Microphysiological pancreas-on-chip platform with integrated sensors to model endocrine function and metabolism

Schlünder, Katharina; Cipriano, Madalena; Zbinden, Aline; Fuchs, Stefanie; Mayr, Torsten; Schenke-Layland, Katja; Loskill, Peter

doi:10.1039/d3lc00838j

Cited by 6 publications

(2 citation statements)

References 72 publications

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“…Most spheroids published of this cell line were generally of variable sizes and poorly defined borders although the methods used for spheroid formation provided useful spheroids in another β-cell lines such as MIN6 (30,(61)(62)(63). A more recent publication reported the generation of uniform spheroids but were maintained in a device that is not compatible with electrophysiological recordings (64,65). It is also of note that most of the previously reported INS-1 aggregates showed either a considerable right shift of glucose dependency or a stark reduction in glucose induced insulin secretion (61,62).…”

Section: Discussionmentioning

confidence: 99%

Extracellular electrophysiology on clonal human β-cell spheroids

Puginier,

Fischer,

Gaitan

et al. 2024

Preprint

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Pancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary material. Close 3D contact and coupling between beta-cells are a hallmark of physiological function improving signal/noise ratios. Extracellular electrophysiology using micro-electrode arrays (MEA) is technically far more accessible than single cell patch clamp, enables dynamic monitoring of electrical activity in 3D organoids and recorded multicellular slow potentials (SP) provide unbiased insight in cell-cell coupling. We have therefore asked whether 3D spheroids enhance clonal beta-cell function such as electrical activity and hormone secretion using human EndoC- betaH1, EndoC- betaH5 and rodent INS-1 cells. EndoC- betaH1 spheroids exhibited increased signals in terms of SP frequency and especially amplitude as compared to monolayers and even single cell action potentials (AP) were quantifiable. Enhanced electrical signature in spheroids was accompanied by an increase in the glucose stimulated insulin secretion index. EndoC- betaH5 monolayers and spheroids gave electrophysiological profiles similar to EndoC- betaH1, except for a higher electrical activity at 3 mM glucose, and exhibited moreover a biphasic profile. Again, physiological concentrations of GLP-1 increased AP frequency. Spheroids also exhibited a higher secretion index. INS-1 cells did not form stable spheroids, but overexpression of connexin 36, required for cell-cell coupling, increased glucose responsiveness, dampened basal activity and consequently augmented the stimulation index. In conclusion, spheroid formation enhances physiological function of the human clonal beta-cell lines and these models may provide surrogates for primary islets in extracellular electrophysiology.

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Section: Discussionmentioning

confidence: 99%

Extracellular electrophysiology on clonal human β-cell spheroids

Puginier,

Fischer,

Gaitan

et al. 2024

Preprint

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“…Therefore, it is necessary to implement more complex in vitro systems to study human physiology and pathophysiology, as well as disease progression that allow for the study of organ crosstalk and interaction. The development of human liver [37][38][39][40][41][42][43] pancreatic islets [44][45][46][47][48] , and coupled [49][50][51][52] biomimetic microphysiology systems (MPS) that can reflect the genomic, as well as environment and lifestyle heterogeneity offer an important opportunity to recapitulate the heterogeneity of disease.…”

Section: Introductionmentioning

confidence: 99%

A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

Aleman,

Ravikumar,

Wiegand

et al. 2024

Preprint

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Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in pancreatic islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with primary islets on a chip (PANIS) enabling MASLD progression and islet dysfunction to be quantitatively assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF), under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion (GSIS) response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived secreted factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying complex disease mechanisms, and advancing precision medicine.

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Engineered microenvironments and pancreatic islet-on-chips for screening sugar substitute and antidiabetic compounds

Shi,

Li,

et al. 2024

Food Research International

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Microphysiological pancreas-on-chip platform with integrated sensors to model endocrine function and metabolism

Abstract: Pancreatic in vitro research is of major importance to advance mechanistic understanding and development of treatment options for diseases such as Diabetes Mellitus. We present a thermoplastic-based microphysiological system aiming...

Cited by 6 publications

References 72 publications

Extracellular electrophysiology on clonal human β-cell spheroids

Extracellular electrophysiology on clonal human β-cell spheroids

A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

Engineered microenvironments and pancreatic islet-on-chips for screening sugar substitute and antidiabetic compounds

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