Abstract
The blood-brain barrier (BBB) is a specialized capillary structure with tight junctions between the endothelial cells that restricts the substance exchange between blood and brain tissue. The BBB protects the brain from harmful substances in the blood but it also hinders potential neuroactive drugs from entering the brain. This presents a major challenge in the development of drugs that target the central nervous system because therapeutic agents must overcome the BBB to reach the site of action. To address this situation, there is a need for test methods to describe the efficacy of substance transporter systems to cross the BBB.
This work describes a new in vivo technique for continuous sampling of the interstitial fluid in brain tissue, named cerebral open flow microperfusion (cOFM). cOFM was developed from sketch to proof of concept in rats within this doctoral thesis. cOFM is based on open flow microperfusion (OFM), a relatively new technique that is based on a probe with macroscopic openings in combination with a push-pull pump. Since OFM requires no membrane, it puts the perfusate into direct contact with the tissue being sampled, which means that lipophilic and high-molecular-weight substances can also be sampled, including antibodies, and even entire cells. OFM does not face problems that can arise due to protein clotting or biofouling, which can lead to membrane occlusion, as described for membrane based technologies. Like all invasive probe techniques, cOFM probe insertion causes tissue trauma, damage to capillaries, and therefore BBB disruption.
Important parts of this work address the topics of:
(a) The determination of the time between cOFM probe insertion and BBB re-establishment
(b) The demonstration of cOFM sampling in the interstitial cerebral fluid with intact BBB
(c)Investigation of brain tissue changes as a reaction to cOFM probe implantation
(d)The conduction of a proof of principle study with a pharmaceutical product in development
This work describes a new in vivo technique for continuous sampling of the interstitial fluid in brain tissue, named cerebral open flow microperfusion (cOFM). cOFM was developed from sketch to proof of concept in rats within this doctoral thesis. cOFM is based on open flow microperfusion (OFM), a relatively new technique that is based on a probe with macroscopic openings in combination with a push-pull pump. Since OFM requires no membrane, it puts the perfusate into direct contact with the tissue being sampled, which means that lipophilic and high-molecular-weight substances can also be sampled, including antibodies, and even entire cells. OFM does not face problems that can arise due to protein clotting or biofouling, which can lead to membrane occlusion, as described for membrane based technologies. Like all invasive probe techniques, cOFM probe insertion causes tissue trauma, damage to capillaries, and therefore BBB disruption.
Important parts of this work address the topics of:
(a) The determination of the time between cOFM probe insertion and BBB re-establishment
(b) The demonstration of cOFM sampling in the interstitial cerebral fluid with intact BBB
(c)Investigation of brain tissue changes as a reaction to cOFM probe implantation
(d)The conduction of a proof of principle study with a pharmaceutical product in development
| Original language | English |
|---|---|
| Qualification | Doctor of Technology |
| Awarding Institution |
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| Supervisors/Advisors |
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| Publication status | Published - 16 Sept 2013 |
| Externally published | Yes |
Keywords
- cerebral
- open flow
- microperfusion
- cOFM
- blood-brain barrier
- pharmacokinetic
- pharmacodynamics
- tissue
- specific sampling