Centre for Nanosciences
Amrita Institute of Medical Sciences,
Amrita Vishwa Vidyapeetham
AIMS Ponekkara P. O., Kochi, Kerala - 682 041, India.

0484 285 8750
researchsecretary@aims.amrita.edu
 

 

Dr. Sahadev Shankarappa joined Amrita Centre for Nanosciences and Molecular Medicine as an assistant professor in May 2013 and currently heads the laboratory of neuronal drug delivery. He is a physician-scientist with post-doctoral training in the laboratories of Professors Robert Langer at MIT and Daniel Kohane at Boston Children's Hospital, Harvard Medical School, Boston. He has a Ph.D. in Neurosciences from Loyola University Chicago, MPH from the University of North Carolina at Chapel Hill, and M.B.B.S. from Bangalore University. He is also the recipient of the prestigious Ramalingaswami re-entry fellowship, administered by the Department of Biotechnology, Government of India. His research interest is in the field of axonal biology and trying to devise strategies to utilize axons as a route for drug delivery for the nervous system to treat disorders such as chronic neuropathic pain. In addition, Dr. Sahadev is also currently working on examining plant-waste as a potential raw material for bio-medical applications. Apart from research, Sahadev is currently working on becoming a long distance runner.

Pain is a critical component of life that is necessary for survival. However, uncontrolled and unwarranted pain secondary to underlying disease conditions is responsible for significant morbidity among people worldwide. Treating such ‘pain conditions’ is extremely difficult; one of the primary challenges being, the inability in delivering drugs to specific neuronal target sites. To address this challenge, the laboratory of neuronal drug delivery focuses on developing novel and cost-affordable avenues to delivery therapeutic drugs to treat pain conditions.

Neurons & Nanoparticles

The emphasis of the lab is to use our understanding of pain neurobiology to design and develop rationale delivery platforms using nano/ micro technology that will better facilitate neural drug delivery with decreased systemic side effects. We have recently established an animal behavioural testing laboratory that is equipped with various pain monitoring equipment to facilitate recording and quantifying pain responses in animal models.

Key focus of the lab includes:

  • Investigating the potential use of metal and polymer-based nanoparticles, as drug delivery agents in pain disorders.
  • Understanding the cellular mechanisms of nano-particulate delivery-vehicle uptake and transport in sensory neurons involved in the pain pathway.
  • Developing innovative approaches to attenuate pain in patients suffering from cancer induced bone-pain.
  • Studying the role of peripheral glial cell response in the pain pathway and effect of nanoparticles on such cellular responses.
  • Bio-medical applications and uses of non-edible plant-derived wastes.
DRG Culture
Gold Nanoparticles
Gold Nanorods
Sensory Neurons in Microfluidic Chamber

Neeraj Katiyar

Neeraj Katiyar, is a Ph.D. student working as a Senior Research Fellow in the lab. His work is focussed on developing neuron-targeting transdermal drug-delivery systems that can be potentially used in conditions such as chronic pain. He has previously worked as a project assistant in the Biosensor Lab, CSIR-Central Food Technological Research Institute, Mysore, India. Neeraj has completed his M.Sc. from Vellore Institute of Technology, VIT University and B.Sc. form M. S. Ramaiah College of Arts, Science and Commerce, Bangalore University. His interests are in nanomedicines and multifunctional nanostructures for drug delivery. Neeraj was recently awarded the ICMR fellowship to pursue his research.

Sumi Mathew

Sumi Mathew, is currently a research scholar working on developing drug delivery systems to attenuate bone cancer-induced pain. She has completed her M.Tech in Nanoscience and Technology at Amrita Centre for Nanosciences and Molecular Medicine, and her B.Tech in Biotechnology and Biochemical Engineering from Sree Buddha College of Engineering, Kerala University. Her interests are in developing long-acting polymeric drug delivery systems.

Shivakumar

Shivakumar is a junior research fellow in the lab. He has previously worked in the Himalaya drug company and Adcock Ingram as an executive in quality control and assurance departments. Shiva has completed his M.Pharm from Sree Siddaganga College of Pharmacy, Rajiv Gandhi University of Health Sciences, Karnataka. His research interests are in polymeric and biomimetic nano drug delivery carriers.

