Elsevier

Science Bulletin

Volume 60, Issue 2, January 2015, Pages 235-240
Science Bulletin

Article
Materials Science
In situ forming chitosan-based hydrogel as a lung sealant for biological lung volume reduction

https://doi.org/10.1007/S11434-014-0548-3Get rights and content

Abstract

Biological lung volume reduction (BLVR) using lung sealant has received more attention recently as a new non-surgical approach to emphysema treatment. Many tissue sealants have been studied but only a few have been proposed for BLVR. In this work, we prepared in situ forming chitosan-based hydrogels (CSG) using covalent cross-linking of chitosan and genipin in the cooperation of ionic interaction between chitosan and sodium orthophosphate hydrate (Na3PO4·12H2O) and characterized by Fourier transform infrared spectroscopy, scanning electron microscopy and rheological methods. CSG showed short gelation time (8 min), high swelling ratio (>100%) and non-toxicity (3T3 mouse fibroblast cell viability >80%) under physiological conditions. The application of lung sealant for BLVR was tested in a Chinese dog and evaluated by chest computed tomography. After 3 weeks of the installation of CSG in bronchopulmonary segment, the gel formation was detected at a localized region of bronchi and the local atelectasis occurred. Our findings indicate that this chitosan-based hydrogel is a promising new candidate for use as a lung sealant for BLVR.

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases with irreversible respiratory condition. According to the latest World Health Organization (WHO) evaluation in 2004, there were more than 60 million COPD patients and three million people died due to this disease [1]. Emphysema, one of many diseases classified under the COPD, is characterized by the loss of elasticity and structures of the alveoli resulting in airway collapse. There is currently no known cure for COPD, it can be only managed to slow the progression, decrease the symptoms and prevent the complications. The general treatments for severe emphysema patients are lung surgery, lung transplantation and non-surgical options such as endobronchial valves, continuous positive airway pressure and airway bypass stents 2., 3., 4.. The biological lung volume reduction (BLVR), which is a non-surgical approach using lung sealant to seal and collapse the damage area, has recently received a lot of attention 4., 5., 6.. It is considered as an alternative new treatment for severe emphysema patients to decrease hyperinflation without complications and the risks from surgery. Although many tissue sealants have been investigated, only a few have been proposed for BLVR 4., 5., 6., 7., 8., 9., 10., 11., 12., 13.. A fibrin-based hydrogel consisting of poly-L-lysine and condroitin sulfate has been reported as an emphysematous sealant which would be administered through a dual lumen catheter 6., 7.. Later, a synthetic polymer, AeriSeal (Aeris therapeutics, USA), has been commercially proposed for BLVR which is now in the late-stage clinical trials 8., 9., 10.. It is a foam sealant that can be prepared before injection through a single-lumen catheter directly to the lungs of emphysema patients. In spite of that, there is few report about using chitosan-based hydrogels as a lung sealant for BLVR.

Chitosan-based hydrogels are versatile in biomedical applications because of their biocompatibility and biodegradability 13., 14., 15., 16.. Their sol-gel transition provides the possibility to fill target regions of the lungs by injection and to produce the sealing effect by in situ gel forming. Moreover, the hydrogel network structure can be modified to achieve desired properties, e.g., stability, mechanical strength and gelation time 17., 18., 19.. Chenite and co-workers 20., 21., 22. discovered a thermosensitive hydrogel based on physical cross-linking (ionic bonds) between chitosan and ß-glycerophosphate (ß-GP) that can form a gel at body temperature, however its stability and mechanical strength was weak. Therefore, genipin, which is a non-toxic cross-linker from a natural product (geniposide), was added to improve the mechanical properties and chemical stability of hydrogel due to the presence of covalent bonds between the chitosan and genipin 23., 24., 25., 26..

In this work, we propose a new in situ forming chitosan-based hydrogel (CSG) consisting of chitosan, sodium orthophosphate hydrate (Na3PO4·12H2O) and genipin as an alternative emphysematous sealant for BLVR 27., 28.. The properties of the hydrogel were investigated and tested for cytotoxicity and BLVR application.

Section snippets

Chemicals

Chitosan was purchased from Jinan Haidebei Marine Bioengineering (China) with the average molecular weight of 3 × 105 Da and the percentage degree of deacetylation (% DDA) of 85%. Genipin was high-performance liquid chromatography grade with purification more than 98%. All other chemicals were of analytical grade.

Cells and animals

3T3 mouse fibroblast cell lines were purchased from the China Center for Type Culture Collection (China) and maintained in RPMI1640 medium (Gibco, USA) supplemented with 10% fetal

Results and discussion

In situ forming CSG were produced straightforward by mixing chitosan (C), sodium orthophosphate hydrate (S) and genipin (G) at room temperature which could be one of the major advantages because of the ease of practical use with the cost reduction of the instrumental design in the future. The optimization of CSG gel formula produced hydrogels with low polymer concentrations, i.e., chitosan concentration (1% (w/v)) which made it easy to handle and prevented clogging of needle upon injection

Conclusions

In summary, a new CSG consisting of chitosan, Na3PO4·12H2O and genipin was successfully prepared and optimized under mild and simple conditions. CSG exhibits a short gelation time, good mechanical strength and no cytotoxicity. SEM images revealed its three-dimensional porous structure with a high swelling ratio. Moreover, CSG solution can be prepared before administration through a single channel bronchoscope, and shows no clogging inside the tube. The hydrogel showed in situ gel forming within

Conflict of interest

The authors declare that they have no conflict of interest.

Animals and human rights

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Acknowledgments

This work was supported by the University of Chinese Academy of Sciences (UCAS) and Royal Thai Government (Office of The Civil Service Commission, OCSC) Scholarship (27012552).

References (28)

  • A. Chenite et al.

    Rheological characterisation of thermogelling chitosan/glycerol-phosphate solutions

    Carbohydr Polym

    (2001)
  • R.A.A. Muzzarelli

    Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids

    Carbohydr Polym

    (2009)
  • World Health Organization (2012) Chronic obstructive pulmonary disease (COPD)....
  • F. Venuta et al.

    Bronchoscopic lung volume reduction. Multimed Man Cardiothorac Surg

    (2007)
  • Cited by (0)

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