Ultrasound-Responsive Hydrogels for On-Demand Sustained Drug Delivery

The primary goal of this proposal is to demonstrate a new and readily translated technology to improve treatments of segmental bone defects. This research explores a new method for bone regeneration using an innovative ultrasound responsive hydrogel drug delivery system to improve bone healing rates and functional outcomes for wounded Warfighters and Veterans. This proposal addresses the Sustained Release Drug Delivery topic area described in the Peer Reviewed Medical Research Program Discovery Award Program Announcement and addresses the area of encouragement for research into techniques to provide sustained release of drugs in tissue repair applications, such as bone or nerve regeneration or vision restoration. Injuries creating segmental long bone (i.e., femur) and calvarial (i.e., skull) defects are common after trauma and combat injuries leaving civilians and Soldiers with significant pain, physical deformities, and functional limitations. Reconstruction of large long bone defects and the craniofacial skeleton remain some of the most challenging clinical dilemmas facing Soldiers with battlefield injuries as well as civilians with craniofacial trauma and cancer reconstruction. Despite improvements in current technologies, off-the-shelf bone substitutes are still plagued by resorption, inflammation, and infection. Donor bone grafts are limited in availability and create a secondary bone defect. Exogenous stem cell-based approaches to bone repair have yet to make substantial clinical impact as a result of unresolved performance, safety, and regulatory challenges. Thus, a significant need exists for an alternative solution that upregulates progenitor cell recruitment and directs differentiation. This study seeks to address this issue through the development of an innovative ultrasound responsive hydrogel drug delivery system for controlled and sustained delivery of bone morphogenic protein (BMP) to enhance the regeneration of large-scale, segmental bone defects. Upregulating osteogenesis and bone regeneration is of particular interest in the design of therapies for bone defects, spinal fusion, and skeletal reconstruction, which are often associated with trauma, cancer, or infection common in our military Service population. A preferred embodiment of this technology would involve localized implantation or injection of the BMP containing hydrogel followed by application of an ultrasound source providing high spatiotemporal resolution for activation. Repeated focused ultrasound activation produces a defined, time resolved dose, providing sustained and controlled induction of osteogenesis and bone regeneration. Focused ultrasound is a safe and non-invasive external stimulus, allowing for deep tissue penetration, accurate targeting and real-time visualization of the ongoing process. BMP is a key mediator of bone development and repair and is already FDA-approved for the treatment of lumbar spine fusion and open tibial shaft fractures. BMP is attractive as a potential therapy for the reconstruction or regeneration of damaged tissues as it is a potent regulator of bone repair processes but current state-of-the-art delivery techniques offer little control of dose and timing leading to well-documented severe side effects. This technology represents a paradigm shift from current methods of delivering diffusible BMP by injection or eluting sponge where there is little spatial or temporal control of drug delivery. The use of uncontrolled differentiation factors such as BMP in the reconstruction of bone defects often results in high rates of heterotopic ossification, or abnormal bone growth in soft tissue, a side effect that is very detrimental for the patient and costly for healthcare providers to resolve. This technique, which leverages focused ultrasound stimulation to control the location, dose, and timing of BMP delivery is attractive therapeutically as it provides precise control of sustained delivery. The use of BMP, which