Applied BioMEMS to Clinical Medicine · Alain Rochefortt, CERCA Steven S. Saliterman 3-D Assembly Steven S. Saliterman Assembling Layers Photolithographic techniques. Microstereolithography,

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Introduction to BioMEMS & Medical Microdevices

Applied BioMEMS to Clinical MedicineCompanion lecture to the textbook: Fundamentals of BioMEMS and Medical Microdevices, by Prof. Steven S. Saliterman, http://saliterman.umn.edu/

Steven S. Saliterman

Individualized Therapy

Song, P. et al. Moving towards individualized medicine with microfluidics technology. RSC Adv., 2014, 4, 11499


Cardiovascular

Heart Failure Management Pressure Sensors

Medtronic Chronicle for RV pressure. St. Jude Medical Heart POD for LA pressure. CardioMEMS EndoSure, a capacitive sensor for

wireless aortic pressure monitoring, PA pressure. Campus Micro Technologies sensor for aortic pressure

and IC pressure. Endotronix MEMS sensor for CHF monitoring. Boston Scientifics ImPressure, a piezoelectric based

sensor for aortic pressure and PA pressure monitoring.Kim, S. and S. Roy. Microelectromechanical systems and nephrology: The next frontier in renal replacement technology. Advances in Chronic Kidney Disease, Vol 20, No 6 (November), 2013: pp 516-535

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(A) CardioMEMS sensor. (B) Transcatheter is implanted into a distal branch

of the descending pulmonary artery.

Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery hemodynamic monitoring in chronic heart failure: a randomized controlled trial. Lancet. 2011.


CardioMEMS wireless pressure sensor.

Park, ES et al. Packaging for BIOMEMS and microfluidic chips. C.P. Wong et al. (eds.), Nano-Bio- Electronic, Photonic and MEMS Packaging. Springer Science+Business Media


Remon ImPressure pressure monitoring system showing the pulmonary artery implant.

Photo courtesy of Boston Scientific Corporation

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(A) Endotronix MEMS sensor(B) Biocompatible housing shown in green.

Photo courtesy of Endotronix, Inc.


Other Cardiovascular Opportunities

Arrhythmia monitoring and therapy. Artificial valves, pumps and other actuators. Auto regulated drug delivery systems for

chronic, preemptive and emergency treatment of conditions.

Coronary artery evaluation and treatment, including novel catheters and drug-eluting stents.

Left ventricular assist devices (LVADS) Novel power and telemetry systems for data and

control. Stem-cell hybrid systems


Neurologic

Intracranial Pressure(ICP) Traditionally intraparenchymal or intraventricular

readings for post traumatic brain injuries, hydrocephalus and idiopathic intracranial hypertension. Integra Life Science Caminco ICP sensor using a fiber

optic transducer. Johnson & Johnson Codman microsensor. Raumedic AG Neurovent P-tel piezoresistive sensor

with wireless telemetry.

Kim, S. and S. Roy. Microelectromechanical systems and nephrology: The next frontier in renal replacement technology. Advances in Chronic Kidney Disease, Vol 20, No 6 (November), 2013: pp 516-535

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(A) Neurovent P-tel implantable piezoresistive ICP monitoring sensor.

(B) Telemetric reader is placed over intact skin and collects intracranial pressure readings.

Photo courtesy of Raumedic, Inc


Ophthalmology

Intraocular Pressure Sensors Sensimed Triggerfish continuous IP with a soft

silicone contact lenses with an embedded microfabricated platinum titanium strain gauge.

Photo courtesy of Sensimed AG


Point-of-Care and Lab-on-a-Chip

iSTAT cartridge and handheld system. Courtesy of Abbot Laboratories.

Kim, S. and S. Roy. Microelectromechanical systems and nephrology: The next frontier in renal replacement technology. Advances in Chronic Kidney Disease, Vol 20, No 6 (November), 2013: pp 516-535

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Chemiluminescence

Integrated opto-microfluidic sensor with a hydrogenated amorphous silicon (a-Si:H) photodetector prepared onto a glass substrate covered by a transparent conductive oxide (TCO) film.

Caputo, D.; de Cesare, G.; Dolci, L.S.; Mirasoli, M.; Nascetti, A.; Roda, A.; Scipinotti, R. Microfluidic chip with integrated a-Si:H photodiodes for chemiluminescence-based bioassays. IEEE Sens. J. 2013, 13, 2595–2602.


