Biological response

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Biocompatibility

Biological response Biocompatibility
tests Sterilization Issues
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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 several
  materials 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 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

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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

• 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.

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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)
• Monocytes? macrophages (months)

Marieb, EN and Mallatt, J. 1997. Human Anatomy
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Acute Inflammation

• Short term (minutes?days)
• 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.

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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 reactions- mediate antibody production.
• Macrophages process and deliver antigen to
  immunocompetent cells mediate immune reactions.

www.lumen.com
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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.

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Biological Response
Corrosion, Wear, Fracture
Osteolysis
DEBRIS
FOREIGN BODY RESPONSE
CYTOKINES
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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
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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 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 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

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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.

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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.

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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

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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 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

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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 defect
  repair)
• Bioactive-glass ceramics (coatings pf orthopedic
  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 bulk structure

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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
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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

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Sterilization
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 --gt R. initiation
• R. --O2--gt RO2. propagation
• RO2. --RH-gt RO2H R.
• RO2H --RH-gt RO. . OH chain branching
• RO. --RH-gt ROH R.
• .OH --RH-gt H2O R.
• RO2H, RO2., R. -----gt scission and
  crosslinking
• 2RO2. ----gt RO2R O2 termination

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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

• Sterile Material has
• greater crystallinity after
• five years
• Implies chain scission
• in sterilized material

Crystallinity
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Density evolution
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TEMmicrostructure evolution (aging)
unaged
aged
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Oxidation Model
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Sterilization affects fatigue resistance
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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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Questions?