Publications by authors named "Tarun Saxena"

27 Publications

  • Page 1 of 1

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus.

Adv Healthc Mater 2021 Aug 2:e2100102. Epub 2021 Aug 2.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332-0363, USA.

The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202100102DOI Listing
August 2021

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth.

Adv Healthc Mater 2019 02 11;8(4):e1801076. Epub 2018 Dec 11.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, 101 Science Drive, Durham, NC, 27705, USA.

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically "walls-off" the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall-off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.201801076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657526PMC
February 2019

Pathophysiology of essential hypertension: an update.

Expert Rev Cardiovasc Ther 2018 Dec;16(12):879-887

b Department Yoga and Physical education , Mittal Hospital and Research Centre , Ajmer , India.

Introduction: Hypertension is caused by increased cardiac output and/or increased peripheral resistance. Areas covered: The various mechanisms affecting cardiac output/peripheral resistance involved in the development of essential hypertension are covered. These include genetics; sympathetic nervous system overactivity; renal mechanisms: excess sodium intake and pressure natriuresis; vascular mechanisms: endothelial cell dysfunction and the nitric oxide pathway; hormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS); obesity, obstructive sleep apnea (OSA); insulin resistance and metabolic syndrome; uric acid; vitamin D; gender differences; racial, ethnic, and environmental factors; increased left ventricular ejection force and hypertension and its association with increased basal sympathetic activity - cortical connections. Expert commentary: Maximum association of hypertension is found with sympathetic overactivity which is directly or indirectly involved in different mechanisms of hypertension including RAAS, OSA, obesity, etc.. It is not overt sympathetic activity but disturbed basal sympathetic tone. Basal sympathetic tone arises from hypothalamus; possibly affected by cortical influences. Therefore, hypertension is not merely a disease of circulatory system alone. Its pathogenesis involves alteration in ANS (autonomic nervous system) and likely in cortical-hypothalamic connections. Assessment of ANS and cortical-hypothalamic connections may be required for better understanding of hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14779072.2018.1540301DOI Listing
December 2018

Toward Functional Restoration of the Central Nervous System: A Review of Translational Neuroscience Principles.

Neurosurgery 2019 01;84(1):30-40

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Injury to the central nervous system (CNS) can leave patients with devastating neurological deficits that may permanently impair independence and diminish quality of life. Recent insights into how the CNS responds to injury and reacts to critically timed interventions are being translated into clinical applications that have the capacity to drastically improve outcomes for patients suffering from permanent neurological deficits due to spinal cord injury, stroke, or other CNS disorders. The translation of such knowledge into practical and impactful treatments involves the strategic collaboration between neurosurgeons, clinicians, therapists, scientists, and industry. Therefore, a common understanding of key neuroscientific principles is crucial. Conceptually, current approaches to CNS revitalization can be divided by scale into macroscopic (systems-circuitry) and microscopic (cellular-molecular). Here we review both emerging and well-established tenets that are being utilized to enhance CNS recovery on both levels, and we explore the role of neurosurgeons in developing therapies moving forward. Key principles include plasticity-driven functional recovery, cellular signaling mechanisms in axonal sprouting, critical timing for recovery after injury, and mechanisms of action underlying cellular replacement strategies. We then discuss integrative approaches aimed at synergizing interventions across scales, and we make recommendations for the basis of future clinical trial design. Ultimately, we argue that strategic modulation of microscopic cellular behavior within a macroscopic framework of functional circuitry re-establishment should provide the foundation for most neural restoration strategies, and the early involvement of neurosurgeons in the process will be crucial to successful clinical translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuros/nyy128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292792PMC
January 2019

Correlation of mRNA Expression and Signal Variability in Chronic Intracortical Electrodes.

Front Bioeng Biotechnol 2018 27;6:26. Epub 2018 Mar 27.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States.

Objective: The goal for this research was to identify molecular mechanisms that explain animal-to-animal variability in chronic intracortical recordings.

