Multilayer 3D electrodes for neural implants

Objective. In many applications, multielectrode arrays employed as neural implants require a high density and a high number of electrodes to precisely record and stimulate the activity of the nervous system while preserving the overall size of the array as little as possible. Approach. Here we present a multilayer and three-dimensional (3D) electrode array, together with its manufacturing method, enabling a higher electrode density and a more efficient signal transduction with the biological tissue. Main results. The 3D structure of the electrode array allows a multilayer placement of the interconnects within a flexible substrate, it narrows the probe size per the same number of electrodes, and it maintains the electrode contacts at the same level within the tissue. In addition, it augments the electrode surface area, leading to a lower electrochemical impedance and a higher charge storage capacity. To characterize the recordings capabilities of the multilayer 3D electrodes, we measured visually evoked cortical potentials in mice and analysed the evolution of the peak prominences and latencies according to different light intensities and recording depths within the brain. The resulting signal-to-noise ratio is improved compared to flat electrodes. Finally, the 3D electrodes have been imaged inside a clarified mouse brain using a light-sheet microscope to visualize their integrity within the tissue. Significance. The multilayer 3D electrodes have proved to be a valid technology to ensure tissue proximity and higher recording/stimulating efficiencies while enabling higher electrode density and reducing the probe size

Photovoltaic stimulation of retinal ganglion cells with wide-field epiretinal prosthesis

Retinal prostheses have become in the past decade a promising and realistic technology to restore vision. Nonetheless, sight restoration with retinal prostheses in a clinically relevant perspective requires resolution and implantation challenges not yet achieved. Our goal is the development of a foldable and wide field-retinal prosthesis capable of achieving a wireless photovoltaic stimulation of retinal ganglion cells and restore at least 40° of visual field, though being injectable trough minimal incision. The 2345 organic photovoltaic stimulating pixels of our retina prosthesis are distributed into biomimetic pattern within an active area of 13 mm (44° of visual field) and the light-triggered current profile generated by those pixels shows a reproducible ability to elicit activity in explanted rodents’ retinas mimicking human retina dystrophies. Extracellular recordings of prosthetic-evoked spiking activity of retinal ganglion cells reveal both direct and network-mediated stimulation when the degenerating retina circuit is explanted on top of the stimulating device, while when retinas are layered on bare PDMS substrates, any light-evoked pattern of response can be detected among retina spontaneous activity. Screening of different conditions of illumination (pulse duration and intensity) with Rd10 retinas explanted on our prosthesis shows a direct activation from the minimal radiant exposure tested - that is 7 times smaller than the maximum permissible retinal irradiance allowed for ophthalmic applications in this case- while network-mediated activation requires higher light exposure and can be supressed using synaptic blockers. The clinical compliance of the so-designed prosthesis and those preliminary results on explanted retinas represent a step forward in building wide-field photovoltaic retinal prostheses

Surface engineering of porous silicon to optimise therapeutic antibody loading and release

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.The proinflammatory cytokine, tumor necrosis factor-α (TNF-α), is elevated in several diseases such as uveitis, rheumatoid arthritis and non-healing chronic wounds. Adding Infliximab, a chimeric IgG1 monoclonal antibody raised against TNF-α, to chronic wound fluid can neutralise human TNF-α, thereby providing a potential therapeutic option for chronic wound healing. However, to avoid the need for repeated application in a clinical setting, and to protect the therapeutic antibody from the hostile environment of the wound, suitable delivery vehicles are required. Porous silicon (pSi) is a biodegradable high surface area material commonly employed for drug delivery applications. In this study, the use of pSi microparticles (pSi MPs) for the controlled release of Infliximab to disease environments, such as chronic wounds, is demonstrated. Surface chemistry and pore parameters for Infliximab loading are first optimised in pSi films and loading conditions are transferred to pSi MPs. Loading regimens exceeding 60 μg of Infliximab per mg of pSi are achieved. Infliximab is released with zero-order release kinetics over the course of 8 days. Critically, the released antibody remains functional and is able to sequester TNF-α over a weeklong timeframe; suitable for a clinical application in chronic wound therapy

