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BIOCOMPATIBILITY & TISSUE DAMAGEBIOCOMPATIBILITY & TISSUE DAMAGE
CHAPTER 4 (LECTURE 2):
MEDICAL PHYSICS AND BIOMEDICAL ENGINEERINGMEDICAL PHYSICS AND BIOMEDICAL ENGINEERING
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
4.3 & 4.4: BIOCOMPATIBILITY4.3 & 4.4: BIOCOMPATIBILITY
BIOMATERIALTISSUE/BIOLOGICALENVIRONMENT
Biomaterial effects induce a tissue response
The tissue response generates a biomaterial effect
The cycle continues until equilibrium is reached or the the
biomaterial is removed
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Mechanisms for biomaterial/tissue interactionMechanisms for biomaterial/tissue interaction
Material releases toxic substance
e.g.unpolymerized monomer of bone cement
Material non-toxic but resorbable
e.g.suture material
Material non-toxic but stimulates inflammation or enhances
infection
any material being resorbed
Mechanical trauma
Non-toxic and non-absorbable
encapsulated
Highly interactive material bonds to tissues
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
4.3. MATERIAL RESPONSE TO THE BIOLOGICAL4.3. MATERIAL RESPONSE TO THE BIOLOGICAL
ENVIRONMENT:ENVIRONMENT:
BIOMATERIAL TISSUE/BIOLOGICALENVIRONMENT
7.4Arterial blood
7.1Venous blood
7.0Interstitial fluid
6.8Intracellular fluid
4.6-6.0Urine
1.0Gastric contents
pHpHTissue componentTissue component
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Effect of host on biomaterial:Effect of host on biomaterial:
Physical mechanical effects:
Abrasive wear
Fatigue
Stress-corrosion cracking
Corrosion
Degeneration and dissolution
Biological effects:
Absorption of substances from tissues
Enzymatic degradation
Calcification
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Copper
Stainless steel
Titanium
Stainless steel, passivated
Silver
Nickel
Low-ally steelZinc
Magnesium
4.3.1. Metals: may fail due to:4.3.1. Metals: may fail due to:
Corrosion
Fracture
Wear
Yielding
Loosening
Infection
Table 4.3. Galvanic series of metals and alloys in sea water.
BEST
WORST
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4.3.2. Polymers4.3.2. Polymers
Non-biodegradable
Biodegradable
Polyethylene oxide/polyethylene tetraphalate (PEO/PET)
Polyglycolic acid (PGA) and polylactic acid (PLA)
Polylysine and poly(glutamic acid)
Applications:
adhesives
sutures
drug carriers
scaffolds
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
4.3.2. Ceramics4.3.2. Ceramics
Three types of bioceramics:
Nearly inert (e.g. alumina, pyrolitic carbon)
Totally resorbable (e.g. calcium phosphate)
Controlled surface activity, bind to tissues (e.g.
bioglass)
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Local effects
Systemic effects
Examples:
Local tissue response Immunological effects
Carcinogenicity
Biomechanical compatibility
4.4. TISSUE RESPONSE TO THE BIOMATERIAL:4.4. TISSUE RESPONSE TO THE BIOMATERIAL:
BIOMATERIAL TISSUE/BIOLOGICALENVIRONMENT
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Blood material interactions
protein adsorption
coagulation
fibrinolysis
platelet activation
complement activation
leukocyte adhesion
hemolysis
Toxicity
Modification of normal healing
encapsulation
foreign body reaction
Infection
Carcinogenicity
Biomechanical compatibility
Local host reaction:Local host reaction:
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Biomechanical compatibility
effect of implant shape
effect of surface finish
role of surface porosity in tissue ingrowth
Osteoblasts adhered better to the rougher surface of the nanophase
version than the conventional sample.
