Riki Toita

Understanding how nano- and microparticles interact with biological systems is essential for advancing the biomedical applications of engineered materials. These interactions are governed not only by the physicochemical properties of the particles – such as size, shape, and surface chemistry – but also by host-specific physiological factors. However, how intrinsic host factors, particularly age and biological sex, affect interactions between immune cells and particles remains poorly understood. In this study, we systematically investigated how these intrinsic host variables influence the cellular uptake of polymeric particles by primary macrophages. Using a library of particles with controlled sizes (25, 250, and 3000 nm) and surface chemistries (unmodified, amine-, and carboxyl-functionalized), as well as with biological particles (bacteria and yeast), we compared uptake efficiencies in macrophages derived from male and female mice of various ages. We observed significant age- and sex-dependent differences in particle internalization. Transcriptomic profiling revealed differentially expressed genes related to receptor-mediated endocytosis and actin cytoskeleton remodeling, suggesting that molecular mechanisms underly these variations. Additionally, protein coronas were formed by incubating polymeric particles with autologous serum, revealing sex-dependent differences in corona composition and resulting macrophage recognition. Our findings highlight the critical interplay between engineered-material properties and host biological variability. Accordingly, this work provides key insights for the rational design of nanomaterials tailored to perform consistently across heterogeneous biological populations, thereby advancing the development of personalized nanomedicine and immunomodulatory materials.

Nanomedicines offer broad therapeutic potential, but key host factors such as age and sex (now recognized as critical factors for efficacy) remain largely overlooked. Aging, which is characterized by systemic chronic inflammation and delayed tissue regeneration, poses significant medical and economic issues in aging societies. Older individuals exhibit impaired macrophage transition from an inflammatory M1 phenotype to an anti-inflammatory/pro-healing M2 phenotype, and this transition is a potential target for rejuvenating tissue repair. Existing therapeutic approaches, such as cytokines and biomaterial surface engineering, effectively promote M1-to-M2 polarization in young individuals, but their efficacy is markedly reduced in older individuals, and sex differences in therapeutic macrophage polarization remain largely unexplored. Here, we show that phosphatidylserine liposomes (PSLs) induced macrophage polarization independent of age (3-4 months old or >21 months old) and sex in mice. In addition, in vitro experiments confirmed that factors secreted by M1 macrophages inhibited osteoblast (OB) differentiation and enhanced osteoclast (OC) differentiation, with older macrophages from both sexes exerting more pronounced effects, while factors secreted by M2 macrophages had the opposite effect. Furthermore, in a critical-sized bone defect model in old mice, PSLs induced macrophage phenotype conversion, improved the balance between OB and OC differentiation, and eventually accelerated bone repair. These findings suggest that PSLs are a universal M2 macrophage inducer and offer a promising therapeutic strategy for restoring bone repair in older individuals as well as potentially promoting tissue regeneration in other organs.

We present a facile method to fabricate stable Ca-alginate hydrogel domes covalently immobilized on glass plates. The system supports non-adherent cell proliferation and reagent delivery, offering a platform for high-throughput analysis.

Implantable biomaterials trigger foreign body reactions (FBRs), which reduces the functional life of medical devices and prevents effective tissue regeneration. Although existing therapeutic approaches can circumvent collagen‐rich fibrotic encapsulation secondary to FBRs, they disrupt native tissue repair. Herein, a new surface engineering strategy in which an apoptotic‐mimetic, immunomodulatory, phosphatidylserine liposome (PSL) is released from an implant coating to induce the formation of a macrophage phenotype that mitigates FBRs and improves tissue healing is described. PSL‐multilayers constructed on implant surfaces via the layer‐by‐layer method release PSLs over a 1‐month period. In rat muscles, poly(etheretherketone) (PEEK), a nondegradable polymer implant model, induces FBRs with dense fibrotic scarring under an aberrant cellular profile that recruits high levels of inflammatory infiltrates, foreign body giant cells (FBGCs), scar‐forming myofibroblasts, and inflammatory M1‐like macrophages but negligible amounts of anti‐inflammatory M2‐like phenotypes. However, the PSL‐multilayer coating markedly diminishes these detrimental signatures by shifting the macrophage phenotype. Unlike other therapeutics, PSL‐multilayered coatings also stimulate muscle regeneration. This study demonstrates that PSL‐multilayered coatings are effective in eliminating FBRs and promoting regeneration, hence offering potent and broad applications for implantable biomaterials.

Bisphenol A (BPA; 4,4′-isopropylidenediphenol) is a well-known endocrine disruptor. Most human exposure to BPA occurs through the consumption of BPA-contaminated foods. Cardiovascular or cardiometabolic diseases such as diabetes, obesity, hypertension, acute kidney disease, chronic kidney disease, and heart failure are the leading causes of death worldwide. Positive associations have been reported between blood or urinary BPA levels and cardiovascular or cardiometabolic diseases. BPA also induces disorders or dysfunctions in the tissues associated with these diseases through various cell signaling pathways. This review highlights the literature elucidating the relationship between BPA and various cardiovascular or cardiometabolic diseases and the potential mechanisms underlying BPA-mediated disorders or dysfunctions in tissues such as blood vessels, skeletal muscle, adipose tissue, liver, pancreas, kidney, and heart that are associated with these diseases.