Physiological Fluid Mechanics Blood Vessels …

Manan Mehta zaHra Hosseini

October 28, 2008

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4http://www.healthcentral.com/video/408/200838.html

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We are covering …

• Physiological properties of blood vessels• Dynamics of Blood Flow• Vascular Pathologies• Measuring Elastic Characteristics of Vessels• History of Tissue Engineering • Approaches to Solutions• Where are we at and where are we headed?

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Layers of Arteries/Veins

1) Tunica Intima- One cell layer thick and consists of endothelial cells- involved in secretion of vasoacive substances, contraction and relaxation of vascular smooth muscles

2) Tunica Media - Made up of primarily smooth muscle cells (living and active)- Also contains elastic tissue- Two main functions include Vasoconstriction and Vasodilation

- This layer is absent in capillaries

3) Tunica Externa (Tunica Adventitia)- Consists of connective tissue - Also contains very stiff collagenouse fibers

- Like tunica media this layer is absent in capillaries

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Layers of Arteries/Veins

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Types of Arteries1) Elastic Arteries

– Most elastic fibers– A chief characteristic is their ability to stretch and hold additional

volume– Very thick tunica media

2) Muscular Arteries– Their tunica media is almost entirely made up of smooth muscle (up

to 40 cell layers)– They perform vasoconstriction and vasodilation

– Most arteries are muscular arteries

3) Arterioles– Smallest in diameter, few layer of smooth muscle tissue and almost

no connective tissue– Do not possess much of a tunica externa

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Endothelium• A special type of

epithelium (recall the four types of tissues found in human body!) - more specifically it is Simple Squamous Epithelium

• An important player in the mechanics of blood flow, blood clotting, and leukocyte adhesion

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Dynamics of Circulation

Dynamics of blood circulation is basically the relationship between flow, pressure, as well as different mechanisms that control this pressure

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FLOW

• Is a measure of how much volume of blood passes by per unit of time– If Q is the flow, V is the velocity, and A is the cross sectional

area, then we have the following relationship:» Q = VA

• Did you know that vascular system obeys an adaptation of Ohm’s Law?

• If dP is the change in pressure and R is the resistance then the following relationship holds:

» Q = dP / R

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Poiseuille’s contribution to this lecture …

• Poiseuille proposed the following expression for flow:

• Q = dP(п)r^4 / 8Lμ– r is the radius of the vessel– μ is the viscosity – L is the length of the vessel

• Since Q = dP / R, we also have the following:– R = 8Lμ / (п) r^4

• So we have resistance being proportional to 1/r^4 !

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Remember from lecture that …

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Turbulent Vs. Laminar Flow• Turbulence

– Random direction of flow of blood

– Produces friction (Increased Sheer Stress)

• Laminar – Streamlined– Most of the movements

occur in the center of the vessel, results in less friction with the walls of the vessel (Less sheer Stress)

• Sheer Stress• The force exerted on

the vessels’ walls

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Reynolds’ Number? What?

• Re = (v.d.ρ) / μ– v is velocity– d is vessel diameter– ρ is density– μ is viscosity

• If Reynolds’ number increases beyond 2,000 turbulent flow will result

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Dynamics Cont’d …

• Blood pressure is the force that blood exerts on the walls of the vessels, DUH!

• Blood pressure is the reason blood can move through the vessels

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Vascular Pathologies

1) Atherosclerosis or simply the hardening of the blood vessels- Is characterized by aggressive narrowing and occlusion of the blood vessels- Fatty substances, cholestrol, cellular waste products, calcium, and fibrin- Normally affects medium sized or large arteries- Blockage of the artery that supplies the heart will result in heart attack and in smaller arteries/veins it will result in stroke!! DUH!

