Biocompatibility

Biological response Biocompatibility tests Sterilization Issues

Biocompatibility
Arises from differences between living and nonliving materials Bioimplants trigger inflammation or foreign body response New biomaterials must be tested prior to implantation according to FDA regulation WWII: Validated biocompatibility of several materials including PMMA

Biomaterial-Tissue Interactions

Definitions
Neutrophil- common leucocyte of the blood- short-lived phagocytic cell Lymphocyte- small cell in blood- recirculates through tissues and back through lymph --polices body for non-self material-- recognizes antigens through surface receptors Antigen- produces antibody- stimulate adaptive immune response Antibody- Serum globulins with wide range of specificity for different antigens-- bind to surface Monocyte- largest nucleated cell of blood-develops into macrophage when it migrates to tissues Macrophage- phagocyte--scavenger cell-- of tissues Lysozyme- enzyme secreted by macrophages- attack cell wall of bacteria natural antibiotic Mast Cell- large tissue cell which releases inflammatory mediators-increases vascular permeability-- allows complement to enter tissues from blood Complement- a series of enzymes in blood- when activated produce inflammatory effects

Response to implantation
Inflammation Acute inflammation Chronic inflammation Granulation tissue Foreign Body Reaction Fibrosis and Encapsulation

Inflammation
Inflammation is the reaction of vascularized living 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.

Inflammation process
Enhanced permeability of vasculature Fluid, proteins, blood cells escape vascular system into the injured tissue Blood clotting --thrombosis is possible Cell response--neutrophils (24-48 hrs) Marieb, EN and Mallatt, J. 1997. Human Monocytes macrophages Anatomy (months)

Acute Inflammation
Short term (minutesdays) Exudation of fluid, plasma, proteins, and leukocytes (neutrophils). Phagocytosis and enzymatic release occurs. Activation of neutrophils and macrophages--digest foreign material--involves recognition, attachment, engulfment, and degradation. Recognition and attachment is enhanced when serum factors, Opsonins presentimmunoglobin G (IgG), complement activated fragment C3b--can adsorb to biomaterials. Neutrophils and macrophages have receptors for these proteins. Due to size disparity, however, frustrated phagocytosis may occurthis results in extracellular release of leukocyte products in a cellular attempt to degrade the biomaterial.

Chronic Inflammation
Long term ( days).
Characterized by the presence of macrophages, monocytes, and mononuclear cells including lymphocytes and plasma cells. Accompanied by the proliferation of blood vessels and connective tissue. Lymphocytes and plasma cells are involved in the immune reactionsmediate antibody production. Macrophages process and deliver antigen to immunocompetent cells mediate immune reactions.

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Cellular pathways
Macrophages along with monocytes belong to the mononuclear phagocytic system (MPS) or the reticuloendothelial system (RES). These systems include the cells in the bone marrow, peripheral blood, and specialized tissues (liver, lung, connective, lymphoid). The macrophage is a key cell in the inflammation process as it can produce a large number of biologically active products including proteases, complement components, coagulation factors, growth factors and cytokines (proteins that regulate immune response). Growth factors include (FBF)-fibroblast growth factor, (TNF) tumor necrosis factor, (IL-1) interleukin-1... These are important for the growth of fibroblasts, blood vessels, epithelial cells... and play a key role in tissue remodeling and wound healing.

Biological Response
Corrosion, Wear, Fracture
Osteolysis

DEBRIS

CYTOKINES

FOREIGN BODY RESPONSE

Wear-Mediated Osteolysis
Wear particles from the replacement head and liner cause inflammation that can lead to pain, bone loss, and ultimately revision surgery

wear particles

bone loss

Archibeck, MJ; Jacobs, JJ; Roebuck, KA; Glant, TT. Journal of Bone & Joint Surgery, 2000

Granulation tissue
Within 24 hrs of implantation, healing initiated by the action of monocytes and macrophages. Fibroblasts and vascular endothelial cells reproduce and form granulation tissue (pink, granular appearance) Neovascularization involves the generation, maturation, and organization of endothelial cells into capillary tubes. Fibroblasts are active in the synthesis of proteoglycans and collagen (type III predominantly). Granulation tissue may be observed within 35 days of implantation of a biomaterialit is often accompanied by wound contraction.

