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Unformatted text preview: Anatomy and Physiology Review Genomics: study of sequence, structure, and function of genes in an organism: SSF of genes, basically the anatomy of genes Proteomics: study of genes encoded by genome, and their changes in protein expression patterns in different environments: genes & expression in diff. environments, its like the physiology of genes Physiome: Quantitative and integrated description of the functional behavior of the physiological state of an individual or species Reductionism: theory that all complex systems can be understood in terms of their components reduced to its components Systems Biology: Integrates all the individual components into a single model and gives a QUANTITATIVE description of interactions List four Key Properties of Systems Biology: System Structure – ntwk of gene intxns System Dynamics – system behavior over time Control Method – control system by modifying certain components Design Method – how to modify/design systems with specific properties Carbohydrates: structural, energy storage Lipids: structural, energy storage, compartmentalization Proteins: structural, transport, defense, metabolism Nucleotides: ATP, DNA/RNA Plasma membrane made up of membrane proteins and a lipid bilayer; ampiphilic – both hydrophobic and hydrophilic; controls internal osmolarity of cell – regulates cell volume Function of plasma membrane: control cell’s volume/provide route for nutrient exchange Osmosis: Water diffuses across selectively permeable membrane along its concentration gradient (from low to high solute conc.) Active Transport: molecules moved across membrane thru protein channels; requires ATP Ion gradients: make ATP, drive transport processes, generates electrical signals Nucleus: nuclear envelope and nucleoplasm; DNA replication center Smooth/rough ER: storage site for calcium ions/processing/storage of proteins Ribosomes: machinery for synthesizing proteins Mitochondria: source of ATP Cytoskeleton (microtubules, intermediate filaments, microfilaments/actin): structural support, cell migration DNA is wound around nucleosomes; organized into pairs of chromosomes. Chromosomes contain thousands of genes. Proteins produced through transcription of DNA to make mRNA Translated to make the protein Four tissue types: Epithelial, connective, muscle, nervous Circulatory System: Delivers nutrients, hormones throughout body, removes waste products from tissues, provides a mechanism for regulating metabolic activities Systemic circulation: circulation to body Pulmonary circulation: circulation to lungs Path of blood: blood flows from arteries arterioles capillaries oxygen, nutrients and waste are exchanged oxygen depleted blood flows to venules/veins oxygen depleted superior/inferior vena cava RA RV pulmonary artery lungs oxygenated blood pulmonary vein LA LV Aorta Artery vs. vein Very expandable Lots more layers Can put lots more pressure Respiratory system: Compliance: refers to ease with which lungs can expand under pressure Elasticity: easy with which lungs return to initial size Tidal volume: amount of air that moves in & out of lungs in normal breathing TLC: amount of gas in lungs at end of max inspiration Vital capacity: max amount of air exhaled from lungs after inspiration Residual volume: amount of gas in lungs after max exhalation Inspiratory reserve volume: amount of gas that can be inhaled after inhalation during tidal breathing Expiratory reserve volume: amount of gas that can be expelled by a maximum exhalation after exhaling during tidal breathing Inspiratory capacity: max amount of gas that can be inspired after a normal exhalation during tidal breathing Functional residual capacity: amount of gas that remains in lungs at all times Partial pressure of O2 in the alveoli is greater than the partial pressure of O2 in the blood. So O2 moves into blood. Partial pressure of CO2 in the alveoli is less than CO2 in blood, so CO2 moves into the air. CNS the brain and spinal cord PNS 12 pairs of cranial/31 pairs of spinal nerves Nerve cells contain: axons, dendrites, and cell bodies Skeletal system: axial – skull, hyoid bone, vertebral column, thoracic cage Appendicular – pectoral/pelvic girdles, upper/lower extremities New bone is deposited by osteoblasts Bone is connective tissue, highly vascularized 3 types of muscle: cardiac, smooth, skeletal Sarcomere is basic functional unit of skeletal muscles Muscles move through actin/myosin cross bridge formations Lecture 1 Biomaterial – nonviable material used in medical device, intended to interact with biological systems. Bioactive – materials property that allows them to react with surrounding materials Need for Biomaterials: to replace body part that has lost function, correct abnormalities, assist in healing, improve the function of existing Bulk Properties: *Chemical Properties – bonds (ionic, covalent, metallic, weak) *Mechanical Properties – strength, stress/strain *Electrical Properties  ­ conduction Surface Properties – targeting, interaction w/ environment hydrophilicity and hydrophobicity, smoothness, surface charge Biological