Micro- & Nano-Systems: From Lab Clinic · 2013. 12. 26. · Micro- & Nano-Systems: From Lab Clinic Dr. Javeed Shaikh Mohammed Assistant Professor, Biomedical Technology College of

Micro- & Nano-Systems: From

Lab Clinic

Dr. Javeed Shaikh Mohammed Assistant Professor, Biomedical Technology

College of Applied Medical Sciences

King Saud University

24 October, 2011

General Outcomes

• Introduce the significance of micro- and nano-

systems in biomedical/clinical applications

• Introduce the challenges in bringing micro- and

systems from lab to the clinic (bench to

bedside)

Bottom-up & Top-down Approaches

Macro-, Micro- & Nano-

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Macro-, Micro- & Nano-

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White blood

cells Skin surface

DNA

Micro-, Nano- …. but why?

• As dimensions go smaller, surface area to volume

ratios increase

• Unique physical, chemical, and biological properties

can emerge in materials at the micro- and nano-scale

– Gold is inert at macroscale, but highly reactive when it is in

the form of 3nm particles

– At low microliter volumes, fluids act more like solids; two

fluids flowing alongside each other in a microchannel will not

mix (except by diffusion)

• Reduced sample size

• Reduced reagent use

• Improved response time

• High throughput


• Integrated multi-functionalities

• Improved performance

• Reduced manufacturing cost and time

• Portability

• Low power consumption

• Reach un-accessible sites

• Short time scales

• On-site analysis


• Nanotechnology

– Improved delivery of poorly water-soluble drugs

– Targeted delivery of drugs to specific cells or

tissues

– Intracellular delivery of macromolecules

– Enhanced half-lives (keeping in circulation at

therapeutic concentrations for longer time)

– Enhance and modulate the distribution of

hydrophobic and hydrophilic drugs into and within

different tissues

– Controlled release profiles

Micro-Technology

• Any technology that employs micro-sized components,

volumes, dimensions, etc.

• MEMS: Micro Electro Mechanical Systems

• BioMEMS: Biological MEMS

• Microtechnology is not new to clinical labs

– Analyzers using micro volumes

– Micro-arrays (sub-microliter volume dispensing)

– valves, tubing, ion-specific electrodes, microparticles in

devices for immunoassays, capillary flow systems in

analyzers, point-of-care testing devices

Micro-Technology

• Fabrication derived from the fabrication techniques

used in the microelectronics or IC industry

www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf

Microtechnology: Microfluidics

• Miniaturization of complex fluid handling and

integrated detection

– Dip stick devices with Lateral flow tests: pregnancy,

cardiac disease, and HIV-1

– POC devices incorporating disposable

microelectronic and microfluidic components

(Metrika, Biosite, iSTAT, unipath)

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Nano-Technology

• Current buzzword

• Any technology that employs 1-100nm sized

components, volumes, dimensions, etc.

• 1 nm is 1 billionth of a meter (5 atoms width)

• Interaction possible with nano-materials with

cells/tissues at molecular level

• Some devices in clinic use nanoparticles or beads as

absorbents and as medium to carry antibodies

• Use of nanotechnology in the clinical laboratory is still

limited

Micro- and Nano-Technologies

• Micro- and nano-technology are being used

interchangeably as they are being used in

concert with each other

• Nanomaterials/components are important in

microscale devices

Nanotechnology: Interdisciplinary Field

Chemistry Physics

Biology Engineering

Nanotechnology

http://lib.bioinfo.pl/app/webroot/img/UserFiles/65944/Image/Figure%203.%20Diverse%20application%20of%20nanotechnology.JPG

Nanoparticles

http://en.wikipedia.org/wiki/File:Mesoporous_Silica_Nanoparticle.jpg

TEM (a, b, and c)

images of prepared

mesoporous silica

nanoparticles with

mean outer diameter:

(a) 20nm, (b) 45nm,

and (c) 80nm. SEM

(d) image

corresponding to (b).

The insets are a high

magnification of

mesoporous silica

particle

Nanotubes

http://en.wikipedia.org/wiki/Portal:Nanotechnology

This animation of

a spinning carbon

nanotube

showcases its 3D

structure

Nanowires

http://en.wikipedia.org/wiki/File:Epitaxial_Nanowire_Heterostructures_SEM_image.jpg

An SEM image

of epitaxial

nanowire

heterostructures

grown from

catalytic gold

nanoparticles

Quantum Dots

http://en.wikipedia.org/wiki/File:QD_mini_rainbow.jpg

Colloidal quantum

dots irradiated with a

UV light; Different

sized quantum dots

emit different color

light due to quantum

confinement

Dendrimers

http://en.wikipedia.org/wiki/File:Graphs.jpg

Fullerenes

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Rotating view of Buckminsterfullerene C60

Nanofibers

http://en.wikipedia.org/wiki/File:N2_2.kesit.JPG

SEM image

of nanofibers

Microtechnology: General Applications

• Accelerometers for air bag sensors

• Tire-pressure sensors

• Gyroscopes for advanced vehicle stability

control

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Micro-Technology: Clinical Applications

