Microfluidics & The Field of Bioengineering

What is Bioengineering? Engineering emphasizes applications in science Engineering focuses on the design of more efficient, cost effective, new, and better tools and processes

Bioengineering Bioengineering combines life sciences with engineering design to produce new, more efficient devices for use in many areas Diagnostic tests for disease (microchips) Environmental monitoring (biosensors) Medical devices/machinery (prosthetics) Military applications (sensors in fabric to monitor soldiers, improved camouflage) Biomimetrics (applying biology concepts to artificial systems)

Microfluidics: Computer Revolution Analogy How did this happen? Semiconductor Microelectronics: Shrinking transistors, higher densities Electrons behave the same on the microscale as they do in big wires. Transistor: Electron Routing Despite decades of ever smaller transistors and higher densities in semiconductor electronics, the industry has yet to reach the length scale where scaling has caused a qualitative change in physical phenomena, e.g., from the classical to the quantum regime. Single electron transistors and other mesoscopic devices have been developed, yet remain exotic objects of laboratory exploration. The microelectronics revolution enabled faster, more practical and efficient computer processing.

What is microfluidics? Major Difference: for fluids, the fundamental physical behavior changes rapidly as the size scale is decreased. Microfluidics: Fluid Routing One important manner in which microfluidics differs from microelectronics is that the fundamental physics changes more rapidly as the size scale is decreased. Fluids move and behave differently on the microscale than the macroscale ?

What is microfluidics? Understanding microfluidic behavior requires knowledge of math, physics, chemistry & engineering. To name a few: Fluid mechanics: How do fluids behave on a small scale? Electrostatics: What is the importance of electricity, magnetism & charged particles ? Materials Science: What are the best materials for making microfluidic devices? Small dimensions cause some physical phenomena that we often neglect to become very important. On the microscale: fluid viscosity, surface tension, & molecular diffusion become more important fluid momentum (inertia) becomes less important.

Microscales Strand of human hair Microchannel 10 mm Caliper Life Sciences Strand of human hair 10 mm Microchannel Introduce audience to the scale of microfluidics. Channels similar to diameter of human hair. Using demos, having devices to pass around is useful to help students visualize the scale and give an example upfront.

What is microfluidics? Essentially dedicated to miniaturized plumbing & fluid manipulation Offers the possibility of solving outstanding issues for biology Enabling fluid automation to save time, increase efficiency and rival electronic integrated circuits in a new lab-on-a-chip system hydraulics open valves [green] between pairs of reservoirs [vertical dumbbell shapes] so that DNA and protein can mix together. GETTING PUMPED:  Just the thing for getting a global view of how a cell works

What is a Microfluidic Chip? made of silicon (PDMS) pattern is engraved into chip inlet channels are punched into the silicon it is attached to glass to form closed channels fluids can flow through the channels and interact according to the chip design http://youtu.be/JIewub-bPKY http://youtu.be/wm2JOuA8K1w

What are the Advantages of Microfluidic Chips? Cost effective Less hazardous materials generated/used Sample collection is easier/less painful for the patient More time efficient diagnostic tests Portable for use in outdoor settings/areas without power supply needed for big machinery

Digital Microfluidics: Bubble Logic Instead of test tubes, chemical reactions can be also performed in droplets. But how do we mix reagents in droplets? Mixing in a straight channel [video] Mixing in a serpentine channel [video] Emphasis engineering design: serpentine channel: more efficient mixing http://ismagilovlab.uchicago.edu/Mixing_straight_channels_files/Mixing_straight_channels_fast.swf http://ismagilovlab.uchicago.edu/Mixing_winding_channels_files/Mixing_winding_channels_fast.swf Prakash and Gershenfeld. “Microfluidic Bubble Logic,” Science 315: 832-835 , 2007.

Lung-on-a-Chip Biomimetic microsystem reproduces functionality of lung alveoli without need for lab animal models for drug screening & toxicity studies. Huh et al. “Reconstituting organ-level lung functions on a chip, “ Science 328: 1662-1668, 2010. A new direction for microfluidics, using the platforms as models of the human body since a lot of physiological processes happen on the micro scale using similar fluid flows (low Reynolds number, laminar flow, diffusion dominated). Ingber lab at Harvard, Dan Huh

Lab-on-a-Chip Micro Total Analysis Systems (µTAS) Protein analysis DNA techniques Drug efficacy studies Single cell analysis Diagnostics, sensors Most importantly, integration of all components on one device! An example of what kinds of samples can be analyzed by microfluidic platforms: Proteins DNA Pharmacokinetics Single cell analysis (because of high sensitivity and limit of detection) [Burns, M.A. et al. "An Integrated Nanoliter DNA Analysis Device," Science 282: 484-487, 1998.]

