The Effect of Glycemic Condition on Substrate Stiffness-Mediated Mechanosensitivity in Macrophages

Abstract

Diabetes is a disease that plagues over 463 million people globally. About 40 million of these patients have Type 1 diabetes, and the global incidence is increasing up to 5% per year. Type 1 diabetes is characterized by the body's immune system targeting the pancreas with antibodies, leading to a disruption in insulin production. While existing treatments, such as exogenous insulin injections, are both successful and popular, the exorbitant insulin costs and need for meticulous administration are driving factors for alternative long-term solutions to glucose dysregulation caused by diabetes. Encapsulated islet transplantation (EIT) is a tissue-engineered solution to address the challenges raised by diabetes. Donor islets are encapsulated in a semi-permeable hydrogel, allowing the diffusion of oxygen, glucose, and insulin but preventing leukocyte infiltration. Despite its successes in small animal models, EIT is still far from commercialization due to the requirements of long-term systemic immunosuppressants and consistent immune rejection from the foreign body response. While most published research has focused on tailoring the characteristics of the capsule material to promote clinical viability, many studies have had a limited scope centered on biochemical changes. Current mechanobiology studies on the effect of substrate stiffness on the function of leukocytes, especially macrophages – primary foreign body response orchestrators, show promise in tailoring a favorable response to tissue-engineered therapies such as EIT. However, before successful integration into the EIT design, it is imperative to determine the impact of external glucose concentrations on substrate stiffness-mediated mechanosensitivity. Glucose plays a critical role in macrophage functionality, impairing or enhancing their function in certain situations. Immunometabolism literature demonstrates that decreasing or inhibiting the uptake of glucose via impairing glycolysis can result in a significant decline in functionality in macrophages. Patients suffering from diabetes experience dysregulation in glycemic maintenance, ranging from hypo-, normo-, and hyperglycemic conditions. As a result, it is imperative to assess whether these changes in external glucose conditions will affect macrophage mechanosensitivity in response to EIT biomaterials to use substrate stiffness as a design parameter for EIT effectively This project investigates the role of glycemic conditions on macrophage mechanosensitivity, considering substrate stiffness factors including morphology, phenotype, phagocytic and inflammatory functionality. These parameters aim to mimic the early stages of foreign body response, particularly the initiation and acute inflammation phases. This work demonstrates that glycemic condition significantly influences the severity of substrate stiffness-mediated mechanosensitivity in reference to macrophage phagocytosis and pro-inflammatory functionality. This study serves to advance the understanding of macrophage functionality, bridging the fields of mechanobiology and immunometabolism. Understanding the role of glycemic conditions on substrate stiffness-mediated mechanosensitivity will assist in EIT design to enhance the clinical viability of the therapy and prevent immune rejection by pericapsular fibrotic overgrowth.