Spatiotemporally-controlled release of regenerative growth factors

Exogenous growth factor therapy has been explored as a treatment for regenerating soft tissue and bone. For example, angiogenic growth factors can promote revascularization in preclinical models of ischemic, cardiovascular disease. During wound healing, regenerative growth factors are expressed in specific spatial and temporal patterns. However, growth factor delivery using conventional injections or implantable hydrogel scaffolds does not enable spatiotemporally-controlled delivery. This critical limitation has decreased the therapeutic efficacy and increased the systemic side effects associated with growth factor-based therapies in tissue regeneration.

We are exploring two approaches where ultrasound is used to control release of growth factors in both space and time. First, we have designed acoustically-responsive scaffolds (ARSs), which are hydrogel scaffolds doped with a sonosensitive emulsion containing angiogenic growth factors. Release of the growth factor from the emulsion, and ultimately angiogenesis, is controlled non-invasively using focused ultrasound via a mechanism termed acoustic droplet vaporization (ADV). Second, we are using ultrasound in combination with cells containing heat-activated gene switches to control the expression of angiogenic and osteogenic factors. This enables patterning of blood vessels and bone using ultrasound-based hyperthermia.

Collaborators: Renny Franceschi, Ph.D. (UM Dental School), Paul Michael Grossman, M.D. (UM Cardiology), Oliver D. Kripfgans, Ph.D. (UM Radiology), Andrew Putnam, Ph.D. (UM BME), Jan Stegemann, Ph.D. (UM BME), Xueding Wang, Ph.D. (UM BME)

Targeted drug delivery

Many clinically-approved drugs, such as chemotherapeutic and immunosuppressive agents, can generate severe side effects due to off target effects. We are using a dual approach to increase localization of these drugs at their intended site. First, the drug is encapsulated into sonosensitive particles containing targeting ligands on the outermost shell of the particles. After the particles are injected in the blood, the targeting ligands enable the particles to bind and accumulate within the vasculature of the target region based on the recognition of specific endothelial markers. Second, focused ultrasound is used to release the drug contained within the bound particles.

Collaborators: Peter D. Higgins, M.D., Ph.D. (UM Internal Medicine), Morand Piert, M.D. (UM Radiology)

Microfluidic production of sonosensitive particles

Micron-sized particles such as microbubbles (i.e., ultrasound contrast agent) or emulsions are commonly used in diagnostic and therapeutic ultrasound applications. Conventional techniques to generate these particles (e.g., sonication, blending) yield polydisperse populations, which have certain disadvantages. For example, the responsiveness of a bubble or droplet to ultrasound is dependent on the size of the particle. Thus, polydisperse particles can have a broad range of responsiveness, which can impact therapeutic efficacy when using these particles as drug delivery vehicles. We are using microfluidic-based techniques to generate monodispersed particles, which yield a more uniform response during ultrasound exposure. This is especially critical for applications regarding the sequential delivery of multiple therapeutic payloads. Additionally, microfluidics enables the production of particles with unique morphologies that are unobtainable with conventional techniques.

Collaborator: Oliver D. Kripfgans, Ph.D. (UM Radiology)

Pulmonary delivery of antibiotics using liquid ventilation

Patients with cystic fibrosis and chronic obstructive pulmonary disease experience chronic bacterial respiratory infections, which can lead to morbidity and mortality. Treatment of these infections using systemic or aerosolized delivery of antibiotics is less than ideal because the drug cannot effectively reach the infection site. In collaboration with Dr. Keith Cook (Carnegie Mellon University), we are developing perfluorocarbon emulsions, containing antibiotics, that can be used in liquid ventilation to better treat respiratory infections. When instilled into the lung, these emulsions can penetrate into infected, pulmonary regions more effectively than systemic or aerosolized antibiotic.

Collaborator: Keith Cook, Ph.D. (Carnegie Mellon University BME)