Yi Jae Lee

Multifunctional hydrogel coatings on the surface of neural cuff electrode for improving electrode-nerve tissue interfaces

UNLABELLED Recently, implantable neural electrodes have been developed for recording and stimulation of the nervous system. However, when the electrode is implanted onto the nerve trunk, the rigid polyimide has a risk of damaging the nerve and can also cause inflammation due to a mechanical mismatch between the stiff polyimide and the soft biological tissue. These processes can interrupt the transmission of nerve signaling. In this paper, we have developed a nerve electrode coated with PEG hydrogel that contains poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with anti-inflammatory cyclosporin A (CsA). Micro-wells were introduced onto the electrode in order to increase their surface area. This allows for loading a high-dose of the drug. Additionally, chemically treating the surface with aminopropylmethacrylamide can improve the adhesive interface between the electrode and the hydrogel. The surface of the micro-well cuff electrode (MCE) coated with polyethylene glycol (PEG) hydrogel and drug loaded PLGA microspheres (MS) were characterized by SEM and optical microscopy. Additionally, the conductive polymers, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT/PSS), were formed on the hydrogel layer for improving the nerve signal quality, and then characterized for their electrochemical properties. The loading efficiencies and release profiles were investigated by High Performance Liquid Chromatography (HPLC). The drug loaded electrode resulted in a sustained release of CsA. Moreover, the surface coated electrode with PEG hydrogel and CsA loaded MP showed a significantly decreased fibrous tissue deposition and increased axonal density in animal tests. We expect that the developed nerve electrode will minimize the tissue damage during regeneration of the nervous system. STATEMENT OF SIGNIFICANCE The nerve electrodes are used for interfacing with the central nervous system (CNS) or with the peripheral nervous system (PNS). The interface electrodes should facilitate a closed interconnection with the nerve tissue and provide for selective stimulation and recording from multiple, independent, neurons of the neural system. In this case, an extraneural electrodes such as cuff and perineural electrodes are widely investigated because they can completely cover the nerve trunk and provide for a wide interface area. In this study, we have designed and prepared a functionalized nerve cuff electrode coated with PEG hydrogel containing Poly lactic-co-glycol acid (PLGA) microspheres (MS) loaded with cyclosporine A (CsA). To our knowledge, our findings suggest that surface coating a soft-hydrogel along with an anti-inflammatory drug loaded MS can be a useful strategy for improving the long-term biocompatibility of electrodes.

Flexible and Highly Biocompatible Nanofiber-Based Electrodes for Neural Surface Interfacing

Polyimide (PI)-based electrodes have been widely used as flexible biosensors in implantable device applications for recording biological signals. However, the long-term quality of neural signals obtained from PI-based nerve electrodes tends to decrease due to nerve damage by neural tissue compression, mechanical mismatch, and insufficient fluid exchange between the neural tissue and electrodes. Here, we resolve these problems with a developed PI nanofiber (NF)-based nerve electrode for stable neural signal recording, which can be fabricated via electrospinning and inkjet printing. We demonstrate an NF-based nerve electrode that can be simply fabricated and easily applied due to its high permeability, flexibility, and biocompatibility. Furthermore, the electrode can record stable neural signals for extended periods of time, resulting in decreased mechanical mismatch, neural compression, and contact area. NF-based electrodes with highly flexible and body-fluid-permeable properties could enable future neural interfacing applications.

Biofunctionalization of Nerve Interface via Biocompatible Polymer-Roughened Pt Black on Cuff Electrode for Chronic Recording

Peripheral nerve cuff electrodes with roughened Pt black (BPt) are coated with polyethylene glycol (PEG) and Nafion (NF). Although the influence of coated PEG and Nafion on roughened BPt on the electrical properties is weak, the cuff electrode with BPt/PEG and BPt/Nafion exhibits some very important properties. For example, it markedly decreases interfacial impedance, increases charge storage capacity (CSC) due to retaining the BPt surface structure, good stability without exfoliation in repetitive cyclic voltammetry scanning because it is protected by PEG or Nafion coating. In cell viability test, Nafion-coated BPt does not show cytotoxicity to rat Schwann cell line (S16) at 24 and 72 h with the Nafion coating ranging from 0.1 to 10 mg cm-2 . In addition, real-time polymerase chain reaction (PCR) analysis indicates that Schwann cell differentiation (S100 calcium-binding protein B, myelin basic protein, peripheral myelin protein 22), proliferation (proliferating cell nuclear antigen, cyclin-dependent kinase 1 (CDK1)), and adhesion molecules (neural cell adhesion molecule, laminin, fibronectin) are upregulated up to 5 mg cm-2 of Nafion. In animal study, the BPt/Nafion reduces infiltration of fibrotic tissue with high axonal maintenance with upregulation of proliferation (CDK1), adhesion (laminin, neuronal cell adhesion molecule), and neurotrophic factor receptor-related (gdnf family receptor alpha 1) mRNA expressions.