Gayathri Raju

Gayathri Raju is a junior research fellow. She has completed her post graduation in Nanoscience and Technology from Amrita Centre for Nanosciences and Molecular Medicine, and her under graduation in Nanotechnology from SRM University. Her research interests are in developing bio-inspired neuron targeted delivery systems.

Pallavi Madhusudanan

Pallavi Madhusudanan is currently working as a Senior Research Fellow in Molecular Medicine at Amrita Centre for Nanosciences and Molecular Medicine. She is working on understanding the influence of metallic nanoparticles on glia-neuron communication, a phenomenon that has direct bearings in gliopathic pain conditions. Pallavi has completed her B.E. in Biotechnology from M. S. Ramaiah Institute of Technology, Visvesvaraya Technological University. She is planning to pursue higher studies in research focused on neuroscience.

Rajyalakshmi

Rajyalakshmi is pursuing her M.Tech in Nanomedical Sciences at Amrita Centre for Nanosciences and Molecular Medicine. Rajyalakshmi is currently working on understanding the interaction between neurons and non-spherical shaped nanoparticles, with specific emphasis on toxicity and neuronal differentiation. She has completed her B. Tech. in Nanotechnology from Lovely Professional University in Punjab and in the future, plans to work in the field of Nanosciences.

Vignesh GP

Vignesh GP is currently pursuing his M.Tech in Molecular Medicine at Amrita Centre for Nanosciences and Molecular Medicine. He is interested in studying the extent of neuritic outgrowth on electrically stimulated scaffolds and further plans to develop constructs that could have applications in nerve repair. Vignesh has a B. Tech. degree in Bioinformatics from VIT University, and plans to pursue Neuroscience for his future studies.

Amata

Amata is currently pursuing M.Tech in Molecular Medicine at ACNSMM. She completed her B. Tech in Genetic Engineering from SRM University, Chennai, Tamil Nadu. Her current work focuses on studying neuritic network formation in confined tubular spaces with possible applications in neural regeneration. In the future, she is planning on pursuing a career in academia that lies at the interface of genetics and neuroscience. In addition, she is actively pursuing a parallel career in music, as a versatile vocalist. If you don't find her working in the laboratory, she probably would be attending workshops or teaching music to kids at a local NGO.

Publications

Publication Type: Journal Article

Year of Publication Title

2019

Anupama Binoy, Nedungadi, D., Katiyar, N., Chinchu Bose, Dr. Sahadev Shankarappa, Dr. Bipin G. Nair, and Dr. Nandita Mishra, “Plumbagin induces paraptosis in cancer cells by disrupting the sulfhydryl homeostasis and proteasomal function”, Chemico-Biological Interactions, p. 108733, 2019.[Abstract]


Plumbagin (PLB) is an active secondary metabolite extracted from the roots of Plumbago rosea. In this study, we report that plumbagin effectively induces paraptosis by triggering extensive cytoplasmic vacuolation followed by cell death in triple negative breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and non-small lung cancer cells (A549) but not in normal lung fibroblast cells (WI-38). The vacuoles originated from the dilation of the endoplasmic reticulum (ER) and were found to be empty. The cell death induced by plumbagin was neither apoptotic nor autophagic. Plumbagin induced ER stress mainly by inhibiting the chymotrypsin-like activity of 26S proteasome as also evident from the accumulation of polyubiquitinated proteins. The vacuolation and cell death were found to be independent of reactive oxygen species generation but was effectively inhibited by thiol antioxidant suggesting that plumbagin could modify the sulfur homeostasis in the cellular milieu. Plumbagin also resulted in a decrease in mitochondrial membrane potential eventually decreasing the ATP production. This is the first study to show that Plumbagin induces paraptosis through proteasome inhibition and disruption of sulfhydryl homeostasis and thus further opens up the lead molecule to potential therapeutic strategies for apoptosis-resistant cancers.

