| Author: | Zhao, Xinyi |
| Title: | Ultrasound-mediated precision stimulation of pancreatic β-cells for non-invasive glycemic control in type 2 diabetes |
| Advisors: | Sun, Lei (BME) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | Department of Biomedical Engineering |
| Pages: | 108 pages : color illustrations |
| Language: | English |
| Abstract: | Diabetes mellitus is a chronic metabolic disorder of widespread concern, with type 2 diabetes (T2D) constituting the majority of cases. While insulin therapy is central to T2D management, its limitations—including rapid degradation and the need for frequent injections—highlight the demand for non-invasive alternatives. This research advances non-invasive alternatives through the development of ultrasound (US)-mediated precision stimulation technologies targeting pancreatic β-cells. Central to this endeavor is achieving cell-type-specific insulin release while circumventing unintended activation of glucagon-secreting α-cells—a critical prerequisite for effective glycemic regulation. Microbubbles (MBs) are one of the most widely used ultrasound amplifiers. The first strategy established the critical importance of spatially confined energy delivery specifically to β-cells for effective ultrasound-mediated glycemic control. Utilizing MBs as ultrasound amplifiers, in vitro studies with RINm5F β-cells demonstrated that MB-conjugated ultrasound exposure induces rapid calcium influx via mechanosensitive ion channel activation, triggering insulin exocytosis. Validation in a murine transplantation model confirmed that MB-mediated ultrasound stimulation significantly attenuated acute hyperglycemia following glucose challenge. Systematic parameter optimization ensured biosafety with no evidence of cellular damage. This work provided essential proof-of-principle for β-cell-specific ultrasound modulation as a viable therapeutic concept. Nevertheless, the instability of MBs and challenges in their systemic delivery challenged their validation and therapeutic application in the T2D mice model. Sonogenetics, another innovative methodology also capable of achieving localized ultrasound energy amplification, more importantly, offers superior cell-type specificity and convenient in vivo targeting through systemic delivery. This strategy employed a pancreatic-tropic adeno-associated virus (AAV) carrying the large-conductance mechanosensitive channel (MscL) gene under the insulin promoter (AAV-INS-MscL). A single intraperitoneal injection achieved specific genetic modification of endogenous pancreatic β-cells in T2D mice. Subsequent non-invasive ultrasound stimulation elicited robust calcium influx and significant insulin release from these sonogenetically engineered cells, leading to rapid reductions in both random and postprandial hyperglycemia. Comprehensive assessments confirmed a favorable safety profile. This approach successfully demonstrated truly non-invasive, ultrasound-regulated glycemic control using endogenous β-cells in a T2D model, offering a clinically attractive paradigm requiring only a single injection for durable sensitization followed by repeated non-invasive treatments. In summary, this thesis established ultrasound-mediated precision activation of pancreatic β-cells as an effective and non-invasive approach for glycemic regulation in type 2 diabetes. The MBs-based approach validates the principle of spatially confined energy delivery, and the subsequent sonogenetic system pioneers truly non-invasive, ultrasound-regulated glycemic control in T2D models. Together, this sequential innovation provides a strong foundation for the development of novel, non-invasive stimulation-based therapeutic options for T2D patients who retain functional β-cells. |
| Rights: | All rights reserved |
| Access: | open access |
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