Thermoresponsive Hydrogels: Current Status and Future Perspectives

Abstract

Thermosensitive hydrogels are intelligent systems with the capacity to react to heat stimuli. The most recent developments in the utilization of these hydrogels, as drug-delivery systems, are outlined in this chapter. Their distinctive advantages, which have been made clear by research, include minimal toxicity, biocompatibility, and good swelling properties. They enable the local delivery of highly hazardous therapeutic agents and are able to shield delicate active ingredients from degradation and deactivation after entering the body. Local medication delivery has been shown to be crucial, particularly in the treatment of cancer, as it can reduce or even prevent the major systemic side effects that are frequently linked to chemotherapeutic drugs. Additionally, depending on the unique features of the disease, the encapsulation of an active molecule in the hydrogel matrix may change its residence period or release rate. To learn more about the safety and effectiveness of thermosensitive polymers in the treatment of the human body, it is crucial that these novel medicines be used in clinical settings.

1. Introduction

Hydrogels are three-dimensional, hydrophilic polymeric networks (Figure 1), which are capable of absorbing huge volumes of water, undergoing swelling and shrinkage, and resisting the dissolution of the network through physical and chemical interactions, due to the presence of interconnections, called crosslinks [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. Hydrogels are commonly used as drug-delivery systems, biosensors, and in tissue engineering [3]. As drug-delivery systems, they are popular because of their ability to release the therapeutic agent locally and continuously at a specific site (Figure 2) [2]. Hydrogels have the ability to encapsulate and protect different substances, including peptides, proteins, and nucleic acids [4]. They have a number of benefits over conventional delivery systems, including the improvement of the bioavailability and the reduction of the toxicity of the drug [4].

Figure 1.

3D network morphology of hydrogel formation (adapted from [1]).

Figure 2.

The drug releases mechanistical explanations from hydrogels (adapted from [27]).

Hydrogels’ classification is based on their composition (homo or copolymeric), their electrical charge (negative, positive, and neutral), the type of crosslinking (physical or chemical), and their size, and they can be either natural or synthetic [5, 6]. Natural hydrogels, such as collagen and chitosan, are characterized by high biocompatibility and biodegradability, making them excellent choices for use, as matrix systems. Synthetic hydrogels can be more precisely controlled over certain properties, such as swelling behavior and rate of degradation [6]. Regarding the type of crosslinking, chemical crosslinked hydrogels are prepared through Michael’s addition reaction, photopolymerization, enzymatic reaction, or formation of disulfide bonds. Physical crosslinking, which does not require the presence of a crosslinking agent, involves hydrophobic interactions and hydrogels can respond to external stimuli, such as changes in pH, temperature, oxidation potential, light, and enzymes (Figure 3) [2].

Figure 3.

The stimuli that are responsible for drug release from hydrogels (adapted from [3]).

Recently, the increasing interest in personalized pharmacotherapy and precision medicine has led to a rise in the development of smart biomaterials. Stimulated, physical crosslinked hydrogels are considered smart drug-delivery systems, due to their ability to control the timing and location of drug release and protect the pharmaceutical agent from biological degradation [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]. Among other stimulated hydrogels, thermosensitive or thermoresponsive hydrogels have become an important research field in biomedical research [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. Thermosensitive hydrogels undergo a sol-gel phase transition (Figure 4) or swell/dwell with a change in the temperature, and they can be further classified into positive or negative, based on whether they have a lower critical solution temperature (LCST) or an upper critical solution temperature (UCST) [6]. The phenomenon of temperature response is a result of the balance between the hydrophobic and hydrophilic portions of the monomers in the hydrogel’s structure. Temperature changes alter the way hydrophilic and hydrophobic portions interact with water molecules, which can lead to a change in the crosslinked network’s solubility and a sol-gel phase transition [6]. Some examples of thermoresponsive hydrogels are poloxamer/pluronic, glycerophosphate, and methoxy poly(ethyleneglycol)-poly(pyrrolidoneco-lactide).

Figure 4.

The illustration of the processes of micelle and hydrogel formation (adapted from [1]).