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Vascular Pathologies Cont’d …

2) Stenosis- Refers to obstruction of flow through a vessel --> when a localized plaque is formed inside a vessel

Some trivia:- An aortic stenosis is typically seen as a restricted systolic opening of the valve with an increased pressure drop across the valve

- To identify and quantify the severity of a valvular stenosis Doppler Echocardiography can be used

3) Aneurysm - Refers to abnormal enlargement of an artery wall- results in weakness or thinning of the blood vessels wall

- Usually occurs in arteries (two types in abdomen -AAA- or the brain CA)

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Vascular Pathologies Cont’d …

4) Thrombosis- Refers to formation/development of an aggregation of blood substances in the blood clot- It often results in vascular obstruction at the point of formation

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Angioplasty

• A therapeutic IR procedure which is commonly used to restore blood flow in organs

• Critical organs in which the arteries become narrowed or blocked

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Measuring Elastic Properties of Blood Vessels

• Consideration of:– The pressure applied

to the vessel; easy part of this task

– wall deformation; not an easy task

• Assumptions are made to make this task easier

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Artificial Blood Vessels

• “Tubes” that are made from synthetic materials, the function of which is to restore blood circulation

• The most successful artificial blood vessels in use today some from surgical techniques that were developed in the 1940’s ad 1950’s

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A Little History:

• French-American surgeon Alexis Carrel won the Nobel Prize in 1912 in medicine for completing a procedure sewing the ends of two blood vessels

- He later made artificial blood vessels with tubes of glass and aluminum

• 1948 Kunlin developed the heart bypass using antilogous veins

• 1952 Arthur Voorhees at Columbia University developed Vinyon-N cloth tubes to substitute diseased arterial segments

- The application was only approved for arteries larger than 5mm in diameter and were un- occluded for more than 10 years

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• 1959 W. S. Edwards introduced Polutetrafluoroethylene (PTFE) graft - also known as Teflon

• 1969 R.W. Gore invented the expanded polytetrafluoroethylene graft (ePTFE) also known as Gore-Tex

• 1978 Herring had described endothelial seeding of synthetic grafts

• 1987 Cryolife Inc. began recovering human greated cephalous veins and cryopreserving them for use in vascular grafts (allograft)

A Little History (#2):

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A Little History (#3)

• 1988 clinical trial of endothelial sodding on ePTFE grafts took place

• 1998 L’Heureux at al. used separately cultured smooth muscle cells and fibroblasts to construct a living blood vessel

• The smooth muscle was wrapped around a tube to produce the tunica media

• A fibroblast sheet was wrapped around that construct to produce the tunica externa

• After maturation, the tube was removed and endothelial cells were seeded onto the lumen

» This process demonstrated viability

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Why Tissue Engineering for Blood Vessels? Because ….

• Transplantation from a donor to a patient - rejection of the newly transplanted artery by the immune system of the patient

• Transplantation from one part of the body of the patients to the other part of their body - Problematic because it requires at least two surgeries to remove and then implant the vessel– Also many patients with circulatory problems had no suitable

vessels that could be transplanted anyway!

• To overcome these problems, researchers began to experiment with synthetic blood vessel materials such as our friend polyethylene and siliconized rubber

» These synthetic fabrics showed the most promise :)

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Where are we at?• In 2002 more than 500,000 patients were undergone surgical

procedure involving replacement of their small-caliber blood vessels; this number has increased to a much higher rate in more recent years!

• Even though there is no SPECIFIC clinical need for this process, success has only been achieved in the replacement of large-caliber vessels

• The lower blood flow velocity in the small-diameter arteries are what have caused the failure of synthetic materials that are successful for larger diameter grafts

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Approaches …

1) Decellulatized Tissue

2) Biodegradable Polymer Scaffolds

3) Cell Sheet

4) Biopolymer Scaffolds or Bio-Artificial Artery (BAA)

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Decellulatized Tissue

PROs:• ECM is used to synthesize the tissue

– Provides complete mechanical properties and biocompatibility

• Can be achieved by treating tissues with a combination of detergents, enzyme inhibitors and buffer

Cons:– Significant shrinkage as a result of proteoglycans

being removed from the tissue by the detergent treatment

» Proteoglycans play an important role in the binding of ions such as Potassium, Calcium, Sodium, etc. - we know how important they are!

