Advanced fabrication approaches to controlled delivery systems for epilepsy treatment

ABSTRACT

Introduction: Epilepsy is a chronic brain disease characterized by unprovoked seizures, which can have severe consequences including loss of awareness and death. Currently, 30% of epileptic patients do not receive adequate seizure alleviation from oral routes of medication. Over the last decade, local drug delivery to the focal area of the brain where the seizure originates has emerged as a potential alternative and may be achieved through the fabrication of drug-loaded polymeric implants for controlled on-site delivery.

Areas covered: This review presents an overview of the latest advanced fabrication techniques for controlled drug delivery systems for refractory epilepsy treatment. Recent advances in the different techniques are highlighted and the limitations of the respective techniques are discussed.

Expert opinion: Advances in biofabrication technologies are expected to enable a new paradigm of local drug delivery systems through offering high versatility in controlling drug release profiles, personalized customization and multi-drug incorporation. Tackling some of the current issues with advanced fabrication methods, including adhering to GMP-standards and industrial scale-up, together with innovative solutions for complex designs will see to the maturation of these techniques and result in increased clinical research into implant-based epilepsy treatment.

Abbreviations: GMP: Good manufacturing process; DDS(s): Drug delivery system(s); 3D: Three-dimensional; AEDs: Anti-epileptic drugs; BBB: Blood brain barrier; PLA: Polylactic acid; PLGA: Poly(lactic-co-glycolic acid); PCL: poly(ɛ-caprolactone); ESE: Emulsification solvent evaporation; O/W: Oil-in-water; W/O/W: Water-in-oil-in-water; DZP: Diazepam; PHT: Phenytoin; PHBV: Poly(hydroxybutyrate-hydroxyvalerate); PEG: Polyethylene glycol; SWD: Spike-and-wave discharges; CAD: Computer aided design; FDM: Fused deposition modeling; ABS: Acrylonitrile butadiene styren; eEVA: Ethylene-vinyl acetate; GelMA: Gelatin methacrylate; PVA: Poly-vinyl alcohol; PDMS: Polydimethylsiloxane; SLA: Stereolithography; SLS: Selective laser sintering.

KEYWORDS:

• Advanced fabrication
• controlled drug delivery systems
• epilepsy
• implant drug delivery
• three-dimensional printing

Article Highlights

• Implantable polymeric drug delivery systems (DDSs) have gained a lot of interest due to their potential ability to treat refractory epilepsy by delivering drugs to the focus area.

• A variety of drug release profiles can be tailored using electrohydrodynamic means to produce micro- and nano-scale particulate and fibrous structures, particularly through the inclusion of a core-shell configuration within the structures.

• Three-dimensional (3D) printing is particularly suitable for DDS fabrication. It enables 3D distribution of drugs and polymer matrix into complex geometries in a controlled manner, which can also be tailored to meet individual patient needs. 3D printing may offer solutions to some of the bottlenecks in epilepsy treatment that are not possible with conventional fabrication methods.

• Various 3D printing techniques are compared, through examples of implant-based drug delivery applications, to explore the advantages and limitations of each technique.

• Current challenges and future perspectives for advanced fabrication techniques in drug delivery for epilepsy treatment are discussed.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank the University of Wollongong Electron Microscopy Centre and the Australian National Fabrication Facility (ANFF) – Materials Node for their support. Professor Gordon Wallace acknowledges the support of the ARC through an ARC Laureate Fellowship (FL110100196). The authors also thank the Australian Government International Education and Training program in relation to project BIOFABrication for Future Manufacturing and the EU ICI ECP International Joint Program for biofabrication mobility.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Australian Research Council (ARC) Centre of Excellence Scheme [grant number CE140100012] and an ARC Laureate Fellowship [grant number FL110100196 to GW].