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Furthermore, the membrane is not a static entity, but is dynamic in a spatially distinct manner. Lateral diffusion of em- bedded components, such as receptors, Biointerface Science enables formation of reversible complexes and clusters; lateral microphase separation, both of the low-molecular-weight con- Ashutosh Chilkoti and Jeffrey A. Hubbell, densed amphiphiles that form the mem- Guest Editors brane and the higher-molecular-weight components that are embedded therein, is also possible. The cell membrane is tem- porally dynamic as well, the embedded bio- Abstract molecules having developed structures to Biointerface science, defined as the study and control of biomolecular interactions at enable the triggering of their functions (e.g., surfaces, is a critical component of many aspects of , but it has only recently by binding additional biomolecules or by begun to attract the attention it deserves as a unique interdisciplinary research area. undergoing structural changes themselves). This issue of MRS Bulletin explores the rich diversity of function provided by biomolecules Thus, the complex cellular biointerface is at interfaces and the unparalleled opportunities for applications, which range from clinical capable of rapid, spatially controlled bio- diagnostics, , and to genomics and proteomics. This molecular remodeling. diversity will continue to drive the evolution of biointerface science. Creating such spatially and temporally dynamic interfaces in which activity can be Keywords: adsorption, biointerfaces, biomaterials, immobilization, patterning, switched on and off in response to external tissue engineering. signals with nanometer spatial resolution and on a millisecond time scale—the spatial and time scales of —is a formidable challenge, and one that is only now being ad- Biointerface science, defined as the study surfaces can be the bane of biomolecules, dressed by a multidisciplinary community. and control of biomolecular interactions yet surfaces are ubiquitous in nature. Some- Two articles in this issue, one by Mrksich with surfaces, is a critical component of how, biology has elegantly solved the and another by Lahann and Langer, provide many aspects of biotechnology, but it has problems faced by practitioners of bio- brief summaries of ongoing work in this only recently begun to attract the attention interface science. In fact, nature offers many area, with a focus on the methods these it deserves as a unique interdisciplinary lessons that are only now beginning to groups developed for the synthesis of dy- research area. Although it is tempting to serve as the inspiration for a new genera- namic biointerfaces. The authors review simply describe biointerface science as a tion of designer biointerfaces, a sampling methods developed to dynamically modu- subdiscipline of surface science, it is rather of which is highlighted in this issue of late biochemical and physicochemical func- a new discipline in its own right because of MRS Bulletin. tionality at surfaces by thermal, electrical, the unique nature of biological macromole- The prototypical example of nature’s de- electrochemical, chemical, and mechanical cules. Whereas classical surface science is sign of a biointerface is the cell membrane. signaling to alter cellular and biomolecular typically studied by ultrahigh-vacuum Even a cursory examination of the cell interactions at surfaces. Mrksich reviews techniques, biomolecules require water to membrane design offers many lessons for work from his group on electrochemical function, and thus they can only be accu- biointerface science. The cell membrane is control of biomolecular presentation, ca- rately studied when bathed in water along composed of a lipid bilayer with receptors pable of dynamically controlling cellular with the surfaces of interest. Compared with and channels that are embedded within or interactions at surfaces with astounding fi- synthetic molecules, they are structurally span across the membrane. Lipid bilayers delity. Lahann and Langer include in their larger and are often significantly more so- are elastic and are capable of enormous de- review work of their own using an applied phisticated in their structure and function, formation and compression, as seen by the electrical potential to alter the conformation despite being created from a limited group ability of blood cells to squeeze through of a surface-constrained monolayer (e.g., of precursors. Furthermore, their structure— narrow capillaries. The highly functional presenting a hydrophobic face under one and hence, activity—are modulated by cell membrane is, however, more than just set of conditions and a hydrophilic face their environment in ways that frequently an elastic membrane, studded as it is with under others). Given that surface electrodes go far beyond what is seen with synthetic myriad that span both sides of the may be integrated within a host of complex molecules. Correspondingly, biomolecules bilayer, biomolecules that shuttle chemical, lab-on-a-chip designs, the approaches pre- are also extremely fragile, which places mechanical, and electrical