Pre‐clinical and clinical applications of thermoreversible hydrogels in biomedical engineering: a review

Abstract

Thermoreversible polymer hydrogels (TRGs) are physical aqueous networks triggered by temperature that find potential applications in tissue engineering (TE) and drug/gene delivery. When systems with lower critical solution temperature (LCST) behaviour are used, the aqueous solution of polymer is mixed with cells or drugs/genes, depending on the desired application, at room temperature and then injected in vivo to form a hydrogel. This in situ forming hydrogel acts as a matrix for tissue regeneration or controlled and targeted release of the compound. This review focuses on discussing the studies in which synthetic TRGs with LCST behaviour have been applied in vivo in model animals. These studies are categorised depending on the general structure of the polymer, as follows: (i) poloxamers (also known as Pluronics®), (ii) degradable polymers, (iii) poly(N-isopropylacrylamide), (iv) poly(organophosphazene) and (v) poly(2-ethyl-2-oxazoline). In general, when the system is optimised, TRGs provide sustained and topical release of the drugs, thus minimising the undesired side effects. When applied in the TE field, tissue formation was observed. Interestingly, two polymers have reached clinical trials, namely poloxamer 407 (P407, Pluronic® F127, often combined with P188, F68) and Regel® (the formulation of Regel® with the anticancer agent paclitaxel is known as Oncogel®), indicating the challenges that need to be overcome before successful application in clinics.

Homopolymer and ABC Triblock Copolymer Mixtures for Thermoresponsive Gel Formulations

“…In some cases, when the temperature is varied, a polymer network is formed, which is called thermoresponsive gel. Of particular interest in the biomedical field are the lower-critical solution temperature (LCST) polymers, and, especially, the LCST thermoresponsive gels, which exist in a solution state at low temperature, but assemble into a physical three-dimensional (3D) network as the temperature rises [8][9][10][11][12]. This transition, known as sol-gel transition, should ideally occur between room temperature and body temperature to ensure that: (i) gelation will occur quickly at body temperature e.g., post injection, and (ii) gelation will not occur at room temperatures; thus, the sample can be easily injected.…”

“…This transition, known as sol-gel transition, should ideally occur between room temperature and body temperature to ensure that: (i) gelation will occur quickly at body temperature e.g., post injection, and (ii) gelation will not occur at room temperatures; thus, the sample can be easily injected. Thermoresponsive gels have received much attention and have been investigated as injectable gels in tissue engineering [3,[12][13][14][15] and in drug delivery [16][17][18][19], and as 3D (bio-)printable materials [20][21][22][23][24][25].…”

“…Several studies have investigated the effect of additives on the thermoresponsive properties of the polymers, with major focus on Pluronic ® F127 (poloxamer 407) [26,27]. Pluronic ® polymers are ABA triblock copolymers, where A and B consist of ethylene glycol (EG) and propylene glycol (PG), respectively [12]. Several Pluronic ® polymers are commercially available differing in the total molar mass (MM) and the ratio of EG/PG.…”

“…Several Pluronic ® polymers are commercially available differing in the total molar mass (MM) and the ratio of EG/PG. Pluronic ® F127 has an EG content of approximately 70% and a total MM of approximately 12600 g mol −1 , and it has gained much attention due to its interesting thermogelling properties and commercial availability [12]. Polymeric additives in solutions of Pluronic ® F127, such as alginate [28][29][30], poly(ethylene glycol) (PEG) [27,[31][32][33][34][35], poly(acrylic acid) (PAA) [27,36], and carbopols, i.e., crosslinked PAA [37], poly(vinyl alcohol) [27,38], and hyaluronic acid [39,40], have been investigated.…”

“…Poloxamers as polymeric additives in solutions of Pluronic ® F127 have also been studied [19,[41][42][43][44][45][46][47][48]. For example, mixtures of Pluronic ® F127 and Pluronic ® F68, EG content 80% and total MM 8350 g mol −1 [12], were tested for suitability in drug delivery [19,27,44,[46][47][48][49][50]. In two of these studies, increasing the content in Pluronic ® F68 while keeping the content in Pluronic ® F127 constant lowered the gelation time at body temperature and drug diffusion kinetics were improved when this formulation was applied in drug delivery [46,47].…”