Thermosensitive hydrogels have several advantages over other stimuli-responsive hydrogels, including good stability, convenience of use by the patients, enhanced local bioavailability, efficacy at low doses, easy preparation, and low costs [7]. Recent research has explored the potential of thermosensitive hydrogels in various drug-delivery applications. As local drug-delivery systems, thermoresponsive hydrogels can be used to release drugs locally, for example, directly to tumors or to wounds. Moreover, they can be designed to release drugs over a prolonged or controlled period of time, allowing the administration of the drug less frequently. Thermosensitive hydrogels can also be combined with phototherapy to enhance the therapeutic effect of a drug. A characteristic example is the preparation of hydrogel loaded with photosensitizers for skin cancer treatment [2]. Overall, such applications can offer a breeding ground for the treatment of several diseases, including cancer, cardiovascular and nervous disorders, or infections.

According to the recent literature, thermoresponsive hydrogels are of paramount importance for the scientific community. Zhang et al. (2019) presented the recent applications of thermoresponsive hydrogel actuators in terms of their chemistry and physicochemical properties, as well as their capability to change their morphological characteristics as a response to environmental stimuli [8]. Special attention to their industrial applications is also given. The usage of thermoresponsive biopolymeric materials for the design and development of thermoresponsive hydrogels is also analyzed in detail. Their application in the traditional pharmacotherapy of China for the transdermal administration of bioactive substances is also presented, presenting another important usage of these biocompatible materials [9]. Another important review manuscript in this field presented the applications of thermogels (this terminology is used by the authors for the thermoresponsive hydrogels) in tissue engineering and three-dimensional cell culture, except for drug-delivery and targeting [10].

Taking into account the recent progress of the scientific community in the area of thermoresponsive hydrogels, the aim of this chapter is to emphasize their preparation protocols, mechanical properties, and applications in the fields of drug delivery. To the best of the author’s knowledge, this is the first report in the literature where the thermoresponive hydrogels are presented in terms of their applications in specific diseases, i.e., cardiovascular, nervous, and psychiatric disorders.

2. Thermoresponsive hydrogels: literature review

In recent years, thermosensitive hydrogels have been extensively studied, as drug-delivery systems. Their main fields of application are cancer treatment, cardiovascular diseases, psychiatric and neurological disorders, inflammatory diseases, allergies as well as musculoskeletal disorders. For this purpose, efforts have been made to create systems, which are assessed based on specific parameters (Figure 5) that improve the bioavailability, release rate, or residence time of the active substances in the body.

Figure 5.

The critical parameters affecting the drug release mechanism from hydrogels (adapted from [27]).

2.1 Cancer and neoplasm disorders

In 2021, Yang et al. [11] investigated the co-delivery of the chemotherapeutic agent cyclophosphamide (CTX), the adjuvant cytosine-phosphate-guanine oligonucleotide (CpGODN), and tumor lysates (TL) in PLEL [poly (D, L-lactide)-poly (ethylene glycol)-poly (D, L-lactide) (PDLLA-PEG-PDLLA, PLEL)] triblock copolymer, to create a cancer vaccine for immunotherapy of solid tumors. After administration in mice, the hydrogel cancer vaccine was able to cause immunogenic cell death (ICD) and to show a better therapeutic effect compared to free CTX, CpG, and TL. The use of PLEL, as a delivery system had as a result a slow and sustained release of substances and the reduction of degradation and inactivation. Specifically, more than 80% of CTX was released on the third day after administration, while no obvious damage was observed in other organs. This combined strategy produced the cytotoxic T-lymphocyte response to effectively inhibit tumor growth and prolonged survival, and significantly improved the tumor cure rate and reduced toxicity of CTX in mice, compared to the free drug. Long-lasting immune memory response was also noticed. These data demonstrated that CpG-TL-PLEL cancer vaccine is possibly suitable for clinical use.

PLEL was also used by Chen et al. [12] to create a biodegradable thermosensitive hydrogel for the co-administration of 5-fluorouracil (5-FU) and cis-platinum (DDP). This formulation was used as intraoperative synergistic combination chemotherapy for gastric cancer. The results showed that 5-Fu-DDP hydrogel compared to free drugs excelled, due to the prolongation of local drug retention, improvement of anti-tumor effect, and reduction of adverse side effects. 5-FU and DDP were encapsulated in PLEL, and PLEL showed self-assembling properties into core-shell-like micelles in water because of its amphipathic characteristics. 5-FU-DDP-PLEL hydrogel demonstrated sol-gel transition at the temperature of 37°C, while at 25°C, the formulation was fluid, allowing administration via injection. 5-FU and DDP were released from the hydrogel following a biphasic pattern: a burst release occurred on the first day and a sustained release over the days following (around 28 days). After administration in mice, the formulation was characterized by low systemic toxicity and improved antitumor effect by prolonging overall survival time and inhibiting the growth and number of metastatic tumors.

