Recent advances of controlled drug delivery using microfluidic platforms☆
Graphical abstract
This article reviews recent advances of controlled drug delivery using microfluidic platforms which can be implanted in human bodies to control drug release in real time through an on-demand feedback mechanism.
Introduction
Drug delivery systems to administer a therapeutic substance to a biological system have been crucial to ensuring that the administered substances/drugs lead to desired therapeutic efficacy with minimal side effects. Drugs can be delivered through various routes including hypodermic injections, oral administration, inhalation, and transdermal administration [1]. Drug delivery systems ensure maximum efficacy of the therapeutic drugs by delivering drugs to the target sites, immediately releasing the drugs, lengthening the release of drugs or making a pulsatile release based upon disease conditions and working mechanisms of the drugs.
Conventional methods of drug delivery possess several drawbacks although they are the most common delivery methods. One of the major drawbacks of conventional drug delivery is the difficulty associated with achieving targeted delivery to specific cells and tissues as they are evenly distributed throughout the body before reaching pathological sites of action and may get inactivated or degraded while crossing different biological barriers [2]. Further, drugs may become less effective as the final effective concentrations at the site of action are lowered. Almost 80% of the drugs are administered orally [1]. Oral administrations have limitations in terms of absorption and metabolism. Enzymatic degradation, degradation due to change in pH within the body, side effects, varying transit times, and first-pass metabolism represent some other limitations associated with oral administration [3]. Hypodermic injections lead to pain because of long needles that pierce through the nerve endings. In addition, conventional drug delivery systems usually have a burst release of drugs instead of sustained release, which decreases the efficacy of therapeutic drugs. Drugs may have to be used at higher concentrations, ultimately increasing cytotoxicity and side effects of the drugs. Finally, conventional methods are also limited by drug's poor solubility, non-specificity, and undesired release profiles [4]. Sustained release of drugs where the drugs' concentrations remain within the therapeutic range for a long time is often required for the desired therapeutic efficacy. For some specific therapeutic effects, it is desired to deliver drugs according to the circadian behavior of the disease. These chrono-therapeutic drugs for diseases such as arthritis, epilepsy, asthma, ulcer, and diabetes, where pharmacokinetics is not constant within 24 h due to rhythmic circadian of the body, may require the pulsatile release of the drugs [5], [6].
Controlled drug delivery systems started in the early 1950s with the development of oral and transdermal sustained release systems, followed by the development of zero-order release systems, microtechnology- and nanotechnology-based delivery, and self-regulated drug delivery systems [7]. The growth in the field has led to the development of numerous novel systems for controlled drug delivery, including micro-reservoir implants, transdermal patches, nanoparticles (NPs), antibody-drug conjugates, and microneedles (MNs) [8]. Controlled drug delivery systems help to improve the administration, efficiency, and pharmacokinetics of therapeutic drugs such as peptides, vaccines, enzymes, and other drugs. They improve the bioavailability of therapeutic drugs by increasing the uptake, preventing the premature degradation, maintaining drugs at the therapeutic window, and reducing the side effects by targeting drugs to particular cells or tissues. A drug delivery system that can be controlled to release the drugs in the desired amount would enable patients to achieve reproducible, on-demand, and tunable dosing at the required time. Such a system allows accurate regulation of dosage for desired effects, minimizes the related side effects, and averts repeated drug administration or implantation of devices, ultimately increasing the patient compliance [9].
Microfluidic lab-on-a-chip (LOC) is a rapidly growing field where a tiny amount of fluids is manipulated within a device with micro-scale structures inside. Microfluidic devices produced by microfabrication techniques integrate multiple components and functionalities ranging from sampling and synthesis to testing within a small device and can be automated to analyze complex biological fluids or deliver therapeutic compounds [10]. In addition, it has several other remarkable features including low-cost, portable, well-controlled microenvironments, and high throughput. Processes within a miniaturized microfluidic device can be controlled precisely and efficiently. LOC finds applications in varieties of fields including drug and gene delivery, particles and drug-carriers synthesis, detection of infectious diseases and cancers, cellular analysis, tissue engineering and so on [9], [11], [12], [13], [14]. The microtechnology for controlled drug delivery involves the fabrication and assembly of various components for drug delivery devices, implantation of the devices within human or animal bodies, synthesis of therapeutic vessels/carriers, and delivery of the drugs to the targeted cells or tissues. Both the synthesis of therapeutic drugs and delivery to specific sites can also be integrated into a single device [15].
To address various drawbacks of conventional drug delivery systems, microfluidic devices are being widely used in controlled drug delivery as they have certain unique features such as the precise control of flow and integrated processing [9], [16], [17], [18]. LOC-based devices can deliver drugs at a sustained rate, increasing the therapeutic efficiency and overcoming the burst release in conventional methods and its associated side effects [19]. Peptides, proteins or DNA-based drugs may be ineffective due to enzymatic degradation while traveling through the long pathway in conventional drug delivery system [20]. Recent developments in microfluidic technologies can help controlled and targeted drug delivery (e.g. through implanted microdevices) and minimize the delivery pathway. As LOC technology can precisely manipulate nano-liter volumes of liquid, it can synthesize drug carriers with precise sizes, shapes, and compositions, leading to a more predictable drug release profile [21], [22]. To obtain a reproducible release profile, mono-dispersed drug carriers are required, which is very challenging without the use of LOC technologies as conventional methods of emulsification generally produce multi-dispersed carriers. In addition, miniaturized microfluidic devices help to reduce pain and improve portability and safety, and in some cases, do not require trained personnel.
