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Review
. 2025 Feb 21;16(1):1861.
doi: 10.1038/s41467-025-57016-0.

Bio-inspired electronics: Soft, biohybrid, and "living" neural interfaces

Dimitris Boufidis #  1   2   3 , Raghav Garg #  3   4 , Eugenia Angelopoulos  3   4 , D Kacy Cullen  5   6   7   8 , Flavia Vitale  9   10   11   12
Affiliations
Review

Bio-inspired electronics: Soft, biohybrid, and "living" neural interfaces

Dimitris Boufidis et al. Nat Commun. .

Abstract

Neural interface technologies are increasingly evolving towards bio-inspired approaches to enhance integration and long-term functionality. Recent strategies merge soft materials with tissue engineering to realize biologically-active and/or cell-containing living layers at the tissue-device interface that enable seamless biointegration and novel cell-mediated therapeutic opportunities. This review maps the field of bio-inspired electronics and discusses key recent developments in tissue-like and regenerative bioelectronics, from soft biomaterials and surface-functionalized bioactive coatings to cell-containing 'biohybrid' and 'all-living' interfaces. We define and contextualize key terminology in this emerging field and highlight how biological and living components can bridge the gap to clinical translation.

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Conflict of interest statement

Competing interests: D.K.C. is a scientific co-founder of Innervace Inc. and Axonova Medical Inc., which are University of Pennsylvania spin-out companies focused on the translation of advanced regenerative therapies to treat nervous system disorders. D.K.C. is an inventor on multiple patents related to the composition, methods, and use of specific technologies described in the paper, with the most relevant being US Patent 12,090,323 “Implantable living electrodes and methods for use thereof”. F.V. is a co-inventor on the US Patent 11,925,466 “Implantable devices using 2D metal carbides and nitrides (MXenes)”. These patents are owned by the University of Pennsylvania and/or the Department of Veterans Affairs. The remaining authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Bio-inspired Electronics.
Schematic overview of emerging strategies for bio-inspired electronics and neural interfaces.
Fig. 2
Fig. 2. Biomimetic and bioactive electronics.
a Schematic of biomimetic electrodes. Materials and designs are optimized for soft and flexible electronics. i. Interpenetration between neurons (β-tubulin; green) and mesh electronics (red) after co-injected into Matrigel for 14 days. ii. Illustration of flexible hydrogel probe design with multifunctional fiber units. iii. Ultra-thin electrode array for long-term recordings from the rat cortical surface. iv. Stretchable, high-density grid of Au-coated titanium dioxide nanowire electrodes in a silicone matrix. v. All-hydrogel bioelectronic interface based on a bi-continuous conducting polymer hydrogel. vi. Electronic dura mater (e-dura) with stretchable Au interconnects, soft Pt/silicone electrodes, and microfluidic drug delivery channel to restore locomotion in paralyzed rats. b Schematic of bioactive electrodes coated with biomolecules. i. SEM image of the cross-section of ECM-coated Au-parylene C microelectrode array. ii. Confocal fluorescent images showing neurite outgrowth, network formation (β-tubulin III; green), and neuronal nuclei presence (Hoechst; blue) for non-coated and collagen I/fibronectin-coated Au-parylene C neural electrodes. iii. Confocal fluorescent images showing reduced response of ECM-coated Au-parylene C microelectrodes at 2 mm below the cortical surface compared to silicon microelectrodes (GFAP – astrocytes: lilac; Iba1 – microglia: red; neurofilament – neuronal axons: green, Hoechst – nuclei: blue). Panels reproduced with permission from (a). i. ref. ., Nature; ii. ref. ., Nature; iii. ref. ., Nature; iv. ref. ., Wiley; v. ref. . Nature; and vi. ref. . Science; and (b). i. ref. ., PLOS; ii. ref. ., Nature; and iii. ref. ., Nature. Panels (a and b) created with BioRender.com and released under a CC BY-NC-ND 4.0 International license (creativecommons.org/licenses/by-nc-nd/4.0/deed.en).
Fig. 3
Fig. 3. Biohybrid electronics.
a Schematic of a biohybrid electrode, seeded with living cells. A cell-containing living layer serves as a biological interface between synthetic electronic components and the host tissue. b Neural stem cell-seeded probe (Hoechst staining nuclei; blue). c Microelectrode with a cell-laden biodegradable fibrin hydrogel coating (DAPI staining nuclei; blue). d Reduced glial scar of silicon-based electrodes with neural progenitor cells grown on a laminin coating. Reactive astrocytes are stained with GFAP (green) and cell nuclei with DAPI (blue). e Flexible biohybrid device seeded with myocytes forms neuromuscular junctions (AChE; pink) for functional nerve restoration after injury. No NMJs are observed in control devices without cells. Panels reproduced with permission from (b). ref. ., IOP; (c). ref. ., Frontiers; (d). ref. ., JNSPG; and (e). ref. ., Science. Panels (a and d) (top) created with BioRender.com and released under a CC BY-NC-ND 4.0 International license (creativecommons.org/licenses/by-nc-nd/4.0/deed.en).
Fig. 4
Fig. 4. Living interfaces.
a Schematic of a living electrode, composed of a hydrogel microcolumn seeded with a neuronal aggregate. Long-distance axonal pathways grow along the microcolumn for synaptic integration with the host tissue. b μTENNs as a platform technology for bidirectional all-optical living electrodes to record and modulate neural activity,. c Dopaminergic μTENNs for restoration of the nigrostriatal pathway in models of Parkinson’s Disease. d Host response at 1-month post-implantation of a Michigan microelectrode, an acellular hydrogel micro-column, and a living electrode, immunolabeled for microglia/macrophages (IBA-1; red) and astrocytes (GFAP; purple). Panels reproduced with permission from b. ref. ., Wiley, and ref. ., Science; c. ref. ., Wiley; and d. ref. ., Wiley. Panel a created with BioRender.com and released under a CC BY-NC-ND 4.0 International license (creativecommons.org/licenses/by-nc-nd/4.0/deed.en).
See this image and copyright information in PMC

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