3D printed electro-responsive system with programmable drug release

Abstract

Precision medicine is the next frontier in pharmaceutical research, aiming to improve the safety and efficacy of therapeutics for patients. The ideal drug delivery system (DDS) should be programmable to provide real-time controlled delivery that is personalised to the patient’s needs. However, little progress has been made in this domain. Herein, we combined two cutting-edge technologies, conductive polymers (CPs) and three-dimensional (3D) printing, to demonstrate their potential for achieving programmable controlled release. A DDS was formulated where the CP provided temporal control over drug release. 3D printing was used to ensure dimensional control over the design of the DDS. The CP used in this study is known to be fragile, and thus was blended with thermoplastic polyurethane (TPU) to achieve a conductive elastomer with sound mechanical properties. Rheological and mechanical analyses were performed, where it was revealed that formulation inks with a storage modulus in the order of 10³–10⁴ Pa were both extrudable and maintained their structural integrity. Physico-chemical analysis confirmed the presence of the CP functional groups in the 3D printed DDS. Cyclic voltammetry demonstrated that the DDS remained conductive for 100 stimulations. in vitro drug release was performed for 180 min at varying voltages, where a significant difference (p < 0.05) in cumulative release was observed between either ±1.0 V and passive release. Furthermore, the responsiveness of the DDS to pulsatile stimuli was tested, where it was found to rapidly respond to the voltage stimuli, consequently altering the release mechanism. The study is the first to 3D print electroactive medicines using CPs and paves the way for digitalising DDS that can be integrated into the Internet of Things (IoT) framework.

Highlights

A 3D printed electro-active drug release formulation was developed.

The formulation was both mechanically sound and conductive.

3D printing achieved dimensional precision.

Applying different voltages resulted in different release kinetics.

The study opens up the opportunity for developing 3D-printed programmable medicines.

Introduction

Precision medicine is the next frontier in healthcare, aiming to precisely tailor therapeutic treatment to meet the patient’s individual needs. Its importance arises from the recognition that traditional one-size-fits-all approach could cause variable treatment responses and outcomes. Despite the progress achieved in precision medicine, the toxicities and resistance of drugs remain significant challenges. The ideal medicine should factor in an individual’s genetic makeup and accommodate their lifestyle habits [1]. Advances in precision medicine brought about high expectations for drug delivery systems (DDSs). Conventional DDSs suffer from safety, efficacy, and patient compliance issues caused by fluctuations in plasma drug levels, poor bioavailability, and repeated administration. Such challenges become more pronounced in chronic diseases that require long-term treatments. Controlled DDSs that release their drug load at the desired site and with specific dose on-demand are potential solution [2].

The development of such systems, which could be referred to as “smart’‘, nowadays is increasingly becoming feasible due to the digital and technological advancement. Smart drug delivery systems (SDDSs) function by releasing their cargo in response to either (endogenous) internal stimulating signal such as plasma glucose levels, pH, redox state, and enzyme, or (exogenous) external stimulating signal, for example, ultrasound, temperature, magnetic, light, and electrical [3]. Among them, electrical stimulation has drawn considerable attention for various reasons including ease of control, repeated drug release, simple, and inexpensive [4]. Additionally, it can be easily integrated with sensors to provide closed-loop drug delivery and monitoring/diagnostic systems [5]. The system comprises an electric responsive carrier where drug(s) is loaded and uses electric field or current to stimulate and control drug release. Different types of drug release are achievable whether sustained over a period of time or pulsed in response to trigger. Overall, SDDSs have a broad applicability and can be developed as ingestible, injectable, implantable, or transdermal [6,7].

Recent advances in materials science have led to the development of smart electroactive biomaterials from which an electric responsive carrier for drug delivery can be made [8]. Different material types fall within this class including conductive polymers (CPs), metal/semiconductors, and carbon-based materials. CPs are class of polymers that are intrinsically conductive with metal-like conductivity, yet offering the advantages of polymers that include processability, lightweight, chemical resistance and low cost [9]. There are around 25 CPs, of which those who have excellent electrical conductivity, good biocompatibility, and enhanced physical and chemical properties such as poly (3,4-ethyelenedioxythiophene) (PEDOT), polypyrrole (PPy), and polyaniline (PANi) are widely explored [10,11]. In healthcare, CPs have been used in biosensors, scaffolds for tissue engineering, actuators for artificial muscles, and drug delivery [4,9].

CPs have also been investigated as SDDS. To release their cargo, CPs undergo a series of conformational changes when electrically stimulated to release the drug by diffusion [4]. Another drug release mechanism could be oxidation or reduction reactions of the polymer caused by electrical stimulation that changes the polymer charge and repel oppositely charged drug molecule. These reactions are usually reversible, and CPs are responsive to repeated stimulations [5,12]. However, current fabrication methods suffer from limited resolution, high cost procedures and material wastage, which have hindered innovation [13].

Three-dimensional (3D) printing, or additive manufacturing, is a cutting-edge technology that transform computer created designs to unique objects in a layer-by-layer manner. Unlike traditional manufacturing processes, 3D printing is able to produce complex structures with high resolution. The technology allows rapid prototyping, and on-demand printing besides being cost effective and simple to operate [[14], [15], [16], [17]]. Indeed, the versatility of the technology has prompted advances in several sectors.

In the pharmaceutical field, a considerable amount of literature has been published showing the ability of 3D printing in the development of personalised dosage forms with different release profiles, geometries, and drug combinations [[18], [19], [20], [21], [22], [23], [24]]. The technology paved the way towards novel solutions to some of the major problems associated with traditional dosage forms including polypharmacy by fabricating 3D polypills [25,26], swallowing difficulties by producing orally disintegrating films/tablets or minitablets [[27], [28], [29], [30], [31]], and acceptability especially in children by creating chewable tablets with different shapes and flavours [32,33]. While intensive efforts have been devoted to 3D printing personalised medicines, only DDS with limited programmability have been achieved.

Here we investigate the potential of merging these two powerful technologies of CPs and 3D printing to achieve the next frontier of personalised medicines. The programmability of 3D printed electroactive DDS was evaluated using poly (3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) as the CP and loaded it with methylene blue as a model drug.

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Materials

Poly (3,4-ethylenedioxythiophene)-poly (styrenesulfonate) (PEDOT:PSS) (768,618-1G), dimethylsulfoxide (DMSO), dimethylformamide (DMF), and methylene blue (MB) (M9140-25G) were obtained from Sigma Aldrich (Gillingham, UK). Thermoplastic polyurethane (TPU) (ElastollanR) was received from BASF (Ludwigshafen, Germany). Deionized water was generated using ELGA water purification system (VWS Ltd., UK). Phosphate-buffered saline (PBS) (pH = 7.4) was prepared using 8.0 g/L NaCl, 0.2 g/L KCl, 1.42 g/L Na2HPO4 and 0.24 g/L KH2PO4, all of which were also purchased from Sigma Aldrich (Gillingham, UK).

Manal E. Alkahtani, Siyuan Sun, Christopher A.R. Chapman, Simon Gaisford, Mine Orlu, Moe Elbadawi, Abdul W. Basit, 3D printed electro-responsive system with programmable drug release, Materials Today Advances, Volume 23, 2024, 100509, ISSN 2590-0498, https://doi.org/10.1016/j.mtadv.2024.100509.