Non-destructive imaging of neuronal forces with unprecedented sensitivity via the Vernier effect

• Applicant: Dr. Mitchell Harling, Ph.D.
• Subject Area: Biophysics ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 579701651

In this project, I will develop a novel ultrasensitive cellular force microscopy technique by leveraging the optical Vernier effect (VE), and then apply it to further our understanding of the mechanobiology of the central nervous system (CNS). This work will build on my background in optical coherence, interference and biophotonics. It will also benefit from the state-of-the-art optical equipment and in-house nano-fabrication facilities of my host lab (the Humboldt Centre for Nano- and Biophotonics), and the expertise of my supervisor (Prof. Malte C. Gather). Thus far, the ultrasmall forces exerted by CNS axons during growth and development have yet to be properly characterized due to current technology lacking the necessary force resolution. This is a pressing issue as recent research is revealing the importance of neuro-mechanobiology for axon extension and synaptic connections, i.e., the wiring of our nervous system, and as neurodegenerative diseases are expected to rise in prevalence with Germany’s aging population. Future medical interventions may be informed by neuro-mechanobiology research that cannot be performed with the currently available tools. The conventional technique of traction force microscopy has unsuccessfully been applied to resolve the forces generated by CNS axons where signal is often situated below measurement noise. My host lab has developed elastic resonator interference stress microscopy (ERISM), a non-invasive low light intensity technique which relies on optical interference to resolve cellular forces at the 10s of pN level. Although ERISM is an impactful innovation, preliminary experiments performed by my host lab show that its current state is not sensitive enough to detect CNS neuron forces. Here, building on ERISM, I propose a new technology called VEERISM that leverages the VE to extend the lower resolution limit of conventional cellular force microscopy techniques by an order of magnitude. Being the optical analog of the Vernier scale used on calipers, the VE has previously been applied to optical fiber interferometry to measure extremely small changes in gas pressure, temperature, and strain. However, it has not yet been used to measure ultrasmall cellular forces. Thus, the proposed approach signifies an original and significant advancement to the fields of force microscopy and mechanobiology, where its unprecedented sensitivity will be crucial for investigating the CNS, among other elusive problems.

• DFG Programme: Position