an introduction to continuum phenomena in biomedical ... · 12 breast cancer is the most commonly...
TRANSCRIPT
An Introduction to Continuum Phenomena in Biomedical
Engineering Eric A. Nauman, Ph.D.,
Director, HIRRT LaboratorySchool of Mechanical Engineering, Weldon School of Biomedical Engineering, Department of
Basic Medical Sciences
A Brief History1972 Moorhead, MN1995 B.M.E. University of Delaware1998 M.S. University of California,
Berkeley2000 Ph.D. University of California,
Berkeley2000 - 2004 Assistant Professor of
Biomedical Engineering Tulane University
2004 – Present Assistant/Associate/Full Professor of Mechanical Engineering, Biomedical Engineering and BMS
Other things I do
The Eye is Even More Amazing Than You Think
• The eye focuses light on the retina which then uses biochemistry to transmit signals through the optic nerve head and on to the brain
• Visual processing requires about 30% of your cortext(compared to 8% for touch and 3% for hearing)
• There is a weak spot
The Lamina Cribrosa Holds the Back of the Eye Together
• Idealized models allow us to calculate the mechanical properties and mass transport characteristics of the tissue.
The Mechanics of the LC are Directly Related to Glaucoma
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Breast Cancer is the Most Commonly Diagnosed Cancer in Women
• More than 200,000 new cases per year1
• 1 in 8 chance of developing breast cancer2
• 40,500 women die each year1
• 1 in 33 chance of dying from breast cancer3
• Nearly 1 in 3 cancers diagnosed1
• 2% per year decrease in the mortality rate since 19904
[1] American Cancer Society, Breast Cancer Facts & Figures 2007-2008.
[2] National Cancer Institute, Cancer Stat Fact Sheets: Cancer of the breast.[3] American Cancer Society, Detailed Guide: Breast Cancer, 2006.
[4] American Cancer Society, Cancer Fact and Figures 2005-2006.
Brain Tumors are Particularly Difficult to Treat
• American Cancer Society estimates that 20,500 new cases of brain and nervous system tumors will be diagnosed this year
• 359,000 Americans have already been diagnosed with brain and nervous system tumors
• Five year survival rates are very low for glioblastomas and astrocytomas:
Glioblastoma – 2%Astrocytoma – 30%Meningioma – 70%
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Figure of capillary mesh adapted from:M. R. Dreher, et al., Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers, J Natl Cancer Inst, 98(5):335-344, 2006.
Capillary wall
Cancer Induces Changes in the Physiology of the Tissue
• Abnormal vasculature– Increased vessel density– Abnormal branching– Defective architecture– Hyperpermeability
• Increased fluid and solute transport
• High extravascularpressure
• Increased stiffness• Increased metabolic generation
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Current Treatment Options (Often Combined) are Effective for Many Types of Cancers
• Surgery• Chemotherapy
– Systemic therapy– Damages healthy tissue– Significant side effects: fatigue, hair loss,
mouth sores, nausea, anemia, low platelet and white blood cell counts, infertility, osteoporosis
• Radiation– Side effects: swelling, radiation burn, fatigue
• Hyperthermia• Hormone therapy
– Limited application– Side effects: blood clots, osteoporosis, fatigue,
muscle and joint pain, mood swings
Figure adapted from:C. Alexiou, et al., Targeting cancer cells: magnetic nanoparticles as drug carriers, Eur Biophys J, 35(5): 446-450, 2006.
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Novel Treatment Options -Application of Nanoparticles to Therapy
• Nanoparticles– Bind chemotherapeutic agents,
radioisotopes, or radiosensitizingagents
– Used in hyperthermia therapy– Targeting
• Passive targeting: changes in the vasculature of cancerous tissue results in increased accumulation
• Active targeting: bind targeting agents to the nanoparticle
• Provide opportunity for prophylactic cancer treatments
Figure adapted from:C. Alexiou, et al., Targeting cancer cells: magnetic nanoparticles as drug carriers, Eur Biophys J, 35(5): 446-450, 2006.
