Biomedical Materials

Organic Biomaterials (1)

Orgnaic Biomaterials
The most widely used materials in biomedical
applications, due to a variety of advantages
possible:
• Complex shapes and structures easily fabricated
• Wide range of bulk compositions and physical
properties
• Surfaces are readily modified, physically or
chemically
• Many ways to immobilize biomolecules or cells
• Many special properties possible (e.g.,
biodegradability and stimuli-response)
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 Contents
• Synthetic polymers
- General structure and properties
- Nondegradables
- Degradables
- Sterilization issue
• Natural/biological polymers

Polymer Synthesis
Monomer = repeating unit
Polymer = macromolecule made by joining monomers

Polymer chemistry:

Condensation polymerization
-- stepwise growth, formed by eliminating a small
molecule (H2O, HCl, CO2) from monomers

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Any other examples??

Typical Condensation Polymers

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 Polymer Synthesis

Addition polymerization (chain reaction)

-- chain reaction, monomer contains a double
bond, polymers formed by addition reaction

Free radical

Synthesis of poly(methyl methacrylate) (PMMA)

Further examples?

Addition Polymerization

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Copolymers
• Copolymer is a polymer
derived from two (or more)
monomeric species, as
opposed to a homopolymer
where only one monomer is
used
• Block copolymers tend to
phase separation into
different domains  unique
properties

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 Molecular Weight
• Number average: Mn
Ni
M n  i xi M i xi 
i N i
• Weight average: Mw


Wi
M  w i M i wi  Wi  N i M i
 i Wi
w
i

• Polydispersity index (PI) Ni: the number of moles of

species i
M Mi: the molecular weight of
PI 
w
species i
M n 11

interchain forces, interchain forces,

entanglements entanglements
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 Tacticity
• The arrangement of substitutents around
the extended polymer chain (configuration).

• What about atactic?

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Crystallinity
Polymers can be either amorphous or semicrystalline.

A model of crystallinity in which the crystallized segments of a

macromolecule belong predominantly to different crystals.

Semicrystalline polymers have true Tm at which the

ordered regions break up and become disordered.

Amorphous polymers do not exhibit Tm, only

Tg – above the Tg, polymers are rubber-like.

Examples: PS, PMMA, PE, PP, PTFE, PET ??

fringed-micelle model
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 Two key thermal transitions of polymers determine
their physical properties at use conditions

 Tg, the glass transition temperature, where the polymer goes

from a hard, glassy material to a soft, rubbery material as T is
raised over a few degrees. All polymers have a Tg since all
polymers have some amorphous content.
 Tm, the crystalline melting temperature, where the polymer goes
from a tough, translucent or opaque material to a clear, soft and
rubbery material. This is a sharp, thermodynamic first order
transition T. Only polymers with regular chain architecture can
crystallize and exhibit a Tm.

Key molecular properties that determine Tg and Tm

 Composition of repeat unit (POLARITY)
 Ability to rotate around backbone C-C bonds (STIFFNESS)
 Ability to pack into crystallites (REGULARITY OF CHAIN) 15

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Tg and Tm of common polymeric
biomaterials

Use examples??
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Dynamic mechanical behavior of polymers

Reinforcing effect of the crystallites

Long-region segmental motion is

occurring but thermal energy is
insufficient to overcome entanglement
interactions that inhibit flow.

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Stress

 , T

Strain
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Types of Polymers
Thermoplastic: materials that can
be shaped more than once. (Used as
replacements for blood vessels.)

Thermosetting: materials that can

only be shaped once
(Used in dental devices, and
orthopedics such as hip
replacements.)

Elastomer: material that is elastic.

If moderately deformed, the elastomer
will return to its original shape.
Used as catheters, and for covering
leads on implanted electronics, like
pacemakers. 22

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 Polymers In Specific Applications
application properties and design requirements polymers used
dental •stability and corrosion resistance, plasticity PMMA-based resins for
•strength and fatigue resistance, coating activity fillings/prosthesis
•good adhesion/integration with tissue
•low allergenicity

ophthalmic •gel or film forming ability, hydrophilicity polyacrylamide gels

•oxygen permeability PHEMA and copolymers

orthopedic •strength and resistance to mechanical restraints PE, PMMA

and fatigue PLA, PGA, PLGA
•good integration with bones and muscles

cardiovascular •fatigue resistance, lubricity, sterilizability silicones, Teflon,

