Novel 3D printed device with integrated macroscale magnetic field triggerable anti-cancer drug delivery system

https://doi.org/10.1016/j.colsurfb.2020.111068Get rights and content

Highlights

  • A triggerable and remotely controllable system for on-demand drug delivery was developed.

  • Drug release was tuned using different magnetic fields.

  • The location of magnetic bar compared to the device had an impact on drug release.

  • 3D printing device containing anticancer drug showed an inhibition effect on Trex cell growth.

Abstract

With the growing demand for personalized medicine and medical devices, the impact of on-demand triggerable (e.g., via magnetic fields) drug delivery systems increased significantly in recent years. The three-dimensional (3D) printing technology has already been applied in the development of personalized dosage forms because of its high-precision and accurate manufacturing ability. In this study, a novel magnetically triggerable drug delivery device composed of a magnetic polydimethylsiloxane (PDMS) sponge cylinder and a 3D printed reservoir was designed, fabricated and characterized. This system can realize a switch between “on” and “off” state easily through the application of different magnetic fields and from different directions. Active and repeatable control of the localized drug release could be achieved by the utilization of magnetic fields to this device due to the shrinking extent of the macro-porous magnetic sponge inside. The switching “on” state of drug-releasing could be realized by the magnetic bar contacted with the side part of the device because the times at which 50%, 80% and 90% (w/w) of the drug were dissolved are observed to be 20, 55 and 140 min, respectively. In contrast, the switching “off” state of drug-releasing could be realized by the magnetic bar placed at the bottom of the device as only 10% (w/w) of the drug could be released within 12 h. An anti-cancer substance, 5-fluorouracil (FLU), was used as the model drug to illustrate the drug release behaviour of the device under different strengths of magnetic fields applied. In vitro cell culture studies also demonstrated that the stronger the magnetic field applied, the higher the drug release from the deformed PDMS sponge cylinder and thus more obvious inhibition effects on Trex cell growth. All results confirmed that the device can provide a safe, long-term, triggerable and reutilizable way for localized disease treatment such as cancer.

Introduction

The objective of drug delivery systems is to provide predetermined drug release profiles ensuring optimal distribution and absorption of pharmaceutical compounds, which enhance therapeutic effectiveness and minimize side effects by offering a safer, more convenient, and efficient drug administration in humans with enhanced patient compliance [1,2]. Predetermined drug release profiles could be achieved by optimizing suitable drug delivery systems (DDSs) as such enhanced efficacy, safety, and patient compliance may be realized through optimal drug distribution and absorption in the targeted location at the (sub)cellular level [2,3]. However, it has been difficult for conventional drug delivery system to maintain drug concentration level within the narrow therapeutic concentration window for avoiding ineffectiveness (underdose) or toxicity (overdose), and it is often impossible to modify the drug release from these systems after administration [1,4,5]. Additionally, it may not always be appropriate for untunable monotonic drug release to be applied in some disease treatments which require variable release kinetics (including cancer, diabetes, pain, and myocardial infarction) [1,4]. Also, drugs are needed to be administered multiple times or continuously for achieving a long-acting drug release profile in some circumstances [4]. This may lead to patients’ discomfort or inconvenience and even the addition of external devices. Therefore, it is important to design a drug delivery system, which can modulate drug release in terms of time, rate, and location. Such a drug delivery system would show considerable advances in delivering drugs, like painkillers, hormones, and chemotherapeutic agents [1].

Triggerable drug delivery systems (TDDSs), capable of releasing drug through applying external physical signals (such as magnetic field, ultrasound, pH, enzymes, temperature, electric, light, and near-infrared radiation) are gaining more and more attention in pharmaceutical sciences [1,6,7]. Such systems containing a large amount of drug can present remote, noninvasive, tunable, and reliable switching of therapeutic compound flux [4]. Hence, spatiotemporal management of drug availability could be realized through these triggerable drug delivery systems by the physicians or patients with the utilization of either the interaction between a ‘responsive’ material and the surrounding environment or a remotely controllable activation device [1,5,8]. Also, these systems loaded with a large amount of drug can achieve multiple dosing after a single administration through repeatable triggering [1]. However, there are still some limitations, like low controllability because of an initial burst release or a drug leakage via diffusion, difficulty in disposing of the systems after therapy, and increasing toxicity-associated risks due to the possible degradation of the matrix and the reduction of stability and reliability of the systems [1,5].

Implantable reservoir-based devices have been designed to overcome these limitations efficiently [9]. Targeted therapy could be achieved through these devices at different length scales with high anatomical variability [10]. The performing procedure and working environment will affect the features, sizes, and operation mechanisms significantly [5]. Herein, it is highly desirable to fabricate untethered macroscale triggerable drug delivery systems with low cost, simple preparation, facile operation, simplified structural morphology, and the ability to move through body channels and perform on-demand drug administration [5,11].

