Friday, May 20, 2011

What comes next in Microfluidic research?

Prof George Whitesides sees the future of microfluidics research in following way. This is an editorial published on Lab on a Chip, a leading Journal in this field ((DOI: 10.1039/c0lc90101f)).


Every field must periodically  reinvent it- self to remain vital. Microfluidics, and the concept of the lab-on-a-chip (LoC), have had a spectacularly successful 15-year run of science and technology.  The combina- tion  has  achieved  much  more  than  one could have imagined at the beginning, but also less than one might have hoped for in the most expansive of visions. There are now two strategies—two  paths—for  it to follow in going forward:  (i) It can gather up the technology  that  is now available, and develop it fully and completely. This strategy  would focus on finding uses for what now exists, and motivate  the devel- opment  of  downstream   technologies— manufacturing at  scale, quality  control, standards,   interfaces,   regulatory clear- ance, and all the others—with  those uses. The   development    of   the   downstream manufacturing technologies  will be chal- lenging,  and absolutely  necessary  before laboratory prototypes become large-scale commercial realities. (ii) It can invent new things, and see if the momentum of new ideas  will carry the  field  forward.  This strategy   does   not   necessarily   directly result in products,  but it demonstrates the components   and  options   which  would support later technologies. Sexy new ideas also  build enthusiasm  for  the  field, and demonstrate capabilities that—in an area that  really is new—are  unique, and  that give  rise  to  applications  that   pull  the science into technology.

Both   paths   are   important  for   LoC technology:   It   must,   of   course,   push technology into products  in order to have the impact that will sustain the field. Still, the period of highly productive  invention and  science in LoC  systems  and  micro- fluidic technology  is hardly over, so new ideas are also important.

Everyone active in the field could make up  a  list  of  exciting  opportunities; the length   of  an aggregated   list,  and   the diversity  of  the opportunities  suggested, would provide one measure of its vitality. I would not presume to offer a canonical list,  but  I  will  summarize a  few of  my favorite topics, to give a sense for where I see attractive  opportunities. Let me give you some of my favorites in both strategies: that  is, in invention  of  new science and technology and in the development of existing technology.

1.  Nanofluidics

Microfluidics is the study of fluids moving in   micron-scale   (usually,   to   be   more accurate,  100-micron-or  submillimeter- scale-)    structures.    There    are    many interesting  characteristics   of  these now- familiar  systems,  of  which  perhaps  the most   different    by    comparison   with macroscopic fluid flows, and thus, so far, the  most  useful,  has  turned   out  to  be laminar,  or low Reynolds-number, flow. The field of ‘microfluidics has  not  yet made  a  concerted  effort  to  understand true nanofluidics (which I will characterize as  the  behaviors  of  fluids  in  structures with dimensions from 1 to 100 nm). It is not   quite clear  why   microfluidics   has extended  only  slowly  into  nanofluidics, but one reason is probably  that there are still no methods of fabrication that would make   it   easy   to   generate   nanofluidic structures,    or   that   would   allow   the behaviors  of  fluids in them  to  be easily characterized.

‘The field of ‘microfluidics’ has not yet   made  a  concerted  effort  to understand true nanofluidics.

And   why  would  one  care?  What  is interesting    to    me   about    nanofluidic systems, in principle, is that the behavior of fluids in nanochannels will probably  be dominated    by   their   proximity   to   the surfaces   making   up   the   walls   of  the channels  (or  other  structures contacting the fluids). Nanofluidic systems will be, in other words, ‘all interface, and the study of  nanofluidics  may  ultimately  become more a branch  of surface science than an extension   of   microfluidics.   Regardless, one  of  the  least understood, and  most important,  areas   of  science  and   tech- nology is that of interfacial fluids. Storage of  energy  in   capacitors   and   batteries, corrosion,  lubrication, molecular  recognition,    sensing, adhesion,   biocompati- bility—all are intimately concerned  with the properties of fluids (and, of course, of the molecules and ions in them) that  are making the transition from a constrained environment (immediately adjacent to the surface) to the bulk fluid.

