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Engineered neural implants have a myriad of potential basic science and clinical neural repair applications. Although there are implants that are currently undergoing their first clinical investigations, optimizing their long-term viability and efficacy remain an open challenge. Functional implants with pre-vascularization of various engineered tissues have proven to enhance post-implantation host integration, and well-known synergistic neural-vascular interplays suggest that this strategy could also be promising for neural tissue engineering . Here, we report the development of a novel bio-engineered neuro-vascular co-culture construct, and demonstrate that it exhibits enhanced neurotrophic factor expression , and more complex neuronal morphology. Crucially, by introducing genetically encoded calcium indicators (GECIs) into the co-culture, we are able to monitor functional activity of the neural network , and demonstrate greater activity levels and complexity as a result of the introduction of endothelial cells in the construct. The presence of this enhanced activity could putatively lead to superior integration outcomes. Indeed, leveraging on the ability to monitor the construct's development post-implantation with GECIs, we observe improved integration phenotypes in the spinal cord of mice relative to non-vascularized controls. Our approach provides a new experimental system with functional neural feedback for studying the interplay between vascular and neural development while advancing the optimization of neural implants towards potential clinical applications.

The inflammatory brain tissue response to implanted neural electrode devices has hindered the longevity of these implants. Zwitterionic polymers have a potent anti-fouling effect that decreases the foreign body response to subcutaneous implants. In this study, we developed a nanoscale anti-fouling coating composed of zwitterionic poly (sulfobetaine methacrylate) (PSB) and polydopamine (PDA) for neural probes. The addition of PDA improved the stability of the coating compared to PSB alone, without compromising the anti-fouling properties of the film. PDA-PSB coating reduced protein adsorption by 89% compared to bare Si samples, while fibroblast adhesion was reduced by 86%. PDA-PSB coated silicon based neural probes were implanted into mouse brain, and the inflammatory tissue responses to the implants were assessed by immunohistochemistry one week after implantation. The PSB-PDA coated implants showed a significantly decreased expression of glial fibrillary acidic protein (GFAP), a marker for reactive astrocytes, within 70 μm from the electrode-tissue interface (p 0.05). Additionally, the coating reduced the microglia activation as shown in decreased Iba-1 and lectin staining, and improved blood-brain barrier integrity indicated by reduced immunoglobulin (IgG) leakage into the tissue around the probes. These findings demonstrate that anti-fouling zwitterionic coating is effective in suppressing the acute inflammatory brain tissue response to implants, and should be further investigated for its potential to improve chronic performance of neural implants.

Devices implanted within the central nervous system (CNS) are subjected to tissue reactivity due to the lack of biocompatibility between implanted material and the cells’ microenvironment. Studies have attributed blood-brain barrier disruption, inflammation, and oxidative stress as main contributing factors that lead to electrode recording failure. The complement cascade is a part of the innate immunity that focuses on recognizing and targeting foreign objects; however, its role in the context of neural implants is substantially unknown. In this study, we implanted a non-functional 4×4 Utah microelectrode array (UEA) into the somatosensory cortex and studied the complement cascade via combined gene and immunohistochemistry quantification at acute (48-hour), sub-acute (1-week), and early chronic (4-weeks) time points. The results of this study demonstrate the activation and continuation of the complement cascade at the electrode-tissue interface, illustrating the therapeutic potential of modulating the foreign body response via the complement cascade.

The capacity to predict in vivo responses to medical devices in humans currently relies greatly on implantation in animal models. Researchers have been striving to develop in vitro techniques that can overcome the limitations associated with in vivo approaches. This review focuses on a critical analysis of the major in vitro strategies being utilized in laboratories around the world to improve understanding of the biological performance of intracortical, brain-implanted microdevices. Of particular interest to the current review are in vitro models for studying cell responses to penetrating intracortical devices and their materials, such as electrode arrays used for brain computer interface (BCI) and deep brain stimulation electrode probes implanted through the cortex. A background on the neural interface challenge is presented, followed by discussion of relevant in vitro culture strategies and their advantages and disadvantages. Future development of 2D culture models that exhibit developmental changes capable of mimicking normal, postnatal development will form the basis for more complex accurate predictive models in the future. Although not within the scope of this review, innovations in 3D scaffold technologies and microfluidic constructs will further improve the utility of in vitro approaches.

Nanostructured neural interfaces, comprising nanotubes or nanowires, have the potential to overcome the present hurdles of achieving stable communication with neuronal networks for long periods of time. This would have a strong impact on brain research. However, little information is available on the brain response to implanted high-aspect-ratio nanoparticles, which share morphological similarities with asbestos fibres. Here, we investigated the glial response and neuronal loss in the rat brain after implantation of biostable and structurally controlled nanowires of different lengths for a period up to one year post-surgery. Our results show that, as for lung and abdominal tissue, the brain is subject to a sustained, local inflammation when biostable and high-aspect-ratio nanoparticles of 5 μm or longer are present in the brain tissue. In addition, a significant loss of neurons was observed adjacent to the 10 μm nanowires after one year. Notably, the inflammatory response was restricted to a narrow zone around the nanowires and did not escalate between 12 weeks and one year. Furthermore, 2 μm nanowires did not cause significant inflammatory response nor significant loss of neurons nearby. The present results provide key information for the design of future neural implants based on nanomaterials.

Devices implanted into the body become encapsulated due to a foreign body reaction. In the central nervous system (CNS), this can lead to loss of functionality in electrodes used to treat disorders. Around CNS implants, glial cells are activated, undergo gliosis and ultimately encapsulate the electrodes. The primary cause of this reaction is unknown. Here we show that the mechanical mismatch between nervous tissue and electrodes activates glial cells. Both primary rat microglial cells and astrocytes responded to increasing the contact stiffness from physiological values (G′ ∼ 100 Pa) to shear moduli G′ ≥ 10 kPa by changes in morphology and upregulation of inflammatory genes and proteins. Upon implantation of composite foreign bodies into rat brains, foreign body reactions were significantly enhanced around their stiff portions in vivo. Our results indicate that CNS glial cells respond to mechanical cues, and suggest that adapting the surface stiffness of neural implants to that of nervous tissue could minimize adverse reactions and improve biocompatibility.

Diamond-like carbon films have been evaluated as coatings to improve biocompatibility of orthopedic and cardiovascular implants. This study initiates a series of investigations that will evaluate diamond-like carbon (DLC) as a coating for improved biocompatibility in chronic neuroprosthetic implants. Studies in this report assess the cytotoxicity and cell adhesion behavior of DLC coatings exposed to glial and fibroblast cell lines in vitro. It can be concluded from these studies that DLC coatings do not adversely affect 3T3 fibroblast and T98-G glial cell function in vitro. We also successfully rendered DLC coatings non-adhesive (no significant fibroblast or glial cell adhesion) with surface immobilized dextran using methods developed for other biomaterials and applications. Future work will further develop DLC coatings on prototype microelectrode devices for chronic neural implant applications.