•lack of thrombus, emboli formation poly(urethanes), PEO
•lack of chronic inflammatory response

drug delivery •appropriate drug release profile PLGA, EVA, silicones,

•compatibility with drug, biodegradability HEMA, PCPP-SA

sutures •good tensile strength, strength retention silk, catgut, PLG, PTMC-G
•flexibility, knot retention, low tissue drag PP, nylon,PB-TE
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 POLYMERS IN OPHTHALMICS

1. Intraocular Lens: replace opaque crystalline lens (“cataract”) of the eye

CH3
CH3 Inflexible IOL: Foldable IOL:
O Si
CH2 C
n Tg = 105 C: Rigid n Tg (PDMS) = -125 C
C O CH3
Flexible
Larger incision needed PDMS +
O PMMA
Smaller incision
CH3
Silicone
PMMA 27
Acrylates

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 Norplant / Jadelle
http://en.wikipedia.org/wiki/Norplant
Birth control type Hormonal
Progestogen implant
First use 1983 (Finland)
Failure rates (first year)
Perfect use 0.05%
Typical use 0.05%
Usage
Duration effect 5 years
Reversibility Provided correctly inserted
User reminders Following product discontinuation, alternative method required after 5 years
Clinic review 3 months following insertion
Advantages and disadvantages
STD protection No
Weight No proven effect
Periods Initial irregular light spotting
Benefits No further user contraceptive action needed
Medical notes 31
Possible scaring and difficulty in removal

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 33

What is Polymer Degradation?

A polymer or
device will
eventually
disappear after
having been
introduced into a
living organism.

Polyglycolides were synthesized

from glycolic acid in 1920s
At that time, polymer degradation was viewed
negatively as a process where properties and
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performance deteriorated with time.

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 In Vivo Degradation of Polymers
– no polymer is impervious to chemical and
physical actions of the body

Mechanisms causing degradation

Physical Chemical

sorption/swelling hydrolysis
softening oxidation
dissolution enzymatic
stress cracking
fatigue cracking
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Definitions
• Degradation: the process of polymer
chain scission by the cleavage of bonds
between the monomers in the polymer
backbone  size reduction in polymer
chains
• Erosion: the mass loss of polymer  can
be the result of biological, chemical, or
physical effects.
• Bio-degradation? Bio-erosion?
… occurs under physiological conditions
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 Definitions
• Bioresorption
• Bioabsorption
-- used interchangeably, polymer or its
degradation products removed by cellular
activity (e.g., phagocytosis) in a biological
environment.

• Elimination: the excretion and metabolism of

polymer and erosion products from mammals.

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 Synthetic or Natural Biodegradable Polymers
Why Do We Prefer Synthetic Ones?

 Tailorable properties
 Predictable lot-to-lot uniformity
 Free from concerns of immunogenicity
 Reliable source of raw materials

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(Bio)degradables

PCL PLA PGA

Any two can form copolymers

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 PDO PHB PHV

PHBV

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Yang et al. Tissue Engrg, 2001, 7(6):679

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 Polyesters

Polyglycolide-co-Trimethylene Carbonate

• Biodegradable, used in
orthopaedic applications.
• Degrade more quickly than
PLLA, PLLA-co-PDLLA or
PDLLA and as a result could
suffer significant loss of
mechanical strength in vivo.

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Mechanism of chemical degradation

Combinations of mechanisms I, II, and III are possible!!! 44

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 Hydrolytic Degradation
• Hydrolysis
– the scission of chemical functional groups by
reaction with water,
– depend on main chain structure: anhydride >
ester > carbonate
• There are a variety of hydrolyzable
polymeric materials:
– esters
– amides
– anhydrides
– carbonates
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– urethanes

accelerates
degradation

Polyglycolic acid as a suture material. Chain scission by

gradual hydrolysis of the ester linkage. 46

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Enzymatic Degradation
•Natural polymers degrade primarily via enzyme action
– collagen by collagenases, lysozyme
– glycosaminoglycans by hyaluronidase, lysozyme
•There is also evidence that degradation of synthetic
polymers is due to or enhanced by enzymes.

