BME350 TT2 Notes (Fall 2024) PDF

University of Toronto Fall Semester 2024 Professor: Dr. Dawn M. Kilkenny BME350 Biomedical Systems Engineering I: Organ Systems ___ 6.1: Cardiac Anatomy & Electrical Activity Objectives Gross anatomy of the heart: myocardium, chambers, & valves Cellular anatomy: contractile & aut...

University of Toronto Fall Semester 2024 Professor: Dr. Dawn M. Kilkenny BME350 Biomedical Systems Engineering I: Organ Systems ___ 6.1: Cardiac Anatomy & Electrical Activity Objectives Gross anatomy of the heart: myocardium, chambers, & valves Cellular anatomy: contractile & autorhythmic cells Myocardial APs: role of Ca2+ Electrical conduction system: pacemakers, cardiac conduction system, correlation to ECG Cardiac Circulatory System Overview 1. Includes: heart, circulatory vessels, blood & lungs 2. Heart is first organ system to develop a. That’s why you can sense a heartbeat in babies 3. Circulation is extensive vessel network (~60k miles end to end) 4. Function: transport, protect and disperse heat Systemic Distribution of Blood - Numbers ~7% body mass (4-5L) In constant motion RBC makes 2 x 105 trips before dying  ○ Travels 19k km/day Every living cell in every organ must be fed by blood or it will die The Heart: hollow muscular organ approximately size of clenched fist Pump that establishes pressure gradient required for blood to flow to tissues i.e. engine of circulatory system Location: between sternum and vertebrae ○ Makes it physically possible to manually drive blood from heart when not pumping effectively Begins beating at 4 weeks, doesn’t stop till death Pericardial Sac: tough fibrous covering with secretory lining Prevent friction between pericardial layers → offers protection to the heart Pericarditis: pericardial sac inflammation Gross Cardiac Anatomy Systemic and pulmonary pumps Each pump composed of two chambers: ○ Atria (entry hall): upper chambers that receive blood returning to the heart, transfer blood to lower chambers ○ Ventricles (little belly): lower chambers that pump blood from heart Continuous muscular septum: prevents blood from mixing in the heart Supporting Cardiac Structures Veins: carry blood to atria (vena cavae, pulmonary veins* → carry O2) Lungs: integrated organ responsible for purifying air blood from right ventricle Arteries: carry blood from ventricles (aorta, pulmonary arteries*→ carry deO2) Heart Wall Layers Myocardium: muscle layer Endocardium: regulates material exchange  Pericardium: protective outer layer Muscle of ventricles has spiral arrangements which allows ventricular contractions to rise/spiral up Thickness of left ventricle > right → faces more workload for having to pump to entire body Heart Valves: interconnecting rings of dense connective tissue that anchor each of the heart valves (fibrous skeleton) Function: maintain unidirectional flow Exist in the same plane One-way valves strategically placed: ○ Atrioventricular valves: between atria and ventricles Tricuspid - right AV Move blood at lower pressure, so need to open more readily, hence tricuspid bicuspid/mitral - left AV Chordae tendinae: fibrous cords, help prevent valve eversion Heartstrings ○ Semilunar valves: at junctions to arteries that exit ventricles Aortic: at junction to body Pulmonary: at junction to lungs Has 3 crescent moon-shaped leaves Eversion prevented by anatomic structure and positioning of cusps History of Heart Valve Replacements Heart is Mechanically active Contractile cells: ○ 99% of cardiac muscle cells ○ do mechanical work of pumping (APs lead to contraction and generation of force) ○ normally do not initiate own AP Autorhythmic cells: ○ do not contract or contribute to force generation ○ spontaneously initiate and conduct action  potentials ○ constitute cells of SA node, AV node, Bundle of His & Purkinje fibers Myocardial Cells Cells branch and join neighbouring cells end-to-end by intercalated discs ○ Contains two membrane junctions: Desmosomes: ‘spot rivets’ help resist shearing forces and hold cells together (transfer force) → need to stick together Gap junctions: permit APs to spread (electrical connection) actin/myosin organized into functional sarcomeres Striated, smaller than skeletal muscle cells Single nucleus/cell Metabolic Requirements of Myocardial Cells SR smaller in cardiac muscle < skeletal as cells depend on extracellular Ca2+ to contract Cells abundant with mitochondria Cardiomyocytes consume 70-80% O2 ○ >2x O2 extracted by other cells Cardiac Excitation-Contraction Coupling (2) opens vg Ca2+ → EC Ca2+ comes in → ∆ Ca2+ in enviro → ∆ effects * no DHP receptor, just vg channels SR still allows Ca2+ to flow out Crossbridge cycling Channels ○ 2° active transport pumps Ca2+ back out → using gradient, channels work together Ca2+ Influences Myocardial Contractions Ca2+ entry to cytosol through L-type channels in T tubules triggers large release of Ca2+ from the SR Ca2+-induced Ca2+ release leads to cross-bridge cycling and contraction Interdigitating actin and myosin filaments slide closer together in the presence of free Ca2+ (similar to skeletal muscle) The regulatory proteins troponin and tropomyosin are involved NOTE: ○ In cardiac muscles, troponin not fully covered with Ca2+ Enough Ca2+ is released to interact with all troponin molecules in skeletal  muscle MAKES CARDIAC