Thermo-responsive Hydrogel System Research Articles

Photothermally modulated drug release kinetics for pH and thermo-responsive hydrogel system

Photothermally modulated drug release kinetics for pH and thermo-responsive hydrogel system

Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS.

Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.

Ultrasound-controlled release of growth factors from lyophilized platelet-loaded thermoresponsive hydrogel

Platelet-rich plasma (PRP) and hyaluronic acid (HA) injection is commonly used for the treatment of osteoarthritis. However, the immediate bolus release of growth factors from PRP and inability of HA to stay in situ limit their beneficial therapeutic effects. An injectable, biocompatible, and thermoresponsive hydrogel (mPEG-PLGA-BOX block copolymer) is applicable for a long-term ultrasound-triggered lyophilized platelet (LP) release. In this study, an US-controlled release thermoresponsive hydrogel system loaded with LPs was evaluated for its long-term pharmacokinetics in a dry culture chamber at 37 °C. At 0.5 wt% constituent ratio of the LP-loaded hydrogels (0.2 ± 0.6 mV positively charged, which would be suitable for the treatments of negatively charged cartilages), the release amount of growth factors (PDGF-B and TGFβ-1) from the hydrogel could be increased to ∼300-folds in the presence of US (1 MHz, 0.4 W/cm2, 5% duty cycle, 5 min) compared to the amount in the absence of US during the 2 weeks of evaluation period. In comparison to 0.5 wt% of the LP-loaded HA (−2.4 ± 1.1 mV negatively charged), which had only a 5-day release ability, the US-controlled release thermoresponsive hydrogel system may be a more suitable platform for diseases that needed long-term treatments.

A novel Thermo-responsive hydrogel system (THS) loaded with the active ingredient of Gardenia jasminoides J. Ellis exhibits anti-depressant effects in vivo via intranasal administration

A novel Thermo-responsive hydrogel system (THS) loaded with the active ingredient of Gardenia jasminoides J. Ellis exhibits anti-depressant effects in vivo via intranasal administration

Silk Fabric Decorated with Thermo-Sensitive Hydrogel for Sustained Release of Paracetamol.

Paracetamol is a safe and widely used antipyretic and analgesic drug, however, with the drawbacks of gastrointestinal first-pass effect and short intervals of administration. Transdermal drug delivery system can effectively avoid the liver metabolism caused by excess oral ingestion of paracetamol. Herein, a silk fabric-based medical dressing decorated by a thermo-responsive hydrogel for sustained release of paracetamol is proposed. Genipin as a bio-safe cross-linker is applied to assist gelation of a thermo-responsive hydrogel system coupled with chitosan and glycerol-phosphate disodium salt around body temperature (37°C), as well as densifying the microporous gel to improve mechanical strength. The in situ sol-gel transition enabled hydrogel well penetrate and coat the silk fabric, forming a hierarchical hydrogel structure capable of prolonging the sustained release of drug to 12h, twice as long as a blank fabric. The silk fabric with a thin gel coating maintains a good water vapor transmission rate, compatible for skin contact application. The drug release properties can be tuned by regulating the genipin content and fabric braiding structure. The silk fabric dressing exhibits temperature-dependent instant release behavior within the first 2h. The sustained release mechanism of paracetamol well matches with the Korsmeyer-Peppas model in a non-Fickian diffusion.

Precise control over tunable translucency and hysteresis of thermo-responsive hydrogel for customized smart windows

In view of global warming and following fossil energy consumption caused by the using of heavy-loaded air conditioners, smart windows, which can intelligently regulate solar radiation, became a highly anticipated strategy to slow down the pressure. As most of the traditional hydrogel-based smart windows abruptly switch between transparent and opaque making a sudden change in temperature and light, we established a poly-N-isopropylacrylamide (PNIPAM) thermo-responsive hydrogel system with additional cross-linking of chitosan and Al3+, which exhibited a smooth thermo-response during heating and a novel recovery hysteresis during cooling. By enabling additional gentle transition in translucency, we are able to retain a comfortable indoor temperature/lightness balance during an increase in outdoor temperature, in avoidance of sudden indoor darkness at elevated temperature. By enabling additional control in the thermo-response hysteresis, this methodology provides a solution to continuously shield the dazzling afternoon sunshine until a comfortable outdoor temperature is reached. And the response degree and response temperature can be adjusted by the contents of chitosan and Al3+, respectively, so that the material can be customized personally. Moreover, we discovered that the hydrogel-based smart window system constructed by this methodology bears notably enhanced strength, toughness and conductivity, making it a comprehensively promising candidate for customizable smart windows.

Cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner

Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity, their development is hindered by the limitations of neoantigens identification, low immunogenicity, and weak immune response. Cyclophosphamide (CTX) not only directly kills tumors but also causes immunogenic cell death, providing a promising source of antigens for cancer vaccines. Herein, a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed. First, CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity, and then 3 days later, PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses. The results confirm that this combined strategy reduces the toxicity of CTX, and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth, prolong survival, and significantly improve the tumor cure rate. Moreover, a long-lasting immune memory response is observed in the mice. About 90% of the cured mice survive for at least 60 days after being re-inoculated with tumors, and the distant tumor growth is also well inhibited. Hence, this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.

A thermoresponsive hydrogel system for long-acting corticosteroid delivery into the paranasal sinuses

Delivering localized treatment to the paranasal sinuses for diseases such as chronic rhinosinusitis (CRS) is particularly challenging because of the small natural openings leading from the sinuses that can be further obstructed by presence of inflammation. As such, oral steroids, topical nasal sprays or irrigation, and surgery can be utilized to treat persistent sinonasal inflammation, but there exists a need for post-operative options for long-term steroid delivery to prevent disease recurrence. In the present study, a Thermogel, Extended-release Microsphere-based-delivery to the Paranasal Sinuses (TEMPS) is developed with the corticosteroid mometasone furoate. Specifically, the bioactive steroid is released for 4 weeks from poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in a poly(N-isopropylacrylamide) (p-NIPAAm)-based hydrogel. The temperature-responsive system undergoes a reversible sol-gel transition at 34–35 °C such that it can be applied as a liquid at ambient temperature, conforming to the sinonasal epithelium as it gels. In a rabbit model of CRS, TEMPS was maintained in rabbit sinuses and effectively reduced sinonasal inflammation as characterized by micro-computed tomography and histopathology analysis. Ultimately, the combination of controlled release microspheres with a thermoresponsive hydrogel provides flexibility for encapsulating therapeutics in a reversible and conforming system for localized delivery to the sinuses.

Decoupled pH- and Thermo-Responsive Injectable Chitosan/PNIPAM Hydrogel via Thiol-Ene Click Chemistry for Potential Applications in Tissue Engineering.

Stimuli-responsive chitosan (CS) hydrogels exhibit great potential for drug delivery and tissue engineering; however, the structure of these stimuli-responsive CS hydrogels, such as dual pH- and thermo-responsive hydrogels, is difficult to control or needs additional crosslinking agents. Here, a new dual pH- and thermo-responsive hydrogel system is developed by combining pH-responsive C6 -OH allyl-modified CS (OAL-CS) with thermo-responsive poly(N-isopropylacrylamide) (PNIPAM). The thiol groups in PNIPAM and the allyl groups in OAL-CS can rapidly form crosslinking hydrogel network by "thiol-ene" click chemistry under UV irradiation. As expected, the swelling ratio of the OAL-CS/PNIPAM hydrogel can be controlled by changing pH and temperature. Moreover, the hydrogel displays non-cytotoxic nature toward human bone marrow mesenchymal stem cells, and the histological analyses reveal the subcutaneous tissue with no signs of inflammation after 5 days of injection in vivo. The results indicate that the new OAL-CS/PNIPAM hydrogel has potential to serve as a smart injectable platform for application in drug delivery and tissue engineering.

Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects.

