Challenges in incompatibility and the Immune Response Flashcards
What is biocompatibility?
The ability of a material to elicit an appropriate biological response in a specific application by NOT producing a toxic, injurious, or immunological response in living tissue
What is an immune response?
The reaction of the cells and fluids of the body to the presence of a substance which is not recognized as a constituent of the body itself
What are the four phases of wound healing?
1) Exudative phase
2) Resorptive phase
3) Proliferative phase
4) Repair phase
What is the exudative phase of wound healing?
The wound is filled with fibrin and coagulated blood
What is the resorptive phase of wound healing?
scavenger cells remove dead cells and germs
What is the proliferative phase of wound healing?
new cells are formed which fill in the wound
What is the repair phase of the wound healing?
cells are formed around the edge of the wound, new skin is created and the wound finally closes
What is the stages of foreign body response?
1) Recognition Inflammation
2) Protein Adsorption
3) Macrophage adhesion
4) Macrophase fusion (FBGC)
5) Crosstalk between FBGC and others
What is the importance of macrophages in biomaterials?
- Macrophages important in wound healing and the foreign body response.
- Dictate the course of wound healing and biomaterial acceptance and rejection.
- Differentiated from monocytes after injury. Macrophages are classed into two types: 1. Classically activated macrophages (M1 macrophages) 2. Alternatively activated macrophages (M2 macrophages)
What are the two types of macrophages?
- Classically activated macrophages (M1 macrophages)
2. Alternatively activated macrophages (M2 macrophages)
What are M1 macrophages?
M1 macrophages are produced during a cell-mediated immune response (pro-inflammatory)
What are M2 macrophages?
M2 macrophages play a role in wound healing and repair (antiinflammatory)
What are the stages of macrophage mediated phagocytosis?
1) Recognition
2) Adhesion
3) Phagocytosis
4) Digestion
What are the stage of giant cell mediated engulfment?
1) Recognition
2) Cell fusion & adhesion
3) Engulfment & digestion
What are the stages of extracellular degradation?
1) Recognition
2) Cell fusion & adhesion
3) Extracellular degradation
What is phagocytosis affected by?
particles size
What happens is phagocytes cannot digest biomaterial?
they fuse into foreign body giant cells (FBGCs)
Foreign body giant cells encapsulate biomaterial in a fibrous capsule
What does the size of fibrous capsules formed from phagocytosis of a biomaterial depend on?
1) Size of the biomaterials
2) Degradabilty
3) Protein adhesiveness
What is process of fibrous capsule formation?
1) Non-Specific serum protein adsorption:
2) Immune cell Infiltration: inflammatory cells (neutrophils and monocyte derived macrophages infiltrate in response to injury.
3) Macrophage Classical Activation (M1): secrete pro-inflammatory cytokines, recruiting immune cells
4) Macrophage Alternate Activation (M2): release IL-10, IL-4 and IL-13
5) Macrophage fusion: forming giant cells, fibroblast recruitment, collagen deposition
6) Fibrous Encapsulation
What does biocompatibility refer to?
ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient or beneficiary of that therapy, but generating the most appropriate beneficial cellular or tissue response in that specific situation, and optimising the clinically relevant performance of that therapy
What are the challenged associated with biomaterials design?
1) Dependent on intended application
2) Degradable and non-degradable devices
3) Increase or decrease cell adhesion
4) Blood contacting or not
What are the effects of biomaterials properties on immune response?
1) Protein adsorption: type, level and conformation of proteins adsorbed can influence attachment and activation of inflammatory cells
2) Chemical activity of implant: corrosion and degradation by products
3) Movement between biomaterial implant and tissue
4) Shape of the implant
How are biomaterial surface properties modified and why?
- limits macrophage adhesion, activation and fusion to FBGCs
= preventing/limiting fibrous capsule formation and therefore the biomaterial becomes vascularised and integrate
What techniques are used to modify biomaterial surface properties?
1) Changing surface chemistry
2) Changing surface topography
3) Incorporation of Bioactive molcules
4) ECM coatings
What does the surface chemistry of a biomaterial control?
type, level and conformation of serum proteins that absorb to biomaterial surfaces.
How can changing the surface chemistry of a biomaterial prevent macrophage attachment and activation?
changing the surface chemistry alters protein confirmation on the surface
Surface chemistry controls the type, level and conformation of serum proteins that adsorb to biomaterial surfaces. Serum proteins adhered to the surface provide binding sites for different cell types, such as macrophages
Why would biomaterials undergo surface modification?
Bioactive functional groups can be introduced to the surface using surface modification techniques. Surface modification does not alter the bulk properties of the material.
What are examples of surface modification techniques?
1) silanization
2) plasma polymerisation
What are the advantages of natural and artificial ECM coatings?
1) Natural coatings can be used to improve biocompatibility of Biomaterials
2) Often ECM proteins, such as collagen, fibronectin and laminin.
3) Mimics extra cellular matrix to provide correct topography, to the native nerve tissue.
4) Derive naturally but can be artificially manufactured
What are the disadvantages of natural and artificial ECM coatings?
1) Batch to batch variation in production, and undesirable immune responses.
2) Expensive to manufacture
What are synthetic polymeric coatings used for?
to immunomodulate biomaterials
- Prevent immune response by preventing initial protein adsorption
- Offer material versatility and processability.