Luo Y and his partners [13] used p(NIPAAm-co-AAc)-g-F68 [poly (Niso-propylacrylamide-co-acrylic acid)-g-F68 nanogel] nano-hydrogel as a drug-delivery system for triptolide (TPL), for the anti-breast cancer enhancement through localized treatment based on “two strikes” effects. Nano-hydrogel showed at 25°C an eversion of the transparent solution into an opaque solution and then into a gel at 35°C. After administration via intra-tumor injection, the low viscosity of the thermosensitive gel led to long retention of the drug in the tumor tissue with ideal rheological properties. In body temperature, the formation of a polymer layer was denser on the surface of micelles, inhibiting the diffusion of TPL from micelles. TPL was released from nanogel in a slow and sustained manner over 14 days. The use of nanogel for the administration of TPL resulted in an increase in the survival rate and reduction of side effects compared to free TPL due to long-term and local delivery of the drug in vivo.

According to Ghorbani et al. [14], methylcellulose-sodium humate hydrogel was used to create an injectable light-assisted thermoresponsive hydrogel for photothermal ablation and localized delivery of the chemotherapeutic drug cisplatin, for the treatment of osteosarcoma. When sodium humate was exposed to laser light, it resulted in a temperature increase which led to gelation of methylcellulose. Thermoresponsive gelation occurred in a temperature range of 30–60°C. Higher concentrations of light absorbance and laser light emission displayed greater storage modulus, possibly because of the higher viscosity of the hydrogels. The release of cisplatin from the hydrogel followed a non-Fickian mechanism with predominant contribution of erosion under the simulation conditions. Toxicity and biocompatibility of the formulation were examined in osteosarcoma cell lines, and the results suggested that there was not considerable toxicity with the use of cisplatin-free polymer, while mild toxicity was detected in cisplatin-loaded hydrogel, which is possibly a result of chemotherapeutic effect of cisplatin. The use of methylcellulose-sodium humate hydrogel in vivo and in vitro improved control over the release of cisplatin and led to a better toxicity profile because of the local delivery. Results also indicated effective inhibition of tumor growth and prolongation of survival time in the mice and a possible synergistic effect between laser emission and cisplatin.

Another thermosensitive hydrogel that has wide use is Pluronic F127 [poly (ethylene oxide)/poly (propylene oxide)/poly (ethylene oxide)]. In 2021, Norouzi et al. [15] examined salinomycin-loaded injectable Pluronic F127 hydrogel, against glioblastoma multiforme (GBM). Based on the study, salinomycin alone (intraperitoneal injection) did not reduce tumor growth, while the pluronic-salinomycin treatment had a dramatic inhibitory impact on it. This effect was a result of sustained local release of salinomycin, which led to enhanced exposure of the drug within the tumor site. Another advantage was the overcoming of the blood brain barrier (BBB) limitations for effective drug delivery into the brain. The prepared hydrogel turned into a gel at a temperature above 10°C. At concentrations above the critical micellar concentration (4 × 10⁻³ g/mL), an increase in temperature led the copolymer molecules to aggregate into micelles, resulting in dehydration of the hydrophobic blocks and so in gelation. In vitro tests indicated that pluronic hydrogel was totally degraded within two weeks, and so encapsulated salinomycin was also released within the same period. Drug release kinetics followed both Fickian diffusion and polymer chain relaxation. Cytotoxicity of the drug-loaded hydrogel was also examined and showed that hydrogel was more effective than free salinomycin to generate apoptosis and intracellular reactive oxygen species (ROS), which could be attributed to the improved drug’s bioavailability and modified micro-viscosity of the plasma membrane.

