Microneedles for Drug Delivery and Biosensing by liaoqinmei

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									Microneedles for Drug Delivery and
Biosensing



Boris Stoeber
Department of Mechanical Engineering and
Department of Electrical & Computer Engineering
University of British Columbia, Vancouver, Canada
Microneedles
Typical dimensions:                         Microneedle research:
  ▪ Length L: 50 – 1500 µm                   ▪ Started in early 1990s
  ▪ Width W: 10 – 250 µm
  ▪ Lumen diameter D: 8 – 200 µm            Motivation:
                                             ▪ Artificial pathway across the skin
                                                barrier
                  W
                                             ▪ Minimally invasive interface with
                                                the body

         H                                  Biomedical Applications:
                                              ▪ Drug delivery
                                              ▪ Biochemical sensing
             D




Microneedles for Drug Delivery and Biosensing
Microneedles vs. Hypodermic Needles



                             Stainless Steel Hypodermic Needle




                                                      Microneedles


Microneedles for Drug Delivery and Biosensing
Structure of the Skin
Target site: Epidermis                          Drug injection
 ▪ Interstitial fluid                             ▪ minimally invasive
 ▪ Above nerve endings                            ▪ low risk
     ▪      painless                          Biomedical sensing
 ▪ No blood contact                             ▪ Sensing system outside the
     ▪     reduced risk of infections             body
     ▪     reduced risk for device                (simplifies approval)
           contamination                        ▪ Fluid extraction: impossible
     Stratum corneum               Microneedle ▪ Dialysis: complex geometry
              ~ 20 µm
                                                ▪ Diffusion: passive
 Epidermis                                        (no control over time)
 ~ 0.1 mm

                                                 Nerve
 Dermis
 ~ 0.6 – 3 mm                                    Capillary
                       Subcutaneous Fat

Microneedles for Drug Delivery and Biosensing
Microneedle Categories
                                              Geometry
                           in-plane                         out-of-plane      application
                Silicon (1989)                       Silicon (1991)
                                                                              electrodes for
                                                                              sensing &
        solid                                                                 stimulation,
                                                                              perforation

Structure
                Silicon [& nitride / oxide] (1993)   Metal (1999)
                Metal (1998)                         Silicon dioxide (1999)
                Polymer (2001)                       Silicon (2000)           injection or
                                                                              sampling of
      hollow                                         Polymer (2005)
                                                                              compounds




                 integration of electronics           high-density arrays
  advantage      in one substrate

Microneedles for Drug Delivery and Biosensing
Fabrication of Hollow out-of-plane Microneedles:
1. Metal
Electroplating of a polymer mold

A)




B)                                                  Kim et al. 2004


 Laser machined
 Mylar




                                                   Davis et al. 2005

Microneedles for Drug Delivery and Biosensing
Fabrication of Hollow out-of-plane Microneedles:
2. Silicon
Needle lumen: DRIE




Needle shape
 DRIE and isotripic                          DRIE and isotripic                    DRIE (frontside)
 Si-etch (frontside)                         Si-etch (frontside)                   Nitride deposition
                                                                                   KOH




                       Stoeber et al. 2000                     Griss et al. 2003           Gardeniers et al. 2003

Microneedles for Drug Delivery and Biosensing
Fabrication of Hollow out-of-plane Microneedles:
3. Polymers




                                                         Moon et al. 2005




                                                   Perennes et al. 2006

Microneedles for Drug Delivery and Biosensing
Drug Injection Through Microneedles – Clinical Trial
Sample drug: Methyl Nicotinate
                                                     % increase in
 ▪ Causes dilation of blood vessel                    blood flow rate
 ▪ Increases blood flow velocity
                            O

                                O
                        N

Measurement of blood velocity
 ▪ Laser Doppler velocimeter
 ▪ Increase in blood velocity

Shaft of conventional                           ▪ Effective drug delivery through
plastic syringe
                                                  microneedles
                                                ▪ Microneedles provide pathway
                                                  through stratum corneum
                                                ▪ Painless
                 Microneedles
Microneedles for Drug Delivery and Biosensing
Concept of a Microneedle-based Biomedical Sensor

▪   Permanently worn
▪   Interstitial fluid of the epidermis is difficult to extract
▪   Diffusion of compounds through the needle lumens
▪   Larger number of needles – larger signal
▪   Sensor electronics off-site
▪   Porous membrane (optional) prevents large molecules such as proteins
    from affecting sensor stability




Microneedles for Drug Delivery and Biosensing
Example:
Electrochemical Enzyme-based Glucose Sensor
Sensor principle                            Advantages:
                                             ▪ High selectivity and sensitivity
                                             ▪ Simple measuring principle
                                             ▪ Simple fabrication
                                             ▪ Currently standard method

                                            Disadvantages:
                                              ▪ Loss of enzyme activity
                                              ▪ Periodic recalibration required
                                              ▪ Short period of operation (72 h)

                                                     Possible solution:
                                                     Disposable,
   WE: working electrode                             self-calibrating,
   RE: reference electrode                           minimally invasive
   CE: counter electrode
                                                     sensor device
Microneedles for Drug Delivery and Biosensing
Glucose Sensor – in vitro Measurements


                               Electrochemical
                            sensor element in
                          cavity under needles
                                                  Calibration curve




▪ High sensitivity in the range:
  0 - 120 mg/dl
▪ Sensor time constant:
  τ = 3 min
    ▪ fast compared to physiological time
      scales                                     Step Response
▪ No in-vivo measurements of
  biochemical quantities reported yet

Microneedles for Drug Delivery and Biosensing
Summary: State of the Art
Arrays of out-of-plan Microneedles
     ▪ Active area of research
     ▪ Different fabrication processes developed
     ▪ Materials: silicon, SiO2, metal, polymers
     ▪ High fabrication cost


Microneedles for Injection
     ▪ Effective – demonstrated in clinical trials
     ▪ Painless


Microneedles for Biomedical Sensing
     ▪ Glucose sensor concepts available
     ▪ Demonstrated fast sensor response in vitro

Microneedles for Drug Delivery and Biosensing
Future Research Directions
New fabrication processes for inexpensive hollow microneedles
  ▪ Polymers?
Biocompatibility
  ▪ Development of coatings
  ▪ Different materials - biocompatible polymers?
Optimize needle shapes
  ▪ Study of skin mechanics
Device integration
  ▪ Sensor & CMOS
      ▪      Size & cost mismatch
      ▪      Increase S/N -> need fewer needles – smaller area?
  ▪ Several sensors
      ▪      Different enzymes for multi-biosensor
      ▪      Include temperature sensor
  ▪ Include self-calibration
  ▪ Include microfluidic networks?
  ▪ Combine with drug delivery functionality
Validate sensor concept through clinical trials




Microneedles for Drug Delivery and Biosensing

								
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