Approach: Microwire electrodes were implanted into Sprague Dawley rats at an acute (1 week) and a chronic (14 weeks) time point. Weekly recordings were conducted, and action potentials were evoked in the barrel cortex by deflecting the rat's whiskers. At 1 and 14 weeks, tissue was collected, and mRNA was extracted. mRNA expression was compared between 1 and 14 weeks using a high throughput multiplexed qRT-PCR. Pearson correlation coefficients were calculated between mRNA expression and signal-to-noise ratios at 14 weeks.

Main Results: At 14 weeks, a positive correlation between signal-to-noise ratio (SNR) and NeuN and GFAP mRNA expression was observed, indicating a relationship between recording strength and neuronal population, as well as reactive astrocyte activity. The inflammatory state around the electrode interface was evaluated using M1-like and M2-like markers. Expression for both M1-like and M2-like mRNA markers remained steady from 1 to 14 weeks. Anti-inflammatory markers, CD206 and CD163, however, demonstrated a significant positive correlation with SNR quality at 14 weeks. VE-cadherin, a marker for adherens junctions, and PDGFR-β, a marker for pericytes, both partial representatives of blood-brain barrier health, had a positive correlation with SNR at 14 weeks. Endothelial adhesion markers revealed a significant increase in expression at 14 weeks, while CD45, a pan-leukocyte marker, significantly decreased at 14 weeks. No significant correlation was found for either the endothelial adhesion or pan-leukocyte markers.

Significance: A positive correlation between anti-inflammatory and blood-brain barrier health mRNA markers with electrophysiological efficacy of implanted intracortical electrodes has been demonstrated. These data reveal potential mechanisms for further evaluation to determine potential target mechanisms to improve consistency of intracortical electrodes recordings and reduce animal-to-animal/implant-to-implant variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2018.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880884PMC
March 2018

Enrichment of endogenous fractalkine and anti-inflammatory cells via aptamer-functionalized hydrogels.

Biomaterials 2017 Oct 10;142:52-61. Epub 2017 Jul 10.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Early recruitment of non-classical monocytes and their macrophage derivatives is associated with augmented tissue repair and improved integration of biomaterial constructs. A promising therapeutic approach to recruit these subpopulations is by elevating local concentrations of chemoattractants such as fractalkine (FKN, CX3CL1). However, delivering recombinant or purified proteins is not ideal due to their short half-lives, suboptimal efficacy, immunogenic potential, batch variabilities, and cost. Here we report an approach to enrich endogenous FKN, obviating the need for delivery of exogenous proteins. In this study, modified FKN-binding-aptamers are integrated with poly(ethylene glycol) diacrylate to form aptamer-functionalized hydrogels ("aptagels") that localize, dramatically enrich and passively release FKN in vitro for at least one week. Implantation in a mouse model of excisional skin injury demonstrates that aptagels enrich endogenous FKN and stimulate significant local increases in Ly6CCX3CR1 non-classical monocytes and CD206 M2-like macrophages. The results demonstrate that orchestrators of inflammation can be manipulated without delivery of foreign proteins or cells and FKN-aptamer functionalized biomaterials may be a promising approach to recruit anti-inflammatory subpopulations to sites of injury. Aptagels are readily synthesized, highly customizable and could combine different aptamers to treat complex diseases in which regulation or enrichment of multiple proteins may be therapeutic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2017.07.013DOI Listing
October 2017

Engineering challenges for brain tumor immunotherapy.

Adv Drug Deliv Rev 2017 05 15;114:19-32. Epub 2017 Jun 15.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, 101 Science Drive, Durham, NC 27708-0271, USA. Electronic address:

Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.addr.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870902PMC
May 2017

Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.

Sci Rep 2017 01 5;7:39810. Epub 2017 Jan 5.

Georgia Institute of Technology, Department of Biomedical Engineering, Atlanta, GA, 30332 USA.

Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep39810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215548PMC
January 2017

Assessment of left ventricular ejection force and sympathetic skin response in normotensive and hypertensive subjects: A double-blind observational comparative case-control study.