A Rapid Diagnostic Device One step diagnostic from IBM Zurich: [Video] Readout One step diagnostic device from IBM Zurich. Play the video: http://www.rsc.org/suppdata/LC/b9/b906523g/b906523g.mov Point out the similarity between the capillary action in the diagnostic device to water flow from tree roots to leaves. Slide courtesy of C. Hou

Making Microfluidic Devices: PDMS Poly(dimethylsiloxane) aka PDMS ≈ Jello for bioengineers! UV light ① Make a mold  via photolithography ② Put in the PDMS precursor ③ Bake to cure ④ Assemble microfluidic layers! Mask A microfluidic processor for gene expression profiling of single human embryonic stem cells Image from Zhong et al, 2008. Source [NBTC: Nanobiotechnology Center - Cornell University]

How do you make a MF Chip? Selecting channel shapes from the AutoCad generated master 2. Pour PDMS slowly over the master

MF Chip Fabrication (con’t.) 3. Put on hot plate in order to get rid of bubbles in the PDMS 4. Cut out chip from mold, punch inlet channels,& mount on glass slide

Additional/supplemental slides Denisin - UC Berkeley

What do microfluidic tools give us? Different fluid handling components such as valves, channels, reservoirs, pumps, etc. can be integrated with sensing mechanisms to produce complex and powerful systems. Here in this microscope image, various micro-fluidic components are highlighted using different colored dyes. Thorsen et al., Science, 2002

What is bioengineering? Designing and creating innovative technologies to advance medicine & clinical research Regenerative medicine -biodegradable mold seeded with human bladder cells Computational biology determines structure-function relationships of proteins, the workhorses of our bodies Hemoglobin model above Microfluidics falls under the field of bioengineering. Bioengineering is a field that focuses on designing and creating new devices to advance medicine and clinical research. Bioengineering is highly multidisciplinary, bringing together many different kinds of researchers. These are examples of bioengineering focus areas. Combining what we know about biological systems, anatomy and physiology, we can build artificial organs, study regeneration in the body, and make new platforms for patient diagnosis. “Lab on a Chip" - sequence large genomes quickly and cost-effectively AbioCor Artificial Heart

Microfluidic Devices Rapid analysis of samples using: small volumes (μl  10-6 L) high sensitivity & specificity fast response time – minutes small device, portable low energy consumption real-time detection capabilities To help students understand microliter volumes, can give examples of average tear is 5-10 microliters. “Point of care” concept: analysis of patients in the clinic, obtaining diagnosis based on protein profiles or cell counts in patient fluids Conventional methods require patient samples to be sent to a clinical laboratory outside of the hospital and thus require up to a week until results are available Microfluidic analysis platforms can enable running these tests within the clinic/hospital in an hour to provide patients and physicians with accurate and rapid information Applications are broad: rapid medical diagnostics, environmental monitoring, detection of biothreats, basic research…

Thought Experiment #1: Does static electricity have more of an effect in moving large or small objects? Why is this true? Factors affecting energy stored as static electricity on an object: object size capacitance Voltage to which the object is charged dielectric constant of the surrounding medium (air, water, etc) Static electricity has different effects on large and small objects because of the relative charge density that can occupy the surface area of the objects. http://www.sciencemadesimple.com/static.html Feynman, 1960

Thought Experiment #2: What would it be like to swim in a pool full of honey? How would it be different from swimming in water? Why? Factors affecting swimming in different media: Density Viscosity Length (characteristic length of the object and size of the pool) speed Feynman, 1960

Molecular Diffusion Thermal motion of particles from an area of high to low concentration to result in gradual mixing tea diffusing into hot water  Diffusion rate depends on: fluid temperature & viscosity size (mass) of the particles Tying macro to micro scale diffusion: You’ve experienced diffusion when making tea: if you leave the bag undisturbed in the hot water, you’ll see a gradient of tea concentration which will equilibrate over time The equilibration takes longer time in cold water Images from http://www.tutorvista.com/content/biology/biology-iii/biomembranes/physical-processes.php and http://en.wikipedia.org/wiki/File:DiffusionMicroMacro.gif