Primary total joint arthroplasties (TJAs) are widely and successfully applied reconstructive procedures to treat end-stage arthritis. Nearly 50 % of TJAs are now performed in young patients, posing a new challenge: performing TJAs which last a lifetime. The urgency is justified because subsequent TJAs are costlier and fraught with higher complication rates, not to mention the toll taken on patients and their families. Polyethylene particles, generated by wear at joint articulations, drive aseptic loosening by inciting insidious inflammation associated with surrounding bone loss. Down modulating polyethylene particle-induced inflammation enhances integration of implants to bone (osseointegration), preventing loosening. A promising immunomodulation strategy could leverage immune cell metabolism, however, the role of immunometabolism in polyethylene particle-induced inflammation is unknown. Our findings reveal that immune cells exposed to sterile or contaminated polyethylene particles show fundamentally altered metabolism, resulting in glycolytic reprogramming. Inhibiting glycolysis controlled inflammation, inducing a pro-regenerative phenotype that could enhance osseointegration.

Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses. Using a bioenergetic model, delayed cellular changes were observed that are not apparent in the short-term. Amorphous and semi-crystalline PLA degradation products, including monomeric l-lactic acid, mechanistically remodel metabolism in cells leading to a reactive immune microenvironment characterized by elevated proinflammatory cytokines. Selective inhibition of metabolic reprogramming and altered bioenergetics both reduce these undesirable high cytokine levels and stimulate anti-inflammatory signals. The results present a new biocompatibility paradigm by identifying metabolism as a target for immunomodulation to increase tolerance to biomaterials, ensuring safe clinical application of PLA-based implants for soft- and hard-tissue regeneration, and advancing nanomedicine and drug delivery.

Spermiogenesis, the post-meiotic stage of sperm development, is critical for normal male fertility. Many genetic defects and environmental assaults that affect spermiogenesis have been shown to be associated with male infertility. In addition, this later stage of spermatogenesis has been proposed to be an ideal target for male contraceptive development. The mouse is a widely used model for studying the mechanisms of spermatogenesis and spermiogenesis. However, due to the complexity and the asynchronous nature of spermatogenesis in adult testis, it is challenging to study molecular processes restricted to this specific developmental stage. It is also challenging to monitor the spermiogenesic activity in live mice, which is critical for screening for fertility-modulating interventions such as contraceptives. Here we reported the development of a Nutm1-T2A- luciferase 2(Luc2)-tandem Tomato(TdTomato) knock-in reporter mouse model that specifically labels post-meiotic spermatids. Homozygous reporter mice are healthy and fully fertile, demonstrating no interference with the normal functions of the Nutm1 gene by the reporter. We demonstrated the visualization of post-meiotic spermatids by fluorescent imaging of the TdTomato reporter in both live and fixed testis tissues. We also demonstrated bioluminescence imaging of Nutm1 expressing cells in live mice. The Nutm1-T2A-Luc2TdTomato reporter mouse can serve as a valuable tool for studying spermiogenesis.