Biomaterials Science, 2nd edition
Part II: Biology, Biochemistry, and Medicine
Questions
Chapter 3: Some Background Concepts
3.1 Introduction
Buddy D. Ratner
3.2 The Role of Adsorbed Proteins in Tissue Response to Biomaterials
Thomas A. Horbett
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3.3 Cells and Cell Injury
Richard N. Mitchell, Frederick J. Schoen
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3.4 Tissues: The Extracellular Matrix and Cell-Biomaterial Interactions
Frederick J. Schoenm Richard N. Mitchell
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3.5 Mechanical Forces on Cells
Larry V. McIntire, Suzanne G. Eskin, Andrew Yee
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Chapter 4: Host Reactions to Biomaterials and Their Evaluation
4.1 Introduction
Frederick J. Schoen
4.2 Inflammation, Wound Healing, and the Foreign Body Response
James M. Anderson
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4.3 Innate and Adaptive Immunity: The Immune Response to Foreign Materials
Richard N. Mitchell
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4.4 The Complement System
Richard J. Johnson
1. A biomaterial is known to activate WBC and result in elevated levels of C5a when incubated
with plasma. What markers or assays would you use to distinguish between classical and
alternative pathway activation for this biomaterial.
2. In clinical hemodialysis the use of cellulosic membranes such as cellulose acetate are known
to produce a more profound WBC activation (eg. neutoropenia) than synthetic membranes such
as polysulfone. Explain why this so and how you modify the CA membrane to make it perform
more like a synthetic.
3. Bacterial colonization of biomaterials is an important clinical complication, often necessitating
removal of the biomaterial/device. Bacteria have evolved a number of mechanisms to protect
them from complement attack, including the binding of complement regulatory proteins to their
surface. Name two complement regulatory proteins that bacteria might use to inhibit complement.
4. Alexion Pharmaceuticals has developed a monoclonal antibody (eculizimab) that inhibits C5.
They have shown in human clinical trials that treating patients with eculizimab results in lower IL6 levels in these patients. How does the antibody lower IL-6 levels.
4.5 Systemic Toxicity and Hypersensitivity
Arne Hensten-Pettersen, Nils Jacobsen
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4.6 Blood Coagulation and Blood-Materials Interactions
Stephen R. Hanson
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4.7 Tumorigenesis and Biomaterials
Frederick J. Schoen
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4.8 Biofilms, Biomaterials, and Device-Related Infections
Bill Costerton, Guy Cook, Mark Shirtliff, Paul Stoodley, Mark Pasmore
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Chapter 5: Biological Testing of Biomaterials
5.1 Introduction to Testing Biomaterials
Buddy D. Ratner
5.2 In Vitro Assessment of Tissue Compatibility
Sharon J. Northup
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5.3 In Vivo Assessment of Tissue Compatibility
James M. Anderson, Frederick J. Schoen
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5.4 Evaluation of Blood-Materials Interactions
Stephen R. Hanson, Buddy D. Ratner
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5.5 Large Animal Models in Cardiac and Vascular Biomaterials Research and Testing
Richard W. Bianco, John F. Grehan, Brian C. Grubbs, John P. Mrachek, Erik L. Schroeder, Clark W. Schumacher,
Charles A. Svendsen, Matt Lahti
1. A large amount of progress in medical research leading to significant advances in
health care has been made using mammalian models in biomedical research. In
order to protect animal subjects the Animal Welfare Act was enacted which covers all
of the following species except:
A)
B)
C)
D)
E)
Canine
Feline
Ovine
Porcine
Rattus
2. The comparative anatomy of dogs, swine, and sheep make them each advantageous
for testing types biomaterials. Choose an animal model for testing 1) a synthetic
coronary artery bypass graft, 2) a new pacemaker, and 3) a new tri-leaflet mechanical
valve. Describe what features of the animal model make it desirable for testing the
specific device.
3. The International Standards Organization mandates that in vivo testing of heart valves
is completed to evaluate the performance of cardiac devices in a uniform manner.
The rationale for in vivo pre-clincal testing is that valuable data on hemodynamic
function, biological compatibility, and catastrophic failure can be obtained. After the
testing is completed an official report is completed. Describe what should be
documented in the report at the conclusion of the in vivo investigation.
5.6 Microscopy for Biomaterials Science
Kip D. Hauch
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Chapter 6: Degradation of Materials in the Biological Environment
6.1 Introduction: Degradation of Materials in the Biological Environment
Buddy D. Ratner
6.2 Chemical and Biochemical Degradation of Polymers
Arthur J. Coury
1. The two major mechanisms of chemical degradation of polymers in vivo are hydrolysis and oxidation. Given the following
polymers, indicate whether they are susceptible to hydrolysis, oxidation or both processes. If they would be highly resistant to both
processes, so indicate.