Indian Heart J 2016 Sep - Oct;68(5):685-692. Epub 2016 Jan 12.

Department of Yoga and Physical Education, Mittal Hospital and Research Centre, Ajmer, India.

Background: Pathophysiology of essential hypertension remains obscure. Correlation among ventricular ejection force, sympathetic activity, and hypertension is less clearly narrated in hypertensive subjects.

Aims And Objectives: To assess correlation among ventricular ejection force, sympathetic activity, and hypertension in hypertensive subjects, and to be compared with normotensive subjects.

Methods: This is a case-control study to assess left ventricular ejection force (LVEF) and sympathetic skin response, in normotensive (group 1; control), and hypertensive subjects (group 2; cases). 100 cases were selected. Subjects having stages 1 and 2 hypertension were categorized in groups 2A and 2B, respectively. LVEF was calculated by using echocardiography observing aortic acceleration time (AT) and peak systolic velocity. Comparison among groups was done by using one-way ANOVA.

Results: Both groups were comparable. In group 2, 60 cases had stage 1 hypertension and 40 had stage 2 hypertension. Significantly short AT and significantly high LVEF were found in hypertension (groups 2A and 2B) (p<0.0001). Sympathetic activity was high in group 2A (p<0.0001). Stroke volume (SV) was high in group 2B (p<0.0001).

Conclusion: Stage 1 hypertension is a stage of increased sympathetic activity, leading to increased LVEF and hypertension (resetting of baroreceptors); stage 2 hypertension is a stage of normal sympathetic activity, increased LVEF, increased SV, and hypertension (possibly a stage of shift of renal equilibrium curve/renal output curve and blood pressure to a newer level).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ihj.2015.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079136PMC
May 2017

Implantable electronics: A sensor web for neurons.

Nat Mater 2015 Dec;14(12):1190-1

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, UA Whitaker Building, 313 Ferst Drive, Atlanta, Georgia 30332, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nmat4454DOI Listing
December 2015

Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells.

Bioconjug Chem 2015 Dec 20;26(12):2336-49. Epub 2015 Oct 20.

Regenerative Bioscience Center, ADS Complex, The University of Georgia , 425 River Road, Athens, Georgia 30602, United States.

Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 ± 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS-GAG hydrogels demonstrated ∼88.5 ± 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.bioconjchem.5b00397DOI Listing
December 2015

Aetiopathogenesis of type-2 diabetes mellitus: could chronic stress play an important role?

J Assoc Physicians India 2014 Jun;62(6):484-9

Objectives: Pathogenesis of type-2 diabetes remains elusive. Various factors including diet, physical exercise, obesity, genetic factors and stress, have been discussed. Among these factors role of stress is still poorly understood in diabetes. Therefore the study was planned to assess effect of stress in diabetic and non-diabetic population in a comparative descriptive manner.

Methods: 1000 diabetic cases (group A) and equal number of healthy individuals were selected as a comparison group (group B). Both groups were examined at 0, 12, 24 months. To assess stress 17 points were examined (factors mainly related to emotions, hurriedness, relaxed status etc.), total 68 points for stress were given; > 30/68 was considered as severe stress. Mental health life style factors like duration of sleep and working mental hours were also examined. EEG and SSR were done at 24 months to assess stress and sympathetic response.

Results: There was presence of chronic stress, (> 90% had > 30/68 scoring) more mental work and less sleep duration in group A. EEG showed synchronised v/s desynchronised basal rhythm in group B v/s group A. SSR suggestive of increased sympathetic activity in group A.

Conclusion: It is concluded that chronic stress leads to increased basal sympathetic activity, resulting from disturbed cortical hypothalamic axis, leading to central insulin resistance and diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2014

Tailoring between network rigidity and nanosecond transient absorption in a-Ge(x)As(35-x)Se₆₅ thin films.

