Abstract

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2–3 times per day, for 4–8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.

Highlights

  • Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia [1]

  • The Fourier-transform infrared spectroscopy (FT-IR) spectra of poloxamer 407 (P407), hyaluronic acid (HA), urokinase, and their physical mixtures (P407 + urokinase and P407 + HA + urokinase) were performed in order to investigate the molecular interactions between P407, HA, and urokinase

  • The aqueous P407 solution converts to a gel status driven by the decline of the solubility of polypropylene oxide (PPO) blocks, in which aggregation occurs in order to minimize their interaction with water molecules [7, 8]

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Summary

Introduction

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia [1]. Pleural effusion is found in 9–30% of cases of bacterial pneumonia, 20% of which progress to empyema. The pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause the proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax [2]. Urokinase instillation therapy through a chest drainage tube is a standard protocol used for fibrinolysis of the deposited fibrin material [3]. Urokinase treatment requires multiple instillation (2–3 times per day, for 4–8 days), and flows out from the chest drainage tube due to its high water solubility [4, 5]. We attempted to develop a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for the loading and release of urokinase and for over 24 hours

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