Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.     

A refillable microfabricated drug delivery device for treatment of ocular diseases

An implantable manually-actuated microfabricated drug delivery device was demonstrated as a new approach for delivering therapeutic compounds to ocular tissue in acute in vitro, ex vivo, and in vivo studies.     

Sacrificial layer microfluidic device fabrication methods

Over the past 15 years, research in the field of microfluidics has experienced rapid growth due to significant potential advantages such as low cost, short analysis times, and elimination of sources of contamination. Although etched and thermally bonded glass substrates have seen widespread use and offer solid performance, device fabrication still remains cumbersome. Recent advances in sacrificial layer microfabrication methods for microfluidics have overcome many disadvantages of conventional fabrication approaches. Phase-changing sacrificial layers have been implemented in making inexpensive and high-performance polymer microchips for electrophoretic analysis, protein focusing, and sample preconcentration. In addition, novel channel fabrication methods based on standard thin-film processes, which are readily integratable with microfabrication techniques used for electrical components, are being applied increasingly for the creation of microfluidic devices. These new sacrificial layer fabrication approaches will be instrumental in making low-cost and high-quality polymer microchips, and in interfacing electrical and fluidic systems on glass or semiconductor substrates.     

Integration of electrochemistry in micro-total analysis systems for biochemical assays: Recent developments

Micro-total analysis systems (μTAS) integrate different analytical operations like sample preparation, separation and detection into a single microfabricated device. With the outstanding advantages of low cost, satisfactory analytical efficiency and flexibility in design, highly integrated and miniaturized devices from the concept of μTAS have gained widespread applications, especially in biochemical assays. Electrochemistry is shown to be quite compatible with microanalytical systems for biochemical assays, because of its attractive merits such as simplicity, rapidity, high sensitivity, reduced power consumption, and sample/reagent economy. This review presents recent developments in the integration of electrochemistry in microdevices for biochemical assays. Ingenious microelectrode design and fabrication methods, and versatility of electrochemical techniques are involved. Practical applications of such integrated microsystem in biochemical assays are focused on in situ analysis, point-of-care testing and portable devices. Electrochemical techniques are apparently suited to microsystems, since easy microfabrication of electrochemical elements and a high degree of integration with multi-analytical functions can be achieved at low cost. Such integrated microsystems will play an increasingly important role for analysis of small volume biochemical samples. Work is in progress toward new microdevice design and applications.     

Responsive microgrooves for the formation of harvestable tissue constructs

Given its biocompatibility, elasticity, and gas permeability, poly(dimethylsiloxane) (PDMS) is widely used to fabricate microgrooves and microfluidic devices for three-dimensional (3D) cell culture studies. However, conformal coating of complex PDMS devices prepared by standard microfabrication techniques with desired chemical functionality is challenging. This study describes the conformal coating of PDMS microgrooves with poly(N-isopropylacrylamide) (PNIPAAm) by using initiated chemical vapor deposition (iCVD). These microgrooves guided the formation of tissue constructs from NIH-3T3 fibroblasts that could be retrieved by the temperature-dependent swelling property and hydrophilicity change of the PNIPAAm. The thickness of swollen PNIPAAm films at 24 °C was approximately 3 times greater than at 37 °C. Furthermore, PNIPAAm-coated microgroove surfaces exhibit increased hydrophilicity at 24 °C (contact angle θ = 30° ± 2) compared to 37 °C (θ = 50° ± 1). Thus PNIPAAm film on the microgrooves exhibits responsive swelling with higher hydrophilicity at room temperature, which could be used to retrieve tissue constructs. The resulting tissue constructs were the same size as the grooves and could be used as modules in tissue fabrication. Given its ability to form and retrieve cell aggregates and its integration with standard microfabrication, PNIPAAm-coated PDMS templates may become useful for 3D cell culture applications in tissue engineering and drug discovery.     

Human Albumin-Based Hydrogels for Their Potential Xeno-Free Microneedle Applications

Nowadays, hydrogels-based microneedles (MNs) have attracted a great interest owing to their outstanding qualities for biomedical applications. For the fabrication of hydrogels-based microneedles as tissue engineering scaffolds and drug delivery carriers, various biomaterials have been tested. They are required to feature tunable physiochemical properties, biodegradability, biocompatibility, nonimmunogenicity, high drug loading capacity, and sustained drug release. Among biomaterials, human proteins are the most ideal biomaterials for fabrication of hydrogels-based MNs; however, they are mechanically weak and poorly processible. To the best of the knowledge, there are no reports of xeno-free human protein-based MNs so far. Here, human albumin-based hydrogels and microneedles for tissue engineering and drug delivery by using relatively new processible human serum albumin methacryloyl (HSAMA) are engineered. The resultant HSAMA hydrogels display tunable mechanical properties, biodegradability, and good biocompatibility. Moreover, the xeno-free HSAMA microneedles display a sustained drug release profile and significant mechanical strength to penetrate the model skin. In vitro, they also show good biocompatibility and anticancer efficacy. Sustainable processible human albumin-based biomaterials may be employed as a xeno-free platform in vivo for tissue engineering and drug delivery in clinical trials in the future.     