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• Nanoparticles as contrast agents– Particles with one or more dimensions of the order
100 nm or less– Bind contrast agents to nanoparticles– Design with desired imaging properties: Magnetic for
MRI, photoemitters for fluorescence microscopy
Figure adapted from:S. E. McNeil. Nanotechnology for the biologist. J of Leukocyte Biology, 78:585-594, 2005
Nanoparticles Utilize Passive and Active Targeting to Detect Tumors
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common drugs ≤ normal capillary pores
normal capillary pores < nanoparticles
nanoparticles ≤ tumor capillary pores
Solute Size is Important to Cancer Detection and Treatment
• Important factors– Passive targeting– Active targeting
• Other applications– Drug delivery– Nutrient delivery
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Porous Media Models Link to Physiological Processes
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VenuleCapillary Mesh
Arteriole Postcapillary Venules
Terminal Arterioles
Lc
Lc
Do
Dt
Dt
Do
Dt
Do
Lc
Idealization of the Capillary Bed
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Unit Cell Division of Tissue into 3 Regions
Intravascular Space
Extravascular Space
Vessel Wall
Cell
Plasma Skimming
Layer
Interstitial Space
Red Blood CellExtravascular
Flux
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Fluid Mechanics Model
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Fluid Mechanics: Intravascular Flow
• Blood– inhomogeneous
• Plasma + solutes– Plasma
• Virtually Newtonian fluid– Red blood cells
• Hematocrit 40 – 45% • Comparable in size to microvessels• Tend to flow single file
Intravascular Space
Plasma Skimming
Layer
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Solute Transport Model
Brain Tumor Types - Meningioma• Arise from cells of the
Meninges• Meninges: the system of
membranes that envelope the central nervous system
• Appear on MRI as a discrete homogenous mass
• Easier to treat due to location and demarcation from other brain tissue
Brain Tumor Types - Glioma• Arise from Glial Cells• Glial Cells: non-neuronal
cells that provide support and nutrition, maintain homeostasis and participate in signal transmission
• Appear on MRI as a heterogeneous mass
Combine Numerical Modeling and Contrast Imaging to Model Transport
Sagittal Plane Axial Plane
Analysis of MRI Images can be Related to Concentration of the Contrast Agent
The Time Between Scans can be Used to Obtain Concentration vs. Time
Axial Plane:Time = TI + 3 mins
Sagittal Plane:Time = TI + 6 mins
Coronal Plane:Time = TI + 9 mins
3D Reconstruction was Used to Track Concentration at the Intersections
Low Shear Model Microgravity
• Provides a low shear environment for motile suspension cultures
• Can we alter the mechanical environment?
Computational Model (FEA)
Shear stress profile
Whole Body Vibration– Typically associated with
back pain• Low strain rate vibration can
cause resonance in spine
– Ovine model• Anabolic to cancellous bone• No effect on cortical bone
– Pilot human studies• Positive effects with low bone
mass• No effect in humans with
normal bone mass
Rubin et al, JBMR, 2004
Potential Mechanisms of Action for Osteogenic Stimulus
• Vibration
• Reintroduction of lost stimulus
• Increased transport
• Additional Strain
• Shear stress
Why Mixture Theory?• Vertebral Body Structure
– Cortical Shell
– Cancellous Bone Core (s)
– Bone Marrow (m)
– Blood (f)
– Lymph, cells
CMET, University of Hull, 2004
Why Mixture Theory
Bone Fractures and Ruptures of Tendons and Ligaments
• Not all bone fractures are traumatic – but most of them are
• There are lots of ways to hurt yourself
Bone Fractures and Ruptures of Tendons and Ligaments
• Not all bone fractures are traumatic – but most of them are
• There are lots of ways to hurt yourself
Basketball Injuries are Related to Head Injuries in Football?
• Kevin Ware• Kevin Ware -
High Definition
Tendon and Ligament Injuries!
Tendon and Ligament Injuries!
Tendon and Ligament Injuries!
Tendon and Ligament Injuries!
45 of 84
The Knee – in Detail
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Multi-scale Models of Vascular Transport for Drug Delivery
Intravascular Space
Extravascular Space
Vessel Wall
Cell
Plasma Skimming
Layer
Interstitial Space
Red Blood CellExtravascular
Flux
Let’s Talk about Brain Injury
– Why is it important?– Military– Sports – Motor Vehicle Collisions
– What can we do?– Develop methods to detect,
prevent, and treat TBI based on quantitative data and continuum level modeling
So Why Do We Study Football Players?
The Original Question…“Why do some players, who have similar magnitude and number of blows to the head, sustain concussions and others do not?”
What we learned …
Our current definitions of TBI need to be re-examined in light of advances in medical imaging.
Traumatic Brain Injury• TBI Case Definition (CDC, 1995):
– Injury to the head with one or more of- Skull fracture,
- Observed or self-reported decrease/loss of consciousness
- Amnesia
- Neurological or neuropsychological abnormality
- Diagnosed intracranial lesion (hemorrhage, contusion, penetrating wound)
- Death resulting from head trauma
“Concussion”
Redefining Brain InjuryOn November 1, 2010, the world’s perception of what constitutes “traumatic brain injury” began to change.
Concussion Biomechanics• Focal Injury
– Coup/contrecoup phenomenon– Primary axotomy & hematoma
• Diffuse injury– Possibly a result of whole-brain
shearing• Rotational acceleration
– Tied to focal & diffuse injury– Rotational strains may induce
motor/consciousness deficits– Not reflected in any head injury criteria
P.V. Bayly, et al. J Neurotrauma. 2005 Aug; 22(8):845-56.
ImagingQuantifiesInjury...
P121 (Season 2)
P213 (Season 4)
Pre-Season
Pre-Season
Concussion! (24 hrs)
“Healthy”
SymptomsDoNot
Normal Control
Concussed Players Exhibit Deficits in Multiple Locations
Scatter plot for COI+/FOI+ group
Scatter plot for COI-/FOI- group
Scatter plot for COI-/FOI+ group
Microstructural Models Must Account for Multiple Cell Types
What Do All These Problems Have in Common?
– Large Deformations– Hierarchical Structure– Fluids and Solids
Interact (sometimes gases too)
– Multiaxial– Nonlinear Constitutive
Laws– Need to Connect to
Medical Imaging
The difference between natural and man-made structures?
– Surfaces are curved– Few right angles– Connectors are not
rigid but compliant– Anisotropic
composites– Very little metal– Air is not structural, but
water often is– Often isothermal
– Vogel, Life’s Devices