Microneedles for drug and vaccine delivery.

This article reviews acoustic microfiuidics: the use of acoustic fields, principally ultrasonics, for application in microfiuidics. Although acoustics is a classical field, its promising, and indeed perplexing, capabilities in powerfully manipulating both fluids and particles within those fluids on the microscale to nanoscale has revived interest in it. The bewildering state of the literature and ample jargon from decades of research is reorganized and presented in the context of models derived from first principles. This hopefully will make the area accessible for researchers with experience in materials science, fluid mechanics, or dynamics. The abundance of interesting phenomena arising from nonlinear interactions in ultrasound that easily appear at these small scales is considered, especially in surface acoustic wave devices that are simple to fabricate with planar lithography techniques common in microfluidics, along with the many applications in microfluidics and nanofluidics that appear through the literature.

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Microscale acoustofluidics: Microfluidics driven via acoustics and ultrasonics

This paper briefly overviews progress on the development of MEMS-based micropumps and their applications in drug delivery and other biomedical applications such as micrototal analysis systems (μTAS) or lab-on-a-chip and point of care testing systems (POCT). The focus of the review is to present key features of micropumps such as actuation methods, working principles, construction, fabrication methods, performance parameters and their medical applications. Micropumps have been categorized as mechanical or non-mechanical based on the method by which actuation energy is obtained to drive fluid flow. The survey attempts to provide a comprehensive reference for researchers working on design and development of MEMS-based micropumps and a source for those outside the field who wish to select the best available micropump for a specific drug delivery or biomedical application. Micropumps for transdermal insulin delivery, artificial sphincter prosthesis, antithrombogenic micropumps for blood transportation, micropump for injection of glucose for diabetes patients and administration of neurotransmitters to neurons and micropumps for chemical and biological sensing have been reported. Various performance parameters such as flow rate, pressure generated and size of the micropump have been compared to facilitate selection of appropriate micropump for a particular application. Electrowetting, electrochemical and ion conductive polymer film (ICPF) actuator micropumps appear to be the most promising ones which provide adequate flow rates at very low applied voltage. Electroosmotic micropumps consume high voltages but exhibit high pressures and are intended for applications where compactness in terms of small size is required along with high-pressure generation. Bimetallic and electrostatic micropumps are smaller in size but exhibit high self-pumping frequency and further research on their design could improve their performance. Micropumps based on piezoelectric actuation require relatively high-applied voltage but exhibit high flow rates and have grown to be the dominant type of micropumps in drug delivery systems and other biomedical applications. Although a lot of progress has been made in micropump research and performance of micropumps has been continuously increasing, there is still a need to incorporate various categories of micropumps in practical drug delivery and biomedical devices and this will continue to provide a substantial stimulus for micropump research and development in future.

https://www.nectec.or.th/mems/download/MEMS-based%20Micropumps%20in%20Drug.pdf

MEMS-based micropumps in drug delivery and biomedical applications

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.

/pdf/microneedle-based-drug-delivery-systems-microfabrication-2hboq0lv61.pdf

Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety.

Industrial lab-on-a-chip: Design, applications and scale-up for drug discovery and delivery

Many of the compounds in drugs cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of the skin. As the primary barrier to transport is located in the upper tissue, Micro-Electro-Mechanical-System (MEMS) technology provides novel means, such as microneedle array and PZT pump, in order to increase permeability of human skin with efficiency, safety and painless delivery, and to decrease the size of the pump. Microneedle array has many advantages, including minimal trauma at penetration site because of the small size of the needle, free from condition limitations, painless drug delivery, and precise control of penetration depth. These will promote the development of biomedical sciences and technology and make medical devices more humanized. So far, most of the insulin pumps being used are mechanical pumps. We present the first development of this novel technology, which can assemble the PZT pump and the microneedle array together for diabetes mellitus. The microneedle array based on a flexible substrate can be mounted on non-planar surface or even on flexible objects such as a human fingers and arms. The PZT pump can pump the much more precision drug accurately than mechanical pump and the overall size is much smaller than those mechanical pumps. The hollow wall straight microneedle array is fabricated on a flexible silicon substrate by inductively coupled plasma (ICP) and anisotropic wet etching techniques. The fabricated hollow microneedles are 200 μm in length and 30 μm in diameter. The microneedle array, which is built with on-board fluid pumps, has potential applications in the chemical and biomedical fields for localized chemical analysis, programmable drug-delivery systems, and very small, precise fluids sampling. The microneedle array has been installed in an insulin pump for demonstration and a leak free packaging is introduced.

