Novel in vitro systems elucidating metabolic health and disease

The convoluted nature of biology warrants improved models that further insights into health and disease. Bioengineered features and platforms allow the modulation and study of a range of biological phenomena. However, there remains a lack of versatile and well-characterised organotypic models and microphysiological systems that recapitulate phenotypes of interest. We have developed and comprehensively characterised a chemically defined, high throughput and stable 3D human adipose model comprising adipocyte spheroids. Adipocyte spheroids exhibit physiologically relevant gene expression signatures and improved phenotypes compared to conventional monolayer counterparts, with 4704 genes being differentially expressed compared to 2D cultures. Moreover, the model closely resembles freshly isolated human in vivo mature adipocytes. Such organotypic models and cellular phenomena can be manipulated using nanotopographies and structured polymer devices. We have demonstrated that nanostructures fabricated via nanoimprint lithography enabled precise modulation of cellular attachment and behaviour. Specific and high resolution structuring of microfluidic platforms is achieved using a novel fabrication approach, NanoRIM, allowing high fidelity generation of systems for organotypic hepatic cultures. The physiological crosstalk between liver and human pancreatic islets was then efficiently captured in an original microfluidic system featuring reciprocal perfusion. The versatile nature of these ensuing models and platforms enables the provision of a toolbox with which biology can be manipulated and studied across the vast temporal and spatial scales on which it exists.

List of scientific papers

I. Shen JX, Couchet M, Dufau J, de Castro Barbosa T, Ulbrich MH, Helmstädter M, Kemas AM, Zandi Shafagh R, Marques M, Hansen JB, Mejhert N, Langin D, Rydén M, Lauschke VM. 3D adipose tissue culture links the organotypic microenvironment to improved adipogenesis. Adv Sci. 2021;8(16):e2100106.
https://doi.org/10.1002/advs.202100106

II. Zandi Shafagh R, Shen JX, Youhanna S, Guo W, Lauschke VM, van der Wijngaart W, Haraldsson T. Facile nanoimprinting of robust high-aspect-ratio nanostructures for human cell biomechanics. ACS Appl Bio Mater. 2020;3(12):8757–67.
https://doi.org/10.1021/acsabm.0c01087

III. Zandi Shafagh R, Shen JX, Youhanna S, Haraldsson T, van der Wijngaart W, Lauschke VM. Nano reaction injection molding enables the rapid high-resolution structuring of multiscalar cell-compatible polymer devices. [Manuscript]

IV. Zandi Shafagh R*, Youhanna S*, Keulen J*, Shen JX, Taebnia N, Preiss LC, Klein K, Büttner FA, Bergqvist M, van der Wijngaart W, Lauschke VM. Bioengineered pancreas-liver crosstalk in a microfluidic coculture chip identifies human metabolic response signatures in prediabetic hyperglycemia. Adv Sci. 2022;9(34):e2203368. *Shared first authorship.
https://doi.org/10.1002/advs.202203368