An integrated biomaterials-centred approach of the ageing thymic microenvironment reveals design principles for regenerative biomaterials

Thymic involution is commonly addressed as a loss of epithelial and lymphoid tissue, yet the accompanying remodelling of the microenvironment remains poorly defined. This work applied a biomaterials-centered approach to compare young and aged bovine thymus by integrating histology, oscillatory rheology, untargeted lipidomics, ICP-MS and AP-MALDI mass spectrometry imaging. This holistic approach connects the mechanical, compositional, and spatial features of the native thymus with the development of thymus-inspired biomaterials. Ageing increased both storage and loss moduli by more than one order of magnitude and reduced the linear viscoelastic region approximately fivefold, defining a markedly stiffer and more strain-sensitive material state. This mechanical transition was accompanied by lipid remodelling, with double realtive contribution of triacylglycerols to the lipid pool doubled and loss of membrane-associated phospholipids. The elemental profile also contracted, with total metal content decreasing by one-third and zinc showing a reduction of 70%. At the architectural level, the corticomedullary ratio was more than halved, while AP-MALDI imaging revealed an approximately 40% reduction in the annotated molecular repertoire and a shift from homogeneous to fragmented distributions of choline and representative phosphatidylcholine species. These results show that thymic ageing emerges from the concomitant variations of viscoelastic behaviour, chemical composition, and molecular organization. By defining these interconnected alterations, this study establishes a materials-based foundation for the design of bioinspired systems aimed at reproducing features of the young thymic niche and supporting future thymic repair. HighlightsO_LIAgeing increased viscoelastic moduli and reduced deformation tolerance. C_LIO_LIThe lipid profile shifted from membrane lipids towards triacylglycerols. C_LIO_LIThe elemental pool contracted, with zinc showing the strongest depletion. C_LIO_LIHistology and AP-MALDI-MSI revealed loss of spatial organization. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/740917v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@70624corg.highwire.dtl.DTLVardef@459d0aorg.highwire.dtl.DTLVardef@493622org.highwire.dtl.DTLVardef@810f0c_HPS_FORMAT_FIGEXP M_FIG C_FIG