Development and validation of a seizure initiated drug delivery system for the treatment of epilepsy
Introduction
Epilepsy is a chronic neurological condition characterized by recurrent seizures. The incidence of epilepsy in most developed countries is between 50 and 100 cases per 100,000 population per year, although it is estimated that up to 5% of a population will experience non-febrile seizures at some point in life [1], [2]. Patients with medically intractable epilepsy have impaired ability to work or function socially [3]. Treatment with available anti-epileptic drugs (AEDs) provides adequate control in only 33% of patients (1,2). Neurostimulation based therapies have also been shown to reduce seizure activity, with typical reductions in seizure frequency of approximately 40% acutely and up to 50–69% after several years [4]. Surgical resection of the seizure focus can be performed in the case of focal seizures, however this procedure can only be applied to specific patients depending on the location of the focus [5]. The success rate of inducing long-lasting seizure remission from epilepsy surgery ranges from 25% for patients exhibiting extrahippocampal seizures origin to 70% in appropriately selected candidates [5].
There have been several potential mechanisms proposed as the basis of drug resistance in epilepsy, but there remains a great deal of uncertainty as to the precise cause [6], [7]. Importantly, the side effects of those drugs prevent large increase in the dose [8]. Alternative therapies aimed at improving the availability of AEDs such as the intracranial implantation of polymer-based drug delivery systems are being investigated [9], [10]. This targeted drug delivery approach has been shown to be useful in the treatment of animal models of several neurological disorders such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease [11]. Also, Halliday et al. [10] used levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats; the results of this study indicated that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy.
Any system that relies on a reservoir of drug has a finite lifetime. Passive implantable drug delivery systems based on degradable polymers that continuously release drug [8], or discrete drug reservoirs with a finite number of doses [14], have very limited device lifetime due to rapid depletion of the reservoir. An intelligent, “on-demand” system, should possess the capability to identify a seizure through a specific biomarker and subsequently trigger drug release only when necessary. Such a system would increase the device lifetime by orders of magnitude when compared with passive implants. Salam et al. [12] describes an implantable detection and delivery device and highlights the release of a range of compounds to suppress epileptic activity. The system described in this paper utilizes a stimuli responsive polymer to deliver AED as opposed to a micropump used by Salma et al. In addition their latency time of approximately 16 s [12] is significantly slower than that reported here.
The schematic shown in Fig. 1 provides an illustrative concept of the system discussed in this paper. Sections 1 and 2 illustrate what occurs in patients with intractable epilepsy while sections 3 through to 6 illustrate how the system operates once implanted in patients. The system is comprised of electrodes and electronics capable of monitoring human ECoG signal and on detection of ECoG activity indicative of an epileptic seizure stimulate a conducting polymer doped with an AED. AED release is facilitated by an implantable microsystem that performs neural signal sensing and processing to detect the features of a seizure and to compute its onset, duration and intensity. The microsystem will then use these features to modulate the release of anti-epileptic drugs from the conducting polymers directly into the cortical tissue.
Polymer structures capable of triggering release in response to discrete thermal transitions [13], [14], pH [15], [16] or electrical stimuli [17], [18], [19] have some potential advantages in that release can be initiated in response to a change in environmental conditions or in response to an external electrical stimuli. Those based on the use of electrical stimulation have the advantage that the release profile can be tuned by the electrical stimulation parameters (current/potential magnitude and frequency) employed.
Conducting organic polymers represent a class of materials capable of responding to electrical stimulation to induce controlled release [20], [21], [22]. Release of incorporated molecules usually involves subjecting the polymer to an oxidation/reduction cycle. The efficiency of this process is determined by several factors such as polymer conductivity and the size of the incorporated molecule [23]. For example, anthraquinone disulphonic acid has been electrochemically released from a polypyrrole matrix [20], with the rate of release determined by the potential applied. The electrically stimulated release of the neurotrophin NT-3 from polypyrrole has also been reported [24]. The anti-inflammatory drug dexamethasone has been incorporated into polypyrrole (PPy) [18] or poly(3,4-ethylenedioxythiophene) (PEDOT) [22] and released using electrical stimulation.
This paper outlines the work conducted to develop an active controlled delivery system for the treatment of epilepsy that has the capability to deliver AEDs only at the time of a detected seizure event. In this study, we verify the system concept with custom prototyped hardware and by detecting the AED released from the PPy with an in-line UV–vis detector.