Treatment of glioblastoma multiforme (GBM) was also the subject of investigation of Lu YJ and his colleagues [16]. Investigators used chitosan-g-poly(N-isopropylacrylamide) (CPN) hydrogel for the co-delivery of irinotecan (CPT-11), cetoximab (CET)-conjugated GO (graphene oxide) and stomatin-like protein 2 (SLP2) short hairpin RNA. Results showed that the use of the hydrogel enhanced in vitro antitumor efficacy, minimized adverse events, and increased cancer selectivity due to localized and sustained release. CPN-GO-CET-CPT11-SLP2 shRNA was prepared by mixing GO-CET-CPT11 and shRNA with the thermosensitive CPN hydrogel. Hydrogel’s sol–gel transition started at 29.6°C. Encapsulating GO-CET-CPT11 and shRNA in CPN retained the thermoresponsive characteristics of CPN and improved the mechanical properties of CPN-GO-CET-CPT11-shRNA because of electrostatic interaction between the positively charged CPN and the negatively charged GO-CET-CPT11 and shRNA. As for the release of pharmaceutical ingredients, at 37°C, CPT-11 was released from CPN in a sustained way for up to 28 days. After CPN degradation and the shedding of GO-CET-CPT11, a high amount of CPT-11 was released from GO-CET-CPT11 in the acid endosomal environment of cancer cells due to improved drug release at pH 5. For shRNA, a burst release was observed for 7 days followed by sustained release up to 28 days. The use of CET, an EGFR antibody, as a ligand also led to higher intracellular uptake of GO-CET. The hydrogel was administered in mice, and no toxicity was observed. Complete degradation occurred after 3 weeks.

In 2020, Yang et al. [17] prepared the PLGA-PEG-PLGA [poly(D, L-lactide co glycolide)-poly(ethylene glycol) poly(D,L-lactide-co-glycolide)] hydrogel as a drug-delivery system for doxorubicin (DOX) and curcumin (CUR). DOX and CUR were encapsulated within a cyclodextrin inclusion complex (CD-DOX-CUR) to improve their solubility and stability and then co-loaded into the hydrogel system, to create a possible localized treatment for osteosarcoma. Co-loading DOX and CD-CUR into hydrogel improved the cytotoxicity efficiency and promoted the pro-apoptotic effect of DOX compared with single drug treatment. In vivo, the hydrogel exhibited a stronger antitumor effect compared with free drugs. Hydrogel offered good systemic safety and local-sustained drug release. The prepared hydrogel flowed freely at room temperature and formed a stable gel rapidly with rising temperatures. At 37°C, DOX-CD-CUR hydrogel obtained gel formation. CUR and DOX were released from the formulation in a sustained manner for 13 days. During toxicity tests, neither histological changes were observed in all treated groups compared with the control groups nor weight loss.

2.2 Cardiovascular disorders

Wang CY and his partners [18] investigated the use of chitosan-gelatin-based hydrogel as a delivery system for ferulic acid (FA), an antioxidant compound, for the treatment of peripheral arterial disease. Results from the study suggested that in vitro FA-gel reduced oxidative stress-mediated damage through decreasing endogenous ROS production, inflammation-related gene expression, and apoptosis level. In vivo, FA-gel could improve blood flow, inflammation level, and fibrotic areas. The prepared hydrogel showed porous microstructure, which allowed small molecules diffusion and release. Specifically, FA was released from the hydrogel in a sustained way for 28 days. Sustained release could lead to a reduction of fibrotic areas of muscle that may be associated with the improvement of blood flow. Hydrogel’s thermosensitive properties included a gelation temperature of 33.56°C and a gelation time of 64.75 s (at 37°C). The addition of gelatin into the chitosan-based hydrogel significantly shortened the gelation time and increased the gel strength without loss of biocompatibility. Toxicity test showed that the prepared hydrogel was safe for in vivo use.

