Peiyi Song

Approaches and Challenges of Engineering Implantable Microelectromechanical Systems (MEMS) Drug Delivery Systems for in Vitro and in Vivo Applications

Despite the advancements made in drug delivery systems over the years, many challenges remain in drug delivery systems for treating chronic diseases at the personalized medicine level. The current urgent need is to develop novel strategies for targeted therapy of chronic diseases. Due to their unique properties, microelectromechanical systems (MEMS) technology has been recently engineered as implantable drug delivery systems for disease therapy. This review examines the challenges faced in implementing implantable MEMS drug delivery systems in vivo and the solutions available to overcome these challenges.

A Self‐Powered Implantable Drug‐Delivery System Using Biokinetic Energy

The first triboelectric-nanogenerator (TENG)-based self-powered implantable drug-delivery system is presented. Pumping flow rates from 5.3 to 40 µL min-1 under different rotating speeds of the TENG are realized. The implantable drug-delivery system can be powered with a TENG device rotated by human hand motion. Ex vivo trans-sclera drug delivery in porcine eyes is demonstrated by utilizing the biokinetic energies of human hands.

Moving towards individualized medicine with microfluidics technology

The development of microfluidics technology has enabled the biomedical research community to create novel strategies for applications ranging from diagnostics to therapy of various human diseases. Recent advances in microfluidic technology will aid in providing new sets of solutions to overcome the shortcomings of conventional detection and treatment methods available in clinics and hospitals. Microfluidic technology is equipped with the ability to precisely control and manipulate fluids and allow medical researchers to engineer a translational medicine platform for rapid biological sample analysis and controlled drug delivery therapy. In addition, the dimensions of microfluidic device can be miniaturized to a desirable size thereby offering the convenience of embedded implant treatment. These unique features of microfluidic technology are valuable assets for advancing individualized medicine plans such as new treatment protocols and diagnosis approaches. Individualized medicine research has been recently explored for applications such as point-of-care testing and individualized drug therapy. By carefully fusing microfluidic technology into these applications, we would be able to improve the effectiveness in detecting biomolecules and monitoring drug delivery profiles in vivo. In this review, we report and discuss the recent development, advancement, and future trends of using microfluidic technology for individualized diagnosis and therapy studies in vitro and in vivo.

An Electrochemically Actuated MEMS Device for Individualized Drug Delivery: an In Vitro Study

Individualized disease treatment is a promising branch for future medicine. In this work, we introduce an implantable microelectromechanical system (MEMS) based drug delivery device for programmable drug delivery. An in vitro study on cancer cell treatment has been conducted to demonstrate a proof-of-concept that the engineered device is suitable for individualized disease treatment. This is the first study to demonstrate that MEMS drug delivery devices can influence the outcome of cancer drug treatment through the use of individualized disease treatment regimes, where the strategy for drug dosages is tailored according to different individuals. The presented device is electrochemically actuated through a diaphragm membrane and made of polydimethylsiloxane (PDMS) for biocompatibility using simple and cost-effective microfabrication techniques. Individualized disease treatment was investigated using the in vitro programmed delivery of a chemotherapy drug, doxorubicin, to pancreatic cancer cell cultures. Cultured cell colonies of two pancreatic cancer cell lines (Panc-1 and MiaPaCa-2) were treated with three programmed schedules and monitored for 7 days. The result shows that the colony growth has been successfully inhibited for both cell lines among all the three treatment schedules. Also, the different observations between the two cell lines under different schedules reveal that MiaPaCa-2 cells are more sensitive to the drug applied. These results demonstrate that further development on the device will provide a promising novel platform for individualized disease treatment in future medicine as well as for automatic in vitro assays in drug development industry.

An in-vivo evaluation of a MEMS drug delivery device using Kunming mice model

The use of MEMS implantable drug delivery pump device enables one to program the desired drug delivery profile in the device for individualized medicine treatment to patients. In this study, a MEMS drug delivery device is prepared and employed for in vivo applications. 12 devices are implanted subcutaneously into Kunming mice for evaluating their long term biocompatibility and drug-delivery efficiency in vivo. All the mice survived after device implantation surgery procedures. Histological analysis result reveals a normal wound healing progression within the tissues-to-device contact areas. Serum analysis shows that all measured factors are within normal ranges and do not indicate any adverse responses associated with the implanted device. Phenylephrine formulation is chosen and delivered to the abdominal cavity of the mice by using either the implanted MEMS device (experimental group) or the syringe injection method (control group). Both groups show that they are able to precisely control and manipulate the increment rate of blood pressure in the small animals. Our result strongly suggests that the developed refillable implantable MEMS devices will serve as a viable option for future individualized medicine applications such as glaucoma, HIV-dementia and diabetes therapy.

Synthesis and characterization of multifunctional hybrid-polymeric nanoparticles for drug delivery and multimodal imaging of cancer.

