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Capadona Research

Capadona Lab: Bio-Inspired Materials for Neural Interfacing

Description of Research Program:

Neural interfaces were originally conceived as basic science tools, and as such, they have been used extensively to enhance the understanding of how the nervous system works in normal and diseased states.1-3  Because many neurological deficits are not addressable pharmacologically, continued development of neural interface technology is critical to defining new interventions that will improve the independence and quality of life of these patients.

Despite their many successful applications in animal preparations and human brain machine interface (BMI) systems, chronic cortical recording with intracortical microelectrodes can be inconsistent. As early as 1974, Burns et al. showed a progressive decline in unit recordings in cat cerebral cortex after implantation, with only 8% of the electrodes functioning after 5 months.4 Forty years later, recording instability is still a commonly documented problem.  Over one hundred studies have described stereotypical features of the brain’s response to microelectrodes that occur irrespective of the type of implant, method of sterilization, species studied, or implantation method. From this rich body of literature, it has become increasing clear that the brain’s response consists of an interconnected, non-linear system of molecular and cellular components, the ultimate result of which is the continuous perpetuation of the response, and the prevention of microelectrode integration into the surrounding tissue. 

Several potential failure modes influence chronic recording stability and quality including: 1) the neuro-inflammatory response that the brain mounts against chronically implanted devices; 2) direct mechanical damage of the electrode; 3) corrosion of electrical contacts; and 4) degradation of passivation layers and insulating coatings.5, 6 Yet, various microelectrode failure modes have largely been studied independently from one another, in spite of the considerable interplay among them, making it difficult to attribute failure to a single mechanism.

My Lab is studying various aspects of microelectrode performance, and pursuing both materials-based and therapeutic-mediated methods to mitigate the inflammatory-mediated microelectrode failure mechanisms. My group has made significant contributions to this field, including our work describing the roles of oxidative stress, innate immunity pathways, tissue/device mechanical mismatch, device sterility (endotoxin contamination), and the contribution of local versus infiltrating inflammatory cells in mediating the neuroinflammatory response to intracortical microelectrodes. Since beginning a tenure track appoint at Case Western Reserve University in 2010, I have generated invention disclosures, patent filings, and over $3.81 M (PI) in new investigator-initiated projects sponsored by the NIH and Department of Veteran Affairs.  The impact of this work is evident in the high quality of journals we repeatedly publish in, the citations to that work, invitations to seminars (local to international), invited review articles and book chapters, as well as international media coverage of our work.

1) Impact of device mechanics on microelectrode failure. My team and I have developed biologically-inspired mechanically-dynamic microelectrodes based on their polymer nanocomposite material. The materials are being used to addresses critical 40 year old questions regarding the interplay between factors that contribute to the brain’s response to chronic intra-cortical interfaces.7-19 Enabled by the novel material system, we are able to independently examine and manipulate the three most recognized critical factors of modulus, geometry, and drug-eluting capabilities. Over the past five years, our team has successfully demonstrated that mechanically-dynamic polymer-based microelectrodes are stiff enough to be inserted into the brain,7, 12, 20 become compliant to reduce micro-motion and inhibit late-stage neuro-inflammatory responses,13, 21 and can be fabricated into functional microelectrodes capable of recording from neural structures in live animals.11  We have recently demonstrated that mechanically-dynamic polymer-based microelectrodes can be utilized to deliver anti-inflammatory therapeutics to further mitigate implant-associated inflammation.8 The goals for the next five years (pending R01 and DoD) are to establish a relationship between microelectrode-induced tissue strain and recording performance, as well as further develop the drug-releasing capabilities of the dynamic materials, in order to ensure a sustained suppression in neuroinflammatory events.

2) Understanding the role of molecular factors on microelectrode failure. Oxidative pathways have been implicated in both neurodegeneration and corrosive damage to both the metallic and insulating materials of current microelectrode technologies. Thus, approaches to mitigate or attenuate the deleterious effects of oxidative inflammatory products are of significant importance. My laboratory has also invested significant energy in understanding the temporal changes in the molecular and cellular level responses to intracortical microelectrodes.7, 8, 22-29 Specifically, we have demonstrated that inflammatory-mediated oxidative stress causes significant neuronal loss at the microelectrode surface, that several anti-oxidants can be delivered systemically or locally to temporally mitigate neuronal damage and loss,8, 22, 26 and that bioactive coatings with mimetic anti-oxidative enzymes can prolong neuroprotection.23 Over the next four years, I am funded under both his VA Merit Review and a PECASE award to explore the connection between antioxidative therapies and long-term microelectrode performance. The resulting information on antioxidative benefits is already being explored in combination with the bio-inspired mechanically-dynamic microelectrode.8 We are also coordinating proof-of-concept studies in non-human primates, critical to pursuing additional funding mechanisms to move this study to larger animals and eventually clinical trials.

3) Understanding cell-specific pathways which contribute to microelectrode failure. Few direct connections have been demonstrated between the neuroinflammatory response to microelectrodes and device performance.30-32 We identified a possible connection between each of these studies to be in large part due to innate immunity-specific toll-like receptor (TLR) pathways of resident microglia or infiltrating macrophages. We have exploited transgenic mouse models and bone marrow chimera models to determine the relative contribution of specific inflammatory pathways common to both myeloid cells and resident glial cells in the brain.29 Through genetic deletion of cluster of differentiation receptor 14 (CD14, a co-receptor to many TLRs) or molecular inhibition using a CD14-antagonist, we have shown that inhibition of CD14 receptor-mediated pathways attenuates neuroinflammation at the microelectrode-tissue interface. Inhibiting CD14 on myeloid cells and not resident microglia reduced blood-brain barrier permeability and increased neuroprotection. Together, we have identified a precise pathway that facilitates stability of the microelectrode-tissue interface, which may lead to new treatment regimens to enable long-term device performance. Over the next three years of our ongoing NIH R01, we will establish the appropriate time course and means of CD14 inhibition, in order to maximize improvements in intracortical recording qualities.

Moving Forward With Continued Success: All of these projects will lead to insight into the design and implementation of robust and effective intracortical microelectrode arrays. The principal objectives of my microelectrode projects fit into goals 1 and 2 of the NIH BRAIN Working Group’s vision for the BRAIN Initiative. Thus, we are well-position for continued support through NIH and VA sponsored awards.  Also, critical insights being gained using intracortical microelectrodes are already being applied to various other central nervous system implants, including ventricular shunts and stimulating electrodes under both private and industrial sponsorship.

 

References:

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