messages from sented in both articles are very powerful for fairly severe constraints on how they can be the outside world to within the cell and out application in cellular and molecular high- manipulated and studied: biomolecules, again. Thus, the functionality of the cellu- throughput screening and bioanalytics. especially proteins, readily adsorb, unfold, lar biointerface is phenomenal. The third article in this issue, by Yang and denature to adopt a new, unfolded Another problem relevant to biointerface et al., is also on the design of a dynamic structure at surfaces, so the utmost care science that nature has solved is the pres- biointerface, highlighting the pioneering must be taken in handling and studying entation of receptors in the correct orienta- work of this group in translating a purely them at surfaces. Likewise, approaches tion in the membrane through the use of two-dimensional approach into the third developed to manipulate synthetic mole- membrane-spanning helices to optimize dimension using a triggered interface. They cules at interfaces may fail miserably in their activity. Thus, specialized motifs have review their approach to creating multi- handling biomolecular interactions. evolved for presentation of biomolecules at cellular tissue constructs by “cell-sheet The paradox of biointerfaces, especially interfaces—and to an extent, within them— engineering,” in which cells that are cul- laboratory-generated ones, is that artificial as in the case of membrane-spanning motifs. tured on a temperature-responsive polymer

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surface can be released simply by ther- studied in a laboratory are presented on a available to position, manipulate, and in- mally triggering the phase transition of the hard organic or inorganic support. The ar- terrogate biomolecules at length scales from immobilized polymer. In this way, entire ticle by Terrettaz and Vogel addresses this, the single molecule upward in two and sheets of cells can be lifted off with their reviewing their work in creating supported three dimensions. Together, this intellec- associated intact. Layer- biomembranes, with water on both sides, tual interplay will lead to a new bio- ing of these sheets then provides an elegant containing embedded ion channels to per- inspired paradigm for the way in which route to recapitulating three-dimensional mit selected chemical and electrical connec- molecules are designed, studied, and ex- tissues. This approach has seen significant tivity between the two sides. These highly ploited for the vast number of biotechno- success in a number of tissue engineering functional materials are useful in studying logical applications in which biomolecules areas, most notably in transplanting cells the basic biophysics of the ion channels and meet surfaces. This objective will only be to the cornea to repair damage to the eye as readout mechanisms in drug screening achieved by the collaborative efforts of caused by disease or injury. and biodiagnostics. This work in many (bio)chemists who synthesize novel classes Spatial confinement of molecules is an- ways exemplifies the integration of biology of biomolecules (, pep- other area of active interest in biointerface into bio-inspired interfaces and highlights tidomimetics, , , and science. Chen et al. review a recently devel- how such designer interfaces are likely to be engineered proteins), with the diverse oped methodology to pattern adhesive of increasing utility in fundamental studies ensemble of scientists who have developed patches on the length scale of the cell and the in cell biology and biophysics, as well as the tools to position biomolecules with mo- subcellular process, which in turn pattern biotechnological applications. lecular precision (proximal probe methods, the attachment of cells as individuals and Myriad challenges in biointerface sci- nanocontact and microcontact methods, as communities. They show that one can use ence remain that make it a fascinating area e-beam and x-ray lithography, and bottom- patterned surfaces to position cells in well- of research and fertile ground for new up self-assembly methods). Included in this defined shapes and proximity for cell bio- applications. collaboration will be scientists who have de- logical studies and use structured surfaces One challenge for the future is to bring to- veloped new spectroscopic techniques to in- as a biomechanical readout for the forces in- gether recent advances in materials science terrogate these molecules at the solid–liquid volved in cell attachment and migration. and molecular biology: sophisticated sur- interface and individuals who integrate Extending to a yet finer scale, many cellu- face and interface analysis methods will these diverse aspects into functional devices lar machines involved in cell sensing, ad- enable new experimental tools which, (applied physicists, analytical chemists, and hesion, and migration exist as combined with advanced theoretical models bioengineers). clusters at the 100 nm length scale, yet our to describe biointerfacial phenomena, will Although biomolecules can be difficult ability to present