Host Response to Material Implantation

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Host Response to Material Implantation

• Implantation of a biomaterial is an invasive
  procedure that initiates a series of events whose
  outcome ultimately determine the biocompatibility
  of the material.
• OBJECTIVES
• to outline the normal wound healing response
• to outline the change in this response in the
  presence of a biomaterial

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Normal Wound Healing

• wound healing is a dynamic cascade of events
  initiated by injury
• it may be divided into phases characterized by
  both cellular population and cellular function
• blood clotting
• inflammation
• cellular invasion and remodeling

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Clotting or Thrombosis

• blood coagulation or clotting is the blood
  response to damaged blood vessels
• objective is to form a patch that isolates the
  leak and stops blood loss

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Coagulation Pathways
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Host Defence

• The body is under constant attack by
  microorganisms in the environment.
• pathogen an infectious agent that causes
  disease
• Infectious disease occurs when a microorganism
  succeeds in evading or overwhelming host defenses
  to establish a local site of infection and
  replication. In order for a pathogen to enter
  the body it must first overcome the epithelium
  and then the innate immune response.

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Intravascular Cells

• white blood cells

Granulocytes
neutrophil
eosinophil
basophil
lymphocyte
monocyte
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First Line of Defence

• Epithelial Tissue
• covers the whole surface of the body
• made up of closely packed cells
• can be divided into simple or stratified
• interior epithelium covered with a mucus layer

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Stratified Epithelium - Skin
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Innate Immune response

• If a pathogen breaches the epithelium,
• then the innate immune response begins.
• The cells of the immune system determine
• self from non-self by recognizing molecules
  on the microbe surface.
• Macrophages and dendritic cells are immune cells
  (phagocytes) that reside within the tissue.
  Neutrophils are phagocytes that reside in the
  blood but can extravasate into tissue during
  inflammation.
• There are circulating proteins, called
  complement, that either kill microbes or mark
  them for effective phagocytization.

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Phagocytosis

• Phagocytosis
• Engulfing and degradation or digestion of
  fragments of tissue or material
• long membrane evaginations, called pseudopodia.
• Ingestion forming a "phagosome," which moves
  toward the lysosome.
• Fusion of the lysosome and phagosome
  (phagolysosome), releasing lysosomal enzymes
• Digestion of the ingested material.
• Release of digestion products from the cell.

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Inflammatory Response

• Pathogen recognition and tissue damage begin an
  inflammation response. This is characterized by
  
• swelling
• pain
• redness
• heat
• Inflammation allows for neutrophil and plasma
  protein extravasation. Both of these effects
  aids the immune response.

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Diapedesis Movie
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Phagocytosis Movie
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Leukocyte Invasion at Wound Site
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Granulation Tissue Deposition - Remodeling

• Due to death of cells following injury, and their
  removal, there is a local decreased tissue mass
• fibroblasts and vascular endothelial cells are
  recruited to site
• Begin to form granulation tissue (ECM and new
  blood vessels)

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Wound Healing
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Foreign Body Reaction

• The presence of the implant changes the healing
  response, and this is called the Foreign Body
  Reaction.
• FBR consists of
• protein adsorption
• macrophages
• multinucleated foreign body giant cells
• fibroblasts
• angiogenesis

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Components of Plasma
Component Typical Concentration (mg/100 ml)
protein 7250
salts 325
lipids 828
glucose 90
urea 25
carbohydrates 85
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Proteins

• are polyamides, composed of amino acids

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Soluble Proteins
(A) A space-filling model of myoglobin with
hydrophobic amino acids shown in yellow, charged
amino acids shown in blue, and others shown in
white. The surface of the molecule has many
charged amino acids, as well as some hydrophobic
amino acids. (B) A cross-sectional view shows
that mostly hydrophobic amino acids are found on
the inside of the structure, whereas the charged
amino acids are found on the protein surface.
albumin
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Surfaces and Protein Adsorption
Immediately after implantation soluble proteins
adsorb to the surface of the biomaterial.
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Protein Adsorption - Example
Figure 2 Adsorption profiles of (a) BSA and (b)
fibrinogen onto CH3 (O) and OH () terminated
surfaces. Initial bulk protein concentration was
1 mg mL-1. Inserts show derivative plots with
corresponding initial adsorption profiles
From Interpretation of Protein Adsorption
Surface-Induced Conformational Changes, P. Roach,
D. Farrar,C.C. Perry JACS 127 (2005)8168.
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Protein Adsorption - Example
From Interpretation of Protein Adsorption
Surface-Induced Conformational Changes, P. Roach,
D. Farrar,C.C. Perry JACS 127 (2005)8168.
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Vroman Effect
From An Introduction to Tissue-Biomaterial
Interactions, Wiley, 2002.
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EXAMPLE
Data from Hydrogels based on poly(ethylene
oxide) and poly(tetramethylene oxide) or
poly(dimethyl siloxane) synthesis,
characterization, in vitro protein adsorption and
platelet adhesion J. H. Park, Y. H. Bae,
Biomaterials 23 (2002) 17971808
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Fibrosis and Fibrous Encapsulation

• End stage of healing response
• Usually four or more weeks after implantation
• A relatively acellular fibrous capsule
• spindle shaped fibroblasts
• small number of macrophages
• Presence of neutrophils suggests persisting
  inflammatory challenge
• Presence of foreign body giant cell suggests
  production of small particles by corrosion,
  depolymerization, dissolution or wear

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Den Dunnen et al. J Biomed Mater Res 36 (1997) 337
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Foreign Body Response - Resolution

• continuing presence of an implant may result in
  the attainment of a final steady-state condition
  called resolution
• there are 3 possible outcomes for the implant
• resorption
• integration
• encapsulation (fibrosis)

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Cell Regeneration After Injury

• Possible outcomes for the injured tissue
• replacement of injured tissue with parenchymal
  cells of the same type
• replacement by connective tissue that constitutes
  the fibrous capsule
• The regeneration of cells in the body is tightly
  controlled
• There are essentially 3 categories of cell
  populations
• Renewing or labile
• Expanding or stable
• Static or permanent

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Fibrosis and Fibrous Encapsulation

• 78-week PMMA histology (sheep) illustrates soft
  tissue encapsulation of prepolymerized PMMA

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Experimental Results
5050 CLLA 18 000 g/mol sterilized with
25kGy rat femur