Index
Abstract ... a
Chapter 1 ... 1
1.1 Introduction: in-vitro models evolution ... 1
1.2 Evolution of devices ... 2
1.3 Bioreactors and in-vitro models ... 3
1.4 In-vitro relevant models: thesis overview ... 5
Chapter 2 ... 10
2.1 Correlation between in-vitro models and physiology ... 10
2.2 Allometry: the missing link between physiology and in vitro models ... 12
2.3 Allometry and bioreactors ... 14
2.1.1 Surface scaling model (SSM) ... 14
2.1.2 Cell number scaling model (CNSM) ... 18
2.4 Gastro intestinal in vitro model ... 20
2.1.3 CNSM versus SSM: experimental validation ... 21
Chapter 3 ... 25
3.1 Overview of the chapter ... 25
3.2 InLiveTox Project ... 25
3.2.1 System specification ... 26
3.3 ILT1 Bireactor ... 29
3.1.1 Bottom chamber ... 30
3.1.2 Upper chamber ... 33
3.1.3 Clamp system ... 36
3.4 ILT2 Bireactor ... 37
3.4.1 Holder system ... 38
3.4.2 Bottom chamber ... 40
3.4.3 Upper chamber ... 41
3.4.4 Clamp system ... 43
3.4.5 Plate ... 44
3.5 MCmB 3.0 ... 45
Chapter 4 ... 49
4.1 Models evaluation: ILT1 ... 49
4.1.1 Model A ... 49
4.1.2 Model B ... 52
4.2 Models evaluation and validation: ILT2... 54
4.2.1 Problem solving: liquid passage ... 55
4.2.2 Problem solving: evaluation of NP concentration on the membrane layer . 57 4.3 In-vitro characterization phase of the systems: materials and methods ... 62
4.3.1 ILT1 characterization ... 64
4.3.1.1 Methylene Blue (ILT1) ... 64
4.3.1.2 FITC-PS Nanoparticles ... 67
4.3.1.3 TEER measurement tests ... 69
4.3.2 ILT2 validation ... 71
4.3.2.1 Methylene Blue... 71
4.3.2.2 FITC-PS Nanoparticles ... 74
4.3.2.3 TEER measurements ... 76
4.3.2.4 Pressure measurements ... 77
4.3.3 MCmB 3.0 validation ... 80
4.3.3.1 Methylene Blue... 80
4.3.3.2 Diclofenac ... 83
4.3.3.3 Urea ... 85
Chapter 5 ... 88
5.1 Overview of in-vitro devices evolution ... 88
5.2 Bioreactor support plate: a new patented device ... 89
5.2.1 Bioreactor plates ... 90
5.2.2 Bioreactor modules ... 94
5.2.3 Control modules ... 97
5.3 System overview.…………...………. 99
Chapter 6 ... 104
6.1 Conclusions: overview ... 104
6.1.1 ILT bioreactors ... 105
6.1.2 Allometry ... 106
6.1.3 Bioreactor support ... 107
6.2 Future improvements ... 108
Bibliography ... 110 Appendix A ... I A.1 ILT1 Protocols ... I Appendix B ... XII B.1 ILT2 Protocols ... XII