biomolecules in hetero- elucidate the physical concepts and rules beasts to tame, the potential rewards of geneous structures at this length scale is lim- that allow predictive, model-driven research, doing so are enormous—the rich diversity ited. The article by Vörös et al. describes a similar to the interfacial understanding that of function provided by biomolecules offers new methodology to accomplish this, pre- has been successfully developed for semi- unparalleled opportunities for applica- senting biological recognition patterns (bind- conductor and catalytic processes. A second, tions, which range from clinical diagnostics, ing sites for biological molecules or cells) on equally important, objective is to accelerate biomaterials, and tissue engineering to ge- a substrate that is nearly perfectly lacking in the rate at which new developments in nomics and proteomics. This diversity will biological recognition at the 100 nm biomolecular design and engineering are continue to drive the evolution of biointer- length scale. brought into the domain of physical scien- face science. ■ In nature, biointerfaces exist with water tists and, conversely, to educate biologists on both sides, whereas most biointerfaces about the precision techniques that are now

Ashutosh Chilkoti, as an assistant professor Chilkoti can be Guest Editor for this of biomedical engineer- reached by e-mail at issue of MRS Bulletin, ing at Duke University ashutosh.chilkoti@duke. has been the associate in 1996 and promoted edu. director of the Center to associate professor for Biologically Inspired in 2002. Jeffrey A. Hubbell, Materials and Materials Chilkoti won a Guest Editor for this Systems at Duke Uni- CAREER Award from issue of MRS Bulletin, is a versity since 2002. He the National Science professor in the Integra- holds a BTech degree in Foundation in 1998, the tive Biosciences Institute chemical engineering 3M non-tenured faculty and the Institute for from the Indian Institute award in 2002, and a Chemical Sciences and of Technology in Delhi distinguished research Engineering at École Ashutosh Chilkoti Jeffrey A. Hubbell and a PhD degree in award from the Pratt Polytechnique Fédérale chemical engineering School of Engineering at de Lausanne (EPFL) in pharmacobiology, in- Hubbell can be from the University of Duke in 2003. He serves Switzerland. He received cluding biomaterials reached by e-mail at Washington. He was a on the editorial board of a BS degree from Kansas and drug delivery sys- [email protected]. postdoctoral fellow in Biomolecular Engineering State University and his tems for tissue engineer- the Department of Bio- and has co-authored PhD degree from Rice ing, novel materials for Thomas Blättler is a engineering at the Uni- more than 85 publica- University. Trained as a targeted drug delivery, materials scientist work- versity of Washington tions. He has 10 patents chemical engineer, he and non-viral approaches ing on his PhD degree from 1992 to 1995. either awarded or in investigates topics in re- to delivery of gene-based in the Laboratory for Chilkoti was appointed submission. generative medicine and pharmaceuticals. Surface Science and

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Thomas Blättler Christopher S. Chen Xingyu Jiang Joerg Lahann Robert Langer

Milan Mrksich Teruo Okano Samuel Terrettaz Marcus Textor Horst Vogel

Technology at the Swiss at the Johns Hopkins Chen can be reached he did postdoctoral work nion in Israel, the Hebrew Federal Institute of University prior to his by e-mail at chrischen@ with Robert Langer at University of Jerusalem, Technology (ETH) Zurich. current appointment at seas.upenn.edu. MIT. Lahann’s research Université Catholique His research is focused Penn. The goal of Chen’s is broadly related to sur- de Louvain in Belgium, on nanochemical pat- research is to identify Xingyu Jiang is a post- face engineering, with and the University of terning, combining selec- the underlying mecha- doctoral research associate strong ties to biomedical Liverpool in England. tive molecular-assembly nisms by which cells at Harvard University. He engineering and nano- He served as a member systems, colloidal lithog- coordinate with each received his BS degree technology. Specific as- of the U.S. Food and raphy for nanoarray other to build tissues, from the University of pects include designer Drug Administration’s technology, and single- and to apply this knowl- Chicago in 1999 and his surfaces, smart materials, Science Board from 1995 protein investigations. edge in fundamental PhD degree from Har- and nanoscale self- to 1999 and then as its Blättler can be studies of stem cell, vard (with G.M. White- assembly. Lahann has chair until 2002. He has reached by e-mail at endothelial cell, and sides) in 2004. His present written 24 scientific arti- also served on 15 boards thomas.blaettler@ cancer cell biology. His research interests are sur- cles and book contribu- of directors and 30 scien- mat.ethz.ch. current interests include face chemistry, analytical tions and has more than tific advisory boards of interfaces, chemistry, microfluidics, a dozen issued or pend- such companies as