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Advanced Drug Delivery Reviews (v.64, #14)

Editorial Board (pp. ii).

Emerging micro- and nanotechnologies at the interface of engineering, science, and medicine for the development of novel drug delivery devices and systems by Yogesh Gianchandani Theme Editor; Ellis Meng Theme Editor (pp. 1545-1546).

Microneedles for drug and vaccine delivery by Yeu-Chun Kim; Jung-Hwan Park; Mark R. Prausnitz (pp. 1547-1568).

Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990's when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications.Display Omitted

Keywords: Microneedle; Microfabricated device; Transdermal drug delivery; Skin vaccination; Ocular drug delivery; Intracellular delivery

Emerging microtechnologies for the development of oral drug delivery devices by Hariharasudhan D. Chirra; Tejal A. Desai (pp. 1569-1578).

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.Display Omitted

Keywords: Bioadhesive devices; Unidirectional release; Sustained release; Pulsatile release; Microfabrication; Photolithography; Gastrointestinal targeting

Self-folding polymeric containers for encapsulation and delivery of drugs by Rohan Fernandes; David H. Gracias (pp. 1579-1589).

Self-folding broadly refers to self-assembly processes wherein thin films or interconnected planar templates curve, roll-up or fold into three dimensional (3D) structures such as cylindrical tubes, spirals, corrugated sheets or polyhedra. The process has been demonstrated with metallic, semiconducting and polymeric films and has been used to curve tubes with diameters as small as 2nm and fold polyhedra as small as 100nm, with a surface patterning resolution of 15nm. Self-folding methods are important for drug delivery applications since they provide a means to realize 3D, biocompatible, all-polymeric containers with well-tailored composition, size, shape, wall thickness, porosity, surface patterns and chemistry. Self-folding is also a highly parallel process, and it is possible to encapsulate or self-load therapeutic cargo during assembly. A variety of therapeutic cargos such as small molecules, peptides, proteins, bacteria, fungi and mammalian cells have been encapsulated in self-folded polymeric containers. In this review, we focus on self-folding of all-polymeric containers. We discuss the mechanistic aspects of self-folding of polymeric containers driven by differential stresses or surface tension forces, the applications of self-folding polymers in drug delivery and we outline future challenges.Display Omitted

Keywords: Abbreviations; 2D; two dimensional; 3D; three dimensional; MEMS; microelectromechanical Systems; MCMS; microchemomechanical systems; LbL; layer by layer; ATRP; atom transfer radical polymerization; PRINT; particle replication in non-wetting templates; SEM; scanning electron microscopy; TEM; transmission electron microscopy; PAA; polyacrylic acid; PHEMA; poly(hydroxyethyl methacrylate); PMAA; poly(methacrylic acid); PCL; polycaprolactone; PDMS; poly(dimethylsiloxane); PEGDMA; poly(ethylene glycol dimethacrylate); PEGMA; poly(ethylene glycol methacrylate); PEGDA; poly(ethylene glycol diacrylate); PMMA; poly(methylmethacrylate); PNIPAM; poly(N-isopropylacrylamide); PSI; polysuccinimide; PS; polystyrene, P4VP, poly(4-vinylpyridine); PVA; polyvinyl alcohol; PPy; polypyrroleLithography; Three dimensional; Spatio-temporal; Controlled release; Origami; Hydrogels

Reservoir-based drug delivery systems utilizing microtechnology by Cynthia L. Stevenson; John T. Santini Jr.; Robert Langer (pp. 1590-1602).

This review covers reservoir-based drug delivery systems that incorporate microtechnology, with an emphasis on oral, dermal, and implantable systems. Key features of each technology are highlighted such as working principles, fabrication methods, dimensional constraints, and performance criteria. Reservoir-based systems include a subset of microfabricated drug delivery systems and provide unique advantages. Reservoirs, whether external to the body or implanted, provide a well-controlled environment for a drug formulation, allowing increased drug stability and prolonged delivery times. Reservoir systems have the flexibility to accommodate various delivery schemes, including zero order, pulsatile, and on demand dosing, as opposed to a standard sustained release profile. Furthermore, the development of reservoir-based systems for targeted delivery for difficult to treat applications (e.g., ocular) has resulted in potential platforms for patient therapy.Display Omitted

Keywords: Controlled release; Implant; MEMS; Microneedle; Micropump; Ocular; On demand; Pulsatile

Polymeric microdevices for transdermal and subcutaneous drug delivery by Manuel Ochoa; Charilaos Mousoulis; Babak Ziaie (pp. 1603-1616).