Although several external stimuli have been studied in TDDSs, controlled drug targeting through magnetic actuation is still one of the principal approaches because of many advantages, such as instantaneous and reversible response, remote actuation, non-destructive and high controllability, which are especially attractive for biomedical fabrication where the noncontact feature is particularly necessary in vivo environment with absolute safety [3,12,13]. Those magnetic systems also play an important role in cancer research due to the superior ability in chemotherapy by realizing: (1) selective delivery of the maximum fraction of anti-cancer molecules to the desired site without any increase in side effects to normal cells; (2) prior distribution of anti-cancer drug to targeted cells; (3) stable systemic drug concentration and (4) elimination of normal tissue clearance with the application of external magnetic field [3]. Various types of magnetic particles have been widely applied in these systems as switching carriers, including Fe3O4 particles [7,14], NdFeB powders [5] and carbonyl iron (CI) powders [12,13]. With the addition of magnetic enclosures, these magnetically responsive systems can move and deform due to applied magnetic fields [15]. Furthermore, with the manipulation of external permanent magnets, magnetically triggered drug delivery systems have the ability to remote locomotion through biological tissues in real-time because magnetic fields can transmit high force or torques wirelessly with multiple degrees of freedom to medical robots [5,16].

In recent years, personalized medicine has attracted increasing attention as it can provide patients with a superior treatment with a comprehensive consideration of their own pharmacogenomics, anatomical, and physical conditions [17]. It is reported that the inappropriate dosing or dosing combination has become the main reason for adverse effects from drug therapy [18]. This leads to an increased demand for a tailored method of dosage forms to suit patient needs instead of “One-size-fits-all” [18,19].

To address these challenges, three-dimensional printing (3DP) technology has been applied successfully because traditional DDSs cannot fulfil such criteria [17,19]. Because of its potential in personalized medicine, its applications in medical devices, implants, tissue engineering, and pharmaceutical dosage forms have attracted a great deal of attention [18]. This technology can achieve detailed and flexible spatial composition, and provide more available starting materials (like colloidal inks, bio-inks, and polymers) for the unprecedented complex and precise manufacture of 3D DDSs [2,20]. Various techniques, namely powder-based (PB), stereolithography (SLA), selective laser sintering (SLS), inkjet printing and fused deposition modelling (FDM) have been explored in the pharmaceutical applications [19]. Among them, FDM 3DP has gained the most attention due to its cost-effective, time-saving and versatile modalities of producing sophisticated solid objects [18,19].

Polylactic acid (PLA) is the most common material used for FDM because it is a non-toxic, renewable, thermoplastic, biodegradable and biocompatible polymer [20,21]. Additionally, its suitable properties like high mechanical strength, low coefficient of thermal expansion and processability for extrusion applications make this material ideal for pharmaceutical and biomedical applications [21]. Furthermore, various polymers, such as Pluronic, poly(vinyl alcohol) and polycaprolactone, could be blended with PLA to provide extra features with the addition of active pharmaceutical ingredients (APIs) to the final composite material in healthcare applications [20,21,22,23].

In this study, a magnetic-field triggerable drug delivery system with a 3D-printed reservoir and magnetic PDMS sponges was designed and characterized. This device can achieve highly precise and dynamic administration of drugs in an active and instant manner with only a permanent magnet.

Section snippets

Materials

A SYLGARD® 184 Silicone Elastomer prepolymer (Sylgard 184A, Mw ≈ 22 000 g·mol-1) and the thermal curing agent (Sylgard 184B, Mw ≈ 15 000 g·mol-1) were purchased from Dow Corning. Carbonyl iron (CI) powder with purity ≥ 97% was purchased from Sigma-Aldrich (Germany). The white granulated sugar was purchased from Sainsbury’s (UK). The model anticancer drug 5-fluorouracil (FLU) with purity > 98% was purchased from Hangzhou Longshine Bio-tech Co., Ltd. (Hangzhou, China). The PLA filament

Fabrication and Characterization of Magnetic PDMS Sponges

Among all prepared magnetic PDMS sponges (Fig. 3), 100 w/w% CI/PDMS sponge was selected for the scaffold in this experiment as it exhibited the most deformation tendency at the given reflux under the given magnetic field. The underlying reasons being that the ferromagnetic particles were homogeneously distributed throughout the PDMS sponges as such it was enough to deform the sponges at a suitable extent to trigger drug release from the system. The lower or higher amount of CI particles in the

Conclusion

In this experiment, we designed and developed a novel implantable drug delivery device assembled from a magnetic PDMS sponge cylinder and a 3D-printed PLA reservoir to provide a triggerable and remotely controllable system for on-demand drug delivery in localized disease treatment. This device utilizes different extrinsic magnetic fields for offering a tunable force to trigger drug release through reversible magnetic sponge deformations. The geometric shape and dimensions of the reservoir could

CRediT author statement

Kejing Shi: Investigation, draft preparation

Rodrigo Aviles-Espinosa: Investigation

Elizabeth Rendon-Morales: Investigation

Lisa Woodbine: Investigation

Mohammed Maniruzzaman: Conceptualization, Supervision, Reviewing and Editing

Ali Nokhodchi: Supervision, Conceptualization, Writing- Reviewing and Editing

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgement

The authors thanks China Scholarship Council (CSC) for financial support of Kejing Shi.

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