02334nas a2200337   4500000000100000000000100001008004100002260001500043653001400058653001600072653001900088653001800107100001900125700002000144700001900164700002000183700001700203700002200220700001800242700001700260700001900277700002000296700001800316700002200334245010700356856005500463300000800518490000600526520145000532022001401982       2025                            d  c2025-05-1510aBiologics10adrug safety10aHaematopoiesis10aLab-on-a-chip1 aLeopold Koenig1 aLaurent Juglair1 aThi Phuong Tao1 aSusanne Fischer1 aInga Clausen1 aSabine Imhof-Jung1 aNiels Janssen1 aRobert Mader1 aDaniel Marbach1 aJens Niewoehner1 aAnnika Winter1 aDesirée Schubert00aA microfluidic bone marrow chip for the safety profiling of biologics in pre-clinical drug development  uhttps://www.nature.com/articles/s42003-025-08137-1  a7540 v83 aHematologic adverse events are common dose-limiting toxicities in drug development. Classical animal models for preclinical safety assessment of immunotherapies are often limited due to insufficient cross-reactivity with non-human homologous proteins, immune system differences, and ethical considerations. Therefore, we evaluate a human bone marrow (BM) microphysiological system (MPS) for its ability to predict expected hematopoietic liabilities of immunotherapeutics. The BM-MPS consists of a closed microfluidic circuit containing a ceramic scaffold covered with human mesenchymal stromal cells and populated with human BM-derived CD34+ cells in chemically defined growth factor-enriched media. The model supports on-chip differentiation of erythroid, myeloid and NK cells from CD34+ cells over 31 days. The hematopoietic lineage balance and output is responsive to pro-inflammatory factors and cytokines. Treatment with a transferrin receptor-targeting IgG1 antibody results in inhibition of on-chip erythropoiesis. The immunocompetence of the chip is established by the addition of peripheral blood T cells in a fully autologous setup. Treatment with T cell bispecific antibodies induces T cell activation and target cell killing consistent with expected on-target off-tumor toxicities. In conclusion, this study provides a proof-of-concept that this BM-MPS is applicable for in vitro hematopoietic safety profiling of immunotherapeutics.  a2399-3642