micro scale: ~µm-~mm nano scale: ~nm-~µm …fangang/new_web_2002/l4/... · y biomems drug...

NTHU ESS5845 Nano/micro Biomecidal and Fluidic System F. G. Tseng Spring/2004, lec 1, p1

Lecture 1 Introduction to Nano/micro Biomedical and Fluidic Systems

Scope of This Course: Introduction and study of the principles and applications of micro/nano sized biomedical/fluidic systems in current stage and potential possibilities in the future.

Goal: To help on your nano/micro biomedical/fluidic system design in choosing right principles and applications from the systematic study for the specific field of life science.

Definition of nano/micro biomedical/fluidic systems:

Micro scale: ~m-~mm

Nano scale: ~nm-~m

Devices/systems point of view:

Miniaturized systems, integrate sensing, control and actuation units on a chip, for bio-molecules or cell process applicable for the purposes of diagnosis, monitoring, drug screening, drug delivery, etc

Do we really need micro/nano biosystems?

>6 billion people on our planet needing all forms of molecular diagnosis including cancer screening, risk profiling and detection Potential pathogens drawn from

~1.5M species of fungi ~800,000 species of bacteria All possibly with drug resistance genes

Food, water, agricultural and environmental testing needs

=>Perhaps the need for >15 billion molecular tests per year!!!


(Peter Gascoyne - UT MDACC)

Why Micro/nano fabricated? Advantages:

a. shorter process time b. scarce sample/assay amount (nl-pl) c. low cost d. automation e. high throughput Challenges:

a. multi-disciplinary b. integration c. weak signal d. relibility comparison between micro process and micro TAS

a. 1950s 1970s: Centralized computers to which the data is brought

b.tories to which sample are brought

(c)

and processed by skilled operators Micro processors (IC) at today.

c. 1900s-2000 : Centralized labora

(b) (a)

(d) (c)


and processed by skilled operators LOC or TAS, at today and in the fd. uture

History of Bio Micro systems (courtesy: A. P. Lee)

efore 1990: Petersen at IBM published "Silicon as a Mechanical

ant

n alanalog

2) satisfactorily solve inherent problems of mechanical reliability

3) fabrication process compatible with standard IC processes.Low

ployed. 1982:

so

owe at U.C. Berkeley presents a chemical vapor ra.

f

Other 1980s: the LIGA process by Germans, Wise and Ko continued

1990-1993 (The Renaissance according to A. Manz)

role. E

M evice based on silicon chambers for

B

1982: KurtMaterial" described applications in sensors and actuators. Importdevices were inkjet nozzles, accelerometers, and microrelays. Pointedout 3 major advantages of silicon-based micromachining:

1) provide functions not easily duplicated by conventioand digital circuit.

and reproducibility.

cost, high yield technologies are preferred only if well-established batch fabrication processes areem Masoyoshi Esashi at Tohoku presents work on catheter-tip

pressure sensors. Many packaging techniques [Esashi 1993] are aldeveloped by Esashis group for microvalves and pressure transducers. 1984: Roger Hsensor which initiates the polysilicon surface micromachining eThis transforms into the micromotor and lateral resonators that launched the explosion of MEMS and inspired the imagination omany researchers today.

development of biomedical sensors.

Manz et al. (1990) first proposed the concept of micro total analysis system in which silicon chip analyzers incorporating sample pretreatment, separation, and detection played a fundamental lectroosmotic pumping was an attractive mode of sample transport

when separation was needed iniaturized thermal cycling d

PCR was developed by Northrup et al. and tested HIV, and cystic


fibrosis (1995) -1997 Growing1994 to critical mass - The number of published

otides, DNA and amino acids and cell

Microreactors for PCR

Biochips and Microfluidic companies appear (many sprung out of

Affymetrix, Nanogen, Caliper,

ace

BioMEMS drug delivery companies,

1990-2002 b technologies developed:

machining through wafer

Py PDMS, PMMA,

M s and

M ndard micromachining (surface,

MEMS is truly integrated in academics, as almost every disciplinary

A major industries

papers increased abruptly Separation of oligonucle

manipulations.