MUSCLES UNABLE TO SUMMATE ⇒ NO TETANUS ⇒ or else BF stop Inc. IC Ca2+ will inc. # of crossbridges that form, inc strength of cardiac contraction Correlation of Electrical and Mechanical Activity *CARDIAC MUSCLE ACTIVITY CANNOT SUMMATE Plateau: sustained period of depolarization ○ prevents restimulation, accounts with long refractory period Quickly achieves maximal change in depolarization Main Features: ○ Long duration compared to somatic APs ○ Shape of AP varies depending on location of myocardium ○ Variation in stability of RMP infers contractile vs autorhythmic ventricle atria SA Node Long Duration Correlates with Function + Prohibits Tenatus Duration of AP determines duration of refractory periods Varies depending upon type of myocardial cell ○ 150 ms - atria  ○ 250 ms - ventricles ○ 300 ms - Purkinhe fibers Nerve AP 1-2 ms Summation + tetanus of cardiac muscle is impossible ○ b/c long refractory period occurs in conjunction with plateau phase ○ Ensures alternating periods of contraction and relaxation ⇒ pump function Ion Diffusion Responsible for Myocardial AP *plateau due to activation of slow L-type Ca2+ channels Muscle Potential Comparisons Skeletal Muscle Contractile Autorhythmic Myocardium Myocardium Membrane Stable at -70 mV -90 mV Unstable pacemaker Potential potential; usually starts at -60 mV Events leading to Net Na+ entry Depolarization enters Net Na+ entry threshold potential through via gap junctions through If channels; ACh-operated reinforced by Ca2+ channels entry Rising phase of AP Na+ entry Na+ entry Ca2+ entry repolarization Rapid, caused by K+ Extended plateau Rapid, caused by K+ efflux caused by Ca2+ entry, efflux rapid phase caused  by K+ efflux hyperpolarization Due to excessive k+ None; resting None, when efflux at high K+ potential is -90mV, repolarization hits permeability when EQ potential for K+ -60 mV, If channels K+ channels close; open again leak of K+ and Na+ restores potential to resting state AP duration Short 1-2 ms Extended 200+ ms Variable, generally 150+ ms Refractory period brief Long b/c resetting of none Na+ channel gates delayed until end of AP SA and AV Nodes + Specialized Conductive Fibers Sinoatrial (SA) node: pacemaker of normal heart; specialized region in right atrial wall near opening of superior vena cava Atrioventricular (AV) node: small bundle of specialized cells located at base of right atrium near septum Bundle of His (AV Bundle): cells originate at AV node and divided into branches that travel down the septum Purkinje Fibers: small, terminal fibers that extend from bundle of His and spread throughout ventricular myocardium Firing Rate of Pacemaker Cells Location Duration of AP (ms) Intrinsic Firing Rate (impulses/min) SA node 150 70-80  AV node 150 40-60 Bundle of His 250 40 Purkinje fibers 300 15-20 *Pacemaker with faster rate of depolarization controls/sets heart rate Pacemaker Potentials, Ion Transport Autorhythmic cells do not have a resting membrane potential ‘Resting’ potential is unstable but starts at ~60 mV Display pacemaker potentials - potential slowly drifts Why membrane potential so labile? ○ Autorhythmic cells contain If = funny current channels: permeable to both K+ and Na+, open (when mp is -60mV) Depolarization to Threshold If channels allow current to flow at negative membrane potentials Na+ influx > K+ efflux = depolarization As mp becomes more +ve, If channels gradually close and Ca2+ channels open Overall result = depolarization to threshold and firing on AP -40 mV = If channels close Feedforward cycle at -40 mV Temporal Distribution of Cardiac Current  Depolarization through septum, then ventricles follows circular upward contraction i.e. RH rule ECG: represents sum of multiple APs taking place in many myocardial cells at one time; records overall spread of electrical activity throughout the heart Extracellular recording Amplitude of ECG electrical signal much smaller than AP signal by time reaches surface of body Bipolar -> difference between signals Records activity during depol and repol events Different phases of ECG waveform correlate to specific cardiac events *ECG at 0 reveals state (b/c means not registering difference between two points but captures same state) Abnormal HR Arrhythmia: variation from normal rhythm and sequence of excitation of the heart ○ Atrial flutter ○ Atrial fibrillation ○ Ventricular fibrillation ○ Heart block ○ Tachycardia (>100 bpm) ○ Bradycardia ( venous pressure = driving force for movement of blood  Greeted decrease in pressure occurs at arteriolds → bottleneck ○ Where things slow down to allow gas exchange at capillaries Capillaries: extensively branched vessels with small radii (single layer of endothelial cells) Sites of exchange between blood and surrounding tissue Enables 1 RBC to pass through Blood flow → maximized SA, low resistance, minimized diffusion distance = low velocity of flow Regulation: surrounded by precapillary sphincters: rings of smooth muscle at beginning of vessel ○ @ rest, capillaries closed ○ Contraction at sphincters reduces blood flowign into capillaries in organ Metarterioles (i.e. bypass vessel): surrounded by smooth muscle and run between arteriole and venules = sunt where no gass exchange occurs = homeostatic regulation Veins: transport blood back to heart capillaries drain into venules which