Design and validation of a foldable and photovoltaic wide-field epiretinal prosthesis

Retinal prostheses have been developed to fight blindness in people affected by outer retinal layer dystrophies. To date, few hundred patients have received a retinal implant. Inspired by intraocular lenses, we have designed a foldable and photovoltaic wide-field epiretinal prosthesis (named POLYRETINA) capable of stimulating wireless retinal ganglion cells. Here we show that within a visual angle of 46.3 degrees, POLYRETINA embeds 2215 stimulating pixels, of which 967 are in the central area of 5 mm, it is foldable to allow implantation through a small scleral incision, and it has a hemispherical shape to match the curvature of the eye. We demonstrate that it is not cytotoxic and respects optical and thermal safety standards; accelerated ageing shows a lifetime of at least 2 years. POLYRETINA represents significant progress towards the improvement of both visual acuity and visual field with the same device, a current challenging issue in the field

Development and Characterization of PEDOT:PSS/Alginate Soft Microelectrodes for Application in Neuroprosthetics

Reducing the mechanical mismatch between the stiffness of a neural implant and the softness of the neural tissue is still an open challenge in neuroprosthetics. The emergence of conductive hydrogels in the last few years has considerably widened the spectrum of possibilities to tackle this issue. Nevertheless, despite the advancements in this field, further improvements in the fabrication of conductive hydrogel-based electrodes are still required. In this work, we report the fabrication of a conductive hydrogel-based microelectrode array for neural recording using a hybrid material composed of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate), and alginate. The mechanical properties of the conductive hydrogel have been investigated using imaging techniques, while the electrode arrays have been electrochemically characterized at each fabrication step, and successfully validated both in vitro and in vivo. The presence of the conductive hydrogel, selectively electrodeposited onto the platinum microelectrodes, allowed achieving superior electrochemical characteristics, leading to a lower electrical noise during recordings. These findings represent an advancement in the design of soft conductive electrodes for neuroprosthetic applications

Development of a new visual prosthesis for preclinical studies on artificial vision

The technological evolution in materials science and microengineering favored the production of advanced visual prostheses useful for fighting blindness and to improve patients quality of life. Visual prostheses aim at replacing lost visual functions by artificial (electrical) stimulation of the remaining circuitry with microfabricated electrodes inducing phosphenes appearance in blind people. In particular, for people affected by retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration, retinal prostheses offer a valuable treatment option thanks to several advantages: among them, the retinotopic organization, the large surface area available for stimulation, and the straightforward surgical and optical access. The latter becomes very convenient for photovoltaic implants, in which amplified light entering the pupil is exploited as wireless source of power and visual information, allowing the implant to lay free-standing and the placement of a large number of stimulating pixels without the inconvenience of electrical connections. However, although all these advancements, there is nowadays no visual implant suited for artificial vision with both high spatial resolution and large visual field coverage. In this thesis, we developed a photovoltaic and foldable wide-field epiretinal prosthesis with a high density of stimulating pixels (more than 10400 and 18600 pixels with a density of 79 and 141 pixels/mm2, respectively) distributed over a very large surface area, covering 46 deg of visual field, greatly improved with respect to state-of-the-art implants. The large size of the implant imposes two major challenges: the necessity of a good contact between the implant and the retina and of a safe implantation procedure. To address these challenges, the photovoltaic interface is placed on a curved and stretchable substrate, able to be folded, injected into the eye through a small scleral cut, and self-unfold to recover the curvature matching the one of the eyes. Consequently, the rigid pixels were mechanically engineered to withstand the required deformation. We investigated the use of organic optoelectronic materials, such as P3HT:PCBM and PCPDTBT:PCBM, to manufacture photovoltaic pixels able to induce retinal ganglion cells activity upon illumination with short pulses of light. For both systems, light pulses of irradiances within the safety limits allowed the photogeneration of currents and voltages suitable for a stimulation frequency up to 20 Hz with green (565 nm) and near-infrared (730 nm) light, respectively. The conjugated polymer PEDOT:PSS and sputtered Ti (with TiN coating) were used for the anodic and cathodic ends correspondingly, with only the Ti-TiN surface exposed to the electrolytic solution. Ex vivo evaluation with blind mice retinas demonstrated that the photovoltaic pixels could induce, together with direct electrical short-latency stimulation, medium-latency spiking activity of retinal ganglion cells as evidence of prosthetic-induced network-mediated responses. Investigations and optimizations about functional, mechanical, thermal, optical, and stability properties of the prosthesis were carried out in vision of in vivo experiments with blind miniature pigs. Blinded by IAA treatment, the miniature pigs recovered light sensitivity when implanted with the prosthesis. This preliminary result motivates further preclinical inquiries with the prosthesis towards clinical applications

