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Biomaterials > Lecture 4 > Flashcards

Lecture 4 Flashcards

1
Q

The first steps of biomaterial-host interactions

A
  1. Water and ions (quasi-instantaneous)
  2. Proteins, arrive rapidly (~1s) by diffusion or convection
  3. Cells reach the surface and the adsorbed proteins.
    • adhesion/non-adhesion
    • activation/inhibition of cell activity
    • internalization (for small objects)
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2
Q

Protein adsorption and host response

A

Adsorption of (adhesion) proteins provides recognition sites for cell integrins at the surface of biomaterials

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3
Q

Controlling protein adsorption: a key to modulate host response.

A

Coatings of cross-linked phosphorylcholine (PC) reduce protein adsorption and cellular adhesion -> reduce thrombus formation

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4
Q

Protein adsorption at solid-liquid interfaces

A

Kinetics of adsorption:
1- Rapid phase in t(1/2) diffusion-controlled process
2- Slower phase where protein adsorption is hindered
(Graph shows rapid growth and then plateau)

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5
Q

Adsorbed proteins usually bind ___

A

tightly to the surface.

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6
Q

Surface physical-chemistry of material ___

A

affects the conformation of adsorbed proteins. (Ex: Hydrophilic surface binds with different side chains than hydrophobic)

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7
Q

Conformation changes

A

alter biological activity of adsorbed proteins. Ex: Variation of the platelet binding to fibrinogen

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8
Q

Degree of denaturation highly depends on:

A
  • protein type
  • surface physical-chemistry
  • time spent on the substrate
  • solvent
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9
Q

In complex mixtures, composition of adsorbed protein layer results
from

A

differences in affinity and in relative concentration

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10
Q

The Vroman effect

A

When a surface is placed in contact with a mixture of proteins, the highest mobility proteins generally arrive first and are later replaced by less motile proteins that have a higher affinity for the surface.

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11
Q

Injury/implantation induces bleeding

A

-> Hemostatic mechanisms to arrest bleeding

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12
Q

Hemostatic process

A

Interdependent reactions between: 12 coagulation proteins & platelets

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13
Q

Platelets

A

(0.3% blood volume) with size of 3microns

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14
Q

Platelet in normal (non-active) state

A

are maintained in discoïd shape by circumferential bundles of microtubules

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15
Q

External surface of platelets is coated with

A

Membrane bound receptors Glycoproteins GPIb (25,000/plt) and GPIIb/IIIa (80,000/plt). Their membrane also form a spongy canalicular structure. Large reactive surface.

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16
Q

Several important molecules for coagulation are stored in cytoplasmic granules

A
  • dense granules (ADP, Ca2+, serotonin)
  • a-granules (PF4, plasma proteins,…)
  • lysosomal granules (enzymes acid hydrolases…)
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17
Q

Platelet activation

A

Platelets respond to minimal stimulation.

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18
Q

Activated platelets:

A
  • change shape
  • become sticky
  • release from the granules (coagulation factors, adhesion molecules…)
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19
Q

Coagulation is __

A

The result of a complex cascade of activations of factors (proteins). 3 main phases lead to the polymerization of a network of fibrin chains including platelets, forming the blood clot (Thrombus)

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20
Q

Intrinsic pathway

A

 Activated by negatively charged surfaces (surface of activated platelets, collagen, glass…)
 It is intrinsic because triggering factors are in the blood itself.
 Slower than extrinsic due to numerous intermediate steps.

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21
Q

Extrinsic pathway

A

 Activated by exposure of blood to factors located below endothelial tissues (e.g. after an injury): the tissue factor (III).
 It is extrinsic because triggering factors are out of the blood.
 Fast (few steps): allows clot formation in 15sec.

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22
Q

What is phase 2 of coagulation?

A

The plasmatic protein Prothrombin is transformed into Thrombin (enzyme)

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23
Q

What is phase 3 of coagulation?