academia):

Aclara, Fluidigm, Nanostream, Cepheid, Orchid, Biotrove, SurfLogix, Biospect, Micronics

e.g. iMED,MicroCHIPS, Therafuse

key -fa integration of surface and bulk micro

bonding and deep reactive ion etching (RIE) of silicon. olymer microfabrication is foundation of many microfluidics/biochip companies (soft lithographSU-8 etc.), medical microdevices still use a lot of silicon

onolithic and hybrid integration of MEMS and electronic New materials integrated in silicon based processes for sensing

actuating advances (soft lithography, SMA, PZT, smart polymers, porous silicon, etc.)

EMS foundry processes for stabulk, LIGA, polymers)

are getting involved (EE, ME, ChE, Mat. etc) n explosion of MEMS-based companies; many

start exploring MEMS (medical, automotive, biotech, computer, displays, etc), particularly in the optical switch business


Alternative names

Micro Total Analysis Systems (TAS)

logy

systems

Review Femmans point view and compared to the goal of NIH,

Feynmans view on Bio micro/nano system:

a. The problems of chemistry and biology can be greatly

b.

Scientific American 2001, 3 visions in nanomedicine:

1. Improve image

Lab on a Chip Bionanotechno Nanobiotechnology Biofluidic Chips Bio Microsystems Bioanalytical Micro

USA

helped if our ability to see what we are doing, and to do things on an atomic level, is ultimately developeda development which I think cannot be avoided Swallowable surgeon

: Improved or new contrast agents would detect

. New ways to treat disease

problems at earlier, more treatable stages. e.g., reveal tumors only a few cells in size

2 : nanoparticles would deliver treatment

plants:

to specifically targeted sites, indluding places that standard drugs do not reach easily. e.g., gold nanoshells that were targeted to tumors might, when hit by infrared light, heat up enough to destroy the growths.

3. Superior im nanometer scale modifications of implant ty

surfaces would improve implant durability and biocompatibilie.g., an atrificial hip coated with nanoparticles might bond to the surrounding bone more tightly than usual, thus avoiding loosening.


Scale comparison: (courtesy: A. P. Lee)

ano amino acid

DNA helix hannel opening

the major cytoskeletal components)

nm) lysosomes (contain enzymes for many

(1 - 10 m) the general sizes for prokaryotes cell (before-nucleus:

N0.8 nm2 nm diameter of a 2.6 nm diameter of membrane c

4 nm globular () protein

6 nm microfilaments (smallest of 10 nm thickness cell membranes

11 nm ribosome ()

25 nm microtubule (straight hollow cylinders with an inner diameter 15 nm, most rigid of the cytoskeletal organizers and backbone element) 50 nm nuclear pore 100 nm large virus

200 nm (200 to 500

chemical reactions to break down proteins, nucleic acids, sugars, lipids, and other complex molecules) Micro


contains no culei and no membrane enclosed organelles)

r power plant)

al cells ()

rog egg

Pharmaceutical industry ental monitoring

Tr hnologies:

Lysing

/biomarkers

on

2 m E.coli - a bacterium

d+a grain, : subcellula3 m mitochondrion (threa

5 m length of chloroplast ()

6 m (3 - 10 micron) the nucleus 8 m human red blood cell

(10 - 30 m) most eukaryotic anim

100 m human egg 1 mm diameter of the squid giant nerve cell 2 mm diameter of a f

Potential applications in:

Military

Environm Medical devices Instrumentation Food monitoring

aditional bioassay tec

Centrifuge

Purification Labeling Extraction Amplification Concentrati Sorting Affinity Assays


Components of Micro biomedical/fluidic systems:

cal/biological monitor systems

1. TAS 2. Chemical sensors 3. Chemi4. IT or electronics

Sampling

Sample transportation

Sample collection

Sample treatment

Separation/mixing or chemical reaction

Detection

Data treatment

Interpretation

1

4

3

2


Fully Automatic Systems: sensing(input), decision making (IC), actuating (output)

Example: transdermal micro drug delivery systems

. sample preparation

. sample array

g rying

Treatment Methodology in tradition (nanotech 1)

.

the patients medical history, personal line, and current complaints.