Poly (carbonate urethane)

Poly (ether urethane)

Poly (ester urethane)

Aromatic polyester, poly (ethylene terephthalate)

Polypropylene

Polyethylene (linear)

Polytetrafluoroethylene

Polydimethylsiloxane
2. What are some common polymer functional groups susceptible to hydrolysis?
3. In the past, investigators have fabricated heart valves from “aromatic polyurethanes” which contain polyether, urethane, and urea
functional groups. These devices were intended to last for several years in use, but have generally failed to perform for those periods.


What physical and chemical forces are acting on the heart valves in vivo?
What are the most likely mechanisms (physical and chemical) of degradation leading to failure of these devices? State at
least three mechanisms.
4. As a materials scientist, you have experience with polyurethanes as biomaterials. Among the readily available commercial
elastomers, they demonstrate the best combination of physical properties, but are susceptible to biodegradation, mostly through their
polyether or polyester soft segments. You are charged with designing a biostable elastomer (polyurethane or otherwise).

Choose an approach to produce a chemically stable elastomer that retains reasonable physical properties for at least 3
years.

Describe 5 tests/analyses (in vitro /in vivo) which may be used to characterize this elastomer and confirm its potential
stability.
6.3 Degradative Effects of the Biological Environment on Metals and Ceramics
David F. Williams, Rachel L. Williams
1.
(a) What are the three most common implant alloys used in structural
applications? For each one, state which element in the alloy is chosen to enhance
corrosion resistance, and how do they do it?
(b) Describe the mechanisms of intergranular corrosion and fretting corrosion.
(c) If you had an orthodontic appliance where Ni-Ti wire was placed in the groove
of a stainless steel bracket, what corrosion problems might you encounter?
2. Consider a situation in which a 316L stainless steel fracture fixation plate has been
used to treat a tibial fracture. Discuss the possible mechanisms of corrosion of the device
with reference to the alloy composition, the geometry of the device and the mechanical
environment. Include a discussion on the fate of any corrosion products and their
possible effect on the patient.
3. Discuss the potential disadvantages of using two different alloys for the components
of modular orthopedic prostheses.
6.4 Pathologic Calcification of Biomaterials
Frederick J. Schoen, Robert J. Levy
none
Chapter 7: Application of Materials in Medicine, Biology, and Artificial Organs
7.1 Introduction
Jack E. Lemons, Frederick J. Schoen
7.2 Nonthrombogenic Treatments and Strategies
Michael V. Sefton, Cynthia H. Gemmell
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7.3 Cardiovascular Medical Devices
Robert F. Padera, Jr., Frederick J. Schoen
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7.4 Implantable Cardiac Assist Devices
William R. Wagner, Harvey S. Borovetz, Bartley P. Griffith
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7.5 Artificial Red Blood Cell Substitutes
Thomas M.S. Chang
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7.6 Extracorporeal Artificial Organs
Paul S. Malchesky
none
7.7 Orthopedic Applications
Nadim J. Hallab, Joshua J. Jacobs, J. Lawrence Katz
1. What are the general qualifications for orthopedic biomaterials
and what are the two major types of orthopedic
implants?
ANS: Generally orthopedic implants must be capable of
load bearing and are used in either in bone fixation or
total joint arthroplasty.
2. (a) What is the primary problem associated with the
longevity of current total joint replacement implants
and why? (b) How could this be solved by improved
biomaterials?
ANS: (a) Particle and wear debris generation at the
articulating surfaces of total joint replacements causes
aseptic loosening of the implants through the induction
of inflammation around the implant (macrophageparticle
overload) which causes a decreased production
of new bone and increased bone resorption. (b) More
wear-resistant materials at the articulating surface while