Summary of Optical Detection Methods

Pires, NM, et al. Recent Developments in Optical Detection Technologies in Lab-on-a-Chip Devices for Biosensing Applications. Sensors 2014, 14, 15458-15479


52. Xiang, A.; Wei, F.; Lei, X.; Liu, Y.; Liu, Y.; Guo, Y. A simple and rapid capillary chemiluminescence immunoassay for quantitatively detecting human serum HBsAg. Eur. J. Clin. Microbiol. Infect. Dis. 2013, 32, 1557–1564.

53. Hao, M.; Ma, Z. An ultrasensitive chemiluminescence biosensor for carcinoembryonic antigen based on autocatalytic enlargement of immunogold nanoprobes. Sensors 2012, 12, 17320–17329.

54. Yang, M.; Sun, S.; Kostov, Y.; Rasooly, A. An automated point-of-care system for immunodetection of staphylococcal enterotoxin B. Anal. Biochem. 2011, 416, 74–81.

55. Caputo, D.; de Cesare, G.; Dolci, L.S.; Mirasoli, M.; Nascetti, A.; Roda, A.; Scipinotti, R. Microfluidic chip with integrated a-Si:H photodiodes for chemiluminescence-based bioassays. IEEE Sens. J. 2013, 13, 2595–2602.

56. Lin, C.C.; Ko, F.H.; Chen, C.C.; Yang, Y.S.; Chang, F.C.; Wu, C.S. Miniaturized metal semiconductor metal photocurrent system for biomolecular sensing via chemiluminescence. Electrophoresis 2009, 30, 3189–3197.

57. Wojciechowski, J.R.; Shriver-Lake, L.C.; Yamaguchi, M.Y.; Füreder, E.; Pieler, R.; Schamesberger, M.; Winder, C.; Prall, H.J.; Sonnleitner, M.; Ligler, F.S. Organic photodiodes for biosensor miniaturization. Anal. Chem. 2009, 81, 3455–3461.

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Fluorescence

Shen, L.; Ratterman, M.; Klotzkin, D.; Papautsky, I. A CMOS optical detection system for point-of-use luminescent oxygen sensing. Sens. Actuators B Chem. 2011, 155, 430–435.

Conceptual design of a fluorescence based detection device showing a lightsource (LED), photodetector (CMOS), polarizers and O2 sensitive PtOEP film arranged in a portable O2 sensing system.


Optical-Microfluidic Detection



41. Lee, L.M.; Cui, X.; Yang, C. The application of on-chip optofluidic microscopy for imaging Giardia lamblia trophozoites and cysts. Biomed. Microdevices 2009, 11, 951–958.

49. Ramalingam, N.; Rui, Z.; Liu, H.B.; Dai, C.C.; Kaushik, R.; Ratnaharika, B.M; Gong, H.Q. Real-time PCR-based microfluidic array chip for simultaneous detection of multiple waterborne pathogens. Sens. Actuators B Chem. 2010, 145, 543–552.

50. Yildirim, N.; Long, F.; Gao, C.; He, M.; Shi, H.C.; Gu, A.Z. Aptamer-based optical biosensor for rapid and sensitive detection of 17β-estradiol in water samples. Environ. Sci. Technol. 2012, 46, 3288–3294.

51. Ishimatsu, R.; Naruse, A.; Liu, R.; Nakano, K.; Yahiro, M.; Adachi, C.; Imato, T. An organic thin film photodiode as a portable photodetector for the detection of alkylphenol polyethoxylates by a flow fluorescence-immunoassay on magnetic microbeads in a microchannel. Talanta 2013, 117, 139–145.

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Microfluidic SPR Biosensor

The configuration encompasses a light source, a prism and a detector, all coupled to a metal-coated sensor microfluidic chip. Surface plasmon resonance (SPR) detection involves variation in the refractive index in the immediate vicinity of the metal layer of the sensor chip.

Cooper, M.A. Optical biosensors in drug discovery. Nat. Rev. Drug Discov. 2002, 1, 515–528.


Optical-Microfluidic Detection



58. Vykoukal, D.M.; Stone, G.P.; Gascoyne, P.R.C.; Alt, E.U.; Vykoukal, J. Quantitative detection of bioassays with a low-cost image-sensor array for integrated microsystems. Angew. Chem. Int. Ed. 2009, 121, 7785–7790.

59. Wang, S.; Zhao, X.; Khimji, I.; Akbas, R.; Qiu, W.; Edwards, D.; Cramer, D.W.; Ye, B.; Demirci, U. Integration of cell phone imaging with microchip ELISA to detect ovarian cancer HE4 biomarker in urine at the point-of-care. Lab Chip 2011, 11, 3411–3418.