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2018

A. Ashok, Mathew, S. E., Shivaram, S. B., Dr. Sahadev Shankarappa, Shantikumar V. Nair, and Dr. Mariyappan Shanmugam, “Cost Effective Natural Photo-sensitizer from Upcycled Jackfruit Rags for Dye Sensitized Solar Cells”, Journal of Science: Advanced Materials and Devices, p. -, 2018.[Abstract]


Abstract Photo-sensitizers, usually organic dye molecules, are considered to be one of the most expensive components in dye sensitized solar cells (DSSCs). The present work demonstrates a cost effective and high throughput upcycling process on jackfruit rags to extract a natural photo-active dye and its application as a photo-sensitizing candidate on titanium dioxide (TiO2) in DSSCs. The jackfruit derived natural dye (JDND) exhibits a dominant photo-absorption in a spectral range of 350 nm-800 nm with an optical bandgap of ∼1.1 eV estimated from UV-Visible absorption spectroscopic studies. The \{JDND\} in \{DSSCs\} as a major photo-absorbing candidate exhibits a photo-conversion efficiency of ∼1.1 % with short circuit current density and open circuit voltage of 2.2 mA.cm-2 and 805 mV respectively. Further, the results show that concentration of \{JDND\} plays an influential role on photovoltaic performance of the \{DSSCs\} due to the significant change in photo-absorption, exciton generation and electron injection into TiO2. The simple, high throughput method used to obtain \{JDND\} and the resulting \{DSSC\} performance can be considered as potential merits establishing a cost effective excitonic photovoltaic technology.

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2017

P. Madhusudanan, Reade, S., and Dr. Sahadev Shankarappa, “Neuroglia as Targets for Drug Delivery Systems: A Review”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 13, pp. 667-679, 2017.[Abstract]


Targeted drug delivery within the nervous system is an emerging topic of research that involves designing and developing vehicular delivery systems that have the ability to target specific neuronal and non-neuronal cell types in the central and peripheral nervous system. Drugs, genetic material, or any other payloads can be loaded onto such delivery systems and could be used to treat, prevent or manage various neurological disorders. Currently, majority of studies in this field have been concentrated around targeted delivery to neurons. However, the non-neuronal cells within the nervous system, collectively called neuroglia, have been largely ignored, though it is well known that they play a significant role in the pathophysiology of almost all neurological disorders. In this review, we present current developments in the specific area of neuroglia targeted delivery systems and highlight the use of polymeric, metallic, liposomal and other delivery systems used for this purpose.

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2016

S. Padmakumar, Joseph, J., Neppalli, M. H., Mathew, S. E., Shantikumar V Nair, Dr. Sahadev Shankarappa, and Menon, D., “Electrospun Polymeric Core-sheath Yarns as Drug Eluting Surgical Sutures”, ACS Applied Materials and Interfaces, vol. 8, pp. 6925-6934, 2016.[Abstract]


Drug-coated sutures are widely used as delivery depots for antibiotics and anti-inflammatory drugs at surgical wound sites. Although drug-laden coating provides good localized drug concentration, variable loading efficiency and release kinetics limits its use. Alternatively, drug incorporation within suture matrices is hampered by the harsh fabrication conditions required for suture-strength enhancement. To circumvent these limitations, we fabricated mechanically robust electrospun core-sheath yarns as sutures, with a central poly-l-lactic acid core, and a drug-eluting poly-lactic-co-glycolic acid sheath. The electrospun sheath was incorporated with aceclofenac or insulin to demonstrate versatility of the suture in loading both chemical and biological class of drugs. Aceclofenac and insulin incorporated sutures exhibited 15% and 4% loading, and release for 10 and 7 days, respectively. Aceclofenac sutures demonstrated reduced epidermal hyperplasia and cellularity in skin-inflammation animal model, while insulin loaded sutures showed enhanced cellular migration in wound healing assay. In conclusion, we demonstrate an innovative strategy of producing mechanically strong, prolonged drug-release sutures loaded with different classes of drugs. © 2016 American Chemical Society. More »»

