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With their increasing adoption, there is a need for non\u2010destructive methods that enable the sequential monitoring of cell death and tumor response over time. This study presents quantifying cell\u2010free DNA (cfDNA) as a proxy for cell death for on\u2010chip 3D sarcoma models. qPCR analysis of media cfDNA from spheroids and micro\u2010dissected tumor explants (MDTs) generated from SK\u2010LMS\u20101 and MCA\u2010205 cell lines cultured on microfluidic chips showed a correlation between baseline cfDNA concentration and on\u2010chip tumor burden. Furthermore, cfDNA levels increased in a dose\u2010dependent manner following cytotoxic treatments, including staurosporine and hydrogen peroxide. Single\u2010dose radiation therapy also raised cfDNA levels in media from MCA\u2010205 but not SK\u2010LMS\u20101 MDTs, in accordance with their 2D culture response. Finally, cfDNA release within the first days of culture was shown to reflect patient\u2010derived MDT survival, addressing a critical unmet need for ex vivo culture. This study suggests that media cfDNA quantification could be used as a reliable, non\u2010disruptive, and rapidly quantifiable measure of cell death for on\u2010chip 3D models, which facilitates more robust use of 3D model systems for pre\u2010clinical assessment of treatment\u2010induced cell death and biological response.<\/jats:p>","DOI":"10.1002\/adhm.71792","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:47:13Z","timestamp":1791172033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell\u2010Free DNA as a Biomarker of Cell Death and Treatment Response for On\u2010Chip Three\u2010Dimensional Tumor Models"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0163-7930","authenticated-orcid":false,"given":"Maryam","family":"Ziaee","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering Polytechnique Montr\u00e9al  Montr\u00e9al Quebec Canada"},{"name":"Centre de Recherche du Centre Hospitalier de L'universit\u00e9 de Montr\u00e9al (CRCHUM)  Montr\u00e9al Quebec Canada"},{"name":"Institut du Cancer de Montr\u00e9al (ICM)  Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6051-3557","authenticated-orcid":false,"given":"Julie","family":"Lafontaine","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de L'universit\u00e9 de Montr\u00e9al (CRCHUM)  Montr\u00e9al Quebec Canada"},{"name":"Institut du Cancer de Montr\u00e9al (ICM)  Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badr","family":"Id Said","sequence":"additional","affiliation":[{"name":"Radiation Medicine Program Princess Margaret Hospital  Toronto Ontario Canada"},{"name":"Department of Radiation Oncology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kousha","family":"Kamal","sequence":"additional","affiliation":[{"name":"Biomaterials and Biomedical Engineering University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-2333","authenticated-orcid":false,"given":"Kim","family":"Tsoi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Mount Sinai Hospital  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2523-309X","authenticated-orcid":false,"given":"Francis","family":"Rodier","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de L'universit\u00e9 de Montr\u00e9al (CRCHUM)  Montr\u00e9al Quebec Canada"},{"name":"Institut du Cancer de Montr\u00e9al (ICM)  Montr\u00e9al Quebec Canada"},{"name":"Department of Radiology, Radio\u2010Oncology and Nuclear Medicine Universit\u00e9 de Montr\u00e9al Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2025-9082","authenticated-orcid":false,"given":"Thomas","family":"Gervais","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de L'universit\u00e9 de Montr\u00e9al (CRCHUM)  Montr\u00e9al Quebec Canada"},{"name":"Institut du Cancer de Montr\u00e9al (ICM)  Montr\u00e9al Quebec Canada"},{"name":"Department of Engineering Physics Polytechnique Montr\u00e9al  Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7761-0283","authenticated-orcid":false,"given":"Philip","family":"Wong","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de L'universit\u00e9 de Montr\u00e9al (CRCHUM)  Montr\u00e9al Quebec Canada"},{"name":"Radiation Medicine Program Princess Margaret Hospital  Toronto Ontario Canada"},{"name":"Department of Radiation Oncology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2020.00033"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2014.573"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/biot.201300492"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44222\u2010024\u201000252\u20108"},{"key":"e_1_2_13_6_1","unstructured":"O. 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