Noel M. Elman

An Implantable MEMS Drug Delivery Device for Rapid Delivery in Ambulatory Emergency Care

We introduce the first implantable drug delivery system based on MEMS (Micro-Electro-Mechanical-Systems) technology specifically designed as a platform for treatment in ambulatory emergency care. The device is named IRD3 (implantable rapid drug delivery device) and allows rapid delivery of drugs. Vasopressin was used as a model drug for in vitro tests as it is a commonly used drug for cardiac resuscitation. Experimental results reveal that the IRD3 provides an effective method for rapid delivery without significant drug degradation. Several medical uses and delivery modalities for IRD3 are proposed.

Carbon nanotubes in drug delivery: focus on infectious diseases

Carbon nanotubes have the potential to address the challenges of combating infectious agents by both minimizing toxicity by dose reduction of standard therapeutics and allowing a multiple payload capacity to achieve both targeted activity and combating infectious strains, resistant strains in particular. One of their unique characteristics is the network of carbon atoms in the nanometer scale, allowing the creation of nano-channels via cellular membranes. This review focuses on the characterization, development, integration and application of carbon nanotubes as nanocarrier-based delivery systems and their appropriate design for achieving the desired drug delivery results in the different areas of infectious diseases. While a more extensive toxicological and pharmacological profile must be obtained, this review will focus on existing research and pre-clinical data concerning the potential use of carbon nanotubes.

The Next Generation of Drug‐Delivery Microdevices

Advances in microelectromechanical systems (MEMS) and miniaturization technologies have enabled the creation of biomedical microdevices intended for use in the treatment of various chronic and acute illnesses. The ability to create very precisely defined micrometer and nanometer features allows for the production of a new generation of biomedical devices that can be implanted using minimally invasive procedures to provide controlled therapeutic drug delivery. We believe that there is a wide variety of pharmacological therapies in which these novel drug‐delivery systems could be implemented, including treatments for cancer and trauma.

Medical applications of implantable drug delivery microdevices based on MEMS (Micro-Electro-Mechanical-Systems).

Drug delivery microdevices based on MEMS (Micro-Electro-Mechanical-Systems) represent the next generation of active implantable drug delivery systems. MEMS technology has enabled the scaling down of current delivery modalities to the micrometer and millimeter size. The complementary use of biocompatible materials makes this technology potentially viable for a wide variety of clinical applications. Conditions such as brain tumors, chronic pain syndromes, and infectious abscess represent specialized clinical diseases that will likely benefit most from such drug delivery microdevices. Designing MEMS microdevices poses considerable technical and clinical challenges as devices need to be constructed from biocompatible materials that are harmless to human tissue. Devices must also be miniaturized and capable of delivering adequate pharmacologic payload. Balancing these competing needs will likely lead to the successful application of MEMS drug delivery devices to various medical conditions. This work reviews the various factors that must be considered in optimizing MEMS microdevices for their appropriate and successful application to medical disease.

Towards toxicity detection using a lab-on-chip based on the integration of MOEMS and whole-cell sensors

A lab-on-chip consisting of a unique integration of whole-cell sensors, a MOEMS (Micro-Opto-Electro-Mechanical-System) modulator, and solid-state photo-detectors was implemented for the first time. Whole-cell sensors were genetically engineered to express a bioluminescent reporter (lux) as a function of the lac promoter. The MOEMS modulator was designed to overcome the inherent low frequency noise of solid-state photo-detectors by means of a previously reported modulation technique, named IHOS (Integrated Heterodyne Optical System). The bio-reporter signals were modulated prior to photo-detection, increasing the SNR of solid-state photo-detectors at least by three orders of magnitude. Experiments were performed using isopropyl-beta-d-thiogalactopyranoside (IPTG) as a preliminary step towards testing environmental toxicity. The inducer was used to trigger the expression response of the whole-cell sensors testing the sensitivity of the lab-on-chip. Low intensity bio-reporter optical signals were measured after the whole-cell sensors were exposed to IPTG concentrations of 0.1, 0.05, and 0.02mM. The experimental results reveal the potential of this technology for future implementation as an inexpensive massive method for rapid environmental toxicity detection.

