Ultrasound responsive hydrogels for stimulated combinatorial drug delivery

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Project Summary This research explores a new and innovative class of ultrasound responsive hydrogels for controlled and sustained delivery of Vascular Endothelial Growth Factor (VEGF) and Bone Morphogenic Protein (BMP) to improve angiogenesis, osteogenesis and healing of segmental bone defects. VEGF and BMP eluting materials and injections have been explored extensively to promote bone regeneration and improve outcomes but the uncontrolled release of these cytokines in bone defects often leads to severe side effects such as postoperative inflammation, heterotopic bone formation, osteoclast-mediated bone resorption, inappropriate adipogenesis and cervical swelling. To address this challenge, we propose rational design of a next generation ultrasound controlled drug delivery system, composed of a VEGF and BMP containing polyethylene glycol (PEG) hydrogel crosslinked by ultrasound sensitive, Diels-Alder (DA) groups. The ultrasound sensitive DA moieties will serve to attach VEGF and BMP-2 into a PEG hydrogel. These DA linkers have been designed such that they are stable under physiological conditions but efficiently undergo a retro reaction when stimulated by focused ultrasound (fUS) at the appropriate energy, resulting in retro DA reaction and VEGF and BMP-2 release. Focused ultrasound stimulation allows for precise spatiotemporal control of activation and repeated ultrasound stimulation allows for sustained delivery during critical periods of bone regeneration. The defined kinetics of retro DA cleavage reaction is the key enabling feature, allowing the hydrogel to remain stable for weeks at physiological conditions, but to undergo a retro reaction and release cytokines with the application of ultrasound energy in regimes that do not damage tissue or inactivate cytokines. There are two hypotheses addressed in this proposal; 1) The retro DA reaction kinetics will correlate with release rates cytokine release when stimulated by fUS, 2) The release of VEGF and BMP-2 can be controlled sequentially by tuning the fUS energy to the DA retro reaction barrier. The hypotheses are tested in two specific aims. Aim 1: Determine the influence of Diels-Alder cross-linkage composition on the fUS response of hydrogels and the associated release kinetics of VEGF and BMP-2. Aim 2: Explore fUS-mediated release of VEGF and BMP-2 from hydrogels on bone regeneration in segmental defect repair. The long-term goal is to develop a new and innovative controlled drug delivery system combining stimuli responsive hydrogels and fUS, to provide a minimally invasive, image guided method to spatially and temporally control the delivery of cytokines in complex, deep tissue wound environments. This technology represents a paradigm shift compared to current autograft or allograft reconstruction methods, which often fail due to poor integration of the graft or the use of BMP eluting sponges wherein the uncontrolled release often results in heterotopic ossification as a consequence of rapid BMP diffusion into surrounding tissue.