• DNA microarrays

• Protein microarrays

• Microfluidics

• Tissue engineering

• Surface modification

• Implantable systems

• Drug delivery systems

• Biomedical sensors

Micro-Technology: Clinical Applications

• BioMEMS

– Electronic nose or tongue

– Neural systems capable of controlling motor or sensory

prosthetic devices

– Painless micro-surgical tools

– Microfluidic systems for total chemical or genetic analysis

• Strain gauges: orthopedic research, study of muscles

• Inertial micro-sensors: determine impact level and

patient posture

• Pressure sensors: blood pressure, bladder pressure,

cerebral spinal fluid pressure…

Microtechnology: Clinical Applications

• Glucose testing: low cost, convenient, fast

turnover time using microtechnology

• Breath sensors for glucose detection

• Abbott: bioresorbable vascular scaffold dubbed

the Absorb

• Drug screening, urine analysis, coagulation,

cardiac assessment, virus detection (HIV)


• Agilent bioanalyzer (DNA, RNA, or protein

sizing…based on capillary electrophoresis

using small microchips)

• Pharmaceutical industry: screening of

thousands of compounds as candidates for

drugs

• i-STAT analyzer: 12 or more analytes


• Clinical applications of Electrophoresis for

manipulating particles and droplets and for

sorting cells

– Isolation of rare circulating tumor cells from blood

– Discrimination of cell subpopulations from tumor

tissues

– Analysis of nanoliter sample droplets by highly-

versatile programmable fluidic processors


Organ Printing


"medical telesensor"

chip on a fingertip can

measure and transmit

body temperature http://www.imec.be

Cortical probe

http://www.ornl.gov/info/ornlreview/rev29_3/graphics/p55.gif


Blood pressure

sensors

http://www.acreo.se


Neural probes

http://actuators.stanford.edu/


Surgical tools

www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf


http://www.angiogenesis-center.org


http://www.nlm.nih.gov/ http://www.mediresource.com


Parallel screening of

40,000 different

compounds on a 1 cm

chip with 50 μm

oligonucleotide probe

areas

Affymetrix


Agilent microarrays


• Rheonix Inc.: Rheonix CARD platform is

complete hands-free operation of molecular

diagnosis across all of potential applications

from infectious disease detection to genotyping

analysis

• Sample in, result out: Cell lysis, DNA extraction

and purification, molecular amplification and

multiplexed end-point detection using

microarrays



Ratio Inc.


BellBrook Labs


BellBrook Labs

Nanotechnology in KSA

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• Nansulate®, a nanotechnology based specialty

coating, provides qualities of thermal insulation,

corrosion prevention, resistance to mold

growth, fire resistance, chemical resistance &

lead encapsulation in a water-based coating

formulation

• KSA: Nansulate for energy saving projects and

for asset protection, especially in harsh

environmental conditions (corrosion prevention

for oil pipelines in marine)

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• Saudi Aramco, the oil-giant, plans to employ

nanotechnology for a better assessment of oil

reservoirs

• Saudi Aramco's EXPEC Advanced Research

Center has been developing the concept of

nanoscale Resbots (reservoir robots) for such

applications and hopes to use them in the field

in the near future

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Nanotechnology: General Applications

www.gtlaw.com/portalresource/nanoeh










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Nanotechnology: Medical Applications

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Nanotechnology: Oncology

http://nano.cancer.gov/learn/understanding/nanotech_nanoparticles.asp


http://nano.cancer.gov/learn/understanding/nanotech_nanoshells.asp


http://nano.cancer.gov/learn/understanding/nanotech_cantilevers.asp


http://nano.cancer.gov/learn/understanding/nanotech_nanowires.asp

Nanotechnology: Current Status

Ind

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Nanotechnology: Status

• PSA Bio-barcode assay (FDA approved after 10

years): detect markers at very low concentration

(prostrate-specific antigen)

• Before: toward fundamental research, exploring

potential of nanotechnologies applied to healthcare,

and understand the medical potential of the interface

between inert matter and living organisms

• Now: towards clinical applications in diagnostics and

therapy

• FDA: medical devices and biologics; cosmetics and

dietary supplements do not

Nanotechnology: Clinical Trials



• Nanosystems Biology Cancer Center (Caltech/UCLA CCNE):

series of PET imaging agents ([18F]-FAC)

• Center of Nanotechnology for Treatment, Understanding, and

Monitoring of Cancer (UC-San Diego CCNE): chemically

engineered adenovirus nanoparticle to deliver a molecule that

stimulates the immune system (Phase I); significant reductions

in leukemia cell counts, reductions in size of all lymph nodes

• Calando Pharmaceuticals: cyclodextrin-based nanoparticle

(CALAA-01) that safely encapsulates a siRNA agent that shuts

down a key enzyme in cancer cells; tested on patients who

have become resistant to other chemotherapies

• Cerulean Pharma, Inc.: cyclodextrin-based polymer conjugated

to camptothecin (CRLX101); patients with solid tumor

malignancies

http://nano.cancer.gov/learn/now/clinical-trials.asp


• Siteman Center of Cancer Nanotechnology Excellence

(Washington U. CCNE): nanoparticle MRI contrast agent that

binds to the αvβ3-intregrin found on the surface of the newly

developing blood vessels associated with early tumor

development (Phase I)

