Highly Biocompatible Extracellular Matrix-based Adhesive Hydrogel for Neural Interfaces

Introduction:: Neural interfaces are the devices that enable communication between the nervous system and external devices. Neural interfaces have a wide range of potential uses such as neuroscience research, and medical and robotic applications. However, one of the major challenges facing neural interfaces is their biocompatibility and sustainability over long periods. The electrodes of the neural interface, that can detect or stimulate neural signals, need to be secured in place without damaging the site to maintain the device's stability and functionality. Also, the implantation of foreign devices may trigger an immune response, leading to inflammation and tissue damage. The damaged nervous tissue may lose its function and the fibrosis formed from inflammation may interrupt the signal from the nervous system. To overcome these limitations, the extracellular matrix-based adhesive hydrogel can play a crucial role in anchoring the electrodes in a biocompatible manner. The extracellular matrix-based hydrogel can help mitigate biocompatible effects by reducing the foreign body response and promoting tissue integration. Through the decellularization process, the extracellular matrix-based hydrogel can mimic the composition and structure of the extracellular matrix (ECM) and create a microenvironment that is more conducive to tissue repair and regeneration. Furthermore, by engineering the extracellular matrix-based hydrogel to achieve adhesiveness, it can integrate the nervous tissue and electrode together.


Materials and Methods:: Tracheal mucosa decellularized extracellular matrix (tmdECM) was used as the basal material. The porcine tracheal mucosa was decellularized using sodium dodecyl sulfate, Triton X, isopropyl alcohol, peracetic acid, and ethanol to get rid of cellular components. The obtained tmdECM was lyophilized to granule form, which was later dissolved in solution form. To achieve adhesiveness, the catechol amino acid of L-3,4-dihydroxyphenylalanine (DOPA) was synthesized using a ruthenium/sodium persulfate (Ru/SPS) system. The tyrosine from tmdECM oxidized to DOPA by photoexcited ruthenium. The tmdECM solution was neutralized and put in a 58 °C water bath for denaturation. The denatured solution was then gelatinized into a low-viscosity liquid form, mixed with 1/10 mM Ru/SPS, and exposed to visible light (450 nm).
The biological, rheological, and mechanical properties of the extracellular matrix-based adhesive hydrogel were evaluated. Proteomic and gene ontology analyses were performed to evaluate the biological factors of tmdECM. Rheological and mechanical analyses were conducted using a rheometer and universal testing machine (UTM) to assess adhesiveness.

Results, Conclusions, and Discussions:: In this research, we have developed a highly biocompatible extracellular matrix-based adhesive hydrogel that can serve as a conduit for connecting electrodes to nervous tissue in neural interfaces. The tmdECM contained a high amount of collagen and other various proteins that can mimic the composition and structure of the native extracellular matrix and create a microenvironment. Our gene ontology analysis indicates that tmdECM provides a range of benefits in relation to tissue development, wound healing, and response to axon injury, among other biological functions. Adhesiveness was successfully achieved through the DOPA synthesis using a Ru/SPS system. After exposing the light to the mixture of gelatinized tmdECM and Ru/SPS, the solution crosslink to the sticky hydrogel. Rheological analysis was performed at each stage of the hydrogel preparation, which confirmed that the DOPA-synthesized hydrogel achieved the desired level of adhesiveness. Finally, we quantified the shear strength as an adhesiveness test, which demonstrated that the slide glasses attached using extracellular matrix-based adhesive hydrogel required a force of approximately 12.2 N to be displaced.
In this study, we have demonstrated the potential of the extracellular matrix-based adhesive hydrogel as a promising solution for neural interfaces. The extracellular matrix-based adhesive hydrogel exhibited promising biological, rheological, and mechanical characteristics that could improve the stability and functionality of neural interfaces. Our results indicate that the tmdECM material can mimic the natural microenvironment of the extracellular matrix, promoting tissue repair and regeneration. The resulting adhesive hydrogel confirmed its suitability for securing electrodes to neural tissue without damaging the site. Our findings suggest that extracellular matrix-based adhesive hydrogel could potentially reduce the foreign body response and promote tissue integration, leading to improved stability and functionality of neural interfaces. Overall, our study contributes to the development of biocompatible and sustainable neural interfaces. Furthermore, as adhesive biomaterials are emerging for a promising potential medical application due to their ability to adhere to biological tissues without causing significant damage or inflammation, the extracellular matrix-based adhesive hydrogel has the potential to be used for various medical applications such as wound healing, drug delivery, and tissue engineering.

Acknowledgements (Optional): : This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2022M3C1A3081359) and by the National Research Foundation of South Korea (NRF) grant funded by the Ministry of Science and ICT (No. 2021R1A2C2004981)

References (Optional): : [1] Kim, Hyeonji, et al. "Extracellular matrix-based sticky sealants for scar-free corneal tissue reconstruction." Biomaterials 292 (2023): 121941.
[2] Tian, Gongwei, et al. "A Nonswelling Hydrogel with Regenerable High Wet Tissue Adhesion for Bioelectronics." Advanced Materials (2023): 2212302.