Opt Lett 2015 Mar;40(5):768-71

In this Letter, we report the first observation of dramatic decrease in nanosecond (ns) pulsed laser-induced transient absorption (TA) in a-Ge(x)As(35-x)Se₆₅ thin films by tuning the amorphous network from floppy to rigid. Our results provide the direct experimental evidence of a self-trapped exciton mechanism, where trapping of the excitons occurs through bond rearrangements. Taken together, a rigid amorphous network with more constraints than degrees of freedom are unable to undergo any such bond rearrangements and results in weaker TA. However, we also demonstrate that excitation fluence can be effectively utilized as a simple tool to lift up enough constraints to introduce large TA even in rigid networks. Apart from this, we also show that TA is tunable with network rigidity as it blueshifts when the mean coordination is increased from 2.35 to 2.6.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1364/OL.40.000768DOI Listing
March 2015

Nanocarrier-mediated inhibition of macrophage migration inhibitory factor attenuates secondary injury after spinal cord injury.

ACS Nano 2015 Feb 28;9(2):1492-505. Epub 2015 Jan 28.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine , Atlanta, Georgia 30332, United States.

Spinal cord injury (SCI) can lead to permanent motor and sensory deficits. Following the initial traumatic insult, secondary injury mechanisms characterized by persistent heightened inflammation are initiated and lead to continued and pervasive cell death and tissue damage. Anti-inflammatory drugs such as methylprednisolone (MP) used clinically have ambiguous benefits with debilitating side effects. Typically, these drugs are administered systemically at high doses, resulting in toxicity and paradoxically increased inflammation. Furthermore, these drugs have a small time window postinjury (few hours) during which they need to be infused to be effective. As an alternative to MP, we investigated the effect of a small molecule inhibitor (Chicago sky blue, CSB) of macrophage migration inhibitory factor (MIF) for treating SCI. The pleiotropic cytokine MIF is known to contribute to upregulation of several pro-inflammatory cytokines in various disease and injury states. In vitro, CSB administration alleviated endotoxin-mediated inflammation in primary microglia and macrophages. Nanocarriers such as liposomes can potentially alleviate systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. However, the therapeutic window of 100 nm scale nanoparticle localization to the spinal cord after contusion injury is not fully known. Thus, we first investigated the ability of nanocarriers of different sizes to localize to the injured spinal cord up to 2 weeks postinjury. Results from the study showed that nanocarriers as large as 200 nm in diameter could extravasate into the injured spinal cord up to 96 h postinjury. We then formulated nanocarriers (liposomes) encapsulating CSB and administered them intravenously 48 h postinjury, within the previously determined 96 h therapeutic window. In vivo, in this clinically relevant contusion injury model in rats, CSB administration led to preservation of vascular and white matter integrity, improved wound healing, and an increase in levels of arginase and other transcripts indicative of a resolution phase of wound healing. This study demonstrates the potential of MIF inhibition in SCI and the utility of nanocarrier-mediated drug delivery selectively to the injured cord.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/nn505980zDOI Listing
February 2015

Intracortical recording interfaces: current challenges to chronic recording function.

ACS Chem Neurosci 2015 Jan 14;6(1):68-83. Epub 2015 Jan 14.

Regenerative Bioscience Center, ADS Complex, The University of Georgia , Athens, Georgia 30602-2771, United States.

Brain Computer Interfaces (BCIs) offer significant hope to tetraplegic and paraplegic individuals. This technology relies on extracting and translating motor intent to facilitate control of a computer cursor or to enable fine control of an external assistive device such as a prosthetic limb. Intracortical recording interfaces (IRIs) are critical components of BCIs and consist of arrays of penetrating electrodes that are implanted into the motor cortex of the brain. These multielectrode arrays (MEAs) are responsible for recording and conducting neural signals from local ensembles of neurons in the motor cortex with the high speed and spatiotemporal resolution that is required for exercising control of external assistive prostheses. Recent design and technological innovations in the field have led to significant improvements in BCI function. However, long-term (chronic) BCI function is severely compromised by short-term (acute) IRI recording failure. In this review, we will discuss the design and function of current IRIs. We will also review a host of recent advances that contribute significantly to our overall understanding of the cellular and molecular events that lead to acute recording failure of these invasive implants. We will also present recent improvements to IRI design and provide insights into the futuristic design of more chronically functional IRIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/cn5002864DOI Listing
January 2015

Extracellular matrix-based intracortical microelectrodes: Toward a microfabricated neural interface based on natural materials.

