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Review
. 2024 Feb 21:12:1294238.
doi: 10.3389/fbioe.2024.1294238. eCollection 2024.

Resorbable conductive materials for optimally interfacing medical devices with the living

Marta Sacchi  1   2 , Fabien Sauter-Starace  1 , Pascal Mailley  1 , Isabelle Texier  1
Affiliations
Review

Resorbable conductive materials for optimally interfacing medical devices with the living

Marta Sacchi et al. Front Bioeng Biotechnol. .

Abstract

Implantable and wearable bioelectronic systems are arising growing interest in the medical field. Linking the microelectronic (electronic conductivity) and biological (ionic conductivity) worlds, the biocompatible conductive materials at the electrode/tissue interface are key components in these systems. We herein focus more particularly on resorbable bioelectronic systems, which can safely degrade in the biological environment once they have completed their purpose, namely, stimulating or sensing biological activity in the tissues. Resorbable conductive materials are also explored in the fields of tissue engineering and 3D cell culture. After a short description of polymer-based substrates and scaffolds, and resorbable electrical conductors, we review how they can be combined to design resorbable conductive materials. Although these materials are still emerging, various medical and biomedical applications are already taking shape that can profoundly modify post-operative and wound healing follow-up. Future challenges and perspectives in the field are proposed.