2.3 Infections

For the treatment of bacterial infections, Zhang S and his colleagues [19], investigated the use of bacterial cellulose nanowhiskers poly(N-isopropyl acrylamide) hydrogel (bacterial cellulose nano whiskers (BCNW)-PNI hybrid nanogel) to create a nanogel for drug delivery. The therapeutic factor was the carbon nanosheets doped with copper ions (Cu-SA), which were demonstrating peroxidase-mimicking catalytic activity and GHS-depletion-mimicking activity. This alternative antimicrobial treatment indicated a novel strategy for antibacterial therapy against compatible antibiotics, the use of which is related to drug resistance, high cost, and biotoxicity. More specifically, the hydrogel was characterized by a phase transition temperature of 33°C. At room temperature, Cu-SA-BCNW-PNI hybrid nanogel acted as a flowable solution, whereas at body temperature, it quickly turned into a gel. The concentration of PNI affected the thermosensitivity, while the addition of BCNW in the formulation resulted in higher water retention and preservation of its shape. The nanogel showed good stability against enzymatic degradation, because of the excellent mechanical properties of bacterial cellulose. Toxicity tests proved that the formulation exhibited blood coagulation ability, which is favored in wound disinfection treatment, hemocompatibility, and biocompatibility. The amount of Cu-SA that was released from the nanogel was high, and it could deactivate bacteria completely after 3 h of cultivation. The antibacterial efficacy was also enhanced due to the extension of catalytic time due to the nanogel’s formulation.

In 2020, Pastor et al. [20] combined Gantrez® poly(methylvinylether co-maleic anhydride) (GZ) with Pluronic® F127 (PF127) polymer to create a delivery system for the intranasal administration of the antigen complex that was obtained from S. flexneri ΔtolR mutant strain (HT-ΔtolR antigens). This system could provide active immunization against microorganisms, and the use of hydrogel could increase the residence of the antigens in nasal epithelium and generate a robust immune response. Due to its formation, hydrogel protected the biomolecules from enzyme degradation and eliminated adverse effects. The hydrogel was characterized by a rapid gel formation at body temperature (37°C) and pH of 2–4.5. HT-ΔtolR antigens released rapidly from the matrix for 30 minutes, and afterward, the release rate was decreased. The release was prolonged compared to free-antigen administration. Toxicity tests showed the absence of nose epithelium morphological histopathological features, and there was neither inflammatory infiltrate in the nasal epithelium nor necrosis and apoptosis signs.

2.4 Inflammatory disorders and allergies

Another intranasal delivery system was created by Schilling and his partners [21]. Investigators synthesized poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in a poly(N-isopropylacrylamide) (p-NIPAAm)-based hydrogel, referred to as TEMPS (Thermo-gel, Extended-release Microsphere-based-delivery to the Paranasal Sinuses). TEMPS were used as a nonbiodegradable polymer matrix for mometasone furoate, a corticosteroid, for the treatment of chronic rhinosinusitis (CRS). TEMPS provided a sustained, local release of mometasone for up to 4 weeks, allowing the application of the treatment once per month. After the 4-week period, the system should be removed. Studies on a CRS rabbit model showed that the inflammation of the submucosal glands was reduced in the mometasone-loaded-TEMPS-treatment group compared to the blank-vehicle-TEMPS one. The intraocular pressure (IOP) was monitored, and the subjects treated with sustained, local steroids from m-TEMPS did not show elevated pressures. The sol-gel transition temperature of PEG-pNIPAAm was 35°C, allowing application as a liquid at room temperature and conforming in the sinonasal epithelium as it gelled. According to the investigators, although the TEMPS formulation was a promising therapy for clinical use, future studies must be conducted focusing on improving the robustness of disease induction, increasing sample sizes, and applying TEMPS to the sinus epithelia in rabbits transnasally to represent the potential clinical efficacy more properly.

Kolliphor® 188 (K188) and Pluronic ® F127 (P127) were combined by Yurtdaş-Kırımlıoğlu G [22] to form an intranasal system for delivery of desloratadine (DSL), an anti-allergic agent. The formulation was used against nasal allergies, and the use of the thermosensitive matrix enhanced the bioavailability of DSL by preventing mucociliary clearance and by increasing the ability of solubilization and dissolution rate while maintaining sufficient plasma levels for DSL. Several formulations with different proportions of DSL-K188-P127 were prepared. The formulations presented quick gelling at 31–33°C, which was ideal for administration in the nasal cavity, and gel maintainability with pseudoplastic flow pattern. The release of the drug from in situ gel systems started with a burst effect followed by a delayed release rate because of the gelation. In vitro release from the formulations followed the Peppas-Sahlin model. The dissolution rate of DSL in formulations was remarkably higher than the one of pure DSL due to several reasons including the reduced size, the increased surface area, the decreasing drug crystallinity, the formation of high energetic amorphous and fine dispersions, and the increased drug solubilization by the hydrophilic carriers. Investigators concluded that DSL-K188-P127 could possibly be a preferable alternative to conventional therapies against nasal allergies, though more animal studies are needed.

