Microfabrication of Individual 200μm Diameter Transdermal Microconduits Using High Voltage Pulsing in Salicylic Acid and Benzoic Acid

We describe an extension of semiconductor fabrication methods that creates individual ≈ 200;μm diameter aqueous pathways through human stratum corneum at predetermined sites. Our hypothesis is that spatially localized electroporation of the multilamellar lipid bilayer membranes provides rapid delivery of salicylic acid to the keratin within corneocytes, leading to localized keratin disruption and then to a microconduit. A microconduit penetrating the isolated stratum corneum supports a volumetric flow of order 0.01;ml per s with a pressure difference of only 0.01;atm (about 102;Pa). This study provides a method for rapidly microengineering a pathway in the skin to interface future devices for transdermal drug delivery and sampling of biologically relevant fluids

Focused Ion Beam Fabrication

Contains reports on four sections of one research project.Microsystems Technology LaboratoriesDefense Advanced Research Projects Agency/Naval Electronics Systems Command (Contract MDA 903-85-C-0215)U.S. Air Force (through Lincoln Laboratory)Defense Advanced Research Projects Agency (through Lincoln Laboratory)Charles Stark Draper Laboratory, Inc. (Contract DL-H-261827)Hitachi Central Research LaboratoryNippon Telegraph & TelephoneU.S. Army Research Office (Contract DAALO3-87-K-0126

Focused Ion Beam Fabrication

Contains reports on eight research projects.DARPA/Naval Electronics Systems Command (Contract MDA 903-85-C-0215)DARPA/U.S. Army Research Office (Contract DAAL03-88-K-0108)U.S. Army Research Office (Contract DAAL03-87-K-0126)Charles Stark Draper LaboratoryInternational Business Machines Corporation - Research Division, General Technologies DivisionU.S. Air ForceDARP

Transdermal microconduits by microscission for drug delivery and sample acquisition

BACKGROUND: Painless, rapid, controlled, minimally invasive molecular transport across human skin for drug delivery and analyte acquisition is of widespread interest. Creation of microconduits through the stratum corneum and epidermis is achieved by stochastic scissioning events localized to typically 250 μm diameter areas of human skin in vivo. METHODS: Microscissioning is achieved by a limited flux of accelerated gas: 25 μm inert particles passing through the aperture in a mask held against the stratum corneum. The particles scize (cut) tissue, which is removed by the gas flow with the sensation of a gentle stream of air against the skin. The resulting microconduit is fully open and may be between 50 and 200 μm deep. RESULTS: In vivo adult human tests show that microconduits reduce the electrical impedance between two ECG electrodes from approximately 4,000 Ω to 500 Ω. Drug delivery has been demonstrated in vivo by applying lidocaine to a microconduit from a cotton swab. Sharp point probing demonstrated full anaesthesia around the site within three minutes. Topical application without the microconduit required approximately 1.5 hours. Approximately 180 μm deep microconduits in vivo yielded blood sample volumes of several μl, with a faint pricking sensation as blood enters tissue. Blood glucose measurements were taken with two commercial monitoring systems. Microconduits are invisible to the unaided eye, developing a slight erythematous macule that disappears over days. CONCLUSION: Microscissioned microconduits may provide a minimally invasive basis for delivery of any size molecule, and for extraction of interstitial fluid and blood samples. Such microconduits reduce through-skin electrical impedance, have controllable diameter and depth, are fully open and, after healing, no foreign bodies were visible using through-skin confocal microscopy. In subjects to date, microscissioning is painless and rapid

Transdermal drug delivery by localized intervention

Both field-confined skin electroporation and microscissioning offer minimally invasive methods for delivering drugs across skin and nail with minimal sensation. Both methods create high permeability pathways in a pain-free manner. These openings are similar in dimension to commonly experienced scratches and nicks on the skin. These localized openings provide pathways for sustained delivery of drugs either passively using a patch or actively using pressure or iontophoresis.IEEE Engineering in Medicine and Biology SocietyCenter for Integration of Medicine and Innovative TechnologyMassachusetts General HospitalNational Institutes of Health (RO1-AR4921 and RO1-GM6387)Lincoln Laborator

Genome sequence of Babesia bovis and comparative analysis of apicomplexan hemoprotozoa

Babesia bovis is an apicomplexan tick-transmitted pathogen of cattle imposing a global risk and severe constraints to livestock health and economic development. The complete genome sequence was undertaken to facilitate vaccine antigen discovery, and to allow for comparative analysis with the related apicomplexan hemoprotozoa Theileria parva and Plasmodium falciparum. At 8.2 Mbp, the B. bovis genome is similar in size to that of Theileria spp. Structural features of the B. bovis and T. parva genomes are remarkably similar, and extensive synteny is present despite several chromosomal rearrangements. In contrast, B. bovis and P. falciparum, which have similar clinical and pathological features, have major differences in genome size, chromosome number, and gene complement. Chromosomal synteny with P. falciparum is limited to microregions. The B. bovis genome sequence has allowed wide scale analyses of the polymorphic variant erythrocyte surface antigen protein (ves1 gene) family that, similar to the P. falciparum var genes, is postulated to play a role in cytoadhesion, sequestration, and immune evasion. The approximately 150 ves1 genes are found in clusters that are distributed throughout each chromosome, with an increased concentration adjacent to a physical gap on chromosome 1 that contains multiple ves1-like sequences. ves1 clusters are frequently linked to a novel family of variant genes termed smorfs that may themselves contribute to immune evasion, may play a role in variant erythrocyte surface antigen protein biology, or both. Initial expression analysis of ves1 and smorf genes indicates coincident transcription of multiple variants. B. bovis displays a limited metabolic potential, with numerous missing pathways, including two pathways previously described for the P. falciparum apicoplast. This reduced metabolic potential is reflected in the B. bovis apicoplast, which appears to have fewer nuclear genes targeted to it than other apicoplast containing organisms. Finally, comparative analyses have identified several novel vaccine candidates including a positional homolog of p67 and SPAG-1, Theileria sporozoite antigens targeted for vaccine development. The genome sequence provides a greater understanding of B. bovis metabolism and potential avenues for drug therapies and vaccine development

Custom-Integrated Circuits

Contains table of contents for Part III, table of contents for Section 1, and reports on five research projects.IBM CorporationW.M. Keck FoundationCatalyst FoundationNational Science Foundation Grant MIP 94-23221National Science Foundation Contract MIP 96-1232Schlumberger Foundatio