2015

M. W. Calik, Dr. Sahadev Shankarappa, Langert, K. A., and Stubbs, Jr, E. B., “Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress”, ASN Neuro, vol. 7, p. 1759091415595726, 2015.[Abstract]


A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain–Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.2 km/day × 3 weeks) prior to P2-antigen induction of EAN. Sedentary rats developed a monophasic course of EAN beginning on postimmunization day 12.3 ± 0.2 and reaching peak severity on day 17.0 ± 0.3 (N = 12). By comparison, forced-exercise preconditioned rats exhibited a similar monophasic course but with significant (p < .05) reduction of disease severity. Analysis of popliteal lymph nodes revealed a protective effect of exercise preconditioning on leukocyte composition and egress. Compared with sedentary controls, forced exercise preconditioning promoted a sustained twofold retention of P2-antigen responsive leukocytes. The percentage distribution of pro-inflammatory (Th1) lymphocytes retained in the nodes from sedentary EAN rats (5.1 ± 0.9%) was significantly greater than that present in nodes from forced-exercise preconditioned EAN rats (2.9 ± 0.6%) or from adjuvant controls (2.0 ± 0.3%). In contrast, the percentage of anti-inflammatory (Th2) lymphocytes (7–10%) and that of cytotoxic T lymphocytes (∼20%) remained unaltered by forced exercise preconditioning. These data do not support an exercise-inducible shift in Th1:Th2 cell bias. Rather, preconditioning with forced exercise elicits a sustained attenuation of EAN severity, in part, by altering the composition and egress of autoreactive proinflammatory (Th1) lymphocytes from draining lymph nodes.

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2015

A. Y. Rwei, Lee, J. - J., Zhan, C., Liu, Q., Ok, M. T., Dr. Sahadev Shankarappa, Langer, R., and Kohane, D. S., “Repeatable and Adjustable on-demand Sciatic Nerve Block with Phototriggerable Liposomes”, Proceedings of the National Academy of Sciences, 2015.[Abstract]


Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has ultrapotent local anesthetic properties. They were made photo-labile by encapsulation of a NIR-triggerable photosensitizer; irradiation at 730 nm led to peroxidation of liposomal lipids, allowing drug release. In vitro, 5.6% of TTX was released upon NIR irradiation, which could be repeated a second time. The formulations were not cytotoxic in cell culture. In vivo, injection of liposomes containing TTX and the photosensitizer caused an initial nerve block lasting 13.5 ± 3.1 h. Additional periods of nerve block could be induced by irradiation at 730 nm. The timing, intensity, and duration of nerve blockade could be controlled by adjusting the timing, irradiance, and duration of irradiation. Tissue reaction to this formulation and the associated irradiation was benign.

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2015

A. Mohandas, Nimal, T. R., Das, V., Dr. Sahadev Shankarappa, Dr. Raja Biswas, and Dr. Jayakumar Rangasamy, “Drug Loaded Bi-layered Sponge for Wound Management in Hyperfibrinolytic Conditions”, Journal of Materials Chemistry B, vol. 3, pp. 5795-5805, 2015.[Abstract]


Excessive bleeding due to premature clot lysis and secondary bacterial wound infection are two significant problems that contribute to increased morbidity in patients with hyperfibrinolytic conditions. In this study, we have developed a bi-layered sponge that promotes fibrin clot stability and prevents secondary bacterial wound infections. Using the technique of freeze-drying, a bi-layer matrix consisting of hyaluronic acid (HA) containing aminocaproic acid (amicar) and chitosan containing tetracycline loaded O-carboxymethyl chitosan nanoparticles (Tet-O-CMC NPs) were produced. We hypothesized that the top chitosan layer with Tet-O-CMC NPs will prevent wound infection and concomitantly act as a matrix for cellular migration and subsequent wound healing, while the amicar-containing layer would promote clot stability. Tet-O-CMC NPs and bi-layer sponges were characterized using Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM) and Fourier Transform Infra Red (FT-IR) spectroscopy. Physiochemical characterization such as porosity, swelling and mechanical testing was performed. The drug release study shows that the bi-layered sponge demonstrates a robust burst release of amicar and a sustained release of tetracycline. The ex vivo muscle permeation study indicated that Tet-O-CMC NPs have enhanced tissue permeation compared to free Tet. In vitro antibacterial activity of the bi-layer sponge towards laboratory and clinical strains of Staphylococcus aureus and Escherichia coli was proved. The ex vivo bacterial sensitivity study using porcine muscles confirmed the antibacterial activity, while the cell viability study using human dermal fibroblast (HDF) cells revealed its biocompatible nature. The in vitro antifibrinolytic study shows that the bi-layered sponge with amicar showed significant protection against streptokinase induced clot lysis. These studies suggest that the prepared amicar and tetracycline loaded chitosan-HA bi-layered sponge can be used effectively to promote better wound healing by simultaneously preventing bacterial infection, and enhancing clot stability. This journal is © The Royal Society of Chemistry 2015.