A

Thrombin catalyzes fibrin polymerization Activated Factor XIII stabilizes the clot

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24
Q

What prevents coagulation from spreading ? Several mechanisms avoid massive thrombus formation:

A
  • Blood flow reduces localized concentration, dilution and removal through the liver.
  • Several reactions are catalyzed near a surface (need the proximity of tissue factor or activated platelets)
  • Blood plasma contains anticoagulant factors.
  • Platelets and endothelial cells also release anticoagulant factors upon activation (plasmin, factor C)
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25
Q

End of hemostasis

A

Fibrinolysis: In normal in vivo situations, clot formation ends 3-6min after vessel injury. After 30-60 min, clot contraction and closing of blood vessels. After 2 days, dissolution of the clot by fibrinolytic enzymes (plasmin…)

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26
Q

When artificial surfaces are in contact with blood,

A

hemostatic mechanisms may have adverse consequences. Ex: Metallic coronary artery stent -> thrombosis

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27
Q

Hemocompatibility

A

Ability of a material or device to perform its proper function in contact with blood, without eliciting adverse reactions (thrombus,…)

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28
Q

Blood coagulation is governed by three factors:

A
  • blood chemistry
  • blood-contacting surface
  • flow regime
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29
Q

Use of blood-compatible materials (non-thrombogenic)

A

does not guarantee blood-compatible device.

30
Q

Intrinsic pathway to coagulation via implant

A
  • Modification of surface by protein adsorption
  • Platelet adhesion
  • Desorption of protein fragments and denatured proteins -> platelet activation
  • Activation of coag. factors (esp. XII) on material surfaces
31
Q

Extrinsic pathway to coagulation via implant

A

Possible lesions during implantation

32
Q

Perturbation o fcoag/anticoag balance via implant (synthetic surfaces do not produce and release coag. inhibitors like endothelial cells of blood vessels)

A

• Flow perturbation (low shear or static regions)

33
Q

Improper blood-implant interactions (esp. thrombosis) continue to limit the potential of many cardiovascular devices for applications in human.

A
  • Cardiopulmonary bypass for oxygenation -> severe bleeding tendency
  • Mechanical heart valves -> emboli -> stroke
  • Synthetic vascular grafts -> thrombosis -> ischemia and death of downstream tissues
  • No existing grafts for small diameter (<4mm) vessels
34
Q

Most often, systemic anticoagulants are needed in addition to the device, but…

A

This leads to inherent bleeding risk

35
Q

Functions of blood clot

A
  • Barrier to infection
  • Arrest of blood flow and exudation
  • Reservoir of chemo-attractants mitogens cytokines growth factors
36
Q

The effect of an injury to a tissue:

A

• Changes in vascular flow
• Escape of fluid, proteins, cells into the injured site (Exudation)
Activates cellular events (inflammantion)

37
Q

Host response to implantation of device (Almost the same as wound healing)

A
  • Injury
  • Blood-material interactions
  • Provisional matrix formation
  • Acute/Chronic inflammation
  • Granulation tissue
  • Foreign-body reaction
  • Fibrosis/fibrous encapsulation
38
Q

Protein adsorption leads to

A

Activation of

  • coagulation cascade
  • complement system
  • platelets
  • immune cells
39
Q

What is the complement system?

A

a group of blood plasma proteins (~30) that can be activated in cascade to stimulate cells of the innate immune system. (IgG, C3)

40
Q

Steps of inflammatory response

A
  1. Protein adsorption: blood coagulation and immune system activation
  2. Release of danger signals (alarmins or DAMPS)
41
Q

Acute inflammation

A

Duration: minutes to days depending on extent of injury normally resolves quickly (<1week) if not, suggests an infection.
Characteristic component: Neutrophils (PMN: PolyMorphoNuclear leukocytes)

42
Q

Major role of PMN

A

Clean the place. The phagocytic response.

43
Q

3-step process of phagocytes

A

1- Recognition and attachment 2- Engulfment 3- Killing or degradation

44
Q

PMN are degraded by release of :

A
  • Proteolytic enzymes (proteases)

- Reactive Oxygen Species (ROS)

45
Q

Consequences of PMN degradation

A

Material corrosion
Damage to surrounding tissues
-Prolonged inflammatory response Exhaustion of PMN killing capacity
-Risk of severe biomat-centered infection

46
Q

Resolution

A

< 2 days after implantation PMNs disappear from implantation site.

47
Q

Chronic inflammation develops as

A

inflammatory stimuli persist at the implant site.

48
Q

Chronic inflammation

A

Characteristic components:
Macrophages / Monocytes Lymphocytes + proliferation of blood vessels and connective tissue.
Activated by inflammatory stimuli biomaterial-related activation depends on:
• chemical and physical properties of the biomaterial
• adsorbed protein layer at biomaterial’s surface
• motion of the implant site
• infection

49
Q

One of the main actors of chronic inflammation?

