Review article
In situ-forming hydrogels—review of temperature-sensitive systems

https://doi.org/10.1016/j.ejpb.2004.03.019Get rights and content

Abstract

In the past few years, an increasing number of in situ-forming systems have been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. There are several possible mechanisms that lead to in situ gel formation: solvent exchange, UV-irradiation, ionic cross-linkage, pH change, and temperature modulation. The thermosensitive approach can be advantageous for particular applications as it does not require organic solvents, co-polymerization agents, or an externally applied trigger for gelation. In the last 2 decades, several thermosensitive formulations have been proposed. This manuscript focuses on aqueous polymeric solutions that form implants in situ in response to temperature change, generally from ambient to body temperature. It mainly reviews the characterization and use of polysaccharides, N-isopropylacrylamide copolymers, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (poloxamer) and its copolymers, poly(ethylene oxide)/(d,l-lactic acid-co-glycolic acid) copolymers, and thermosensitive liposome-based systems.

Introduction

In the past few years, an increasing number of in situ-forming systems have been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These systems are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling within the desired tissue, organ, or body cavity. Injectable gel-forming matrices offer several advantages over systems shaped into their final form before implantation. For example, injectable materials do not require a surgical procedure for placement (and withdrawal if not biodegradable), and various therapeutic agents can be incorporated by simple mixing. When they are used to fill a cavity or a defect, their flowing nature enables a good fit. In situ implant formation can occur as a result of either a physical or chemical change of the system.

There are several possible mechanisms leading to in situ implant formation. The solvent exchange approach consists of dissolving a water-insoluble polymer in a water-miscible, biocompatible solvent. Upon contact with body fluids, the solvent diffuses out of the polymer while water permeates the liquid polymer matrix. Due to its insolubility in water, the polymer precipitates, resulting in the formation of a solid polymeric implant [1], [2], [3], [4], [5]. However, incomplete implant formation can be observed in vivo resulting in a high initial release and local or systemic toxicity. Also, the organic solvent used to solubilize the polymer can physically denaturate labile compounds such as proteins. Photopolymerization has also been proposed to prepare in situ implants. This approach has been taken to produce depot formulations [6], biological adhesives for soft tissues [7], [8], [9], [10], and orthopaedic biomaterials [11]. However, photopolymerization requires the presence of a photoinitiator at the gelation site, which can be toxic. Furthermore, the penetration capacity of the radiation source limits the number of application sites, and the reaction can evoke enough heat to damage surrounding tissues.

In situ-forming systems that do not require organic solvents or copolymerization agents have gained increasing attention. These are liquid aqueous solutions before administration, but gel under physiological conditions. Gelation can occur in situ by ionic cross-linking [12], [13] or after a change in pH [14], [15] or temperature. The latter approach exploits temperature-induced phase transition.

Some polymers undergo abrupt changes in solubility in response to increases in environmental temperature (lower critical solution temperature, LCST). This phase separation is generally viewed as a phenomenon governed by the balance of hydrophilic and hydrophobic moieties on the polymer chain and the free energy of mixing [16], [17], [18]. The free energy of association varies with enthalpy, entropy and temperature (ΔGHTΔS). As the positive enthalpy term (ΔH) is smaller than the entropy term (ΔS), an increase in temperature results in a larger TΔS, making ΔG negative and favoring polymer chain association. The temperature dependence of certain molecular interactions, such as hydrogen bonds and hydrophobic effects, contribute to phase separation. At the LCST, hydrogen bonding between the polymer and water becomes unfavorable, compared to polymer–polymer and water–water interactions, and an abrupt transition occurs as the solvated macromolecule quickly dehydrates and changes to a more hydrophobic structure [18], [19]. Alternatively, some amphiphilic polymers, that self-assemble in solution, show micelle packing and gel formation because of polymer–polymer interactions when temperature is increased [20].