The efficacy of antidepressant therapy is frequently limited by challenges related to the potential to reach the brain. The development of new strategies to deliver more antidepressants to the brain so as to bypass the blood-brain barrier (BBB) is beneficial for the treatment of nervous system diseases, especially depression. Here, we have reported an unconventional strategy by the intranasal delivery of berberine with an in situ thermoresponsive hydrogel as the holder in the nasal cavity to improve its antidepressant-like activity. A berberine/hydroxylpropyl-β-cyclodextrin (HP-β-CD) inclusion complex was first prepared to improve the solubility of berberine and loaded into a thermoresponsive hydrogel system of poloxamers. A radioactive tracer of 125I-labeled berberine was used to investigate brain targeting. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to study the pharmacokinetic change in the hippocampus. Monoamine neurotransmitters were analyzed in a reserpine-induced depression model, and metabolomic analysis of the hippocampus was performed in a chronic unpredictable mild stress (CUMS)-induced depression model. The radioactive tracer analysis manifested that the thermoresponsive hydrogel administered intranasally could maintain a high concentration gradient of berberine to the brain, and the relative bioavailability of berberine was enhanced approximately by 110 times that of the oral berberine/HP-β-CD inclusion complex in the hippocampus. The thermoresponsive hydrogel system resulted in similar or better antidepressant-like efficacy even with a lower dosage in reserpine and CUMS-induced depression in rats. The pharmacometabolomics analysis revealed that in addition to increasing the hippocampal monoamine levels, berberine via intranasal administration exhibited a unique mechanism by restoring the mitochondrial dysfunction as well as phospholipid and sphingolipid abnormalities as compared to intragastric (IG) administration. We consider this a safer and more effective strategy with a lower dosage than traditional oral drugs for the treatment of depression.

Controlled Release of Vancomycin From a Thermoresponsive Hydrogel System for the Prophylactic Treatment of Postoperative Acute Endophthalmitis.

PurposeTo investigate the efficacy of a poly(ethylene glycol) diacrylate and poly(N-isopropylacrylamide) based thermo-responsive hydrogel drug delivery system (DDS) to deliver prophylactic vancomycin (VAN) following ocular surgery.MethodsVAN was encapsulated in a hydrogel DDS and characterized in terms of initial burst, release kinetics, bioactivity, and cytotoxicity. Long-Evans rats received an intravitreal injection of Staphylococcus aureus to produce acute endophthalmitis in four experimental groups. One of four treatments were then applied: (1) bolus subconjunctival injection of VAN, (2) blank DDS, (3) saline treatment, and (4) subconjunctival injection of VAN DDS. Animals were scored for infection (0–3) at 12, 24, 48, and 72 hours, and eyes were harvested at 24 and 48 hours for histology.ResultsFollowing a 36% initial burst, VAN release from the DDS continued at a steady rate for 2 weeks plateauing at 84% after 504 hours. Bioactivity was maintained for all release samples and cytotoxicity analysis for the DDS revealed cell viability >90%. Not until after 12 hours did any of the groups show evidence of infection; however, at 24 hours, animals that received the VAN DDS had significantly lower infection scores (0 ± 0) than those that received a bolus VAN injection, blank DDS, or saline (1.5 ±1.5, 2.3 ± 0.87, and 2.9 ± 0.25; respectively). At 48 and 72 hours, the VAN DDS and bolus VAN treatment groups performed comparably and showed significantly better infection scores than the control groups.ConclusionsThis DDS appears to have promise as a vehicle for short term, prophylactic antibiotic delivery.Translational RelevanceThis DDS may prevent the development of postoperative endophthalmitis.

ID:4005 Injectable Cell Delivery Constructs for Myocardial Tissue Engineering

Cell transplantation via direct intramuscular injection is a promising therapy for patients with ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. In this presentation, a thermo-responsive hydrogel system composed of aqueous methylcellulose (MC) blended with phosphate-buffered saline is constructed to grow cell sheet fragments and cell bodies for the treatment of ischemic diseases. The as-prepared MC hydrogel system undergoes a sol–gel reversible transition upon heating or cooling at approximately 32 °C. Via this unique property, the grown cell sheet fragments (cell bodies) can be harvested without using proteolytic enzymes; consequently, their inherent extracellular matrices (ECMs) and integrative adhesive agents remain well preserved. In animal studies using rats and pigs with experimentally created myocardial infarction, the injected cell sheet fragments (cell bodies) become entrapped in the interstices of muscular tissues and adhere to engraftment sites, while a minimal number of cells exist in the group receiving dissociated cells. Moreover, transplantation of cell sheet fragments (cell bodies) significantly increases vascular density, thereby improving the function of an infarcted heart.
 These experimental results demonstrate that cell sheet fragments (cell bodies) function as a cell-delivery construct by providing a favorable ECM environment to retain transplanted cells locally and consequently, improving the efficacy of therapeutic cell transplantation

Time-resolved SANS analysis of micelle chain exchange behavior: thermal crosslink driven by stereocomplexation of PLA–PEG–PLA micelles

A TR-SANS study has revealed the initial stage of non-equilibrium micelle chain exchange for the thermo-responsive hydrogel system by stereocomplexation.