Foreign Body Reaction

Indicated by the presence of multinucleated foreign body giant cells and the components of granulation tissue (macrophages, fibroblasts, and capillaries) Observed in silicone breast implants Surface of the biomaterial will often determine the composition of the foreign body response

Surface structure important for biocompatibility

High surface to volume ratio of fabrics 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.

Fibrosis and Encapsulation

The final stage of the foreign body response and healing process is the development of a fibrous encapsulation (porous structures may be excluded from this stage due to tissue ingrowth). Repair involves two separate processes: replacement of tissue by parenchymal cells of the same type or replacement by connective tissue that constitute the fibrous capsule. These processes are controlled by the growth capacity of the cells in the tissue receiving the implant, the persistence of the tissue framework and degree of injury.

Response to the inflammatory challenge

Decreased tissue mass and formation of new tissue through granulation Collagen and other molecules are synthesized Formation of scar tissue Remodeling process differs for various tissues

Implant Factors
Bulk properties: chemical composition, structure, purity and presence of leachables. Surface properties: smoothness, COF, geometry, hyrophilicity, surface charge Mechanical properties: match properties of component being replaced, such as elastic modulus. Stability and fixation. Long-term structural integrity: design for fatigue and fracture loading, wear, creep, and stress corrosion cracking

Bioactivity spectra for bioceramics

Reactivity of Ceramics
Bioinert- Pyrolytic carbon (heart valves), Alumina/Zirconia (orthopedic femoral heads) Biodegradable- Calcium phosphate (artificial bone), tricalcium phosphate (peridontal defect repair) Bioactive-glass ceramics (coatings pf orthopedic devices, bone plates).

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

Implant reactions in the body

Host Factors

Age and health status Immunological/metabolic status Choice of surgeon: minimize tissue damage and contamination, proper implantation

Biocompatibility testing
Cell toxicity Thromobogenecity Inflammatory response Animal tests Clinical trials FDA regulations ASTM/ISO standards

Device sterility
Minimizes bacterial contamination Reduces likelihood for infection Can alter the material surface and bulk structure

Design Issues

Shelf Aging-- Post Sterilization --Manufacturing issues-- what is the best sterilization method? What is shelf life for the device?

Pre-Surgical Implant Life

medical grade UHMWPE resin
compression molded extruded direct compression molded

blocks of UHMWPE

rod of UHMWPE
machined

component sterilization
shelf aging

implanted

STERILIZATION
One of the greatest challenges for devices is ensuring sterility Many in-vivo degradation schemes have been linked to loss of mechanical properties due to post-sterilization aging

Sterilization

Sterility

Definition: the state in which the probability of any one bacterial endospore surviving is 10 -6or lower
Common

Method: 25 kGy of radiation in air

60

Co gamma

STERILIZATION SCHEMES
Eto Gas Steam Autoclaving E-beam radiation Gamma Radiation*

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

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-> H O + R. 2 RO2H, RO2., R. -----> scission and crosslinking 2RO2. ----> RO2R + O2} termination

Structural changes due to gamma sterilization and aging in UHMWPE

Increased crystallinity and density Increased oxidation levels Loss of fatigue and fracture properties

DSC: Crystallinity
60 50
Sterile

40 % Crystallinity 30 20 10 0 Nonsterile Sterile

Material has greater crystallinity after five years

Implies

chain scission in sterilized material

Density evolution
0.98 0.97 0.96 0.95 0.94 0.93 0 1 2 3 Aging Time (Weeks) 4 Unsterilized Sterilized in N 2 Sterilized in Air n=18

Density (g/cc)

TEM:microstructure evolution (aging)

unaged

aged

Oxidation Model

Sterilization affects fatigue resistance

GUR4 150HP unage d 10

-3

da/dN (mm/cycle)

10

-4

10

-5

G415Gi G415NS G415GA G415P G415Eto

-6

10

2 K (M Pam)

Current Trends
Sterilization with EtO or Gas Plasma Controlled crosslinking with ionizing schemes (Gamma inert, melt irradiated, E-beam-controlled crosslinking)

Questions?