Sahadev A. Shankarappa
Amrita Institute of Medical Sciences and Research Centre
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Featured researches published by Sahadev A. Shankarappa.
Nano Letters | 2014
Jung-Jae Lee; Kyung Jae Jeong; Michinao Hashimoto; Albert H. Kwon; Alina Y. Rwei; Sahadev A. Shankarappa; Jonathan H. Tsui; Daniel S. Kohane
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.
Proceedings of the National Academy of Sciences of the United States of America | 2014
Brian P. Timko; Manuel Arruebo; Sahadev A. Shankarappa; James Brian McAlvin; O.S.a c Okonkwo; Boaz Mizrahi; Cristina F. Stefanescu; Leyre Gomez; Jia Zhu; A.c Zhu; Jesus Santamaria; Robert Langer; Daniel S. Kohane
Significance Devices that release a drug in response to a remote trigger would enable on-demand control of the timing and dose of drug released. They would allow the patient or physician to adjust therapy precisely to a target effect, thus improving treatment and reducing toxicity. We have developed implantable reservoirs that release a drug when irradiated with near-infrared laser light. The release rate was correlated to laser intensity, with negligible leakage between doses. Devices containing aspart, a fast-acting analog of insulin, were implanted in diabetic rats and were able to achieve glycemic control upon irradiation. Such devices can be loaded with a wide range of drugs to treat a variety of clinical indications. 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 on-state 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.
Journal of Controlled Release | 2012
Christopher B. Weldon; Jonathan H. Tsui; Sahadev A. Shankarappa; Vy T. Nguyen; Minglin Ma; Daniel G. Anderson; Daniel S. Kohane
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 12 days and maintained approximately 12% of their initial tensile strength after 14 days of incubation in vitro. In a rat skin wound model, local analgesia was achieved 1 day after surgery and lasted approximately 1 week in 90% of treated animals (n=10, p<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.
Proceedings of the National Academy of Sciences of the United States of America | 2012
Sahadev A. Shankarappa; Jonathan H. Tsui; Kristine N. Kim; Gally Reznor; Jenny C. Dohlman; Robert Langer; Daniel S. Kohane
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.
Anesthesia & Analgesia | 2013
J. Brian McAlvin; Gally Reznor; Sahadev A. Shankarappa; Cristina F. Stefanescu; Daniel S. Kohane
BACKGROUND:Local tissue injury from sustained-release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats. METHODS:Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly(lactic-co-glycolic) acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weightbearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured. RESULTS:Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90–540) minutes versus 840 (277–1215) minutes for 50% (w/w) bupivacaine (P = 0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared with 50% (w/w) bupivacaine at 4 days were 3.4 (2.1–4.2) vs 3.3 (2.9–3.5) (P = 0.44) and at 14 days 1.9 (1.8–2.4) vs 1.7 (1.3–1.9) (P = 0.23), respectively. CONCLUSIONS:Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve.
Proceedings of the National Academy of Sciences of the United States of America | 2015
Alina Y. Rwei; Jung-Jae Lee; Changyou Zhan; Qian Liu; Meryem Tyrrasch Ok; Sahadev A. Shankarappa; Robert Langer; Daniel S. Kohane
Significance We demonstrate an injectable drug-delivery system that would allow patients to adjust the timing, duration, and intensity of local anesthesia in painful parts of the body. Such on-demand analgesia could greatly enhance the management of a variety of pain states. Light-sensitive liposomes containing the potent local anesthetic tetrodotoxin induced sensory and motor nerve block in vivo upon irradiation with a 730-nm laser. The timing, duration, and intensity of the nerve blockade were adjustable by the timing, irradiance, and duration of irradiation. Tissue reaction to the formulation and associated irradiation was benign. 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.
Regional Anesthesia and Pain Medicine | 2012
Sahadev A. Shankarappa; Itay Sagie; Jonathan H. Tsui; Homer H. Chiang; Cristina F. Stefanescu; David Zurakowski; Daniel S. Kohane
Background and Objectives Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the coapplication of extracellularly acting site 1 sodium-channel blocker, resulting in prolonged block duration but with minimal tissue toxicity. Methods Quaternary lidocaine derivatives (QX-314 or QX-222), site 1 sodium-channel blockers (tetrodotoxin [30 &mgr;M] or saxitoxin [12.5 &mgr;M]), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment. Results Coapplication of 25 mM QX-314 or 100 mM QX-222 with site 1 sodium-channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P < 0.05), compared with QLDs or site 1 blockers alone. Quaternary lidocaine derivatives elicited severe myotoxicity; this was not exacerbated by coinjection of the site 1 sodium-channel blockers. Conclusions Coadministration of site 1 sodium-channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.
ACS Applied Materials & Interfaces | 2016
Smrithi Padmakumar; John Joseph; Madhuri Harsha Neppalli; Sumi Elizabeth Mathew; Shantikumar V. Nair; Sahadev A. Shankarappa; Deepthy Menon
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.
Cornea | 2013
Liqiang Wang; Sahadev A. Shankarappa; Rong Tong; Joseph B. Ciolino; Jonathan H. Tsui; Homer H. Chiang; Daniel S. Kohane
Purpose: Ocular local anesthetics currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect of the site 1 sodium channel blocker tetrodotoxin (TTX) on the duration of corneal anesthesia, applied with either proparacaine (PPC) or the chemical permeation enhancer octyl-trimethyl ammonium bromide (OTAB). The effect of test solutions on corneal healing was also studied. Methods: Solutions of TTX, PPC, and OTAB, singly or in combination, were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet–Bonnet esthesiometer, and the duration of corneal anesthesia was calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo after corneal debridement. Results: Combination of TTX and PPC resulted in corneal anesthesia that was 8 to 10 times longer in duration than that from either drug administered alone, whereas OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed after coadministration of TTX and PPC. Conclusions: Coadministration of TTX and PPC significantly prolonged corneal anesthesia, but in view of delayed corneal reepithelialization, caution is suggested in the use of the drug combination.
Nanomedicine: Nanotechnology, Biology and Medicine | 2017
Pallavi Madhusudanan; Samuel Reade; Sahadev A. Shankarappa
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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