123. sample sensing 4. decision makin5. actuating/delive

Six phases in clinical pratice:

1 Examination ()

Examination offunctional and structural base

Classical: interview and observation. New tools for nanomedical testing:


surveys laboratory-quality data on the patient

nd solutes,

d. e. ding organelle counts)

messenger

Bi roach: single-molecule DNA assay techniques

billions of nanoscale

. Diagn

nation of the cause and nature of a disease in treatment and prognosis.

s,

3. rogn

ect injury, and of

a. in vivo cytography b. real-time whole-body microbioticc. immediate access to

(blood tests: blood counts, dissolved gases avitamin and ion assays) physiological function and challenge tests tissue composition (inclu

f. quantitative flowcharts of in cyto secondarymolecules

g. extracellular hormones and neuropeptides ological app

(recombinant DNA techniques) Nanomedicine approach: lightwight handheld device consists

a ramifying probe tip containingmolecular assay receptors mounted on hundreds of self-guiding retractile stalks.

osis () 2

The determiorder to provide a logical basis for

In 20th century, diagnoses frequently involved a high degree of uncertainty, largely due to lack of comprehensive molecular diagnostic tools. Diagnosis would be guided by statistical analyses-large uncertainty. Nanomedicine can reduce diagnosis uncertainty by the following possible instruments: a. in-office comprehensive genotyping and real-time whole-body scans for particular bacterial coat markers, tumor cell antigens, mineral deposits, suspected toxinhormone imbalances of genetic or lifestyle origin.

osis () and Treatment () P

Prognosis is a judgment or forecast, based upon a corrdiagnosis, of the future course of a disease orthe patients prospects for partial or full recovery. Treatment: the physicians ability to intervene.


ften did

e medical intervention was rational

ble ents.

e

cases of

with a

. Valid

ocedure for eatment was

r are self-curing or

s not

unization programs, amelioration of

res are needed to discover, diagnose,

18th: treatments were almost purely empirical and omore harm than good.

19th and early 20th century: treatments were scientific but largely homeostaticthbut served mainly to assist the body in healing itself. Remaining 20th century: truly curative treatments began to rescue some patients from conditions from which their unaided bodies would not have been able to recover. Early 21st century: Conventional biotechnology will enasome important tissue and cellular replacement treatm

21st century: nanomedicine may enable major reconstructivand restorative procedures at the tissue, cellular and molecular levels and will employ active antibiotic devices.the prognosis will almost be good, except insevere neural damage and a few other specialized circumstgances. Therapeutic treatment will be selected to reverse all pathological effects of disease or injury,minimum of pain, discomfort, side-effects, intrusiveness andtime, and with a maximum of effectiveness, efficiency, andlikelihood of success. It can also correct molecular defects.

ation () and Prophylaxis () 4

A proper therapeutic protocol will include a prfollow up to ensure that the prescribed trcorrectly executed with good results. Often neglected for saving cost because 80-90% of all illnesses which take patients to the doctoself-limiting. (for example, common cold)treatment ito provide a cure, but rather to speed the healing process, improve comfort, and avoid complications. Nanomedical treatments will require supervision and run quickly to completion.

Prophylaxis is the prevention of disease, typically includingpatient education, immoccupational hazards. nano/micro scale tools are required for a. Preventative procedu


ases, and a variety

b.