In 2021, Chen et al. [23] investigated the delivery of simvastatin (SIM), a 3-hydroxy-3-methylglutaryl-cosenzyme A reductase inhibitor, in Pluronic F127-pyrophosphate hydrogel (F127-PPi). The drug-delivery system was used for the treatment of periodontitis in rat models because of the simvastatin’s anti-inflammatory effect and new bone formation capacity. F127 hydrogel was organized in sheet-like structures, while SIM-loaded PF127 hydrogel exhibited network-like structures with large porosity. SIM-loaded PF127 was in liquid phase at 10°C and transitioned into a gel at 20°C. The biocompatibility of SIM-loaded PF127 hydrogel was assessed on MC3T3-L1 and Raw 264.7 cells using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay, and there was a slight reduction in viability after 24 h and 48 h (above 80%). Histological analysis confirmed the anti-inflammatory effect and the remarkable bone preservation effect of SIM-loaded PF127 in the region of use. SIM was released from the hydrogel sustainably. Higher polymer concentration led to a slower SIM release. Based on the study, the thermoresponsive hydrogel system could effectively encapsulate SIM and demonstrate strong osteotropicity and excellent biocompatibility. SIM-PF127 seemed to effectively preserve the periodontal bone and reduce inflammation. For this reason, SIM-F127-PPi could be a promising treatment for clinical use, as until now, the usual handling has included a surgical procedure for debridement of bony defect and establishment of a microenvironment for bone regeneration.

2.5 Nervous and psychiatric disorders

Ribeiro et al. [24] studied the nasal delivery of curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) in thermosensitive hydrogel based on Poloxamer 407 (18%) and chitosan (1%), for Alzheimer’s disease. The prepared hydrogel was characterized by viscoelastic properties, allowing easy administration. Sol-gel transition occurred at 23°C. The highest values of hardness, compressibility, cohesion, and adhesiveness were observed at 32°C, which indicated that the hydrogel had excellent mechanical properties for use at body temperature. Chitosan was characterized by good mucoadhesive properties because of its positively charged amino groups which interact with negatively charged sialic acid residues in the mucin layer. Poloxamer 407 mucoadhesion was related to covalent bonds with mucin. Polymer-MSN formulation increased the drug’s solubility, and bioavailability, and protected curcumin from degradation. Free curcumin was characterized by water insolubility, extensive metabolization, low bioavailability, and instability in the biological environment. The release of the drug was controlled, and it could be administered via the nasal route, which led to higher absorption. In vitro tests showed that MSN-CCM did not present cytotoxicity. The hydrogel (HG) formulations (HG, HG-MSNs, and HG-MSN-CCM) showed slight cytotoxicity (degree of cytotoxicity 1 ISO 10993-5:2009), whereas in vitro cytotoxicity studies using human nasal epithelial cells indicated polymer’s biosafety.

Verekar RR and his colleagues [25] used a formulation of 17% w/v Pluronic® F127, 2% w/v Pluronic F68®, and 0.1% w/v carboxymethyl chitosan to create a thermosensitive mucoadhesive in situ gel for intranasal delivery of almotriptan malate (AM), a serotonin 5-HT(1B/1D) receptor agonist. The formulation could be used as a treatment for migraine. Results from the study indicated that hydrogel improved the nasal residence time and bioavailability of AM, contrary to common AM nasal sprays. The prepared formulation acted as a gel in the nasal mucosa and as a liquid at room temperature. The gel transition time was 57 s. Gel strength was 95 s and was influenced by concentrations of PF68 and carboxymethyl chitosan. The hydrogel showed pseudoplastic rheological characteristics and low viscosity before application in the nasal cavity and retention to the area after use. Specifically, the polymer chain penetrated the mucin network and created adhesive bonds due to the rapid fluid uptake from the mucus layer. Such an effect led to prolonged retention and increased absorption of the formulation system across mucosal tissue. The release of AM from the matrix started with a burst release within the first 30 minutes, followed by a sustained release throughout 6 h. Drug release was controlled by the diffusion rate and the relaxation rate of the pluronic polymer matrix. The release pattern is appropriate for the treatment of migraine because of the rapid onset of action for the management of acute migraine pain followed by sustained release for the maintenance of the loading dose. Moreover, the use of this hydrogel led to the minimization of adverse events, such as nausea and vomiting, caused during oral administration. Further studies showed the absence of toxicity and damage of epithelial cells of sheep nasal mucosa.

