Controlled Delivery of Immunomodulatory Factors for Mineralized Tissue Formation in an Inflammatory Microenvironment

Abstract

Mesenchymal stromal cells (MSCs) are a promising cell-based therapy for bone healing, contributing to tissue regeneration through direct differentiation or immunomodulatory factor secretion. However, diseases that feature chronic or dysregulated inflammation, such as non-union fractures and osteonecrosis of the jaw (ONJ), have proven difficult to treat with current MSC-based approaches. Here, it is investigated whether controlled delivery of immunomodulatory factors allows MSCs to simultaneously undergo osteogenic differentiation and modulate inflammation. First, a Design of Experiments approach is used to identify the type and concentrations of immunomodulatory factors (IMFs) that most effectively induce concurrent pro-regenerative macrophages and MSC osteogenic differentiation, then these IMFs are loaded into polymeric microparticles for controlled release. Through in vitro models, it is demonstrated that microparticles releasing IL-10 and IL-4 promote naïve MSC osteogenesis and modulate immune response, even in chronic, physiologically relevant, inflammatory conditions. Then this approach is applied to an in vivo rat model of ONJ as a clinically relevant example of such conditions. Clinically relevant sex-based differences in inflammation and bone formation are observed that have not yet been reported. These data represent key findings that will facilitate the reversal of diseases that are linked to chronic bone loss and inflammation, such as ONJ.

Keywords: bisphosphonate; immune modulation; mesenchymal stromal cells; osteogenesis; pro‐regenerative macrophages.