In vitro biocompatibility and electrical stability of thick-film platinum/gold alloy electrodes printed on alumina

OBJECTIVE: High-density electrode arrays are a powerful tool in both clinical neuroscience and basic research. However, current manufacturing techniques require the use of specialised techniques and equipment, which are available to few labs. We have developed a high-density electrode array with customisable design, manufactured using simple printing techniques and with commercially available materials. APPROACH: Electrode arrays were manufactured by thick-film printing a platinum-gold alloy (Pt/Au) and an insulating dielectric on 96% alumina ceramic plates. Arrays were conditioned in serum and serum-free conditions, with and without 1kHz, 200µA, charge balanced stimulation for up to 21 days. Array biocompatibility was assessed using an extract assay and a PC-12 cell contact assay. Electrode impedance, charge storage capacity and charge injection capacity were before and after array conditioning. MAIN RESULTS: The manufactured Pt/Au electrodes have a highly porous surface and exhibit electrical properties comparable to arrays manufactured using alternative techniques. Materials used in array manufacture were found to be non-toxic to L929 fibroblasts by extract assay, and neuronal-like PC-12 cells adhered and extended neurites on the array surfaces. Arrays remained functional after long-term delivery of electrical pulses while exposed to protein-rich environments. Charge storage capacities and charge injection capacities increased following stimulation accounted for by an increase in surface index (real surface area) observed by vertical scanning interferometry. Further, we observed accumulation of proteins at the electrode sites following conditioning in the presence of serum. SIGNIFICANCE: This study demonstrates the in vitro biocompatibility of commercially available thick-film printing materials. The printing technique is both simple and versatile, with layouts readily modified to produce customized electrode arrays. Thick-film electrode arrays are an attractive tool that may be implemented for general tissue engineering and neuroscience research

Conducting Polymer‐Ionic Liquid Electrode Arrays for High‐Density Surface Electromyography

Abstract: Surface electromyography (EMG) is used as a medical diagnostic and to control prosthetic limbs. Electrode arrays that provide large‐area, high density recordings have the potential to yield significant improvements in both fronts, but the need remains largely unfulfilled. Here, digital fabrication techniques are used to make scalable electrode arrays that capture EMG signals with mm spatial resolution. Using electrodes made of poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) composites with the biocompatible ionic liquid (IL) cholinium lactate, the arrays enable high quality spatiotemporal recordings from the forearm of volunteers. These recordings allow to identify the motions of the index, little, and middle fingers, and to directly visualize the propagation of polarization/depolarization waves in the underlying muscles. This work paves the way for scalable fabrication of cutaneous electrophysiology arrays for personalized medicine and highly articulate prostheses

Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics

The implantation of any foreign material into the body leads to the development of an inflammatory and fibrotic process—the foreign body reaction (FBR). Upon implantation into a tissue, cells of the immune system become attracted to the foreign material and attempt to degrade it. If this degradation fails, fibroblasts envelop the material and form a physical barrier to isolate it from the rest of the body. Long-term implantation of medical devices faces a great challenge presented by FBR, as the cellular response disrupts the interface between implant and its target tissue. This is particularly true for nerve neuroprosthetic implants—devices implanted into nerves to address conditions such as sensory loss, muscle paralysis, chronic pain, and epilepsy. Nerve neuroprosthetics rely on tight interfacing between nerve tissue and electrodes to detect the tiny electrical signals carried by axons, and/or electrically stimulate small subsets of axons within a nerve. Moreover, as advances in microfabrication drive the field to increasingly miniaturized nerve implants, the need for a stable, intimate implant-tissue interface is likely to quickly become a limiting factor for the development of new neuroprosthetic implant technologies. Here, we provide an overview of the material-cell interactions leading to the development of FBR. We review current nerve neuroprosthetic technologies (cuff, penetrating, and regenerative interfaces) and how long-term function of these is limited by FBR. Finally, we discuss how material properties (such as stiffness and size), pharmacological therapies, or use of biodegradable materials may be exploited to minimize FBR to nerve neuroprosthetic implants and improve their long-term stability