Keywords: bioelectronics; biopolymer; conducting polymers; conductive; implanted sensors; resorbable; tissue engineering; wearable sensors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Examples of applications in the field of medical devices requiring the use of resorbable conductive materials. Bioelectronic systems: brain: reproduced with permission, Copyright 2019, John Wiley and Sons (Xu K. et al., 2019). Heart: adapted with permission, Copyright 2023, the Authors, published by Science Advances (Chen et al., 2023). Skin: reproduced with permission, Copyright 2019, John Wiley and Sons (Wang Q. et al., 2019). Bone: adapted with permission, Copyright 2021, the Authors, published by PNAS (Yao et al., 2021). Muscle: adapted with permission from Huang et al. (2022), Copyright 2022, the American Chemical Society. Peripheral nerve: Copyright 2022, the Authors, published by Science Advances (Lee et al., 2022). Tissue engineering substitutes: Heart: adapted from Xu Y. et al. (2019), Copyright 2019, John Wiley and Sons. Skin: adapted with permission from Huang et al. (2018), Copyright 2018, the American Chemical Society. Spinal cord: adapted from Chen et al. (2022), Copyright 2022, Springer Nature. Bone: reproduced from eSilva et al. (2021), Copyright 2021, Springer Nature. Peripheral nerve: reproduced with permission, Copyright 2020, John Wiley and Sons (Park et al., 2020), created with BioRender.com.
FIGURE 2
FIGURE 2
Quantification and comparison of the mechanical modulus (Pascal, Pa), viscoelasticity (loss modulus/storage modulus, G″/G′), and water content (percentage of weight) of tissues with those of materials classically employed in bioelectronic devices and tissue engineering (i.e., metals, plastic, elastomers, and hydrogels). Data taken from literature. Mechanical modulus: brain (Hall et al., 2021), heart (Jacot et al., 2010), spinal cord (Karimi et al., 2017), nerve (Rosso et al., 2019), skin (Kalra et al., 2016), bone (Morgan et al., 2018), and materials classically employed in bioelectronic devices and tissue engineering (Tringides et al., 2022). Viscoelasticity: adapted from Tringides et al. (2022). Water content: bone (Surowiec et al., 2022), nerve (Anand et al., 1988), spinal cord (Mbori et al., 2016), skin (Téllez-Soto et al., 2021), heart (Eitel et al., 2011), and brain (Gottschalk et al., 2021). Created with Octave (software version 8.2.0) and adapted on BioRender.com.
FIGURE 3
FIGURE 3
Overview of main materials employed for the construction of resorbable substrates and scaffolds at the interface with tissues.
FIGURE 4
FIGURE 4
Overview of typical resorbable electrical conductors used in the design of bioresorbable conductive materials.
FIGURE 5
FIGURE 5
Examples of processes and strategies used to obtain resorbable conductive materials for their application in bioelectronics. (A) Interpenetrating networks of scaffolding and conducting polymers: conducting polymer PEDOT is chemically synthetized in a solution of modified hyaluronic acid (HA) polymer. The PEDOT:HA ink can be further photo-cross-linked to achieve non-water soluble resorbable conductive hydrogels (Leprince et al., 2023b). Adapted with permission from Leprince et al. (2023a), Copyright 2023, Elsevier, and Leprince et al. (2023b), Copyright 2023, the Royal Society of Chemistry. (B) Extrusion printing: (i) a bioprintable conductive ink is obtained by mixing thiolated gelatin and defect-rich MoS2 nano-assemblies. This ink can be further extrusion-printed as a stand-alone material to design wearable sensors. ii) Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS) images of a transverse cross-section of the hydrogel: gelatin scaffold (top), molybdenum (Mo, middle), and sulfur (S, bottom). Scale bar: 100 µm. Reprinted with permission from Deo et al. (2022), Copyright 2022, the American Chemical Society. (C) Fiber electrospinning and coating: electrospun PCL-collagen fibers coaxially reinforced with MWCNTs. i) Electrospinning parameters were modulated to deposit random or parallel fibers. ii) SEM images of the random (CPR, left) and aligned (CPA, right) MWCNT-reinforced fiber scaffolds. Scale bar: 1 μm. iii) TEM images of scaffolds without (left) and with (right) MWCNT fibers. Scale bar: 200 nm, inset: 100 nm. Adapted with permission from Ghosh et al. (2020), Copyright 2020, the American Chemical Society. (D) Laser sintering: laser sintering process to integrate zinc or iron microparticle inks into hydrogels (i). The microparticle ink (black) was spin-coated onto the hydrogel substrate (blue), and the device was washed in the appropriate solvent after laser sintering to reveal the pattern. ii) Scheme illustrating the sintering process. Scale bar: 10 μm. iii) Examples of Zn patterns obtained on different polymer substrates [PVA, PLGA, PVP, cellulose acetate (CA), and sodium carboxymethyl cellulose (Na-CMC)]. iv and v) Resistance and conductivity of Zn line patterns with different thicknesses (iv) and widths (v) onto PVA substrate. Adapted with permission from Feng et al. (2019), Copyright 2019, the American Chemical Society. (E) Photolithography micro-patterning: i) scheme depicting the microfabrication of silk sericin/PEDOT:PSS patterns onto a silk fibroin substrate. ii) SEM image of a complex resorbable device (ii, scale bar: 100 µm). iii) Conductive AFM image