2.    Digital microfluidics

The   microfluidics/LoC   community   has begun  actively  to  embrace  the  study  of dispersed    phases    moving    in    micro- channels.  The  invention of a number  of simple  structures  (flow-focusing nozzles, T-junctions,  and others) opened the door to this field by making it possible—for the first   time—to    generate    monodisperse droplets  or bubbles in virtually unlimited numbers, very rapidly (bubble generation rates  now  approach  100  kHz);  micro- fluidic   channels   make   it   possible   to manipulate  and  sort  and  combine  these droplets with remarkable  sophistication. Each  of  these droplets,   in  principle,  is a  micro-reactor,  and  the  potential  for using droplets  for a wide range of appli- cations—genomics,   proteomics,    single- cell                     analysis,       cell           selection, phage selection, many others—seems very large, albeit   still  at   an  early   stage.  ‘Digital PCR’   (from which    phrase     adapt ‘Digital   Microfluidics’)   is   developing rapidly, but other uses for these systems— in  biology,  in  food  science,  in  a  wide variety  of  different  types  of  analyses— coupled  with  the  remarkable  self-orga- nizing  properties   of  large  numbers   of droplets  in  microfluidic  systems,  makes this area, to me, extraordinarily attractive for exploratory research.

3.    Inside biology

One of the long-term justifications for the relevance of microfluidics to biology has always been that  it provides information concerning fluid flows in cells and organ- isms. Organisms with a circulatory system are,   essentially,   networks   of  pipes   of various sizes which transport fluid among its   various   parts.   Flows   of  fluids   in biology  range  from  turbulent  in  large pipes (e.g., the aorta),  to laminar in small

ones (e.g., capillaries); these flows can be either                 highly      non-Newtonian       (the contents  of the bowel, the cytosol filling the  interior  of  the  cell)  or  Newtonian (normal  urine);  they  can  have multiple dispersed phases (cells or clots in blood or lymph,  or pathogens  in the  circulation), or   be   (we   think)   homogeneous;    the structures of the channels can range from simple tubes to complex, networked,  gel- filled   capillaries,  and  the immensely complex    networks    of   structure    and architecture     constituting   the    human circulatory  and lymphatic systems (which we   barely   understand). Most serious observations of fluidics in biology  have discovered behaviors  that  are interesting and unexpected.  Since almost  everything in biology  has  layers of complexity  that extend  apparently without   limit,  if  the first  surveys  of  biological  microfluidics have revealed as much of interest as they have, we can  only  begin  to  guess what more serious investigation  will reveal.

Most of the cards in the microfluidic deck have still not been revealed!

4.    New types  of uses

Partially as a reflection of the history of its origin  (and  partly,  probably,  since it  is where the money for start-up companies has  largely  been), developments  in LoC technology  have strongly emphasized bi- oanalysis,  particularly  bioanalysis   rele- vant to human healthcare and to research biomedicine.  This field is enormous  and diverse,   and   these   developments   will certainly continue. The field should think about opportunities in other areas as well. In  applied  biology,  there  are  a  range  of opportunities in plant and animal health, and largely untouched potential for use in public health  (as  opposed  to  high-tech- nology medicine): vaccination  status and nutritional   status    are   two   in   which convenience and  very low cost  are espe- cially important. Fluidic  optics—the  use of fluid-filled  channels  as optical  wave- guides  and  lasers,  and  of  droplets   for lasing, and for uses of lasing such as in- cavity detection—is attracting substantial interest. Systems of droplets or bubbles in complex  microfluidic behaviors indicate massively   parallel   interactions   among them, and suggest the possibility of use in new  kinds  of  analog  computation, and possibly  in  transmission of information.

The use of microfluidic systems in organic synthesis  is no  longer  a  new  idea,  but applications  successful  enough  to  drive the field still remain to be developed. The uses of magnetic separations in all areas of  microanalysis  have  just  begun  to be examined. Combinations of microfluidic systems,  compressed   gases,  and   liquid metals, offer potential  routes to the solu- tions of problems in soft robotics. Most of the  cards  in the  microfluidic  deck  have still not been revealed!

5.    Cheap, interconnectable, stackable systems

One of the surprises of microfluidic systems is that  although the technology has devel- oped well, LoC systems are still not being used  extensively. There are variouargu- ments for what is now required to make the next  step,  but  one  guiding  lesson  from other  fields of  microscience  is cheap  is good; the second is they should be easy to build  with.’  Microelectronics   has  pros- perebecause  it learned  (in fact,  taught) both lessons; silicon MEMS, by contrast, has developed much more slowly, in part because  cheap has  been  difficult.  And eve in    microfluidicspolymers  have essentiall displace silicon   an glass, largely because of cost.