Low cost manufacturing of polymeric microdevices for transdermal and subcutaneous drug delivery is slated to have a major impact on next generation devices for administration of biopharmaceuticals and other emerging new formulations. These devices range in complexity from simple microneedle arrays to more complicated systems incorporating micropumps, micro-reservoirs, on-board sensors, and electronic intelligence. In this paper, we review devices currently in the market and those in the earlier stages of research and development. We also present two examples of the research in our laboratory towards using phase change liquids in polymeric structures to create disposable micropumps and the development of an elastomeric reservoir for MEMS-based transdermal drug delivery systems.Display Omitted

Keywords: Polymeric microdevices; BioMEMS; Microfluidics; Transdermal drug delivery; Micropumps

Osmotic micropumps for drug delivery by Simon Herrlich; Sven Spieth; Stephan Messner; Roland Zengerle (pp. 1617-1627).

This paper reviews miniaturized drug delivery systems applying osmotic principles for pumping. Osmotic micropumps require no electrical energy and consequently enable drug delivery systems of smallest size for a broad field of new applications. In contrast to common tablets, these pumps provide constant (zero-order) drug release rates. This facilitates systems for long term use not limited by gastrointestinal transit time and first-pass metabolism. The review focuses on parenteral routes of administration targeting drug delivery either in a site-specific or systemic way. Osmotic pumps consist of three building blocks: osmotic agent, solvent, and drug. This is used to categorize pumps into (i) single compartment systems using water from body fluids as solvent and the drug itself as the osmotic agent, (ii) two compartment systems employing a separate osmotic agent, and (iii) multi-compartment architectures employing solvent, drug and osmotic agent separately. In parallel to the micropumps, relevant applications and therapies are discussed.Display Omitted

Keywords: MEMS; Drug delivery; Osmotic pump; Zero-order release; Microactuator; Microfluidics; Osmosis; Micropump

MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications by Ellis Meng; Tuan Hoang (pp. 1628-1638).

Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications.Display Omitted

Keywords: Drug delivery; Infusion pumps; On-demand release; Electrolysis actuators; Localized delivery; MEMS; BioMEMS; Micropumps; Microvalves

Compact, power-efficient architectures using microvalves and microsensors, for intrathecal, insulin, and other drug delivery systems by Tao Li; Allan T. Evans; Srinivas Chiravuri; Roma Y. Gianchandani; Yogesh B. Gianchandani (pp. 1639-1649).

This paper describes a valve-regulated architecture, for intrathecal, insulin and other drug delivery systems, that offers high performance and volume efficiency through the use of micromachined components. Multi-drug protocols can be accommodated by using a valve manifold to modulate and mix drug flows from individual reservoirs. A piezoelectrically-actuated silicon microvalve with embedded pressure sensors is used to regulate dosing by throttling flow from a mechanically-pressurized reservoir. A preliminary prototype system is demonstrated with two reservoirs, pressure sensors, and a control circuit board within a 130cm³ metal casing. Different control modes of the programmable system have been evaluated to mimic clinical applications. Bolus and continuous flow deliveries have been demonstrated. A wide range of delivery rates can be achieved by adjusting the parameters of the manifold valves or reservoir springs. The capability to compensate for changes in delivery pressure has been experimentally verified. The pressure profiles can also be used to detect catheter occlusions and disconnects. The benefits of this architecture compared with alternative options are reviewed.Display Omitted

Keywords: Multidrug delivery; Microvalve manifold; Liquid flow control; MEMS; Implantable drug pump; Wearable drug pump; Power transfer; Piezoelectric

Microsystems technologies for drug delivery to the inner ear by Erin E. Leary Pararas; David A. Borkholder; Jeffrey T. Borenstein (pp. 1650-1660).

The inner ear represents one of the most technologically challenging targets for local drug delivery, but its clinical significance is rapidly increasing. The prevalence of sensorineural hearing loss and other auditory diseases, along with balance disorders and tinnitus, has spurred broad efforts to develop therapeutic compounds and regenerative approaches to treat these conditions, necessitating advances in systems capable of targeted and sustained drug delivery. The delicate nature of hearing structures combined with the relative inaccessibility of the cochlea by means of conventional delivery routes together necessitate significant advancements in both the precision and miniaturization of delivery systems, and the nature of the molecular and cellular targets for these therapies suggests that multiple compounds may need to be delivered in a time-sequenced fashion over an extended duration. Here we address the various approaches being developed for inner ear drug delivery, including micropump-based devices, reciprocating systems, and cochlear prosthesis-mediated delivery, concluding with an analysis of emerging challenges and opportunities for the first generation of technologies suitable for human clinical use. These developments represent exciting advances that have the potential to repair and regenerate hearing structures in millions of patients for whom no currently available medical treatments exist, a situation that requires them to function with electronic hearing augmentation devices or to live with severely impaired auditory function. These advances also have the potential for broader clinical applications that share similar requirements and challenges with the inner ear, such as drug delivery to the central nervous system.Display Omitted

Keywords: Cochlea; Intracochlear; Intratympanic; Hearing; Local drug delivery; Device; Micropump; Implantable

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Advanced Drug Delivery Reviews (v.64, #14)