converge to form small veins that exit organs  Smaller veins merge to larger vessels → larger radius offers little resistance to flow → also blood reservoir Promote uni-direction flow ○ Varicose veins when blood pools and valves don’t work Interrupting skeletal muscle pump Change in anatomy Blood Pressure Regulation MAP, PP monitored by baroreceptors → strategically placed ○ At normal pressure, vessel valels stretched at receptors are active ○ Receptors send nerve signals affecting activity of cardiac muscle to regulate blood flow ○ As pressure decreases, sensory nerve signals decrease adn CV brain centers response by increasing SNS activity ○ @ normal BP, mechanoreceptors tonically fire Control Mechanisms Short term: control within seconds ○ CO, total peripheral resistance ○ Mediated by ANS influences on heart, veins, arterioles Long term: control within min to days ○ Total BV adjusted by resoting normal salt and water balance through mechanisms that regulate urine output and thirst Aortic body arch of arta Carotid body located near bifurcation of cartoid artery Chemical receptors sens amoun of CO2, O2, H+ (pH) in blood Clustered in masses of tissue with rich blood supply Involved in maintaining blood flow Increase CO2 content enhances respiratory rate, HR and force of cardiac contraction ○ Need more O2 to displace CO2 Higher CNS Contrl of MAP Cardiovascular control centre in brain stem = medulla: integrating center for blood pressure regulation Hypothatlamus: controls blood flow to skin to adjust heat loss to enviro ○ Left atrial receptors and hypothatlamic osmoreceptors control long-term regulation of blood pressure by adjusting plasma volume Associated with behaviours/emotions mediated through cerebral-hypothalamic pathway Density of ANS Innervation Blood vessels to brain and coronary circulation non-resonsive to sympathetic stimulation because changes in BP and vascular resistance not needed there Engineering Blood Vessels: growth factors, inc oxygen → hyperoxic enviro , sheart stress/fluid dynamic effects, stem cells, collagen grafts, scaffolds University of Toronto Fall Semester 2024 Professor: Dr. Dawn M. Kilkenny BME350 Biomedical Systems Engineering I: Organ Systems ___ 8.1 Respiratory Anatomy Objectives Respiratory system anatomy Conducting & respiratory zones Role of surfactant Tissue characteristics Control mechanisms Functions Obtains O2 for use by the millions of cells in the body Eliminates CO2 and H2O produced by cellular respiration ‘Respiration’ is the body’s essential link to the outside environment Represents direct dependence upon our environment Other functions ○ Smell, olfactory, vocalization ○ Water loss, heat elimination ○ Venous return ○ Maintenance of normal acid-base balance ○ Defenze against inhaled foreign matter  ○ Removal, modification (in)activation of materials passing through pulmonary structures Respiration: he sum of processes that accomplish ongoing passive movement of O2 from the atmosphere to the tissues, as well as the continual passive movement of metabolically produced CO2 from the tissues to the atmosphere Internal + external respiration → physical and chemical processes External Respiration 1. Movement of air in and out of lungs by bulk flow = ventilation 2. O2 and CO2 are exchanged by diffusion between air in the alveoli and blood within the pulmonary capillaries 3. Blood transports O2 and CO2 between lungs and tissues by bulk flow 4. O2 and CO2 are exchanged between tissues and blood by process of diffusion across systemic capillaries Internal Respiration O2 used to release energy stored in nutrient molecules such as glucose CO2 produced as energy is derived Energy is given off in the form of heat as body temperature Cellular respiration Respiratory Gross Anatomy 1. Airway leading to lungs 2. Lungs a. Lobed → 2 left (because heart there), 3 right b. Highly branched airways, alveoli, pulmonary vessels, lots of elastic connective tissue to enable movement c. Pleural sacs: double-walled closed sac separating each lung from thoracic wall i. Thin membranes made of tough endothelial cells ii. Pleural cavity filled with intrapleural fluid iii. Fluid prevents friction between membranes during rubbing during breathing  iv. Pleurisy: inflammation of pleural sac causing friction and painful breathing 3. Thoracic structures involved in producign movement of air through aiwards into and out of lungs Conducting Zone: trachea and large bronchi  Rigid tubes with some smooth muscle and rings of cartilage Epithelial cell lining exhibits minute hairlike cilia that protect surface ○ Secrete mucus → coordinated mvt of cilia cause trapped particulate to move upward → escalator Functions: ○ Filters out foreign material prevents bacteria, viruses and inorganic particles from reaching the alveoli ○ Warms air to body temperature and protects alveoli from damage due to cold air exposure ○ Adds water vapour until the air reaches 100% humidity so that the moist exchange epithelium do not dry out ○ NO GAS EXCHANGE Bronchitis: bronchial inflammation Acute viral illness characterized by development of a cough to expectorate the mucous (i.e., flu, cold) Chronic obstructive pulmonary disease associated with airway injury via inhaled irritants (i.e, pollution, smoking, cold air) Terminal and Respiratory Bronchioles Walls contain