Transcytolemmal water exchange is a critical process for maintaining cellular homeostasis and function, serving as a potential biological marker for tumor proliferation, prognosis, and cellular states. The use of magnetic resonance imaging (MRI) to measure transcytolemmal water exchange can be traced back to the 1960s, when researchers first measured the residence time of intracellular water molecules in erythrocyte suspensions. Meanwhile, the multi-exponential nature of nuclear magnetic resonance signals in biological tissues was discovered. Studies suggested that transcytolemmal water exchange could be one of the factors explaining this characteristic, marking the beginning of research into measuring transcytolemmal water exchange by using magnetic resonance techniques. After decades of development, the current MRI techniques for measuring transcytolemmal water exchange can be broadly classified into two types: relaxation time based and diffusion based magnetic resonance measurement methods. This review introduces the development of these technologies, and discusses the principles, mathematical/biophysical models, results, and validation of representative methods. Regarding relaxation-based MR techniques, this review systematically organizes MRI methods to quantify transcytolemmal water exchange through chronological developments of three biological substrates: ex vivo cell suspensions, ex vivo biological tissues, and in vivo biological tissues. The modeling section emphasizes two frameworks, including the two-site-exchange model and the three-site-two-exchange shutter-speed model. Regarding diffusion-based MR techniques, this review introduces the research progress of diffusion-encoding and modeling for water exchange measurement. The diffusion-encoding methods are introduced according to single diffusion encoding sequences and the double diffusion encoding sequences. For modeling, it covers three types, including the Kärger model based on the two-component Gaussian diffusion assumption, the modified Kärger model incorporating restricted diffusion effects, and first-order reaction kinetic model. Additionally, comparative studies among different diffusion-based methodologies are also discussed. Finally, this review evaluates their respective clinical applications, advantages, and limitations. The future prospects for technological development in this field are also proposed.
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