Section snippets
Materials and methods
The anti-epileptic drug fos-phenytoin (FOS) was a purchased from Sigmal-Aldrich and used as received. Pyrrole was purchased from Merck (Germany) and distilled prior to being used. The chemmicals used in preparartion of the artificial cerebrospinal fluid (aCSF) were purchased from Sigma Aldrich. The aCSF contained NaCl (0.866% w/v), KCl (0.224% w/v), CaCl2-2H2O; (0.0206% w/v) and MgCl2-6H2O (0.0164% w/v) in 1 mM phosphate buffer (pH 7.4) (tablets from Sigma Aldrich), all prepared in Milli-Q water
Polymerisation and characterisation of polypyrrole doped with fos-phenytoin (PPy.FOS)
Optimization (data not presented) of the polymerisation conditions resulted in the ideal conditions for synthesis, being a FOS concentration of 2.5 mM and a current density of 0.5 mA/cm2. Higher FOS concentrations resulted in non-uniform film formation whilst current densities above this resulted in excessive oxidation voltages being generated leading to over oxidised polymer.
Cyclic voltammetry using PPy.FOS as the working electrode shows a redox couple associated with the oxidation (−0.25 V) and
Conclusions
An anti-epileptic drug was successfully incorporated into PPy with the release demonstrated to be linear with the duration of stimulation current applied. A low negative current was shown to release small amounts of FOS with long latencies while at higher current the latency is reduced, however larger amount of FOS are released. This highlights the need to combine the appropriate current stimulation magnitude with the stimulation duration in order to obtain the most appropriate dosage in the
Acknowledgements
Funding from the Australian Research Council Centre of Excellence Scheme (Project Number CE 140100012) and the McKenzie Postdoctoral Fellowship are gratefully acknowledged. GGW is grateful to the ARC for support under the Australian Laureate Fellowship scheme (FL110100196). The authors also wish to acknowledge the design and fabrication facilities accessed through the Australian National Fabrication Facilities (ANFF) Materials Node. Dr Stephen Beirne and Dr Patricia Hayes are thanked for their
Rikky Muller is an Assistant Professor of Electrical Engineering and Computer Science (EECS) at UC Berkeley. She received her bachelor's and master's degrees at MIT and her Ph.D. degree at UC Berkeley in EECS. She was a McKenzie fellow and Lecturer of Electrical and Electronic Engineering at the University of Melbourne. Prof. Muller co-founded Cortera Neurotechnologies, a medical device company where she held positions as CEO and CTO. She is the winner of numerous awards and fellowships and was
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Cited by (0)
Rikky Muller is an Assistant Professor of Electrical Engineering and Computer Science (EECS) at UC Berkeley. She received her bachelor's and master's degrees at MIT and her Ph.D. degree at UC Berkeley in EECS. She was a McKenzie fellow and Lecturer of Electrical and Electronic Engineering at the University of Melbourne. Prof. Muller co-founded Cortera Neurotechnologies, a medical device company where she held positions as CEO and CTO. She is the winner of numerous awards and fellowships and was named one of 35 global innovators under the age of 35 (TR35) by the MIT Technology Review for her work in the field of technology and medicine.
Zhilian Yue is a senior research fellow at the institute of Intelligent Polymer Research Institute, the ARC Centre of Excellence for Electromaterials Science, University of Wollongong, Australia. She received her PhD from Heriot-Watt University, UK, in 2002. Her current research interests are in the area of functional polymers for controlled release of bioactive molecules and 3D bioprinting for tissue repair and regeneration.
Sara Ahmadi is a PhD student who is perusing her doctorate degree under the supervision of Profs Wallace, Moulton and Cook. Her studies involve investigating the use of conducting polymer structures to control the delivery of antiepilepsy drug.
Winston C.W. Ng is a graduate of The University Of Melbourne, Australia, having received his Masters of Engineering (Electrical) (Distinct) in 2014. Having particular skills and passion in signal processing and electronics design, Winston is currently working at Melbourne based company Tekt Industries, which provides engineering services in areas including embedded systems and IoT.
Willo Grosse graduated with a PhD from University of Wollongong in 2014 and has since moved to work in the finance sector with Ernst and Young as part of the Research & Development Team.
Mark Cook is a Professor of Medicine, University of Melbourne, and Director of Neurology, St. Vincent’s Hospital Melbourne. His current interests are in polymer based drug delivery systems, imaging, brain modelling, and neurophysiology.
Gordon Wallace is Director of the ARC Centre of Excellence for Electromaterials science headquartered at the University of Wollongong. His research interests include the design and synthesis of new electromaterials and the development of additive fabrication protocols to enable assembly of novel structures and devices containing them-for use in energy and medical bionics.
Simon Moulton is Professor of Biomedical Electromaterials Science at Swinburne University of Technology. His field of research is developing organic conducting materials for use in a variety of applications ranging from sensors to biomedical application. He has a strong track record in materials chemistry research spanning electroactive materials as well as conventional biomaterials.
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Current address: Biomedical Engineering Faculty of Science, Engineering and Technology Swinburne University of Technology Hawthorn, Victoria, 3122, Australia.