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Herein, thermosensitive blends of poloxamer 407 (P407)/poloxamer 188 (P188)/polycarbophil (PCB) were developed in terms of maximized content of PCB (a mucoadhesive polymer) and desired temperature-dependent rheological properties of the blends as in situ gelling matrices. Maximizing PCB content while achieving the preferable rheological characteristics was accomplished through the Box–Behnken design. The quantitative effect of the polymer composition in the blends on the thermosensitive characteristics was evaluated using the fitted design model and the corresponding surface plots. The optimized P407/P188/PCB blend (OPT) was the mixture of 20.000, 7.349 and 0.595% (w/w) of P407, P188, and PCB, respectively. The thermosensitive micellization of OPT was investigated using differential scanning calorimetry which revealed an overlapping double endothermic peak caused by the temperature-induced micellization of pure micelles in co-existence with the micelles with attached PCB. Mixing PCB with the P407/P188 matrix promoted a more intense mucoadhesion of the blend. After incorporating metronidazole, a model hydrophilic drug, into OPT, the temperature-dependent characteristics of the hydrogel did not change. Metronidazole release from OPT was sustained by an anomalous mechanism. This optimal ternary hydrogel benefiting from thermosensitive gelling and mucoadhesive matrix might be used as a viable platform for mucoadhesive in situ gelling drug delivery.

Thermosensitive hydrogels, having unique sol–gel transition properties, have recently received special research attention. These hydrogels exhibit a phase transition near body temperature. This feature is the key to their applications in human medicine. In addition, hydrogels can quickly gel at the application site with simple temperature stimulation and without additional organic solvents, cross-linking agents, or external equipment, and the loaded drugs can be retained locally to improve the local drug concentration and avoid unexpected toxicity or side effects caused by systemic administration. All of these features have led to thermosensitive hydrogels being some of the most promising and practical drug delivery systems. In this paper, we review thermosensitive hydrogel materials with biomedical application potential, including natural and synthetic materials. We describe their structural characteristics and gelation mechanism and briefly summarize the mechanism of drug release from thermosensitive hydrogels. Our focus in this review was to summarize the application of thermosensitive hydrogels in disease treatment, including the postoperative recurrence of tumors, the delivery of vaccines, the prevention of postoperative adhesions, the treatment of nervous system diseases via nasal brain targeting, wound healing, and osteoarthritis treatment.

Photothermal therapy (PTT) is a fledgling therapeutic strategy for cancer treatment with minimal invasiveness but clinical adoption has been stifled by concerns such as insufficient biodegradability of the PTT agents and lack of an efficient delivery system. Here, black phosphorus (BP) nanosheets are incorporated with a thermosensitive hydrogel [poly(d,l‐lactide)‐poly(ethylene glycol)‐poly(d,l‐lactide) (PDLLA‐PEG‐PDLLA: PLEL)] to produce a new PTT system for postoperative treatment of cancer. The BP@PLEL hydrogel exhibits excellent near infrared (NIR) photothermal performance and a rapid NIR‐induced sol–gel transition as well as good biodegradability and biocompatibility in vitro and in vivo. Based on these merits, an in vivo PTT postoperative treatment strategy is established. Under NIR irradiation, the sprayed BP@PLEL hydrogel enables rapid gelation forming a gelled membrane on wounds and offers high PTT efficacy to eliminate residual tumor tissues after tumor removal surgery. Furthermore, the good photothermal antibacterial performance prevents infection and this efficient and biodegradable PTT system is very promising in postoperative treatment of cancer. A sprayable and biodegradable photothermal therapy (PTT) system composed of a thermosensitive hydrogel incorporated with black phosphorus (BP) nanosheets is presented for post‐surgical treatment of cancer. The obtained hydrogel enables rapid gelation and offers high PTT efficacy to eliminate residual tumor after surgery. This efficient and biodegradable PTT system is very promising in the postoperative treatment of cancer.

Chitin-derived hydrogels are commonly used in bone regeneration because of their high cell compatibility; however, their poor mechanical properties and little knowledge of the interaction between the materials and host cells have limited their practical application. To evaluate osteoinductivity and enhance the mechanical properties of a newly synthesized thermosensitive hydroxypropyl chitin hydrogel (HPCH), a mesenchymal stem cell (MSC)-encapsulated HPCH was infused into a three-dimensional-printed poly (ε-caprolactone) (PCL)/ nano-hydroxyapatite (nHA) scaffold to form a hybrid scaffold. The mechanical properties and cell compatibility of the scaffold were tested. The interaction between macrophages and scaffold for angiogenesis and osteogenesis were explored and . The hybrid scaffold showed improved mechanical properties and high cell viability. When MSCs were encapsulated in HPCH, osteo-differentiation was promoted properly via endochondral ossification. The co-culture experiments showed that the hybrid scaffold facilitated growth factor secretion from macrophages, thus promoting vascularization and osteoinduction. The Transwell culture proved that MSCs modulated the inflammatory response of HPCH. Additionally, subcutaneous implantation of MSC-encapsulated HPCH confirmed M2 activation. evaluation of calvarial defects confirmed that the repair was optimal in the MSC-loaded HPCH + PCL/nHA group. PCL/nHA + HPCH hybrid scaffolds effectively promoted vascularization and osteoinduction via osteogenesis promotion and immunomodulation, which suggests promising applications for bone regeneration.