smooth muscle innervated by ANS (not held open by cartilage) Sensitive to certain hormones and local chemicals No cilia or mucous: invading particles are removed by wandering ‘alveolar macrophages’ Alveolar Exchange Zone ie. dead end of respiratory branch Intermittently flushed with fresh air as we breathe Extensive capillary supply → need to transpor o2 Alveoli : Single layer of flat Type I alveolar cells ○ Type II secrete pulmonary surfactant Reduces surface tension at alveolar air-water interface Surfactant - surface active agent  ○ Seek surface and allow it to expand Prevents alveoli from collapse Decreases resistance to stretch and breathing work At constant surface tension, small alveoli will generate internal pressrues greater than larger alveoli → Laplace ○ Alveolar macrophages guard lumen ○ Pulmonary capillaries encircle each alveolus ○ Pores of Kohn permit airflow between adjacent alveoli Inflamed alveoli → pneumonia : mucous interferes with efficient diffusion and gas exchange Infant Respiratory Distress Syndrome: infants without enough surfactant Can’t breathe ue to stiffness or collapse of lungs Surfactant replacement therapy is given via an endotracheal tube → has led to 40% reduction in mortality Prof. Fred Possmayer (UWO) developed BLES and showed its efficacy and safety in humans Work of Breathing Breathing normally requires ~ 3% of total energy expenditure for quiet breathing Lungs normally operate “half full” Work of breathing is increased in the following situations: 1. when there is a need for ↑ ventilation 2. ↑ airway resistance 3. ↓ pulmonary compliance 4. ↓ elastic recoil Airway Resistance Primary determinant of airflow resistance is the radius of the conducting airway ANS controls contraction of smooth muscle bronchiole walls Chronic obstructive pulmonary disease abnormally increases airway resistance in lower airways making expiration more difficult than inspiration: ○ chronic bronchitis ○ Asthma  ○ emphysema Pulmonary Compliance: amount of effort required to stretch or distend the lungs Dec by pulmonary fibrosis When lungs less compliant → greater work to inflate Lungs have elastic recoil and rebound if stretched Lung Elasticity Lungs exhibit elastic behaviour and return to their normal volume when distending forces are relaxed due to ○ (1) elastic tissue that resists stretching ○ (2) surface tension that resists surface expansion Autonomic Control of Respiration Respiratory centres located in the brain stem (pons & medulla) establish a rhythmic breathing pattern ○ Medulla: dense network of neurons I inspiration neurons generate primitive rhythm for involuntary breathing “E” expiration neurons regulate primitive rhythm Impulses descend to motor neurons along tracts lying in lateral and ventral parts of the spinal cord ○ I.e. innervate secondary muscles to aid in breathing (i.e. intercostals) Medullary Respiratory Centres 1. Transection above medulla & all cranial nerves severed regular breathing continues 2. Transection below medulla a. all breathing stops Central Chemoreceptors Detect H+ Levels (i.e. inc H+ → inc CO2 → inc ventilation) Central receptors on the ventral surface of the medulla  Sensitive to H+ ions in the cranial ECF and in arterial blood arising from the conversion of CO2 Increase in H+ ions causes a rapid increase in ventilation to compensate for associated increase in CO2 Peripheral Arterial Chemoreceptors: Sense and respond to a variety of molecules in arterial blood Carotid bodies (carotid sinus) & aortic bodies (aortic arch) are sensitive to changes in O2 ○ Low O2 stimulates impulses → increase in ventilation An important sensory component in a negative feedback loop controlling respiratory activity Voluntary Control of Respiration Impulses from cerebral cortex sent down corticospinal tracts to motor neurons in the spinal cord Excitatory impulses sent to intercostal muscles and the diaphragm, which are inspiratory muscles ___ 8.2 Respiratory Mechanics Objectives Ventilation and pressure gradients Respiratory mechanics Ventilation + Pleural Sacs + Pressure Lungs mostly involuntary, but lots of voluntary control Passive relaxation causes expiration Pleura are very important to reduce friction ○ Helps inflate/expand lungs → cohesiveness of fluid helps hold lungs close to thoracic walls  ○ Lungs nor chest never in desired natural position at same time I.e. glasses stuck together are very hard to separate ○ Intrapleural pressure is negative → lymphatic system drains intrapleural fluid → negative pressure which helps keep lungs inflated Lymphatic System: extensive network of one-way valve-like vessels that empties to venous system near entrance at right atrium Provide accessory route for leaked fluid (lymp) to be returned from interstitium to blood Defence against disease ○ Phagocytes in nodes destroy bacteria filtered from interstitial fluid Transport absorbed fat (from digestion) and return filtered protein Transmural pressure gradients More pronounced on lung + more influenced compared to chest wall by smaller pressure difference ○ Prevents chest wall and lungs from being in same position at same time #1 stimulus, diaphragm #2 Alveolar Pressure Gradients 1. Atmospheric pressure (barometric) 2. Intra-alveolar Pressure/intra pulmonary 3. Intrapleural pressure/intrathoracic a. Always lowest pressure