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To address the safety concern, this study aims to establish a proof-of-concept for a glucose-responsive, insulin-secreting cell line integrated with a built-in FailSafe kill-switch.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Method<\/jats:title>\n                <jats:p>We generated \u03b2 cell-induced progenitor-like cells (\u03b2iPLCs) from primary mouse pancreatic \u03b2 cells through interrupted reprogramming. Then, we transcriptionally linked our FailSafe (FS) kill-switch, HSV-thymidine kinase (TK), to Cdk1 gene using\u00a0a CRISPR\/Cas9 knock-in strategy, resulting in a FailSafe \u03b2iPLC line, designated as FS\u03b2iPLCs. Subsequently we evaluated and confirmed the functionality of the drug-inducible kill-switch in FS\u03b2iPLCs at different ganciclovir (GCV) concentrations using our PDMS-based transcapillary microfluidic system. Finally, we assessed the functionality of FS\u03b2iPLCs by characterizing the dynamics of insulin secretion in response to changes in glucose concentration using our microfluidic perfusion glucose-stimulated insulin secretion (GSIS) assay-on- chip.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The \u03b2iPLCs exhibited <jats:italic>Ins1<\/jats:italic>, <jats:italic>Pdx1<\/jats:italic> and <jats:italic>Nkx6.1<\/jats:italic> expression, and glucose responsive insulin secretion, the essential properties of pancreatic beta cells. The \u03b2iPLCs were amenable to genome editing which allowed for the insertion of the kill-switch into the 3\u2019UTR of Cdk1, confirmed by PCR genotyping. Our transcapillary microfluidic system confirmed the functionality of the drug-inducible kill-switch in FS\u03b2iPLCs, showing an effective cell ablation of dividing cells from a heterogeneous cell population at different ganciclovir (GCV) concentrations. The Ki67 expression assessment further confirmed that slow- or non-dividing cells in the FS\u03b2iPLC population were resistant to GCV. Our perfusion glucose-stimulated insulin secretion (GSIS) assay-on-chip revealed that the resistant non-dividing FS\u03b2iPLCs exhibited higher levels of insulin secretion and glucose responsiveness compared to their proliferating counterparts.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This study establishes a proof-of-concept for the integration of a FailSafe kill-switch system into a glucose-responsive, insulin-secreting cell line to address the safety concerns in stem cell-derived cell replacement treatment for T1D. The microfluidic systems provided valuable insights into the functionality and safety of these engineered cells, demonstrating the potential of the kill-switch to reduce the risk of tumorigenicity in pluripotent cell-derived insulin-secreting cells.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13287-024-04059-7","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T18:25:41Z","timestamp":1734546341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microfluidic chip systems for characterizing glucose-responsive insulin-secreting cells equipped with FailSafe kill-switch"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-4335","authenticated-orcid":false,"given":"Mohammad","family":"Izadifar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Massumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacey J.","family":"Prentice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Oussenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Elbaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Puri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-0413","authenticated-orcid":false,"given":"Andras","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"issue":"8","key":"4059_CR1","volume":"15","author":"F Sugandh","year":"2023","unstructured":"Sugandh F, Chandio M, Raveena F, Kumar L, Karishma F, Khuwaja S, et al. 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