maintaining current available levels of other mechanical
properties.
3. What are the primary cytokines associated with particleinduced
osteolysis, and what is the primary cell type
involved in this process?
ANS: The primary cytokines associated with osteolysis
are TNF-alpha, IL-6 IL-1, prostaglandin E2, etc., produced
by macrophage interaction with particulate debris
from implants.
4. What are the seven primary orthopedic implant biomaterials?
ANS: (a) Co-base alloys, Ti-base alloys, stainless steel,
PMMA, UHMWPE, alumina, and zirconia.
5. Name one new orthopedic biomaterial and why it
was introduced (i.e., what specific problem/deficit it is
attempting to solve).
ANS: Zirconium alloy was introduced to decrease the
amount of metallic wear debris being generated at the
bearing surface and as an alternative metal less likely to
induce hypersensitivity reactions.
6. What is one way in which current designs of
orthopedic implants are creating more challenging
conditions for biomaterials to overcome and
why?
ANS: Increasing popularity and degree of orthopedic
implant component modularity is creating more interfacial
surfaces from which implant debris can be generated
through fretting corrosion and interact both locally and
systemically.
7.8 Dental Implantation
A. Norman Cranin, Jack E. Lemons
1. What are the most popular metals in use today in dental
implantology?
2. How well does bone tolerate invasive procedures? Is heat
generated? Are there safe limits to induced temperatures?
How can the health of host bone be assured?
3. What are some of the presurgical diagnostic techniques
used to assist in planning?
4. Name some of the less frequently used dental implant
modalities.
7.9 Adhesives and Sealants
Dennis C. Smith
none
7.10 Ophthalmological Applications
Miguel F. Refojo
none
7.11 Intraocular Lens Implant: A Scientific Perspective
Anil S. Patel
1. What are the advantages of IOL implantation over
spectacles for correction of vision after removal of
cataract? What other improvements have been achieved
in cataract surgery over the past 30 years?
2. Which was the first biomaterial selected for IOL
implant? What was the basis for this selection?
3. What is the rationale for foldable IOLs? Which foldable
soft hydrophobic materials are preferred over soft
hydrophilic materials and why?
7.12 Burn Dressings and Skin Substitutes
Jeffrey R. Morgan, Robert L. Sheridan, Ronald G. Tompkins, Martin L. Yarmush, John F. Burke
none
7.13 Sutures
Mark S. Roby, Jack Kennedy
none
7.14 Drug Delivery Systems
Jorge Heller, Allan Hoffman
1. You are working at AntiKoag, Inc., a company that has developed a new transdermal reservoir
patch containing a rate-controlling membrane. The patch is to deliver an anti-coagulant drug
whose plasma concentration needs to be carefully monitored due to its narrow therapeutic index.
The FDA is coming next week to check on your quality control (e.g.,reproducibility of release rate
profiles of the drug from the patch, both in vitro and in animals), and your boss has asked you to
spend the weekend randomly sampling patches from batches that have been fabricated,
packaged and stored over the past two months, and then measuring their in vitro release rates.
You find there are two types of behavior, shown as A and B in the figure below.
Release Rate
A
(%/hr)
B
Time (hrs)
You know that all patches are supposed to have the same composition and structure, so how do
you explain these two different behaviors to your boss? Can you suggest a way to produce a
product with one consistent behavior, and if so, which behavior would you select, A or B?
2. A degradable copolymer of lactide and glycolide is being tested as a disc-shaped drug depot
that has been implanted in sub-cutaneous sites in rats. Some implants have been retrieved after
about two weeks, and are found to have a hollow core inside of a strong shell of polymer. Your
colleague thinks the reason for this is simply that the drug has leaked out and left the empty core,
but the drug only makes up 1% by weight of the sample, so you know he cannot be right. What
other reason(s) could explain this phenomenon, and how might you avoid it?
