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Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

ABSTRACT: Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications.

SUBMITTER: Haley RM

PROVIDER: S-EPMC7279014 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

Haley Rebecca M RM Zuckerman Sean T ST Dakhlallah Hassan H Dakhlallah Hassan H Capadona Jeffery R JR von Recum Horst A HA Ereifej Evon S ES

International journal of molecular sciences 20200519 10

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclo ...[more]

PMID: 32438593

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Project description:One of the most successfully procedures used to increase the production of t-resveratrol in Vitis vinifera suspension-cultured cells is the application of cyclodextrins (CDs) and methyl jasmonate (MJ) as elicitors. In particular, β-CDs are characterized by their chemical structure which makes them special, not only by acting as elicitors, but also because they are compounds capable of trapping high added-value hydrophobic molecules such as t-resveratrol. However, the use of β-CDs as elicitors increases the production costs of this compound, making their industrial exploitation economically unfeasible. Therefore, the development of β-CDs recovery strategies is necessary to provide a viable solution to their industrial use. In this work, carboxymethylated and hydroxypropylated β-CDs have been used to form polymers using epichlorohydrin (EPI) as a cross-linking agent. The polymers were coated to Fe3O4 nanoparticles and were jointly used with MJ to elicit V. vinifera suspension-cultured cells. Once elicitation experiments were finished, a magnet easily allowed the recovery of polymers, and t-resveratrol was extracted from them by using ethyl acetate. The results indicated that the production of t-resveratrol in the presence of free carboxymethyl-β-CDs was much lower than that found in the presence of carboxymethyl-β-cyclodextrins-EPI polymer coated magnetic nanoparticles. In addition, the maximal levels of t-resveratrol were found at 168 h of elicitation in the presence of 15 g/L hydroxypropyl-β-CDs polymer coated magnetic nanoparticles and MJ, and non-t-resveratrol was found in the extracellular medium, indicating that all the t-resveratrol produced by the cells and secreted into the culture medium was trapped by the polymer and extracted from it. This work also showed that polymers can be regenerated and reused during three cycles of continuous elicitation since the induction and adsorption capacity of hydroxypropyl-β-CDs polymer-coated magnetic nanoparticles after these cycles of elicitation remained high, allowing high concentrations of t-resveratrol to be obtained.

Project description:Single-unit recording neural probes have significant advantages towards improving signal-to-noise ratio and specificity for signal acquisition in brain-to-computer interface devices. Long-term effectiveness is unfortunately limited by the chronic injury response, which has been linked to the mechanical mismatch between rigid probes and compliant brain tissue. Small, flexible microelectrodes may overcome this limitation, but insertion of these probes without buckling requires supporting elements such as a stiff coating with a biodegradable polymer. For these coated probes, there is a design trade-off between the potential for successful insertion into brain tissue and the degree of trauma generated by the insertion. The objective of this study was to develop and validate a finite element model (FEM) to simulate insertion of coated neural probes of varying dimensions and material properties into brain tissue. Simulations were performed to predict the buckling and insertion forces during insertion of coated probes into a tissue phantom with material properties of brain. The simulations were validated with parallel experimental studies where probes were inserted into agarose tissue phantom, ex vivo chick embryonic brain tissue, and ex vivo rat brain tissue. Experiments were performed with uncoated copper wire and both uncoated and coated SU-8 photoresist and Parylene C probes. Model predictions were found to strongly agree with experimental results (<10% error). The ratio of the predicted buckling force-to-predicted insertion force, where a value greater than one would ideally be expected to result in successful insertion, was plotted against the actual success rate from experiments. A sigmoidal relationship was observed, with a ratio of 1.35 corresponding to equal probability of insertion and failure, and a ratio of 3.5 corresponding to a 100% success rate. This ratio was dubbed the "safety factor", as it indicated the degree to which the coating should be over-designed to ensure successful insertion. Probability color maps were generated to visually compare the influence of design parameters. Statistical metrics derived from the color maps and multi-variable regression analysis confirmed that coating thickness and probe length were the most important features in influencing insertion potential. The model also revealed the effects of manufacturing flaws on insertion potential.

Dataset Information

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

Publications

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes.

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