A

Macrophages

50
Q

Marcophage characteristics

A
  • Phagocytosis
  • Produce many biologically active products - neutral proteases - chemotactic factors - coagulation factors - growth promoting factors - cytokines - …
  • Stimulate migration, differentiation of other cells for formation of granulation tissue.
51
Q

Macrophages can take on 2 different states

A

M1 (classically activated phenotype) Killing! Inflammation!
M2 (alternatively activated phenotype)
Phagocytosis of wound debris
Promotion of wound-healing Limitation of inflammation. Repair :) Anti-inflammatory :)

52
Q

The granulation tissue

A
  • Within 1 day, proliferation of fibroblasts and endothelial cells to form the granulation tissue.
  • Formation ~3-5 days following implantation.
53
Q

When a biomaterial is >5μm

A

not phagocytable, leads to formation of foreign body giant cells

54
Q

Foreign Body Reaction characteristics

A

Characteristic components:
• Foreign Body Giant Cells formed by fusion of macrophages.
• Components of the granulation tissue
(macrophages, fibroblasts, capillaries…)

55
Q

FBR depends on the form and topography of the foreign body

A

• Flat and smooth surfaces
(e.g. silicone breast implants)
Layer of macrophages (1-2 cells thick)

• Rough surfaces
Macrophages
+ FBGC

• Fabric materials
Macrophages
+ FBGC + granulation tissue

56
Q

Putative mechanism of FBR

A

Important release of proteases by FBGC
• Alter surrounding tissues
• Activate fibrosis

57
Q

Design of materials with “immunomodulating” capacities

A

Passive way: By physico-chemical modification of surface

Active way: By using molecules or matrices to target specific cell behavior.

58
Q

Immuno-modulation by surface modification

A

General approach: Reduce macrophage adhesion, activation, fusion to FBGC

59
Q

Rat cage implant example of PASSIVE immuno-modulation by surface modification

A

On hydrophilic and anionic surfaces

DECREASE macrophage adhesion and fusion INCREASE macrophage apoptosis

60
Q

ACTIVE Immuno-modulation using bioactive molecules

A
  • Providing integrin adhesion sites
  • Grafting/Release of anti-inflammatory drugs
  • Grafting/Release of growth factors
61
Q

Providing integrin adhesion sites

A

Short oligonucleotide sequences can be recognized by cell receptors (integrins)

62
Q

Grafting/release of anti-inflammatory drugs

A

Nitric Oxide (NO) is a natural mediator in wound healing and angiogenesis

63
Q

Grafting/Release of growth factors

A

Growth factors stimulate tissues/cells to modulate macrophages. Generally successful but need of non-physiologically high amounts (expensive, possible side effects)

64
Q

What is the idea of immuno-modulation using ECM coating

A

mimic the regulating properties of ECM

65
Q

What is infection?

A

The process of invasion and multiplication of pathogenic microorganisms such as bacteria, viruses, and parasites within the body

66
Q

The number of device-related infections is increasing due to:

A
  • Longer lifetimes and implantation durations.

* Increasing number of invasive surgical operations

67
Q

Bacterial biofilms

A

are communities of bacteria which attach and grow on surfaces of abiotic materials or soft tissues

68
Q

Problematic bacterial infections by staph

A
  • Propensity to form biofilms.

* INCREASE of multi drug resistant forms

69
Q

Infection routes w/ implant

A

Early infection
• Airborne sources
• Non-sterile surgery
• Post-op. complications like wound infection

Late infection
• Hematogeneous (through blood) route
• Often initiated by therapeutic dental or genitourinary procedures.

70
Q

Implants could facilitate infection in several ways

A
  • by providing access to the circulation and to deeper tissue due to damage of natural barriers during implantation or device function.
  • by limiting phagocyte migration into the infected tissues
  • by altering the phagocytic mechanisms of inflammatory cells
71
Q

3 approaches to infection resistant materials

A

1: Killing planktonic cells before they adhere and form a biofilm (insert antibiotic solution just before implantation)
2: Blocking bacteria in a planktonic state to allow destruction by host cells or by antibiotics (polymer coating that release interference with sig. ptwy.)

3: Making surfaces that resist bacterial adhesion and biofilm
formation (self-assembled monolayers, nano-textured surfaces)

72
Q

Neoplasia

A

(“new growth”) is the process of excessive and

uncontrolled cell proliferation.

Biomaterials (10 decks)

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