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2014

Dr. Sahadev Shankarappa, Dr. Manzoor K., and Shantikumar V Nair, “Efficacy versus Toxicity - The Yin and Yang in translating nanomedicines,”, Nanomaterials and Nanotechnology, vol. 4, no. 23, 2014.[Abstract]


Nanomedicine, as a relatively new offshoot of nanotechnology, has presented vast opportunities in biomedical research for developing novel strategies to treat diseases. In the past decade, there has been a significant increase in in vitro and preclinical studies addressing the benefits of nanomedicines. In this commentary, we focus specifically on the efficacy- and toxicity-related translational challenges of nanocarrier-mediated systems, and briefly discuss possible strategies for addressing such issues at in vitro and preclinical stages. We address questions related specifically to the balance between toxicity and efficacy, a balance that is expected to be substantially different for nanomedicines compared to that for a free drug. Using case studies, we propose a ratiometric assessment tool to quantify the overall benefit of nanomedicine as compared to free drugs in terms of efficacy and toxicity. The overall goal of this commentary is to emphasize the strategies that promote the translation of nanomedicines, especially by learning lessons from previous translational failures of other drugs and devices, and to apply these lessons to critically assess data at the basic stages of nanomedicinal research.

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2014

J. - J. Lee, Jeong, K. Jae, Hashimoto, M., Kwon, A. H., Rwei, A., Dr. Sahadev Shankarappa, Tsui, J. H., and Kohane, D. S., “Synthetic Ligand-Coated Magnetic Nanoparticles for Microfluidic Bacterial Separation from Blood”, Nano Letters, vol. 14, pp. 1-5, 2014.[Abstract]


Bacterial sepsis is a serious clinical condition that can lead to multiple organ dysfunction and death despite timely treatment with antibiotics and fluid resuscitation. We have developed an approach to clearing bacteria and endotoxin from the bloodstream, using magnetic nanoparticles (MNPs) modified with bis-Zn-DPA, a synthetic ligand that binds to both Gram-positive and Gram-negative bacteria. Magnetic microfluidic devices were used to remove MNPs bound to Escherichia coli, a Gram-negative bacterium commonly implicated in bacterial sepsis, from bovine whole blood at flows as high as 60 mL/h, resulting in almost 100% clearance. Such devices could be adapted to clear bacteria from septicemic patients.

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2014

B. P. Timko, Arruebo, Md, Dr. Sahadev Shankarappa, McAlvin, J. B., Okonkwo, O. S., Mizrahi, B., Stefanescu, C. F., Gomez, L., Zhu, J., Zhu, A., Santamaria, J., Langer, R., and Kohane, D. S., “Near-Infrared-Actuated Devices for Remotely Controlled Drug Delivery”, Proceedings of the National Academy of Sciences of the United States of America, vol. 111, pp. 1349-1354, 2014.[Abstract]


A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained onstate drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. Implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

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2014

J. Bab c McAlvin, Padera, R. Fd, Dr. Sahadev Shankarappa, Reznor, Gbc, Kwon, A. Hfg, Chiang, H. Hbc, Yang, Jh, and Kohane, D. Sbc, “Multivesicular liposomal bupivacaine at the sciatic nerve”, Biomaterials, vol. 35, pp. 4557-4564, 2014.[Abstract]


