Transdermal Fluid Extraction and the Study of Subcutaneous Interstitial Fluid

Abstract

Fluid dysregulation is common in certain long-term diseases. Renal failure and heart failure for instance can lead to the accumulation of fluid within the extracellular fluid compartment. The resulting excess fluid or fluid overload can lead to significant morbidity and mortality. Current treatment for fluid overload is limited by our lack of understanding of the reservoir for excess fluid accumulation, i.e. the interstitial fluid compartment. The work here sets out to improve our understanding of this compartment, by accessing it via a transdermal approach, with the use of microneedles, from patients with fluid overload, extracting or removing the fluid and analysing such interstitial fluid for its constituents. The first section sets out to review current knowledge of the pathophysiology of fluid accumulation in disease states such as kidney and heart disease. It reveals that most fluid accumulation occurs in the interstitial compartment, of which the skin or subcutaneous interstitium retains the most fluid. It shows there is paucity of data on interstitial fluid composition. It also highlights some of the limitations of current approaches to fluid removal such as diuretics, blood based extracorporeal methods and ultrafiltration. This supports the rationale for exploring alternative methods of accessing the fluid reservoir in disease states. We then set out to test consistent access to subcutaneous interstitium and removal of interstitial fluid, using a microneedle array to create micropores in the skin with an applied negative pressure. 13 out of 20 patients had successful fluid removal with 85% of these sessions removing greater than 10mls of fluid. There was correlation between the volume of fluid removed and time, and oedema grade. In the final study, we analysed the composition of the extracted interstitial fluid in comparison to paired plasma samples. The key findings were novel evidence of significant equilibration between compartments for a range of small water soluble molecules such as creatinine and urea but a significant discrepancy with some larger molecules, with albumin concentration in interstitial fluid up to 7.5 times lower than plasma. The findings from the thesis inform future studies in exploration of the science of human interstitial fluid for potential diagnostics and therapeutic purposes in disease states.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sandip Mitra (Supervisor) & Leonard Ebah (Supervisor)