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Zhang et al. Soft Sci 2024;4:39 https://dx.doi.org/10.20517/ss.2024.34 Page 19 of 28

Adewole et al. at the University of Pennsylvania developed “living” electrodes for micro-tissue-engineered
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neural networks (μTENN) . The electrodes are fabricated by forming agarose microcolumns with designed
geometries in custom acrylic molds. These microcolumns solidify and form hollow structures upon cooling.
The in vivo experiment shows that the electrodes optically modulate synaptic transmission and neural
activity as illustrated in Figure 11A and B.

Park et al. at the MIT developed a multifunctional sensing and stimulation platform based on a soft
hydrogel matrix, as shown in Figure 11C and D . The elastic modulus of the device in its dry state is three
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orders of magnitude higher than in its swollen state, which allows the device to be implanted into deep
brain structures directly. Also, benefiting from the low elastic modulus after swelling and the outstanding
biocompatibility, the issue of chemical and mechanical mismatch between the synthetic device and neural
tissue can be addressed. In addition, minimal stress and strain in the surrounding neural tissue was induced
with micro-movements of the brain relative to the skull. As a result, minimum tissue damage associated
with brain micro-motion after implantation was observed.

For implantable devices, stability is one of the most effective approaches for diagnosing and treatment of
various neurological disorders and diseases. However, in the moist physiological environment, an inferior
interface stability between conductive neural tissue and electrodes is a challenge and the instability becomes
more severe during electrical stimulation. For example, PEDOT:PSS coating can continuously expand and
lead to structural damage, such as cracks and coating delamination within the hydrogel layer at the
interface. This phenomenon will result in a significant deterioration in electrochemical performance, as well
as brain scarring and inflammatory reactions. These challenges limit the reliability of neural disease
diagnosis and treatments. Zhang et al. proposed a strategy to overcome the issue by chemically grafting a
functional long-chain polymer, poly (styrene sulfonic acid-co-4-vinylpyridine) [Poly(SS-4VP)], onto a
metal substrate . In detail, they electrochemically deposited the conductive polymer PEDOT and further
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chemically cross-linked PEDOT to create a PEDOT:Poly(SS-4VP) interpenetrating network hydrogel, as
shown in Figure 11E and F. This method not only enables the formation of a resilient conformational
interface between the conductive hydrogel and rigid electrodes but also provides mechanical flexibility, high
conductivity, and long-term electrochemical stability. Furthermore, the research team implanted
bioelectrodes modified with PEDOT:Poly(SS-4VP) hydrogel into the brains of living organisms. Under low-
voltage stimulation, the conductive hydrogel/electrode interface remained stable, which provides a
foundation for stable electrophysiological recording and electrical stimulation.

LFP is crucial and attritive in the scientific research to investigate neural dynamics. These interfaces
enhance the ability to capture synchronized activity from neuronal populations, which provides insights
into the intricate neural circuits that underlie cognitive processes and behaviors. The development of
flexible, biocompatible hydrogel electrodes addresses challenges related to mechanical mismatch between
the devices and soft neural tissues, minimizing tissue damage during brain micro-movements. Innovations
such as living electrodes and multifunctional sensing platforms are paving the way for more effective neural
recordings and stimulation, while addressing stability issues inherent in moist physiological environments.
By enhancing interface stability through advanced polymer grafting techniques, researchers are creating
resilient, conductive networks that maintain their electrochemical performance over time. This stability is
essential for reliable diagnostics and therapeutic interventions in various neurological disorders. Overall,
implantable hydrogel interfaces for LFPs represent a promising frontier in neurotechnology, with the
potential to revolutionize our understanding of brain function and the treatment of neurological conditions.