bio compa tibi lty

7/28/2019 Bio Compa Tibi Lty

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Biological response

Biocompatibility tests

Sterilization Issues

Biocompatibility


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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


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Biomaterial-Tissue Interactions


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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


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Response to implantation

Inflammation

Acute inflammation

Chronic inflammation

Granulation tissue

Foreign Body Reaction

Fibrosis and Encapsulation


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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.


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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


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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.


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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


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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.


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Biological Response

Corrosion, Wear, Fracture

DEBRIS

FOREIGNBODYRESPONSE

CYTOKINES

Osteolysis


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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


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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.


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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


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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.


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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


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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


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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


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Bioactivity spectra for bioceramics


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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).


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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


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Implant reactions in the body


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Host Factors

Age and health status

Immunological/metabolic status Choice of surgeon: minimize tissue

damage and contamination, proper

implantation


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Biocompatibility testing

Cell toxicity

Thromobogenecity

Inflammatory response

Animal tests

Clinical trials

FDA regulations

ASTM/ISO standards


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Device sterility

Minimizes bacterial contamination

Reduces likelihood for infection

Can alter the material surface and bulkstructure


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Design Issues

Shelf Aging-- Post Sterilization --Manufacturing

issues-- what is the best sterilization method?

What is shelf life for the device?


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Pre-Surgical Implant Life

sterilization

direct compression moldedextruded

machinedblocks of UHMWPE

medical grade UHMWPE resin

rod of UHMWPE

component

implanted

compression molded

shelf aging


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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


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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


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STERILIZATION SCHEMES

Eto Gas

Steam

Autoclaving

E-beam radiation

Gamma Radiation*


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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


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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


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Structural changes due to gamma

sterilization and aging in UHMWPE

Increased crystallinity and density

Increased oxidation levels Loss of fatigue and fracture properties


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DSC: Crystallinity

0

10

20

30

40

50

60

Nonsterile Sterile

Sterile Material hasgreater crystallinity after

five years

Implies chain scissionin sterilized material

% Crystallinity


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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


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TEM:microstructure evolution

(aging)

unaged aged


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Oxidation Model


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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


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Current Trends

Sterilization with EtO or Gas Plasma Controlled crosslinking with ionizing schemes

(Gamma inert, melt irradiated, E-beam--

controlled crosslinking)


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