Online Master's in Biomedical Engineering @ Case.edu
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Capadona Research

Capadona Lab: Bio-Inspired Materials for Neural Interfacing

Summary of Research Activities to Date:

To date, the most important contributions from my work include these:

  • The development of bioinspired materials and systems for neural interfaces (issued patents; and thousands of popular press articles).
  • The first in vivo demonstration of the role of device mechanics on microelectrode failure (issued patents; and thousands of popular press articles).
  • The first to establish the role of reactive oxygen species and oxidative stress in the biotic and abiotic failure modes for intracortical microelectrode (multiple invention disclosures filed)
  • The first to demonstrate the role of the systemic innate immune system in the response to brain-dwelling microelectrodes (multiple invention disclosures filed)
  • First demonstration that motor deficits result from intracortical microelectrode implantation
  • Established a new Gordon Conference series as the Inaugural Chair of “Neuroelectronic Interfaces: Beyond Feasibility - Bridging the Gap in Neuroelectronic Interfaces”

My laboratory focuses on developing a molecular level understanding of the neuroinflammatory response to implantable neuromoduluator/rehabilitative devices.  My belief is that a spatiotemporal understanding of the degenerative neuroinflammatory response to implanted devices must be implicit before targeted and responsive systems can be developed to integrate within neural tissue.  Therefore, I have built a strong multi-disciplinary, multi-institutional team consisting of government, private-public, and academic-commercial partnerships across engineering, basic science, and clinical domains.

To accomplish this complex work, I am committed to actively developing and growing local, domestic, and international collaborations.  I have an extensive list of contributing collaborators on research awards.  Additionally, within the Cleveland research community I have had and am currently maintaining funded grants as either a Co-I or a Co-PI with many collaborators. Collaborators and productivity are tabulated in my full CV.

 Overall Research Summary: My laboratory is dedicated to understanding and mitigating the neuroinflammatory response to implanted devices within the central nervous system. Neural devices range in material type, size, architecture, function, and placement.  Regardless of any of these variables, the neuroinflammatory response to the implant plays a significant role on the integrity of the healthy tissue and the longevity of device performance – and thus is critical to the ultimate rehabilitation of patients. A major portion of my work has focused on studying various aspects of intracortical microelectrode performance and pursuing both materials-based and therapeutic-based methods to mitigate the inflammatory-mediated intracortical microelectrode failure mechanisms. Examples include the roles of tissue/device mechanical mismatch, oxidative stress, and specific immunity pathways in mediating neuroinflammation and device performance.

1) Role of tissue/device mechanical mismatch on microelectrode failure.

Project Rationale: It is widely accepted that propagation of the neuroinflammatory response may be due to perpetual motion-induced damage at the interface of traditional microelectrodes. The base materials used in traditional microelectrodes are significantly stiffer than cortical tissue. Therefore, starting with Goldstein and Salcman’s work in 1973, a number of groups have suggested that motion of the brain with respect to the microelectrode may induce damage to the surrounding tissue. In silico studies support the hypothesis that micromotion of the brain relative to a stiff microelectrode could induce strain on the surrounding tissue. The in silico work proposed that softer more compliant implants could minimize the tissue strain and mitigate the neuroinflammatory response.  Simply using softer materials to create intracortical microelectrode significantly diminishes the ability to implant the device without damaging the implant or the surrounding tissue.

Project History: In 2005, I began working as a postdoctoral trainee at CWRU with Drs. Dustin Tyler (BME), Christoph Weder (Macro) and Stuart Rowan (Macro). My goal was to develop a new class of materials that would be stiff enough to allow for insertion into the brain, but then mechanically soften to more closely match the stiffness of native brain tissue, based on controlled chemical interactions between the materials and the biological environment.  This work represented a foundational project for the newly organized VA APT Center, was eventually supported by several external mechanisms (NIH R21 to Tyler, and two VA Career Development awards to me as the PI), and resulted in well over a dozen manuscripts and two patents.  The most notable manuscripts were published on the cover of Nature Nanotechnology and in Science with me as first author. Over the following 10 years, my collaborators and I (Drs. Tyler, Weder, Rowan, Zorman, Miller, and Muthuswamy) have successfully demonstrated that mechanically-dynamic polymer-based intracortical microelectrodes such as this first class of materials: 1) are stiff enough to be inserted into the brain, 2) become compliant to reduce micro-motion in live animals, 3) inhibit late-stage neuroinflammatory responses, 4) can be fabricated into functional intracortical microelectrodes capable of recording from neural structures in live animals, and 5) can be utilized to deliver anti-inflammatory therapeutics.