Clinical translation of sustained release formulations for local anesthetics has been limited by adverse tissue reaction. Exparel™ (DepoFoam bupivacaine) is a new liposomal local anesthetic formulation whose biocompatibility near nerve tissue is not well characterized. Exparel™ injection caused sciatic nerve blockade in rats lasting 240mincompared to 120minfor 0.5% (w/v) bupivacaine HCl and 210minfor 1.31% (w/v) bupivacaine HCl (same bupivacaine content as Exparel™). On histologic sections four days after injection, median inflammation scores in the Exparel™ group (2.5 of 4) were slightly higher than in groups treated with bupivacaine solutions (score 2). Myotoxicity scores in the Exparel™ group (2.5 of 6) were similar to in the 0.5% (w/v) bupivacaine HCl group (3), but significantly less than in the 1.31% (w/v) bupivacaine HCl group (5). After two weeks, inflammation from Exparel™ (score 2 of 6) was greater than from 0.5% (w/v) bupivacaine HCl (1) and similar to that from 1.31% (w/v) bupivacaine HCl (1). Myotoxicity in all three groups was not statistically significantly different. No neurotoxicity was detected in any group. Tissue reaction to Exparel™ was similar to that of 0.5% (w/v) bupivacaine HCl. Surveillance for local tissue injury will be important during future clinical evaluation. © 2014 Elsevier Ltd.

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2013

Dr. Sahadev Shankarappa and DS, K., “Can Nerve Blockade be Used to Manage Neuropathic Pain?”, Pain management, vol. 3, no. 2, pp. 91-93, 2013.

2013

B. Mizrahi, Dr. Sahadev Shankarappa, Hickey, J. M., Dohlman, J. C., Timko, B. P., Whitehead, K. A., Lee, J. - J., Langer, R., Anderson, D. G., and Kohane, D. S., “A Stiff Injectable Biodegradable Elastomer”, Advanced Functional Materials, vol. 23, pp. 1527-1533, 2013.[Abstract]


Injectable materials often have shortcomings in mechanical and drug-eluting properties that are attributable to their high water contents. A water-free, liquid four-armed PEG modified with dopamine end groups is described which changes from liquid to elastic solid by reaction with a small volume of Fe3+ solution. The elastic modulus and degradation times increase with increasing Fe3+ concentrations. Both the free base and the water-soluble form of lidocaine can be dissolved in the PEG4-dopamine and released in a sustained manner from the cross-linked matrix. PEG4-dopamine is retained in the subcutaneous space in vivo for up to 3 weeks with minimal inflammation. This material's tailorable mechanical properties, biocompatibility, ability to incorporate hydrophilic and hydrophobic drugs and release them slowly are desirable traits for drug delivery and other biomedical applications.</p>

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2013

Dr. Sahadev Shankarappa, Wang, L., R, T., JB, C., JH, T., HH, C., and DS, K., “Topical Drug Formulations for Prolonged Corneal Anesthesia”, Cornea, 2013, 2013.

2013

Dr. Sahadev Shankarappa, B, M. A., G, R., C, S., and DS, K., “Local Toxicity from Local Anesthetic Polymeric Microparticles”, Anesthesia and Analgesia, no. 116, pp. 794-803 , 2013.

2013

B. Tian, Dr. Sahadev Shankarappa, Chang, H. H., Tong, R., and Kohane, D. S., “Biodegradable Mesostructured Polymer Membranes”, Nano Letters, vol. 13, pp. 4410-4415, 2013.[Abstract]


The extracellular matrix (ECM) has a quasi-ordered reticular mesostructure with feature sizes on the order of tenths of to a few hundred nanometers. Approaches to preparing biodegradable synthetic scaffolds for engineered tissues that have the critical mesostructure to mimic ECM are few. Here we present a simple and general solvent evaporation-induced self-assembly (EISA) approach to preparing concentrically reticular mesostructured polyol–polyester membranes. The mesostructures were formed by a novel self-assembly process without covalent or electrostatic interactions, which yielded feature sizes matching those of ECM. The mesostructured materials were nonionic, hydrophilic, and water-permeable and could be shaped into arbitrary geometries such as conformally molded tubular sacs and micropatterned meshes. Importantly, the mesostructured polymers were biodegradable and were used as ultrathin temporary substrates for engineering vascular tissue constructs.