– Can undergo aneurysm, infection and thrombosis

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Copyright ©2005 American Physiological Society

Roy, S. et al. Am J Physiol Heart Circ Physiol 289: H1567-H1576 2005;doi:10.1152/ajpheart.00564.2004

Fig. 4. Distal artery (1.41 mm ID) before (A) and after (B) decellularization

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Biodegradable Polymer Scaffold

• Seeding the cells onto degradable polymer scaffolds which supports the tissue growth and remodeling

PRO:• Porosity of 97% plus sufficient structural integrity to maintain their

dimensions (8 weeks)» Able to keep their dimension when seeded with

sufficient isolated cartilage cells (chondrocytes)• The largest grown in vitro to date is 1 cm in diameter and 0.36 cm

thickCON’s• PGA (Polyglycolic Acid) is widely used fro polymer scaffolds

• BUT! It is rapidly reabsorbed - leads to weakening of tissues before the cells have a chance to complete remodeling process

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• CONs … Cont’d …

• Post-implantation of remodeling of these constructs are not easily monitored in human patients

• As a result potential long term complications cannot be assessed

• As a second issue these constructs are aimed to be implanted into the low pressure environment, which is less demanding than the higher pressure environment of the coronary artery

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Application of Biodegradable Polymer Scaffolds

• Watanabe et al. used hybrid scaffolding consisting of PGA sheet and polycaprolascetone-copolyactic acid copolymer and seeded with a mixed population of cells derived from femoral vein of a dog– The scaffold was cultured for 7 days and then implanted into

inferior vena cava of the same dog• Scaffold completely degraded after 3 months, the graft, on the

other hand, remained for up to13 months with no evidence of dilation or Stenosis

• The same application was used to treat a 4 year old girl’s pulmonary artery

• The graft was prepared from the scaffold and peripheral vein cells (no signs of Stenosis or Aneurysm) - first success in clinical application of a tissue engineered graft

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Cell Sheets• Francois A. Auger and his colleges at Faculty of Medicine Laval

University, Quebec City

– Growth of passage human neonatal SMCs on culture plates with elevated ascorbic acid

– Sheet is removed and wrapped around a porous, tubural mandrel to the tissue construct

– Same is done to fibroblast to produce adventitia – After a few weeks these two layers are fused to

create one cohesive layer• Result is a well defined multilayer in addition to abundant

ECM position

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PROs• First time that all three layers of blood vessels were constructed• More compliant than the expanded polytetrafluorethylene grafts

CONs• These implants are less compliant than the small-caliber vessels

they are supposed to replace• Result in a condition called Anastomotic Intimal Hyperplasia

• Insufficient elastic fiber deposition results in aneurysm formation• Over 2000mmHg pressure and you have yourself a burst blood

vessel!

Cell Sheets

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Biopolymer Scaffolds / BAA• Trilayered tubular scaffolds of Gelatin/Elastin,

Gelatin/Elastin/Maxon, and Gelatin/Maxon (GE/GEM/GM) that mimic the complex trilayer matrix structure of natural artery is prepared in a process referred to as electrospinning

• Tests under dry conditions showed the following outcome:– Tensile strength of 2.71 +/- 0.2 MPa– Modulus of 20.4 +/- 3 MPa

– Failure Strength of 140 +/- 10%• However tested under wet conditions (soaked in a phosphate

buffered saline medium) at 37 deg. and for 24 h exhibited mechanical properties that were comparable to those of native femoral artery

» Tensile Strength of 2.5 MPa and Tensile Modulus of 9 MPa

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Biopolymer Scaffolds / BAA

• Pros:– Follows particular mechanical properties,

depending on the structure and its composition like native artery functions

– Provides directional template to guide the remodelling process into a functional bio- artificial artery at implantation

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Neoplasm Case Study

• The case of Neoplasm (abnormal proliferation of cells) which was never taken into consideration while creating artificial blood vessels

• A 69 year old woman who had undergone artificial graft as a replacement for aortic aneurysm was presented with transient left hemisphere

• MRI revealed small infarction in the right frontal lobe, however major cerebral and cervical arteries seemed unaffected

• On 21 day, she started suffering from subarachnoids hemorrhage (bleeding between arachnoids and pia matter)

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• Angiogram reveals aneurysm lesions in the distal middle cerebral artery due to found B-cells lymphoma in the dilated arterial lumen

• After ischemic attacks, on the 71 day inracranial hemorrhage reoccurred and she died!