Microsyst Nanoeng 2015 29;1(1). Epub 2015 Jun 29.

Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332, USA.

Extracellular matrix (ECM)-based implantable neural electrodes (NEs) were achieved using a microfabrication strategy on natural-substrate-based organic materials. The ECM-based design minimized the introduction of non-natural products into the brain. Further, it rendered the implants sufficiently rigid for penetration into the target brain region and allowed them subsequently to soften to match the elastic modulus of brain tissue upon exposure to physiological conditions, thereby reducing inflammatory strain fields in the tissue. Preliminary studies suggested that ECM-NEs produce a reduced inflammatory response compared with inorganic rigid and flexible approaches. intracortical recordings from the rat motor cortex illustrate one mode of use for these ECM-NEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/micronano.2015.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258041PMC
June 2015

Nanosecond light induced, thermally tunable transient dual absorption bands in a-Ge₅As₃₀Se₆₅ thin film.

Sci Rep 2014 Oct 10;4:6573. Epub 2014 Oct 10.

Department of Physics, Indian Institute of Science Education and Research, Bhopal 462023, India.

In this article, we report the first observation of nanosecond laser induced transient dual absorption bands, one in the bandgap (TA₁) and another in the sub-bandgap (TA₂) regions of a-Ge₅As₃₀Se₆₅ thin films. Strikingly, these bands are thermally tunable and exhibit a unique contrasting characteristic: the magnitude of TA₁ decreases while that of TA₂ increases with increasing temperature. Further, the decay kinetics of these bands is strongly influenced by the temperature, which signifies a strong temperature dependent exciton recombination mechanism. The induced absorption shows quadratic and the decay time constant shows linear dependence on the laser beam fluence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep06573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192641PMC
October 2014

Chondroitin sulfate glycosaminoglycans for CNS homeostasis-implications for material design.

Curr Med Chem 2014 ;21(37):4257-81

Regenerative Bioscience Center, Edgar L. Rhodes Center for Animal and Dairy Sciences, The University of Georgia, Athens, GA 30602-2771, USA.

Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the "peri-neuronal nets" (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/0929867321666140815124447DOI Listing
June 2015

Relationship between intracortical electrode design and chronic recording function.

Biomaterials 2013 Nov 26;34(33):8061-74. Epub 2013 Jul 26.

Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, 313 Ferst Drive, Atlanta, GA 30332-0535, USA.

Intracortical electrodes record neural signals directly from local populations of neurons in the brain, and conduct them to external electronics that control prosthetics. However, the relationship between electrode design, defined by shape, size and tethering; and long-term (chronic) stability of the neuron-electrode interface is poorly understood. Here, we studied the effects of various commercially available intracortical electrode designs that vary in shape (cylindrical, planar), size (15 μm, 50 μm and 75 μm), and tethering [electrode connections to connector with (tethered) and without tethering cable (untethered)] using histological, transcriptomic, and electrophysiological analyses over acute (3 day) and chronic (12 week) timepoints. Quantitative analysis of histological sections indicated that Michigan 50 μm (M50) and Michigan tethered (MT) electrodes induced significantly (p < 0.01) higher glial scarring, and lesser survival of neurons in regions of blood-brain barrier (BBB) breach when compared to microwire (MW) and Michigan 15 μm (M15) electrodes acutely and chronically. Gene expression analysis of the neurotoxic cytokines interleukin (Il)1 (Il1α, Il1β), Il6, Il17 (Il17a, Il17b, Il17f), and tumor necrosis factor alpha (Tnf) indicated that MW electrodes induced significantly (p < 0.05) reduced expression of these transcripts when compared to M15, M50 and FMAA electrodes chronically. Finally, electrophysiological assessment of electrode function indicated that MW electrodes performed significantly (p < 0.05) better than all other electrodes over a period of 12 weeks. These studies reveal that intracortical electrodes with smaller size, cylindrical shape, and without tethering cables produce significantly diminished inflammatory responses when compared to large, planar and tethered electrodes. These studies provide a platform for the rational design and assessment of chronically functional intracortical electrode implants in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2013.07.016DOI Listing
November 2013

The impact of chronic blood-brain barrier breach on intracortical electrode function.