Although    the   field  of   microfluidics strives to  draw  analogies  between  LoC systems    and  integrated    circuits,    the analogy   is   fundamentally   weak.   The parallel  fabrication,  and  ease  of  inter- connection, available  with silicon micro- electronics   simply,  at   present,   has   no parallel   in  LoC  technology,   and  even inexpensive polymer systems are dramat- ically  more  expensive than  microcircuits of                comparable         functionality       and complexity. Taking microfluidics to a new plateau of cost and interconnectivity may not  require  fundamentally new  science, but it will require  a change in the objec- tives of the engineering: the rapid devel- opment   of  simple  microfluidic  systems based on patterned paper for applications  in  public  health  in developing  countries provides   an  example  of  the  power  of
‘cheapand ‘simple.

‘Taking  microfluidics  to  a  new plateau of cost and interconnectivity may ... require a change in the objectives of the engineering.

6.    New fluids, fluidics, and materials

The field of microfluidics has had a very restricted view of fluids and the materials used  to  contain   them,  and  LoC  tech- nology       has                 worn   complementary blinders.  Much  of  the  work  in  micro- fluidic systems is implicitly focused on the objective  of  bioanalytical  systems,  and thus has found it quite satisfactory  to use commercial   polymers,   and   to   assume water   or   an   aqueous   solution   as  the working  fluid. What could be done with fundamentally different  fluids, and what materials might be required to work with them?  As one  example,  many  inorganic materials  (for   example,   glass,  calcium phosphate,   silicon)   form   low-viscosity fluids  at  sufficiently  high  temperatures. What   could  be  done  by  manipulating such  high-temperature  fluids  using  mi- crofluidic  systems?  What  would  be  the behaviors  of  high-temperature melts  of glasses or metals moving through  appro- priate  systems? Could  one  make  micro- electronic systems, or silicon MEMS, by molding   liquid   semiconductors?   Solar cells? LEDs?  Could  one  assemble  more complex systems using techniques related to cofabrication?  What  about  the micro- fluidics of flames and  plasmas?  Most  of these  exploratory  efforts  would  require new methods  of fabricating  microfluidic systems   in   unfamiliar    materials    (e.g. zirconium oxide, thorium oxide, graphite, and niobium have excellent high temper- ature   properties,   but   how   would   one fabricate   microsystems   in  them?  Even more to the point,  how would one char- acterize the movement of fluids in them?). On a more mundane  level, is it incon- ceivable to make microsystems fabricated  in glass as inexpensive as those fabricated  in  polymers?  To  do  so  would  certainly solve many of the problems that  appear when using reactive solvents in polymer-based microfluidic systems.

7.    Interfaces  and standards

The  subject  of interfaces  and  standards might seem boring,  but to a technologist they are  not,  they are  essential  parts  of building any  new  technology.  Think  of what   the   simple   USB   connector has done   for   microelectronics.    Think   (or learn) about  all of the standards that go into  microelectronics,  or components automobiles,    or    open    software,    or household   electrical  systems.   Complex technologies almost      always     have multiple    parts,    and    the   parts    must connect  with  one  another   transparently and  effortlessly,  so that  designers  know that  the  component they  are  designing can   be  connected,   and   so  that   users know  how  to  put  components   together (with  the ssurance  that  they  will work once   connected).   The   field  of  micro- fluidics   is   beginning   to   think   about interfaces and standards, but there is still disagreement  about  whether  the  time  is ripe for a serious effort to design and set standards.   Setting    standards   is,    in a sense, imposing a freeze on design, and one does not want to do it in a way that limits  creativity  and  slows  the  develop- ment  of new  systems. Nonetheless,  until there   are   standards,  it   is   effectively

impossible  to  build  a  technology  of  in- terconnected components, and  the crea- tivity  of  down-stream   designers    the designers  whose  skill is to  take  existing components  and  put  them  together   in creative  new ways is blocked  without understood standards. There  is also  no free  lunch,  and  building  interfaces  and standards requires   work.       It              may, however,  be appropriate,  and  necessary, now.  Thinking   through   standards and interfaces, prototyping systems  demon- strating   them,   and  developing  a  tech- nology  for  them  for  LoC  systems  will

Lack of standards and inter-connectivity poses a potential barrier to  the creativity of designers.

require  great ingenuity,  and  will be  very important for the field.

These seven topics are purely personal choice: any reader could come up with an equally   good   list, and   the   list  would probably  be  quite  different.  That  fact— that there is a wide range of opportunities, and a wide range of opinions  on what is more  important and  what  is  less impor- tant—gives a measure of the health of the field. So long as there are lots of oppor- tunities, and lots of differences in opinion, the  broad area  encompassing  LoC  and microfluidic   technology   (and   plausibly extending into a range of other  subjects, from energy storage and robotics  to low- cost MEMS)  is in good shape.  Disputa-  tion is good.

George M. Whitesides 
Chair, Editorial  Board Harvard University, USA

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