• Diagnostic company Nanosphere: received FDA approval for a

nanosensor test for the drug Coumadin; clinical study using

human tissue samples to monitor very low levels of PSA

• MIT-Harvard Center for Cancer Nanotechnology Excellence:

lymphotrophic superparamagnetic nanoparticles to identify

small and otherwise undetectable lymph node metastases

• Integrated Blood Barcode (IBBC) chip: (Caltech/UCLA CCNE):

validation tests to measure the levels of approximately 800

miRNAs from melanoma patients before and after therapy



• Carolina Center of Cancer Nanotechnology Excellence

(University of North Carolina CCNE): CT scanner that uses

carbon nanotubes as the x-ray source (increases the precision

and speed of CT scanning) for detecting small tumors

• Center for Cancer Nanotechnology Excellence Focused on

Therapy Response (Stanford University CCNE): carbon

nanotubes to improve colorectal cancer imaging

• BIND Biosciences (MIT-Harvard CCNE): targeted nanoparticles

consist of a polymer matrix, therapeutic payloads, functional

surface moieties, and targeting ligands which allow for particle

optimization (i.e., accumulation in target tissue, avoidance of

being cleared by immune system, and delivery of drug with

desired release profile)


Nanotechnology: Regulatory Stage

• MagForce Nanotechnologies (EU regulatory

approval): injecting aminosilane-coated iron oxide

nanoparticles into a tumor; subject to high-frequency

alternating magnetic field; causing vibration of

particles and generation of heat to damage the tumors

• Magnetofluid NanoTherm: iron oxide nanoparticles

• NanoActivator: magnetic field applicator for warming

the nanoparticle loaded tissue

• NanoPlan: software for thermal treatment planning

Nanotechnology: Regulatory Stage


Nanotechnology: Approved Drugs

• Two approved nanotechnology based drugs for

cancer treatment

– Doxil (liposome preparation of doxorubicin)

– Abraxane (paclitaxel in nanoparticle formulation)


Example1: Lab to Clinic

• Islet characterization: viability, purity, and sterility

• Transplant η ↔ Islet function

• Our goal: high-throughput platform for use in islet isolation arena

Shaikh Mohammed, J., Wang, Y., Oberholzer, J., Eddington, D.T., Lab on a Chip 2009

Islet Quantification: Pre Implantation


Experimental Setup

Shaikh Mohammed, J., Wang, Y., Oberholzer, J., Eddington, D.T., Lab on a Chip 2009


Non potent

islets

Potent

islets

Mice transplantation data: 1000 human islets transplanted into nude mice

Example2: Lab Clinic

PDB: 3cln PDB: 1lin

50Å 15Å

Protein, Calmodulin (CaM)


King W.J., Shaikh Mohammed, J., Murphy W.L., Soft Matter 2009

CaM Hydrogel:

Growth Factor

Delivery


0

25

50

75

100

0 10 20 30 40 50

% V

EG

F R

ele

as

ed

Time (hr)

Collapsed Hydrogel

Expanded Hydrogel

Conformation Change Induced Release

King W.J., Shaikh Mohammed, J., Murphy W.L., Soft Matter 2009

Challenges: Lab to Clinic

• Environmental health, human health, animal

health, and safety (EHS) concerns

• Stability of nanoparticles in physiological

conditions

• Scalability for large-scale production

• Cost of drug

• Long FDA approval times (10 years or more)


• Toxicity of nanomaterials:

– short term- no toxicity in animals

– long term- not known

• Conjugation Chemistry Challenges:

– Making nanoparticles that are application-specific

– Putting the ‘drug’ in the particle

– Maintaining drug activity in the particle

– Making the drug come off the particle once

application is done


• Patient understanding and willingness

• Lack of patient awareness regarding novel

technologies

• Patient willingness to try the novel technologies

• Knowledge of associated risks is still in early

phase

• Ethical and societal aspects

• Safety of patients and clinicians


• Failure to develop low-cost and convenient

devices that compete with current systems

• POC devices require extreme simplicity in use:

making many technologies not come to clinic

• Healthcare workers accept the point-of-care

devices when assay time is important and

technology is convenient

• Safety and manufacturing feasibility

• Industry interest


• Collaboration between academic researchers

and industry

• Interdisciplinary interactions

• Collaboration among scientists is critical

– Material science experts

– Nanotechnology researchers

– Biomedical scientists

– Medical device engineers

– Practicing clinicians

– Medical entrepreneurs

– Corporate R&D managers

Documents

Micro- & Nano-Systems: From Lab Clinic · 2013. 12. 26. · Micro- & Nano-Systems: From Lab Clinic Dr. Javeed Shaikh Mohammed Assistant Professor, Biomedical Technology College of