In vivo biocompatibility and in vitro characterization of poly-lactide-co-glycolide structures containing Levetiracetam, for the treatment of epilepsy Amy J. Halliday, 1,2 Toni E. Campbell, 3 Joselito M. Razal, 3 Karen J. McLean, 2 Timothy S. Nelson, 4 Mark J. Cook, 1,2 Gordon G. Wallace 3 1 Department of Medicine, University of Melbourne, St. Vincent’s Hospital, 35 Victoria Parade, Fitzroy, Victoria 3065, Australia 2 Clinical Neurosciences, 5th Floor, Daly Wing, St. Vincent’s Hospital, 35 Victoria Parade, Fitzroy, Victoria 3065, Australia 3 Intelligent Polymer Research Institute and ARC Centre of Excellence for Electromaterials Science, University of Wollongong, AIIM Facility, Innovation Campus, Wollongong, New South Wales 2522, Australia 4 The Bionic Ear Institute, 384-388 Albert Street, East Melbourne, Victoria 3002, Australia Received 17 January 2011; revised 3 June 2011; accepted 10 June 2011 Published online 21 November 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.a.33208 Abstract: Epilepsy is a chronic neurological disorder charac- terized by recurrent seizures, and is highly resistant to medi- cation with up to 40% of patients continuing to experience seizures whilst taking oral antiepileptic drugs. Recent research suggests that this may be due to abnormalities in the blood–brain barrier, which prevent the passage of thera- peutic substances into the brain. We sought to develop a drug delivery material that could be implanted within the brain at the origin of the seizures to release antiepileptic drugs locally and avoid the blood brain barrier. We produced poly-lactide-co-glycolide drop-cast films and wet-spun fibers loaded with the novel antiepileptic drug Levetiracetam, and investigated their morphology, in vitro drug release charac- teristics, and brain biocompatibility in adult rats. The best performing structures released Levetiracetam constantly for at least 5 months in vitro, and were found to be highly brain biocompatible following month-long implantations in the motor cortex of adult rats. These results demonstrate the potential of polymer-based drug delivery devices in the treat- ment of epilepsy and warrant their investigation in animal models of focal epilepsy. V C 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A: 424–431, 2012. How to cite this article: Halliday AJ, Campbell TE, Razal JM, McLean KJ, Nelson TS, Cook MJ, Wallace GG. 2012. In vivo biocompatibility and in vitro characterization of poly-lactide-co-glycolide structures containing Levetiracetam, for the treatment of epilepsy. J Biomed Mater Res Part A 2012:100A:424–431. INTRODUCTION Epilepsy is a neurological disorder characterized by recur- rent seizures that affects approximately 1% of the popula- tion, making it the world’s most common serious neurologic condition. 1 It is a particularly challenging condition to man- age medically, since over one-third of patients continue to experience seizures despite taking multiple antiepileptic drugs (AEDs). 1 The mechanisms underlying this drug resist- ance are not well understood; however, one theory with a growing body of supporting evidence is that the blood– brain barrier plays a significant role. There are many fea- tures of the normal blood–brain barrier that make it partic- ularly impervious to substances in the plasma, and there is also evidence that repeated seizures further decrease its permeability in patients with epilepsy. 2 Administering higher oral doses of AEDs can overcome this decreased per- meability and usually has a beneficial effect on seizures; however, this also produces side effects that prohibit the maintenance of this treatment regimen and is therefore not an appropriate solution to refractory seizures. Administration of therapeutic substances directly to the pathological region of the brain is a concept that has gar- nered increasing research attention in recent years. This route of administration has been shown in animal models to permit high drug concentrations in the brain whilst reducing the incidence of side effects. 3–6 These findings ini- tiated interest in implantable drug delivery devices for drug-resistant neurological disorders with focal pathologies, including epilepsy. 7 Such devices permit long-term delivery of AEDs directly to the region of the brain responsible for producing the seizures, whilst drastically reducing the con- centration of AED in unrelated areas of the body. Previous efforts to design drug-eluting implants for neu- rological disorders have achieved some success using Correspondence to: M. J. Cook; e-mail: mark@neurology.net.au Contract grant sponsors: Victorian Government through its Science Technology and Innovation Initiative from the Department of Industry, Innovation, and Regional Development; ARC Federation Fellowship (to G.G.W.); Australian Research Council for the APD Fellowship (to J.M.R.) 424 V C 2011 WILEY PERIODICALS, INC.