Structures and Applications of Thermoresponsive Hydrogels and Nanocomposite-Hydrogels Based on Copolymers with Poly (Ethylene Glycol) and Poly (Lactide- Co-Glycolide) Blocks

Abstract

Thermoresponsive hydrogels showing biocompatibility and degradability have been under intense investigation for biomedical applications, especially hydrogels composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(lactic acid-co-glycolic acid) (PLGA) as first-line materials. Even though various aspects such as gelation behavior, degradation behavior, drug-release behavior, and composition effect have been studied for 20 years since the first report of these hydrogels, there are still many outputs on parameters affecting their gelation, structure, and application. In this review, the current trends of research on linear block copolymers composed of PEG and PLGA during the last 5 years (2014-2019) are summarized. In detail, this review stresses newly found parameters affecting thermoresponsive gelation, findings from structural analysis by simulation, small-angle neutron scattering (SANS), etc., progress in biomedical applications including drug delivery systems and regeneration medicine, and nanocomposites composed of block copolymers with PEG and PLGA and nanomaterials (laponite).

Keywords: PEG; PLGA; block copolymer; degradation; drug delivery; laponite; nanocomposite; regeneration medicine; structural analysis; thermoresponsive hydrogel.

Figure 1

Structural analysis of PLGA–PEG–PLGA solution (20 wt%) by SANS. Reprinted from [24] Micromolecular Bioscience, 16, Neda Khameh Khorshid et al., Novel structural changes during temperature induced self-assembling and gelation of PLGA-PEG-PLGA triblock copolymer in aqueous solutions, 1838–1852, Copyright (2016), with permission from Wiley.

Figure 2

Morphology of PLGA–PEG–PLGA in water at different concentrations revealed by DPD simulation. Reprinted from Journal of Applied Polymer Science, 132, Yang Cao et al., In Vitro evaluation and dissipative particle dynamics simulation of PLGA–PEG–PLGA, 41280, Copyright (2014), with permission from Wiley.

Figure 3

Mesoscopic structure of PEG–PLGA in water at different temperatures revealed by Monte Carlo simulation: (A) typical snapshots of the systems and (B) corresponding cluster size distribution. Reprinted from [25] Macromolecules, 51, Shuquan Cui et al., Semi-bald micelles and corresponding percolated micelle networks of thermogels, 6405–6420, Copyright (2018) American Chemical Society.

Figure 4

Schematic image of thermoresponsive hydrogels with PLGA–PEG–PLGA–drug conjugate. Reprinted from [37] Acta Biomaterialia, 77, Yanbo Zhang et al., Tumor microenvironment-labile polymer–doxorubicin conjugate thermogel combined with docetaxel for in situ synergistic chemotherapy of hepatoma, 63–73, Copyright (2018), with permission from Elsevier.

Figure 5

Schematic image of thermoresponsive hydrogels with vesicles/emulsomes: (A) a solution preparation method and (B) sustained release and tumor growth inhibition achieved by thermoresponsive hydrogels with vesicles/emulsomes. Reprinted from [38] ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY, 47, Dinglingge Cao et al., Liposomal doxorubicin-loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer, 181–191, Copyright (2019).

Figure 6

Schematic image of the application of thermoresponsive hydrogels as a submucosal cushion for endoscopic submucosal dissection (ESD): (a,b) injection of thermoresponsive hydrogels into the submucosal layer for mucosal elevation, (c,d) circumferential resection by cutting open via an insulation-tripped (IT) knife, and (e,f) suction of the gel under the mucosa and resection of lesion en bloc. Reprinted from [54] Acta Biomaterialia, 10, Lin Yu et al., Poly(lactic acid-co-glycolic acid)–poly(ethylene glycol)–poly(lactic acid-co-glycolic acid) thermogel as a novel submucosal cushion for endoscopic submucosal dissection, 1251–1258, Copyright (2013), with permission from Elsevier.

Figure 7

Graphical abstracts of nanocomposite systems reported in (a) June 2014 (reproduced from [64] with permission from the Royal Society of Chemistry), (b) February 2015 (reprinted with permission from [65] Biomacromolecules, 16, Koji Nagahama et al., Self-assembling polymer micelle/clay nanodisk/doxorubicin hybrid injectable gels for safe and efficient focal treatment of cancer, 880–889, Copyright (2015) American Chemical Society), (c) March 2017 (reprinted from [66] Polymer, 115, Makoto Miyazaki et al., PEG-based nanocomposite hydrogel: Thermoresponsive sol-gel transition controlled by PLGA–PEG–PLGA molecular weight and solute concentration, 246–254, Copyright (2017),with permission from Elsevier), (d) November 2017 (reprinted from [67] Polymer Degradation and Stability, 147, Kitagawa Midori et al., PEG-based nanocomposite hydrogel: Thermo-responsive sol-gel transition and degradation behavior controlled by the LA/GA ratio of PLGA–PEG–PLGA, 222–228, Copyright (2017), with permission from Elsevier), (e) January 2018 (reproduced from [68] with permission from the Royal Society of Chemistry), and (f) February 2019 (reprinted from [69]).