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!

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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