Foreign Body Response to Biomaterials

Question 1

List ONE reason why biomedical engineers need to consider the body’s foreign body response to implanted biomaterials when developing medical devices and implants. (1 mark)

Answer 1

The foreign body response can result in the formation of a fibrous tissue capsule surrounding the implant, which can lead to its loosening from its fixed location within the body.

Other:

• safety
• function
• integrity
• extent of FBR dependent on material surface (e.g. material chemistry & surface topology) –> safety

Question 2

List ONE reason why biomedical engineers need to consider a biomaterial’s blood compatibility when choosing materials for devices such as intravenous catheters and heart valves. (1 mark)

Answer 2

• Devices cannot trigger clotting which could impede blood flow to areas surrounding implant
• Clots/ thrombus formation is undesirable as can compromise implantation site as well as lead to issues elsewhere such as stroke.

Question 3

Define the term ‘interleukin’ (1 mark)

Answer 3

Proteins that are involved in cell signalling’. The majority are produced by immune cells
e.g. macrophages, lymphocytes

Question 4

4. Which of the following cells is NOT a lymphocyte? (1 mark)
   (A) T cell
   (B) B cell
   (C) Natural killer cell
   (D) Macrophage

Answer 4

(D) Macrophage

Lymphocytes are a form of small leucocyte (white blood cell) with a single round nucleus, occurring especially in the lymphatic system.

(macrophages are large)

Question 5

Name one of the primary functions of the complement system. (1 mark)

Answer 5

Complement system: a system of small proteins that responds to an immunogenic event: responsible for attacking bacteria and attracting macrophages and neutrophils to a site of an immune response.

1. Initially inactive in blood
2. Triggered complement ‘cascade’ reaction of proteins (cytokines, proteases) ultimately leading to:

• attract neutrophils and macrophages
• opsonise antigens for phagocytosis when activated
• break down bacterial cell membranes

Question 6

Which of the following cells fuse to form foreign body giant cells during the foreign body reaction? (1 mark)
(A) Lymphocytes
(B) Neutrophils
(C) Macrophages
(D) Mast cells

Answer 6

(C) Macrophages

Question 7

7. List TWO classes of inflammation mediators or systems that are triggered at the onset of damaging vascularized connective tissues. (2 marks)

Answer 7

• Vasoactive agents, such as histamines
• Coagulation and fibrinolytic systems, and platelets
• Complement system - cascades of proteins
• Kinin-generating system

Question 8

List FOUR (4) plasma proteins found in the human blood (2 marks, 0.5 each)

Answer 8

• albumin
• transferrin
• fibrinogen
• complement protein
• fibronectin
• gamma-globulin

Question 9

True or False?

Proteins adsorb and bind onto the biomaterial substrate through covalent bonds. (1 mark)

Answer 9

False.

Covalent bond is intermolecular so proteins have to break existing bonds within the biomaterial in order to form covalent bond to allow cross-linking to happen (this might be true if it’s a toxin ).

Normally, proteins are attracted to biomaterials electrostatically, i.e. with hydrogen bonds, ionic bonds etc.

Question 10

Define the Vroman effect in the context of protein adsorption (2 marks)

Answer 10

Protein adsorption occurs first by the high motility proteins, but are replaced by proteins with a higher affinity leading towards a general adsorption equilibrium

The higher concentration of protein, the higher the initial adsorption. Likewise, the higher the affinity of protein to the surface, the higher the adsorption.

Question 11

11. Arrange the following stages of foreign body response in order, for an implanted, bioinert material (3 marks. – minus 0.5 for every incorrect placement)

• Injury/implantation
• Foreign body reaction
• Chronic inflammation
• Granulation tissue formation
• Blood/material interaction
• Provisional matrix formation
• Acute inflammation
• Fibrous capsule formation

Answer 11

1. Injury/implantation
2. Blood/material interaction
3. Provisional matrix formation
4. Acute inflammation
5. Chronic inflammation
6. Granulation tissue formation
7. Foreign body reaction
8. Fibrous capsule formation

**NB: Note the difference between ‘foreign body response’ – which is the whole process that encompasses the overall response to foreign material; and ‘foreign body reaction’, which is characterized by the presence of macrophages, FBGC, and the components of the granulation tissue (fibroblasts, capillaries).

Question 12

Which of the following timeframes best represents the time needed to form a protein layer on the surface of the biomaterial, upon contact with a protein-rich biofluid? (1 mark)

(A) Seconds
(B) Minutes
(C) Hours
(D) Days

Answer 12

(A) Seconds

Question 13

Which of the following timeframes best represents the time needed to establish an equilibrium protein layer on the surface of the biomaterial? (1 mark)

(A) Seconds
(B) Minutes
(C) Hours
(D) Days

Answer 13

(B) Minutes

Question 14

Briefly describe how a macrophage will try to destroy a particulate foreign material that is considerably smaller than the macrophage (< 10 micron) (2 marks)

Answer 14

Phagocytosis - macrophage adheres to the foreign bodies and eat them when the particles are considerably smaller.

Question 15

Briefly describe how a macrophage will try to destroy a foreign material that is larger than the dimensions that allow for phagocytosis (> 10 micron) (2 marks)

Answer 15

When the particle is considerably larger, macrophages either:

• fuse together to form FBGC to engulf larger foreign body, or they
• secrete enzymes to destroy the surface of the material then slowly degrade it.

