lec 15

Question 1

3 methods of drug elimination

Answer 1

3 methods of elimination of drugs:

- Urine
- Faeces
- Exhalation

Question 2

4 causes of drug recall

Answer 2

Cardiotoxicity
Hepatotoxicity
Nephrotoxicity - kidney damage can lead to electrolyte imbalance
Dermatologic toxicity - dermal inflammation results in dermal epidermal separation, toxic epidermal necrolysis.

Question 3

Where is the research into organs on chips going?

Answer 3

• Focus on representative organ chips
  
  • Integration of systems together onto one chip
  • Development of vascularized system
    Focus on cell types into the chips (patient specific medicine)

Question 4

What does the bioassay system 2010 seek out to do?

Answer 4

Measure intestinal absorption
Hepatic metabolism
Bioactivity of metabolized products

Question 5

problems of the bioassay of 2010?

Answer 5

This system was developed before the organoid research therefore uses single cell lines.
So it is useful but not fully accurate.
There is no topological accuracy but still has an apical and basal side

Question 6

How is the model made?

Answer 6

This system consists of two entry points, one for the sample/drug and one for the medium that acts as the blood. The 2 outputs are used to measure the concentration of sample at each stage.

A microchip is made of 2 PDMS sheets and a glass slide
The channels are fabricated by photolithography
The membrane between the two PDMS layers are coated with collagen, the inner surface that will store the ‘liver’ is coated with fibronectin and the glass surface that will store the cancer cells is coated with fibronectin

Question 7

What happens when each component works

Answer 7

If the intestine model works:
The sample in and out will be different as the drug will be taken in from the apical side and out the basal side into the medium.

If the liver model works:
The prodrug will be metabolized into the active drug, which can be detected at the end of the bioassay.

If the cancer cell model works:
The bioactivity of the sample will be assessed, the drug should kill the cancer cells and be used up.

Question 8

use of 3D instead of 2D for the cancer cells?

Answer 8

If we had 3D models and structures we could measure the invasive potential as we measure the cancer by its invasive potential and metastases not growth.

Question 9

Why do we use the HeLiVa model?

Answer 9

To model integrated human tissue physiology
Assess cardiotoxicity of drugs metabolised in liver by diverse genotype pool of patients
However, these chips are usually just connected by tubes and do not take into account the vasculature of the organs.
The liver is made up of 75% capillaries, therefore it is important that we model this.

Question 10

Modelling vasculature of liver?

Answer 10

We use 3D sacrificial moulding:

- The fabrication of 3D channel networks which can then be sacrificed to reveal a network within a larger bulk material. 
- Needs to be strong enough to support its own weight
- Use of sugar is good
- As sugar dissolves with water

Question 11

What is the method to make vasculature network?

Answer 11

Method:
Make a lattice using carbohydrates
Coat it with fibrin to protect during sugar dissolving
Encapsulate with bulk tissue
Sacrifice the sugars
Flow the medium through providing nutrients

The vascularised solid consists of 3 key components:
- Vascular lumen
- Cells and matrix residing in the interstitial zone
Endothelial cells lining the vascular wall.