Biomaterials 2013 Jul 2;34(20):4703-13. Epub 2013 Apr 2.

Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology, Emory University School of Medicine, Atlanta, GA 30332-0535, USA.

Brain-computer interfaces (BCIs) have allowed control of prosthetic limbs in paralyzed patients. Unfortunately, the electrodes of the BCI that interface with the brain only function for a short period of time before the signal quality on these electrodes becomes substantially diminished. To truly realize the potential of BCIs, it is imperative to have electrodes that function chronically. In order to elucidate the physiological determinants of a chronically functional neural interface, we studied the role of the blood-brain barrier (BBB) in electrode function, because it is a key mediator of neuronal hemostasis. We monitored the status of the BBB and the consequences of BBB breach on electrode function using non-invasive imaging, electrophysiology, genomic, and histological analyses. Rats implanted with commercially available intracortical electrodes demonstrated an inverse correlation between electrode performance and BBB breach over a period of 16 weeks. Genomic analysis showed that chronically functional electrodes elicit an enhanced wound healing response. Conversely, in poorly functioning electrodes, chronic BBB breach led to local accumulation of neurotoxic factors and an influx of pro-inflammatory myeloid cells, which negatively affect neuronal health. These findings were further verified in a subset of electrodes with graded electrophysiological performance. In this study, we determine the mechanistic link between intracortical electrode function and failure. Our results indicate that BBB status is a critical physiological determinant of intracortical electrode function and can inform future electrode design and biochemical intervention strategies to enhance the functional longevity of BCIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2013.03.007DOI Listing
July 2013

The upregulation of specific interleukin (IL) receptor antagonists and paradoxical enhancement of neuronal apoptosis due to electrode induced strain and brain micromotion.

Biomaterials 2012 Sep 6;33(26):5983-96. Epub 2012 Jun 6.

Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, Atlanta, 313 Ferst Drive, GA 30332-0535, USA.

The high mechanical mismatch between stiffness of silicon and metal microelectrodes and soft cortical tissue, induces strain at the neural interface which likely contributes to failure of the neural interface. However, little is known about the molecular outcomes of electrode induced low-magnitude strain (1-5%) on primary astrocytes, microglia and neurons. In this study we simulated brain micromotion at the electrode-brain interface by subjecting astrocytes, microglia and primary cortical neurons to low-magnitude cyclical strain using a biaxial stretch device, and investigated the molecular outcomes of induced strain in vitro. In addition, we explored the functional consequence of astrocytic and microglial strain on neural health, when they are themselves subjected to strain. Quantitative real-time PCR array (qRT-PCR Array) analysis of stretched astrocytes and microglia showed strain specific upregulation of an Interleukin receptor antagonist - IL-36Ra (previously IL-1F5), to ≈ 1018 and ≈ 236 fold respectively. Further, IL-36Ra gene expression remained unchanged in astrocytes and microglia treated with bacterial lipopolysaccharide (LPS) indicating that the observed upregulation in stretched astrocytes and microglia is potentially strain specific. Zymogram and western blot analysis revealed that mechanically strained astrocytes and microglia upregulated matrix metalloproteinases (MMPs) 2 and 9, and other markers of reactive gliosis such as glial fibrillary acidic protein (GFAP) and neurocan when compared to controls. Primary cortical neurons when stretched with and without IL-36Ra, showed a ≈ 400 fold downregulation of tumor necrosis factor receptor superfamily, member 11b (TNFRSF11b). Significant upregulation of members of the caspase cysteine proteinase family and other pro-apoptotic genes was also observed in the presence of IL-36Ra than in the absence of IL-36Ra. Adult rats when implanted with microwire electrodes showed upregulation of IL-36Ra (≈ 20 fold) and IL-1Ra (≈ 1500 fold) 3 days post-implantation (3 DPI), corroborating in vitro results, although these transcripts were drastically down regulated by ≈ 20 fold and ≈ 1488 fold relative to expression levels 3 DPI, at the end of 12 weeks post-implantation (12 WPI). These results demonstrate that IL receptor antagonists may be negatively contributing to neuronal health at acute time-points post-electrode implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2012.05.021DOI Listing
September 2012

