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
Main causes of mortality (statistics department of WHO)
May 14 – 15 Moscow, Russia
Cardio-vascular Cancer Infectionus diseases Injuries
http://www.who.int/whr/en/index.html
May 14 – 15 Moscow, Russia
(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».
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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.
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].
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
Основные классы микроаналитических систем May 14 – 15 Moscow, Russia
Microfluidic chips Prof. Andreas Manz laboratories-on-a-chip, 1990
Основные классы микроаналитических систем May 14 – 15 Moscow, Russia
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.
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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.
Основные классы микроаналитических систем May 14 – 15 Moscow, Russia
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.
May 14 – 15 Moscow, Russia
According to Rospotrebnadzor, the number of registered cases of infections (incl. acute resp.
inf.) per year in Russia: 30 000 000
May 14 – 15 Moscow, Russia
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.
May 14 – 15 Moscow, Russia
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.
May 14 – 15 Moscow, Russia
(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)
May 14 – 15 Moscow, Russia
Nutrient
Air
1 2
4
3
5
6
1 – AAO, 2 – pore, 3 – matrix with nutrient, 4 – cell, 5 – jet, 6 – nanoporous AAO plate
May 14 – 15 Moscow, Russia
Amplification of cell biomaterial
Juvenile colony of S. aureus after 2 h growth time, intensity along intersection line, autocorrelation function
Image analysis program screenshot:
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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.
Основные классы микроаналитических систем May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
PCR analysis in Russia
БП чипа
БП насоса
Насос
Программа «Реактор»
Программа «Мульти-
хром»
ПЦР чип
Функциональная схема
нагреватель датчик
контактные площадки
May 14 – 15 Moscow, Russia
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.
Основные классы микроаналитических систем May 14 – 15 Moscow, Russia
Микрочиповые платформы для флюоресцентного анализа
1 – нанолунка, 2 –линза,
плоские окна
система линз
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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∆=
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
Measurement scheme
1 – лазер, 2 – диафрагма, 3 – линза, 4 – пучок излучения, 5 – измерительный капилляр, 6 – ФПУ, 7
– сенсор, 8 – АЦП, 9 - ПК
May 14 – 15 Moscow, Russia
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
May 14 – 15 Moscow, Russia
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
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.
Основные классы микроаналитических систем 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.