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2012

M. W. Calik, Dr. Sahadev Shankarappa, and Stubbs, E. B., “Forced-exercise attenuates experimental autoimmune neuritis.”, Neurochem International, vol. 61, no. 2, pp. 141-145, 2012.[Abstract]


Physical inactivity in combination with a sedentary lifestyle is strongly associated with an increased risk of development of inflammatory-mediated diseases, including autoimmune disorders. Recent studies suggest that anti-inflammatory effects of physical exercise may be of therapeutic value in some affected individuals. In this study, we determined the effects of forced-exercise (treadmill running) on the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats were subjected to sedentary (control) or forced-exercise (1.2 km per day, 5 days a week) for three weeks prior to induction of EAN. P2 (53-78)-immunized sedentary control rats developed a monophasic course of EAN beginning on post-injection day 12.33 ± 0.59 (n = 18) and reaching peak severity on day 15.83 ± 0.35 (n = 18). At near peak of disease, ankle- and sciatic notch-evoked compound muscle action potential (CMAP) amplitudes in sedentary control rats were reduced (~50%) while motor nerve conduction velocity (MNCV) was slowed (~30%) compared with pre-induction evoked responses. In marked contrast, rats undergoing forced-exercise exhibited a significantly less severe clinical course of EAN beginning on post-injection day 12.63 ± 0.53 (n = 16) and reaching peaking severity on day 14.69 ± 0.73 (n = 16). At near peak of disease, ankle- and sciatic-notch-evoked CMAP amplitudes in forced-exercised rats were preserved while EAN-associated slowing of MNCV was modestly attenuated by exercise. Three weeks of forced-exercise reduced by 46% total plasma corticosterone content while elevating the levels of corticosteroid binding globulin. We conclude from this study that forced-exercise administered prior to and during development of EAN affords a novel measure of protection against autoimmune-associated deficits in peripheral nerve evoked responses independent of steroid-induced immune suppression.

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2012

C. B. Weldon, Tsui, J. H., Dr. Sahadev Shankarappa, Nguyen, V. T., Ma, M., Anderson, D. G., and Kohane, D. S., “Electrospun Drug-eluting Sutures for Local Anesthesia”, Journal of Controlled Release, vol. 161, pp. 903 - 909, 2012.[Abstract]


We have developed a local anesthetic-eluting suture system which would combine the function and ubiquity of the suture for surgical repair with the controlled release properties of a biodegradable polymeric matrix. Drug-free and drug-loaded poly(lactic-co-glycolic acid) (PLGA) sutures were fabricated by electrospinning, with or without the local anesthetic bupivacaine. The tensile strength of the electrospun sutures decreased as drug content increased, but strains remained relatively similar across all groups. Sutures released their entire drug payload over the course of 12days and maintained approximately 12% of their initial tensile strength after 14days of incubation in vitro. In a rat skin wound model, local analgesia was achieved 1day after surgery and lasted approximately 1week in 90% of treated animals (n=10, p&lt;0.05), and all wounds were able to heal normally without the need for further reinforcement. The sutures caused tissue reaction in vivo that was comparable to that seen with a commercially available suture composed of PLGA. Such sutures may enhance perioperative analgesia and mitigate the need for standard postoperative opioid analgesics.

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2012

Dr. Sahadev Shankarappa, I, S., JH, T., H, C., C, S., D, Z., and DS, K., “Duration and Local Toxicity of Sciatic Nerve Blockade with Co-injected Site 1 Sodium Channel Blockers and Quaternary Lidocaine Derivatives”, Regional Anesthesia and Pain Medicine, vol. 37, no. 5, 2012.

