Miroelectronics and MEMS based Medical Technologies in Russia · Miroelectronics and MEMS based Medical ... Implications (NBR Project Report, ... Matrix chips (gene chips, biochips)

Miroelectronics and MEMS based Medical

Technologies in Russia Тatiana М. Zimina, Ph.D., head research fellow

St. Petersburg State Electrotechnical University “LETI”

May 14 – 15 Miscow, Russia

40,0

45,0

50,0

55,0

60,0

65,0

70,0

75,0

80,0

85,0

90,0

40,0 50,0 60,0 70,0 80,0 90,0

Men, years

Wom

en, y

ears

Life expectancy at birth of population: 195 countries/2004–2008 гг.

(statistics department of UN)

http://unstats.un.org/unsd/demographic/products/dyb/dyb2008.htm

May 14 – 15 Moscow, Russia

http://unstats.un.org/unsd/demographic/products/dyb/dyb2008.htm

Main causes of mortality (statistics department of WHO)


Cardio-vascular Cancer Infectionus diseases Injuries

http://www.who.int/whr/en/index.html

http://www.who.int/whr/en/index.html


(Nicholas Eberstadt, Russia’s Peacetime Demographic Crisis: Dimensions, Causes, Implications (NBR Project Report, May 2010)

«Correction of the demographic situation will demand political and economical measures as well as reasonable improvements in health care».

http://www.nbr.org/publications/element.aspx?id=446




What technologies of microelectronics could offer,

to contribute into these reasonable measures for healthcare improvement?

A new concept and stepwise increase in performance

N – effective resolution parameter

0,001

0,1

10

1000

100000

10000000

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

Год

lg(N/

t). тт

/мм.

с


Class Technology Matrix chips (gene chips, biochips) [Fodor; Mirzabeckov, 1986]

1. Topologically coded synthesisof chaine molecules (probes, ligands) using multistep photolithography, micropositioning. 2. Photoinitiation of reactions. 3. Molecular biorecogbition. 4. Videoregistration of the data, computer image recognition.

Capillary microchips (including hybrid systems with functional elements, i. e. PCR reactors, chemical reactors) [A. Manz, 1990]

1. Capillary transport. 2. Microfluidics. 3. Micromechanics. 4. Optoelectronics. 5. Sensorics 6. ….

Основные классы микроаналитических систем May 14 – 15 Moscow, Russia

Directions of technological progress

Matrix systems - GeneChip Stephen P.A. Fodor, PhD, CEO of Affymetrix In 1989, he joined the Affymax Research Institute in Palo Alto, where he spearheaded the effort to develop high-density arrays of biological compounds. Dr. Fodor and his colleagues were the first to develop and describe microarray technologies and combinatorial chemistry synthesis.


Technology and operation Основные классы микроаналитических систем May 14 – 15

Moscow, Russia

Biochips Acad. Andrei Mirzabekov In late 1980-ties launched a new scientific field – technology of micromatrics-sensors or biochips [Лысов, Ю., Флорентьев В., Хорлин, A., Храпко, K., Шик, В., Мирзабеков, A. Определение нуклеотидной последовательности ДНК гибридизацией с олигонуклеотидами. Новый метод. (1988) Докл. Aкад. Наук СССР, 303, 1508-1511].


Detection principle Основные классы микроаналитических систем May 14 – 15

Moscow, Russia

Application example: diagnostics of resistant forms of tuberculosis

Обычная форма туберкулеза Лекарственно-устойчивая форма туберкулеза

Маркер микобактерий


Microfluidic chips Prof. Andreas Manz laboratories-on-a-chip, 1990


Manufacturer Technology Parameters

3M™,Inc.USA Integtrated micro-thermocycler 31x21x31 сm, 8 kg, 96 wells on a disk, 10 µl, 30-75 min, Cost: 75000 /50 USD - instrument/assay

Abaxis, Inc.USA Disc with capillaries and volumes. Microfluidics, spectrophotometry

15х20х33 см, 6 kg, 26 samples, 12 min, 100 µl of blood, 2400/20 USD: instrument/assay

STM, Mobidiag, EU

In-Check, lab-on-a-chip technology, micro PCR, gene-library

AST on the basis of DNA analysis. 30’–1 hour.

i-STAT® 1 Critical Blood Analyzer, Inc. USA

Biosensor technology, electrochemical registration, microfluidics

10 µl of blood: gases, biochemistry, coagulability, cardiomarckers, 1 – 5 min, 10 µl, 4–20 USD/cartridge.

LabNow, Inc. USA PETF nucleopore membranes, immunofluorescent analysis, image recognition, microfluidics.

Express diagnostics of HIV/AIDS by CD3/CD4/CD8. 10 ml of blood, 10 min.


Industrial realization – 20 years past

Now: main applications of POCT with laboratories on a chip include: express testing determination of blood gases (O2, N2, CO2) infections identification (particularly in remote cites) medical examination decentralized clinical tests military medicine


Main problems of biomedical analysis

1.Express identification of pathogenic microorganisms;

2.Antibiotic succeptibility testing, selection of correct antibacterial therapy;

3.Express-identification of viruses; 4.Express- biochemical and genetic analysis; 5.Telemedicine.


Actual tasks (pp. 1, 2): • Implementation of a new method for

automated total express-microbiological analysis;

• Development of decentralized portable means of express-diagnostics of infections.


According to Rospotrebnadzor, the number of registered cases of infections (incl. acute resp.

inf.) per year in Russia: 30 000 000


A new goal in microbiological analysis based on ME technology

of anodic oxidation :

Analysis time reduction – 1/10 Decentralization of analysis – POCT format. Total automaiton to start with sample load and to complete with result reading. Total analysis time 6 hours.