Electro-thermally induced structural failure actuator (ETISFA) for implantable controlled drug delivery devices based on Micro-Electro-Mechanical-Systems

A new electro-thermally induced structural failure actuator (ETISFA) is introduced as an activation mechanism for on demand controlled drug delivery from a Micro-Electro-Mechanical-System (MEMS). The device architecture is based on a reservoir that is sealed by a silicon nitride membrane. The release mechanism consists of an electrical fuse constructed on the membrane. Activation causes thermal shock of the suspended membrane allowing the drugs inside of the reservoir to diffuse out into the region of interest. The effects of fuse width and thickness were explored by observing the extent to which the membrane was ruptured and the required energy input. Device design and optimization simulations of the opening mechanism are presented, as well as experimental data showing optimal energy consumption per fuse geometry. In vitro release experiments demonstrated repeatable release curves of mannitol-C(14) that precisely follow ideal first order release kinetics. Thermally induced structural failure was demonstrated as a feasible activation mechanism that holds great promise for controlled release in biomedical microdevices.

Recombinant tissue plasminogen activators (rtPA): A review

INTRODUCTION Acute ischemic stroke (AIS), acute myocardial infarction (AMI), and pulmonary embolism (PE) represent main causes of morbidity and mortality worldwide. These clinical conditions result from an imbalance of the hemostatic system, leading to thrombosis. Recombinant tissue plasminogen activators (rtPAs) are used in patients with AIS, AMI, and PE to treat thrombus. This review focuses on the pharmacology and clinical applications of rtPAs, and therapeutic strategies to improve thrombolytic therapy.

Clinical Applications of Biomedical Microdevices for Controlled Drug Delivery

Miniaturization of devices to micrometer and nanometer scales, combined with the use of biocompatible and functional materials, has created new opportunities for the implementation of drug delivery systems. Advances in biomedical microdevices for controlled drug delivery platforms promise a new generation of capabilities for the treatment of acute conditions and chronic illnesses, which require high adherence to treatment, in which temporal control over the pharmacokinetic profiles is critical. In addition, clinical conditions that require a combination of drugs with specific pharmacodynamic profiles and local delivery will benefit from drug delivery microdevices. This review provides a summary of various clinical applications for state-of-the-art controlled drug delivery microdevices, including cancer, endocrine and ocular disorders, and acute conditions such as hemorrhagic shock. Regulatory considerations for clinical translation of drug delivery microdevices are also discussed. Drug delivery microdevices promise a remarkable gain in clinical outcomes and a substantial social impact. A review of articles covering the field of microdevices for drug delivery was performed between January 1, 1990, and January 1, 2014, using PubMed as a search engine.

Optical and Electrical Interfacing Technologies for Living Cell Bio-Chips

Whole-cell bio-chips for functional sensing integrate living cells on miniaturized platforms made by micro-system-technologies (MST). The cells are integrated, deposited or immersed in a media which is in contact with the chip. The cells behavior is monitored via electrical, electrochemical or optical methods. In this paper we describe such whole-cell biochips where the signal is generated due to the genetic response of the cells. The solid-state platform hosts the biological component, i.e. the living cells, and integrates all the required micro-system technologies, i.e. the micro-electronics, micro-electro optics, micro-electro or magneto mechanics and micro-fluidics. The genetic response of the cells expresses proteins that generate: a. light by photo-luminescence or bioluminescence, b. electrochemical signal by interaction with a substrate, or c. change in the cell impedance. The cell response is detected by a front end unit that converts it to current or voltage amplifies and filters it. The resultant signal is analyzed and stored for further processing. In this paper we describe three examples of whole-cell bio chips, photo-luminescent, bioluminescent and electrochemical, which are based on the genetic response of genetically modified E. coli microbes integrated on a micro-fluidics MEMS platform. We describe the chip outline as well as the basic modeling scheme of such sensors. We discuss the highlights and problems of such system, from the point of view of micro-system-technology.

Intelligent drug-delivery devices based on micro- and nano-technologies

This review focuses on the current drug-delivery modalities in R&D, as well as commercially available. Intelligent drug-delivery systems are described as novel technological innovations and clinical approaches to improve conventional treatments. These systems differ in methodology of therapeutic administration, intricacy, materials and patient compliance to address numerous clinical conditions that require various pharmacological therapies. These systems have been primarily described as active and passive microelectrical mechanical system devices, injectors and nanoparticle-based therapies, optimized to tailor specific pharmacokinetic profiles. The most critical considerations for the design of these intelligent delivery systems include the controlled release, target specificity, on-demand dosage adjustment, mass transfer and stability of the pharmacological agents. Drug-delivery systems continue to be developed and enhanced to provide better and more sophisticated treatments, promising an improvement in quality of life and extension of life expectancy.