in lung because closed cavity Intra-alveolar pressure > intrapleural pressure → but always equalizes with atmospheric pressure Greater collective outward pressure exists on the walls, causing lung expansion Pneumothorax: condition where air enters pleural cavity Interferes with pressure differences across lung wall ○ No pressure forces present and lung collapses while chest wall springs outward  ○ Because more pressure in pleural cavity, less of tendency for lung to inflate because there isn’t that pressure different, so it deflates Associated with shortness of breath, chest pain, drop in O2 saturation Occurs when: puncture chest wall/hole in lung Pulmonary vacuum + Quiet Breathing As pleural cavity expands by mechanisms (i.e. diaphragm mvt), thoracic vacuum increases Intrapleural pressure decreased because fluid within cavity cannot expand to fill larger volume Boyle’s Law: at any constant temperature, pressure exerted by gas varies inversely with volume of the gas Intra-alveolar + intrapleural pressures fluctuate ○ Intra-alveolar changes first, then causes intrapleural to change Thoracic Ventilation Structures Diaphragm: dome-shaped sheet of muscle separating thoracic and abdominal cavities ○ Contraction + flattening create 60-75% inspiratory volume change during normal quiet breathing Outer chest wall (thorax) formed by 12 pairs of ribs joining sternum (front) and thoracic vertebrae (back) ○ When stimulated to contract → flattens Rib cage mvt: creates 25-40% remaining volume change Negative Feedback Inhibits Over-Inflation Phrenic nerve: provides exclusive motor control of diaphragm  Receptors in smooth muscle of bronchi + bronchioles sensitive to stretch Hering-Breuer Reflex ○ Don’t overinflate because no more space → upper limit Expiratory Mechanics 1. Relaxation of inspiratory muscles 2. Thoracic cavity decreases in size b/c a. Diaphragm + chest wall muscles relax b. Elastic recoil of alveoli 3. Intrapleural pressure increase causing lungs to compress 4. As intra-alveolar pressure increase, air driven out of lungs when > atmospheric pressure = expiration 5. Active expiration through contraction of expiratory muscles Active Expiration During exercise/force expiration Uses internal intercostal muscles + other abdominal muscles Contraction pulls rib cage inward → reduces thoracic volume Ex: situps - blow out air when sitting up → helps contract abdominals, what you’re strengthening Measuring Ventilation Spirometer: measure long volumes + discerns pulmonary function ○ Mouthpiece attached to inverted bell filled with oxygen → bell and respiratory tract volume create closed system Spirogram: graph that records inspi and expiration Lung Volumes Acronym Name Definition TD / VT Tidal Volume air moved in single  inspiration/expiration during quiet breathing IRV Inspiratory reserve volume additional volume that can be inhaled above VT at the end of quiet inspiration (~6 fold VT) → physiological sign IC Inspiratory Capacity = TV + max volume that can be RV inhaled FRC Functional residual capacity max volume remaining in lung after normal breath ERV Expiratory Reserve Volume air you can forcefully exhale after end of normal expiration RV Residual Volume Air remaining in lungs after ERV *tidal volume same for men and women Normal Pulmonary Ventilation: volume of air breathed in and out per minute Alveolar 4200; 5250; 0 → why some people fait Alveolar Respiration: volume of air exchanged between atmosphere and alveoli per minute < pulmonary ventilation due to anatomic dead space (volume of air in conducting airways that is useful for exchange) Alveolar dead space quite small an little important in healthy people Factors Influencing Ventilation (unrelated to GE requirements) Protective reflexes (sneezing, coughing) Inhalation of noxious agents → trigger immediate cessation of breathing Pain originating anywhere in body reflexively stimulates respiratory centre Involuntary modification of breathing occurs during expression of various emotional states Inhibited during swallowing 8.3 Blood Anatomy and Functions: RBCs Objectives Blood composition Function of blood solutes/molecules Red blood cells Hemoglobin and gas transport Erythropoiesis Blood typing Blood: liquid connective tissue, principal ECF of body 8% of body weight More viscous than water pH 7.35 - 7.45 Men > women BV; cellular (5.6 L > 4.5 L) (45% > 42%)  Function: ○ transport: deliver nutrients, hormones/peptides O2; removal of metabolites and waste CO2 ○ Regulation: pH, temperature, osmotic pressure, etc. ○ Protection: fighting infection (i.e. WBC) clotting Homeostasis: mix of cells and chemicals in blood is key indicator of overall body health Composition: plasma 55%, buffy coat 37.6°C) ○ Buffy coat: WBCs and platelets ○ RBCs have largest mass Plasma: ECF of blood Components ○ H2O (50-90%) → heat retention, BV, osmotic pressure, pH buffer ○ Proteins (4-7%) → produced in liver Large (prevents exit) + disperse as colloid Same charge so not aggregation Generate osmotic gradient between blood and interstitial fluid Colloid osmotic pressure: primary force preventing excessive loss of plasma from capillaries; helps maintain plasma/blood volume Albumins 60%: non-specific binding to substances that are non-soluble for transport purposes ○ Greatest contribution to colloid osmotic pressure ○ Transport