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1.
Micromachines (Basel) ; 15(2)2024 Feb 17.
Article in English | MEDLINE | ID: mdl-38399008

ABSTRACT

Compound nerve action potentials (CNAPs) were used as a metric to assess the stimulation performance of a novel high-density, transverse, intrafascicular electrode in rat models. We show characteristic CNAPs recorded from distally implanted cuff electrodes. Evaluation of the CNAPs as a function of stimulus current and calculation of recruitment plots were used to obtain a qualitative approximation of the neural interface's placement and orientation inside the nerve. This method avoids elaborate surgeries required for the implantation of EMG electrodes and thus minimizes surgical complications and may accelerate the healing process of the implanted subject.

2.
Front Neurosci ; 17: 1096097, 2023.
Article in English | MEDLINE | ID: mdl-37090803

ABSTRACT

Intracortical recordings can be used to voluntarily control external devices via brain-machine interfaces (BMI). Multiple factors, including the foreign body response (FBR), limit the stability of these neural signals over time. Current clinically approved devices consist of multi-electrode arrays with a single electrode site at the tip of each shank, confining the recording interface to a single layer of the cortex. Advancements in manufacturing technology have led to the development of high-density electrodes that can record from multiple layers. However, the long-term stability of neural recordings and the extent of neuronal cell loss around the electrode across different cortical depths have yet to be explored. To answer these questions, we recorded neural signals from rats chronically implanted with a silicon-substrate microelectrode array spanning the layers of the cortex. Our results show the long-term stability of intracortical recordings varies across cortical depth, with electrode sites around L4-L5 having the highest stability. Using machine learning guided segmentation, our novel histological technique, DeepHisto, revealed that the extent of neuronal cell loss varies across cortical layers, with L2/3 and L4 electrodes having the largest area of neuronal cell loss. These findings suggest that interfacing depth plays a major role in the FBR and long-term performance of intracortical neuroprostheses.

3.
Front Neurosci ; 16: 908858, 2022.
Article in English | MEDLINE | ID: mdl-35769707

ABSTRACT

Intracortical microstimulation (ICMS) of the somatosensory cortex (S1) can restore sensory function in patients with paralysis. Studies assessing the stability of ICMS have reported heterogeneous responses across electrodes and over time, potentially hindering the implementation and translatability of these technologies. The foreign body response (FBR) and the encapsulating glial scar have been associated with a decay in chronic performance of implanted electrodes. Moreover, the morphology, intrinsic properties, and function of cells vary across cortical layers, each potentially affecting the sensitivity to ICMS as well as the degree of the FBR across cortical depth. However, layer-by-layer comparisons of the long-term stability of ICMS as well as the extent of the astrocytic glial scar change across cortical layers have not been well explored. Here, we implanted silicon microelectrodes with electrode sites spanning all the layers of S1 in rats. Using a behavioral paradigm, we obtained ICMS detection thresholds from all cortical layers for up to 40 weeks. Our results showed that the sensitivity and long-term performance of ICMS is indeed layer dependent. Overall, detection thresholds decreased during the first 7 weeks post-implantation (WPI). This was followed by a period in which thresholds remained stable or increased depending on the interfacing layer: thresholds in L1 and L6 exhibited the most consistent increases over time, while those in L4 and L5 remained the most stable. Furthermore, histological investigation of the tissue surrounding the electrode showed a biological response of microglia and macrophages which peaked at L1, while the area of the astrocytic glial scar peaked at L2/3. Interestingly, the biological response of these FBR markers is less exacerbated at L4 and L5, suggesting a potential link between the FBR and the long-term stability of ICMS. These findings suggest that interfacing depth can play an important role in the design of chronically stable implantable microelectrodes.