Properties –bulk and surface properties Bulk Properties: Chemical Compositions Bonds Microstructure Purity Mechanical Properties Surface properties: Determine tissue interactions Smoothness Surface charge Hydrophilicity/hydrophobicity You’ll find stronger bonds (covalent and ionic) inside ceramics and polymers You’ll find weaker bonds (van der waals and hydrogen) inside metals, polymer chains, and water Biocompatibility – extent of adverse physiological reactions (inflammation, immune response, toxicity) There is no general set of criteria, which if met, qualify a material as being biocompatible. Biodegradability – ability of polymers to break down into smaller units that are either adsorbed by the body or excreted Metals – bone plates, screws Pro – strong, ductile (bonds found as a could so bonds can shift easily) Con – may corrode, difficult to make Ceramics – dental, joint replacement Ex. Sapphire, alumina, silica, pyrolytic carbon Pro – biocompatible Con – brittle Polymers – sutures, blood vessels Pro – easy to make Con – can deform with time Composites – combination of two or more materials Pro – strong, tailored Con – difficult to make Polymer advantages over metals and ceramics: • Easily designed • Non ­corrosive in body • Can be made biocompatible/degradable Polymer disadvantages: • Lower young’s modulus • Trace contamination Make sure your ultimate strength and yield strength are close to one another** Area under graph = work to fracture /toughness Brittle Fracture: as stress is increased, microscopic defects increase and the material fails or fractures suddenly fracture stress for ceramics, glass, PMMA Plastic deformation: beyond elastic region, small applied stress causes larger strain, non ­linear region, no recovery after removal of stress ductility or malleability for metals and alloys Transducer: measures force Strain Gauge: measures Displacement Visco ­elastic behavior – property of materials that exhibit both viscous and elastic characteristics (fluid and solid like) Creep –continuous, time ­dependent extension under constant load takes time to achieve equilibrium. Elongation/strain after a fixed load is applied. Stress relaxation – when material is stretched to a fixed length and load is monitored. Stress declines continuously until equilibrium. Isotropic – can be stretched in all directions and will have the same stress/strain curve Anisotropic – allows a material to be much stronger along the grain; directional dependence of a physical property. Dependence of young’s modulus on the direction of the load. Young’s modulus – Predicts how much a wire extends under tension or buckles under compression – ratio of stress to strain Fatigue – process by which material structures fail/fracture as a result of cyclic stresses; important for implants Properties of a Successful graft include: Ability to stretch Ability to resist kinking/squashing Flexibility (stiffness) Tensile/shear strength Circumferential strength to resist arterial pressures Lecture 3 Importance of surface properties: • direct interaction with environment • PMMA for intraocular lens : possibly inflammatory cells migration and adhesion formation between PMMA and iris Hydrophilicity: water loving, high surface tension Hydrophobicity: water hating, low surface tension Wettability: related to surface tension values, all materials have Surface tension: due to imbalance in molecular forces that occurs when two materials are brought into contact with each other forming and interface Contact angle: measurement of the angle formed between the surface of a solid and the line tangent to the droplet radius from the point of contact with the solid. When giving the contact angle, you must state the liquid used. Cell adhesion – after proteins come the cells Encourage cell attachment: coat with polystyrene Surface modification has little or no effect on bulk properties and functionality of device*** Why do surface modification? Modify cell adhesion and growth Control protein adsorption Improve lubricity Improve resistance and corrosion resistance Alter transport properties Modify electrical characteristics Modify blood compatibility Immediately upon implantation of biomaterial: Protein adsorption Vroman effect: displacement of initial adsorbed proteins with other proteins of high affinity and low concentration when exposed to internal environment Can be controlled by coating with PEG (poly ethylene glycol via steric hindrance) Acute inflammation: neutrophils enter site (always have) Chronic inflammation: presence of macrophages, low grade inflammation (do not want) Granulation tissue: small round masses of tissue (normal wound healing) Foreign body rxn: foreign body giant cells (fused macrophages) – (normal wound healing) Fibrosis and fibrous encapsulation: dense fibrotic connective tissue (scarring) :( Polymers: organic carbon based compounds that are long chains of covalently linked molecular units. Examples aren’t just plastics, but proteins, nucleic acids, and carbs Basic unit of polymer is a monomer Macro = lots Oligo = few Thermoplastics: (linear branched) can be heated and when cooled will take the shape that