- Cheaper to manufacture than natural ECM coatings
What are synthetic polymeric coatings made from?
Polymers that are non-fouling (protein adsorption-resistant) used
Polyethylene Glycol (PEG) most commonly used.
Other polymers used include:
- poly(acrylamide)
- PVA
- Hydrogels
What is an examples of synthetic polymeric coatings?
p(NIPAM-co-AAc-co-PEGDA) microgels used to functionalize the PET disks. Microgel-coated disks had significantly less leukocyte adhesion and fewer macrophages around the implant compared to plain PET discs.
Why is surface topography very important in biomaterials?
Surface roughness can affect protein adsorption and consequently cell adhesion.
Variation of surface topography has been shown to guide macrophage responses to Biomaterials.
In the natural environment, cells respond to ECM components in the nanometer scale.
Porous materials tend to show increased levels of macrophages and FBGCs than smoother implants.
Why are bioactive molecules added to a biomaterial surface?
- Used to direct responses of immune cells.
- Also improve biocompatibility by promoting cell-specific adhesion.
What are some examples of bioactive molecules that are added to a biomaterial surface?
1) integrin adhesion sites
2) growth factors
3) anti-inflammatory mediators/drugs
What are integrins?
transmembrane a and β subunit comprised receptors for distinct extracellular matrix proteins.
They link cells with the extracellular matrix
What are integrin adhesion sites?
Receptor binding domains, within adhesive proteins, are made up of short oligopeptide sequences. The RGD (arginine-glycine-aspartic acid) sequence and the PHSRN (proline-histidine-serine-arginine-asparagine) are the most commonly used.
Why are integrin adhesion sites added to biomaterial’s surface?
They have been shown to promote cell-specific adhesion and function on biomaterials.
Direct responses of inflammatory cells
What are integrin adhesion sites often used in combination with?
non-fouling coatings such as polyethylene glycol (PEG)
What are growth factors?
- usually hormones or proteins
- Stimulating cellular growth, proliferation, healing, and cellular differentiation
- Important for regulating a variety of cellular processes.
- Act as signalling molecules between cells
Why are growth factors added to the surface of biomaterials?
Epidermal growth factor (EGF), TGFb, VEGF, and PDGF control adhesion, migration, proliferation, and differentiation of fibroblasts, keratinocytes, and endothelial cells in wound healing
Activity of monocytes and macrophages linked to wound healing cell function.
TGF-b1 and PDGF have been shown to have an effect on macrophage activation during wound repair .
What are anti-inflammatory used for?
to reduce inflammation
What are some examples of anti-inflammatory drugs?
nitric oxide (NO), dexamethasone and Glucocorticoids
Why would nitric oxide be added to a biomaterial surface?
= anti-inflammatory drug
Nitric Oxide been shown to reduce inflammatory cell recruitment and performance at the implant surface reservoir
Why would dexamethasone be added to a biomaterial surface?
= anti-inflammatory drug
Reduced implant-associated inflammation has been seen with the use of dexamethasone by the absence of macrophages, lymphocytes, and fibrous capsule formation.
Why would Glucocorticoids be added to a biomaterial surface?
= anti-inflammatory drug
potent suppressors of immune responses
What is a common combination of anti-inflammatory and growth factor?
Dexamethasone and VEGF is a common combination in rendering biomaterial immunomodulatory.
What is immunoisolation?
Donor cells (such as pancreatic islet cells) can be transplanted to treat a variety of human diseases.
What are the benefits of immunoisolation?
1) No need for immunosuppression
2) Use of cells from nonhuman species (xenograft) due to limited supple pf human donor cells
What is the most common applied procedure for immunoisolation?
Microencapsulation of cells or tissues in alginate-based capsules.
Cells can also be encapsulated in polymers, proteins and hydrogels
What other factors affect immune response?
1) Surgical implant procedure: damage to nearby tissue can trigger immune response
2) Implantation site: vascular or avascular
3) Infection: postoperative infections after surgery can increase immune response and cause implant rejection
What are glucose biosensors?
measure blood glucose levels in diabetic patients. Devised after inconvenience and pain when using external monitoring systems.
6 systems approved by the FDA but in vivo lifetime is 7 days.
Why is the in vivo lifetime of glucose biosensors only 7 days?
This is due to fibrous capsule formation restricting the transport of glucose to the sensor surface.
Current research focuses on coating sensors with ‘smart’ coatings to prevent the foreign body response.
How is osteolysis and therefore implant loosening caused?
1) Major cause of late revisions in THA.
2) Particulate debris and wear particles trigger inflammatory response.
3) Activated macrophages release cascade of pro-inflammatory cytokines leading to recruitment of more inflammatory cells.
4) Cytokines and chemokines released from inflammatory cells recruit osteoclasts to site.
5) Bone resorption occurs at a higher frequency than remodelling.
6) Osteoblast function is suppressed increasing osteolysis.
7) Osteolysis leads to joint loosening and pain for the patient.
Why is a fibrous encapsulation of breast implants formed?
- Breast augmentation most common cosmetic procedure.
- Capsular contracture is the most common complication following surgery.
- Arises from excessive fibrotic foreign body reaction to the implant.
- Leads to deformation of the implant and results. Causes pain and can require reoperation.
How is fibrous encapsulation of breast implants reduced?
Textured implants have been shown to reduce fibrous capsule formation.