Soft Three-dimensional self-opening intraneural peripheral interface for optic nerve stimulation

Retinitis Pigmentosa and age-related macular degeneration are two of the principal causes of blindness in industrialized countries, for which there is still no established prevention, treatment or cure. In the past decade, retinal prostheses emerged as promising technology to restore vision1. On the contrary, optic nerve stimulation has been proposed as an attractive alternative to retinal prostheses, by acting directly on the axons of the ganglion cells2. Our research group is currently testing a self-opening intraneural electrode array for optic nerve stimulation (OpticSELINE)2. The implant consists of a flexible polyimide-based structure embedding gold interconnects and active sites. Although polyimide provides flexibility to the device, the use of a softer and stretchy material would greatly help in the integration of the array inside the nerve tissue. A commonly used material to fabricate soft neural interfaces is polydimethylsiloxane (PDMS); however, it presents challenging steps in the microfabrication process, especially for the encapsulation of the active sites. On the other hand, off-Stochiometric-Thiol-Ene Epoxy polymers (OSTE+)3 represent a promising replacement for the polyimide structure thanks to their tunable mechanical properties. In fact, by adjusting the stoichiometry of the constituting monomers, the Young’s modulus of OSTE+ can be decreased down to a few MPa at physiological temperature4. The preparation of OSTE+ consists of two curing steps3 in which (1) thiol-ene photopolymerization allows to pattern the polymer surface and remove the non- polymerized areas before (2) thermal curing. Thus, it is possible to encapsulate the electrode array simply using photolithographic techniques. Furthermore, the off-stoichiometric formulation introduces an excess of reactive thiol groups in the bulk and on the surface3. In this way, OSTE+ can covalently bind to other surfaces without the use of bonding strategies such as plasma activation. Therefore, the versatility of OSTE+ makes it a promising alternative to PDMS. Taking advantage of these properties, we used direct writing photolithography to fabricate implantable multielectrode arrays in OSTE+ (Figure 1). The functional characteristics of the array have been tested by electrochemical characterization. In conclusion, the introduction of OSTE+ in the OpticSELINE aims at minimizing the mechanical mismatch between the electrode array and the optic nerve. This technology has the potential to allow stable and selective stimulation (or recording) of the optic nerve during chronic implantations. The advancement will improve the use of the OpticSELINE as visual prosthesis for blind patients and as tool to further investigate the effect of the electrical stimulation in the visual system

Polymer-based optoelectronic interface and methods for its manufacture

A polymer-based optoelectronic interface comprises an elastomeric substrate (10) and a plurality of discrete photovoltaic pixel elements (20) disposed on top of the substrate. Each pixel element comprises at least one active layer comprising a semiconducting polymer or polymer mixture. The pixel elements are excitable by light to generate an electric signal via a photovoltaic process. For mechanically protecting the pixel elements, an elastomeric encapsulation layer (30) can be disposed on top of the substrate, the encapsulation layer defining access openings (31) for the pixel elements (20). Pillar-like structures (40) can be disposed on the pixel elements. Methods for fabricating such an optoelectronic interface are also disclosed. The optoelectronic interface can be used as a retinal prosthesis