2) Role of oxidative stress on microelectrode failure.

Project Rationale: The neuroinflammatory response to intracortical microelectrodes contributes to materials breakdown and biological damage leading to unreliable recording performance, regardless of the electrode type. Importantly, my group has identified the role of inflammation-mediated oxidative stress products in microelectrode-initiated neuroinflammation to be the most comprehensive source contributing to poor recording reliability caused by both materials and biological damage. The degradative effects of oxidative stress products include these: 1) corroding the microelectrode materials, 2) facilitating blood-brain barrier damage (biological damage), and 3) damaging surrounding neurons (biological damage). To realize the potential of intracortical microelectrodes, the side effects caused by oxidative stress products must be minimized.

Project History: I am exploring several antioxidative approaches to improve microelectrode reliability. My preliminary data indicates antioxidative approaches as a highly promising strategy. Specifically, we have successfully applied a variety of antioxidant treatments to reduce intracortical microelectrode-mediated oxidative stress and preserve neuron viability. Our newest strategy for improving intracortical recording reliability is a new biomimetic antioxidative coating. Our coating was developed as a platform technology that could be applied to any intracortical microelectrode substrate with simple modifications to the attachment chemistry.  Our initial efforts focused on planar silicon substrates for ease of characterization, cost, and the recent popularity of such devices in the literature and research community. Preliminary results suggest that the novel antioxidative-coated microelectrodes reduce the initial inflammatory response, preserve neuron populations adjacent to the electrodes, and improve initial recording quality. However, we have yet to demonstrate that the coatings can be applied to other popular microelectrode types, such as Blackrock arrays used clinically in humans. We also still need to characterize the long-term effects of our coatings on both neuroinflammation and the reliability of recording.

3) Role of specific immunity pathways in microelectrode failure.

Project Rationale: A number of groups have investigated possible strategies for reducing the inflammatory response to microelectrodes, with varying degrees of success. To date, the most successful approaches have indicated a dominant role of reactive microglia cells and infiltrating macrophages, as well as the stability of the local blood-brain barrier.  To elucidate the biological mechanisms resulting in microelectrode failure, I have utilized several transgenic mouse lines to investigate receptor-mediated pathways known to propagate the pro-inflammatory response to microelectrodes.  Specifically, we have studied the role of inflammatory pathways on reactive microglia cells and infiltrating macrophages that respond to necrotic cells, infiltrating blood-derived components, and bacterial contaminants. My preliminary results indicate that the cluster of differentiation 14 (CD14) co-receptor located on many glial and peripheral immune cells, is a necessary component in propagating the neuroinflammatory response to microelectrodes.

Project History: In collaboration with Drs. Tyler, Miller, Taylor, Selkirk, Ziats, Huang, and Sidik, I have demonstrated that over stimulation of CD14 with lipopolysaccharide (LPS) negatively impacted the quality of chronic neural recordings. Further, complete removal of CD14, and molecular inhibition of CD14-mediated pathways attenuated the neuroinflammatory response to microelectrodes. These observations suggested that CD14 is a promising molecular target for improving tissue response and performance of intracortical microelectrodes and were the foundation for my active NIH R01. As a result of the R01, we demonstrated that CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance. Moreover, mice receiving a small molecule CD14 antagonist exhibited significant improvements in recording performance over the entire study. Additionally, via a mouse bone marrow chimera model to selectively knockout CD14 from either brain resident microglia or blood-derived macrophages, I demonstrated that inhibiting CD14 from the blood-derived (not brain-derived) macrophages improves recording quality over the entire study. Therefore, we concluded that targeting CD14 in blood-derived cells should be part of the strategy to improve the performance of intracortical microelectrodes and that the daunting task of delivering therapeutics across the blood-brain barrier may not be needed to increase microelectrode performance.