The microdialysis principle was first employed in the early 1960s, when push-pull canulas and dialysis sacs were implanted into animal tissues, especially into rodent brains, to directly study the tissues biochemistry. While these techniques had a number of experimental drawbacks, such as the number of samples per animal or no/limited time resolution, the invention of continuously perfused dialytrodes in 1972 helped to overcome some of these limitations. Further improvement of the dialytrode concept resulted in the invention of the "hollow fiber", a tubular semipermeable membrane with a diameter of ~200-300μm, in 1974. Todays most prevalent shape, the needle probe, consists of a shaft with a hollow fiber at its tip and can be inserted by means of a guide cannula into the brain and other tissues. An alternative method, open flow micro-perfusion (OFM), replaces the membrane with macroscopic openings which facilitates sampling of lipophilic and hydrophilic compounds, protein bound and unbound drugs, neurotransmitters, peptides and proteins, antibodies, nanoparticles and nanocarriers, enzymes and vesicles.