Mild cool air--a risk factor for asthma exacerbations: results of a retrospective study.

J Assoc Physicians India 2011 Oct;59:624-8

Mittal Hospital and Research Centre, Ajmer, Rajasthan.

Background And Objectives: Worldwide incidence of bronchial asthma is on rise. Infections either viral or bacterial and various environmental factors are considered as major risk factors for exacerbations in various studies. Despite of awareness and preventive strategies to risk factors, exacerbations largely remain uncontrolled, therefore the study was planned to review the existing risk factors and to find out some other risk factor/factors which could help us in understanding the other causes of exacerbations.

Methods: The study was done in Ajmer, the central part of Rajasthan state, India, at Mittal Hospital & Research Centre and J. L. N. Medical college hospital by collecting data for the period of four years (January 2006 - December 2009). Monthly record of 300 regular cases of bronchial asthma was taken. This record included symptoms, history of exposure to various risk factors, and PEFR. Environmental data was also collected. On the basis of record monthly attack rate was calculated. RESULTS/OBSERVATIONS: Maximum attack rate (> 90%) was found in October, November (early winter) and February and March (spring) during all the four years studied except in October 2009. A common precipitant present during these months was mild cool air (environmental temperature of 23-27 degrees c). Attack rate was very less above and below of this temperature. No clear association was present with any other known precipitants.

Conclusion: It is concluded that inhalation of mild coolair (23-27 degrees c) may be an important risk factor besides other risk factors for asthma exacerbation.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2011

Mechanical characterization of the injured spinal cord after lateral spinal hemisection injury in the rat.

J Neurotrauma 2012 Jun 21;29(9):1747-57. Epub 2012 May 21.

Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York 13244, USA.

The glial scar formed at the site of traumatic spinal cord injury (SCI) has been classically hypothesized to be a potent physical and biochemical barrier to nerve regeneration. One longstanding hypothesis is that the scar acts as a physical barrier due to its increased stiffness in comparison to uninjured spinal cord tissue. However, the information regarding the mechanical properties of the glial scar in the current literature is mostly anecdotal and not well quantified. We monitored the mechanical relaxation behavior of injured rat spinal cord tissue at the site of mid-thoracic spinal hemisection 2 weeks and 8 weeks post-injury using a microindentation test method. Elastic moduli were calculated and a modified standard linear model (mSLM) was fit to the data to estimate the relaxation time constant and viscosity. The SLM was modified to account for a spectrum of relaxation times, a phenomenon common to biological tissues, by incorporating a stretched exponential term. Injured tissue exhibited significantly lower stiffness and elastic modulus in comparison to uninjured control tissue, and the results from the model parameters indicated that the relaxation time constant and viscosity of injured tissue were significantly higher than controls. This study presents direct micromechanical measurements of injured spinal cord tissue post-injury. The results of this study show that the injured spinal tissue displays complex viscoelastic behavior, likely indicating changes in tissue permeability and diffusivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/neu.2011.1818DOI Listing
June 2012

Raman spectroscopic investigation of spinal cord injury in a rat model.

J Biomed Opt 2011 Feb;16(2):027003

Syracuse University, Department of Biomedical and Chemical Engineering, Syracuse, New York 13244, USA.