Thomas J. Webster et al., Expert Rev. Medical Devices 1(1), 2004
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Infection usually require reoperation
May result in amputation, osteomyelitis, or death
Vascular prostheses infections result in death
25-50% of the time
Intravenous catheters, periotoneal dialysis, and
urologic devices frequently become infected or
cause secondary infections
Total artificial heart causes 100% infection after 90
days
Artificial organs at a critical crossroads due to
infection
ImplantImplant--associated infection:associated infection:
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Implants reduce number of bacteria required to begininfection
Implants and dead tissue provide framework for
microorganisms to proliferate
Infection caused by adherence to surface by bacteria
Bacteria and tissue may compete for surface space
Bacteria on surface kill tissues and are resistant to
antibodies and defense mechanisms
Bacteria within biofilms are sometimes resistant to
antibiotic levels ~ 1,000 fold higher than those
required to kill their planktonic counterparts
Bacteria prefer surfaces, tissues do not
Thus, potential for infection very high
ImplantImplant--associated infection (continue):associated infection (continue):
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Features of implant-associated infections
Biomaterial or damaged tissue
Adhesive colonization
Resistance to host defense and antibiotics
Specific materials, organisms, host location
Transformation of nonpathogens to virulent form by
biomaterial
Infection persistence
Polymicrobiality
Tissue integration at biomaterial surface
Tissue cell damage or necrosis
ImplantImplant--associated infection (continue):associated infection (continue):
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Implant-associated infection mechanisms
Bacteria adhere to surface through a variety of interactions
Rough surfaces, grains, and other discontinuities increase
adherence
Form a biofilm 2 to hundreds of bacteria thick
Forms a 3-D structure that holds bacteria
Groups of bacteria have better survival than individuals
Varied species may interact
Damage by wear, corrosion, toxins, etc provide an interface
bacteria may exploit
Biomaterials may disrupt natural microbe preventatives (free
iron or other nutrients) Infection may then spread as bolus, etc.
Host defense may be exhausted by prolonged inflammation
Response to biomaterial may reduce efficacy of macrophages
ImplantImplant--associated infection (continue):associated infection (continue):
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Orthopaedic device-related infections remain one of the
most common and potentially problematic
complications faced by the more than 750,000 U.S.
patients who receive orthopaedic procedures for joint
replacements annually.
Infection rates are 7-9% for elbow replacements and 1-2%
for hip replacements. Patients with open fractures
clearly show a significantly higher risk of infection.
These infections are caused by relatively common
biofilm-forming bacterial pathogens (e.g. S. aureus, S.
epidermidis, P. aeruginosa, and E. coli).
ImplantImplant--associated infectionassociated infection orthopaedicsorthopaedics::
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Antibiotics, systemic or in situ
Precolonization by healthy tissues
Peptides and sugars on surface to encourage tissue adhesion and
discourage pathogen adhesion
Coating surface to direct biological activity
Genetic modification of local tissue adhesion
Better understanding of surface phenomenon and structure
ImplantImplant--associated infection prevention strategies:associated infection prevention strategies:
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Approaches to attach to
various (biomedical) devicesmonolayerformation
Self-assembly ofpolypeptide
multilayernanocoatingsStabilization cross-linking
Molecular
recognition
DNA/gene
protein/peptide
cell
drug
SURFACE MODIFICATION & MULTI-FUNCTIONALIZATION
BASED ON
POLYPEPTIDE DESIGN & ELECTROSTATIC SELF-ASSEMBLY
Substrate
BIOENGINEERING NANOCOATINGS FOR IMPLANT-
ASSOCIATED INFECTION PREVENTION
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Drug loading & release:
Antibiotics (e.g. cefazolin, gentomycin) Antimicrobial polypeptides (e.g. Histatin 5)
Cytokines (e.g. IL-12)
Multi-drug loading
Growth factors: (e.g. BMP, TGF-1, IGF-I) RGD peptides
competing for spaceBacterial cell
Osteoblast cell
Fig. Plot of drug concentration vs.
time for different release systems.
