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Painless Drug Delivery through Microneedle-based Transdermal Patches featuring Active Infusion
KTH, School of Electrical Engineering (EES), Microsystem Technology.
KTH, School of Electrical Engineering (EES), Microsystem Technology.
Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University.
Zühlke Engineering AG, Zurich.
Show others and affiliations
2008 (English)In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 55, no 3, p. 1063-1071Article in journal (Refereed) Published
Abstract [en]

This paper presents the first microneedle-based transdermal patch with integrated active dispensing functionality. The electrically controlled system consists of a low-cost dosing and actuation unit capable of controlled release of liquid in the microliter range at low flow-rates and minimally invasive, side-opened, microneedles. The system was successfully tested in vivo by insulin administration to diabetic rats. Active infusion of insulin at 2 mu l/h was compared to passive, diffusion-driven, delivery. Continuous active infusion caused significantly higher insulin concentrations in blood plasma. After a 3-h delivery period, the insulin concentration was five times larger compared to passive delivery. Consistent with insulin concentrations, actively administered insulin resulted in a significant decrease of blood glucose levels. Additionally, insertion and liquid injection was verified on human skin. This study shows the feasibility of a patch-like system with on-board liquid storage and dispensing capability. The proposed device represents a first step towards painless and convenient administration of macromolecular drugs such as insulin or vaccines.

Place, publisher, year, edition, pages
2008. Vol. 55, no 3, p. 1063-1071
Keyword [en]
drug delivery; insulin; intradermal; microneedles; transdermal; HOLLOW MICRONEEDLES; MEMS MATERIALS; IN-VIVO; DEVICES; BIOCOMPATIBILITY; IMMUNIZATION; PENETRATION; TECHNOLOGY; TRANSPORT; FUTURE
National Category
Medical Laboratory and Measurements Technologies
Identifiers
URN: urn:nbn:se:kth:diva-7461DOI: 10.1109/TBME.2007.906492ISI: 000253733800023PubMedID: 18334398Scopus ID: 2-s2.0-39749199632OAI: oai:DiVA.org:kth-7461DiVA: diva2:12492
Note
QC 20100624Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2017-12-14Bibliographically approved
In thesis
1. A Fully Integrated Microneedle-based Transdermal Drug Delivery System
Open this publication in new window or tab >>A Fully Integrated Microneedle-based Transdermal Drug Delivery System
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. However, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. By using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulins or vaccines. These microneedles only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors of the lower skin. Thus, microneedle insertions are perceived as painless.

The thesis presents research in the field of microneedle-based drug delivery with the specific aim of investigating a microneedle-based transdermal patch concept. To enable controllable drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system includes a small active dispenser mechanism. The dispenser is based on a novel thermal actuator consisting of highly expandable microspheres. When actuated, the microspheres expand into a liquid reservoir and, subsequently, dispense stored liquid through outlet holes.

The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching. The needles are organized in arrays situated on a chip. To allow active delivery, the microneedles are hollow with the needle bore-opening located on the side of the needle. This way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further requirement to achieve microneedle insertion into skin by hand.

The thesis presents fabrication and evaluation of both the microneedle structure and the transdermal patch as such. Issues such as penetration reliability, liquid delivery into the skin and microneedle packaging are discussed. The microneedle patch was also tested and studied in vivo for insulin delivery. Results show that intradermal administration with microneedles give rise to similar insulin concentration as standard subcutaneous delivery with the same dose rate.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. p. x, 82
Series
Trita-EE, ISSN 1653-5146 ; 2007:046
Keyword
Microneedle, Transdermal, Intradermal, Drug delivery, DRIE, MEMS, Microsystem
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-4484 (URN)978-91-7178-751-4 (ISBN)
Public defence
2007-09-28, F3, Lindstedsvägen 26, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100623Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2010-06-28Bibliographically approved
2. Novel Microfluidic Devices Based on a Thermally Responsive PDMS Composite
Open this publication in new window or tab >>Novel Microfluidic Devices Based on a Thermally Responsive PDMS Composite
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

The field of micro total analysis systems (μTAS) aims at developments toward miniaturized and fully integrated lab-on-a-chip systems for applications, such as drug screening, drug delivery, cellular assays, protein analysis, genomic analysis and handheld point-of-care diagnostics. Such systems offer to dramatically reduce liquid sample and reagent quantities, increase sensitivity as well as speed of analysis and facilitate portable systems via the integration of components such as pumps, valves, mixers, separation units, reactors and detectors.

Precise microfluidic control for such systems has long been considered one of the most difficult technical barriers due to integration of on-chip fluidic handling components and complicated off-chip liquid control as well as fluidic interconnections. Actuation principles and materials with the advantages of low cost, easy fabrication, easy integration, high reliability, and compact size are required to promote the development of such systems.

Within this thesis, liquid displacement in microfluidic applications, by means of expandable microspheres, is presented as an innovative approach addressing some of the previously mentioned issues. Furthermore, these expandable microspheres are embedded into a PDMS matrix, which composes a novel thermally responsive silicone elastomer composite actuator for liquid handling. Due to the merits of PDMS and expandable microspheres, the composite actuator's main characteristic to expand irreversibly upon generated heat makes it possible to locally alter its surface topography. The composite actuator concept, along with a novel adhesive PDMS bonding technique, is used to design and fabricate liquid handling components such as pumps and valves, which operate at work-ranges from nanoliters to microliters. The integration of several such microfluidic components promotes the development of disposable lab-on-a-chip platforms for precise sample volume control addressing, e.g. active dosing, transportation, merging and mixing of nanoliter liquid volumes. Moreover, microfluidic pumps based on the composite actuator have been incorporated with sharp and hollow microneedles to realize a microneedle-based transdermal patch which exhibits on-board liquid storage and active dispensing functionality. Such a system represents a first step toward painless, minimally invasive and transdermal administration of macromolecular drugs such as insulin or vaccines.

The presented on-chip liquid handling concept does not require external actuators for pumping and valving, uses low-cost materials and wafer-level processes only, is highly integrable and potentially enables controlled and cost-effective transdermal microfluidic applications, as well as large-scale integrated fluidic networks for point-of care diagnostics, disposable biochips or lab-on-a-chip applications.

This thesis discusses several design concepts for a large variety of microfluidic components, which are promoted by the use of the novel composite actuator. Results on the successful fabrication and evaluation of prototype devices are reported herein along with comprehensive process parameters on a novel full-wafer adhesive bonding technique for the fabrication of PDMS based microfluidic devices.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. p. xii, 68
Series
Trita-EE, ISSN 1653-5146 ; 2007:31
Keyword
MEMS, microsystem technology, micro total analysis system, lab-on-a-chip, microfluidics, composite actuator, expandable microspheres, PDMS, poly dimethylsiloxane, disposable, wafer bonding, adhesive bonding, PDMS bonding, adhesive PDMS bonding, selective PDMS bonding, microcontact printing
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-4470 (URN)978-91-7178-732-3 (ISBN)
Public defence
2007-09-07, F3, Lindstedtsvägen 26, KTH, 10:00
Opponent
Supervisors
Note
QC 20100817Available from: 2007-08-21 Created: 2007-08-21 Last updated: 2010-08-17Bibliographically approved

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