80.0

in vitro
60.0 in vivo PCL
% weight loss

40.0

20.0

0.0

-20.0
-5 0 5 10 15 20 25
time (weeks)
Z Gan et al., Polymer 40 (1999) 2859
C.G. Pitt et al.,
J. Control. Rel. 1 (1984) 3-14
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 Degradation Schemes
• Surface erosion
– Degrades only at polymer-water interface
– Mass loss is faster than the ingress of water into the
bulk

• Bulk erosion
– Degradation takes place throughout the whole of the
sample
– Ingress of water is faster than the rate of degradation
– Diffusion of oligomers and fragmentation of device
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Erodible Matrices or Micro/Nanospheres

• (a)
– Bulk-eroding system

• (b)
– Surface-eroding system

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Factors affecting
hydrolytic degradation rate
– hydrophobicity
– crystallinity
– Tg
– impurities
– initial molecular weight, polydispersity
– degree of crosslinking
– manufacturing procedure (defects)
– Geometry/size
– site of implantation 54

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 Methods for Evaluating Polymer
Degradation
 Morphological changes (swelling, deformation, bubbling,
disappearance…)
 Weight lose
 Thermal behavior changes
 Differential Scanning Calorimetry (DSC)
 Molecular weight changes
 Dilute solution viscosity
 Size exclusion chromatograpgy(SEC)
 Gel permeation chromatography(GPC)
 MALDI mass spectroscopy
 Change in chemistry
 Infared spectroscopy (IR)
 Nuclear Magnetic Resonance Spectroscopy (NMR)
 TOF-SIMS
 Decrease in mechanical performance 55

Medical Applications of
Biodegradable Polymers
 Wound management  Dental applications
 Sutures  Guided tissue
 Staples regeneration
 Clips Membrane
 Adhesives  Void filler following
tooth extraction
 Surgical meshes
 Orthopedic devices  Cardiovascular
applications
 Pins
 Stents
 Rods
 Screws  Intestinal applications
 Tacks  Anastomosis rings
 Ligaments  Drug delivery system
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 Tissue engineering

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 Classification of Degradable
Medical Implants

• The temporary support device

• The temporary barrier
• The drug delivery device
• The tissue engineering scaffold
• The multifunctional implant
-- Biomaterials Science, 2nd edition. Edited
by BD Ratner et al 57

A temporary support device is used in those circumstances in which the

natural tissue bed has been weakened by disease, injury, or surgery and
requires some artificial support.

A healing wound, a broken bone, or a damaged blood vessel are examples of

such situations.

Sutures, bone fixation devices (e.g., bone nails, screws, or plates), and vascular
grafts would be examples of the corresponding support devices.

In all of these instances, the degradable implant would provide temporary,

mechanical support until the natural tissue heals and regains its strength.

In order for a temporary support device to work properly, a gradual stress

transfer should occur: As the natural tissue heals, the degradable implant
should gradually weaken.

The need to adjust the degradation rate of the temporary support device to the
healing of the surrounding tissue represents one of the major challenges in the
design of such devices.
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 Sutures
• The largest group of devices implanted
in humans, repairing damaged tissues,
cut vessels, and surgical incisions;
• By definition, a suture is a filament that
either approximates or maintains tissues
in juxtaposition (并排) until the natural
healing process has provided a sufficient
level of wound strength or compresses
blood vessels in order to stop bleeding;
• The first synthetic, degradable sutures
made of PGA, commercial available
under trade name “Dexon” in 1970

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Vicryl (PGLA) (90:10)

after 7 days in rat muscle

Vicryl (PGLA) (90:10)

after 56 days in rat muscle

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Major Material of Bone Plates

1. Co-
Co-Cr alloy
2. Stainless-
Stainless-steel (316L)
Bending Modulus (GPa)

3. Titanium alloy (Ti-

(Ti-6Al-
6Al-4V) 250
Cortical Bone
200

150
280
100 200

50 116

0
Co-
Co-Cr S-S Ti-
Ti-6Al-
6Al-4V

Stiffness mismatch between metal

materials and cortical bone
occasionally causes bone atrophy
or bone refracture after implant.

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 Poly(L-lactic) acid (PLLA)
Bone Plates, Screws & Pins

 Do not require a
second surgery for
removal
 Avoid stress
shielding, allowing
the gradual transfer http://www.gunze.co.jp/medical/japanese.html

of stress to the
BONE+PLATE
healed tissue
Mechanical Strength
 Offer tremendous Degradable Polymer
potential as the Plate

basis for controlled BONE PLATE

drug delivery
Time 63

A temporary barrier has its major medical use in adhesion prevention.

