A stimulus actuated polymeric device for the prolonged therapeutic management of moderate to severe chronic pain

Abstract
Chronic pain may be defined as pain which persists in a patient for a prolonged period of time. Although this period of time may range from 3-12 months, it is most commonly described as pain which extends beyond the time required for healing. Chronic pain may also be classified into two different categories depending on the cause. The first category is nociceptive, which is chronic pain caused by activation of nociceptors. This may be due to several factors such as trauma or temperature. The second category is neuropathic chronic pain. These are chronic pains which are not necessarily caused by trauma, but more likely due to the malfunction of the nervous system. For this study, our aim is to develop a patient-controlled, externally actuated hydrogel system which is capable of ‘ON-OFF’ drug release. The model drug which was incorporated into the SAPD was a Non- Steroidal Anti-Inflammatory Drugs (NSAID), and thus our drug release system would be beneficial primarily for nociceptive chronic pain. This subcutaneously implanted SAPD is produced with an electroactive polymer which allows drug release in the presence of electrical stimulation. This would result in direct availability of drug at the site of actuation with reduced side-effects and increased drug bio-availability. The SAPD was formed by crosslinking polyvinyl alcohol (PVA) with diethyl acetamidomalate (DAA). The result was a hydrogel which was capable of swelling while remaining insoluble when placed in various solvents. After the hydrogel was synthesized, indomethacin was incorporated as the model drug. Indomethacin exhibited superior Drug Entrapment Efficiency (DEE) (±70-90%) and responsive release in the presence of an electrical stimulus. Finally, polyaniline (PANi) was used as the electroactive polymer in order to enhance the conductivity and allow sufficient release of the drug. Optimization of the SAPD was undertaken with a 3-factor Box-Behnken Design which measured the rate of erosion, drug release and DEE. The optimized SAPD was synthesized using PVA (0.8g) crosslinked with DAA (0.0689g) and a concentration of 1.3418%w/w PANi. Indomethacin was used and the DEE achieved was 76.32±10.46% (target 80.5381%). The drug release profile was 1.622%±0.1857% (target 1.7%) per release cycle and erosion rate was 5.73±1.26% (target 6.3201%) when actuated with a potential difference of 1V for a duration of 1 minute. Chemometric modelling performed on the SAPD showed that drug release may be attributed to erosion of the SAPD in the presence of an electrical stimulus. The polymeric strands usually rest as a coiled state within the SAPD. This coiled state may be the reason the hydrogel remained intact in the absence of electrical stimulation. However, external electrical fields may adduct to form a coil rather than an extended chain resulting in the formation of a globular aniline-vinyl complex. This formation thus leads to a weakened form of the hydrogel structure, resulting in breakdown and ultimately erosion. This erosive phenomenon ceased once the electrical stimulation was removed. The end result of this hydrogel erosion is the liberation of the entrapped indomethacin. In vivo animal studies on the SAPD indicated an ‘ON-OFF’ drug release profile. The drug release was consistent and drug quantity of ±0.15mg per release cycle in the Sprague-Dawley rat model. The SAPD was implanted subcutaneously under the left flank and an electrical stimulation was triggered with the use of a 2-in-1 galvano/potentiostat in order to ensure the electrical stimulus was constant. The potential difference used was 1V over a period of 1 minute. The rats were assessed for signs of illness or swelling after the implantation procedure to determine the biocompatibility of the SAPD. The rats were monitored for 10 days and weighed daily. Results have shown that the rats did not experience any considerable swelling and the weights of each rat were steady, thus indicating biocompatibility of the SAPD. Histopatholgical samples indicated mild inflammation around the site of implantation 10 days after implantation. This may have been due to minor surgery at site of implantation. The biocompatibility of the SAPD was generally good and there were no signs of tumour or long term tissue inflammation. Future application of the SAPD may include an external actuation device to be worn as a watch which allows actuation of the SAPD when required by the patient.
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