A PZT insulin pump integrated with a silicon microneedle array for transdermal drug delivery

To achieve high output performance at low actuation voltage, serial-connection multi-chamber piezoelectric micropumps (SCMCP micropumps) with cantilever valves were introduced. The SCMCP micropumps, which can be produced using conventional production techniques and materials, have a multi-layer circular planar structure. The border-upon piezoelectric diaphragm actuators (PZT actuators) of a SCMCP micropump work in anti-phase, as a result of which the output performance is equal to that of several single-chamber piezoelectric micropump (SCP micropump) running in series. The theoretic study suggests that pumping performance of a SCMCP micropump depends on not only the characteristic and geometrical parameters of the PZT actuators, but also the number of the pump chambers. Both flowrate and backpressure of a SCMCP micropump can be enhanced to a certain extent in this way. Four piezoelectric micropumps with different chambers were fabricated and tested for comparison. The testing results show that all of the flowrate, backpressure and even optimal frequency of the SCMCP micropumps increase greatly with the rising of the chamber number. Both the maximum flowrate and pressure of the 4-chamber piezoelectric micropump are about four times of those of the SCP micropump at their respective optimal frequencies. The great advantage of a SCMCP micropump over a SCP micropump is that it can achieve high performance at a comparatively low driving voltage, which is helpful for the portable applications such as an implantable drug-delivery system.

Development of serial-connection piezoelectric pumps

This paper presents a novel and disposable piezoelectric micropump with high performance for a new closed-loop insulin therapy system. The micropump was designed using four chambers in a serial connection structure, and was manufactured using the materials with good bio-compatibility. The major advantages of the proposed micropump include: possessing high performance under lower working voltage, low-cost, high resolution of flow rate. A maximum backpressure of 22 kPa was recorded at an applied voltage of 36 V pp and a driving frequency of 200 Hz, the maximum resolution of outflow can obtain 6.23 × 10 −5  mL per pulse. Through in vivo animal tests, the new closed-loop insulin therapy system has shown a qualification on controlling blood glucose. The proposed micropump also demonstrated necessary characteristics in terms of stability, accuracy and bio-compatibility, for use in precision insulin delivery.

A disposable piezoelectric micropump with high performance for closed-loop insulin therapy system

Many of the compounds in drugs cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of the skin. Because the primary barrier to transport is located in the upper tissue, micro-electro-mechanical-system (MEMS) technology provides novel means in terms of both micro needles array and PZT pump, with the former one to increase permeability of human skin with efficiency, safety and painless delivery, and the latter one to decrease the size of the pump. Micro needles array has many advantages, including minimal trauma at penetration site due to the small size in needle, no condition limit, painless drug delivery for penetration depth with few nerves, and precise control of penetration depth for micro needle extension length. The micro needles array drug delivery is precise, painless, effective, clean and neatness, without any inconvenience. This promotes the development of biomedical sciences and technology and makes medical devices more humanized. So far most of the insulin pump has been using mechanical pump in clinical practices. We present the first development of this novel technology which can assemble the PZT pump and the micro needles together for diabetes mellitus. The micro needle array based on a flexible substrate can be mounted on non-planar surface or even on flexible objects such as a human fingers and arms. The PZT pump can pump the precision insulin much more accurately than the mechanical pump and the overall size is much smaller than those mechanical pumps. The hollow wall straight micro needles array is fabricated on a flexible substrate by deep-reactive ion etching (DRIE) and anisotropic wet etching techniques. The fabricated hollow micro needles are 200/spl mu/m in length and 30/spl mu/m in diameter. The micro needle array, which may be built with on-board fluid pumps, have potential applications in the chemical and biomedical fields for localized chemical analysis, programmable drug-delivery systems, and very small, precise fluids sampling. The micro needles array has been installed in an insulin pump for demonstration and a leak free packaging is introduced.

A PZT insulin pump integrated with a silicon micro needle array for transdermal drug delivery

Active micromixers have been widely used in chemistry, biomedicine and many micro analyses as it offers low reagent consumption, controllable mixing process, safe, and reliable. Based on piezoelectric (PZT) drive technology and numerical simulation results, a self-circulation micromixer with high frequency vibration has been designed and fabricated. The micromixer is composed of PZT micropump, vibration substrate, mixing pool with double U-shaped inlet and outlet, upper cover plate and lower substrate. The performance of the micromixer's self-circulation and high frequency vibration is evaluated by experimental tests. Experimental results show that: When the drive voltage and frequency of the self-circulation reflux micropump are set to 100 V and 100 Hz, respectively, a significant vortex flow is generated in the mixing pool, and the vortex flow speed is as high as 320 r min−1. When the driving frequency of the vibration substrate is set to its first resonance frequency, the displacement of its center point is the largest up to 28.1 µm. Furthermore, the vortex flow speed of the fluid in the mixing pool and the vibration intensity of the vibration substrate can be adjusted separately by regulating the driving voltage of the PZT micropump and vibration substrate.

https://iopscience.iop.org/article/10.1088/1361-6439/aabf18/pdf

Guojun Liu

Papers

A PZT insulin pump integrated with a silicon microneedle array for transdermal drug delivery

Development of serial-connection piezoelectric pumps

A disposable piezoelectric micropump with high performance for closed-loop insulin therapy system

A PZT insulin pump integrated with a silicon micro needle array for transdermal drug delivery

Piezoelectric driven self-circulation micromixer with high frequency vibration