• Postmortem examination showed growth of similar lymphoma cells in intimal layer of the artificial artery, which resulted into intravascular large B-cells lymphoma

• B-cells lymphoma traveled in the blood vessel and resulted in blockage of middle cerebral artery resulting into Cerebral Infarction

Neoplasm Case Study Continued…

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Some New Technologies & Research areas …

• A group of scientists from Cryptographs Tissue Engineering of Novato, California

• Growing Blood Vessels using one’s own skin tissue• A well performance in a study of six patients over 3 months

period• Purpose was to demonstrate that tissue-engineered vessels

produced in vitro could withstand the challenge of arterial pressure produced by an arteriovenous fistula for at least 3 months

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Technology & Research cont’d …

• Chris Mason (a medical research council clinical fellow - University College London)

• Developed a technique to grow vessels in a mould• Less chance of contamination and the procedure is more

efficient!• Automated Technology!!

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Technology & Research cont’d …

• Methodist DeBakey Heart Center (GG)

– A method to decrease the risk of blood clotting

– Gore Grafts, first vascular graft available in the United States that has blood thinner permanently bonded to its surface to prevent blood clotting in long term

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WITFL

• Despite all the achievements in this field, it is still of interest to mimic the structure and characteristics of native ECM such as:

• Fibrillar structure• Viscoelasticity• Cell adhesion domains• Growth factor binding and • Proteolytic sensitivity

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With Very Special Thanks to Wikipedia

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• You have questions?

– We have answers!!

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References1. http://www.texmedctr.tmc.edu/root/en/TMCServices/News/2007/02-

01/New+Artificial+Artery+Reduces+Risk+of+Blood+Clots.htm2. http://www.ncbi.nlm.nih.gov/pubmed/18458479?ordinalpos=1&itool=

EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_D efaultReportPanel.Pubmed_RVDocSum

3. http://www.ncbi.nlm.nih.gov/pubmed/18759582?ordinalpos=2&itool= EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_D efaultReportPanel.Pubmed_RVDocSum

4. http://www.healthcentral.com/video/408/200838.html5. http://www.ncbi.nlm.nih.gov/pubmed/3370777?ordinalpos=6&itool=E

ntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Def aultReportPanel.Pubmed_RVDocSum

6. http://www.innovations- report.de/html/berichte/medizin_gesundheit/bericht-41249.html

7. http://www.wyff4.com/health/14768213/detail.html

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References8. http://www.engineeringservicesoutsourcing.com/oth/pv/pic/blog/byps

s.jpg9. http://www.ivanhoe.com/channels/p_channelstory.cfm?storyid=1737

810. http://www.biosurfaces.us/product-pipeline/11. http://www.trossenrobotics.com/images/blogposts/2007/artificial-

organs.jpg12. http://www.gvg.org.uk/pics.htm13. http://www.web-

books.com/eLibrary/Medicine/Physiology/Cardiovascular/artery.jpg14. http://news.bbc.co.uk/2/hi/health/2005108.stm15. http://www.dukehealth.org/HealthLibrary/News/11316. http://medgadget.com/archives/2007/10/natural_artificial_blood_vess

els.html17. http://www.wipo.int/pctdb/en/wo.jsp?IA=IL1998000210&DISPLAY=D

ESC

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References18. http://www.cvphysiology.com/Hemodynamics/H007.htm19. http://ieeexplore.ieee.org/stamp/stamp.jsp?arnumber=01615911

Books1. Myers, G. H. & Parsonnet, V. (1969). Engineering In The

Heart and Blood Vessels. Toronto: Wiley-Interscience.2. Waite, L. (2006). Biofluid Mechanics in Cardiovascular Systems.

Toronto: McGraw-Hill Companies, Inc.