2.6 Musculoskeletal disorders

In 2022, Cheng et al. [26] developed the thermosensitive copolymer mPEG-PA-PLL [methoxy poly(ethylene glycol)-poly(L-alanine)-poly(L-lysine)] to encapsulate calcitonin. Calcitonin is a 32-amino-acid peptide produced by the thyroid and is used as a treatment for Paget’s disease of bone, high levels of calcium in the blood (hypercalcemia), and osteoporosis in postmenopausal women. According to the study, calcitonin, which was encapsulated in the hydrogel, could be administered orally as the copolymer protected the pharmaceutical substance from degradation and improved absorption. Investigators prepared two different PLL chain lengths for the copolymer: mPEG-PA-PLL10 and mPEG-PA-PLL20. The prepared mPEG-PA-PIL copolymer was characterized by a higher gel transition temperature compared to mPEG-PA. Moreover, the addition of the PPL group improved the adherence of the polymer to gastrointestinal (GI) mucus, a gel-like barrier rich in negative charge on its surface, due to its electronic effect. The degradation of hydrogel was slow because of the charge interaction with enzymes and its complicated 3D structure. Encapsulation of calcitonin was above 96%. Calcitonin showed sustained release from the hydrogels within 24 h, which was also pH-dependent. Release from mPEG-PA-PLL10 was slower than mPEG-PA-PLL20. This characteristic indicated that the formulation could achieve better bioavailability. Toxicity tests proved that the copolymer could possibly be used for oral administration, as no toxic effect was noticed, improving, in this way, the compliance of the patients to the treatment.

Yang R and his partners [1], combined modified Poloxamer 407 and hyaluronic acid (PHA hydrogel) to create a matrix for the delivery of keratinocyte growth factor 2 (KGF-2) to improve knee osteoarthritis (OA) in rats. The investigators prepared three different hydrogels consisting of different concentrations of P407. Results from the study indicated that the injection of KGF-2 had a positive therapeutic effect on OA. Moreover, PHA-KGF-2 compared to KGF-2 alone improved the morphology and inflammation of the articular cartilage, reduced the loss of proteoglycan, and balanced collagen metabolism, partially because of the protection and sustained release of KGF-2. PHA hydrogel also had a beneficial effect on collagen metabolism, reducing the expression of matrix metalloproteinase 9 and 13 (MMP-9, MMP 13) and increasing the secretion of plasminogen activator inhibitor 1 (PAI-1) and tissue inhibitor of metalloproteinases 1 (TIMP-1). The hydrogels showed ideal thermosensitive properties. The phase transition temperatures of the 14.5% (w/w), 15% (w/w), and 15.5% (w/w) P407 formulations were 33.0°C, 30.3°C, and 30.6°C, respectively. At 4°C, the PHA was liquid, and, after injecting in the human body, it quickly formed a hydrogel. The use of PHA improved the stability of KGF-2 significantly compared with the HA or P407 alone. PHA hydrogels loaded with KGF-2 (PHA-KGF-2) dissolved into the phosphate-buffered saline (PBS) very slowly, and KGF-2 was released in a sustained way. Toxicity tests in rabbit blood showed that the hemolysis rates were significantly lower for PHA formulations than the standard threshold of 5% hemolysis required for blood-contact materials, which indicates that PHA had good blood compatibility. The osmotic pressures of PHA formulations met the osmotic pressure requirements for in vivo injection, and in vivo studies in rats showed that 15% (w/w) PHA injection to the knee joints did not cause swelling nor other abnormalities or inflammatory response. According to the investigators, this formulation could be the first disease-modifying treatment as there is no other medication available on the market.

2.7 Release kinetics from thermoresponsive hydrogels

Extensive research has been conducted on thermoresponsive hydrogels aiming at the development of intelligent drug carriers and achieving controlled drug release [28]. Comprehending the kinetics of drug release and the associated transport mechanisms of nanoparticles, within a hydrogel network that is responsive to temperature, is crucial for the efficacious development of intelligent drug-delivery systems.