of a 50-μm-thick ink line deposited on a glass surface. Reproduced with permission, Copyright 2015, John Wiley and Sons (Pal et al., 2016). (F) Multiphoton lithography: i) schematics illustrating the composition of the organic semiconductor (OS) resin, featuring PEDOT:PSS, photoinitiator (3-(trimethoxysilyl)propyl methacrylate), dimethyl sulfoxide (DMSO), laminin, glucose oxidase, and the experimental setup for multiphoton lithography, resulting in the formation of 3D OS composite microstructures (OSCM) upon resin removal (depicted in yellow). ii) SEM images showcasing diverse conductive and bioactive complex microstructures. Scale bar: 20 μm. iii) Fluorescent microscopy images depicting laminin-incorporated OS (LM-OS) microstructures in green. Scale bar: 20 μm. iv) Epifluorescence microscopy images showing endothelial cells on LM-OS microstructures after 48 h of culture, stained with DAPI (red, indicating cell nuclei) and phalloidin (green, representing F-actin). Scale bar: 100 µm. Reproduced with permission, Copyright 2022, John Wiley and Sons (Dadras-Toussi et al., 2022). Created with BioRender.com.
FIGURE 6
FIGURE 6
Examples of resorbable wearable sensors. (A) Wearable resorbable tattoo sensors based on silk and graphene materials: i) silk fibroin (SF) was extracted from B. mori cocoons and mixed with Ca2+ and graphene aqueous suspension to obtain a conductive ink that could be used to directly write or mask-print conductive patterns onto a SF/Ca2+ cross-linked membrane. ii) The resistivity of the obtained devices was sensitive to strain, humidity, and temperature, which makes them useful in designing an electrocardiogram (ECG) recording device (a,b), or respiration (c,d) and temperature (e,f) sensors. Interestingly, the materials presented self-healing properties that made it possible to continue signal recording with conductive pattern fracture and healing. Reproduced with permission, Copyright 2019, John Wiley and Sons, (Wang Q. et al., 2019). (B) Strain sensors based on Galistan metal liquid tracks embedded in gelatin or PGS acrylate (PGSA) films: (i) the gelatin-based sensor was then applied on a volunteer subject to monitor elbow bending. (ii) The device withstood important bending without rupture. (iii) The motion could be monitored by recording the resistivity of the conductive track. Reproduced with permission, Copyright 2022, John Wiley and Sons (Held et al., 2022).
FIGURE 7
FIGURE 7
Examples of resorbable implanted medical devices. (A) Bioresorbable nerve cuff as a stimulator to electronically block pain. i) Schematic representation of the device, showing the Mg/Mo woven electrode structure connected through C-wax. ii) Schematic of the process of the nerve conduction block in the cuff-geometry device. iii) Illustration of the functioning and progressive bioresorption of the device through various stages of its lifetime. iv) Illustration of the in vivo implantation: a subcutaneous pathway for the placement of nerve cuffs and wire interconnects (top) and cuffs wrapping around nerves for stimulation, blockage, and recording (bottom). v) Representative compound nerve action potential (CNAP) measurements at days 1, 5, and 9 after implantation, without (w/o) or with electrical stimulation of the pain-blocking device. Copyright 2022, the Authors, published by Science Advances (Lee et al., 2022). (B) Self-powered implant to stimulate and monitor the resorption of bone fracture. i) Representative scheme of the device, showing the two parts: the self-powering generator (top) and the interdigitated electrode dressing for electrical stimulation (bottom). ii) Triboelectric working principle of the self-powering generator part. iii) X-ray photographs of bone fracture healing (right tibia) with time in rodents, when treated with an active device (i.e., implantation of the fully active device, top row), when treated with the inactive device (i.e., implantation of the device for which the self-powering unit has been disconnected from the interdigitated electrode pattern, middle row), when not treated (no device implantation, bottom row). Reproduced with permission, Copyright 2021, the Authors, published by PNAS (Yao et al., 2021). (C) Resorbable microneedle-based device for in-depth and wireless electrotherapy and drug delivery into injured muscle tissue. i) The device is composed of a drug-loaded PLGA microneedle array assembled with a PLGA sheet comprising magnesium coils acting as an antenna for wireless power transmission. ii) Invasive surgical procedure for the implantation of the device in rat muscle injury models. Scale bar: 1 cm. iii) Muscle healing assessment with (+ES) or without (−ES) electrostimulation at days 5 (D5) and 9 (D9) after treatment: representative H&E staining section images (scale bar: 500 µm) and statistical analysis of muscle injury depth. iv) Photographs of microneedle-based devices implanted in rats at different times after therapy (9 days, 2 weeks, 8 weeks, and 12 weeks). Scale bar: 5 mm. Adapted with permission from Huang et al. (2022), Copyright 2022, the American Chemical Society.
FIGURE 8
FIGURE 8
