Fabrication of micropatterned polymeric nanowire arrays for high-resolution reagent localization and topographical cellular control.

Herein, we present a novel approach for the fabrication of micropatterned polymeric nanowire arrays that addresses the current need for scalable and customizable polymer nanofabrication. We describe two variations of this approach for the patterning of nanowire arrays on either flat polymeric films or discrete polymeric microstructures and go on to investigate biological applications for the resulting polymeric features. We demonstrate that the micropatterned arrays of densely packed nanowires facilitate rapid, low-waste drug and reagent localization with micron-scale resolution as a result of their high wettability. We also show that micropatterned nanowire arrays provide hierarchical cellular control by simultaneously directing cell shape on the micron scale and influencing focal adhesion formation on the nanoscale. This nanofabrication approach has potential applications in scaffold-based cellular control, biological assay miniaturization, and biomedical microdevice technology.

Multi-reservoir bioadhesive microdevices for independent rate-controlled delivery of multiple drugs.

A variety of oral administrative systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, they suffer from poor intestinal localization and therapeutic efficacy due to the various physiological conditions and high shear fluid flow. Fabrication of novel microdevices combined with the introduction of controlled release, improved adhesion, selective targeting, and tissue permeation may overcome these issues and potentially diminish the toxicity and high frequency of conventional oral administration. Herein, thin, asymmetric, poly(methyl methacrylate) (PMMA) microdevices are fabricated with multiple reservoirs using photolithography and reactive ion etching. They are loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices is observed in the presence of a conjugated of targeting protein (tomato lectin) to the PMMA surface. As compared to drug encompassing hydrogels, an increase in drug permeation across the caco-2 monolayer is noticed in the presence of a microdevice loaded with the same drug-hydrogel system. Also, the release of multiple drugs from their respective reservoirs is found to be independent from each other. The use of different hydrogel systems in each reservoir shows differences in the controlled release of the respective drugs over the same release period. These results suggest that, in the future, microfabricated unidirectional multi-drug releasing devices will have an impact on the oral administration of a broad range of therapeutics.

Nanoscale characterization of the equilibrium and kinetic response of hydrogel structures.

The use of hydrogel nanostructured patterns and films in biomedical micro- and nanodevices requires the ability to analyze and understand their response properties at the nanoscale. Herein, the thermoresponse behavior of atom transfer radical polymerization (ATRP) grown poly(ethylene glycol) n dimethacrylate (PEGnDMA) cross-linked poly(N-isopropyl acrylamide) (PNIPAAm) hydrogel thin films over gold was studied. By controlling the mesh size of the hydrogel matrix through tuning the cross-linking density (i.e., using different molecular weight cross-linker and/or various amounts of cross-linker), the hydrogel volume swelling ratio was tailored for response applications. Thermoresponsive patterns exhibited a broad lower critical solution temperature (LCST) swelling transition, while rms roughness analysis of the hydrogel surface showed a sharp LCST transition. Mass and viscoelastic property changes were monitored using quartz crystal microbalance with dissipation (QCM-D), and the rapid response behavior of the thin hydrogel films was observed. The tunable response behavior along with the controlled growth of the hydrogel achieved via ATRP at the nanoscale make them applicable as functional components in diagnostic and therapeutic devices.

Fabrication of Sealed Nanostraw Microdevices for Oral Drug Delivery.

The oral route is preferred for systemic drug administration and provides direct access to diseased tissue of the gastrointestinal (GI) tract. However, many drugs have poor absorption upon oral administration due to damaging enzymatic and pH conditions, mucus and cellular permeation barriers, and limited time for drug dissolution. To overcome these limitations and enhance oral drug absorption, micron-scale devices with planar, asymmetric geometries, termed microdevices, have been designed to adhere to the lining of the GI tract and release drug at high concentrations directly toward GI epithelium. Here we seal microdevices with nanostraw membranes-porous nanostructured biomolecule delivery substrates-to enhance the properties of these devices. We demonstrate that the nanostraws facilitate facile drug loading and tunable drug release, limit the influx of external molecules into the sealed drug reservoir, and increase the adhesion of devices to epithelial tissue. These findings highlight the potential of nanostraw microdevices to enhance the oral absorption of a wide range of therapeutics by binding to the lining of the GI tract, providing prolonged and proximal drug release, and reducing the exposure of their payload to drug-degrading biomolecules.

Micro/nanofabricated platforms for oral drug delivery.

The oral route of drug administration is most preferred due to its ease of use, low cost, and high patient compliance. However, the oral uptake of many small molecule drugs and biotherapeutics is limited by various physiological barriers, and, as a result, drugs suffer from issues with low solubility, low permeability, and degradation following oral administration. The flexibility of micro- and nanofabrication techniques has been used to create drug delivery platforms designed to address these barriers to oral drug uptake. Specifically, micro/nanofabricated devices have been designed with planar, asymmetric geometries to promote device adhesion and unidirectional drug release toward epithelial tissue, thereby prolonging drug exposure and increasing drug permeation. Furthermore, surface functionalization, nanotopography, responsive drug release, motion-based responses, and permeation enhancers have been incorporated into such platforms to further enhance drug uptake. This review will outline the application of micro/nanotechnology to specifically address the physiological barriers to oral drug delivery and highlight technologies that may be incorporated into these oral drug delivery systems to further enhance drug uptake.

Planar bioadhesive microdevices: a new technology for oral drug delivery.