Immobilized liquid coatings for implantable neural electronics

Statement of Purpose: Implantable neural electronics are clinically important in many treatments such as deep brain stimulation for Parkinson’s disease, mapping of epileptic foci for surgical resection of the zone as well as in the development of brain-machine interfaces (BMI) for paralyzed individuals. Traditionally, implantable electronics much more resemble the electronics that are used in our everyday technology (computers, phones) than the tissue that surrounds such devices. For this reason, implantable electronics suffer from many limitations that prevent them from realizing full clinical impact. Such limitations include chronic biocompatibility, chronic electronic performance (e.g. biofouling, dielectric degradation) and significant surgical trauma from their implantation. Here, we have investigated immobilized liquid coatings on implantable electronics. Such coatings consist of a water-immiscible liquids (oil) that are anchored to the implant surface by being infused within an elastomer network to shield neural probes from surrounding tissue. Immobilized liquid coatings are slippery (ultralow sliding angles); others have been shown these coatings resist blood cell adhesion and bacterial biofouling. We investigate how such liquid coatings can benefit neural probe applications

Mechanically compliant implants as a strategy to decrease foreign body reaction to nerve interfaces

Statement of Purpose: Neural interfaces are unique tools capable of establishing connections between the nervous systems and electronics; offering great potential in both clinic and basic research. Peripheral nerves are particularly attractive sites to position a neural interface, given the ease of access of these structures and the direct correlation between action potential transmission and activity at their target structure. Although many designs for peripheral nerve interfaces have been developed, they all face a major challenge upon chronic implantation: the foreign body reaction (FBR). This response, characterized by inflammation and fibrosis around the implanted body resulting in a build-up of a dense fibrotic capsule, occurs irrespective of the implanted material’s chemical properties. Implantable materials are, however, orders of magnitude stiffer than body tissues, which may tag them as foreign and trigger the foreign body response. In order to avoid this FBR, we have tested low-stiffness materials as potential components for neural interface manufacture. We prepared nerve implants coated with polyacrylamide hydrogels and silicone elastomers with very low mechanical stiffnesses, and evaluated the resulting FBR when chronically implanted in vivo

When Bio Meets Technology: Biohybrid Neural Interfaces

The development of electronics capable of interfacing with the nervous system is a rapidly advancing field with applications in basic science and clinical translation. Devices containing arrays of electrodes can be used in the study of cells grown in culture or can be implanted into damaged or dysfunctional tissue to restore normal function. While devices are typically designed and used exclusively for one of these two purposes, there have been increasing efforts in developing implantable electrode arrays capable of housing cultured cells, referred to as biohybrid implants. Once implanted, the cells within these implants integrate into the tissue, serving as a mediator of the electrode–tissue interface. This biological component offers unique advantages to these implant designs, providing better tissue integration and potentially long-term stability. Herein, an overview of current research into biohybrid devices, as well as the historical background that led to their development are provided, based on the host anatomical location for which they are designed (CNS, PNS, or special senses). Finally, a summary of the key challenges of this technology and potential future research directions are presented

Tissue stiffness at the human maternal-fetal interface.