Wyeth, Christopher S. Chen is the application of micro- and cell biology. ing patents worldwide. Alkermes, Mitsubishi the Skirkanich Associate and to Jiang can be reached Lahann can be Pharmaceuticals, Professor of Innovation at cells, cell adhesion, and by e-mail at xjiang@ reached by e-mail at Warner-Lambert, and the University of Pennsyl- cell mechanics. gmwgroup.harvard.edu. [email protected]. Momenta vania. He holds an AB Chen has received nu- Pharmaceuticals. degree in biochemistry merous honors for his Joerg Lahann is an Robert Langer is the Langer has received from Harvard University, research, including the assistant professor in Kenneth J. Germeshausen numerous awards for an MS degree in mechani- Presidential Early Career chemical engineering, Professor of Chemical his work, including the cal engineering from Award for Scientists materials science and and Biomedical Engi- Lemelson–MIT Prize MIT, and a PhD degree and Engineers and the engineering, and macro- neering at MIT. He re- and the Charles Stark in medical engineering Office of Naval Research molecular science and ceived his BS degree Draper Prize, and he is and medical physics Young Investigator engineering at the Uni- from Cornell University the only engineer to re- from the Harvard–MIT Award. He serves on the versity of Michigan. He in 1970 and his ScD de- ceive the Gairdner Health Sciences and Board of Trustees for the received his PhD degree gree from MIT in 1974, Foundation Interna- Technology Program. Society for BioMEMS in 1998 in macromolecu- both in chemical engi- tional Award. In 1989, He earned his MD from and Biomedical Nano- lar chemistry from neering. He has received Langer was elected to Harvard Medical School, technology, and he is a Aachen University in honorary doctorates the Institute of Medicine and he was an assistant fellow for the DARPA Germany, where he from the Swiss Federal of the U.S. National professor in biomedical Defense Sciences Re- worked with Hartwig Institute of Technology Academies, and in 1992, engineering and oncology search Council. Hoecker. Subsequently, (ETH) Zurich, the Tech- he was elected to both

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the National Academy of Engineering and the National Academy of Sciences. He is one of the few people elected to all three National Academies and the youngest in history (at age 43) to achieve this distinction. Forbes (1999) and Bio World (1990) named Langer as one of the 25 most important individuals in biotech- Janos Vörös George M. Whitesides Masayuki Yamato Joseph Yang nology in the world. In 2001, Time Magazine and mental studies of cell idics, and cell-based on- and Chemical Research the University of CNN named Langer as adhesion, applications chip assays. at Tsukuba in Japan. Würzburg in Germany. one of the 100 most im- in biochip microarrays Okano is the president Terrettaz can be After his diploma thesis portant people in America and exploration of pro- of the Japanese Society reached by e-mail at in physical chemistry, he as well as one of the top tein-assembled nanos- for Tissue Engineering [email protected]. went to the Max Planck 18 people in science or tructures. and was formerly the Institute for Biophysical medicine in America. In Mrksich serves on the president of the Japanese Marcus Textor is a pro- Chemistry in Göttingen, 2002, Discover named him board of governors of Society for Biomaterials. fessor of biologically ori- where he performed his as one of the 20 most im- Argonne National Labo- He is the author or co- ented surface science at PhD work on the struc- portant people in biotech- ratory, as vice chair of author of 360 peer- the Swiss Federal Insti- ture of lipid membranes nology, and Forbes the DARPA Defense Sci- reviewed journal articles, tute of Technology (ETH) under M. Eigen and A. selected Langer as one ences Research Council, as well as 109 books or Zurich. He graduated Weller. He then worked at of the 15 innovators and as a member of the book chapters. He re- with a PhD degree in the Max Planck Institute worldwide who will editorial boards of Lang- ceived the 1997 Clemson chemistry from the for Biology in Tübingen, reinvent our future. muir, IEEE Transactions Award for Basic Research University of Zurich, at the Biocenter of the Langer has written more on NanoBioscience, Chem- from the Society for followed by two years University of Basel, and than 800 articles and has istry & Biology, and Biomaterials. at the University of Sus- at the Karolinska Institute over 500 issued or pend- Chemical Society Reviews. Okano can be reached sex, England, in catalysis in Stockholm, studying ing patents worldwide. He also serves on the by e-mail at tokano@ on single-crystal sur- the structure and dy- Langer can be scientific advisory boards abmes.twmu.ac.jp. faces. From 1978 to 1994, namics of membrane reached by e-mail at of ChemoCentryx, Sur- he worked for the com- proteins. [email protected]. face Logix, and Helicos. Samuel Terrettaz has pany Alusuisse in the Vogel can be reached Among his many honors been studying ligand–- development of new by e-mail at horst.vogel@ Milan Mrksich is a pro- are the Camille Dreyfus receptor interactions