Carbon Fiber Microelectrode Arrays for Neuroprosthetic and Neuroscience Applications.

The aim of this work is to develop, validate, and characterize the insertion mechanism, tissue response, and recording longevity of a new high-density carbon fiber microelectrode array. This technology was designed to significantly improve the field of penetrating microelectrodes while simultaneously accommodating the variable needs of both neuroscientists and neural engineers. The first study presents the fabrication and insertion dynamics of a high-density carbon fiber electrode array using a dual sided printed circuit board platform. The use of this platform has pushed electrode density to limits not seen in other works. This necessitated the use of an encapsulation method that served to temporarily stiffen the fibers during insertion, but did not enter the brain as many other shuttles do for other probe designs. The initial findings in this work informed the development of an even higher density array using a silicon support structure as a backbone. The second study reports on the tissue reaction of chronically implanted carbon fiber electrode arrays as compared to silicon electrodes. Due to their smaller footprint, the reactive response to carbon fibers should be greatly attenuated, if not non-existent. Results show a scarring response to the implanted silicon electrode with elevated astrocyte and microglia activity coupled to a local decrease in neuronal density. The area implanted with the carbon fiber electrodes showed a varied response, from no detectable increase in astrocytic or microglial activity to an elevated activation of both cell types, but with no detectable scars. Neuronal density in the carbon fiber implant region was unaffected. The data demonstrates that the small carbon fiber profile, even in an array configuration, shows an attenuated reactive response with no visible scaring. The final study reports on the viability of chronically implanted high-density carbon fiber arrays as compared to more traditional silicon planar arrays with comparable site sizes. While most new probe technologies or designs are able to demonstrate proof of concept functionality in acute preparations, very few show the ability to record chronic unit activity. This study aims to provide a comprehensive analysis of electrophysiology data collected over implant durations ranging from 3 – 5 months.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111557/1/parasp_1.pd

Development, Characterization of Hydroxyl Terminated Dendritic Macromolecules as Prospective Drug Carriers

The principal aspiration is to develop triazine dendrimers as potential drug carriers for sustained release. Triazine based dendrimer was synthesized by divergent method evading protection/ deprotection or functional group interconversion. Synthesized dendrimers were characterized by FTIR, 1H-NMR, 13C-NMR and ESI-Mass spectrometry. Synthesized full generation dendrimers G1, G2 and G3 were applied as solubility enhancers of hydrophobic drug ketoprofen. Ketoprofen was loaded by G3 dendrimer by inclusion complex method. Sustained release of ketoprofen from ketoprofen loaded dendrimer was studied and compared to of free ketoprofen. Cytotoxicity and hemolytic assay of dendrimer was studied to evaluate toxicity of dendrimer as drug vehicle

A NANOSCALE DENDRITIC MACROMOLECULES BASED ON ETHANE 1,2-DIAMINE AS POTENTIAL DRUG CARRIERS FOR NSAIDS: SYNTHESIS, CHARACTERIZATION AND APPLICATIONS

Objective: The present work deals with the objective of development and characterization of novel dendritic macromolecules as solubility enhancer and carrier for sustained release of Ketoprofen. Cytotoxicity and hemolytic assay of dendritic macromolecules were also estimated as an objective to evaluate its toxicity and biocompatibility. Methods: Dendritic macromolecules were synthesized using divergent method. Synthesized macromolecules were characterized by spectral techniques such as FTIR, 1H-NMR, 13C-NMR electro-spray ionization mass spectrometry and elemental analysis. Enhanced aqueous solubility of ketoprofen was evaluated with respect to pH, generation number and concentration of dendrimer using Higuchi and Connors method. Sustained release of ketoprofen from ketoprofen loaded dendrimers was measured and compared with that of free ketoprofen. Hemolytic assay and cytotoxicity of G3 dendrimer on A-549 cell lines were studied to evaluate toxicity and biocompatibility of dendrimer. All dendritic macromolecules were fully characterized by spectral techniques. Results: Solubility study revealed that aqueous solubility of ketoprofen by dendrimer increased with increase in pH, concentration and generation of dendrimer. Ketoprofen was released slowly from ketoprofen loaded dendrimer compared to that of free ketoprofen. Dendritic macromolecules were less cytotoxic and showed less hemolytic potential. Conclusion: It can be concluded that dendrimer have high potential as carriers and solubility enhancers of hydrophobic drug. Keywords: Triazine based dendrimer, Ketoprofen, Drug Carrier, Cytotoxicity, Hemolysis

Nav1.1 and Nav1.6: electrophysiological properties, epilepsy-associated mutations and therapeutic targets