they have been formed into; acrylics, styrenes Thermosets: (crosslinked ­rigid) like rubbers that will degrade when you heat them Elastomers: (low crosslink ­density) rubber that will recover upon stress withdrawal Polymers are named after function group linkage in backbone i.e. bonds between monomers Higher the molecular weight of the polymer the more difficult to process NOTE: Mw IS GREATER THAN or EQUAL TO Mn Number Average Molec. Weight: arithmetic mean of molar mass distribution Mn = ΣXiMi , where Xi = mole fraction of molecules having a molar mass of Mi If Ni = Number of moles with mass Mi, then Mn = ΣNiMi / ΣNi Example 1: Polymer sample consisting of 9 moles with molecular weight 30,000 and 5 moles with molecular weight 50,000. Mn = {[9 mol x 30000 g/mol] + [5 mol x 50000 g/mol]} / (9+5) mol = 37,000 g/mol Example 2: Sample with 9 grams of molecular weight 30,000 and 5 grams with molecular weight 50,000 Mn = (9 + 5) g / {[9g / 30,000 g/mol] + [5g / 50000 g/mol] = 35,000 g/mol Weighted Molecular Weight: second order average Defined as Mw = ΣWiMi , where Wi = weight fraction of molecules having a molar mass of Mi If Ni = Number of moles with mass Mi, then Wi = NiMi / ΣNiMi = wi / ΣNiMi ……………………………………(2) Therefore, Mw = ΣNiMi2 / ΣNiMi = ΣwiMi / Σwi………………….(3) Example 1: Polymer sample consisting of 9 moles with molecular weight 30,000 and 5 moles with molecular weight 50,000. Mw = {9 mol (30000 g/mol)2+ 5 mol (50000 g/mol)2} divided by {9 mol (30,000 g/mol) + 5 mol (50,000 g/mol)} = 40,000 g/mol Example 2: Sample with 9 grams of molecular weight 30,000 and 5 grams with molecular weight 50,000 Mw = {9g (30,000 g/mol) + 5g ( 50000 g/mol)} / (9 + 5) g = 37,000 g/mol Importance of molar mass distribution: we need to know for polymers that are non ­ degradable because there are limitations for renal clearance Polydisperity Index (PI) : measure of the width of a molecular weight distribution ALWAYS greater than 1 since Mw >= Mn; greater it is; wider the MWD Defined as ratio between weight and number average; Mw/Mn Can heat polymers to form more crystalline substances as crystallinity increases, it becomes more opaque due to scattering of light “looks” white Tm = crystalline melting point – melt transition temperature – temperature at which all crystalline regions melt; crystallinity disappears As degree of crystallinity increases, Tm increases, increased stiffness, less flexible, less permeable, low penetration and slow hydrolysis Amorphous – glassy polymers, lack crystalline domains that scatter light so they are transparent, when you heat they transform from a hard glass (soft, brittle) into a soft, flexible, rubbery state Amorphous polymers don’t form an ordered structure when cooled form a melt like crystalline polymers do Tg = temperature at which a polymer undergoes a transition from a hard glassy state (amorphous solid) to a rubbery state Motion of polymer chains possible above Tg, while only small molecule motions below it Brittle below Tg , flexibly (rubbery) above Tg Diffusion less below Tg, greater above Tg Density, heat capacity, permeability, dielectric constant change at Tg Copolymerization: chemical and mechanical properties can be adjusted by varying the polymer composition Lecture 4 Crystallinity: polymers with strong IMF; polymers cooled from melt state; compact structures; As crystallinity increases, polymer becomes more opaque due to scattering of light Crystallinity increases stiffness *higher young’s modulus* Less flexibility; diffusion rates are less permeable to molecules *necessary for drug delivery sometimes* Low penetration of h2o; slow hydrolysis Ex. PLGA, Polyethylene Teraflate Bone implants, bad for optics Amorphousness: called glassy polymers; brittle; when heated become soft; rubbery Lack crystalline domains that scatter light *transparent* Ex. Poly(methyl methacrylate) Optics, PMMA, PDMS, poly Syrene Tm : crystalline melting point; temperature at which all crystalline regions melt; as crystallinity inc., so does Tm Tg : glass transition temperature; temp at which a polymer changes from a solid glassy state to a rubbery state Heat capacity, density, permeability, dielectric constant, etc. change at Tg Silicones have low Tg and Tm, always fluid at relative temps (breast implants); Biodegradable polymers: PLGA (hydrolytically degradable because of esters bonds); proteins – peptide bonds PLGA put together by ester bonds Ester bonds are hydrolytically cleaved More hydrophobic (due to methyl group); looses water less; Slower rate of hydrolysis To increase rate of drug release, increase G amount because it is more hydrophilic driven by hydrolysis Can also increase drug release rate by creating micro particles increasing surface area increases degradation There are isomeric forms of lactide in PLA If uniform, several strands come together arrange more crystalline, more uniform means more crystalline Applications of biodegradable polymers: Sutures, drug delivery, scaffolds Surgical devices and implants Drug delivery Organ replacements Biosensors Bioadhesives, ocular devices Tissue engineering: development of biological substitutes that restore, maintain or