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A Fully Integrated Microneedle-based Transdermal Drug Delivery System
KTH, School of Electrical Engineering (EES), Microsystem Technology.
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. , x, 82 p.
Series
Trita-EE, ISSN 1653-5146 ; 2007:046
Keyword [en]
Microneedle, Transdermal, Intradermal, Drug delivery, DRIE, MEMS, Microsystem
National Category
Biomedical Laboratory Science/Technology
Identifiers
URN: urn:nbn:se:kth:diva-4484ISBN: 978-91-7178-751-4 (print)OAI: oai:DiVA.org:kth-4484DiVA: diva2:12495
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
List of papers
1. A Compact, Low-cost Microliter-range Liquid Dispenser based on Expandable Microspheres
Open this publication in new window or tab >>A Compact, Low-cost Microliter-range Liquid Dispenser based on Expandable Microspheres
Show others...
2006 (English)In: Journal of Micromechanics and Microengineering, ISSN 0960-1317, E-ISSN 1361-6439, Vol. 16, no 12, 2740-2746 p.Article in journal (Refereed) Published
Abstract [en]

This work presents a new low-cost liquid dispenser for the dispensing of microliters to milliliter volumes. The dispensing mechanism is based on a thermal actuator where highly expandable microspheres expand into a liquid reservoir consequently displacing any stored liquid. All device components are made out of low-cost materials and the fabrication process has the potential for high volume batch manufacturing. The device utilizes the property of the expandable microspheres to form a heat insulating layer between the heat source and the delivered liquid. Moreover, it does not require any feed back or complicated flow metering. The device was successfully tested showing a mean dispensed volume of 101 mu 1 with a standard deviation of 3.2% and with a maximum temperature of 59 degrees C in the liquid during actuation. It was shown that the dispenser is strong enough to deliver against counter pressures as high as 75 kPa. The device can also function as a low flow rate dispenser as demonstrated in a microfluidic dye laser application. The flow rate can be controlled between 1 mu 1 h(-1) and 2400 mu 1 h(-1) by adjusting the actuation power.

Keyword
FLOW-CONTROL; VALVE; Actuators; Dye lasers; Fluidics; Pressure effects; Reservoirs (water); Thermal insulating materials; Expandable microspheres; Heat insulating layers; Milliliter volumes; Volume batch manufacturing; Dispensers
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-7458 (URN)10.1088/0960-1317/16/12/030 (DOI)000242475200030 ()2-s2.0-33846117051 (Scopus ID)
Note

QC 20100623

Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2015-09-23Bibliographically approved
2. A Method for Tapered Deep Reactive Ion Etching using a Modified Bosch Process
Open this publication in new window or tab >>A Method for Tapered Deep Reactive Ion Etching using a Modified Bosch Process
2007 (English)In: Journal of Micromechanics and Microengineering, ISSN 0960-1317, E-ISSN 1361-6439, Vol. 17, no 5, 1087-1092 p.Article in journal (Refereed) Published
Abstract [en]

This paper presents a method for etching tapered sidewalls in silicon using deep reactive ion etching. The method is based on consecutive switching between anisotropic etching using the Bosch process and isotropic dry etching. By controlling the etch depths of the anisotropic and isotropic etch sessions, the sidewall angle can be controlled over a relatively large range. Tapered sidewalls are useful in microfabrication processes such as metal coating of 3D structures (e. g. for electrical connections or vias), mold tool fabrication or as a tool to compensate for reentrant etching. The method was tested and characterized by etching basic test structures in silicon wafers. Based on the investigated anisotropic and isotropic etch depths the sidewall angle could be varied between 0 degrees (straight vertical) and 36 degrees. The sidewall angle was well predicted by a model using the etch depths as parameters. Due to the alternating etch procedure a scalloping pattern is generated on the sidewalls. By frequent switching and short etch sessions this scalloping can be reduced to less than 1 mu m. The process represents an easy method to tailor the sidewall angle in deep etching of silicon. The etch scheme is run in a single etch system and can be implemented in ICP systems of most manufactures. The method can also be used in conjunction with the standard Bosch process as demonstrated herein, where the method was applied to compensate for reentrant etching of high out-of-plane mesa-structures.

Keyword
Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Instruments & Instrumentation; Materials Science, Multidisciplinary; Mechanics
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-7459 (URN)10.1088/0960-1317/17/5/031 (DOI)000246551600033 ()2-s2.0-34247505036 (Scopus ID)
Note
QC 20100624Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2010-08-24Bibliographically approved
3. Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery
Open this publication in new window or tab >>Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery
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2007 (English)In: Journal of microelectromechanical systems, ISSN 1057-7157, E-ISSN 1941-0158, Vol. 16, no 6, 1429-1440 p.Article in journal (Refereed) Published
Abstract [en]

