The Bacteriostatic, Regenerative, and Immunomodulatory Properties of Extracellular Matrix Particles for Lung Injury

Acute respiratory distress syndrome (ARDS) is a prevalent, life-threatening lung condition, affecting nearly 200,000 Americans annually, with a 40% international mortality rate. There is no cure for ARDS, and current pharmacological treatments have limited effectiveness. Symptoms can be mitigated with mechanical ventilation, though this often leads to ventilator-induced lung injuries (VILI) and puts critically ill patients at risk of infections, including ventilator-associated pneumonia (VAP). A promising therapeutic is the extracellular matrix (ECM), a complex network of structural proteins and bioactive molecules that has been shown to have anti-inflammatory properties and prevent fibrosis. We aim to utilize the regenerative and immunomodulatory effects of decellularized extracellular matrix (dECM) obtained from both pig lung (PL) and mouse mesenchymal stromal cell (mMSC) matrices. Through various fabrication methods, we have found that dECM particles have a wide range of immunomodulatory and antimicrobial properties. The mMSC and PL dECM nanoparticles were fabricated via electrospray deposition with tunable sizes ranging from 145-275 nm and negative zeta potentials (~ -11 mV), giving them the ability to reach distal respiratory regions and penetrate the surfactant and mucus membranes in the lungs. We also fabricated an aerosolized powder of PL dECM via spray drying, which has shown similar pro-regenerative effects on damaged tissue. We found that the mMSC ECM nanoparticles have a dose-dependent bacteriostatic effect on gram-negative bacteria strains, inhibiting the growth of common pneumonia-causing pathogens Pseudomonas aeruginosa and Escherichia coli. Both the mMSC dECM nanoparticles and PL dECM spray-dried particles have demonstrated accelerated wound healing on injured cultures of both mMSCs and human lung epithelial cells. Our mMSC ECM treatments demonstrated immunomodulatory properties that show promise in suppressing inflammation and promoting resolution in a pro-inflammatory induced environment. Due to the versatile formulation options and matrix sources, our ECM particles can be tailored for different lung applications and demonstrate improved healing of injured lungs while inhibiting bacterial growth, making them a promising therapeutic biomaterial for aiding VAP recovery and treating ARDS patients.