improve tissue function 3 basic tissue-engineering strategies: 1) Cell infusion: artificial blood; transplantation of cells that produce desired protein or substance 2) Infusion of substances to aid tissue repair/function: gene therapy 3) Cells placed on or within matrices Systems: open & closed Closed: immunological isolation from body Open: cells and matrix integrated within body or implanted following tissue formation; completely interacts with body most common Also closed system: Need hepatocytes from animals/cadaver Immunoisolote cells Use macrocapsules: implant inside body Implanted permanent Microcapsules > macro because easier to admin (inject) and permanent solution Closed system: Use pig liver to function outside of body Not integrated w/in body temporary solution Open System: Goals of tissue engineered open system: permanent solutions! Key challenges in tissue engineering: Vascularization (continuously supply oxygen and nutrients), immune system response, proliferation, cell adhesion Materials: mechanical, control of porosity, diffusion Lecture 5 Scaffolds: Provide mechanical support for cells, permanent, controlled degradation, promoters of cell adhesion, differentiation, and function Ex vivo: taken out from inside In vivo: inside the body In vitro: outside (cultures outside) Autologous: from the same owner Allogenic: same species Xenogenic: different species Morbidity: sick Angiogenesis: generation of blood vessels Extracorporeal: outside the body Use of biomaterials in Tissue Engineering: Goal is to be Biomimetic: trying to mimic what is happening during tissue development What you want in scaffold: Biocompatible, biodegradable, porous, cell adhesion/migration, mechanical properties Challenges: control of diff/prolif, immune response, vascularization, cell adhesion Pro/cons of using patient’s own cells in tissue engineering: Pros: immune response Cons: not enough, morbidity, cells could be bad, multiple surgeries Functions of scaffolds: Shape/mechanical support, cell adhesion, change of differentiation VEGF – vascular endothelial growth factor Cartilage is very difficult to replace using synthetic polymers only because it cannot substitute load bearing cartilage In reference to scaffolds: proliferation and differentiation are inversely proportional to one another How can you encourage cells to attach to scaffold? RGD peptides fibronectin (interact with integrins), collagen (gelatin), laminin How does altering porosity affect the properties of a scaffold? Increase porosity, decrease strength, but increase diffusion rate Porosity is important for creating a network of tubes so that nutrients are able to flow to all cells on the scaffold How can you alter the degradation properties of PLGA scaffold? Change ratio of L:G (75:25), crystallinity Lactide is more hydrophobic; DEGRADES SLOWER Polyglycolide – Hydrophilic, and is driven by hydrolysis, so they degrade FASTER If there is more Polyglycolide, it degrades easier PLA or PDLA – which will degrade faster? PLA is more crystalline because polymerized from same material Two methods of creating scaffolds: Salt leeching and gas formation Salt Leeching: Using a polymer, PLA, PLG Dissolve in organic solvent (chloroform, acetone, not alcohols) Heat higher than Tm/Tg and cool at controlled rate to control crystallinity Evaporate solvent Place scaffold into water and salt is dissolved away leaving pores Gas Forming: Controlling porosity; Mold w/ polymer and evaporate solvent Instead of NaCl use NH4Cl Dip into acidic solution, like citric acid Citric acid + NH4Cl Ammon. + Co2 gas bubbles Bubbles creates pores Mechanical strength decreases as you increase the citric acid concentration Lecture 6 Diffusion is defined as the movement of solute molecules from a higher to A lower concentration gradient Occurs by a “random walk” mechanism in which molecules are continually colliding with each other while moving “on average” towards a particular direction Brownie in motion – “random walk” – random movement of a molecule by its energy state – molecules colliding with each other And gradually diffuse out as it goes on The diffusive flux, mass per unit time of solute movement Where dC/dx is the concentration gradient in the direction of solute movement And D is the constant of proportionality and is defined as the Diffusion constant or Diffusion coefficient root mean square displacement; X is the distance (length) Diffusion constant depends on what the solute is, where it is (liquid, water, oil) A property of the solute, but depends on what the solute is Depends on temperature Diffusion prop. To energy you give it Provide heat energy, collides more, moves more Negative sign in front? By convention, if movement is high to low, direction of solute movement, the concentration decreases You use microscopy techniques to follow its random movement over time. If diffusion coeff. Is high  ­> diffuse much more distance If diffusion coeff. Is low diffuse much less Flux proportional to conc. Gradient It is a steady state condition. You let it sit for a long period of time, and you see what it looks like. Doesn’t give you a time dependent flux. Not