2012

Dr. Sahadev Shankarappa, Tsui, J. H., Kim, K. N., Reznor, G., Dohlman, J. C., Langer, R., and Kohane, D. S., “Prolonged Nerve Blockade Delays the Onset of Neuropathic Pain”, Proceedings of the National Academy of Sciences, 2012.[Abstract]


Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain. Pharmacological blockade of that activity has been shown to mitigate the onset of associated molecular events in the nervous system. However, results in preventing onset of pain behaviors by providing prolonged nerve blockade have been mixed. Furthermore, the experimental techniques used to date to provide that blockade were limited in clinical potential in that they would require surgical implantation. To address these issues, we have used liposomes (SDLs) containing saxitoxin (STX), a site 1 sodium channel blocker, and the glucocorticoid agonist dexamethasone to provide nerve blocks lasting \~{}1 wk from a single injection. This formulation is easily injected percutaneously. Animals undergoing spared nerve injury (SNI) developed mechanical allodynia in 1 wk; nerve blockade with a single dose of SDLs (duration of block 6.9 ± 1.2 d) delayed the onset of allodynia by 2 d. Treatment with three sequential SDL injections resulting in a nerve block duration of 18.1 ± 3.4 d delayed the onset of allodynia by 1 mo. This very prolonged blockade decreased activation of astrocytes in the lumbar dorsal horn of the spinal cord due to SNI. Changes in expression of injury-related genes due to SNI in the dorsal root ganglia were not affected by SDLs. These findings suggest that formulations of this kind, which could be easy to apply clinically, can mitigate the development of neuropathic pain.

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2011

Dr. Sahadev Shankarappa, ES, P. - R., and EB, S., “Forced-Exercise Alleviates Neuropathic Pain in Experimental Diabetes : Effects on voltage-activated calcium channels,”, Journal of Neurochemistry, vol. 118, no. 2, 2011.[Abstract]


Physical exercise produces a variety of psychophysical effects, including altered pain perception. Elevated levels of centrally produced endorphins or endocannabinoids are implicated as mediators of exercise-induced analgesia. The effect of exercise on the development and persistence of disease-associated acute/chronic pain remains unclear. In this study, we quantified the physiological consequence of forced-exercise on the development of diabetes-associated neuropathic pain. Euglycemic control or streptozotocin (STZ)-induced diabetic adult male rats were subdivided into sedentary or forced-exercised (2-10 weeks, treadmill) subgroups and assessed for changes in tactile responsiveness. Two weeks following STZ-treatment, sedentary rats developed a marked and sustained hypersensitivity to von Frey tactile stimulation. By comparison, STZ-treated diabetic rats undergoing forced-exercise exhibited a 4-week delay in the onset of tactile hypersensitivity that was independent of glucose control. Exercise-facilitated analgesia in diabetic rats was reversed, in a dose-dependent manner, by naloxone. Small-diameter (< 30 μm) DRG neurons harvested from STZ-treated tactile hypersensitive diabetic rats exhibited an enhanced (2.5-fold) rightward (depolarizing) shift in peak high-voltage activated (HVA) Ca(2+) current density with a concomitant appearance of a low-voltage activated (LVA) Ca(2+) current component. LVA Ca(2+) currents present in DRG neurons from hypersensitive diabetic rats exhibited a marked depolarizing shift in steady-state inactivation. Forced-exercise attenuated diabetes-associated changes in HVA Ca(2+) current density while preventing the depolarizing shift in steady-state inactivation of LVA Ca(2+) currents. Forced-exercise markedly delays the onset of diabetes-associated neuropathic pain, in part, by attenuating associated changes in HVA and LVA Ca(2+) channel function within small-diameter DRG neurons possibly by altering opioidergic tone.

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Dr. Sahadev Shankarappa,MBBS, MPH, Ph.D.,
Assistant Professor
Center for Nanosciences and Molecular Medicine
Amrita Institute of Medical Sciences and Research Center
Ponekkara P.O., Kochi,
Kerala 682041, India

91-4842-801234 (Ext - 8705)
91-4842-808720 (lab))