In a study, poloxamines were modified appropriately for controlling the discharge of bevacizumab [29]. The hydrogel mechanical properties and stability were adjusted by varying the ratios of the four-armed and eight-armed macromonomers. The stability of hydrogels was effectively regulated within a span of 14 to 329 days, demonstrating the attainment of controlled release of the model antibody bevacizumab within the timeframes of 7, 21, and 115 days [29]. The objective of a similar study was to assess the effectiveness of a thermoresponsive hydrogel drug-delivery system containing poly(ethylene glycol) diacrylate and poly(N-isopropylacrylamide) in administering prophylactic vancomycin subsequent to ocular surgery [30]. Vancomycin was enclosed within a hydrogel drug-delivery system and assessed for its kinetics and pharmacological activity. This novel delivery system demonstrated significantly superior infection scores compared to the control groups, implying its potential as a means of administering prophylactic antibiotics for a brief duration.

Gajic et al. investigated the potential of p(NIPAM-co-AA) (poly(N-isopropylacrylamide-co-acrylic acid)) as a carrier for the controlled release of biochanin A, an isoflavone known for its estrogenic and other pharmacological properties [31]. This study showed the swelling behavior of p(NIPAM-co-AA) copolymer as a function of the temperature and pH values of the surrounding medium. The release of biochanin A, from the hydrogel, was observed to be comparatively faster at pH 7.9 as opposed to pH 4.5. Approximately half of the biochanin A that was integrated into the lyophilized hydrogel was discharged under conditions of pH 7.9 and a temperature of 37°C within the first 6 h. The study of Dahan et al. investigated the kinetics of release from hydrogels that exhibit thermoresponsive behavior [32]. This study was conducted to investigate chitosan-amide-modified stimuli-responsive polymers that carry insulin. After synthesizing and characterizing several fatty acid amides with varying degrees of unsaturation, a comparison was made between the loading and release effects of insulin drugs in NIPAm. Also, the mechanisms of drug release were investigated by employing several distinct pharmacokinetic models (e.g., zero-order and Korsmeyer–Peppas). It was shown that NIPAm and AMPS matrices effectively facilitated insulin delivery, as evidenced by the validity of the Higuchi and Hixson models [32].

A recent study focused on the creation of a durable, injectable, and 3D printable hydrogel network utilizing cellulose nanocrystals and amphiphilic copolymers, such as PCLA [33]. It was demonstrated that the utilization of biodegradable hydrogels in copolymers results in adjustable extended-release profiles with distinct release kinetics for both hydrophobic and hydrophilic biologics. In the same context, another study analyzed the efficacy of injectable thermoresponsive hydrogel compositions that form in situ for the controlled release of protein therapeutics, with the aim of enhancing patient comfort, convenience, and adherence [34].

3. Conclusion

Thermosensitive hydrogels are smart materials that have the ability to respond to heat stimuli. Τhermoresponsive hydrogels have grown in importance as a field of study in the biomedical sciences [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27]. In this review, the latest advances, related to the use of these systems, as drug-delivery carriers, have been summarized, and their unique advantages are highlighted. Thermoresponsive hydrogels are biocompatible, have low toxicity, and exhibit good swelling properties. They can protect sensitive active substances from degradation and inactivation, after entering the body, and they allow the administration of highly toxic therapeutic agents locally. Local drug delivery has been proven to be of high importance, especially in the treatment of cancer, as it can help to substantially minimize the serious systemic adverse events that are often associated with chemotherapeutics. Moreover, the encapsulation of an active substance in the hydrogel matrix could modify the residence time or the release rate, according to the disease’s specific characteristics.

Additionally, a total number of 17 literature reports, which have been published in the last 5 years and concern the application of thermoresponsible hydrogels in specific therapeutic areas, were selected and included in this review. As revealed from the review of the reports, six therapeutic categories have received the most attention, with the category of cancer and neoplasm disorders being the most significant (Figure 6). However, it is important to be noted that these innovative treatments, need to be applied at a clinical level in order to gain more information about their safety and efficacy.

Figure 6.

Percentage of reports included in this review for each therapeutic category.

Conflict of interest

The authors declare no conflict of interest.

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