3. You are working for a drug delivery company that has discovered a new anti-inflammatory
bowel disease (IBC) drug to be delivered orally. You are fabricating an elementary osmotic pump
capsule by encapsulating lyophilized particles of the drug in a cellulose acetate (CA) coating and
drilling a tiny hole in the CA with a laser. Water permeates through the CA and creates a
saturated drug solution inside the capsule, which is delivered out of the hole. Excess drug
particles remain in suspension inside the capsule. Your boss wants the company to market a
range of capsules with high, medium and low delivery rates for the new drug, since the severity of
IBC varies from patient to patient. The transit time through the GI tract and the influence of food
intake on it are assumed to be fixed, average values for all patients. Also assume that only one
capsule having the desired dosage is to be taken by each patient, and that the laser drilled hole
has a fixed diameter, which is designed to permit liquid flow out but to prevent drug particles from
escaping from the tablet during its transit through the gut. How could you (a) increase or (b)
decrease the amount of drug delivered during transit through the gut?
7.15 Bioelectrodes
Ramakrishna Venugopalan, Ray Ideker
1. What material would you choose for a deep brain stimulating
electrode and why? Develop a simplistic equivalent
circuit model for such an electrode–electrolyte
interface. You do not have to model the tissue. Model
only the interface.
2. Calculate the increase in charge injected by decreasing
the frequency of a symmetric sinusoidal waveform by
an order of magnitude assuming all other parameters
remain constant.
3. Compare and contrast the region of oxide stability
(potential range) for titanium alloy and 316L stainless
steel electrodes. Assume that the oxides on titanium
electrode and stainless steel electrodes are predominantly
TiO2 and Cr2O3, respectively. (Hint: Refer to
the Pourbaix diagrams for titanium and chromium.)
4. Would a material used for a radio-frequency ablation
electrode also be ideal for a cryoablation electrode
(ablation due to freezing)?
5. Develop an equivalent circuit model for a capacitively
coupled device used for healing nonunion fractures. You
do not have to model the tissue. Model only the interface.
7.16 Cochlear Prostheses
Francis A. Spelman
1. Sound at the level of the tympanic membrane demonstrates
a pressure peak at a frequency of 2.5 kHz in the
human. Consider the boundary conditions of the ear
canal and explain why that resonance occurs.
2. Considering the areas of the stapes and the tympanic
membrane, as well as the properties of the ossicular
chain, compute the approximate ratio of pressures that
is found when the tympanic membrane is driven at low
frequency. Note that this is an approximate calculation
that does not consider the dynamics of the system.
3. Focusing stimuli has been proposed by several people
(Suesserman and Spelman, 1993; Jolly et al.,
1996) as a solution to the problem of field interference
between monopole sources. Consider using dipole
and quadrupole sources. Assume that the sources are
50-µm hemispheres located on the surface of an insulating
boundary. Let the hemispheres be separated by
200 µm in both cases. Plot the potential fields along
two lines: one that is 100 µm above and parallel to the
sources, another that is 200 µm above and parallel to
the sources. Describe the properties of the fields that
are produced. Look particularly at the peak potentials
and the half-amplitude widths of the fields. Hints: A
dipole consists of two sources, one carrying current I
and the other carrying current –I. A quadrupole is a
special case of a tripole. Three sources are used. The
central source carries current I, while the two flanking
sources carry current –I/2. For ease of calculation,
place one of the sources at the origin, and let the other
sources lie on, e.g., the x-axis.
4. Wiley and Webster (1982) give an equation that
describes the potential field produced by an electrode
of radius a located at the origin of a cylindrical coordinate
system. The electrode is placed on the surface of
an insulating boundary.
V (r , z ) 