molecules Globulins 36% ○ Alpha, beta forms provide molecular transport and involved in blood clotting Antibodies: gamma forms are immunoglobulins  Fibrinogen 4% → blood clotting ○ Other solutes (1-3%) → electrolytes, nutrients, hormones, waste Cellular Composition + Other Components Element Diameter (µm) Average Number Function (/mm3) RBCs 7-8 (smallest cells) 4.5-52.5 10^6 Gas transport WBCs 9-12 7 - 10 10^3 Microorganism defense Platelets 2-4 (not whole cells) 3 10^5 Blood clotting Bulk Flow Pressures in Blood Vessels 1. Capillary blood pressure (Pc exerted by blood = OUT) a. Exerted by volume in blood vessel 2. Plasma-colloid osmotic pressure (πp due to plasma proteins = IN) a. Dependent on protein composition 3. Interstitial fluid hydrostatic pressure (PIF pressure by ISF against capillary = IN) a. Pressure for aqueous environment outside 4. Interstitial fluid-colloid osmotic pressure (πIF due to proteins = OUT) a. Protein outside Net Filtration and Reabsorption Shift in balance inward pressure remains constant along length of capillary Outward pressure slowly declines Normally, slightly more fluid is leaked than reabsorbed Exceptions: ○ Kidney glomerulus → high pressure favours filtration ○ Low pulmonary pressures → absorption Lymphatic system: extensive network of one-way, valve-like vessels Provides accessory route by which leaked fluid (lymph) can be returned from interstitium to the blood Empties to the venous system near entrance at right atrium Initial lymphatics: small blind-ended terminal lymp vessels ○ Permeate almost all tissues Edema: tissue swelling when abnormal amount of interstitial fluid accumulates in body tissues Causes: excessive salt intake, sunburn, kidney/heart failure, pregnancy, lymph node problems, standing/walking in excessive heat → Kim Kardashian prego Compromises circulation by increase distant that solutes/molecules must travel to diffuse Occurs when Na+/K+ ATPase impaired → Na+ ions enter cells → hyperosmolar enviro More causes 1. Increase capillary/venous blood pressure Pc 2. Decreased plasma oncotic (plasma protein) pressure (i.e. starvation) pip 3. Increase permeability of capillary walls to protein (decreases oncotic pressure gradient) 4. Disturbed lymph drainage → surgery, parasitic invasion, blockage Erythrocytes: RBCs GE for O2 and CO2 Stats: ○ >99% of cellular component → hematocrit ○ 5 10^9 /mL blood ○ Takes 20-60s for 1 RBC to travel entire body Structure: bioconcave shape provides large SA for GE ○ Thin ⇒ optimal diffusion ○ Ability to squeeze through small capillaries ○ No nucleus/intracellular organelles → no need + can carry more O2 ○ Has Hemoglobin protein (250 10^6/ RBC = ~2lbs/person) Globin protein + heme (iron compound) Iron-containing pigment found only in RBCs → red colour One heme group bound to each polypeptide chain is capable of reversibly binding one O2 molecule Transports: CO2, CO, NO, acidic-hydrogen ion (H+) of ionized carbonic acid With different affinities  Ex: CO poisoning → binds well to hemoglobin → kicks out O2 and CO2 Erythropoiesis: RBC synthesis Pluripotent stem cells in red bone marrow give rise to 3 types of hematopoietic (blood) cells Route of differentiation depends upon presence of hormones and other factors ○ If EPO not present in marrow, RBCs → WBCs Erythropoietin (EPO): hormone that promotes RBC formation → stimulates differentiation of nucleated RBC progenitor cells ○ Low [O2] ⇒ kidneys release EPO hormone ○ Cells mature within few days, lose nucleus + stack hemoglobin ○ Ex: Lance Armstrong EPO blood doper → more RBCs in blood Blood Changes Colour During Circulation Oxygenated → bright red ○ oxygenated-HB absorbs light in blue-green range → reflect red-orange light → conformational changes in Hb shifts absorption deoxygenated → dark maroon  If vein sufficiently deep appears blue because low energy of long, red wavelengths filtered out by subcutaneous fat and skin RBC Catabolism: body creates and destroys millions of RBCs every second Newborns jaundiced from increased bilirubin because cycle doesn’t work yet Blood Typing: different blood types exist due to presence/absence of antigens and antibodies (protein molecules) Antigens → on surface of RBC ○ Blood type defined by the expressed antigens Antibodies → located in plasma If A gives to B, RBCs aggregate → can’t pass through capillaries ○ Clump, separate from plasma, precipitate ○ I.e. incompatible; lethal O best RBC donor but not plasma  +/- ve blood Rh factor: RBC surface protein antigen ○ -ve doesn’t have Rh antibodies If Rh+ blood donates to Rh-, RH antibody production will be induced ○ Bad for pregancy Can determine blood type by multiplex ………. allele-specific PCR University of Toronto Fall Semester 2024 Professor: Dr. Dawn M. Kilkenny BME350 Biomedical Systems Engineering I: Organ Systems ___ 9.1 Gas Exchange Mechanisms Objectives Partial pressure of gasses in solution Local regulation of alveolar ventilation (V)/Perfusion (Q) Understand causes of hypoxia Examine blood-gas transport at the cellular level Sensory control of ventilation Normal Blood Gas/pH Values Arterial Venous PO2 95 mm Hg (85-100) 40 mm Hg PCO2 40 mm Hg (35-45) 46 mm Hg pH 7.4 (7.38-7.42) 7.37 P = partial pressure Behaviour of Gases in Solution  Movement of gas molecules from air to liquid proportional to ○ Pressure gradient of