60. Jokerst, J.C.; Adkins, J.A.; Bisha, B.; Mentele, M.M.; Goodridge, L.D.; Henry, C.S. Development of a paper-based analytical device for colorimetric detection of select foodborne pathogens. Anal. Chem. 2012, 84, 2900–2907.

61. Krupin, O.; Asiri, H.; Wang, C.; Tait, R.N.; Berini, P. Biosensing using straight long-range surface plasmon waveguides. Opt. Express 2013, 21, 698–709.

62. Ouellet, E.; Lausted, C.; Lin, T.; Yang, C.W.T.; Hood, L.; Lagally, E.T. Parallel microfluidic surface plasmon resonance imaging arrays. Lab Chip 2010, 10, 581–588.

63. Foudeh, A.M.; Daoud, J.T.; Faucher, S.P.; Veres, T.; Tabrizian, M. Sub-femtomole detection of 16s rDNA from Legionella pneumophila using surface plasmon resonance imaging. Biosens. Bioelectron. 2014, 52, 129–135.

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Survey: Role of “Lab-on-a-Chip”

Hoffman, W. et al. Opportunities and risks of diagnostic lab-on-a-chip systems in healthcare from a health systems stakeholder’s perspective. Personalized Medicine (2014) 11(3), 273–283.

Interviews with 30 experts in the field of personalized medicine were conducted, addressing the requirements, potentials and risks of LOCs.


“Need” Continued



“Potential”


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Synthetic Heart

Abiomed’s AbioCor


BioMEMS to BioNEMS Evolution

Thick-films

Lab-on-a-Chip

Micro-bioreactors

Metallic Conductors

MEMS Actuators

Micromachining

Hybrid Integration

Thin-films

Lab-in-a-Membrane

Surface Bioreactions

Organic Conductors

Electroactive Polymers

Self-Assembly

Layer-by-Layer Assembly


Classification of Artificial Organs

Class I – Replacement of natural tissues and organs.

Class II – Support for regeneration of natural tissues and organs.

Class III – Bridge to regeneration of natural tissues and organs.

Class IV – For acceleration of the regeneration of natural tissues and organs.

Class V – Hybrids with natural tissues and cells.

Nose Y., Okubo H., 2003

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Artificial Heart

Artifical heart recipient Dr. Barney Clark and the Jarvik-7, 1983

J. Willard Marriott Library and Texas Heart Institute.


Current Generation

Abiomed’s AbioCor Replacement Heart Normal Heart Anatomy


“High-Tech” or “Stone-Age”

2001 A Space Odyssey. Image Courtesy of Metro-Goldwyn-Mayer

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Large-Scale BioMEMS Integration

Macro-functioning systems by multiplication of millions of micro-sized units.

New Materials. Environmentally Sensitive “Smart” Polymers

e.g. Hydrogels

Electroactive Polymers Artificial Muscles

Structural Polymers Functional unit enclosure

Tendons and ligaments

Artificial valves

Carbon nanotubules for charge conduction.

Novel power systems. Fuel Cells


Synthetic Heart

Dartmouth Medical School

Sternum

Right ventricle

Interventricular septum

Right atrium

Left ventricle

Mitral valve

Left atrium

Right pulmonary vein

Descending aorta


2-D Layer-by-Layer Fabrication

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Main & Branch Charge Carriers

Carbon nanotube with metal-semiconductor junction .

Structure of a multi-walled nanotube.

Alain Rochefortt, CERCA


3-D Assembly


Assembling Layers

Photolithographic techniques. Microstereolithography, photodeprotection, micromachining.

“Soft” fabrication techniques Molding, “ink jet” printing, other droplet dispersion techniques.

Surface modification Plasma treatments, coatings, hydrophobicity, hydrophilicy.

Self-assembled monolayers. Covalent, noncovalent and ionic bonding and van der Walls

forces. Monolithic integration

Combining MEMS, bioMEMS, electronics, and other components onto a single substrate.

Integration by packaging. Conduits, stacking, dual-inline discrete components.

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Design Components

Artificial Heart – Polymer Based

Embedded Controller

Software

Power Source

Data Telemetry

Sensors

Alarms


Summary

Individualized Therapy

Systems Cardiovascular

Neurologic

Ophthalmologic

Point of Care and Lab-on-a-Chip

Synthetic Heart

Documents

Applied BioMEMS to Clinical Medicine · Alain Rochefortt, CERCA Steven S. Saliterman 3-D Assembly Steven S. Saliterman Assembling Layers Photolithographic techniques. Microstereolithography,