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BMEN 511 Midterm 2 > Second Half > Flashcards

Second Half Flashcards

1
Q

Host response to biomaterial implantation

A
  1. Injury
  2. Protein adhesion/blood material interaction
  3. Acute/chronic inflammation
  4. Granulation Tissue
  5. Foreign body reaction
  6. Fibrosis/fibrous capsule development
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2
Q

Leukocytes

A

-White blood cells
-made in the bone marrow and found in the blood and lymph tissue
-Immune

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3
Q

Neutrophil

A

Most abundant type of leukocytes (granulocyte)
-First responders (innate - non specific)
-Phagocytosis, ingest foreign bodies
-early stages of the immune response

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4
Q

Eosinophil

A

Acid loving, allergies (leukocyte, granulocyte)

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5
Q

Basophil

A

Base loving, allergies (leukocyte, granulocyte)

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6
Q

Monocyte

A

-Largest leukocyte
-Innate/adaptive immune system
-Found in circulation
-Differentiate into macrophages at the site of inflammation

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7
Q

Macrophage

A

-Phagocytosis, tissue residing
Types: M1 (inflammatory), M2 (wound healing/remodeling)

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8
Q

Lymphocyte

A

-Adaptive immune response
-Produce antibodies
Types: T & B

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9
Q

Two types of responses you can get to biomaterials

A
  1. Foreign body response
  2. Acute or Chronic Inflammation
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10
Q

Foreign body response

A

Isolate the foreign body from healthy tissue
-non-specific inflammation
-very broad recognition capabilities and no direct mechanism

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11
Q

Acute or Chronic Inflammation

A

Macrophages (M1/M2), Foreign Body Giant Cells, Frustrated Macrophages

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12
Q

M1 Macrophage

A

inflammatory, gets rid of foreign bodies

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13
Q

M2 Macrophage

A

wound healing/remodeling

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14
Q

Foreign Body Giant Cells (FBGC)

A

-Infused monocytes + macrophages that become multi nucleated singe cells (severe inflammatory reaction)
-involved in less biocompatible materials

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15
Q

Frustrated Macrophages

A

-phagocyte (ingest foreign bodies)
-mass dependent - creates frustration!
-release harmful enzymes/chemical mediators, deteriorate both the implant/surrounding tissue

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16
Q

Specific Response Immunity to Tissue Derived Biomaterials

A

Specific markers called antigens, our body is trained to recognize the foreign body even before we are exposed to them (flu)
-May express foreign antigens capable of eliciting an immune
response (immune reaction does not necessarily cause device
disfunction or rejection)

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17
Q

Modified Koch’s Postulates for Biomaterials

A
  1. Determine the antigen specific elements (antibodies/cells) that are directly associated with a failed biomaterial
  2. The antibodies/cells from the first experiment animal (host) should be transferred to a second animal (host) and should cause the same failure
  3. The transferred elements (antigen, specific elements) should be detectable on the failed device (biomaterial) in the second host
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18
Q

How to determine if a failure of a device is linked to an immunological reaction?

A

Biomaterial scientist have adapted postulates developed by German physician Robert Koch (1843-1910) :
-Originally used to determine if an infectious agent (e.g. pathogen) was responsible for a specific disease

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19
Q

Sequence of host responses following biomaterial implantation
1. Protein adsorption, blood/biomaterial interaction

A

-protein adsorption within seconds of contact
-controlling protein adsorption key to controlling host response
-as little as 5ng/cm2 protein increases platelet adhesion 20x

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20
Q

Amino Acid Structure

A

-amino (nitrogen group)
-R group
-Carboxyl group

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21
Q

Primary Protein Structure

A

Sequence of a chain of amino acids

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22
Q

Secondary Protein Structure

A

Local folding of the polypeptide chain into helices or sheets

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23
Q

Tertiary Protein

A

3D dimensional patter due to side chain interactions

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24
Q

Quaternary Protein

A

Protein consisting of more than one amino acid chain

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25
Q

Amino Acids have different

A

charges, hydrophobicity, functional groups, reactivities

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26
Q

Plasma

A

Whole blood minus erythrocytes (RBCs), leukocytes (WBCs) and thrombocytes (platelets)

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27
Q

How much water/solids does plasma contain

A

91%-92& water, 8%-9% solids

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28
Q

Three common proteins

A

albumin, globulins, fibrinogen

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29
Q

Alubmin

A

4-6g/100mL plasma, 60% of proteins
-MW = 66kDA, 580 amino acids, single chain
-Regulate osmotic pressure (80% of osmotic gradient)
-Transport fatty acids (liver tissues)

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30
Q

Globulins

A

1g/100ml plasma, 20% of proteins
-General 4-chain structural unit = 160kDA
-Immune response (antigen binding)

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31
Q

Fibrinogen

A

-0.2-0.4g/100ml plasma, 10% proteins
MW = 340kDA, 30000 amino acids, 6 polypeptide chains
-Clotting response