Adhesions are formed between two tissue sections by clotting of blood in the
extravascular tissue space followed by inflammation and fibrosis.

If this natural healing process occurs between surfaces that were not meant to
bond together, the resulting adhesion can cause pain, functional impairment, and
problems during subsequent surgery.

Surgical adhesions are a significant cause of morbidity and represent one of the
most significant complications of a wide range of surgical procedures such as
cardiac, spinal, and tendon surgery.

A temporary barrier could take the form of a thin polymeric film or a meshlike
device that would be placed between adhesion prone tissues at the time of
surgery.

To be useful, such as temporary barrier would have to prevent the formation of

scar tissue connecting adjacent tissue sections, followed by the slow resorption
of the barrier material
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 Temporary barriers

Artificial skin
http://media.gizmodo.com.au/wp//20
11/02/artificial-skin.jpg

Poly(lactic acid) anti-adhesion membrane

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http://www.hongjianbio.com

An implantable drug delivery device is by necessity a temporary

device, as the device will eventually run out of drug or the need for the
delivery of a specific drug is eliminated once the disease is treated.

Since poly(lactic acid) and poly(glycolic acid) have an extensive

safety profile based on their use as sutures, these polymers have been
very widely investigated in the formulation of implantable controlled
release devices.

Polyanhydride, used for formulation of an intracranial implantable device

for the adminstration of BCNU (a chemotherapeutic agent) to patients
suffering from glioblastoma multiformae, a usually lethal form of brain
cancer

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A tissue engineering scaffold is a degradable implant
that is designed to act as an artificial extracellular matrix
by providing space for cells to grow into and to
reorganize into functional tissue

Manmade implantable prostheses do not function as

well as the native tissue or maintain the functionality of
native tissue over long periods of time.

Tissue engineering has emerged as an interdisciplinary

field that utilizes degradable polymers, among other
substrates and biologics, to develop treatments that will
allow the body to heal itself without the need for
permanently implanted, artificial prosthetic devices.
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Multifunctional devices, combine several of the

functions within one single device.

Biodegradable stents for implantation into coronary

arteries are currently being investigated to combine a
mechanical support function with site specific drug
delivery.

The stents are designed to mechanically prevent the

collapse and restenosis (reblocking) of arteries that have
been opened by balloon angioplasty. Ultimately, the
stents could deliver an anti-inflammatory or anti-
thrombogenic agent directly to the site of vascular injury.

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 Stent: inserted into a blocked
artery to improve blood flow

Permanent Stainless Steel Stents:

• Stainless Steel 316L: E = 193 GPa
• Restenosis: re-blocking of artery due to the formation of (a) “neointima”: thick
smooth muscle tissue inside lumen or (b) late-stage “thrombosis”: blood clot

Biodegradable Polymer Stents:

• Present long enough for vessel to
re-model and then it dissolves
• Can be “drug-loaded” to prevent
growth of cells around the stent 
minimize restenosis
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Disadvantages of Polymeric
Biomaterials
• Contain leachable compounds
• Can absorb water and biomolecules (as
lipids) from the bioenvironment
• Surface contamination
• Mechanical wear and breakdown
• Chemical or biochemical biodegradation
• Physical dissolution (may be desirable)
• Sometimes difficult to sterilize
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Sterilization of Polymer Biomaterials
• Important aspect to consider (lower
thermal and chemical stability)
• Sterilization techniques: dry heat,
autoclaving, radiation, EO
• Dry heat: 160-190C, safely sterilizable
polymers – PTFE, silicone rubber
• Autoclaving: high steam pressure,
temperature 125-130C, water vapor pose
problems for PVC, POM, Nylon, LDPE, etc.
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Sterilization of Polymer Biomaterials

• EO: used at low temperature; most polymeric
impants can be sterilized with this method
• Radiation (e.g., isotopic 60Co): may cause
polymer chains dissociated or cross-linking
according to the characteristics of the chemical
structures.
-- PE: brittle & hard
-- PP: discoloring, embrittlement (flange,tip
breakage, luer cracking)
-- Physical properties continue to deteriorate
with time following irradiation.

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