Thermosensitive sol–gel reversible hydrogels
Introduction
Hydrogels preformed by chemical or physical crosslinking are a special class of polymers that imbibe a considerable amount of water while maintaining their shape. The research on hydrogels with respect to drug delivery and biomedical devices has been extensive over the last few decades because of their biocompatible properties and easy control of solute transport. One of the more recent trends in hydrogel research is in situ hydrogel formation by photopolymerization [1] or by phase transition [2], [3]. In situ hydrogel formation makes it more feasible to apply hydrogels for macromolecular drug delivery, tissue barriers, and tissue engineering. A particularly interesting and important polymeric system is hydrogel forming solutions by a simple phase transition (sol–gel transition) in water without any chemical reaction or external stimulation. This system provides simplicity and safety in in vivo situations.
The sol phase is defined as a flowing fluid, whereas the gel phase is non-flowing on an experimental time scale, while maintaining its integrity. Above the critical concentration (critical gel concentration, CGC) of a polymer, the gel phase appears. The CGC is most often inversely related to the molecular weight of the polymer employed. The development of physical junctions in the system is regarded as one of the prerequisites in determining gelation, which must be sufficiently strong with respect to the entropically driven dissolving forces of the solvent. The gelation of organic or aqueous polymer solutions occurs by various mechanisms that have been reviewed extensively and summarized [4], [5].
The determination of the boundary between the sol and gel phases depends on the experimental method. A simple test-tube inverting method was employed to roughly determine the phase boundary [6]. When a test tube containing a solution is tilted, it is defined as a sol phase if the solution deforms by flow, or a gel phase if there is no flow. The flow is a function of time, tilting rate, amount of solution, and the diameter of the test tube. Considering the time–temperature superposition principle in polymer deformation, the test parameters should be fixed before determining the sol–gel boundary. The falling ball method is another simple way to determine the sol–gel transition condition [7]. When a small heavy ball resting on top of a solution (gel phase) begins to penetrate into the gel under specific conditions, it can be regarded as a gel–sol transition, again being dependent on the relative ball density compared to the gel strength. When gelation is induced by temperature, the endothermic peak during heating obtained from differential scanning calorimetry (DSC) determines the transition temperature as well as the enthalpy of gelation [8]. Recently, a dynamic mechanical analysis was used to determine the sol–gel transition in a more reproducible manner [9]. An abrupt change in the storage modulus or viscosity reflects the sol–gel transition.
In this review, the sol-to-gel transition of aqueous polymer solutions primarily induced by temperature will be stressed, covering the natural or seminatural polymeric systems, N-isopropylacrylamide (NiPAAM) copolymers, poly(ethylene glycol-b-propylene glycol-b-ethylene glycol) (Poloxamer) and its analogs, and poly(ethylene glycol)/poly(d,l-lactic acid-co-glycolic acid) block copolymers.
Section snippets
Natural and modified natural polymers
Historically, natural biopolymer gels have been used as food and food processing aids as well as in pharmacy. Thermoreversible gelation has been reported for gelatin (a protein prepared from the partial hydrolysis of collagen and containing proline, glycine, and hydroxy proline as its major amino acids) and polysaccharides such as agarose (extracted from red sea weed; alternating copolymer of 1,4-linked 3,6-anhydro-α-l-galactose and 1,3-linked β-d-galactose), amylose (a 1,4-linked α-d-glucan
N-Isopropylacrylamide copolymers
Polymer precipitation in solution on raising the temperature often occurs in aqueous systems and results from the balance of intermolecular forces between the polymer and the solvent as well as between polymers. Table 1 shows some examples of polymers showing a low critical solution temperature (LCST) in water.
N-Isopropylacrylamide homopolymer (poly(NiPAAM); Fig. 2) and its copolymers are most often investigated for the structure–property relationship [19], [20], drug delivery [21], tissue
PEG/PPO block copolymers and related derivatives
The commercial poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (PEO–PPO–PEO, Fig. 3; Pluronic (BASF) or Poloxamer (ICI)) series with various molecular weights and PEG/PPO block ratios was used as a non-ionic surfactant, and the aqueous solutions of some Poloxamers exhibited phase transitions from sol to gel (low temperature sol–gel boundary) and from gel to sol (high temperature gel–sol boundary) as the temperature increased monotonically when the polymer concentration was above a
PEG/PLGA block copolymers
A novel concept, which combines thermogelation, biodegradability, and no toxicity, has been proposed for an injectable gel system with better safety and longer gel duration [86]. Poly(ethylene glycol-b-l-lactic acid-b-ethylene glycol) (PEG–PLLA–PEG) was synthesized by ring-opening polymerization of l-lactide onto monomethoxy poly(ethylene glycol) (MW 5000), which produced PEG–PLLA diblock copolymers, followed by coupling of the resulting diblock copolymers with hexamethylene diisocyanate to
Summary
Polymer solutions in water (sol phase) that transform into a gel phase on changing the temperature (thermogelation) have been briefly reviewed. Various aqueous polymeric systems exhibit a gel region in temperature–concentration phase diagrams, either by elevating or lowering the temperature. Some polymers, particularly Poloxamers and PEO/PLGA block copolymers, show the gel region in an intermediate temperature range, thus being dissolved both at low and high temperatures. The thermogelation
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