The ideal system would be a solution that is a free-flowing, injectable liquid at ambient temperature. It should then gel at body temperature with minimal syneresis. Moreover, loading with drugs or cells should be achieved by simple mixing. When administered parenterally, these systems should exhibit a pH close to neutrality and should be bioresorbable. This paper focuses on polymeric solutions that can form implants in situ in response to temperature change, from ambient to body temperature. It mainly reviews the characterization and use of polysaccharides, N-isopropylacrylamide (NIPAM) copolymers, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (PEO-PPO-PEO) and its copolymers, poly(ethylene oxide)/(d,l-lactic acid-co-glycolic acid) (PEO/PLGA) copolymers, and thermosensitive liposome-based systems (Fig. 1).

Section snippets

Cellulose derivatives

Thermoreversible gels can be prepared with naturally occurring polymers. Most natural polymer aqueous solutions form a gel phase when their temperature is lowered. Classic examples of natural polymers exhibiting a sol–gel transition include gelatin and carrageenan. At elevated temperatures, these polymers adopt a random coil conformation in solution. Upon cooling, a continuous network is formed by partial helix formation [21], [22]. Some cellulose derivatives are an exception to this gelation

N-isopropylacrylamide copolymers

Poly(N-isopropylacrylamide) (PNIPAM) (Fig. 1F) is a non-biodegradable polymer with a LCST ∼32 °C in water [17], and cross-linked gels of this material collapse around this temperature [49], [50]. The PNIPAM LCST can be controlled by copolymerization with other monomers. The addition of hydrophilic monomers typically increases the LCST whereas the incorporation of more hydrophobic units has the opposite effect [51].

Poloxamer (Pluronic®)

The poloxamers (Fig. 1H) consist of more than 30 different non-ionic surface-active agents. These polymers are ABA-type triblock copolymers composed of PEO (A) and PPO units (B). The poloxamer series covers a range of liquids, pastes, and solids, with molecular weights and ethylene oxide-propylene oxide weight ratios varying from 1100 to 14,000 and 1:9 to 8:2, respectively. Concentrated aqueous solutions of poloxamer form thermoreversible gels.

The gelation mechanism of poloxamer solutions has

Poly(ethylene oxide)/poly(d,l-lactic acid-co-glycolic acid)

Jeong and co-workers described different thermosensitive, biodegradable hydrogels based on poly(lactic acid). Block copolymer solutions of PEO and poly(l-lactic acid) were shown to be in the sol state at 45 °C, and in the gel state at body temperature [108]. However, the need to heat the solution limits the nature of the drugs that can be incorporated in this delivery system, and makes the injection procedure not practical. Later, PEO-b-(d,l-lactic acid-co-glycolic acid)-b-PEO (PEO-PLGA-PEO) (

Thermosensitive liposomes as a physical barrier between reactive species

In a series of studies, Messersmith and co-workers [122], [123], [124], [125], [126] exploited a rise in temperature to initiate a reaction cascade leading to the formation of a biomaterial in situ. Their approach was based on the use of temperature-sensitive liposomes to compartmentalize reactive species (Fig. 9A). The physical barrier imposed by the vesicle membrane prevented the chemical reaction from proceeding. Destabilization of the lipid membrane upon an increase in temperature triggered

Poly(organophosphazene) derivatives

Recently, poly(organophosphazene) (PPZ) derivatives were shown to exhibit sol–gel phase transitions as a function of temperature. PPZ bearing methoxy-PEO and amino acid esters as substituents were synthesized by Song et al. (Fig. 1N) [127], [128]. The polymers were hydrolytically degradable and displayed a LSCT in the 25.2–98.5 °C range. The same group demonstrated that oligomeric cyclophosphazenes with proper orientation of substituents were also thermosensitive (Fig. 1P) [129]. PPZ bearing

Conclusion

Over the last decade, an impressive number of novel, thermosensitive, in situ gel-forming solutions have been described in the literature. Each system has its own advantages and drawbacks. The choice of a particular hydrogel depends on its intrinsic properties and envisaged therapeutic use. For instance, the formation of a transparent gel is particularly important when ophthalmic applications are considered. Non-biodegradable gels could prove useful for administration routes other than

Acknowledgements

Financial support from the National Sciences and Engineering Research Council of Canada, BioSyntech Inc. and the Canada Research Chair Program is acknowledged.

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