Indiana University-Purdue University Indianapolis (IUPUI)Voltage-‐gated sodium channels (VGSCs) are critical for the initiation and propagation of electrical signals in neurons; consequently they are significant regulators of neuronal excitability. They are exquisitely tuned and aberrations in their activity can lead to pathophysiological conditions. This dissertation highlights the roles of two prominent brain isoforms of VGSCs, Nav1.1 and Nav1.6. These isoforms have distinct localization in the brain. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment (AIS) of GABAergic neurons, while Nav1.6 is found at the distal AIS and nodes of Ranvier of both GABAergic and excitatory neurons. Several mutations have been identified in Nav1.1 and recently mutations in Nav1.6 have been discovered in patients with distinct epileptic phenotypes that respond poorly to current anti-epileptics. There is a need to better understand mechanistically how mutations in these channel isoforms lead to epilepsy in order to identify more efficacious treatment strategies. Therefore, the aims of this dissertation were to 1) examine the differential biophysical properties of Nav1.1 and Nav1.6, 2) determine the biophysical consequences of epilepsy-­associated mutations in Nav1.1 and Nav1.6 and examine the effects of cannabinoids on wildtype and mutant channel activity and 3) test the effects of selective inhibition of Nav1.1 versus Nav1.6 on epileptiform activity. To address these aims, whole­‐cell electrophysiology and mutlielectrode array recordings were used. The results demonstrate that 1) Nav1.1 and Nav1.6 have important differences in their biophysical properties that may be important in the fine­‐tuning of neuronal excitability, 2) epilepsy-­‐associated mutations in Nav1.1 and Nav1.6 alter several biophysical properties of the channels but have differential effects on resurgent current generation suggesting a divergence in the mechanism by which they induce epileptogenesis and cannabidiol can inhibit aberrant channel activity and reduce neuronal excitability and 3) pharmacological inhibition of Nav1.6, but not Nav1.1, abolishes epileptiform activity. Overall, this dissertation provides insight into the distinct contributions of Nav1.1 and Nav1.6 to physiological and pathophysiological firing activity and their ability to be targeted for therapeutic purposes. This knowledge is critical for understanding the potential role of VGSCs in epilepsy syndromes and identifying possible drug targets for more efficacious treatment strategies

Development of a Novel Handheld Device for Active Compensation of Physiological Tremor

In microsurgery, the human hand imposes certain limitations in accurately positioning the tip of a device such as scalpel. Any errors in the motion of the hand make microsurgical procedures difficult and involuntary motions such as hand tremors can make some procedures significantly difficult to perform. This is particularly true in the case of vitreoretinal microsurgery. The most familiar source of involuntary motion is physiological tremor. Real-time compensation of tremor is, therefore, necessary to assist surgeons to precisely position and manipulate the tool-tip to accurately perform a microsurgery. In this thesis, a novel handheld device (AID) is described for compensation of physiological tremor in the hand. MEMS-based accelerometers and gyroscopes have been used for sensing the motion of the hand in six degrees of freedom (DOF). An augmented state complementary Kalman filter is used to calculate 2 DOF orientation. An adaptive filtering algorithm, band-limited Multiple Fourier linear combiner (BMFLC), is used to calculate the tremor component in the hand in real-time. Ionic Polymer Metallic Composites (IPMCs) have been used as actuators for deflecting the tool-tip to compensate for the tremor

Design and performance evaluation of a prototype MRF-based haptic interface for medical applications

This paper describes the construction and stability and transparency evaluation of a prototype two degrees-of-freedom (DoF) haptic interface, which takes ad-vantage of magneto-rheological fluid (MRF)-based clutches for actuation. These small-scale clutches were designed in our lab, and their evaluation were reported previously [1],[2]. MRF-based actuators exhibit superior characteristics,which can significantly contribute to transparency and stability of haptic devices. Based on these actuators, a distributed antagonistic configuration is used to develop the2-DoF haptic interface. This device is incorporated in a master–slave teleoperation setup intended for medical per-cutaneous interventions and soft-tissue palpation. Preliminary studies on the stability and transparency of the haptic interface in this setup using phantom and ex vivo samples show the great potential of MRF-based actuators for integr-tion in haptic devices that require reliable, safe, accurate,highly transparent, and stable force reflection

GC MS Based Comparative Phytochemical Profiling of Rhodiola Imbricata Roots Collected from Different High Mountain Passes of Ladakh India and a First Report of Apocynin from Genus Rhodiola

Rhodiola imbricata is a high value medicinal plant of trans-Himalayan mountain passes in Ladakh. This plant is a highly sought after in national and international herbal product market due to its unique phytochemical composition and resultant medicinal properties. However, compositional variation in the raw material from different geographical locations results in variation in quality as well as efficacy of the final products. The current study was designed to generate the comparative GC-MS profiles of hydro-methanolic extracts of Rhodiola imbricata root samples collected from various locations in Ladakh i.e., Chang La (17605 ft), Khardung La (18,379 ft), and Shashi La (13908 ft) mountain passes. The study highlighted variations in volatile phytochemical composition in root samples collected from different locations, especially with respect to phenols, terpenes and fatty acids. Samples from Chang La had maximum amount of phenolic compounds (96.78 per cent), followed by samples from Khardung La (77.05 per cent) while they were undetected in samples from Shashi La pass. Specifically, comparative GC-MS profiling revealed that peak area percentage of two important bioactive compounds (i.e. piceol and apocynin) varied amongst samples. In the samples collected from Chang La, the piceol covered (94 per cent) and apocynin covered (2.78 per cent) peak area whereas in samples collected from Khardung La, piceol covered (73.8 per cent) and apocynin covered (3.25 per cent) peak areas respectively, however, samples collected from Shashi La showed none of these compounds. Interestingly, in the present study, apocynin (a potent NADPH oxidase inhibitor) is being reported for the first time from Rhodoila genus. On the basis of present findings, samples collected from Chang La and Khardung La passes showed better phytochemical composition of pharmacological active phenolic compounds than Shashi La sample