gas ○ Solubility of gas in liquid ○ Temperature Ex: CO2 has much greater solubility compare to O2 ⇒ ∆PCO2 smaller because solubility is more noticeable Oxygen Diffusion Oxygen moves down its partial pressure/concentration gradient from the alveoli into the capillaries, to equilibrium PO2 of arterial blood leaving the lungs is the same as in the alveoli When arterial blood arrives at tissue capillaries, gradient is reversed Cells are continuously using O2 for oxidative phosphorylation; ○ at rest, intracellular PO2 is ~ 40 mm Hg Because PO2 is lower in the cells, O2 diffuses down its partial pressure gradient from plasma into cells, to equilibrium Venous blood has same PO2 as cells it flowed past CO2 Diffusion High in cells than in systematic capillaries because of metabolic CO2 production → cellular respiration → internal respiration  Diffuses down concentration gradient out of cells into systemic venous circulation at 46 Arterial Blood Transport Total blood oxygen content includes: O2 dissolved in plasma → 2% O2 bound to hemoglobin (Hb) → 98% Hemoglobin Quaternary protein: 4 polypeptide chains ○ 2 alpha, 2 beta → each have their own heme Binds gases with varying affinities Weak bond Fe-O2→ reversible → can bump gases easily ○ N atoms hold Fe in center of heme → more accessible to gases ○ Doesn’t alter Hb Each heme binds 1 O2 Oxygen Transport by Hemoglobin Oxygen consumption at rest is 250 ml/min of O2 O2 brought to the cells dissolved in plasma provides less than 10% of what the cells consume If cardiac output is 5L/min, HbO2 delivery to cells is ~1000ml/min = 4x oxygen consumption of tissues at rest ○ Homeostatic range provided if tissues need lots of O2 quickly i.e. during exercise O2-Hb Dissociation Curve As long as PO2 in the alveoli (and pulmonary capillaries) stays above 60 mm Hg, Hb will be more than 90% saturated and will maintain near normal levels of O2 transport  If PO2 is < 60 mm Hg, the slope increases and even a small decrease in PO2 will cause a relatively large release of O2 Obeys Law of Mass Action ○ If [O2 ] increases, the reaction shifts to the right and more O2 binds to Hb Factors that might induce change: temperature, plasma pH, Pco2 Warm wants to hold O2 for longer, same with higher CO2 In babies higher stored O2 because don’ have same capacity to get o2 via respiration Affinity at lugs not affected much but tissues yes pH ⇒ becomes more acidic when muscles under maximal exertion → anaerobic metabolism ○ Produce lactic acid, release H+ into cytoplasm and ECF ○ As [H+] inc, pH dec, Hb affinity for O2 decreases → right shift ○ More O2 released at tissues: Bohr Effect Blood Transfusion 2,3-disphosphoglucerate (2,3-DPG): intermediate of glycolysis pathway Chronic hypoxia: extended periods of low oxygen ○ Triggers increase in 2,3DPG production in RBCs → lowers binding affinity for O2 so more can be released In blood banks, loses DPG → Hb binds more tightly to oxygen at PO2 values found in cells Acidosis CO2 more soluble in body fluids ○ Cells produce more CO2 than can dissolve in venous plasma Remaining CO2 diffusions in RBCs ○ Attaches to Hb → decreasing O2 binding (5-25%) Carbaminohemoglobin: when CO2 bind to Hb Facilitated by presence of CO2 and H+ → decrease binding affinity for O2 ○ Dissolves as bicarbonate (75-95%) Carbonic anhydrase (CA): enzyme responsible for CO2 conversion to bicarbonate Two purposes: Transports Co2 from cells to lungs HCO3- acts as buffer to metabolic acids to stabilize body’s pH Rate depend on relative [] of substrates and obeys law of mass action Major Steps from the figure Hb buffering → prevents large changes in body’s pH ○ If blood Pco2 significantly elevated, excess H+ in plasma causes respiratory acidosis Co2 conversion to bicarbonate ○ Law of Mass action Carbinohemoglobin ○ Decrease binding affinity for O2 combined with the presence of H+ Removal at the lungs ○ Co2 diffuses down pressure gradient out of plasma into alveoli and plasma Pco2 veins to fall ○ Enables Co2 to diffuse out of RBC ○ Aw Co2 levels in RBC decrease, EQ of Co2-HCO3 reaction disturbed → shifted towards production of CO2 See diagram CO2, O2 pH Effects  Sensory input from chemoreceptors modify rhythmicity of respiratory central pattern generator ○ Peripheral chemoreceptors for O2, CO2 associated with arterial circulation Central chemoreceptors located in brain stem ∆[CO2] primary stimulus for changes in ventilation Pulse oximeter: determine effectivies of GE in lungs Measures O in arterial blood throuhg surface of skin/finger/earlobe Measures light absorbance 8.2 White Blood Cell Anatomy + Function and Immunity Objectives White blood cell anatomy Leukopoiesis Innate immnity + inflammation Active immunity, B-T-cell function Platelets and hemostasis Buffy Coat: WBCs, Platelets Should be thin if healthy Platelets: 2.5*10^8 /ml blood Leukocytes: (4-11 ~7)*10^6 /ml blood Leukocytes: WBCs, fight foreign microbial infections → immune system NOT associated with any particular organ/tissue Function: capture cellular debris, foreign particles/invading microorganisms ○ function like single-celled organisms ○ Blood transports from storage to site Cannot reproduce on their own Blood Cell Development From same stem cells as RBCs Lymphocytes from lymphoid stem cell Leukopoiesis: lymphocytes migrate into lymph organs (thymys/lymph