Is a new artificial kidney model the future for drug toxicity studies?
A world-first in vitro model could offer “boundless potential” for future studies into drug toxicity and kidney disease.
Scientists at POSTECH in South Korea have successfully built a glomerular ‘microvessel-on-a-chip’ that replicates the vital blood filtering function performed by human kidneys.
Its makers say that, by recapitulating the human glomerular filtration barrier (GFB), the new structure provides the “ultimate tool” for screening drugs for nephrotoxicity and for studying kidney dysfunction.
Attempts to produce an effective in vitro model for studying renal disease and drug toxicity have to date been thwarted by the complex workings of the GFB – including “complex cell-matrix interaction and cellular crosstalk among its constituents” – and technical problems with engineering a synthetic alternative. The POSTECH group resolved these issues by employing the promising technique of 3D coaxial cell printing – making use of nozzles equipped with concentric layers that enable the generation of a wide range of structures, and allowing the printing of co-cultures, perfusable tubular constructs, and high-resolution scaffold. Using this technique for the first time on a GFB model, and employing a customised kidney bioink featuring primary human podocytes and glomerular epithelial cells, they fabricated a bilayer glomerular microvessel-on-a-chip (bGOAC) that mimics both the GFB’s inner monolayer and outer podocyte layer.
As well as creating the bGOAC “in a single, continuous process”, the researchers carried out extensive testing to assess whether it could replicate the essential functions of the GFB. They found that the model not only generated the major collagen type IV and laminin proteins associated with the glomerular basement membrane, but was also able to replicate the GFB’s crucial ability to filter molecules in the blood based on their size.
“The perfusable bGOAC prevented the large molecules (albumin and dextran) from leaking,” they reported in the journal Biofabrication. Moreover, “More than 99% of albumin was retained within the bilayer glomerular microvessel after perfusion for 1 h(our).
“Furthermore, inulin, a small-sized molecule… can freely pass the GFB-containing bilayer glomerular microvessel to the urinary compartment of bGOAC.
“These findings suggest that the cell printed bGOAC specifically replicates the normal function of the in vivo GFB.”
In order to establish whether their bGOAC could be used in drug-induced nephrotoxicity studies - and thus potentially help patients avoid renal damage from the drugs they take – the group also administered the cancer chemotherapeutic drug adriamycin to the kidney model to assess whether it would be harmed in the same way as a human GFB. These results were also encouraging in that “Cell viability in the bilayer glomerular microvessel was reduced after Adriamycin treatment” – most notably for podocyte functional genes, endothelial cell-specific genes, and the tight junction marker ZO-1. The bGOAC also mimicked the development of proteinuria that would occur in a normal kidney when treated with both adriamycin and (FITC)-albumin. Furthermore, when exposed to varying concentrations of glucose to mimic the damage caused by hyperglycaemia-related diabetes, the in vitro model’s filtration barrier became so enlarged as to promote albumin clearance – “the key clinical sign of diabetic nephropathy”.
“We have successfully replicated glomerular units of the kidney, which offer boundless potential for drug screening and nephrotoxicity testing in clinical practice,” said study leader Professor Dong-Woo Cho.
“This development will enable us to detect drug toxicity early by facilitating glomerulus disease modeling and to provide personalized treatment for patients.”
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