Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/1/23 → 8/31/25 |
Funding
- National Institute of Dental and Craniofacial Research: $361,317.00
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