Biological assessments of multifunctional hydrogel-decorated implantable neural cuff electrode for clinical neurology application

The implantable cuff electrode is an effective neuroprosthetic device in current nerve tissue engineering. However, biocompatibility and stability are still a serious dispute in terms of in vivo function and continuous monitoring. In this regard, assessing the host’s biological response to biomaterials is one of the key factors of chronic implantation. In this article, we analyzed the peripheral nerve specific-biological responses to the application of multi-functional hydrogel-coated electrodes. The surface of the cuff electrode was modified using a multifunctional hydrogel composed of PEG hydrogel, cyclosporin A(CsA)-microsphere(MS) and electrodeposited PEDOT:PSS. Through our approach, we have found that the multifunctional hydrogel coatings improve the neural electrode function, such as peak-to-peak amplitude increase. Additionally, the multifunctional hydrogel coated electrodes exhibited improved biocompatibility, such as reduced apoptotic properties and increased axonal myelination. Furthermore, 12 genes (BDNF, Gfra1, IL-6, Sox 10, S100B, P75NTR, GAP43, MBP, MPZ, NrCAM, NE-FL, CB1) were upregulated at 5 weeks post-implant. Finally, double immunofluorescence revealed the effect of endocannabinoid system on neuroprotective properties and tissue remodeling of peripheral nerves during cuff electrode implantation. These results clearly confirmed that multifunctional hydrogel coatings could improve electrode function and biocompatibility by enhancing neuroprotective properties, which may provide a valuable paradigm for clinical neurology application.

A new MEMS neural probe system integrated with push-pull microfluidic channels and biosensors for real-time monitoring of neurochemicals

We present a new MEMS neural probe integrated with two microfluidic channels, a mixer, and biosensors for real-time monitoring of neurochemicals and neural activities. The microfluidic channels for push-pull operation of fluids enable infusion of drugs and extraction of brain fluid at the same time. Also, we can simultaneously monitor neural activities modulated by the infused drug. The real-time monitoring of neurochemicals using the monolithically integrated sensors is a new concept we propose which is enabled through the MEMS technology. The proposed system will provide an important new set of information for brain disease investigation and functional brain-mapping.

A cuff-shaped enzymeless glucose sensor integrated with chronically implantable peripheral nerve cuff electrode for inflammation monitoring

This paper reports on a recently developed cuff-shaped enzymeless glucose sensor integrated with chronically implantable peripheral nerve cuff electrode for the reflecting nerve signal degradation, particularly in the time immediately following implantation. The cuff-shaped enzymeless glucose sensor with black Pt working electrode (WE) showed the roughness factor (RF) of 16.413 and extremely lowered impedance of 40 ohm at 1 kHz compared to the plain Pt (RF: 1, impedance 600 ohm). The enzymeless glucose sensor with black Pt WE operated without any enzyme and mediators. It exhibited dramatically increased glucose sensitivity of 38.26 μA/mMcm2 and detection limit of 25 μM in the glucose range up to 16 mM. These results indicate that the fabricated glucose sensor is promising for the inflammation monitoring application in the immediate vicinity of the implantable nerve cuff electrodes.

Fabrication and characterization of stimulus nerve cuff electrode with highly roughened surface for chronic implant

Nerve cuff electrodes for peripheral nerve prostheses are required chronically implanted electrodes which simultaneously stimulate and record nerve activity. It is inevitable challenge to investigate electrode material with low interfacial impedance and enhanced charge transfer capacity. In this study, stimulus nerve cuff electrodes on polyimide with Pt, conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT), black Pt, and IrOx were fabricated and characterized. The electrochemical properties were investigated using cyclic voltammetry, electrochemical impedance spectroscopy, and voltage transient measurements. From th experimental results, stimulus nerve cuff electrodes with black Pt showed the highest charge delivery capacity (80 times higher than Pt), charge injection capacity (6 times higher than Pt), and lowest interfacial impedance (3.8 times lower than Pt).

Implantable Nerve Cuff Electrode with Conductive Polymer for Improving Recording Signal Quality at Peripheral Nerve

Abstract This study demonstrates a polyimide nerve cuff electrode with a conductive polymer for improving recording signal quality at periph-eral nerve. The nerve cuff electrodes with platinum (Pt), iridium oxide (IrOx), and poly(3,4-ethylenedioxythiophene): p-toluene sul-fonate (PEDOT:pTS) were fabricated and investigated their electrical characteristics for improving recorded nerve signal quality. Thefabricated nerve cuff electrodes with Pt, IrOx, and PEDOT:pTS were characterized their impedance and CDC by using electrochemicalimpedance spectroscopy (EIS) and cyclic voltammetry. The impedance of PEDOT:pTS measured at 1 kHz was 257Ω, which wasextremely lower than the value of the nerve cuff electrodes with IrOx (15897 Ω) and Pt (952Ω), respectively. Furthermore, the chargedelivery capacity (CDC) of the nerve cuff electrode with PEDOT:pTS was dramatically increased to 62 times than the nerve cuff elec-trode with IrOx. In ex-vivo test using extracted sciatic nerve of spaque-dawley rat (SD rat), the PEDOT:pTS group exhibited higher sig-nal-to-interference ratio than IrOx group. These results indicated that the nerve cuff electrode with PEDOT:pTS is promising foreffective implantable nerve signal recording.Keywords: Nerve cuff electrode, Neural signal recording, Iridium oxide, PEDOT:pTS, ex-vivo test