02201nas a2200361   4500000000100000000000100001008004100002260001500043653001700058653002000075653002300095100002000118700001300138700002300151700002100174700001500195700002500210700001600235700002400251700002500275700002100300700002200321700002400343700001600367700002200383700002000405245010900425856005500534300000900589490000700598520122000605022001401825       2025                            d  c2025-09-1210abiomaterials10aDifferentiation10aTissue engineering1 aClaire Richards1 aHao Chen1 aMatthew O’Rourke1 aAshley Bannister1 aGrace Owen1 aAlexander Volkerling1 aArnab Ghosh1 aCatherine A. Gorrie1 aDavid Gallego-Ortega1 aAmy L. Bottomley1 aMatthew P. Padula1 aKristine C. McGrath1 aLouise Cole1 aPhilip M. Hansbro1 aLana McClements00aMatrix directs trophoblast differentiation in a bioprinted organoid model of early placental development  uhttps://www.nature.com/articles/s41467-025-62996-0  a82670 v163 aTrophoblast organoids can provide crucial insights into mechanisms of placentation, however their potential is limited by highly variable extracellular matrices unable to reflect in vivo tissues. Here, we present a bioprinted placental organoid model, generated using the first trimester trophoblast cell line, ACH-3P, and a synthetic polyethylene glycol (PEG) matrix. Bioprinted or Matrigel-embedded organoids differentiate spontaneously from cytotrophoblasts into two major subtypes: extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STBs). Bioprinted organoids are driven towards EVT differentiation and show close similarity with early human placenta or primary trophoblast organoids. Inflammation inhibits proliferation and STBs within bioprinted organoids, which aspirin or metformin (0.5 mM) cannot rescue. We reverse the inside-out architecture of ACH-3P organoids by suspension culture with STBs forming on the outer layer of organoids, reflecting placental tissue. Our bioprinted methodology is applicable to trophoblast stem cells. We present a high-throughput, automated, and tuneable trophoblast organoid model that reproducibly mimics the placental microenvironment in health and disease.  a2041-1723