2025 Theses Doctoral

Sensing and Treatment Modalities Toward a Closed-Loop Wound Healing System

Jakus, Margaret Annaleura

Chronic wounds pose a major threat to healthcare systems, and can be caused by a variety of factors, from diabetes to battlefield injuries. Traditional wound care does not account for a patient’s specific circumstances, and is only effective in up to 50% of cases. As such, there is a growing need for smarter wound healing technologies that can be used in a wide array of settings, from low resource hospitals to at home, and that provide customized treatments that can be administered without trained professionals. In this dissertation, we detail the development of technologies for customized treatments to accelerate wound healing.

In Aim 1, we used a water-activated, electronics-free dressing to accelerate wound healing in a diabetic mouse model. Electrical stimulation has previously been used to improve wound healing; however, common dressings often require that the wearer be physically connected to large benchtop electronics, are expensive to produce, and/or contain toxic elements. We demonstrated that this device, developed by our collaborators, accelerated time to wound closure by approximately 30%, on par with other, more complex devices, and further improved angiogenesis, collagen intensity, and reduced inflammation when compared with the controls. Furthermore, we demonstrated that this device is biocompatible and does not affect mouse behavior; the device does not heat up when activated, and did not impact the distance the mice traveled during a ten-minute measurement window. We are exploring additional use cases for this technology to further accelerate wound healing, including through iontophoresis, the use of electric currents to transmit drugs through the skin.

In Aim 2, we developed ultrasound-responsive, perfluorocarbon-based nanoparticles for spatiotemporal control of payload release. Focused ultrasound can be used to selectively and noninvasively trigger perfluorocarbon vaporization, releasing the payload from the triggered nanoparticles without disrupting nearby nanoparticles. Furthermore, these systems can be designed to remain stable when not in use, and to then release their payloads at safe acoustic pressures. We developed PLGA-coated, perfluorocarbon-based nanoparticles of various sizes, geometries, and with payloads. We used B-mode imaging and acoustic signal analysis to determine the acoustic thresholds of these nanoparticles, and then incorporated the nanoparticles into gels, from which we measured their payload release upon exposure to focused ultrasound. Initial in vivo testing of these nanoparticles showed that they remained stable until application of focused ultrasound. Such a technology has the potential to customize healing treatments, releasing specific payloads when and where they are most needed.

In Aim 3, we integrated components of a closed-loop wound healing system in vitro and in vivo. This system comprises an ultrasound bandage to provide both sensing of the wound and treatment to the wound, sensors to analyze the wound state, drug delivery depots to selectively release payload into the wound, and a machine learning algorithm to guide treatment based on sensor values. We developed ultrasound-responsive microcapsules to selectively release drugs, and tested these in vitro and in a diabetic mouse wound model. We tested the ultrasound-responsiveness of alginate-acrylamide hydrogels in vitro and in vivo. We additionally tested versions of the ultrasound bandage and lactate sensors in vivo, and tested various combinations of these technologies. We tested the release of growth factor from the hydrogels using focused ultrasound while collecting ultrasound images for analysis, and demonstrated that a commercial-grade ultrasound probe can differentiate between wound healing states, which suggests that this technology will be translatable beyond the lab. Future work could demonstrate a truly closed-loop system, and could move beyond the diabetic mouse model, to one more similar to healing in humans.

In this dissertation, we demonstrated technologies that can, individually or together, be used to improve wound healing in a variety of settings. Overall, this work advances the field of wound healing and demonstrates a suite of tools that can be used to provide customized treatments based on a patient’s needs, towards a vision for closed-loop wound healing systems.