Micro s e (research examples)

2. Drug screening (microarray)

and treat apparently symptomless diseof molecular-based physiological malfunctions and structural micropathologies. Ongoing supervisions and adjustment (for example:hormone balance)

ystems in life scienc

1. Examination and diagnosis (loc, utas, array)

i-STATs handheld clinical analyzer and

disposable cartridge

Biolsensor cube and

ogixs pH

Porton Diagnostics potassium sensor and reader

reader


3. Drug delivering (LOC, utas)

Micorpump drug delivery system, Debiotech, Sitzerlad

5. In vivo monitorin

4. Sequencing of bio molecules

Streched S-D

SiO Si

DNA PCR

C C D
DNA
g (neuro probe, well, bioe

NA

Optical fiber

Transparent peak

3 4

2

lectri
0 bp/s:100
cal interface)


Optical Spectrum Analyzer (OSA)

IgG

Au

COOH-Thiol

EDC /Sulfo-NHSCy

3 Anti-Rabbi

t

PDMS OpticalFiber R1

R2

I

TNF and receptor (antibody)

Valley shift

SMF

Optical Circula

W toELED / 1550nm / 8uFWHM :150nm

Current Controller

SMF

Sensing Fiber

Electrochemcial sensor/electrodes for stimulation

Integrated needle/fiber

immunosensors/drug delivery system

Fiber bundle 1 m

Drug delivery system

m rInput

Ot

utpu

1 2 3 Output Bare Fiberconnecto

r

Input

Nanomedical Perspetive (nanotech 1)

BioMEMS or Nanomedical instrumentalities should not

significantly alter the classical medical treatment methodology, although the patient experiences and outcomes will be greatly improved.

Treatment will become faster and more accurate, efficient, and effective.

1. Nanomedicine and Molecular Nanotechnology

A mature nanomedicine will require the ability to build structures and devices to atomic precision, hence molecular nanotechnology and molecular


manufacturing are key enabling technologies for nanomedicine.

Top-dow vs. bottom-up approach:

Top-down: 1960s-1970s, increasing precise machining and of materials, progressing from large

to smaller scales and ultimate to nanoscale tolerances.Richard Feynman.

ttom 0s-1990s, molecular manipulation and

ild o achines and molecular devices ecision.---K. E. D (settling the term of molecular

n approach

finishing

r

Bo -up: 198molecular engineering in the context of bu ing m

with atomic prlecular m

rexler.nanotechnology in 1991, molecular machine systems in 1992)

Note: this approach is differe from nanostructured bulk materials,

romachinery, polymeric self-assemblnology, nanolithography,

Langmuir-Blodgett thin films Definition of Molecular nanotechnology

nt

micp

y, ure biotech

by Drexler: The control of atomic and

molecular structure to create materials and devices with

three-dimensional positional

molecular precision. Vision of Molecular nanotechnology by Drexler: ---require molecular assembler (10-15 years from nonanomedicine may emerge by 2020.

w),

chines: ral immune system, cell herding

machines:stimulate rapid healing and tissue reconstruction, cell repair machines: genetic surgery.

. Paths to nanomedicine:

BioloUsin g tools to build

Possible applications: programmable immune masupplementing the natu

2

gical approach: the wet process g biological engineering/genetic engineerin up micro/nano biorobots: such as


At m cui. Determining or designing the DNA sequence for the genome. ii. Syniii. Introducing the

host cell, then in

At Celiv. Design enzyme

ole lar level (Glen A. Evans, 1998):

thesizing and assembling the genome synthetic DNA into an enucleated pluri-potent

troducing the host cell into an organism.

l levels (by Nonaldson, 1976): s to produces specific repair functions: tured proteins, joining broken lipoprotein aling broken strands of DNA or RNA, rng or special types onto RNA and replica cell the ability to metabolize new substrates, rs, or construct ess

renaturing denacomplexes, anne eading proteins of existi ting them, and givinguse novel cofacto ential amino acids.

v. Spe ially constrc ucted bacteria or microphages able to ead through a specific target tissirs according to the programs designed intoOperate at unnatural temperatures o pathways not present found in na

replicate themselves, dspr ue, and carry out specific repa their DNA/RNA r to utilize metabolic ture.

vi. Re-introduce lost DNA or lost organelles, or introduce entire new

vii. Modi forms of organelles.

fy at will the development of a cell. ir bacteriaviii. Repa able to work together to apply optimal to every body cell. repairs

At whole o

i. Undrganism levels(by Nonaldson, 1976): erstanding the physiology of aging combined with the

ii. Conorg

iii. Nokeep a given tissue alive and healthy in vitro for an

mporary replacements for any body organ which may have been lost.

