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Acoustic Biosensors for Noninvasive Imaging of Molecular Processes


Jin, Zhiyang (2024) Acoustic Biosensors for Noninvasive Imaging of Molecular Processes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/b51h-q307.


Understanding biology in its native context has been a major scientific endeavor. Yet, it is challenging to visualize cellular dynamics at the molecular scale in the context of a living organism at the macroscopic scale. Ultrasound imaging represents a promising candidate to address this challenge, with its unique advantages of large imaging volume, deep penetration, and good spatiotemporal resolution. However, ultrasound was historically limited in retrieving molecular information that biology carries. Until very recently, the discovery of the first ultrasound-interacting biomolecules, gas vesicles (GVs), established a connection between connect cellular function and ultrasound signals, which later enabled ultrasound imaging of gene expression and thus the location of GV-expressing cells. Going beyond location tracking, this thesis describes the engineering of GV-based acoustic biosensors that made it possible to noninvasively image the dynamics of cellular signaling in living organisms.

GVs are genetically encoded intracellular air-filled “balloons” that are encapsulated by protein shells. The acoustic biosensor design leverages the GV surface protein GvpC, which controls GVs' ultrasound scattering by setting the stiffness of their protein shell. We developed the first acoustic biosensors by engineering GvpC to change its confirmation and thereby GVs’ ultrasound contrast in response to the activity or concentration of specific molecules. Specifically, we first built the biosensors for three different types of enzymes and demonstrated noninvasive imaging of enzyme activity inside probiotic cells in the mouse colon in vivo. Next, we engineered the acoustic biosensors for calcium, a ubiquitous signaling molecule that is essential in many cellular processes (e.g., neural activity). With the first generation of this calcium sensor for ultrasound, we demonstrated imaging of receptor-specific calcium signaling deep inside the mouse brain through the intact skull noninvasively, which opened up the possibility of whole-brain neuroimaging that can lead to many breakthroughs in neuroscience. Last, we established a high-throughput engineering platform to develop all these GV-based imaging agents in a much shorter time frame. Collectively, this thesis presents the first demonstration of noninvasively imaging dynamic cellular signaling with acoustic biosensors and the feasibility of efficiently improving them for potential real-world applications with our engineering pipeline, opening up a new route towards understanding biology across scales.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Ultrasound, molecular imaging, gas vesicles, biosensors, high-throughput screening
Degree Grantor:California Institute of Technology
Division:Engineering and Applied Science
Major Option:Medical Engineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Shapiro, Mikhail G.
Thesis Committee:
  • Wang, Lihong (chair)
  • Lester, Henry A.
  • Gradinaru, Viviana
  • Shapiro, Mikhail G.
Defense Date:18 April 2024
Funding AgencyGrant Number
NIH BRAIN1R01NS120828-01
Record Number:CaltechTHESIS:05152024-052419062
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Ch.1 adapted for Ch.2 adapted for Ch.3 adapted for Ch.4 of the article included for Ch.1 of the article included for Ch.1 of the article included for Ch.1 of the article included for Ch.1
Jin, Zhiyang0000-0002-4411-6991
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16384
Deposited By: Zhiyang Jin
Deposited On:28 May 2024 18:07
Last Modified:04 Jun 2024 18:43

Thesis Files

[img] PDF (Full thesis) - Final Version
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[img] Video (MPEG) (Video 3-S1. Receptor-specific calcium signaling in vivo) - Supplemental Material
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[img] MS Excel (Table 3-S2. List and sequences of genetic constructs used in Chapter 3) - Supplemental Material
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[img] Video (MPEG) (Video 4-S1: Example Acoustic Plate Reader scan) - Supplemental Material
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[img] MS Excel (Table 4-S1,2,3,4) - Supplemental Material
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