Elsevier

Journal of Controlled Release

Volume 190, 28 September 2014, Pages 139-149
Journal of Controlled Release

Review
Engineering and evaluating drug delivery particles in microfluidic devices

https://doi.org/10.1016/j.jconrel.2014.04.030Get rights and content

Abstract

The development of new and improved particle-based drug delivery is underpinned by an enhanced ability to engineer particles with high fidelity and integrity, as well as increased knowledge of their biological performance. Microfluidics can facilitate these processes through the engineering of spatiotemporally highly controlled environments using designed microstructures in combination with physical phenomena present at the microscale. In this review, we discuss microfluidics in the context of addressing key challenges in particle-based drug delivery. We provide an overview of how microfluidic devices can: (i) be employed to engineer particles, by providing highly controlled interfaces, and (ii) be used to establish dynamic in vitro models that mimic in vivo environments for studying the biological behavior of engineered particles. Finally, we discuss how the flexible and modular nature of microfluidic devices provides opportunities to create increasingly realistic models of the in vivo milieu (including multi-cell, multi-tissue and even multi-organ devices), and how ongoing developments toward commercialization of microfluidic tools are opening up new opportunities for the engineering and evaluation of drug delivery particles.

Introduction

Through nanotechnology, synthetic functional structures can be engineered at the nanometer-level, thus creating materials that can interact with, and influence, biological systems at their very core [1]. The application of nanotechnology to diagnose and treat diseases – nanomedicine – has moved from being solely an academic endeavor to making an impact in the clinic [2]. Examples include: (i) biomaterials for medical implants, such as nanocomposites used as dental fillers; (ii) in vitro diagnostics, such as gold nanoparticles that enhance sensitivity in genetic assays; (iii) in vivo imaging, such as superparamagnetic iron oxide nanoparticles for use as contrast agents in magnetic resonance imaging; and (iv) drug delivery, where nanostructured carriers can be used for the controlled delivery of therapeutics [1], [2].

Encapsulating or attaching a therapeutic to an engineered drug delivery carrier can improve the safety and efficacy of a drug, thus enabling new and improved therapies [3], [4], [5]. However, the translation of engineered multifunctional drug delivery vehicles from in vitro to the preclinical and finally the clinical setting has proven to be a considerable challenge. Reasons for this are the difficulties associated with predicting the behavior of an engineered carrier in a system as complex as the human body. Built up of a hierarchy of structures with functional dimensions that differ by many orders of magnitude, the human body is a multi-level, feedback-regulated compartmentalized system, both highly dynamic and interconnected. For example, receptor–ligand interactions at the nanometer scale can cause the release and distribution of hormones that can, ultimately, lead to organism-level changes. To work at, and understand, all of these length scales, especially at the smallest dimensions, requires a highly interdisciplinary approach [6].

In this review, we discuss current challenges facing particle-based drug delivery systems and review strategies where microfluidic technologies have been used to address some of these issues. We provide an overview of both the production and evaluation of drug delivery particles, with a focus on microfluidics as an enabling technology. Emphasis is placed on how microfluidics can complement existing technologies by providing new ways to reliably and reproducibly engineer drug delivery particles and new in vitro models that can mimic important aspects of the in vivo situation. These features of microfluidic technologies that enable detailed analysis of mechanisms that govern interactions of particles with biological systems can facilitate the correlation between in vitro and in vivo studies. Additionally, we provide an outlook of this growing interface between drug delivery and microfluidics, as well as discuss the impact of the evolution within microfluidics, from highly specialized “home-built” systems to easily accessible “off-the-shelf” instruments. This increase in accessibility is facilitating interdisciplinary work, thus accelerating the development of new and improved rationally designed drug delivery particles.

Section snippets

Drug delivery particles and challenges ahead

The objective of a drug delivery particle is to deliver a therapeutic to where it is needed, when it is needed. The archetypical example is to selectively deliver a cytotoxic compound to a tumor, at a high enough concentration and for long enough to kill the tumor, while at the same time leaving healthy tissue unharmed. A drug delivery particle can provide a different means toward realizing this, including: (i) facilitating formulation of the therapeutics; (ii) increasing specificity; and (iii)

Microfluidics as an enabling technology

Microfluidics is a multidisciplinary field where small amounts of fluids are handled in channels with dimensions typically from tens to hundreds of micrometers [26]. At these length scales novel, and sometimes nonintuitive, properties appear. Examples include laminar flow and the relative importance of diffusion. This is because the competition between various phenomena that dictate the behavior of fluids do not scale linearly with changes in dimensions [27]. Using soft lithography,

Engineering drug delivery particles through microfluidics

Both the materials and the methods used to engineer drug delivery particles determine their properties. As all methods have both strengths and drawbacks, there is an ongoing process in improving existing – and developing new – techniques toward more reliable and reproducible production of particles with highly tuned properties. One example of an area where there is significant ongoing activity is the fabrication of polymer capsules [40].

Microfluidic devices offer new possibilities for the

Evaluating bio-interactions of drug delivery particles through microfluidics

An objective of an engineered particle-based drug delivery system is to guide the interactions between a therapeutic and a biological system. Two important aspects of this are improving the localization and kinetics of drug exposure. Ideally, a drug should be released only at the intended site of action, for example at a tumor for a cancer drug, and at a concentration and over a time frame that optimizes the therapeutic effect while minimizing toxicity. This dose–response relationship is

Conclusion and outlook

Engineered drug delivery particles have over the last half century moved from being primarily within the realm of science fiction to technological reality [128]. This development has been fueled by convergence of several disciplines, including biology, chemistry, engineering, materials science, and medicine. This highly interdisciplinary nature introduces some significant challenges but also provides ample opportunities, provided that researchers from disparate fields can coalesce around a

Acknowledgments

This work was supported by the Australian Research Council under the Australian Laureate Fellowship scheme (F.C., FL120100030) and the Discovery Early Career Researcher Award (Y.Y., DE130100488), as well as the Australian Government through an International Postgraduate Research Scholarship (M.B.) and an Australian Postgraduate Award (M.B.).

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