=> w

Mechanical approach: the dry process

ability to reverse it. trol over growth and development: grow of new ans/tissues npermanent substitute organs for (a) the ability to

indefinite time (b) te

hole body repair


mic precision.

1959, Richard Feynman: It does not violate any physics

ne

sensors, programs,

nents of individual cells.

Nanotechnology

T ranches of nanotechnology for

Artificially fabricate nanodevice with ato

i. Is it possible? 1952, Erwin Schrodinger:we would never experiment with just one electron, atom, or molecule

laws. ii. Feynmans view on nanomedicine:

a. The principles of physics, as far as I can see, donot speak against the possible of maneuvering things atom by atom. It is not an attempt to violate any laws; it is something, in principle, that can be done; but practice, it has not been dobecause we are too big.

b. top-down processleading to todays Micro Systemtechnology, and nanotechnology

c. Swallowable surgeon

iii. Drexlers vision: a. bottom-up process b. cell-repair machines: combines

and molecular tools to examine and repair the ultimate compo

3. Comparison of Biotechnology and Molecular

hree contemporary bbiomedical application:

Nanoscale materials technology: biocompatible materials aalytical techniques, surgical and dental practice, nesearch using intracellular electrodes, biostructures search and biomolecular research

nd an rve cell rere using intracellular electrodes, biostructures research and biomolecular research

tical microscopy, scanning-probe microscopy and optical tweezers, and vaccine design, bulk

and classical

using near-field op

chemical and biochemical manufacturing,pharmacology.


Biotechnology: an established medical capability, many applic Molec

ations and products in the market.

ular nanotechnology: The engineering of all complex mechanical systems constructed from the molecular level.

Advantages of molecular nanotechnology: i. speed of medical treatment


e nical therapeutic

systems can be expected 103-105 faster.

sec, but mechanical nanomanipulators can operat4e at 1-10 cm/sec, a 4-5 higher orders of magnitude. Strongest biological fibers (e.g. intermediate filaments) have a failure strength 3 orders of magnitude below the strongest mechanical fibers (fullerene nanotubes)

systems may employ simple cable-pulling, winches(), or ratchets (), much faster and direct. Muscle contraction is irreversible and can not generate power, but electric motor can be power generator, loudspeakers can be used as microphones.

.

e strengths

Dermal wound repair via natural fibroblasts may requirweeks to run to completion, but mecha

Because of: Typical fibroblasts movements occur at 0.1-1 microns/

Biological cilia beat at ~30 Hz while mechanical nanocilia may cycle up to ~20 MHz, (but in pratical~10 kHz.)

In either biological or mechanical systems, large numbers of devices of comparable physical size (e.g. ~microns) may be employed to do the work, so numbers alone cannot offset the mechanical speed advantage.

ii. power density and transduction

Biological cell typically employ power densities of 103-104 W/m3, with maximum densities of ~106 W/m3 in honeybee flight muscle cells and bacterial flagellar motors. Nanomechanical power systems can produce power densities of 109-1012 W/m3.

Conducting polymer-based actuators generated 20-100 times the force for a given cross-sectional area as mammalian skeletal muscle.

Amoebic locomotion in motile cells requires diffusion-limited cytoskeletal disassembly and reassembly to achieve movement, mechanical motility

iii superior building materials Typical biological materials have tensile failur

in the 106-107 N/m2 range, compare to 109 of steel, 1011 for


iv. Nondegradation of treatment agents v. C trvi. Nanovii. Avoviii.ix. Morx. Morexi. R uxii. Assu

4 Examples 1. DNA nanopore technology: Coll ies and Harvard University nanopor eqelectronic sigindividual, c eds and for a low

diamond.

on ol of nanomecial treatment device versatility

iding overspecialization Faster and More Precise diagnosis

e Sensitive Response threshold for high-speed action reliable operation

ed ced replicator danger red patentability

for bionanotechnology

aboration between Agilent Technologe s uencing converts nucleic-acid sequences directly into

natures and could make it possible to easily sequence hromosome-length molecules of DNA at very high spe cost

2. Quantum

dots:


Latex beads filled with quantum dots, Scientific America, Sep. 2001

ons,

on with organic dye and bulk semiconductors:

excitation emission

Organic dye: single single Bulk semi. : multiple single (band gap) Quantum dot: multiple single (size)

=>a single type of semiconducting material can yield an entire family of distinctly colored labels

signal would not decay after multiple excitation

. color can be custom-built, almost no limitation on color types and numbers.