in materials and fabrication epfl.ch. fessor of chemistry at Teacher–Scholar Award lipid layers with surface- technologies for auto- the University of Chicago. (2000), the TR100 Young sensitive techniques in motive and packaging Janos Vörös is the senior He earned his BS degree Innovator Award (2002), Horst Vogel’s group at applications. scientist leading the in chemistry at the and the ACS Arthur C. École Polytechnique His current research Dynamic Biointerfaces University of Illinois, Cope Young Scholar Fédérale de Lausanne and teaching interests Group at the Laboratory Urbana-Champaign, Award (2003). (EPFL) since 1998. He cover the modification for Surface Science and and his PhD degree in Mrksich can be began his studies in bio- and characterization of Technology within the organic chemistry at the reached by e-mail at chemistry at the Swiss surfaces and interfaces, Swiss Federal Institute California Institute of [email protected]. Federal Institute of Tech- quantitative techniques of Technology (ETH) Technology before spend- nology (ETH) Zurich. In to sense in situ inter- Zurich. He holds an MS ing two years as a post- Teruo Okano is a profes- the group of M. Grätzel facial reactions, and degree in physics and a doctoral fellow at sor and the director of at the Institute of Physical the application of func- PhD in biophysics from Harvard University. In the Institute of Advanced Chemistry at EPFL, his tional surfaces in the the Eötvös University in 1996, he joined the fac- Biomedical Engineering work on sensitive lipid fields of biomaterials, Budapest, Hungary. He ulty at the University of and Science at Tokyo electrodes earned him a , and drug joined ETH Zurich in Chicago as an assistant Women’s Medical Uni- PhD degree in 1993. He delivery. 1998. Vörös’s interests professor of chemistry. versity in Japan. He then spent his postdoc- Textor can be reached include understanding He currently leads a re- currently oversees a toral years investigating by e-mail at marcus. and controlling cellular search group working multidisciplinary re- electron transfer kinetics [email protected]. and biomolecular surface on the interface between search group that uses in the context of organic processes at the nanoscale materials and biological temperature-responsive thin films at the Univer- Horst Vogel is a professor by physical and chemical environments. His group polymers for various sity of Maryland at of physical chemistry at means. His research designs and synthesizes applications such as College Park and photo- École Polytechnique covers aspects such as surfaces having well- tissue engineering, drug induced dye aggrega- Fédérale de Lausanne the creation of nano- defined structures and and gene delivery, chro- tion at the National (EPFL) in Switzerland. patterned nonfouling properties for funda- matography, microflu- Institute of Materials He studied chemistry at surfaces with functional

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arrays of macromolecules, Professor at Harvard gwhitesides@gmwgroup. fields throughout Japan and Science at Tokyo the development of novel University. His present harvard.edu. in studies on the regen- Women’s Medical Uni- experimental techniques research interests are in eration of various tis- versity in Japan. He re- for the study of molecular physical organic chem- Masayuki Yamato is an sues and organs. He ceived his ScB degree in and cellular interactions, istry, materials science, associate professor in the received the 2002 Award biochemistry and molecu- the dynamic control of biophysics, complexity, Institute of Advanced for Young Researcher lar biology from Brown macromolecule–surface surface science, micro- Biomedical Engineering from the Japanese Soci- interaction by electronic fluidics, self-assembly, and Science at Tokyo ety for Biomaterials University. His current means for applications micro- and nanoscience, Women’s Medical Uni- and the 2003 Young research interests include in neurobiology, and cell biology, and optics. versity in Japan. His re- Investigator Award pre- the applications of cell- the use of micro/nano/ He holds an AB degree search interests include sented by the Society for sheet engineering, par- biotechnology in pro- from Harvard Univer- tissue engineering, Biomaterials. ticularly related to the teomics and tissue sity and a PhD from the nanobiotechnology, and Yamato can be reached cornea, as well as the cell by e-mail at myamato@ engineering. California Institute of the study of interactions biology and biochemistry Vörös can be reached Technology. He worked between cells and bio- abmes.twmu.ac.jp. of epithelial progenitor by e-mail at janos. at MIT from 1963 to materials. His work on and stem cells. [email protected]. 1982, at which time he cell-sheet engineering Joseph Yang is an assis- returned to Harvard. has led to his collabora- tant lecturer in the Yang can be reached by George M. Whitesides Whitesides can be tion with over 30 medi- Institute of Advanced e-mail at jyang@abmes. ■ is the Flowers University reached by e-mail at cal doctors in various Biomedical Engineering twmu.ac.jp.

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