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32
Q

Clot formation on medical implants (3 steps)

A
  1. protein adsorption
  2. platelet and leukocyte adhesion and activation
  3. thrombin generation
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33
Q

Initiating event

A

Rapid adsorption of plasma proteins such as fibrinogen is known to be the initiating event

34
Q

Platelets

A

-Occupy <1% of the blood volume – also called thrombocytes
-Their surface contains membrane-bound receptors which mediate surface adhesion and aggregation reactions
- They can bind to connective tissue in the activated state (e.g. collagen)

35
Q

Draw the coagulation cascade

A
36
Q

Intrinsic Pathway (Contact pathway) initiating step

A

attachment of multiple plasma proteins (serum proteases) on biomaterial
-surface contact (often negative charged surfaces)

37
Q

Intrinsic Pathway

A

-FXII absorbed to the surface autoactivation, to FXIIa
-converts prekallikrein to kallikrein and initiates coagulation and thrombin generation (cofactor high molecular weight kininogen HMWK)
-fibrin deposition on the surface
-thrombin promotes platelet activation
-platelet aggregates deposited on the surface are stabilized by fibrin strands to form a platelet-fibrin thrombus
-Kallikrein, thrombin, activate a local inflammatory response
-Leukocytes adhere to the surface

38
Q

Controlling clotting on medical implants

A
  1. Medical interventions
  2. Bioengineering solutions - Engineering blood/clot repellent surfaces
39
Q

Medical Interventions

A

-Prophylactic treatment with antiplatelet agents such as aspirin or clopidogrel or anticoagulants such as heparin or warfarin is often required to prevent complications induced from medical implants
-increases risk of bleeding (fatal)

40
Q

Bioengineering solution - Active approach

A

-deactivating factors/thrombin
-thrombin deactivation both inhibits the progress of the clotting cascade and up regulates natural anti-coagulation process (protein C inhibition of factor V)

41
Q

Bioengineering solutions - Passive approach

A

Use surface coating to indirectly prevent clot formation by preventing blood protein and cell adhesion (coating the surface of the implant with a lubricant infused coating or PEG)

42
Q

Thrombin deactivation (2 ways)

A

-directly binding deactivating agents to thrombin
-disrupting agents in the clotting cascade which are required for producing thrombin

43
Q

Thrombin deactivation by binding

A

Thrombin can be described schematically as having one catalytic center (fibrinogen - fibrin) and three binding sites:
1. catalytic center (active site)
2. fibrin binding site (exosite 2)
3. heparin-binding site
4. substrate recognition site (exosite 1)

44
Q

Heparin

A

-unfractionated heparin (UFH)
-highly sulfated naturally occurring glycosaminoglycan
-highest negative charge density of any molecule
-acts as a catalyst for antithrombin, increasing its activity

45
Q

What does Heparin do

A

binds to lysine sites on antithrombin resulting in conformational change in AT (supports binding of AT to active site of thrombin)
-inactivation by AT 1000x faster

46
Q

Low molecular weight heparin (LMWH)

A

-short chains of the polysaccharide with an average molecular weight of less than 8000Da
-LMWH is obtained by fractionation of polymeric heparin
-mainly inactivates FXa

47
Q

Medical advantages/disadvantages of LMWH to heparin

A

-molecular weight is lower
-need for only once or twice daily dosing
-lower risk of beading

48
Q

Oral direct thrombin inhibitors (DTI)

A

-Bind directly to thrombin and do not require a cofactor such as antithrombin to exert their effect
-can inhibit both soluble thrombin and fibrin-bound thrombin

49
Q

Oral direct Fxa inhibitors

A

-bind to the active site of FXa, which blocks the interaction with its substrate, inhibiting the final effects of thrombin generation

50
Q

Advantages of DOACs (direct oral anticoagulants)

A

-oral administration
-predictable effect
-lack of frequent monitoring or dose adjustment
-few known drug interactions

51
Q

Tissue factor pathway

A

blood comes in contact with traumatized vascular wall or extravascular tissues

52
Q

Anastomosis

A

connection made surgically between adjacent blood vessels, part of the intestine or other channels of the body

53
Q

Coagulopatic conditions

A

-due to external factors or genetics
-anticoagulant or blood thinning medication
-blood cancers
-long term use of antibiotics
-liver disease
-infection
-vitamin K deficiency
-haemophile (genetic factor difficiency)
-thrombocytopenia, low platelet count

54
Q

Hemostasis

A

acceleration of coagulation cascade to stop bleeding

55
Q

Injectables - Current strategy (hemostasis)

A

-prepolymer solution
-crosslinker (chemical, photo crosslinking, thermal, shear thinning)

56
Q

Patches (wound dressings) - Current strategy (hemostasis)

A

-Wet crosslinked hydrogels
-Dry planar membranes
-Microneedle arrays
-Electrospun mats
-Textiles and gauzes
-Sponges, aerogels, cryogels

