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Kim et al. Soft Sci 2023;3:18 https://dx.doi.org/10.20517/ss.2023.08 Page 3 of 19

both electrical and mechanical characteristics of the organic conductive hydrogel composites [42-44] . Although
a few cases of the application of injectable conductive hydrogels (ICHs) to diverse tissues for effective
treatment have been reported recently, on-cortex neural sensing with MRI compatibility has not yet been
performed [45-49] .

In this study, we developed an ICH composed of tyramine-conjugated hyaluronic acid (HATYR) and
poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) for MRI-compatible brain-
interfacing electrodes [Figure 1A]. Hyaluronic acid (HA) is a natural polymer abundant in the extracellular
[50]
matrix of the brain . In particular, chemically modified HA backbones (e.g., functionalization using
photocurable methacrylate, norbornene, and other phenolic groups) have been widely used for forming
biocompatible hydrogels as 3D bio-printable inks in tissue engineering and drug delivery carriers [45,51-56] .
Among them, the tyramine modification of HA can be adopted for the enzymatic crosslinking of polymers,
enabling their injectability in a time-dependent manner [57-62] . However, while there are few studies of
conductive HA hydrogels [63,64] , no study has focused on HATYR to engineer conductive materials for the in
vivo recording of electrophysiological signals. We hypothesized that the phenol groups (e.g., hydrogen bond
donors) in HATYR mediate additional intermolecular interactions with the sulfonyl groups (e.g., hydrogen
bond acceptors) of negatively charged PSS via hydrogen bonds, resulting in the reversible ionic crosslinking
of the polymers, HATYR and PEDOT:PSS, followed by conductive and injectable gelation as brain-
interfacing electrodes. Furthermore, stability both in electrical conductance and against hydrolysis was
achieved by the addition of glycerol in the hydrogel to meet the final ICH composition. The fully organic
ICH could be in situ patternable by syringe injections on a stretchable and flexible poly(vinylidene fluoride-
co-hexafluoropropylene) (PVDF-HFP) substrate layer to fabricate an MRI-compatible implantable ECoG
multi-channel electrode array on demand. In addition, the ICH-based ECoG array was highly
biocompatible and conformally adhered to the soft dura mater, and the T2-weighed MRI did not show any
artifacts [Figure 1B]. Furthermore, the array device was capable of successfully recording brain ECoG
signals from the visual cortex under light stimulation [Figure 1C], indicating the potential of MRI-
compatible hydrogel electrodes for further advanced ECoG arrays.

EXPERIMENTAL
Materials
HA at a molecular weight of 700 kDa was purchased from Lifecore Biomedical. Tyramine hydrochloride
(TYR) (98%), PEDOT:PSS (high-conductivity grade, 1.1% in H O), N-hydroxysuccinimide (NHS), and
2
glycerol were purchased from Sigma-Aldrich. Poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-
HFP: “FC-2145”) was purchased from 3M Korea. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)
hydrochloride (98%) was purchased from Tokyo Chemical Industry.

Synthesis of HATYR
The conjugation of tyramine moiety onto the HA backbone was performed using EDC/NHS chemistry, as
previously reported . First, 1 g of HA was weighed and dissolved at 1% (w/v) in 100 mL of pH 4.7 MES
[65]
buffer solution (0.1 M) at room temperature. Next, HA equivalent moles of EDC and NHS were added to
the mixture and allowed to dissolve for 30 min, after which HA equivalent moles of TYR were added and
stirred overnight in a nitrogenous environment. After overnight stirring, the conjugated solution was
dialyzed using a 6-8 kDa MWCO membrane in 100 mM NaCl dialysate for two days. After two days, the
dialysate was replaced with only deionized distilled water for 4 h, and HATYR was obtained via
lyophilization.