique gelling behavior of thermogels, in which body heat is used to induce a sol-gel transition, the limited control over hydrogel properties such as mechanical properties, degradability and biological functionality remains a challenge, hampering their medical applications. This project aims to establish a modular design approach for thermogels that show controllable gelation/dissolution behaviors and biological functionalities. The central hypothesis is that fine-tuning of material properties can be achieved by developing polymeric micelles with well-defined multiple binding domains (patchy domains) that can modulate intermicellar interactions in response to temperature and biological stimuli as well as provide binding sites for bioactive motifs. This hypothesis has been formulated based on the PI’s recent reports on polymeric micelles with a shell containing phase-separated thermosensitive domains, which served as “patches” to induce percolated 3D network formation resulting in gelation at 37oC. The rationale that underlies the proposed research is that the developed technology will provide a new material design for functional in-situ gelling systems that will be broadly applicable in biomedical technologies, such as controlled drug delivery systems and scaffolds for tissue engineering. The hypothesis will be tested by pursuing three aims: 1) Establish design criteria for polymeric micelles with thermosensitive patchy domains that assemble into hydrogels with controlled mechanical properties, 2) Control dissolution of patchy micelle-based thermogels by biologically relevant stimuli, and 3) Develop a facile approach to introduce bioactive motifs in the patchy micelle-based thermogels. Upon the completion of the proposed research, we will have successfully established a novel avenue to design thermogelling systems with fine-tuned material properties, which meet the requirement for clinical translations. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.