This article reviews recent advances in controlled drug delivery using microfluidic platforms. After a brief description of drug delivery systems and microfabrication techniques, this article reviews different microfluidic controlled drug delivery platforms based upon three broad categories, i.e. drug carrier-free microfluidic systems, drug carrier-integrated microfluidic LOC systems, and MNs-based drug delivery systems. Because MNs have attracted a lot of attention, we separate MNs into a stand-alone section. Drug carrier-free microfluidic systems further include micro-reservoir systems and microfluidic LOC devices, because of different degree of integrations. Certain drug carriers can improve the delivery and effectiveness of drugs. Hence, different kinds of drug carriers including microcapsules, nanoemulsions, and NPs, are discussed within drug carriers-integrated microfluidic systems. Similarly, MNs-based drug delivery systems include different varieties of MNs including solid, porous, hollow, coated, and dissolvable MNs, based upon their structures and modes of delivery of therapeutics drugs. Lastly, we briefly discuss current limitations and future trends in the field of controlled drug delivery using microfluidic platforms.
Currently, there are a variety of techniques to fabricate these microsystems, including micromilling, micromachining, photolithography, etching, deposition, mold replication, laser ablation, and assembly [10], [23], [24], [25], [26]. In general, there are basically four processes to fabricate these microsystems, involving patterning, deposition, etching, and bonding [23]. Particularly, in microfabrication techniques, patterning is the fundamental process, which is applied to transfer the designed sketches of each component, like microchannels, onto a chip substrate such as silicon, glass, metals, and polymers [24], [27]. Photolithography and soft lithography have been widely used for patterning by transferring a pattern from a photomask onto a photoresist layer under the exposure to ultraviolet illumination [21], [24], [28], [29]. In addition, deposition of thin films is another crucial procedure, in which thin films with the thickness of micrometers are deposited usually via the physical deposition or chemical deposition or grown on a substrate. Evaporation, sputtering and electroplating are commonly used as deposition techniques for metal substrates [23]. Besides, etching methods such as isotropic and anisotropic etching are applied to remove materials selectively to create different types of features for defined patterns, with a complementary set of materials and etchants [16]. Most structures can be displayed after the sequential etching processes. Moreover, in many situations, there is a need to form a closed system. Therefore, two or even more substrates are required to be bonded together reversibly or irreversibly via various bonding processes, such as thermal bonding, anodic bonding, and photopolymer adhesives [30], [31], [32], [33], [34]. Since microfabrication is not the focus of this review article, more detailed information regarding microfabrication techniques can be found from these review articles and books [10], [35], [36].
Section snippets
Drug carrier-free microfluidic systems for controlled drug delivery
Microfluidic platforms have been increasingly applied for controlled drug delivery, either through the direct drug carrier-free delivery, or the integration of drug carriers on a chip [21]. Drug carrier-free microfluidic systems can be separated into two categories, namely simple micro-reservoir-based devices and highly integrated microfluidic LOC devices, with tremendous interest in implantable devices [16], [23], [25], [37].
Integration of drug carriers in microfluidic platforms
Drug carriers are defined as the substances which are incorporated to improve the delivery and the effectiveness of drugs [88], [89], [90]. A wide variety of drug carriers have been studied and employed in controlled drug delivery with some significant features such as the precise targeting ability, the accurate release of drugs, and the improved pharmacokinetic and biodistribution characteristics of drugs, and so on. Microfluidic platforms offer great opportunities especially for production
Microneedle-based drug delivery
Transdermal administration is one of the most preferred routes of drug delivery because of the ease of use and convenience. It is minimally invasive and causes less discomfort to patients. It also avoids first pass metabolism and gastrointestinal degradation. It has significant advantages over hypodermic injections that are generally painful, produce medical waste, and pose a risk of disease transmission in underdeveloped countries by the reuse of the needles [182]. In addition, the transdermal
Conclusion & future prospects
An ideal goal of a controlled drug delivery system is to provide clinically relevant drug formulations at desired kinetics to help treat patients effectively from different pathological conditions, reduce side effects, and increase patient convenience and compliance. With the rapid development of microtechnology, numerous microfluidic platforms have been developed for controlled drug delivery, including drug carrier-free micro-reservoir-based drug delivery systems, highly integrated drug
Acknowledgements
The authors would like to acknowledge the financial support of the NIH/NIAID under award number R21AI107415, the NIH/NIGMS under award number SC2GM105584, and the NIH/NIMHD/RCMI under award number 5G12MD007593-22. Financial support from the Emily Koenig Meningitis Fund from the Philadelphia Foundation, Emily's Dash Foundation, the Medical Center of the Americas (MCA) Foundation, the U.S. NSF-PREM program (DMR 1205302), the NIH BUILD program, the NIH BUILDing Scholar Summer Sabbatical Award (
Declaration of interest
All the authors declare no conflict of interest.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Microfluidic Devices for Drug Delivery Systems”.
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Denotes those authors contribute equally to this work.