57
Q

Powders - Current Strategy (hemostasis)

A

-clays, self-propelling particles

58
Q

Invasive current techniques

A

sutures, staples (damaging healthy tissue, scar formation, may need removal/replacement, unable to stop heavy bleeding, risk of infection)

59
Q

Non-invasive current techniques

A

wound dressings (bulky, chronic burn wounds, diabetic, decubitus)
adhesive tapes
zippers (only for external use, loss of adhesion upon wetting, low fatigue stability, only applicable to skin)

60
Q

Mechanism of hemostasis in hemostatic biomaterials

A

-negative charges activate factor XII
-Cationic charges promote adhesion to platelets
-Chemical bonding to bind platelets or RBCs or to activate coagulation factors
-Adsorption
1. Fast adsorption, charge simulation, physical sealing

61
Q

Acute vs Chronic Inflammation

A

Acute: considered to be early events occurring in the innate immune response

Chronic: occurs as a prolonged response after the initial immune response (acute) fails to clear the foreign body or resolve the effect

62
Q

Acute inflammation

A

-short response: minutes/days
-secretion of fluid and plasma proteins to site
-emigration of leukocytes (neutrophils, macrophages)
-phagocytosis and the release of proteolytic enzymes

63
Q

Main role of neutrophils in acute inflammation

A

phagocytose microorganisms/foreign materials
(1) recognition and attachment
(2) engulfment
(3) killing/degradation
(2)/(3) are biomaterial dependent

64
Q

leukocyte emigration assisted by____

A

adhesion molecules on leukocyte/endothelial surfaces
-surface expression of adhesion molecules can be induced/enhanced/altered by inflammatory agents/chemical mediators

65
Q

Acute inflammation biomaterial (time frame)

A

Biomaterials are not phagocytosed by neutrophils or macrophages because of the size (surface of the biomaterial is greater the cell) and if the biomaterial is non-degradable
-resolves less than 1 week
-beyond 1 week→ infection (chronic inflammation)

66
Q

Chronic Inflammation

A

-macrophages, monocytes , and lymphocytes , with the proliferation of blood vessels and connective tissue

67
Q

Reasons for chronic inflammation

A

-motion of the implant/infection
-chemical/physical properties of the biomaterial themselves
-toxic degradation products

68
Q

Most important cell in chronic inflammation

A

macrophage
-neutral proteases
-reactive oxygen metabolites
-coagulation factors
-growth-promoting factors → important to the growth of fibroblasts and blood vessels and the regeneration of epithelial cells

69
Q

Granulation Tissue

A

1 day following implantation of a biomaterial healing response is initiated by the action of monocytes and macrophages
-Fibroblasts and vascular endothelial cells in the implant site proliferate and begin to form granulation tissue

70
Q

Angiogenesis

A

Proliferation and formation of new small blood vessels of preexisting vessels
-Proliferation, maturation, and organization of endothelial cells into capillary vessels

71
Q

2 steps to granulation tissue

A

(1) Proliferation and formation of new small blood vessels of preexisting vessels→ Angiogenesis
(2) Fibroblast proliferation → active in synthesizing
collagen and proteoglycans (collagen forms the fibrous capsule, myofibroblasts secret and organize extracellular
matrix)

72
Q

Foreign-body reaction

A

foreign-body giant cells (FBGCs) and the components of granulation tissue (e.g., macrophages, fibroblasts), depending upon the form and topography of the implanted material.

73
Q

What determines the composition of Foreign Body reaction?

A

-surface properties (topography, chemical/physical properties) -size
-high surface area to volume implants have higher ratios of macrophages and FBGC than smooth surface implants

74
Q

Which step is frustrated phagocytosis part of

A

Acute inflammation

75
Q

Fibrosis/Fibrotic Encapsulation

A

Fibrosis (i.e., fibrotic encapsulation) surrounds the biomaterial/implant with its interfacial foreign-body reaction, isolating the implant and FBR from the local tissue environment.

76
Q

Local factors, wound healing

A
  • Anatomic site (tissue or organ) of implantation
  • The adequacy of blood supply
  • Potential for infection
77
Q

Systemic factors, wound healing

A
  • Nutrition
  • Preexisting diseases such as atherosclerosis, diabetes, and infection.
78
Q

Fibrosis/Fibrotic Encapsulation

A

fibrous capsule surrounding a biomaterial, may be a positive or negative response

79
Q

Advantages to development of fibrous capsule

A

-stabilize the biomaterial
-reduces motion of the implant relative to the tissue
(reduce the chronic inflammatory)
-Inadequate fibrous capsule - lead to migration

80
Q

Capsular contracture

A

excessive fibrotic capsule formation leading to stiffening and
distortion of the surrounding tissues as well as displacement of the breast implants

BMEN 511 Midterm 2 (2 decks)

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