Turning tissues into conducting matter.
Item Type Article
Authors Inal, Sahika
Citation Inal, S. (2023). Turning tissues into conducting matter. Science, 379(6634), 758–759. https://doi.org/10.1126/science.adg4761 Eprint version Post-print
DOI 10.1126/science.adg4761
Journal Science (New York, N.Y.)
Rights This is an accepted manuscript version of a paper before final publisher editing and formatting. The version of record is available from Science (New York, N.Y.).
Download date 2024-01-12 22:51:51
Link to Item http://hdl.handle.net/10754/689151
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M AT E R I AL S SC I E N CE
Turning tissues into conducting matter
An electrically conducting soft polymer is synthesized within living tissue
By Sahika Inal
Electronic devices implanted into a tissue, close to neurons of interest, are meant to ex- change signals with the nervous system. Such bioelectronic devices not only facilitate the study of neural communication but these de- vices can also hijack neural circuitry in a thera- peutic approach known as bioelectronic medi- cine. The success of these applications relies on the robustness of the implanted devices and their compatibility with the body. Conven- tional bioelectronic devices comprise electron- ic wires or solid substrates that carry conduct- ing films. Their rigidity can damage soft tissues and reduce the implant’s long-term perfor- mance. On page XXX of this issue, Strakosas et al. (1) address the mechanical mismatch be- tween soft and wet biological matter and sol- id-state electronics and describe an approach that generates electronics directly inside a tis- sue without a substrate, with very little dam- age to the tissue.
State-of-the-art implants are mostly made of stiff and hard materials, and the insertion site in human tissues can undergo inflamma- tion. This results in a new microenvironment, with altered cell types and densities that may harm the implant’s electrical properties and disrupt its contact with target neurons (2) (see the figure). However, with a minimized foot- print and better structural and mechanical compatibility, the implant could appear as less
“foreign” to the tissue. The substrate of im- planted electronic devices is the solid shuttle onto which electrodes are fabricated. It consti- tutes the bottom part of an electronic chip, so it carries the electronics. It is the passive com- ponent of the device and imparts mechanical rigidity. Flexible polymeric substrates, coatings such as elastomers, hydrogels with softness matching that of the tissue, and mechano- adaptive materials that change stiffness upon implantation are means to overcome mechan- ical mismatches and improve device longevity (3). Electrode materials can also be more me- chanically compliant. Semi-conducting poly-
mers, such as poly(3,4-
ethylenedioxythiophene) (PEDOT), are soft al- ternatives to inorganic counterparts. They have an inherently low electrochemical im- pedance (resistance to current flow), which eases bidirectional communication with neu-
rons. Electrodes made of soft conducting pol- ymers can be patterned on ultra-thin sub- strates (4) and even on substrates that dis- solve in the body over time (5), although the former is primarily designed to conform hori- zontally on top of tissues or to wrap around (rather than penetrate) a tissue.
Unfortunately, devices that are too tissue- compliant, with small dimensions and soft ma- terials, are problematic because they can buckle at the tissue surface, making them hard to implant. One solution is to remove the sub- strates altogether so that the mechanical property mismatch of the implant with that of the tissue is no longer a design consideration.
For example, a mesh-like, porous construct that embeds the electronics has enough vis- cosity to be injected through a syringe and can also provide space for cells to invade the elec- tronics after implantation (6).Removing sub- strates altogether may also help overcome a major device failure mode-- the mechanical or chemical degradation of the physical device. A typical implant has at least two layers of de- posited films, one of which is the patterned electrode on the substrate (the other is an in- sulating film). Although this increases its com- plexity (which is required to eliminate water contact with certain parts of the implant) the layers create degradation pathways through delamination, cracks, water ingress, and redox reactions. These can be mitigated if there are no substrate or solid film coatings.
Semiconducting polymers can be generat- ed in an aqueous medium as well as in a living tissue if conditions are conducive for polymer- ization (7). One way to polymerize them relies on electrical fields applied through an elec- trode. PEDOT films, for example, have been generated on a gold electrode tip that was al- ready implanted in a rat brain. (8) However, this process, known as electropolymerization, requires a substrate and application of a cur- rent. The electropolymerization can also cause scar tissue formation, which is attributed to the harsh deposition conditions necessary to make a low-impedance polymer. One solution is to use a substrate- and current-free route that supports enzymatic polymerization. This process has been demonstrated using a perox- idase enzyme and hydrogen peroxide (H2O2), two compounds inherent to living organisms.
A mixture of a monomer, an acid, and H2O2
was injected into a living animal (the nema- tode Caenorhabditis Elegans) that was genet-
ically engineered to express the peroxidase enzyme (9). When injected close to neurons that secrete peroxidase, the mixture turned into a solid, conducting film. Another method involves injecting a solution of an elasto- mer/metal particle composite into a target tis- sue, where it solidifies to form a conductive tissue interface (10). This strategy, however, requires a technique for noninvasive align- ment of the mixture in the tissue.
Strakosas et al. demonstrate an implant fabrication method implantation method that integrates conducting polymer-based gels di- rectly inside genetically unmodified tissues.
The novelty lies in the injected cocktail, which contains redox enzymes that break down me- tabolites already present in the target tissue (see the figure, right). This reaction generates H2O2, which then acts as the oxidant of the en- zymatic polymerization that is catalyzed by horseradish peroxide (another agent in the mix). The authors selected a monomer that bears certain functional units so that as it pol- ymerizes, it also reacts with the primary amines of a biocompatible polymer, poly-L- lysine, which is also in the injected mixture.
Crosslinking of these polymers results in a sta- ble, soft conducting gel rather than a brittle conducting film. The mixture also contains polyvinyl alcohol, which inhibits the aggrega- tion of its constituents and renders the gel in- jectable. Using the metabolites lactate or glu- cose present in the tissue, gel polymerization proceeded in the brain, fin, and heart of living zebrafish as well as in living leeches and isolat- ed mammalian tissues, showing the universal applicability of the approach. In all cases, the volume of the conducting gel extended be- yond that of conventional, two-dimensional implants and blended into the tissue. Three days after gel polymerization in the brain, fish behavior did not show abnormalities, and the injection site had no signs of tissue damage.
Future work may address shortcomings and leverage opportunities. For example, Strakosas et al. implanted flexible metallic electrodes to contact the gel. Making contact should instead involve a wireless method. It will also be a challenge to grow the gel pre- cisely in a targeted area. This will require in- jecting known amounts and limiting diffusion of the mixture to off-target regions. The acces- sibility of human tissues to a syringe will differ from the animal models studied by Strakosas et al., which may increase the invasiveness of Biological and Environmental Science and Engineering
Division King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900, Saudi Arabia;
Email:[email protected]
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the approach and cause implantation damage.
Another critical point concerns the chronic use of the platform. During extended periods, the body's products can chemically alter the na- ture of the conducting gel, which could trigger decomposition and/or release cytotoxic by- products. Safety and stability analysis over long periods will be essential to answering whether such technology is useful for chronic implantations. However, the strategy of Strakosas et al. suggests that any living tissue can turn into electronic matter and brings the field closer to generating seamless bio- tic/abiotic interfaces with a potentially long lifetime and minimum harm to the tissue.
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10.1126/science.adg4761