sin 1 

 r  a 2  z 2
2V0

2a
  r  a 
0.5
2

0. 5 
 z 2 
and
J z (r ,0) 
2V0
J0
1

2 0.5
2
 (a  r )
2 1  r a 
2


0. 5
where
J0 
I0
a 2
I0 is the total current flowing into the electrode, J0 is
a current density (defined earlier), ρ is the resistivity of
the medium, and r is the radial distance [x2 + y2]0.5.
Place a point source at the origin and compare it to a circular,
planar electrode with its center at the origin. Let
the radius of the circular electrode be 100 µm. Compute
the potential field for −1 mm≤ x ≤ 1 mm at altitudes
of 50 and 750 µm. What can you say about the shapes
and the peak potentials?
5. A cochlear electrode array employs contacts that are
hemispheres 100 µmin diameter. As the designer of the
array, you compare Pt–Ir contacts with IrOx contacts.
In one stimulus mode, you will use sinusoids of 100
and 1000 Hz. What is the maximum current that you
can tolerate for each material at each frequency? Hint:
compute charge per phase of the sinusoid.
6. A measurement of the IrOx electrode produces an
impedance magnitude of 5 kilohms at 1000 Hz. If
you drive a dipole pair with a 1-kHz sinusoid, what
voltage range must the current source have if you
drive the maximum allowable current that the electrode
can tolerate? Assume that the tissue impedance
of the cochlea is small compared to the impedance of
the electrodes.
7. Two electrode array designs are considered. One uses a
silicone substrate and the other a liquid crystal polymer
substrate. If a circular cross section is used, with an
outside diameter of 200 µm, find the force that would
be exerted on a free end whose length is 1 mm and
whose deflection is 20 µm. The modulus of elasticity of
silicone is 2.76 MPa and that of liquid crystal polymer
is 158 MPa. The polar moment of inertia is

Ip 
d 4
32
8. A simple model of electrode impedance is the Warburg
model (Macdonald, 1987). This diffusion model can
take the form of a parallel resistance/capacitance
circuit in which the resistance and capacitance are
both inversely proportional to the square root of frequency,
i.e.,
R( f ) 
R0
C( f ) 
C0
f
f
Compute the magnitude and phase of the electrode’s
impedance if its impedance is 1 megohm at 10 Hz.
Compute for frequencies from 10 Hz to 10 kHz.
Assume that the electrode is circular in shape, and that
its diameter is 100 µm. If it is covered with a membrane
whose specific capacitance is that given in the text, how
does the character of the impedance change? Plot the
magnitudes and phases for both situations.
9. If the time constant of the membrane that covers the
electrode is 125 msec, recompute the impedance for
problem 8, accounting for the membrane resistance
that parallels the membrane capacitance.
10. Consider the uncoated electrode of problem 8. If a controlled
sinusoidal current were applied to the electrode,
what would be the peak-to-peak voltage necessary
to drive the current, undistorted, over the full frequency
range? Assume that the electrode is driven as a
monopole and that its counterelectrode has negligible
impedance.
7.17 Biomedical Sensors and Biosensors
Paul Yager
none
7.18 Diagnostics and Biomaterials
Peter J. Tarcha, Thomas E. Rohr
none
7.19 Medical Applications of Silicones
Jim Curtis, André Colas
1. Which material property was the basis for Charles Holter's selection of silicone
rubber for the hydrocephalic shunt valve?
a. biostability
b. hemocompatibility
c. thermal stability
d. viscoelasticity
e. all of the above
2. Epidemiology has shown silicone breast implants cause which of the following
complications?
a. breast cancer
b. connective tissue disease
c. autoimmune disease
d. all of the above
e. none of the above
3. Among the following applications where silicones are still in use today, which
was the first reported human implantation of a silicone elastomer medical device?
a. breast augmentation
b. bile duct repair
c. hydrocephalus shunt
d. urethra repair
Chapter 8: Tissue Engineering
8.1 Introduction
Frederick J. Schoen
8.2 Overview of Tissue Engineering
Simon P. Hoerstrup, Joseph P. Vacanti
none
8.3 Immunoisolation
Michael J.Lysaght, David Rein
none
8.4 Synthetic Bioresorbable Polymer Scaffolds
Antonios G. Mikos, Lichun Lu, Johnna S. Temenoff, Joerg K. Tessmar
none