lec_1 - Molecular, Cellular & Tissue Biomechanics...

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Unformatted text preview: Molecular, Cellular & Tissue Biomechanics Patrick Doyle (ChemE), Roger Kamm (ME & BE) Maxine Jonas (BE) Goal: Develop a fundamental understanding of biomechanics over a wide range of length scales. MOLECULAR MECHANICS I II III IV Biomolecules and intermolecular forces Single molecule biopolymer mechanics Formation and dissolution of bonds Motion at the molecular/macromolecular level TISSUE MECHANICS I II III IV V Molecular structure --> physical properties Continuum, elastic models (stress, strain, constitutive laws) Viscoelasticity Poroelasticity Electrochemical effects on tissue properties CELLULAR MECHANICS I II III IV V VI Structure/function/properties of the cell Biomembranes The cytoskeleton Cell adhesion and aggregation Cell migration Mechanotransduction Typical Length Scales in Biology microtubule DNA width width 10-9 10-7 histone proteins chromatin width typical animal cell 10-5 nucleus length of DNA in a chromosome 10-3 10-1 human 101 meters length of DNA contained in a typical human cell Similar spectra exist in time scales or energy scales. Muscles: Spanning from Macro to Nano Actin: semiflexible polymer Myosin: molecular motor Titin: resting elasticity Macro-scale applications 108 bpm Cardiovascular mechanics 72 bpm Computational fluid mechanics used to study shear stresses in the carotid artery Image removed due to copyright considerations. Image removed due to copyright considerations. Peak flow Image removed due to copyright considerations. Image removed due to copyright considerations. Maximum deceleration …or tissue stresses in the wall of a diseased vessel Image removed due to copyright considerations. Stress (Pa) Computational mesh for finite element analysis Image removed due to copyright considerations. Image removed due to copyright considerations. Histological section obtained from surgery MRI images Vessel cross-sections Boundary data (x,y,z) IGES boundary : Quilting / Knitting Finite element mesh 3D model ParaSolid Model Modeling Complex Material Properties� Microstructural� Continuum entangled polymer bending plate Constitutive relations and force balance Viscoelastic or poroelastic solid t 21( t) strut model Typical Eukaryotic Cell� 10-30 mm 1 mm = 10-6 m� 1 nm = 10-9 m� 1 Å = 10-10m� Plasma Membrane� Plasma Membrane 2-D Elastic Plate ~5 nm Cytoskeleton� Cytoskeletal fibers TEM cytoskeleton photograph, J. Hartwig, Harvard University. Courtesy of J. Hartwig. Used with permission. “rigidity” actin Diameter (nm) 6-8 Persistence Length (mm) 15 microtubule 10 60,000� intermediate filament 20-25 1-3 When stressed, cells form stress fibers, mediated by a variety of actin-binding proteins. TEM cytoskeleton photograph, J. Hartwig, Harvard University. Courtesy of John Hartwig. Used with permission. Structure of actin.� Image courtesy of Dr. Willy Wriggers. Used with permission. � Measuring Complex Material Properties� Aspiration Cell Poking� Thermal tracers� 4 2 0 -2 -4 -6 -6 -4 -2 0 2 4 Cell Adhesion� Physical forces effect bond association/dissociation Finite contact times Cell deformation After Orsello, Lauffenburger and Hammer, 2001. Dynamic Processes: Cell Migration Cell Motility Fluorescently marked actin • Actin is a polymer • The cytoskeleton is active • Coordinated processes: adhesion, (de-) polymerization Active Cell Contraction Cardiac myocyte (Jan Lammerding) Courtesy of Jan Lammerding, Harvard Medical School. Used with permission. Cytoskeletal Mechanics Probed by External Force Image removed due to copyright considerations. Fibroblast with fluorescent mitochondria forced by a magnetic bead D. Ingber, P. LeDuc Mechanotransduction: Hair cell stimulation tip link tension in tip link increases stereocilium Image removed due to copyright considerations. SEM of the stereocilia on the surface of a single hair cell (Hudspeth) Image removed due to copyright considerations. Tension in the tip link activates a stretch-activated ion channel, leading to intracellular calcium ion fluctuations. Molecular dynamics simulation of channel regulation by membrane tension Images removed due to copyright considerations. See Figures 1 and 9 in Gullingsrud, Justin, Dorina Kosztin, and Klaus Schulten. "Structural Determinants of MscL Gating Studied by Molecular Dynamics Simulations." Biophys J, Vol. 80, No. 5 (May 2001), p. 2074-2081. http://www.biophysj.org/cgi/content/full/80/5/2074 But other evidence suggests that the pore increases to >20 angstroms! Steered molecular dynamics of fibronectin Images removed due to copyright considerations. See Figures 2 and 3 in Gao, Mu, David Craig, Viola Vogel, and Klaus Schulten. "Identifying unfolding intermediates of FN-III10 by steered molecular dynamics." Journal of Molecular Biology, 323:939-950 (2002). Constant applied force = 500 pN Unfolding has been thought to be important in exposing buried cryptic binding sites. The Orders of Magnitude in DNA Organization Image removed due to copyright considerations. Diagram showing range of size magnitudes, from metaphase chromosome (1400 nm) down to short region of DNA double-helix (2 nm). Compaction of a stretched DNA after histones are introduced. Image removed due to copyright considerations. See Figure 1 in Ladoux, B., P. Doyle et al. "Fast kinetics of chromatin assembly revealed by single-molecule videomicroscopy and scanning force microscopy." Proc Natl Acad Sci U S A. 97(26):14251-6 (2000 Dec 19). Dynamic Processes: Molecules Single T4-phage DNA in solution Stretching a Single DNA • Thermal forces are important (kT/ 1 nm ~ 4 x 10 -12 N ) • Entropic & enthalpic effects • Generic/specific mechanical responses • Single molecule experiments are possible Bustmante 1996 Doyle Group Image removed due to copyright considerations. Motor Proteins Mechanochemical (Enzyme) Engines ATP hydrolysis->conformation change Image removed due to copyright considerations. Yanagida 1999 Rotary Motor (F0F1) Linear Motor Myosin II Image removed due to copyright considerations. Actin filament Motor Proteins Reoccurring Themes in Biomechanics • Multiple length/time/energy scales • Polymers play an important role • Thermal energy is important • Interplay of chemical, electrical, mechanical interactions • Quantitative (single molecule) experiments Molecular, Cellular & Tissue Biomechanics Biology is soft, wet & dynamic Using Engineering/Physics to Unravel & Manipulate Biology • Scaling arguments • Mechanical models (polymer physics) • Experimental techniques • Importance of the stochastic nature of biology Readings There is no single text which covers all of this material ! Texts: Y. C. Fung, Biomechanics: Mechanical Properties of Living Tissues, 2nd Edition, Springer -Verlag, 1993R. Nossal and L. Lecar, Molecular and Cellular Biophysics, Wiley, 1990.H. Lodish, D. Baltimore, L. Zipurksy, P. Matsudaira, Molecular Cell Biology, 1996. K. Dill and S. Bromberg, Molecular Driving Forces, 2003 Manuscript Drafts: P.C. Nelson, Biological Physics: Energy, Information Life A. Grodzinksy, R. Kamm, L. Mahadevan: BEH 410 Research Articles: Posted/linked on the web Notes: Periodically posted ...
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This note was uploaded on 11/27/2011 for the course CHEMICAL E 20.410j taught by Professor Rogerd.kamm during the Spring '03 term at MIT.

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