International Journal of Pharmaceutics 403 (2011) 268–275 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology In vitro and in vivo evaluation of anti-inflammatory agents using nanoengineered alginate carriers: Towards localized implant inflammation suppression Rahul Dev Jayant a , Michael J. McShane b , Rohit Srivastava a,∗ a Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Powai, Mumbai 400076, India b Biomedical Engineering Department & Materials Science and Engineering Program, Texas A & M University, College Station, TX 77843-3120, USA article info Article history: Received 1 September 2010 Received in revised form 19 October 2010 Accepted 19 October 2010 Available online 2 November 2010 Keywords: Alginate Microspheres Controlled release Anti-inflammatory drugs Layer-by-layer (LbL) abstract The aim of this research was to develop nanoengineered alginate microspheres for localized delivery of anti-inflammatory drugs (dexamethasone and diclofenac sodium) for implantable “Smart tattoo” glucose biosensor used for continuous glucose monitoring. The formulation was prepared and characterized for in vitro drug release from uncoated and polyelectrolyte-coated microparticles. Biocompatibility was then tested using L929 cell-line; pilot in vivo studies with Sprague–Dawley (SD) rat subjects were performed to test the suppression of inflammation and fibrosis associated with implantation and was analyzed using standard hematoxylin and eosin staining method. The drug-loaded microspheres were able to deliver the drug for 30 days at a controlled rate with zero-order kinetics. The layer-by-layer self-assembly technique was used to effectively limit the burst release of drug from the matrix. Cell culture studies prove that the material are not cytotoxic and showed acceptable >80% cell viability in all the tested samples. In vivo studies show that both drugs were successful in controlling the implant/tissue interface by suppressing inflammation at the implant site. It was clearly evident that the combined approach of drug loaded carriers along with implanted biosensor shows promise in improving sensor biocompatibility and functionality. Thus, suggesting potential application of alginate microspheres as “smart-tattoo” glucose sensors. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Currently, most diabetics measure their blood glucose concen- trations by intermittent “finger-prick” capillary blood sampling, a method that is painful and uncomfortable. The development of technology for minimally or non-invasive and continuous glucose sensing is, therefore, considered a priority in diabetes care (Abel and Woedtke, 2002). Interest in implantable biosensors has gained popularity owing primarily to the continuous monitoring capa- bility that aids in identifying trends in glucose excursions, and enables patients to take pre-emptive action to avoid dangerous hypoglycemia. Continuous blood glucose monitoring is also becom- ing a more integral part of diabetes management for understanding specific patient glucose patterns and aids in determining dosage frequency and time of administration of insulin dosage. However, there are significant problems with the performance of commer- cially available subcutaneously implanted in vivo glucose sensors, including inaccurate results, low precision, and requirements for frequent calibration (Pickup, 2004; Gilligan et al., 2004). ∗ Corresponding author. Tel.: +91 22 25767746; fax: +91 22 25723480. E-mail address: rsrivasta@iitb.ac.in (R. Srivastava). Another key issue with the use of these devices is the series of inflammatory events generated in response to tissue injury dur- ing implantation. This generally results in compromised device functionality and subsequent device failure (Sharkawy et al., 1997, 1998a,b). During the initial acute response, fluid carrying plasma proteins and inflammatory cells migrate to the implanted site. In many cases, proteins adsorb to the implant surface and then phago- cytic cells (neutrophils, monocytes and macrophages) surround the biosensor, affecting its functionality (Anderson, 2001). Phagocyto- sis is the foremost body defense occurring upon implantation, since for large implants phagocytosis is not possible, the cells attack these implants by the release of reactive oxygen species and enzymes that are intended to degrade the implant. The exact timing, action, and intensity of the process are dependent on the nature of the foreign body, size, shape, and physical and chemical properties (Gerritsen, 2000). The acute response lasts about three days, after which a chronic inflammatory response may set in or a modified version of the healing process begins (Anderson, 2001; Gerritsen, 2000). Even- tually, a fibrotic capsule is formed, which is a characteristic feature of the steady-state foreign body response. Fibrous encapsulation can impede transport of glucose and fluid to sensor causing com- promised device functionality. Calcification and protein fouling of implanted biosensors may occur (Wisniewski and Reichert, 2000; Wisniewski et al., 2000) and these processes induce the outer mem- 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.10.035