7/28/2019 Bio Compa Tibi Lty
1/41
Biological response
Biocompatibility tests
Sterilization Issues
Biocompatibility
7/28/2019 Bio Compa Tibi Lty
2/41
Biocompatibility
Arises from differences between living and non-living materials
Bioimplants trigger inflammation or foreign body
response New biomaterials must be tested prior to
implantation according to FDA regulation
WWII: Validated biocompatibility of severalmaterials including PMMA
7/28/2019 Bio Compa Tibi Lty
3/41
Biomaterial-Tissue Interactions
7/28/2019 Bio Compa Tibi Lty
4/41
Definitions
Neutrophil- common leucocyte of the blood- short-lived phagocytic cell
Lymphocyte- small cell in blood- recirculates through tissues and backthrough lymph --polices body for non-self material-- recognizesantigens through surface receptors
Antigen- produces antibody- stimulate adaptive immune response
Antibody- Serum globulins with wide range of specificity for differentantigens-- bind to surface
Monocyte- largest nucleated cell of blood-develops into macrophagewhen it migrates to tissues
Macrophage- phagocyte--scavenger cell-- of tissues
Lysozyme- enzyme secreted by macrophages- attack cell wall ofbacteria natural antibiotic
Mast Cell- large tissue cell which releases inflammatory mediators--increases vascular permeability-- allows complement to enter tissuesfrom blood
Complement- a series of enzymes in blood- when activated produceinflammatory effects
7/28/2019 Bio Compa Tibi Lty
5/41
Response to implantation
Inflammation
Acute inflammation
Chronic inflammation
Granulation tissue
Foreign Body Reaction
Fibrosis and Encapsulation
7/28/2019 Bio Compa Tibi Lty
6/41
Inflammation
Inflammationis the reaction of vascularizedliving tissue to injury.
The inflammation process includes a sequence of
events that can heal the implant site. This is done through the generation of new tissue
via native parenchymal cells or the formation of
fibroblastic scar tissue.
7/28/2019 Bio Compa Tibi Lty
7/41
Inflammation process
Enhanced permeability ofvasculature
Fluid, proteins, blood cells
escape vascular system intothe injured tissue
Blood clotting --thrombosis ispossible
Cell response--neutrophils(24-48 hrs)
Monocytes macrophages
(months) Marieb, EN and Mallatt, J. 1997. HumanAnatomy
7/28/2019 Bio Compa Tibi Lty
8/41
7/28/2019 Bio Compa Tibi Lty
9/41
Acute Inflammation
Short term (minutesdays) Exudation of fluid, plasma, proteins, and
leukocytes (neutrophils).
Phagocytosis and enzymatic release occurs.
Activation of neutrophils and macrophages--digest foreignmaterial--involves recognition, attachment, engulfment, anddegradation.
Recognition and attachment is enhanced when serum factors,Opsonins presentimmunoglobin G (IgG), complementactivated fragment C3b--can adsorb to biomaterials.
Neutrophils and macrophages have receptors for theseproteins.
Due to size disparity, however, frustrated phagocytosis mayoccurthis results in extracellular release of leukocyte productsin a cellular attempt to degrade the biomaterial.
7/28/2019 Bio Compa Tibi Lty
10/41
Chronic Inflammation
Long term ( days). Characterized by the presence ofmacrophages, monocytes, andmononuclear cells includinglymphocytes and plasma cells.
Accompanied by the proliferation ofblood vessels and connective tissue.
Lymphocytes and plasma cells areinvolved in the immune reactions-
mediate antibody production. Macrophages process and deliverantigen to immunocompetent cellsmediate immune reactions.
www.lumen.com
7/28/2019 Bio Compa Tibi Lty
11/41
Cellular pathways
Macrophages along with monocytes belong to the mononuclearphagocytic system (MPS) or the reticuloendothelial system(RES).
These systems include the cells in the bone marrow, peripheralblood, and specialized tissues (liver, lung, connective,lymphoid).
The macrophage is a key cell in the inflammation process as itcan produce a large number of biologically active productsincluding proteases, complement components, coagulation
factors, growth factors and cytokines (proteins that regulateimmune response).