This paper presents penetration-enhanced hollow microneedles and an analysis on the biomechanical interaction between microneedles and skin tissue. The aim of this paper is to fabricate microneedles that reliably penetrate the skin tissue without using penetration enhancers or special insertion tools that were used in the previous studies. The microneedles are made of silicon and feature ultrasharp tips and side openings. The microneedle chips were experimentally tested in vivo by injection of dye markers. To further investigate the penetration, the insertion progression and the insertion force were monitored by measuring the electrical impedance between microneedles and a counter electrode on the skin. The microneedle design was also tested using a novel simulation approach and compared to other previously published microneedle designs. The purpose of this specific part of the paper was to investigate the interaction mechanisms between a microneedle and the skin tissue. This investigation is used to predict how the skin deforms upon insertion and how microneedles can be used to create a leak-free liquid delivery into the skin. The fabricated microneedles successfully penetrated dry living human skin at all the tested sites. The insertion characteristic of the microneedle was superior to an earlier presented type, and the insertion force of a single microneedle was estimated to be below 10 mN. This low insertion force represents a significant improvement to earlier reported results and potentially allows a microneedle array with hundreds of needles to be inserted into tissue by hand.

Keyword
drug delivery, microneedles, skin modeling, transdermal
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-7460 (URN)10.1109/JMEMS.2007.907461 (DOI)000252012800016 ()2-s2.0-36949000879 (Scopus ID)
Note
QC 20100624Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2011-11-03Bibliographically approved
4. Painless Drug Delivery through Microneedle-based Transdermal Patches featuring Active Infusion
Open this publication in new window or tab >>Painless Drug Delivery through Microneedle-based Transdermal Patches featuring Active Infusion
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2008 (English)In: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 55, no 3, 1063-1071 p.Article 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.

Keyword
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:nbn:se:kth:diva-7461 (URN)10.1109/TBME.2007.906492 (DOI)000253733800023 ()18334398 (PubMedID)2-s2.0-39749199632 (Scopus ID)
Note
QC 20100624Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2010-08-17Bibliographically approved
5. Novel Microneedle Patches for Active Insulin Delivery are Efficient in Maintaining Glycaemic Control: An Initial Comparison with Subcutaneous Administration
Open this publication in new window or tab >>Novel Microneedle Patches for Active Insulin Delivery are Efficient in Maintaining Glycaemic Control: An Initial Comparison with Subcutaneous Administration
2007 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 7, 1381-1388 p.Article in journal (Refereed) Published
Abstract [en]

Purpose. Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array.

Materials and Methods. Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia.

Results. Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 +/- 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 +/- 4.2, n=9, and intradermal 11 +/- 1.8, n=9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 +/- 22, 81 +/- 34, and 87 +/- 20 mu IU/ml), as compared to the first measurement (26 +/- 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 +/- 3.5 mu IU/ml from 21 +/- 18).

Conclusion. This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients' glycaemic control.

Keyword
diabetes; insulin lispro; intradermal; microneedles; rats; transdermal; DIABETES-MELLITUS; TRANSDERMAL DELIVERY; HOLLOW MICRONEEDLES; IN-VITRO; INHALED INSULIN; RAT DERMIS; INJECTION; TYPE-1; SKIN; STREPTOZOTOCIN
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-7462 (URN)10.1007/s11095-007-9256-x (DOI)000247429700015 ()2-s2.0-34249872741 (Scopus ID)
Note
QC 20100628Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2010-06-28Bibliographically approved
6. Membrane-sealed Hollow Microneedles and Related Administration Schemes for Transdermal Drug Delivery
Open this publication in new window or tab >>Membrane-sealed Hollow Microneedles and Related Administration Schemes for Transdermal Drug Delivery
2008 (English)In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 10, no 2, 271-279 p.Article in journal (Refereed) Published
Abstract [en]

This paper presents fabrication and testing of membrane-sealed hollow microneedles. This novel concept offers the possibility of a sealed microneedle-based transdermal drug delivery system in which the drug is stored and protected from the environment. Sealed microneedles were fabricated by covering the tip openings of out-of-plane silicon microneedles with thin gold membranes. In this way a leak-tight seal was established which hinders both contamination and evaporation. To allow drug release from the microneedles, three different methods of opening the seals were investigated: burst opening by means of pressure; opening by applying a small voltage in the presence of physiological saline; and opening as a result of microneedle insertion into the skin. It was found that a 170 nm thick gold membrane can withstand a pressure of approximately 120 kPa. At higher pressures the membranes burst and the microneedles are opened up. The membranes can also be electrochemically dissolved within 2 min in saline conditions similar to interstitial fluid present in the skin. Moreover, through in vivo tests, it was demonstrated that 170 nm thick membranes break when the microneedles were inserted into skin tissue. The proposed concept was demonstrated as a feasible option for sealing hollow microneedles. This enables the realization of a closed-package transdermal drug delivery system based on microneedles.

Keyword
transdermal drug delivery; intradermal drug delivery; microneedles; membrane; MEMS; OF-PLANE MICRONEEDLES; IN-VIVO; MICROFABRICATED MICRONEEDLES; IMMUNIZATION; FABRICATION; TECHNOLOGY; TRANSPORT; EFFICIENT; SKIN
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:kth:diva-7463 (URN)10.1007/s10544-007-9133-8 (DOI)000253525500015 ()2-s2.0-40349099997 (Scopus ID)
Note
QC 20100628Available from: 2007-09-10 Created: 2007-09-10 Last updated: 2010-06-28Bibliographically approved

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