Injectable Cell Constructs Fabricated via Culture on a Thermoresponsive Methylcellulose Hydrogel System for the Treatment of Ischemic Diseases

Cell transplantation via direct intramuscular injection is a promising therapy for patients with ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. In this Progress Report, a thermoresponsive hydrogel system composed of aqueous methylcellulose (MC) blended with phosphate-buffered saline is constructed to grow cell sheet fragments and cell bodies for the treatment of ischemic diseases. The as-prepared MC hydrogel system undergoes a sol-gel reversible transition upon heating or cooling at ≈32 °C. Via this unique property, the grown cell sheet fragments (cell bodies) can be harvested without using proteolytic enzymes; consequently, their inherent extracellular matrices (ECMs) and integrative adhesive agents remain well preserved. In animal studies using rats and pigs with experimentally created myocardial infarction, the injected cell sheet fragments (cell bodies) become entrapped in the interstices of muscular tissues and adhere to engraftment sites, while a minimal number of cells exist in the group receiving dissociated cells. Moreover, transplantation of cell sheet fragments (cell bodies) significantly increases vascular density, thereby improving the function of an infarcted heart. These experimental results demonstrate that cell sheet fragments (cell bodies) function as a cell-delivery construct by providing a favorable ECM environment to retain transplanted cells locally and consequently, improving the efficacy of therapeutic cell transplantation.

Halloysite Nanotube Composited Thermo-responsive Hydrogel System for Controlled-release

Halloysite nanotube-composited thermo-responsive hydrogel system has been successfully developed for controlled drug release by copolymerization of N-isopropylacrylamide (NIPAM) with silane-modified halloysite nanotubes (HNT) through thermally initiated free-radical polymerization. With methylene blue as a model drug, thermo-responsive drug release results demonstrate that the drug release from the nanotubes in the composited hydrogel can be well controlled by manipulating the environmental temperature. When the hydrogel network is swollen at temperature below the lower critical solution temperature (LCST), drug releases steadily from lumens of the embedded nanotubes, whereas the drug release stops when hydrogel shrinks at temperature above the LCST. The release of model drug from the HNT-composited hydrogel matches well with its thermo-responsive volume phase transition, and shows characteristics of well controlled release. The design strategy and release results of the proposed novel HNT-composited thermo-responsive hydrogel system provide valuable guidance for designing responsive nanocomposites for controlled-release of active agents.

Injectable and Thermoresponsive Self-Assembled Nanocomposite Hydrogel for Long-Term Anticancer Drug Delivery

The purpose of this study is to develop an injectable thermoresponsive hydrogel system that can undergo sol-gel phase transition by the stimulation of body temperature with improved mechanical stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. Hexamethylene diisocyanate (HDI) was introduced into Pluronic F127 as a chain extender to improve the mechanical stability. HDI-Pluronic F127 copolymer was then incorporated with hyaluronic acid to develop a thermoresponsive nanocomposite hydrogel system. The physiochemical properties were characterized. The anticancer drug release profile and effect to inhibit tumor cells growth were analyzed in vitro and in vivo. The results showed that HDI-Pluronic F127/hyaluronic acid thermoresponsive hydrogel could undergo sol-gel transition as temperature increased to 37 °C. The nanocomposite polymer can spontaneously self-assemble into micellar structure with size of 100-200 nm. The release of doxorubicin (DOX) from HDI-PF127/HA composite hydrogel was a zero-order profile and maintained sustained release for over 28 days. The viability of tumor cells and size of tumor significantly decreased with incubation time, indicating the potential to have a therapeutic effect for cancer therapy. The injectable thermoresponsive nanocomposite hydrogel system was biocompatible and degradable and had the slow controlled release property for anticancer drugs with potential applications in the field of drug delivery.