4.
Sci Rep ; 8(1): 7182, 2018 05 08.
Article in English | MEDLINE | ID: mdl-29739975

ABSTRACT

To screen the complex central nervous system (CNS) injury responses, we created a quadruple-labelled 'PrismPlus' mouse line with a genetically encoded distinct fluorescent tag in oligodendrocytes, microglia, neurons, and astrocytes. Cx3cr1-gfp and Prism mice originally developed by Jung et al., 2000 and Dougherty et al., 2012, respectively, were cross-bred. First, we confirmed the presence of fluorophores in appropriate cell types in PrismPlus mice. PrismPlus mice were then used to examine the cellular responses to brain implanted micro-devices. We observed an increase in microglial response at earlier time points as compared to 4 weeks, a progressive astrocytic response, and fewer neurons at the vicinity of an implanted device. These results are similar to what has been described in literature using other rodent strains, previously attainable only through time-consuming and variable immunohistochemistry methods. Finally, we demonstrate the compatibility of PrismPlus brain tissue with CLARITY, an advanced tissue clearing technique, opening the door to future thick tissue imaging studies. This report confirms PrismPlus transgenic fluorescence and highlights the utility of these mice to study CNS injuries. The work herein seeks to establish a novel transgenic mouse line to improve experimental scope, consistency, and efficiency for CNS researchers.


Subject(s)
Astrocytes/metabolism , Brain Injuries, Traumatic/genetics , Founder Effect , Microglia/metabolism , Neurons/metabolism , Oligodendroglia/metabolism , Recombinant Fusion Proteins/genetics , Animals , Astrocytes/ultrastructure , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Brain/metabolism , Brain/pathology , Brain Injuries, Traumatic/diagnosis , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , CX3C Chemokine Receptor 1/genetics , CX3C Chemokine Receptor 1/metabolism , Crosses, Genetic , Disease Models, Animal , Electrodes, Implanted , Female , Gene Expression , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice , Mice, Transgenic , Microglia/ultrastructure , Neurons/ultrastructure , Oligodendroglia/ultrastructure , Recombinant Fusion Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transgenes
5.
MRS Commun ; 8(3): 1043-1049, 2018 Sep.
Article in English | MEDLINE | ID: mdl-34386296

ABSTRACT

The goal of this study was to perform in situ electrochemical polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT) in peripheral nerves to create a soft, precisely located injectable conductive polymer electrode for bi-directional communication. Intraneural PEDOT polymerization was performed to target both outer and inner fascicles via custom fabricated 3D printed cuff electrodes and monomer injection strategies using a combination electrode-cannula system. Electrochemistry, histology, and laser light sheet microscopy revealed the presence of PEDOT at specified locations inside of peripheral nerve. This work demonstrates the potential for using in situ PEDOT electrodeposition as an injectable electrode for recording and stimulation of peripheral nerves.

6.
Front Neurosci ; 11: 513, 2017.
Article in English | MEDLINE | ID: mdl-28959183

ABSTRACT

Poly(ethylene glycol) (PEG) is a frequently used polymer for neural implants due to its biocompatible property. As a follow-up to our recent study that used PEG for stiffening flexible neural probes, we have evaluated the biological implications of using devices dip-coated with PEG for chronic neural implants. Mice (wild-type and CX3CR1-GFP) received bilateral implants within the sensorimotor cortex, one hemisphere with a PEG-coated probe and the other with a non-coated probe for 4 weeks. Quantitative analyses were performed using biomarkers for activated microglia/macrophages, astrocytes, blood-brain barrier leakage, and neuronal nuclei to determine the degree of foreign body response (FBR) resulting from the implanted microelectrodes. Despite its well-known acute anti-biofouling property, we observed that PEG-coated devices caused no significantly different FBR compared to non-coated controls at 4 weeks. A repetition using CX3CR1-GFP mice cohort showed similar results. Our histological findings suggest that there is no significant impact of acute delivery of PEG on the FBR in the long-term, and that temporary increase in the device footprint due to the coating of PEG also does not have a significant impact. Large variability seen within the same treatment group also implies that avoiding large superficial vasculature during implantation is not sufficient to minimize inter-animal variability.

7.
J Neural Eng ; 14(3): 036026, 2017 06.
Article in English | MEDLINE | ID: mdl-28470152

ABSTRACT

OBJECTIVE: Flexible neural probes are hypothesized to reduce the chronic foreign body response (FBR) mainly by reducing the strain-stress caused by an interplay between the tethered probe and the brain's micromotion. However, a large discrepancy of Young's modulus still exists (3-6 orders of magnitude) between the flexible probes and the brain tissue. This raises the question of whether we need to bridge this gap; would increasing the probe flexibility proportionally reduce the FBR? APPROACH: Using novel off-stoichiometry thiol-enes-epoxy (OSTE+) polymer probes developed in our previous work, we quantitatively evaluated the FBR to four types of probes with different softness: silicon (~150 GPa), polyimide (1.5 GPa), OSTE+Hard (300 MPa), and OSTE+Soft (6 MPa). MAIN RESULTS: We observed a significant reduction in the fluorescence intensity of biomarkers for activated microglia/macrophages and blood-brain barrier (BBB) leakiness around the three soft polymer probes compared to the silicon probe, both at 4 weeks and 8 weeks post-implantation. However, we did not observe any consistent differences in the biomarkers among the polymer probes. SIGNIFICANCE: The results suggest that the mechanical compliance of neural probes can mediate the degree of FBR, but its impact diminishes after a hypothetical threshold level. This infers that resolving the mechanical mismatch alone has a limited effect on improving the lifetime of neural implants.