dependent on time. A flux is coming in (3), each flux you are dividing it by the x, y, and z directions respectively. Generation of solute = cells that are generating oxygen (neg term) [consume the solute] Generation = cells that are generating CO2 (pos. term) Write the diffusion equations (Fick’s Laws of Diffusion) Delta y, delta z are the surface areas where its coming in Multiply by the areas, first part is (in ­out) Psi = accumulation or consumption term dC/dt = concentration gradient times whole volume of the cube Divide both sides by the by dy, dx, dz And then limit the volume of the differential volume to zero. Jx ­Jx/dx as dx turns to zero Jx/dx Jx = D(dC/dx) Think you are injecting 10 molec. of a drug into your pat. At t = 0, you gave a bolus injection of drug At diff. time points, how does that drug distribute? Conc. of drug with respect to distance? Derive the kinetic diffusion equation from first principles Understand how the diffusion constant varies with different parameters Stokes ­Einstein equation: Diffusion of a spherical particle of radius a in a solution with viscosity mu. This equation is only valid where the diffusing particle is large compared to surrounding solvent molecules (diffusion in aqueous medium). What ends up changing is capital D = diffusion coeff. = dependent on viscosity Very viscous diff. very slow D is proportional to KT D is inversely prop. To radius (a) Stokes einstein = gives you diffusion of a spherical molecule a =Hydrodynamic radius – changes with the type of liquid Say you have a protein in solution ( chain of amino acids that fold) In another solvent, it may be compact You can’t say what the radius is, unless you know the solvent Radius around that sphere is the hydrodynamic radius Based on the properties of the solvent **** Define and explain what is meant by controlled release of drugs Delivery of the drug at a specific rate and/or at a specific location Two things that a controlled release system should have: 1. Components that can be engineered to regulate specific properties like release rate, duration, targeting 2. Duration of action longer than a day Focus on the orange line first, that looks sinusoidal These are your bolus curves that you are taking twice a day Plasma conc. Of drug goes up, down, take another, up and then down again… Any drug you take – all of them have a minimum effective concentration – minumum amount needed to do job All drugs have a toxic concentration – your goal as a BME is to keep the concentration of drug in pts. Blood in between those two levels Your goal is to be the dotted line Sustained release of drug is red line, doesn’t last for weeks Principles of controlled drug delivery : delivered at specific rate and at specific location Temporal delivery – time delivery, over a few days, if not weeks, months, years Spatial delivery – targeted to specific organ Outline the advantages of controlled release concepts 1. less frequent administration 2. Less invasive (effective through needle ­free routes) 3. Decrease drug tolerance 4. Decrease drug accumulation – prevents toxicity 5. Localize drugs to target site 6. Economical 7. Increase patient compliance 8. employ less total drug 9. improve efficiency in treatment Define and mathematically express the release kinetics from controlled release drug delivery devices Zero order release: Rate of drug release is independent of the mass of drug remaining in the device; rate of release is constant Ex. Pumps, reservoir systems Mt = mass of drug released your device at time t First order release: Rate of drug release is proportional to the amount of drug remaining within the implant; yielding means degrading M inf. – Mt = amount of drug left Square root of time release: Release rate decreases proportionally to the square ­root of time Bulk eroding vs. surface eroding Polymeric device… if you put this in water (hydrolytic deg) only degrades on surface all the time… how will device look like after a week? It will be still a cube, just shrunken. That’s called surface eroding device Bulk eroding – both from inside and surface… can’t really tell what the shape of device is going to be at certain time points, but mass will decrease at steady rate, degrades throughout the matrix at same rate Explain and discuss in the various methods of controlled drug delivery Polymer controlled drug release: diffusion controlled (reservoir devices) – molecules unable to freely diffuse due to insoluble polymer matrix solvent ­controlled (osmotically/swelling controlled) – drug molecules dissolve in H2O and flow through pore at controlled rate chemically controlled (drug covalently attached to a polymer backbone) – using a bio erodible device by some chemical reaction List the advantages and disadvantages of a Reservoir System and name a commonly used polymer for this system? A supersaturated drug reservoir, surrounded by a non degradable polymer membrane Most commonly used polymers: Silicone elastomers, EVAc Advantages Zero order (constant) release Easy to control kinetics by device design parameters Disadvantages Non ­degradable, must be removed, must be hydrophilic and lycophilic Impermeable