Cell-conductive material interactions in advanced hydrogels and scaffolds for in vitro 3D culture models. (A) Biohybrid hydrogel composed of collagen, alginate, and PEDOT:PSS for in vitro hiPSCs-derived cardiomyocyte maturation. (i) Schematic of the conductive biohybrid hydrogel formation (eCA-gel). (ii) Maturation of hiPSC-derived cardiomyocytes in the non-conductive hydrogel control (CA-gel) and electroconductive hydrogels (eCA-gel). Confocal images projection of tissue constructs stained for cardiomyocyte-specific markers troponin I, sarcomeric-α-actin, and connexin 43. Scale bars: 25 µm. Adapted with permission, Copyright 2018, John Wiley and Sons (Roshanbinfar et al., 2018). (B) Porous, conductive scaffold made of alginate and carbon nanomaterials (CNTs and carbon flakes) for the electromechanical differentiation of neural progenitor cells (NPCs). (i) Schematic of the porous scaffold and scanning electron microscopy (SEM) images of the internal structure, showing the entrapment of carbon flakes (red) and CNT (blue) into alginate (gray). Scale bar: 1 µm. (ii) 3D reconstruction of NPC micrographs in scaffolds of different mechanical properties (viscoelastic and elastic) and carbon content (%) after 6 weeks in culture. Staining for oligodendrocyte markers TuJ1 (green), myelin basic protein (MBP, magenta), and NPC (red). Scale bars: 180 µm. (iii) Quantification of the length of myelin for different carbon contents (%) and mechanical properties (viscoelastic, elastic) of the scaffolds. Adapted with permission, Copyright 2022, John Wiley and Sons (Tringides et al., 2023). (C) Characteristics of PEDOT:PSS/peptide-PEG conductive dynamic hydrogels. (i) Self-assembling and representative hydrogel formation through reversible and non-covalent interactions. (ii) Transmission electron microscopy (TEM) images of MSCs encapsulated in the PEDOT:PSS/peptide-PEG hydrogel showing the formation of nanofiber bundles around cells. Scale bars: 500 nm (left) and 1 µm right). Adapted with permission from Xu et al. (2018), Copyright 2018, the American Chemical Society.
FIGURE 9
FIGURE 9
Conductive hydrogels for tissue engineering applications. (A) Co-administration of an injectable hydrogel (HA-CHO/HA-CDH) and an adhesive conductive hydrogel patch (Gel-DA/DA-PPy) to treat myocardial infarction. (i) Schematic depicting the synthesis and co-administration of the two hydrogels. (ii) Masson's trichrome-stained sections showing infarct size and related fibrotic tissue (blue stained infarct scar) of the myocardium for the untreated group (top) and the hydrogels co-administration group (bottom). Scale bars: 1 mm. Adapted with permission from Wu et al. (2020), Copyright 2020, the American Chemical Society. (B) Injectable, conductive, self-healing hydrogel (ICH) scaffold for spinal cord injury repair. (i) Schematic illustration of the hydrogel, based on amino-modified gelatin (NH2-gelatin) and aniline tetramer-grafted oxidized hyaluronic acid (AT-OHA), loaded with exogenous neural stem cells (NSCs) and its administration in a rat model of total spinal cord injury (SCI). (ii) Total spinal cord resection samples 6 weeks after implantation of ICH, NSCs-loaded ICH (ICH-NSCs), and without any treatment (control group). (iii) Semi-quantitative analysis of the proportion of neurofilament 200 (NF200)-positive regions in rats by immunofluorescence staining. Adapted with permission from Liu H. et al. (2023), Copyright 2023, the American Chemical Society. (C) Conductive hydrogels for skin repair and wound dressing. (Top) Trans-epithelial potential and electric field at the wound site before and after the healing process. Reproduced with permission, Copyright 2020, John Wiley and Sons (Korupalli et al., 2021). (Bottom) (i) Diagrammatic sketch of soft hemostatic antioxidant conductive HA-DA/rGO@polydopamine (PDA) hydrogel preparation, macroscopic characteristics, and implantation at the wound site. Scale bar: 5 mm. (ii) Pictures of wounds at days 3, 7, and 14 post-implantation. (iii) Granulation tissue (red arrows) thickness for the different groups on day 14 post-implantation. Scale bar: 500 µm. Tegaderm: commercial film dressing (control); HA-DA/rGO0: HA-DA hydrogel in the absence of rGO, HA-DA/rGO3; HA-DA hydrogel cross-linked with rGO@PDA, HA-DA/rGO3/Doxy: doxycycline-loaded HA-DA/rGO@PDA hydrogel. Adapted with permission, Copyright 2019, John Wiley and Sons (Liang et al., 2019). (D) In vivo study of conductive 3D-printed PCL/MWCNTs scaffolds for bone tissue engineering. (i) Schematic illustration of the experimental setup: synthesis of the conductive scaffolds and their implantation with electrical stimulation (ES) treatment. (ii) Bone defect formation in the animal model and bone tissue formation with and without conductive scaffold after 60 days. (iii) Cross-section histological images of bone tissue formation at the bone defect for all groups (PCL, PCL/MWCNTs 0.75% wt and PCL/MWCNTs 3% wt) after 60 and 120 days, with and without electrical stimulation (ES). Adapted from eSilva et al. (2021), Copyright 2022, Springer Nature.
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The authors that declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the CEA internal funding “Organoids on chip” focus program (PhD grant for MS). LETI-DTIS was supported by the French National Research Agency in the framework of the STRETCH project (ANR- 8-CE19-0018-01), the LabEx Arcane (grant ANR-17-EURE-0003) and Glyco@Alps (ANR-15-IDEX-02) programs.

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