title: Influence of resveratrol release on the tissue response to mechanically adaptive cortical implants.
abstract: The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results demonstrate that local delivery of resveratrol can provide an additive advantage by providing a consistent reduction in the tissue response.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106, USA; Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd, 151 W/APT, Cleveland, OH 44106-1702, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Nguyen
authors.affiliation: Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Jorfi
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106, USA; Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd, 151 W/APT, Cleveland, OH 44106-1702, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Buchanan
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland; Virginia Tech, Department of Materials Science & Engineering & Macromolecules and Interfaces Institute, 445 Old Turner Street, 213 Holden Hall, Blacksburg, VA 24061, USA.
authors.forename: E Johan
authors.initials: EJ
authors.lastname: Foster
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106, USA; Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd, 151 W/APT, Cleveland, OH 44106-1702, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Tyler
authors.affiliation: Department of Macromolecular Science and Engineering, Case Western Reserve University, 2100 Adelbert Road, Kent Hale Smith Bldg, Cleveland, OH 44106-7202, USA.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Rowan
authors.affiliation: Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Weder
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr. Drive, Wickenden Bldg, Cleveland, OH 44106, USA; Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 10701 East Blvd, 151 W/APT, Cleveland, OH 44106-1702, USA. Electronic address: jeffrey.capadona@case.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Capadona
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008839:Microelectrodes / Q000009:adverse effects; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D053761:Nanocomposites / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D000077185:Resveratrol
keywords: Intracortical microelectrodes; Mechanically adaptive nanocomposite; Neuroinflammation; Resveratrol