to high molecular weight drugs (low porosities) Leaks can be dangerous Costly/Surgeries How to control microsized particles: You take the water-soluble drug (dissolved in water) and mix it with your polymer that should be dissolved in an organic solvent. You mix these. You then add this mixture to another water phase. If you were using surfactants, here is where they would be. You then create an emulsion of this mixing. At this point you would evaporate the solvent. This is when you would harvest your microparticles There is no slab when creating microparticles. At this point in the process you've got your microparticles, you would probably wash off the surfactants if you've got them there and then dry them off. If you put the microparticles back into a water phase, the drug will diffuse out of them. The drug is actually incorporated within your PLGA particle and putting it in water will result in a loss of the drug due to diffusion. Lecture 7 Non –degradable polymers Either putting in as patch , outside body, pt. can go back and remove…oral pill that releases drug and passes through, or implants Implants – have to surgically go back and remove implant after drug has been released Degradable polymers – Administered through different routes Hydrogels – network polymers – hydrophilic Non ­erodible matrix systems – encapsulating drug in matrix Advantages – easy to fabricate Less severe leaks Better for high molecular weight drugs (high loading to make interconn. pores) Disadvantages – non ­degradable Release rate gen. not zero order Bio ­erodible systems – surface eroding Advantages – injectable, zero order, pt. compliance Disadvantages – dictated by diffusion and degradation (gets complex) Release kinetics difficult to control Swelling controlled matrix (hydrogel) Advantages – low burst effects – initial release (1st) Burst effect – a spike Predictable swelling rate Diffusion with hydrophilic drugs inc. w/ more drug Disadvantage – short release period Not for all delivery routes Polymer conjugates – Take drug and conjugate polymer with drug Mostly synthetic polymers used Water soluble (hydrophilic), biocompatible Advantages: very high drug loading Increase half life Improved targeting Improved cellular uptake Reduced renal excretion Disadvantage :new chemical entity if you change material Purification necessary before in ­vivo application Drug can lose activity during conjugation process Polymer needs to be eliminated from body Polymer can sterically interfere with bioactivity PEGylation: Conjugate polymers to the surface of protein – cover it PEG – protects the protein from getting attacked by other things Called PEGylation – process of attaching polyethylene glycol to protect a protein Shields protein, doesn’t kill drug efficacy, prevents surface adhesion, biochemical and immunologic protection, prevents approach of deleterious macromolecules When Injecting protein into blood stream, first encapsulate with interferin, then conjugate polymer to the surface (PEG) Biomechanics is the science that deals with the action of FORCES on biological solids, fluids, and visco ­elastic materials Statics – deals with forces acting on bodies in equilibrium In any direction, sum of forces must equal zero In any direction, sum of moments must equal zero Dynamics – deals with forces acting on bodies in motion Solid – if you apply a constant force is going to deform according to the elastic region of the curve… if you further apply force it is going to move to plastic region Fluid if you apply force it is Going to move Constitutive Laws Fundamental descriptor of the properties of the constituents of a material  ­ independent of the size or shape of the material A mathematical description of the relationship between the applied loads (stresses) and the resulting deformations (strains) Having the law, one can predict the deformation from the applied force (and vice versa) for any structure made from that material How to Obtain Constitutive Law? Measure geometry Measure forces in response to a variety of length changes Convert to stresses and strains Examine relationship between stresses and strains Derive the mathematical relationship among the stresses and strains Test the predictions with other experimental tests Cells align perpendicular to the direction of stretch when subjected to a uniaxial stretch. Actin Filaments are responsible for this. Cells are responding – sensing mechanical force – but also direction, not just amplitude. If you look at all the cells: at lower forces, they are oriented at 65 ­70 degree angles and with more force 85 ­90 degree angles Endothelial cells (inner lining of blood vessels) respond to the flow of blood, and are directly exposed to shear forces (mechanical forces) Muscle cells depolymerize and repolymerize perpendicular to the force. If we stain with red we can see actin sitting on substrate, if it tents (you are stretching in more one direction and confuses the cell) Focal adhesion – anchor points (where cell grabs substrate) – that’s where cell senses substrate and decides what to turn into (bone, fat) Insert BIOMECHANICS problem Mia Markey Informatics »The