Subject(s)
Brain Injuries/etiology , Brain Injuries/pathology , Electrodes, Implanted/adverse effects , Foreign-Body Reaction/etiology , Foreign-Body Reaction/pathology , Microelectrodes/adverse effects , Neural Prostheses/adverse effects , Animals , Brain Injuries/prevention & control , Elastic Modulus , Electrodes, Implanted/classification , Equipment Design , Equipment Failure Analysis , Foreign-Body Reaction/prevention & control , Mice , Microelectrodes/classification , Neural Prostheses/classification , Reproducibility of Results , Sensitivity and Specificity , Stress, Mechanical
8.
Mol Ther ; 22(11): 1900-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25048217

ABSTRACT

Methodologies to improve existing adeno-associated virus (AAV) vectors for gene therapy include either rational approaches or directed evolution to derive capsid variants characterized by superior transduction efficiencies in targeted tissues. Here, we integrated both approaches in one unified design strategy of "virtual family shuffling" to derive a combinatorial capsid library whereby only variable regions on the surface of the capsid are modified. Individual sublibraries were first assembled in order to preselect compatible amino acid residues within restricted surface-exposed regions to minimize the generation of dead-end variants. Subsequently, the successful families were interbred to derive a combined library of ~8 × 10(5) complexity. Next-generation sequencing of the packaged viral DNA revealed capsid surface areas susceptible to directed evolution, thus providing guidance for future designs. We demonstrated the utility of the library by deriving an AAV2-based vector characterized by a 20-fold higher transduction efficiency in murine liver, now equivalent to that of AAV8.


Subject(s)
Capsid Proteins/genetics , DNA, Viral/analysis , Dependovirus/genetics , Genetic Vectors/administration & dosage , Liver/virology , Amino Acid Sequence , Amino Acids , Animals , Gene Library , Genetic Therapy , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Male , Mice , Mice, Inbred C57BL , Organ Specificity , Sequence Analysis, DNA , Transduction, Genetic
9.
J Neurosci ; 33(47): 18368-80, 2013 Nov 20.
Article in English | MEDLINE | ID: mdl-24259562

ABSTRACT

Hormone peptide tyrosine-tyrosine (PYY) is secreted into circulation from the gut L-endocrine cells in response to food intake, thus inducing satiation during interaction with its preferred receptor, Y2R. Clinical applications of systemically administered PYY for the purpose of reducing body weight were compromised as a result of the common side effect of visceral sickness. We describe here a novel approach of elevating PYY in saliva in mice, which, although reliably inducing strong anorexic responses, does not cause aversive reactions. The augmentation of salivary PYY activated forebrain areas known to mediate feeding, hunger, and satiation while minimally affecting brainstem chemoreceptor zones triggering nausea. By comparing neuronal pathways activated by systemic versus salivary PYY, we identified a metabolic circuit associated with Y2R-positive cells in the oral cavity and extending through brainstem nuclei into hypothalamic satiety centers. The discovery of this alternative circuit that regulates ingestive behavior without inducing taste aversion may open the possibility of a therapeutic application of PYY for the treatment of obesity via direct oral application.


Subject(s)
Feeding Behavior/drug effects , Peptide Fragments/pharmacology , Peptide YY/deficiency , Saliva/enzymology , Aminophylline , Animals , Conditioning, Psychological/drug effects , Eating/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glucagon-Like Peptide 1/metabolism , Humans , Iodine Isotopes/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Oxytocin/metabolism , Peptide YY/chemistry , Proto-Oncogene Proteins c-fos/metabolism , Satiation/drug effects , Tyrosine 3-Monooxygenase/metabolism , Vasopressins/metabolism , alpha-MSH/metabolism
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