Growth factors include (FBF)-fibroblast growth factor, (TNF)tumor necrosis factor, (IL-1) interleukin-1... These are importantfor the growth of fibroblasts, blood vessels, epithelial cells... and
play a key role in tissue remodeling and wound healing.
7/28/2019 Bio Compa Tibi Lty
12/41
Biological Response
Corrosion, Wear, Fracture
DEBRIS
FOREIGNBODYRESPONSE
CYTOKINES
Osteolysis
7/28/2019 Bio Compa Tibi Lty
13/41
Wear-Mediated Osteolysis
Wear particles from
the replacement head
and liner cause
inflammation that can
lead to pain, boneloss, and ultimately
revision surgerywear
particles
bone loss
Archibeck, MJ; Jacobs, JJ; Roebuck, KA; Glant, TT. Journal of Bone & Joint Surgery, 2000
7/28/2019 Bio Compa Tibi Lty
14/41
Granulation tissue
Within 24 hrs of implantation, healinginitiated by the action of monocytes andmacrophages.
Fibroblasts and vascular endothelial cellsreproduce and form granulation tissue (pink,
granular appearance)Neovascularization involves the generation,maturation, and organization of endothelialcells into capillary tubes.
Fibroblasts are active in the synthesis of
proteoglycans and collagen (type IIIpredominantly).
Granulation tissue may be observed within 3-5 days of implantation of a biomaterialit is
often accompanied by wound contraction.
7/28/2019 Bio Compa Tibi Lty
15/41
Foreign Body Reaction
Indicated by the presence of multinucleatedforeign body giant cells and the componentsof granulation tissue (macrophages,fibroblasts, and capillaries)
Observed in silicone breast implants
Surface of the biomaterial will oftendetermine the composition of the foreign
body response
S f f
7/28/2019 Bio Compa Tibi Lty
16/41
Surface structure important for
biocompatibility
High surface to volume ratio offabrics and porous structures can
result in higher ratios of
macrophages than a smooth
component made of the identical
material but can also encourage
tissue ingrowth --this is observed in
vascular grafts.
7/28/2019 Bio Compa Tibi Lty
17/41
Fibrosis and Encapsulation
The final stage of the foreign body response and healingprocess is the development of a fibrous encapsulation(porous structures may be excluded from this stage due totissue ingrowth).
Repair involves two separate processes: replacement of
tissue by parenchymal cells of the same type or replacementby connective tissue that constitute the fibrous capsule.
These processes are controlled by the growth capacity ofthe cells in the tissue receiving the implant, the persistenceof the tissue framework and degree of injury.
R t th i fl t
7/28/2019 Bio Compa Tibi Lty
18/41
Response to the inflammatory
challenge
Decreased tissue mass and formation of newtissue through granulation
Collagen and other molecules are synthesized
Formation of scar tissue
Remodeling process differs for various tissues
7/28/2019 Bio Compa Tibi Lty
19/41
Implant Factors
Bulk properties: chemical composition, structure,purity and presence of leachables.
Surface properties: smoothness, COF, geometry,hyrophilicity, surface charge
Mechanical properties: match properties ofcomponent being replaced, such as elasticmodulus. Stability and fixation.
Long-term structural integrity: design for fatigueand fracture loading, wear, creep, and stresscorrosion cracking
7/28/2019 Bio Compa Tibi Lty
20/41
Bioactivity spectra for bioceramics
7/28/2019 Bio Compa Tibi Lty
21/41
Reactivity of Ceramics
Bioinert- Pyrolytic carbon (heart valves),Alumina/Zirconia (orthopedic femoral heads)
Biodegradable- Calcium phosphate (artificial
bone), tricalcium phosphate (peridontal defectrepair)
Bioactive-glass ceramics (coatings pforthopedic devices, bone plates).