Visible light-curable polymers for biomedical applications

Photocurable systems, which offer advantages such as microfabrication and in situ fabrication, have been widely used as dental restorative materials. Because the visible light-curable (VLC) system causes no biological damage, it is popular as a dental material and is being investigated by many researchers for other medical applications. Here, the principle of the VLC system is explained and recent progress in key components including photoinitiators, monomers, macromers, and prepolymers is discussed. Finally, biomedical applications for drug delivery and soft tissue engineering are reviewed. Considering the recent development of VLC systems, its importance in the field of medical applications is expected to continue to increase in the future.     

Biodegradable elastomers for tissue engineering and cell-biomaterial interactions

Synthetic biomaterials serve as a cornerstone in the development of clinically focused regenerative medicine therapies that aim to reduce suffering and prolong life. Recent improvements in biodegradable elastomeric materials utilize natural extracellular matrix proteins as inspiration to yield a new class of materials with superior degradation kinetics, desirable biocompatibility profiles, and mechanical properties that closely match those of soft tissues. This review describes several classes of synthetic biodegradable elastomers and associated fabrication techniques that are relevant to scaffold development. The application of these materials to select tissue engineering models is also discussed.     

Magnetic micropillars as a tool to govern substrate deformations

Magnetic actuated microdevices can be used to achieve several complex functions in microfluidics and microfabricated devices. For example, magnetic mixers and magnetic actuators have been proposed to help handling fluids at a small scale. Here, we present a strategy to create magnetically actuated micropillar arrays. We combined microfabrication techniques and the dispersion of magnetic aggregates embedded inside polymeric matrices to design micrometre scale magnetic features. By creating a magnetic field gradient in the vicinity of the substrate, well-defined forces were applied on these magnetic aggregates which in turn induced a deflection of the micropillars. By dispersing either spherical aggregates or magnetic nanowires into the gels, we can induce synchronized motions of a group of pillars or the movement of isolated pillars under a magnetic field gradient. When combined with microfabrication processes, this versatile tool leads to local as well as global substrate actuations within a range of dimensions that are relevant for microfluidics and biological applications.     

Challenges and Perspectives of DNA Nanostructures in Biomedicine

DNA nanotechnology holds substantial promise for future biomedical engineering and the development of novel therapies and diagnostic assays. The subnanometer‐level addressability of DNA nanostructures allows for their precise and tailored modification with numerous chemical and biological entities, which makes them fit to serve as accurate diagnostic tools and multifunctional carriers for targeted drug delivery. The absolute control over shape, size, and function enables the fabrication of tailored and dynamic devices, such as DNA nanorobots that can execute programmed tasks and react to various external stimuli. Even though several studies have demonstrated the successful operation of various biomedical DNA nanostructures both in vitro and in vivo, major obstacles remain on the path to real‐world applications of DNA‐based nanomedicine. Here, we summarize the current status of the field and the main implementations of biomedical DNA nanostructures. In particular, we focus on open challenges and untackled issues and discuss possible solutions.     

Mechanoresponsive Drug Delivery Systems for Vascular Diseases

Mechanoresponsive drug delivery systems (DDS) have emerged as promising candidates to improve the current effectiveness and lower the side effects typically associated with direct drug administration in the context of vascular diseases. Despite tremendous research efforts to date, designing drug delivery systems able to respond to mechanical stimuli to potentially treat these diseases is still in its infancy. By understanding relevant biological forces emerging in healthy and pathological vascular endothelium, it is believed that better-informed design strategies can be deduced for the fabrication of simple-to-complex macromolecular assemblies capable of sensing mechanical forces. These responsive systems are discussed through insights into essential parameter design (composition, size, shape, and aggregation state) , as well as their functionalization with (macro)molecules that are intrinsically mechanoresponsive (e.g., mechanosensitive ion channels and mechanophores). Mechanical forces, including the pathological shear stress and exogenous stimuli (e.g., ultrasound, magnetic fields), used for the activation of mechanoresponsive DDS are also introduced, followed by in vitro and in vivo experimental models used to investigate and validate such novel therapies. Overall, this review aims to propose a fresh perspective through identified challenges and proposed solutions that could be of benefit for the further development of this exciting field.     

Polymer microfabrication technologies for microfluidic systems

Polymers have assumed the leading role as substrate materials for microfluidic devices in recent years. They offer a broad range of material parameters as well as material and surface chemical properties which enable microscopic design features that cannot be realised by any other class of materials. A similar range of fabrication technologies exist to generate microfluidic devices from these materials. This review will introduce the currently relevant microfabrication technologies such as replication methods like hot embossing, injection molding, microthermoforming and casting as well as photodefining methods like lithography and laser ablation for microfluidic systems and discuss academic and industrial considerations for their use. A section on back-end processing completes the overview.     