Raman spectroscopy was used to study temporal molecular changes associated with spinal cord injury (SCI) in a rat model. Raman spectra of saline-perfused, injured, and healthy rat spinal cords were obtained and compared. Two injury models, a lateral hemisection and a moderate contusion were investigated. The net fluorescence and the Raman spectra showed clear differences between the injured and healthy spinal cords. Based on extensive histological and biochemical characterization of SCI available in the literature, these differences were hypothesized to be due to cell death, demyelination, and changes in the extracellular matrix composition, such as increased expression of proteoglycans and hyaluronic acid, at the site of injury where the glial scar forms. Further, analysis of difference spectra indicated the presence of carbonyl containing compounds, hypothesized to be products of lipid peroxidation and acid catalyzed hydrolysis of glycosaminoglycan moieties. These results compared well with in vitro experiments conducted on chondroitin sulfate sugars. Since the glial scar is thought to be a potent biochemical barrier to nerve regeneration, this observation suggests the possibility of using near infrared Raman spectroscopy to study injury progression and explore potential treatments ex vivo, and ultimately monitor potential remedial treatments within the spinal cord in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1117/1.3549700DOI Listing
February 2011

The effect of various breathing exercises (pranayama) in patients with bronchial asthma of mild to moderate severity.

Int J Yoga 2009 Jan;2(1):22-5

Department of Internal Medicine, Swamy Consultant Physician Mittal Hospital, Ajmer, India.

Background/aim: The incidence of bronchial asthma is on increase. Chemotherapy is helpful during early course of the disease, but later on morbidity and mortality increases. The efficacy of yoga therapy though appreciated is yet to be defined and modified.

Aim: To study the effect of breathing exercises (pranayama) in patients with bronchial asthma of mild to moderate severity.

Materials And Methods: Fifty cases of bronchial asthma (Forced Expiratory Volume in one second (FEV1) > 70%) were studied for 12 weeks. Patients were allocated to two groups: group A and group B (control group). Patients in group A were treated with breathing exercises (deep breathing,Brahmari, and Omkara, etc.) for 20 minutes twice daily for a period of 12 weeks. Patients were trained to perform Omkara at high pitch (forceful) with prolonged exhalation as compared to normal Omkara. Group B was treated with meditation for 20 minutes twice daily for a period of 12 weeks. Subjective assessment, FEV1%, and Peak Expiratory Flow Rate (PEFR) were done in each case initially and after 12 weeks.

Results: After 12 weeks, group A subjects had significant improvement in symptoms, FEV1, and PEFR as compared to group B subjects.

Conclusion: Breathing exercises (pranayama), mainly expiratory exercises, improved lung function subjectively and objectively and should be regular part of therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0973-6131.53838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017963PMC
January 2009

A versatile mesoindentation system to evaluate the micromechanical properties of soft, hydrated substrates on a cellular scale.

J Biomed Mater Res A 2009 Sep;90(4):1206-17

Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York, USA.

It has become increasingly important to study mechanical properties of substrates on the cellular scale since cells sense and respond to changes in the microenvironment in which they are grown. To study the effects of mechanical substrate properties on the cellular scale, an existing microindentation system has been modified to perform indentation tests on highly hydrated polymeric substrates and tissues. The highly sensitive, modified indentation system, labeled as a mesoindenter, is versatile and can be customized to perform a variety of tests useful for studying tissue mechanics, stress relaxation in polymers, and interfacial adhesion phenomena. To validate the efficacy and accuracy of the system, soft, hydrated hydrogels made from agarose (1-5 wt %), poly(2-hydroxyethyl methacrylate) (p(HEMA)) (60-90% water), and unfixed, saline-perfused rat spinal cord tissue were tested. The results demonstrate that moduli vary with water content and are in line with previously published studies. We also demonstrate that the modulus of hydrogels is sensitive to the preload applied, with modulus increasing with preload. Stress relaxation indentation testing of p(HEMA) showed relaxation behavior that can be modeled using a heredity integral and standard linear model. The mesoindenter is versatile, capable of scanning and testing immersed samples, and easily customized to ascertain mechanical properties of substrates ranging from the kPa to GPa range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm.a.32178DOI Listing
September 2009
-->