Biomaterial strategies for regulating the neuroinflammatory response.

Injury and disease in the central nervous system (CNS) can result in a dysregulated inflammatory environment that inhibits the repair of functional tissue. Biomaterials present a promising approach to tackle this complex inhibitory environment and modulate the mechanisms involved in neuroinflammation to halt the progression of secondary injury and promote the repair of functional tissue. In this review, we will cover recent advances in biomaterial strategies, including nanoparticles, hydrogels, implantable scaffolds, and neural probe coatings, that have been used to modulate the innate immune response to injury and disease within the CNS. The stages of inflammation following CNS injury and the main inflammatory contributors involved in common neurodegenerative diseases will be discussed, as understanding the inflammatory response to injury and disease is critical for identifying therapeutic targets and designing effective biomaterial-based treatment strategies. Biomaterials and novel composites will then be discussed with an emphasis on strategies that deliver immunomodulatory agents or utilize cell-material interactions to modulate inflammation and promote functional tissue repair. We will explore the application of these biomaterial-based strategies in the context of nanoparticle- and hydrogel-mediated delivery of small molecule drugs and therapeutic proteins to inflamed nervous tissue, implantation of hydrogels and scaffolds to modulate immune cell behavior and guide axon elongation, and neural probe coatings to mitigate glial scarring and enhance signaling at the tissue-device interface. Finally, we will present a future outlook on the growing role of biomaterial-based strategies for immunomodulation in regenerative medicine and neuroengineering applications in the CNS.

Mesenchymal stromal cells for bone trauma, defects, and disease: Considerations for manufacturing, clinical translation, and effective treatments.

Bone is a complex tissue capable of natural repair to injury, however, the healing process is often impaired by the untoward effects of trauma, defects, and disease. Thus, therapeutic modalities, including the use of cells involved in the body's natural healing processes, are investigated to promote or complement natural bone repair. Herein, several modalities and innovative approaches for using mesenchymal stromal cells (MSCs) to treat bone trauma, defects, and diseases are discussed. Given the evidence that supports the promising potential of MSCs, we highlight important considerations for advancing the clinical use of MSCs including the standardization of procedures from the harvest to delivery to patients and realized solutions to manufacturing. A better understanding of the current approaches implemented to address the challenges of using therapeutic MSCs will help improve study designs and, ultimately, achieve effective outcomes for restoring bone health.

Systemic Immune Modulation Alters Local Bone Regeneration in a Delayed Treatment Composite Model of Non-Union Extremity Trauma.

Bone non-unions resulting from severe traumatic injuries pose significant clinical challenges, and the biological factors that drive progression towards and healing from these injuries are still not well understood. Recently, a dysregulated systemic immune response following musculoskeletal trauma has been identified as a contributing factor for poor outcomes and complications such as infections. In particular, myeloid-derived suppressor cells (MDSCs), immunosuppressive myeloid-lineage cells that expand in response to traumatic injury, have been highlighted as a potential therapeutic target to restore systemic immune homeostasis and ultimately improve functional bone regeneration. Previously, we have developed a novel immunomodulatory therapeutic strategy to deplete MDSCs using Janus gold nanoparticles that mimic the structure and function of antibodies. Here, in a preclinical delayed treatment composite injury model of bone and muscle trauma, we investigate the effects of these nanoparticles on circulating MDSCs, systemic immune profiles, and functional bone regeneration. Unexpectedly, treatment with the nanoparticles resulted in depletion of the high side scatter subset of MDSCs and an increase in the low side scatter subset of MDSCs, resulting in an overall increase in total MDSCs. This overall increase correlated with a decrease in bone volume (P = 0.057) at 6 weeks post-treatment and a significant decrease in mechanical strength at 12 weeks post-treatment compared to untreated rats. Furthermore, MDSCs correlated negatively with endpoint bone healing at multiple timepoints. Single cell RNA sequencing of circulating immune cells revealed differing gene expression of the SNAb target molecule S100A8/A9 in MDSC sub-populations, highlighting a potential need for more targeted approaches to MDSC immunomodulatory treatment following trauma. These results provide further insights on the role of systemic immune dysregulation for severe trauma outcomes in the case of non-unions and composite injuries and suggest the need for additional studies on targeted immunomodulatory interventions to enhance healing.

Neutrophil-targeted, protease-activated pulmonary drug delivery blocks airway and systemic inflammation.

Pulmonary drug delivery presents a unique opportunity to target lower airway inflammation, which is often characterized by the massive recruitment of neutrophils from blood. However, specific therapies are lacking modulation of airway neutrophil function, and difficult challenges must be overcome to achieve therapeutic efficacy against pulmonary inflammation, notably drug hydrophobicity, mucociliary and macrophage-dependent clearance, and high extracellular protease burden. Here, we present a multistage, aerodynamically favorable delivery platform that uses extracellular proteolysis to its advantage to deliver nanoparticle-embedded hydrophobic drugs to neutrophils within the lower airways. Our design consists of a self-regulated nanoparticle-in-microgel system, in which microgel activation is triggered by extracellular elastase (degranulated by inflammatory neutrophils), and nanoparticles are loaded with Nexinhib20, a potent neutrophil degranulation inhibitor. Successful in vivo delivery of Nexinhib20 to the airways and into neutrophils promoted resolution of the inflammatory response by dampening neutrophil recruitment and degranulation, proinflammatory cytokine production in both airway and systemic compartments, as well as the presence of neutrophil-derived pathological extracellular vesicles in the lung fluid. Our findings showcase a new platform that overcomes challenges in pulmonary drug delivery and allows customization to match the proteolytic footprint of given diseases.