nodes) → differentiate and mature ○ acquired immune reactions specialize into function WBC Granularity Basophil Neutrophil Eosinophil Monocyte → Lymphocyte Macrophage (T, B cells) Release Kill bacteria Attack Enter tissues and eat Attack allergic and fungi parasites bacteria/dead/damaged cells viruses and histamine cancer cells and heparin Polynuclear, more granular Mononuclear, less granular  3-4 days in tissue days/years in tissue 100-300 days in lymphoid tissue Low specificity High specificity Immunity: ability of the body to resist/eliminate potentially harmful foreign materials/abnormal cells Tiered defence: 1st: skin, mucosal linings (ex: in lungs, alveoli, colon) 2nd: phagocytes (engulfing cells, i.e. neutrophils, eosinophil_ 3rd: adaptive responses (lymphocytes) Classification of Disease: Innate Adaptive what Inborn, non-specific Acquired, specific Immune responses to infections and Targets each pathogen in inflammations caused by tissue injury specialized manner who Granulocytes (neutrophils, basophil, Lymphocytes ( b - antibody; t - eosinophil), phagocytic agranulocytes cell mediated) (macrophages, monocytes) how Prompts emergency response to Learned, active/passive incoming pathogens Requires prior Doesn’t require prior sensitization to antigen sensitization Defends host by targeting Doesn’t increase efficiency over specific pathogens time, just gets the job done Increases efficiency of defence How 1. Immune cells recruited to sites Immune system produces specifically of infection and inflammation antibodies against specific through product of chemical agents factors Can be acquired via: a. I.e. cytokines: ○ contracting an  speicalized chemical infectious disease mediators (i.e., chicken pox) 2. Activation of complement ○ receiving a cascade identifies bacteria, vaccination (i.e., activates cells and promotes polio) clearance of dead cells/antibody complexes Passive immunity: immunity 3. Identification and removal of produced by transfer of antibodies foreign substances present in produced by one person to organs, tissues, blood, lymph another Protection diminishes in few weeks/months Ex: antibodies from mother to baby before birth cover passive immunity to baby for first 4-6 months of life B cells adn t cells B&T Cells → fighting force with a memory B cells: lymphocytes derived from bone marrow that move to secondary lymphoid organs to mature and T cells: derived from/multiply at thymus and Each antibody/lymphocyte recognises ONE type of antigen B-Cell T-Cell From where Bone marrow → secondary Thymus, 2-3 days lymphoid organs to mature mediated antibody Cell → they attack directly Attack who Extracellular microbes Intracellular microbes; slow-acting bacteria (tuberculosis, fungus)  how Bacteria contain surface Directly attack and destroy antigens recognized by B-Cell foreign cells by receptors in lymph nodes lysing/summoning macrophages When match is found → b cells rapidly multiply Tag pathogens for destruction by phagocytes activation Enlarging and becoming Become sensitized and plasma cells that produce proliferate into family of antibodies ‘killer t cells’ Helper t cells bind to other immune cells and release chemical that augment their activity Virus: nucleic acid wrapped in protein sheath; causes disease by entering host cell and taking over its replication machinery → destroys host Platelets: anuclear thrombocytes that contain contain organelles Shed from megakaryocytes (large bone marrow cells) Initiate blood-clotting process  Contain chemicals that allow discovery of damaged blood vessels, clot formation and tissue repair ⅓ stored in spleen, released by SNS stimulation Hemostasis in Response to Vascular Injury 1. Platelets adhere to exposed collagen fibers of damaged blood bessel wall adn release serotonin a. Vascular spasm: 2. ADP attracts neighbouring platelets, makes them sticky 3. Temporary hemostatic plug prevents blood leakage Essentially: with cut vessel wall 1. Expose collagen from wall 2. Platelets bind to collagen and release serotonin 3. Tells vessels to vasoconstrict → decrease blood flow 4. Gives chance for platelets to release ADP (also comes from endothelial cells), become sticky → make platelets aggregate 5. Voila clot Blood Clotting Process Abnormalities:  - Hemophilia: deficiency of clotting factor → bleeding sickness - Ex: queen victoria, inbred, mainly in male but all had it - Thrombocytopenia: reduced platelet production + increased platelet destruction - Vitamin K deficiency: required for prothrombin synthesis in liver - Ex: give babies Viktamin k booster for increased clotting abilities later on (because don’t have much vitamin k to begin with) Hematopoietic Stem Cells Pluripotent stem cells differentiate into different blood cells Immature cells can not ‘escape’ the marrow Differentiated cells contain specific membrane proteins required to attach to/pass through blood vessel endothelium Hematopoietic stem cells may also cross the bone marrow barrier and may be harvested from blood There is ~1 stem cell/105 blood cells Erythrocyte engineering Surface modifications, biomaterials, biocarriers for diagnostic probes + drug distribution Leukocyte engineering Strategies to enhance healing, immunity, inflammatory response Ex: macrophages to target cancer cells Immunoengineering: how to manipulate immune system