The oral route is the most convenient and least expensive route of drug administration. Yet, it is accompanied by many physiological barriers to drug uptake including low stomach pH, intestinal enzymes and transporters, mucosal barriers, and high intestinal fluid shear. While many drug delivery systems have been developed for oral drug administration, the physiological components of the gastro intestinal tract remain formidable barriers to drug uptake. Recently, microfabrication techniques have been applied to create micron-scale devices for oral drug delivery with a high degree of control over microdevice size, shape, chemical composition, drug release profile, and targeting ability. With precise control over device properties, microdevices can be fabricated with characteristics that provide increased adhesion for prolonged drug exposure, unidirectional release which serves to avoid luminal drug loss and enhance drug permeation, and protection of a drug payload from the harsh environment of the intestinal tract. Here we review the recent developments in microdevice technology and discuss the potential of these devices to overcome unsolved challenges in oral drug delivery.

Planar microdevices for enhanced in vivo retention and oral bioavailability of poorly permeable drugs.

The development of novel oral drug delivery platforms for administering therapeutics in a safe and effective manner through the harsh gastrointestinal environment is of great importance. Here, the use of engineered thin planar poly(methyl methacrylate) (PMMA) microdevices is tested to enhance oral bioavailability of acyclovir, a poorly permeable drug. Acyclovir is loaded into the unidirectional drug releasing microdevice reservoirs using a drug entrapping photocross-linkable hydrogel matrix. An increase in acyclovir permeation across in vitro caco-2 monolayer is seen in the presence of microdevices as compared with acyclovir-entrapped hydrogels or free acyclovir solution. Cell proliferation studies show that microdevices are relatively nontoxic in nature for use in in vivo studies. Enhanced in vivo retention of microdevices is observed as their thin side walls experience minimal peristaltic shear stress as compared with spherical microparticles. Unidirectional acyclovir release and enhanced retention of microdevices achieve a 4.5-fold increase in bioavailability in vivo as compared with an oral gavage of acyclovir solution with the same drug mass. The enhanced oral bioavailability results suggest that thin, planar, bioadhesive, and unidirectional drug releasing microdevices will significantly improve the systemic and localized delivery of a broad range of oral therapeutics in the near future.

Emerging microtechnologies for the development of oral drug delivery devices.

The development of oral drug delivery platforms for administering therapeutics in a safe and effective manner across the gastrointestinal epithelium is of much importance. A variety of delivery systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, orally administered drugs suffer from poor localization and therapeutic efficacy due to various physiological conditions such as low pH, and high shear intestinal fluid flow. Novel platforms combining controlled release, improved adhesion, tissue penetration, and selective intestinal targeting may overcome these issues and potentially diminish the toxicity and high frequency of administration associated with conventional oral delivery. Microfabrication along with appropriate surface chemistry, provide a means to fabricate these platforms en masse with flexibility in tailoring the shape, size, reservoir volume, and surface characteristics of microdevices. Moreover, the same technology can be used to include integrated circuit technology and sensors for designing sophisticated autonomous drug delivery devices that promise to significantly improve point of care diagnostic and therapeutic medical applications. This review sheds light on some of the fabrication techniques and addresses a few of the microfabricated devices that can be effectively used for controlled oral drug delivery applications.

Catalase-coupled gold nanoparticles: comparison between the carbodiimide and biotin-streptavidin methods.

The use of proteins for therapeutic applications requires the protein to maintain sufficient activity for the period of in vivo treatment. Many proteins exhibit a short half-life in vivo and, thus, require delivery systems for them to be applied as therapeutics. The relative biocompatibility and the ability to form functionalized bioconjugates via simple chemistry make gold nanoparticles excellent candidates as protein delivery systems. Herein, two protocols for coupling proteins to gold nanoparticles have been compared. In the first, strong biomolecular binding between biotin and streptavidin was used to couple catalase to the surface of gold nanoparticles. In the second protocol the formation of an amide bond between carboxylic acid-coated gold nanoparticles and free surface amines of catalase using carbodiimide chemistry was performed. The stability and kinetics of the different steps involved in these protocols were studied using UV-visible spectroscopy, dynamic light scattering, and transmission electron microscopy. The addition of mercapto-undecanoic acid in conjugation with (N-(6-(biotinamido)hexyl)-3'-(2'-pyridyldithio)-propionamide increased the stability of biotinylated gold nanoparticles. Although the carbodiimide chemistry-based bioconjugation approach exhibited a decrease in catalase activity, the carbodiimide chemistry-based bioconjugation approach resulted in more active catalase per gold nanoparticle compared with that of mercapto-undecanoic acid-stabilized biotinylated gold nanoparticles. Both coupling protocols resulted in gold nanoparticles loaded with active catalase. Thus, these gold nanoparticle systems and coupling protocols represent promising methods for the application of gold nanoparticles for protein delivery.

Fabrication of hydrogel microstructures using polymerization controlled by microcontact printing (PCmicroCP).

Hydrogels are widely applied as functional biomaterials in the diagnostic and therapeutic fields. For example, intelligent hydrogels containing ionic groups (pH responsive) and poly(ethylene glycol) have promising applications as pH responsive materials in the biomedical and pharmaceutical fields. For potential use of hydrogels in micro- and nano devices, methods are needed to fabricate structures of various geometries at the micro- and nano scale. In this work, polymerization controlled by microcontact printing (PCmicroCP) is utilized, which is a method that uses microcontact printing to spatially define polymerization zones. Specifically, gold surfaces were modified by a hydrophobic thiol self assembled monolayer via microcontact printing and then a hydrophilic prepolymer solution was applied and only spatially occupied the regions confined by the hydrophobic thiol. Subsequently, polymerization reactions were carried out to create hydrogel microstructures. The patterned hydrogel produced using these methods are highly uniform in size and shape, having potential application in the field of biomedical microdevices.