Question 16

16. List the FOUR primary constituents of a provisional matrix (2 marks, 0.5 marks each)

Answer 16

• Fibrin
• Activated Platelets
• Proteins of the complementary system
• Inflammatory cells

Question 17

Which of the following cells are most active during acute inflammation? (1 mark)

(A) Neutrophils
(B) Fibroblasts
(C) Monocytes/macrophages
(D) Endothelial cells

Answer 17

(A) Neutrophils

Question 18

Which of the following cells are most active during chronic inflammation?

(A) Neutrophils
(B) Fibroblasts
(C) Monocytes/macrophages
(D) Endothelial cells

Answer 18

(C) Monocytes/macrophages

Question 19

True or False:

Macrophages are able to release cytokines and interleukins to mediate the inflammatory response.

Answer 19

True

Question 20

True or False:

Macrophages are able to release histamines to mediate the inflammatory response.

Answer 20

False

(NB macrophages can actually induce histamine release, thanks again to the involvement of cytokines and interleukins, but not release histamine themselves)

Question 21

True or False:

Macrophages are able to release growth factors to recruit fibroblasts and endothelial cells.

Answer 21

False

Macrophages do release growth factors, but growth factors do not recruit cells, rather, they enhance cell proliferation

Question 22

What is the predominant type of collagen that fibroblasts lay down during the granulation tissue formation stage?

(A) Collagen type I
(B) Collagen type II
(C) Collagen type III
(D) Proteoglycans

Answer 22

(C) Collagen type III

Later on, it is replaced with collagen type I in fibrous capsule formation

Question 23

Name one strategy that biomedical engineers can employ to either minimise or prevent the formation of a fibrous capsule (except using toxic materials, obviously).

Answer 23

• Material consideration = Use a bioactive material or bioactive surface where the connective tissue integrates directly.
  
  • e.g. use porous surfaces for cellular ingrowth
• Use biodegradable material so the fibrous capsule cannot be formed as the material is constantly degrading.
• Surface treatment: elute antithrombotic drugs, to prevent protein adsorption and consequent FBR altogether.

Question 24

What is the predominant type of collagen that is present in the final stage of fibrous capsule development in the foreign body response?

(A) Collagen type I
(B) Collagen type II
(C) Collagen type III
(D) Proteoglycans

Answer 24

(A) Collagen type I

type I is present in the final stage of fibrous capsule development

Question 25

The following is a histologically stained image of the cross-section of a fibrous implant. The cross-section has been stained with a set of dyes known as ‘haematoxylin’ and ‘eosin’. Circle in the image:

(a) a foreign body giant cell (FBGC) or an FBGC cluster, and
(b) fibrous tissue layer

(2 marks total)

Answer 25

see image, (a) circled, (b) highlighted

Question 26

Name one detrimental impact the presence of a significant fibrous capsule can have in the context of implanted biomaterials. (1 mark)

Answer 26

• Fibrous capsule formation often leads to implant loosening –> Loose interaction between implant and tissue
• influences the function e.g. in electronic devices –> it alters the impedance

Question 27

Briefly describe how the presence of heavy metal ions can trigger the adaptive immune response (2 marks)

Answer 27

1. Metal ions can penetrate skin
2. Metal ions then interact with proteins in skin
3. Metal-ion-protein compound - metalloprotein compound –> Antigen!
4. Triggers immune response

• Dendritic cells and antigen-presenting cells give this to T-cells
• Specialised T-cells targeting this metal-protein compound now clones and multiplies
• In the case of future events, the body is capable of rapidly generating these specialised T-cells, making the immune response “adaptive”
• (As a paragraph):* Metal ions penetrate skin and forms metalloprotein in the body, which is recognised as an “antigen”. The immune system then generates specialised T cells to target these compounds, causing an immune response. After the attack, the body is now capable to make these specialised T cells rapidly in case of future events, thus making it an “Adaptive” immune response. Generally speaking, more metal exposure, more T-cell build-up so more antibodies and immune cells for the future immune response.
• Generally speaking,* more metal exposure, more T-cell build-up so more antibodies and immune cells for the future immune response.

Question 28

Briefly describe how the presence of a wear-particle generating implant can lead to osteolysis (2 marks)

Answer 28

Wear particles will trigger an innate immune response:

1. Macrophages are recruited
2. Macrophages start phagocytosing
   
   1. Continue to release more and more inflammatory cytokines and interleukins (if the foreign body outnumbers the macrophages)
   2. Surrounding tissue is damaged/necrotized due to inflammatory factors
3. Eventually leads to osteolysis

Question 29

List two biological factors that have contributed to the long-term failure of synthetic ligament/tendon prosthesis materials that have been used in the clinic during the 1980s and 1990s, but are now no longer being clinically approved because of these factors (2 marks)

Answer 29

1. There is poor infiltration of the collagen into the material. The collagen spaces out the fibres and this weakens the synthetic ligament/tendon
2. Wear particles are produced due to abrasion between the fibres (creates wear particles). This results in macrophage infiltration and degradation of the fibres.

Question 30

List two strategies to prevent thrombosis on blood-contacting materials. (2 marks)

Answer 30

• Use of a polyethylene glycol or hydrophobic layer on the device to reduce the extent of protein adsorption.
• Increase the smoothness of the material to reduce the attachment of proteins to the surface.
• Release antithrombotic drugs.