collection, classification, storage, retrieval, and dissemination of recorded knowledge treated both as a pure and as an applied science. Study of the optimal storage and use of data. biomedical informatics = bioinformatics + medical informatics bioinformatics: study of the optimal storage and use of biological data in biomedical research medical informatics: study of the optimal storage and use of medical data for clinical decision making and related tasks. Now more commonly called “clinical informatics”. Accuracy  ­ Number correctly classified samples divided by the total number of samples Accuracy just counts up the number of times the right answer was obtained But, there are two kinds of mistakes… –Could classify as positive when actually negative –Or, could classify as negative when actually positive Another disadvantage of accuracy is that it depends upon the prevalence of the population, i.e., the frequency with which the two classes occur Prevalence  ­ Number positive (disease) samples divided by the total number of samples sensitivity and specificity that separate the two kinds of errors and do not depend on prevalence When Prevalence and accuracy are high Sensitivity dominates, when they are both low, Specificity dominates. Sensitivity (TPF)  ­ Number samples classified as positive that were actually positive divided by the number of samples that were actually positive. Specificity  ­ Number samples classified as negative that were actually negative divided by the number of samples that were actually negative false negative fraction and false positive fraction that also separate the two kinds of errors and do not depend on prevalence FNF  ­ Number samples classified as negative that were actually positive divided by the number of samples that were actually positive FPF  ­ Number samples classified as positive that were actually negative divided by the number of samples that were actually negative decision variable  ­ a continuous variable that we will use to make our decision about whether to classify the sample as + or – (ROC) curve shows the trade off in sensitivity and specificity achieved for different thresholds on the decision variable. Graph Sensitivity (y ­axis) vs. 1 ­Specificity (x ­ axis) P (+ | D) P ( D) Predict anything less than or equal to P ( D | +) = the threshold as being – P (+ | D) P ( D) + P (+ | Dc ) P ( Dc ) Predict anything above the threshold as being + Accuracy = P (+ | D) P ( D) + P (− | Dc ) P ( Dc ) € positive predictive value and negative predictive value Separate the two kinds of errors, but DO depend on prevalence € PPV  ­ Number samples classified as positive that were actually positive divided NPV  ­ Number samples classified as negative that were actually negative divided by the number of samples classified as negative Sensitivity = P(+|D) Specificity = P( ­|Dc) Prevalence = P(D) PPV = P(D|+) FPF = P(+|Dc) 1 ­Prevalence = P(Dc) Spina bifida occurs in about 7 out of every 10,000 live births in the United States. The prevalence of disease is given as 7 / 10,000 = 0.07% P(D) = .0007 P(Dc) = 1 ­.0007 = .9993 The test has sensitivity = 79% P(+|D) = .79 The test has specificity = 97% P(+|Dc) = 1 – P( ­|Dc) = 1 ­0.97 = 0.03 Dr. Aaron Baker Stent – small meshed metal tube that is inserted into an occluded artery to restore blood Types: Coil/helix, slotted tube, Wire Mesh Atherosclerosis – build up of plaque in arteries that can block blood flow Catheter – inserted through the femoral artery in the groin and threaded to the occluded section of the artery Elastic recoil – after balloon deflation, the large number of elastic fibers in the tunica media cause a mechanical collapse Neointimal proliferation – formation of an inner layer at the site of injury, composed of cells and ECM on the intimal surface Negative remodeling – constriction of the vessel by the formation of a fibrotic scar within the adventitia Restenosis – re ­occlusion of arterial lumen after stenting or balloon angioplasty Optimal Material: *High elastic modulus *Low Yield strength – stent expansion *fatigue resistance *biocompatible *radiopaque – no radiation Stent Design Considerations: *Low profile to prevent flow disturbance *Amount of metal minimized to limit thrombotic response *high radial stiffness to prevent elastic recoil *flexibility to conform to vessel geometry *good scaffolding properties *radiopacity for precise tracking – blocks radiation from entering Stent Design to Prevent Restenosis: *Alter arrangement, number of struts, and thickness of struts *Coatings Lecture 11 Stroke volume: volume of blood heart puts out with each beat Cardiac output: stroke volume * heart rate Each heartbeat = 80 ml (Stroke Volume) How many beats does it take for the average red blood cell to make one complete cycle through the body? (Avg adult has 5 L) 5000 ml / 80 ml = ~62 beats LVAD – left ventricular assist device – tube that goes into LV that pulls blood from ventricle into a pump. Pump sends blood to aorta. Bypasses the weak ventricle. pump placed in upper part of abdomen. Another tube brought outside abdomen to outside the body attached to control system. Artificial valves – pyrolytic carbon – clotting and blood thinners infections Porcine valves – pig valves – veins/arteries are similar in size, causes immune response, immunosuppresants, doesn’t last as long as mechanical valves Zenogenic tissues – no generation/proliferation mechanisms Valves have to withstand circular and shear stresses Blood compatibility necessary We have failed to create small vessels – more clotting in small vessels not solved yet Solid deforms w. applied force – strain is a function of applied stress , elastic limit is not exceeded, strain indep. Of time over which force applied, deformation disappears when force removed if elastic limit not exceeded Fluid – rate of strain is proportional to applied stress (Newtonian fluids), fluid continues to flow and will not recover original form when force removed Non ­N fluid – rate not constant, doesn’t recover to original form once force is recovered, pastes, gels, polymer solutions, blood Red cell aggregates (with fibrinogen as the glue) cause the blood to be non ­ Newtonian at low shear rates Volume Fraction: RBC – hematocrit High count – not good for circulation Low Count – acts like water emulsion Non ­newt – pastes, gels Reynolds – ratio of inertial forces to viscous forces – describes laminar vs. turbulent flow where V is a typical velocity of the fluid, D is a typical dimension of the flow geometry, ρ is the density of the fluid and μ is the viscosity coefficient. R < 2500 laminar; R > 2500 turbulent Thixotropic: dynamic viscosity decreases with the time for which shearing forces applied blood Rheopectic: viscosity increases with time for which shear force applied; gypsum suspension in H20 Newtons Law of visc. Tau = = delta P*r / 2L Tau = shear stress dVx/dy = sheer rate, rate of strain, velocity gradient ex. Ethyl alcohol, benzene, hexane, H20 Newtonian Fluid: trz =  ­µ(duz/dr) µ = constant for fluid at given T Non ­Newtonian Fluid: trz =  ­h(duz/dr) h = f(duz/dr) or h = f(trz) Power rule: pseudoplastic: n <1 polymers – most non ­newtonion fluids, polymer sol, blood viscosity dec. with inc. velocity gradient, more viscous at low shear rate dilatant: n>1 dispersions – viscosity increases with increasing velocity gradient, shear thickening fluids Bingham Plastic: T= T0 + m (du/dy), tooth pastes, blood (due to fibrinogen) T0 = mag of stress need to make fluid move For high flow, vessels make large D to put Re in laminar range Turbulent flow in arteries, plaques and lipids will stick to vessel walls Apparent viscosity : mu = tau/gamma Blood is both Newtonian and NN – also thixotropic! Poiseulle's Equation: Lecture 12 Q = KdPD4/L Hagenbach-Poiseulle's Equation Q = pi*a4(p1-p2)/8muL K = pi/128mu = Q is the flow rate, Dp is the drop in pressure in a tube of length L and diameter D. where μ is the coefficient of viscosity and a is the tube radius Assumptions used: Newtonian fluid Laminar flow No slip at the vascular wall Steady flow Cylindrical shape Rigid wall Fully developed flow Vascular resistance: R = dP/Q analogous to electrical resistance R = 8muL/pia^4 Resistances in series are added, inverse resistances are added for parallel Complexity in Soft tiss model Nonlin – stress/strain in elastic region non-lin Heterogeneity – consists of many materials with own mechanical beh. (cell/muscle/fibers) active nature – tissues are living, active Elastin - taut, low stiff, bears load, tubular Collagen - Tortuous, high stiff, wavy, large YM uniaxial extension test – cut artery longitudinally and grip between clamps, tissue extended in one direction. Record the force and displacements at regular intervals, until tissue tears. wavier collagen later recruited nonlin elastic reg for skin due to large num of collagen and elastin anisotropy - vascular tiss stiffer in circumferential than longitud direction viscoelasticity – solid and fluid like properties solid - resists deformation like an elastic body liquid - flows due to sustained force CREEP = Continuous, time-dependent extension under constant load takes time to achieve “equilibrium” elongation/strain after a fixed load is applied Abdominal Aortic Aneurysm – Not sure if collagens were already taut, or if elastin is stiffer than usual Collagen is getting recruited faster Ultimate strength and yield strength are much lower, will snap easier, not as mechanically apt as usual La Place's Law measures circumferential stress p is blood pressure (N/cm2) divide mmHg/75 R is radius of vessel (cm) t is wall thickness (cm) sigma = pR/t for cylinder sigma = pr/2t for sphere Derive from first principles the equation that governs flow rate in blood vessel and state all assumptions: Assumptions: Shear stress in opposition to pressure drop Cylindrical shape Newtonian fluid Laminar flow Steady flow Rigid wall No slip at vascular wall Across = πr 2 P πr 2 P1 − πr 2 P2 = τ * 2πrl Δ Pr τ= 2l dV τ = −µ dr Δ Pr dV = −µ 2l dr Δ Pr dV = ∫ − dr ∫ 2 µl Δ Pr 2 V =− +C 4 µl v = 0, r = a ΔPa 2 ∴C = 4 µl ΔP 2 V= (a − r 2 ) 4 µl dA = π ( r + dr) 2 − πr 2 dA = πr 2 + 2πrdr + πdr 2 − πr 2 dA = 2πrdr a ∫ dQ = ∫ V ⋅ dA = ∫ 0 ΔP 2 ( a − r 2 )⋅ 2πrdr 4 µl πa 4 ΔP Q= 8 µl ...
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