(14g) Mechanophore-Based Biomaterials for In Vivo Ultrasound-Triggered Light Generation

Mechanical forces are constructively generated in various biopolymer systems such as muscle development. In synthetic polymers, however, mechanical forces have been considered destructive until the development of mechanophores, the molecular units that selectively exhibit chemical responses to mechanical perturbations. To date, mechanophores have endowed polymers with a variety of stress-responsive properties including color changing, chemiluminescence and small molecule releasing, etc.

In contrast to the great success in materials science, the application of mechanophores in biomaterials was underdeveloped. Recently, our groups reported that a widely used non-invasive medical tool, high-intensity focused ultrasound (HIFU), is applicable to the activation of mechanophores. An interesting candidate—dioxetane mechanophore developed by Sijbesma and coworkers, attracted our attention for its ability to generate light from chemical energy via force-induced chemiluminescence. Under HIFU stimulation, blue light was clearly observed in our dioxetane containing polydimethylsiloxane (PDMS) materials at the focal spot of the ultrasound beam, providing excellent spatial and temporal control. This preliminary result opens a pathway towards biomedical applications of mechanophores such as non-invasive sono-optical treatments for optogenetics therapy. To achieve this final goal, we have two aims from the materials science perspective:

Aim 1: Improving light intensity.

In our previous experiments the light intensity did not meet the minimum threshold for optogenetics or other photo therapies. In our recent studies, we discovered that the poor solubility (max. ca. 0.5 wt%) of the energy acceptor, diphenylanthracene (DPA), was a limiting factor in the light intensity, presumably due to low energy transfer efficiency. By replacing DPA with a more soluble hexyl-functionalized DPA (HDPA), we can now incorporate up to 7.5 wt% HDPA into PDMS. As a result, the light intensity from HIFU activation was increased by 70-fold, up to 14 µW/cm². The increased intensity is higher than the reported threshold of many channelrhodopsins and thus is promising for optogenetics applications. For practical applications, however, small molecular energy accepters may diffuse out of the polymer network. We are chemically attaching DPA moieties besides the dioxetane mechanophore (within efficient energy transfer distance) and then crosslinking into the polymer network. With this chemical modification, we expect simultaneously immobilization of energy acceptor and maximization of light intensity.

Aim 2: Designing an injectable and biocompatible hydrogel.

In our previous design, none of the three components (polymer backbone, dioxetane mechanophore and DPA energy acceptor) are water soluble. For biomedical applications, we adapt the injectable hydrogel system reported by Hubbell and coworkers based on thia-Michael reaction between terminated multi-arm polyethylene glycol thiol (PEG-thiol) and diacrylate crosslinkers. In our preliminary study, a dioxetane mechanophore was crosslinked into a DMSO-swollen PEG gel network, which successfully generates blue light upon HIFU sonication. We are modifying the molecular structure of dioxetane and DPA derivatives to improve their water solubility without sacrificing the light intensity.