7/28/2019 Bio Compa Tibi Lty
22/41
Host can affect the implant
Physically Abrasive, adhesive, delamination wear
Fatigue and Fracture
Stress Corrosion cracking
General corrosion Biologically Absorption of substances from the tissues Enzymatic degradation Calcification
7/28/2019 Bio Compa Tibi Lty
23/41
Implant reactions in the body
7/28/2019 Bio Compa Tibi Lty
24/41
Host Factors
Age and health status
Immunological/metabolic status Choice of surgeon: minimize tissue
damage and contamination, proper
implantation
7/28/2019 Bio Compa Tibi Lty
25/41
Biocompatibility testing
Cell toxicity
Thromobogenecity
Inflammatory response
Animal tests
Clinical trials
FDA regulations
ASTM/ISO standards
7/28/2019 Bio Compa Tibi Lty
26/41
Device sterility
Minimizes bacterial contamination
Reduces likelihood for infection
Can alter the material surface and bulkstructure
7/28/2019 Bio Compa Tibi Lty
27/41
Design Issues
Shelf Aging-- Post Sterilization --Manufacturing
issues-- what is the best sterilization method?
What is shelf life for the device?
7/28/2019 Bio Compa Tibi Lty
28/41
Pre-Surgical Implant Life
sterilization
direct compression moldedextruded
machinedblocks of UHMWPE
medical grade UHMWPE resin
rod of UHMWPE
component
implanted
compression molded
shelf aging
7/28/2019 Bio Compa Tibi Lty
29/41
STERILIZATION
One of the greatest challenges for devices isensuring sterility
Many in-vivo degradation schemes have been
linked to loss of mechanical properties due topost-sterilization aging
7/28/2019 Bio Compa Tibi Lty
30/41
Sterilization
Sterility Definition: the state in which the
probability of any one bacterial endospore
surviving is 10 or lower
Common Method: 25 kGy of Co gamma
radiation in air
-6
60
7/28/2019 Bio Compa Tibi Lty
31/41
STERILIZATION SCHEMES
Eto Gas
Steam
Autoclaving
E-beam radiation
Gamma Radiation*
7/28/2019 Bio Compa Tibi Lty
32/41
Gamma Radiation
Advantages:
deeply penetrating
no residuals
no post-sterilization treatment
crosslinking- good for wear resistance
Disadvantages:
chain cleavage, loss of molecular weight and higher crystallinity
embrittlement
7/28/2019 Bio Compa Tibi Lty
33/41
Oxygen aids in high reactivity towards free radical
generation in radiation sterilization schemes
R --g --> R.} initiation
R. --O2--> RO2. } propagation
RO2. --RH-> RO2H + R
. }
RO2H --RH-> RO. + . OH } chain branching
RO. --RH-> ROH + R. }
.OH --RH-> H2O + R.
RO2H, RO2., R. -----> scission and crosslinking
2RO2. ----> RO2R + O2} termination
St t l h d t
7/28/2019 Bio Compa Tibi Lty
34/41
Structural changes due to gamma
sterilization and aging in UHMWPE
Increased crystallinity and density
Increased oxidation levels Loss of fatigue and fracture properties
7/28/2019 Bio Compa Tibi Lty
35/41
DSC: Crystallinity
0
10
20
30
40
50
60
Nonsterile Sterile
Sterile Material hasgreater crystallinity after
five years
Implies chain scissionin sterilized material
% Crystallinity
7/28/2019 Bio Compa Tibi Lty
36/41
Density evolution
0.93
0.94
0.95
0.96
0.97
0.98
0 1 2 3 4
Unsterilized
Sterilized in N2
Sterilized in Air
Aging Time (Weeks)
n=18
TEM:microstructure evolution
7/28/2019 Bio Compa Tibi Lty
37/41
TEM:microstructure evolution
(aging)
unaged aged
7/28/2019 Bio Compa Tibi Lty
38/41
Oxidation Model
7/28/2019 Bio Compa Tibi Lty
39/41
Sterilization affects fatigue resistance
10-6
10-5
10-4
10-3
1 2 3
G415Gi
G415NS
G415GA
G415P
G415Eto
da/dN(mm/cycle)
K (MPam)
4
GUR4150HP unage d
7/28/2019 Bio Compa Tibi Lty
40/41
Current Trends
Sterilization with EtO or Gas Plasma Controlled crosslinking with ionizing schemes
(Gamma inert, melt irradiated, E-beam--
controlled crosslinking)
7/28/2019 Bio Compa Tibi Lty
41/41
Questions?
Top Related