Core–shell cell bodies composed of human cbMSCs and HUVECs for functional vasculogenesis

Rapid induction and creation of functional vascular networks is essential for the success of treating ischemic tissues. The formation of mature and functional vascular networks requires the cooperation of endothelial cells (ECs) and perivascular cells. In the study, we used a thermo-responsive hydrogel system to fabricate core–shell cell bodies composed of cord-blood mesenchymal stem cells (cbMSCs) and human umbilical vascular ECs (HUVECs) for functional vasculogenesis. When seeded on Matrigel, the shelled HUVECs attempted to interact and communicate vigorously with the cored cbMSCs initially. Subsequently, HUVECs migrated out and formed tubular structures; cbMSCs were observed to coalesce around the HUVEC-derived tubes. With time progressing, the tubular networks continued to expand without regression, indicating that cbMSCs might function as perivascular cells to stabilize the nascent networks. In the in vivo study, cbMSC/HUVEC bodies were embedded in Matrigel and implanted subcutaneously in nude mice. At day 7, visible blood-filled vessels were clearly identified within the implant containing cbMSC/HUVEC bodies, indicating that the formed vessels anastomosed with the host vasculature. The cored cbMSCs were stained positive for smooth muscle actin, suggesting that they underwent smooth muscle differentiation and formed microvessels with the shelled HUVECs, as the role of perivascular cells. These data confirm that the formation of mature vessels requires heterotypic cooperation of HUVECs and MSCs. This study provides a new strategy for therapeutic vasculogenesis, by showing the feasibility of using cbMSC/HUVEC bodies to create functional vascular networks.

A strategy for fabrication of a three-dimensional tissue construct containing uniformly distributed embryoid body-derived cells as a cardiac patch

Growing three-dimensional (3D) scaffolds that contain more than a few layers of seeded cells in vitro is crucial for the creation of thick and viable cardiac tissues in vivo. Embryonic stem cells (ESCs) have been used as an alternative cell source for cardiac repair; however, dissociated ESCs show poor viability in the scaffold and do not form the embryoid body (EB)-like structures. In this study, a strategy intended for cultivating EB-derived cells (EBDCs) uniformly in a porous 3D tissue scaffold was developed. This strategy employed techniques of formation of spherically symmetric EBs in a thermo-responsive hydrogel system, production of cell sheets of EBDCs in a similar hydrogel system coated with collagen and fabrication of sliced porous tissue scaffolds. The prepared EBs were collected and plated evenly in the cell-sheet culture system. After 8 days in culture, a continuous sheet of EBDCs with cell beating was obtained; our qPCR and flow cytometric analyses showed that the collagen-coated on the cell-sheet culture system can significantly enhance the population of cardiac-lineage cells. The produced EBDC sheets were then sandwiched into the sliced porous tissue scaffold. After reculture, the seeded EBDCs were redistributed uniformly throughout the scaffold, with a significant increase in mechanical strength. Cardiac-specific myosin heavy chain and α-actinin were expressed for some cells grown in the scaffold, while connexin 43 was clearly expressed at the cell borders. Additional studies such as employing purification techniques to enrich the population of cardiomyocytes are needed to further improve the developed tissue constructs as a bioengineered cardiac patch.

Spherically Symmetric Mesenchymal Stromal Cell Bodies Inherent with Endogenous Extracellular Matrices for Cellular Cardiomyoplasty

Cell transplantation via direct intramyocardial injection is a promising therapy for patients with myocardial infarction; however, retention of the transplanted cells at the injection sites remains a central issue following injection of dissociated cells. Using a thermoresponsive hydrogel system with a multiwell structure, we successfully developed an efficient technique to generate spherically symmetric bodies of mesenchymal stromal cells (MSCs) inherent with endogenous extracellular matrices (ECMs) for direct intramyocardial injection. After injection through a needle and upon transferring to another growth surface, the time required to attach, migrate, and proliferate was significantly shorter for the MSC bodies than the dissociated MSCs. Employing a syngeneic rat model with experimental myocardial infarction, an intramyocardial injection was conducted with a needle directly into the peri-infarct areas. There were four treatment groups (n = 10): sham, phosphate-buffered saline, dissociated MSCs, and MSC bodies. The results obtained in the echocardiography and catheterization measurements demonstrated that the MSC body group had a superior heart function to the dissociated MSC group. Histologically, it was found that MSC bodies could provide an adequate physical size to entrap into the interstices of muscular tissues and offer a favorable ECM environment to retain the transplanted cells intramuscularly. Additionally, transplantation of MSC bodies stimulated a significant increase in vascular density, thus improving the cardiac function. These results indicated that the spherically symmetric bodies of MSCs developed in the study may serve as a cell-delivery vehicle and improve the efficacy of therapeutic cell transplantation.