In this study, multifunctional hybrid-polymeric nanoparticles were prepared for the treatment of cultured multicellular tumor spheroids (MCTS) of the PANC-1 and MIA PaCa-2 pancreatic carcinoma cell lines. To synthesize the hybrid-polymeric nanoparticles, the poly lactic-co-glycolic acid core of the particles was loaded with Rhodamine 6G dye and the chemotherapeutic agent, Paclitaxel, was incorporated into the outer phospholipid layer. The surface of the nanoparticles was coated with gadolinium chelates for magnetic resonance imaging applications. This engineered nanoparticle formulation was found to be suitable for use in guided imaging therapy. Specifically, we investigated the size-dependent therapeutic response and the uptake of nanoparticles that were 65 nm, 85 nm, and 110 nm in size in the MCTS of the two pancreatic cancer cell lines used. After 24 hours of treatment, the MCTS of both PANC-1 and MIA PaCa-2 cell lines showed an average increase in the uptake of 18.4% for both 65 nm and 85 nm nanoparticles and 24.8% for 110 nm nanoparticles. Furthermore, the studies on therapeutic effects showed that particle size had a slight influence on the overall effectiveness of the formulation. In the MCTS of the MIA PaCa-2 cell line, 65 nm nanoparticles were found to produce the greatest therapeutic effect, whereas 12.8% of cells were apoptotic of which 11.4% of cells were apoptotic for 85 nm nanoparticles and 9.79% for 110 nm nanoparticles. Finally, the study conducted in vivo revealed the importance of nanoparticle size selection for the effective delivery of drug formulations to the tumors. In agreement with our in vitro results, excellent uptake and retention were found in the tumors of MIA PaCa-2 tumor-bearing mice treated with 110 nm nanoparticles.

A sustainable approach to individualized disease treatment: The Engineering of a multiple use MEMS drug delivery device

Individualized disease diagnosis and therapy has emerged as a new direction in the research of future medication. Over the past several years, innovative approaches based on microelectromechanical system (MEMS) technology have demonstrated promising potential in individualized therapy. In this contribution, a sustainable approach for the individualized treatment of chronic disease is presented using a compact, implantable and refillable MEMS drug delivery device with an electrolysis based actuator. As a demonstration, we utilized the device for programmable delivery of a chemotherapy drug for the treatment of pancreatic cancer with an in vitro configuration based on cancer cell colonies. After the delivery of drug using the device, the growth of the colonies has been greatly inhibited as compared with the control samples. These results show that our new approach has a great potential for future in vivo studies and opens up promising opportunities for future medication.

Pressure-driven particle focusing in lab-on-a-chip flow cytometers: The choice between sheath-assisted and inertial focusing

We describe two different particle focusing approaches in microfluidic channels: sheath-assisted and inertial forces-assisted, for lab-on-a-chip flow cytometry applications. The conditions and ranges of all parameters that define these focusing techniques are discussed. Simulation and experimental results for particle focusing using both techniques are presented.

An optofluidic approach for gold nanoprobes based-cancer theranostics

Suppression of overexpressed gene mutations in cancer cells through RNA interference (RNAi) technique is a therapeutically effective modality for oncogene silencing. In general, transfection agent is needed for siRNA delivery. Also, it is a tedious and time consuming process to analyze the gene transfection using current conventional flow cytometry systems and commercially available transfection kits. Therefore, there are two urgent challenges that we need to address for understanding and real time monitoring the delivery of siRNA to cancer cells more effectively. One, nontoxic, biocompatible and stable non-viral transfection agents need to be developed and investigated for gene delivery in cancer cells. Two, new, portable optofluidic methods need to be engineered for determining the transfection efficiency of the nanoformulation in real time. First, we demonstrate the feasibility of using gold nanorods (AuNRs) as nanoprobes for the delivery of Interleukin-8 (IL-8) siRNA in a pancreatic cancer cell line- MiaPaCa-2. An optimum ratio of 10:1 for the AuNRs–siRNA nanoformulation required for efficient loading has been experimentally determined. Promising transfection rates (≈88%) of the nanoprobe-assisted gene delivery are quantified by flow cytometry and fluorescence imaging, which are higher than the commercial control, Oligofectamine. The excellent gene knockdown performance (over 81%) of the proposed model support in vivo trials for RNAi-based cancer theranostics. In addition to cancer theranostics, our nanoprobe combination can be also applied for disease outbreak monitoring like MERS. Second, we present an optical fiber-integrated microfluidic chip that utilizes simple hydrodynamic and optical setups for miniaturized on-chip flow cytometry. The chip provides a powerful and convenient tool to quantitatively determine the siRNA transfection into cancer cells without using bulky flow cytometer. These studies outline the role of AuNRs as potential non-viral gene delivery vehicles, and their suitability for microfluidics-based lab-on-chip flow cytometry applications.

Study of inertial hydrodynamic focusing in sheath-driven flows for lab-on-a-chip flow cytometry

Miniature flow cytometer models enable fast and cost-effective management of diseases in vulnerable and low-end settings. The single-line focusing of cell or particle samples is achieved using hydrodynamic forces in the microfluidic channels. The two common configurations among them are the single-sheath and dual-sheath flows wherein the sample is directed through the main channel, and the surrounding sheath fluids are directed into the main channel through inlets on either side of the main channel. Most models predict the width of the focused sample stream based on hydrodynamic focusing in the low Reynolds number regime (Re << 1), where the viscous forces dominate the inertial forces. In this work, we present comparative analysis of particle focusing by single-sheath and dual-sheath configurations for focusing of micron-sized cells/particles in the range 2 to 20 μm in the higher Re (10 < Re < 80) laminar regime. A quantitative analysis of the relative focused stream width (wf/wch) as a function of flow rate ratio (FRR = Sample flow rate/Sheath flow rate) for the two configurations is presented. The particle tracing results are also compared with the experimental fluorescent microscopy results at various FRR. The deviations of the results from the theoretical predictions of hydrodynamic focusing at Re << 1, are explained analytically. These findings clearly outline the range of flow parameters and relative particle sizes that can be used for cytometry studies for a given channel geometry. This is a highly predictive modeling method as it provides substantial results of particle positions across the microchannel width according to their size and FRR for single-line focusing of particles. Such information is crucial for one to engineer miniaturized flow cytometry for screening of desired cells or particles.