蛋白质图案构筑及其应用研究进展

蛋白质作为生物体内一类重要的大分子已被广泛地应用于构筑图案化结构, 所得到的蛋白质图案在医疗诊断、组织工程、生物传感和药物筛选等领域均表现出了巨大的应用价值. 目前, 蛋白质图案的构筑方法主要有两种： （1） 在利用微加工技术制备的微结构上进行蛋白质的后续接枝实现蛋白质图案的构筑; （2） 直接用蛋白质分子构筑图案化结构. 本文对当前常用的蛋白质图案构筑技术进行了综述, 并对蛋白质图案的实际应用进行了总结, 最后对蛋白质图案构筑技术的发展方向以及蛋白质图案的应用前景进行了展望.     

Transdermal drug transfer from a polymer device: study of the polymer and the process

Special polymer devices containing a drug are able to deliver the drug to the patient through transdermal delivery. Two points are of interest: the nature of the polymer device, and the process of drug delivery. The polymer device considered in this paper is able to maintain a constant drug concentration on the patient's skin surface. The process of drug delivery is studied through in vitro and in vivo tests. In vitro tests show that the skin plays the role of a membrane, with a steady state for the drug transfer following a non-steady state. The parameters of diffusion through the skin are thus calculated from this test. In vivo tests are described by a process of drug transfer consisting of two stages: the stages of absorption into, and elimination out of, the blood. The polymer device plays a major role, as it should maintain a constant concentration of drug on the skin.     

Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications

Nanostructure fabrication from block copolymers is discussed in this review paper. Particularly, novel approaches for the construction of functionalized poly(ethylene glycol) (PEG) layers on surfaces were focused to attain the specific adsorption of a target protein through PEG-conjugated ligands with a minimal non-specific adsorption of other proteins. Furthermore, surface organization of block copolymer micelles with cross-linking cores was described from the standpoint of preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited non-fouling properties and worked as a reservoir for hydrophobic reagents. These PEG-functionalized surface in brush form or in micelle form can be used in diverse fields of medicine and biology to construct high-performance medical devices including scaffolds for tissue engineering and matrices for drug delivery systems.     

溶液加工型有机电致发光材料与器件研究进展

有机电致发光器件（OLEDs）在平板显示和固体照明领域有着广阔的应用前景,发展十分迅速,已实现了商业化．而可溶液加工的OLEDs采用喷墨打印、卷对卷印刷等低成本方式进行加工,在实现低成本、大面积显示及照明器件等方面具有巨大的应用潜力,引起了广泛关注．实现高效溶液加工型OLEDs的实用性需要在光电材料设计合成及器件制备方法上进一步深入研究．本文总结了发光材料与器件国家重点实验室可溶液加工型OLEDs材料及器件的研究进展．     

Robust polymer microfluidic device fabrication via contact liquid photolithographic polymerization (CLiPP)

Microfluidic devices are commonly fabricated in silicon or glass using micromachining technology or elastomers using soft lithography methods; however, invariable bulk material properties, limited surface modification methods and difficulty in fabricating high aspect ratio devices prevent these materials from being utilized in numerous applications and/or lead to high fabrication costs. Contact Liquid Photolithographic Polymerization (CLiPP) was developed as an alternative microfabrication approach that uniquely exploits living radical photopolymerization chemistry to facilitate surface modification of device components, fabrication of high aspect ratio structures from many different materials with numerous covalently-adhered layers and facile construction of three-dimensional devices. This contribution describes CLiPP and demonstrates unique advantages of this new technology for microfabrication of polymeric microdevices. Specifically, the procedure for fabricating devices with CLiPP is presented, the living radical photopolymerization chemistry which enables this technology is described, and examples of devices made using CLiPP are shown.     

Stop-flow lithography to generate cell-laden microgel particles

Encapsulating cells within hydrogels is important for generating three-dimensional (3D) tissue constructs for drug delivery and tissue engineering. This paper describes, for the first time, the fabrication of large numbers of cell-laden microgel particles using a continuous microfluidic process called stop-flow lithography (SFL). Prepolymer solution containing cells was flowed through a microfluidic device and arrays of individual particles were repeatedly defined using pulses of UV light through a transparency mask. Unlike photolithography, SFL can be used to synthesize microgel particles continuously while maintaining control over particle size, shape and anisotropy. Therefore, SFL may become a useful tool for generating cell-laden microgels for various biomedical applications.     

Parylene C coating for high-performance replica molding

This paper presents an improvement to the soft lithography fabrication process that uses chemical vapor deposition of poly(chloro-p-xylylene) (parylene C) to protect microfabricated masters and to improve the release of polymer devices following replica molding. Chemical vapor deposition creates nanometre thick conformal coatings of parylene C on silicon wafers having arrays of 30 μm high SU8 pillars with densities ranging from 278 to 10,040 features per mm(2) and aspect ratios (height : width) from 1 : 1 to 6 : 1. A single coating of parylene C was sufficient to permanently promote poly(dimethyl)siloxane (PDMS) mold release and to protect masters for an indefinite number of molding cycles. We also show that the improved release properties of parylene treated masters allow for fabrication with hard polymers, such as poly(urethane), that would otherwise not be compatible with SU8 on silicon masters. Parylene C provides a robust and high performance mold release coating for soft lithography microfabrication that extends the life of microfabricated masters and improves the achievable density and aspect ratio of replicated features.