C2-HC7 Flashcards
What are the 4 phases of natural healing?
1 Hemostasis (1h) + 2 inflammation (1d): coagulation, immune cells infiltration, pathogen killing, debris clearance 3 proliferation (1w): fibroblast proliferation, scar formation and wound contraction, collagen synthesis, angiogenesis 4 remodeling (1m-1y): re-epithelialization, ECM remodeling, apoptosis
What are the keyplayers in.. 1 homeostasis 2 inflammation 3 angiogenesis 4 remodeling/fibrosos
1 Homeostasis: thrombin (important factor in creating blot clots), PDGF-b (growth factor).
2 Inflammation: HIF-1a (it’s the inflammatory process, but also important in the pathway to VEGF).
3 Angiogenesis: FGF-2 (fibroblast growth factor, stimulates fibroblast growth), VEGF (stimulates angiogenesis).
4 Remodelling/fibrosis: TGF-b (important for stimulating the immune response), MMPs (1, 2, 7; metal matrix proteases, which are released easily with the platelet burst).
2 pathways of the immune system:
myeloid (innate) & lymphoid (adaptive)
Properties of the myeloid (innate) pathway:
Myeloid; innate
• ‘quick reaction’
• Non-specific: against foreign bodies, injuries and pathogens
• Immediate action
• Physical barriers
• Activated by chemical properties of the antigen
• Bacteria-killing substances
• Protection on the outside: skin
• Protection on the inside: all mucous membranes
First attack in the tissue: scavenger cells
Properties of the lymphoid (adaptive) pathway:
Lymphoid; adaptive
• ‘slow reaction’
• Antigen-specific: against specific pathogens or changed body cells (virus)
• Processing involved
• Traditionally associated with memory
• Defense cells in the blood: B lymphocytes
• Antibodies
Defense cells in the tissue: T lymphocytes
What are the main cells involved in the immune response (order & function)?
1 polymorphonuclear neutrophils (PMN): - phagocytosis - chemokine production - short lived 2 macrophages: - phagocytosis - cytokine production - immune modulatory function 3 T lymphocytes - antigen specific responses - provide memory - chronic inflammation
Complements:
Complements:
- “Activate all the proteins!”
- Almost all biomaterials used in (orthopaedic) (regenerative) medicine activate the host immune system
- Don’t learn the pathways. Classical and alternative pathways are most used.
- System simplified:
○ Pathway activation depends on stimulus
○ CP: provisional matrix on which IgG binds
○ AP: (wear) debris of biomaterials such as in orthopaedic implants
The complement system is mostly biomaterial-driven;
The complement system is mostly biomaterial-driven;
- Activation is triggered by molecules of the initially absorbed protein film. Usually when you implant something a lot of proteins will stick to it due to the charge. - Consist of immunoglobulins, fibrinogen and human serum albumin - Generated C5a and sC5b-9 recruit and activate platelets as well as granulocytes and monocytes - They bind to the protein-bound iC3b
Protein film - provisional matrix:
Protein film - provisional matrix:
- The provisional matrix is a ECM that secretes proteins. In the beginning it's fibrinogen, usually by platelets when they burst. But due to all these growth factors, other cells are also attracted; fibroblasts, monocytes, macrophages, T-, and B-cells. - Fibroblast are important because they produce a lot of ECM, they are the band aid. The collagen is crosslinked and keep things together.
Monocyte subtypes:
Macrphages subtypes:
Monocyte subtypes: (don’t know the specifics)
- Classic (CM): (90%) involved with phagocytose and adhesion. - Intermediate (IM): (5%) anti-microbial response. - Non-classical (NCM): (5%) involved in the complement, does phagocytose and migrate.
Monocytes differentiate to macrophage. There are multiple subtypes, which are classified by function. M1 & M2 are most important (pro-inflammatory & anti-inflammatory).
The classifications of macrophages are difficult/ not so rigid as they may seem. It is not black and white (not M1 OR M2, but probably some M1 AND some M2)!
Macrophages are involved in almost everything: Alzheimer’s, COPD, cancer, atherosclerosis, obesity, etc.
T-cells:
T-cells:
- Not directly involved
- Different types of T cells: helper cells, regulatory cells
- Collectively, the T lymphocytes play and/or facilitate a central role within the adaptive immune system. Functions:
○ Promotion of inflammation by cytokine production (Th1 and Th17 cells)
○ Helping B lymphocytes (Th2 cells)
○ Regulating immunosuppressive responses (T regulatory cells)
○ Killing of unwanted target cells (CTL)
Definition of biocompatibility:
Definition of biocompatibility:
- Appropriate host response (absence of toxicity, chronic inflammation, irritation and/or carcinogenesis)
- The ability of (bio)materials to perform the specific task for which they are intended
Stepps of the FBR:
Stepps of the FBR:
1. Implantation of a biomaterial 2. Protein (such as albumin and fibrinogen) are absorbed on the surface 3. A few minutes after implantation there are macrophages. They release messengers which serve to initiate the FBR. After a few hours the surface is fully covered with macrophages. During release of the messengers other important cells are also attacked: a. Fibroblasts: responsible for the thicker envelopment of the mesh. They form an early scar. b. T lymphocytes and polymorphonuclear granular sites. 4. As the process continues, the number of cells increases. After 1 week the early granuloma can be recognized by a typical layering: fibroblasts & ECM. The granuloma now starts to age and there is increased vascularization. 5. The intensity of stimulus by the macrophages determined the size of the granuloma.
Foreign body giant cell formation (FBGC):
Phagocytotic cells find a giant particle and want to eat it, but when this particle is bigger than themselfs they have generate a multinucleated cell and capsulate it. They still excrete the same enzyme, because they want to degrade it. This process is called the Foreign body giant cell formation (FBGC). Thus, the fibroblasts and myofibroblasts encapsulate the material with ECM and cells, so other cells cannot reach it and cannot begin a new immune reaction. So, you end up in a quiet state.
(negative) outcomes of FBR:
(negative) outcomes of FBR:
- Unwanted material degradation (because you get these giant cells that secrete a lot of reactive O2 species and proteases).
- Can lead to implant failure
- Implant dysfunction (e.g. Prevents proper interaction material and body such as motorfunction)
- Increased susceptibility to infection (e.g. Dysregulation of neutrophils and macrophages)
- Chronic inflammation
- Pain