STUDY QUESTION: What is the stiffness (elastic modulus) of human nonpregnant secretory phase endometrium, first trimester decidua, and placenta? SUMMARY ANSWER: The stiffness of decidua basalis, the site of placental invasion, was an order of magnitude higher at 103 Pa compared to 102 Pa for decidua parietalis, nonpregnant endometrium and placenta. WHAT IS KNOWN ALREADY: Mechanical forces have profound effects on cell behavior, regulating both cell differentiation and migration. Despite their importance, very little is known about their effects on blastocyst implantation and trophoblast migration during placental development because of the lack of mechanical characterization at the human maternal-fetal interface. STUDY DESIGN, SIZE, DURATION: An observational study was conducted to measure the stiffness of ex vivo samples of human nonpregnant secretory endometrium (N = 5) and first trimester decidua basalis (N = 6), decidua parietalis (N = 5), and placenta (N = 5). The stiffness of the artificial extracellular matrix (ECM), Matrigel®, commonly used to study migration of extravillous trophoblast (EVT) in three dimensions and to culture endometrial and placental organoids, was also determined (N = 5). PARTICIPANTS/MATERIALS, SETTING, METHODS: Atomic force microscopy was used to perform ex vivo direct measurements to determine the stiffness of fresh tissue samples. Decidua was stained by immunohistochemistry (IHC) for HLA-G+ EVT to confirm whether samples were decidua basalis or decidua parietalis. Endometrium was stained with hematoxylin and eosin to confirm the presence of luminal epithelium. Single-cell RNA sequencing data were analyzed to determine expression of ECM transcripts by decidual and placental cells. Fibrillin 1, a protein identified by these data, was stained by IHC in decidua basalis. MAIN RESULTS AND THE ROLE OF CHANCE: We observed that decidua basalis was significantly stiffer than decidua parietalis, at 1250 and 171 Pa, respectively (P < 0.05). The stiffness of decidua parietalis was similar to nonpregnant endometrium and placental tissue (250 and 232 Pa, respectively). These findings suggest that it is the presence of invading EVT that is driving the increase in stiffness in decidua basalis. The stiffness of Matrigel® was found to be 331 Pa, significantly lower than decidua basalis (P < 0.05). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Tissue stiffness was derived by ex vivo measurements on blocks of fresh tissue in the absence of blood flow. The nonpregnant endometrium samples were obtained from women undergoing treatment for infertility. These may not reflect the stiffness of endometrium from normal fertile women. WIDER IMPLICATIONS OF THE FINDINGS: These results provide direct measurements of tissue stiffness during the window of implantation and first trimester of human pregnancy. They serve as a basis of future studies exploring the impact of mechanics on embryo implantation and development of the placenta. The findings provide important baseline data to inform matrix stiffness requirements when developing in vitro models of trophoblast stem cell development and migration that more closely resemble the decidua in vivo. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Centre for Trophoblast Research, the Wellcome Trust (090108/Z/09/Z, 085992/Z/08/Z), the Medical Research Council (MR/P001092/1), the European Research Council (772426), an Engineering and Physical Sciences Research Council Doctoral Training Award (1354760), a UK Medical Research Council and Sackler Foundation Doctoral Training Grant (RG70550) and a Wellcome Trust Doctoral Studentship (215226/Z/19/Z)

Multishank Thin-Film Neural Probes and Implantation System for High-Resolution Neural Recording Applications

Silicon probes have played a key role in studying the brain. However, the stark mechanical mismatch between these probes and the brain leads to chronic damage in the surrounding neural tissue, limiting their application in research and clinical translation. Mechanically flexible probes made of thin plastic shanks offer an attractive tissue-compatible alternative but are difficult to implant into the brain and struggle to achieve the electrode density and layout necessary for the high-resolution applications their silicon counterparts excel at. Here, we present a multi-shank high-density flexible neural probe design which emulates the functionality of stiff silicon arrays for neural population recordings across multiple sites within a given region. The flexible probe is accompanied by a detachable 3D printed implanter which delivers the probe by means of hydrophobic-coated shuttles. The shuttles can then be retracted with minimal movement, and the implanter houses the electronics necessary for in vivo recording applications. Validation of the probes through extracellular recordings from multiple brain regions and histological evidence of minimal foreign body response opens the path to long-term chronic monitoring of neural ensemble

Multishank Thin-Film Neural Probes and Implantation System for High-Resolution Neural Recording Applications

Funder: Cambridge Trust; Id: http://dx.doi.org/10.13039/501100003343Funder: University of Cambridge; Id: http://dx.doi.org/10.13039/501100000735Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269Funder: University of Cambridge Borysiewicz Interdisciplinary FellowshipFunder: Infinitus China LtdSilicon probes have played a key role in studying the brain. However, the stark mechanical mismatch between these probes and the brain leads to chronic damage in the surrounding neural tissue, limiting their application in research and clinical translation. Mechanically flexible probes made of thin plastic shanks offer an attractive tissue-compatible alternative but are difficult to implant into the brain and struggle to achieve the electrode density and layout necessary for the high-resolution applications their silicon counterparts excel at. Here, we present a multi-shank high-density flexible neural probe design which emulates the functionality of stiff silicon arrays for neural population recordings across multiple sites within a given region. The flexible probe is accompanied by a detachable 3D printed implanter which delivers the probe by means of hydrophobic-coated shuttles. The shuttles can then be retracted with minimal movement, and the implanter houses the electronics necessary for in vivo recording applications. Validation of the probes through extracellular recordings from multiple brain regions and histological evidence of minimal foreign body response opens the path to long-term chronic monitoring of neural ensemble