Miniaturization: Micro-Petri dish (US2005/255445A1).

A.SEM of AAO, d pore 200 nm; B.Matrix of microcompartments for cell

growth: 20 х 20 microns; C.SEM of microcompartments 7 х 7

microns, PMMA on AAO; D.Culture of L. plantarum, labled with

Syto9.


(a) Basic specification of reader; (b) Basic specification of disposable lab-on-a-chip. 1 – power supply, 2 – control module, 3 – modules of wireless communication, memory, 4 – computer, 5 – monitor, 6 – sample

reservoir, 7 – incubator, 8 – sensors, 9 – CMOS sensor, 10 – port for lab-on-a-chip, 11 – containers for reagents and waste, 12 – semiconductor light sources, 13 - micropump, 14 – inlet sample resevoir, 15 – module of sample pre-treatment, 16 – base, 17 – growth platform, 18 – optical window for lensless monitoring by CMOS, 19 – optical window with lens, 20 – optical window with filter, 21- electrodes for impedance measurement, 22 – channel for colobies transport, 23 – electrodes for cells viability testing,

24 – matrix of wells for AST, 25 – waste container, 26 – safe waste.

Portable device for microbiological analysis

(a) (b)


Colonies growth on the porous AAO substrate

2 h


PAA growth platform elements


Array of growth sites (20 um) with nanoporous PAA bed


PAA growth growth sites for bacteria


Nanoporous PAA cross-section


Nutrient

Air

1 2

4

3

5

6

1 – AAO, 2 – pore, 3 – matrix with nutrient, 4 – cell, 5 – jet, 6 – nanoporous AAO plate


Amplification of cell biomaterial

Juvenile colony of S. aureus after 2 h growth time, intensity along intersection line, autocorrelation function

Image analysis program screenshot:


Bacteria viability testing in slurry

1 – speckle, 2 – informative speckle set, 3 – MEMS collimator, 4 – coherent light beam, 5 – windoew, 6 – cell slurry, 7 – fluctuating beam.

Speckle intensity fluctuations

In chip

In cilindrical cell







DNA method (“In-Check”, STM/Mobidiag - 2008)

Restricted number of species. Result on AST: “yes”/”no” by coincidence with library data (indirect) Analysis time : 2 hours


PCR analysis in Russia

БП чипа

БП насоса

Насос

Программа «Реактор»

Программа «Мульти-

хром»

ПЦР чип

Функциональная схема

нагреватель датчик

контактные площадки


Profiles of sorting channel: SU-8 2035 on Si







Spectral analysis of bioclasters Решетка

ФЭУ

Круг Роуланда

Triptophane


Микрочиповые платформы для флюоресцентного анализа

1 – нанолунка, 2 –линза,

плоские окна

система линз


SAW actuation and sensing

6

1,2 – load and sygnal, 3 – interdigitated transducers (IDT), 4 – direction of drift, 5 – Li niobate, 6 – liquid drop, FITC 10-5 M/NAOH. f = 30 MHz


Microtitration 2N

2I1

R1

R2

R3

E1

E2

I0

I1

I1

I

II

R5

R4

R6 R

7

2I1 4I1

4I1

R8

8I1

IV I

II

48

RlpQ

νπ∆=


3 2

1

1 – Li niobate, 2 – interdigitated transducers (IDT), 3 – liquid drop, FITC 10-5 M/NAOH. f = 30 MHz

Accoustic mixer

t = 0 с 1 с 2 с


Оптическая схема и вид ДЭЛС

1 – подложка микрочипа, 2 – сечение капилляра, 3 – лазер, 4 – светоделительная пластинка, 5 – линза, 6 – опорный луч, 7 – фотодиод с предусилителем, 8 –

электрод


1 – E = 0; 2 – E = 1000 В см-1;

Фурье-спектр корреляционной функции электрофоретического Доплеровского светорассеяния нормальной сыворотки крови человека (а). Максимальное

смещение частоты 1500 Гц.

Диагностический экспресс-анализ фракций крови


Measurement scheme

1 – лазер, 2 – диафрагма, 3 – линза, 4 – пучок излучения, 5 – измерительный капилляр, 6 – ФПУ, 7

– сенсор, 8 – АЦП, 9 - ПК


Sample of near-field spleckle optics analyzer

1 – лазер, 2,3 – диафрагма и линза, 5 – капилляр, 7 – сенсор, 13 – чип, 14 – база, 15 – рельеф, 16 – крышка, 17 – отверстия вход/выход, 18 - капилляр


Экстракт биопробы

Водно-солевой Раствор, pH 6-14 Слив

Фотометр λ = 280 нм

Реагент (коричный альдегид)

Флюориметр Реактор

Analysis of biomarkers May 14 – 15 Moscow, Russia






Polyclinic

GP

Conference of doctors Ambulance Accidents Risqué service

Nursing home

Confidential data base

Smart clothes ─ monitoring of body parameters

Home

Мedical telephone inquiry center

Server

School nurse

Farm

remote vet. station

POCT

POCT POCT

POCT

POCT POCT

Application Service Provider (ASP)

POCT

Conclusions: May 14 – 15 Moscow, Russia

• Development and bringing to market miniature analytical devices is actual and in demand because: • Accelerate biomedical analysis • Makes it mobile and accessible • Help to operatively make correct decisions

• Implementation of miniature analytical devices will demand a heterogeneous integration of physical backgrownd, technologies, materials, life organisms and MEMS structures.


Miroelectronics and MEMS based Medical Technologies in Russia · Miroelectronics and MEMS based Medical ... Implications (NBR Project Report, ... Matrix chips (gene chips, biochips)

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