. Exited color is very uniform.

A. Paul Alivisatos, a. Developed since 1970, originally for optoelectronics applicati

but now with high potential for disease diagnosis and drug screening.

b. The comparis

c. d

e


3. Nano drug delivery system

Mauro Ferrari, Mechanical Engineering, Dec. 2001

remarks

integrated circuits cessors are ubiquitous stics to environmental

chronic

olecular processors requires training of a new

generation work force

atures: Journals:

romechanical Systems, IEEE/ASME joint publication (ISSN 1057-7157), quarterly from March 1992. JMM: Journal of Micromechanics and Microengineering, American Institute of Physics (ISSN 0960-1317), quarterly from March 1991.

rs A and B, Elsevier Sequoia (ISSN

Conclusion

1. Integrated microfluidics has the potential to rival

2. Applications for biomolecular proranging from point-of-care diagnosensing, from acute (combat casualty care) to (early detection of cancer)

3. Design tools are necessary to predict complex behavior and allow biologists to become chip designers

4. The development of biomthe multidisciplinary (Bio:Info:Nano)

Related liter

JMEMS: Journal of Microelect

S&A: Sensors and Actuato


0924-4274), 5 Vol. Per year, 3 issues per volume.

, Japan

,

ConferMEMS##: IEEE Micro Electro Mechanical Systems 1987 and annual form 1989, held in February (Abstract due in Sep.)

E winter annual meeting Annual (MEMS symposium from 1990), in Nov/Dec (Abstract due in Feb.) Trans e actuators (T ial from 1981, in June (Abstract due in Dec.) HH##: IEEin June (AbSPIE##: In ngineering, conference for MEM EURO senActua #Harmst'##Nanotech#IEEEnano##:

Referen 1. Robe , Landes

Bios2. Micr McGraw Hill,

19983. Greg 9.

LOC:Lab on a Chip, Royal Society of Chemistry S&M: Sensors and Materials, Scientific Publishing Division of MY(ISSN 0914-4935). 6 issues per volume. B&B: Biosensors and Bioelectronics, Elsevier Science (ISSN 0956-5663), 12 issues per year from 1986 BM: Biomedical Microdevices-BioMEMS and Biomedical NanotechnologyKluwer Academic Publishers (ISSN: 1387-2176), 2 issues per year from1999. MST: Micro system Technology, Germany. Nanotechnolgy, Institute of Physics IEEE Transactions On NanoBioscience, IEEE.

ences:

ASME IMECE: ASM

duc rs##: International Conference on Solid-State Sensors andransducers xx) bienn

E Solid-State Sensor and Actuator Workshop, biennial from 1984, stract due in Jan.) ternational Society for Optical E

S or Optical MEMS, annual sor

tor' #, Europe conference , follow transducer #:

ces:

rt A. Freitas Jr., Nanomedicine volume I: Basic Capabilitiescience, USA, 1999. omachined Transducers source book, Gregory T.A. Kovacs,. ory Timp edited, Nanotechnology, AIP press, 199

NTHU ESS5845 Nano/micro Biomecidal and Fluidic System F. G. Tseng Spring/2004, lec 1, p25 4. Davi re, Wiley-Liss, 2004. 5. A. P.6. Fan-

d S. Godsell, Bionanotechnology, lessons from natu Lee, class notes of UCI BME295. Gang Tseng, research proposals.

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micro scale: ~µm-~mm nano scale: ~nm-~µm …fangang/new_web_2002/l4/... · y biomems drug...

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