Toxic level
Therapeutic level
Ineffective level Single dose
Prolonged
Time
Controlled
Drugconcentration
GOAL
BIOENGINEERING NANOCOATINGS FOR IMPLANT-
ASSOCIATED INFECTION PREVENTION
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Toxicity distant from implant site
Causes
Chemical toxicity
Accumulation of wear products
Corrosion or degradation
Excess inflammation
Vasoactive products from complement
Immune response
Symptoms
General: swelling, itching, rashes, sneezing
Lungs: changed breathing patterns
Kidneys: changed urine excretion or pain
Joints: pain swelling, loss of function
GI tract: diarrhea or constipation
Systemic toxicity:Systemic toxicity:
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Bone interactions with bioceramics
Implant
Tissue response
Toxic: tissue dies
Inert: capsule forms
Bioactive: interfacial bond forms
Dissolves: replaced by tissue
Bioceramic Tissue attachment
Dense, nonporous, inert: bone grows into surface irregularities,
cementing
o Relative motion and capsule cause failure
Porous, inert: bone growth mechanically connects materials
(biological fixation)
o More stable, best as coating
Dense, nonporous, surface reactive: chemical bonding to bone
(bioactive fixation)o Active surface, bioglass, HA, and composites
Dense, nonporous, resorbable: slowly replaced by bone
o Must engineer strength, resorption rate, metabolites
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Irritation
Produces mild to moderate pain or discomfort
(e.g. itching)
Usually surface phenomenon
Chemical or physical incompatibility
Inflammation
More severe response than irritation
Signals include redness, heat, swelling, pain
Defensive response
Occurs with all resorbable materials
Necrosis
Cell/tissue death
Undesirable biomaterial results:Undesirable biomaterial results:
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Pyrogenicity
Tendency to produce fever
IL-1 and tumor necrosis factor from activated
macrophages
Lipopolysaccharides from gram negative
bacterial cell walls
Some polymers (PE, PTFE) selectively absorb
endotoxin
Sensitization
Generally a delayed reaction
Immunologically mediated
Allergies a typical example
May require repeated exposure
Amines and metals significant
Undesirable biomaterial results (continue):Undesirable biomaterial results (continue):
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Mutagenicity
Tendency to produce genetic mutation
Combination of dose and frequency of exposure
o plasticizers cause lethal mutation in mice
Carcinogenicity or tumorigenesis
Tendency to produce tumors or cancer
Related to dose, exposure and genetic susceptibility
Related to characteristics of materials
Solid state carcinogenesis in rodents
Undesirable biomaterial results (continue):Undesirable biomaterial results (continue):
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4.5.2. IN VIVO AND CLINICAL TRIALS
In vivo (Latin: (with)in the living) means that which takes place
inside an organism. In science, in vivo refers to
experimentation done in or on the living tissue of a whole, living
organism as opposed to a partial or dead one. Animal testing
and clinical trials are forms of in vivo research.
A fracture setup and an open fracture rat model of osteomyelitis.
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
Inn Vivo Tests:ivo Tests:Toxicity
Sensitization
Rabbit Pyrogen
USP Class Testing
Sub-Chronic/Chronic
Intracutaneous
Reactivity
Irritation Testing
Histology Examination
Etc.
InnVitro Tests:itro Tests:Cytotoxicity
Hemolysis
PT/PTT Testing
AMES Mutagenicity
Carcinogencity Testing
Etc.
Test animals:est animals:Rabbits
Mice/rat
Pig
People
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Voluntary standards, e.g. established by
interested organizations:
ASTM
ANSI
AAMI
ISO
Government standards
Vary from country to country
Generally not voluntary
Approval of government required formarketing device
In US, the FDAis responsible for regulating
medical devices
BIOMATERIAL REGULATION:BIOMATERIAL REGULATION:
BIOMATERIALS BIOCOMPATIBILITY TISSUE DAMAGE BIOCOMPATIBILITY BIOMATERIALS
WHAT ARE SOME OF THE CHALLENGES?WHAT ARE SOME OF THE CHALLENGES?
To more closely replicate complex tissue
architecture and arrangement in vitro
To better understand extracellular and
intracellular modulators of cell function
To develop novel materials and processing
techniques that are compatible with biological
interfaces
To find better strategies for infection prevention
and immune acceptance
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