Intra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug administration. The objective of this work is to prepare injectable thermosensitive hydrogels for the long-term application of dexamethasone. The hydrogels were prepared by mixing chitosan (CS) and Pluronic-F127 (PF) physically. In addition, tripolyphosphate (TPP) was used as a crosslinking agent. Chitosan added to the mix increased the gel time compared to the pluronic gel alone. The incorporation of TPP into the material modified the morphology of the hydrogels formed. Subsequently, MTS and Live/Dead® experiments were performed to investigate the toxicity of hydrogels against human chondrocytes. The in vitro releases of dexamethasone (DMT) from CS-PF and CS-PF-TPP gels had an initial burst and took more time than that from the PF hydrogel. In vivo studies showed that hydrogels retained the fluorescent compound longer in the joint than when administered in PBS alone. These results suggest that the CS-PF and CS-PF-TPP hydrogels loaded with DMT could be a promising drug delivery platform for the treatment of osteoarthritis.

The scientific community has widely recognized thermosensitive hydrogels as highly biocompatible material with immense potential in drug delivery systems. When the temperature of these hydrogels approaches that of human body, a phase change occurs, enhancing their usefulness in a range of medical scenarios. This review article highlighted the background of thermosensitive hydrogels, their properties, and their applications in transdermal, oral, ophthalmic, intravaginal, nasal, rectal, cancer therapy, and cell‐loaded drug delivery systems. The literature suggests numerous advantages of these hydrogels over conventional drug delivery systems and find applications in various fields, such as therapeutic systems, filling processes, and sustained drug delivery systems. One of their key benefits is the ability to eliminate invasive procedures like surgery, providing a noninvasive alternative for drug administration. Moreover, they streamline the formulation process for both hydrophilic and hydrophobic drug delivery systems, simplifying the development of effective treatments. The thermosensitive hydrogels have been found to be green materials with negligible side effects and desirable drug delivery properties. The thermosensitive hydrogel's sustained‐release characteristics, immunogenicity, and biodegradability have also gained increased interest. Some of the disadvantages of thermosensitive hydrogels include delayed temperature response, weak mechanical characteristics, and poor biocompatibility, which limits their potential use in drug delivery applications.

In recent years, thermosensitive polysaccharide-based injectable hydrogels have gained increasing attention in biomedical applications, including wound healing, drug delivery, and cartilage repair. These hydrogels have favorable biocompatibility, biodegradability, and tunable physical and chemical properties. Thermosensitive polysaccharide-based injectable hydrogels are a class of intelligent soft matter material. They can undergo a reversible liquid-solid transition when exposed to temperature stimuli. Therefore, their precursor solutions can be accurately inserted into target sites with irregular geometries in a minimally invasive way and then transformed into gels in situ by the organism’s temperature stimulation to deliver biologically active molecules. This review summarizes the recent developments of thermosensitive injectable polysaccharide-based hydrogels. The focus is on the mechanism of sol-gel phase transition, as well as the design and preparation of thermosensitive polysaccharides and their applications in biomedical fields. In addition, the outlook of the challenges in biomedical applications is provided at the end of the paper.

This work describes the development of an injectable nanocomposite system based on a chitosan thermosensitive hydrogel combined with liposomes for regenerative medicine applications. Liposomes with good physicochemical properties are prepared and embedded within the chitosan network. The resulting nanocomposite hydrogel is able to provide a controlled release of the content from liposomes, which are able to interact with cells and be internalized. The cellular uptake is enhanced by the presence of a chitosan coating, and cells incubated with liposomes embedded within thermosensitive hydrogels displayed a higher cell uptake compared to cells incubated with liposomes alone. Furthermore, the gelation temperature of the system resulted to be equal to 32.6 °C; thus, the system can be easily injected in the target site to form a hydrogel at physiological temperature. Given the peculiar performance of the selected systems, the resulting thermosensitive hydrogels are a versatile platform and display potential applications as controlled delivery systems of liposomes for tissue regeneration.

Thermosensitive hydrogels undergo reversible sol-gel phase transitions in response to changes in temperature. Owing to their excellent biocompatibility, mild reaction conditions, and controllable gelation properties, these hydrogels represent a promising class of biomaterials suitable for minimally invasive treatment systems in diverse biomedical applications. This review systematically summarizes the gelation mechanisms of thermosensitive hydrogels and optimization strategies to enhance their performance for broader application requirements. In particular, we highlight recent advances in injectable thermosensitive hydrogels as a carrier within stem cells, bioactive substances, and drug delivery for treating various tissue defects and diseases involving bone, cartilage, and other tissues. Furthermore, we propose challenges and directions for the future development of thermosensitive hydrogels. These insights provide new ideas for researchers to explore novel thermosensitive hydrogels for tissue repair and disease treatment.