F127 Hydrogel Research Articles

Development of transdermal based hydrogel formulations of vinorelbine with an evaluation of their in vitro profiles and activity against melanoma cells and in silico prediction of drug absorption

The primary course of melanoma treatment involves surgery in association with chemotherapy. One potential agent is vinorelbine (VNR). While it displays anti-proliferative activity against melanoma cell lines, it presents a low oral bioavailability and intravenous administration often causes irritation, phlebitis and pain at the injection site. The aim of this study was to develop Pluronic® F-127 (PF-127) hydrogels containing VNR for the transdermal route of administration. Hydrogels composed of either 15% (G15), 20% (G20), 23% (G23) or 25% (G25) PF-127 aqueous solutions were loaded with a VNR propylene glycol solution. Their release and permeation profiles for VNR were evaluated in a Franz diffusion cell. In addition, their rheological behavior, visual aspect during storage and the in silico prediction of VNR absorption using GastroPlus® were evaluated. The G20 and G23 formulations showed similar release and permeation profiles with the G20 demonstrating a higher permeation of VNR at 8h (p < 0.05) and cumulative permeated drug amount of 495.2 ± 46.7 μg/cm2 at 24h. Further, their activity was tested on the melanoma cell lines SK-MEL28 and MV-3 to evaluate cell viability and proliferation. At VNR concentrations of 75 and 100 μg/mL, cell viability of both melanoma cells was lower in the presence of the G20 formulation than G23 after 24h of treatment although the proliferation profiles were similar. When combined with an in silico pharmacokinetic model, the results suggest that the transdermal administration of VNR could be a promising alternative to intravenous administration and that the G20 formulation would be an excellent candidate for the direct application onto melanomas.

Adventitial delivery of nanoparticles encapsulated with 1\u03b1, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D3, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C–C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-μL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson’s trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.

1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas.

Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model. Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF. Encapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways. Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

Thermally induced and physically cross-linked hydrogel doped with graphene oxide for controlled release.

Graphene oxide (GO) is an ideal hydrogel material because of its water solubility, non-toxicity, and excellent mechanical properties. Here, we added GO to oligo(lysine)-modified F127 to prepare a series of FLGO composite hydrogels. The FLGO hydrogel was thermally induced, stable and injectable. And the content of GO would affect the sol-gel transition, rheological properties and glass transition temperature of the FLGO hydrogel. GO was connected to the matrix through electrostatic interactions and hydrogen bonds. The cross-linking effect of GO enhanced the FLGO hydrogel. We also studied the release properties of the FLGO hydrogel loaded with anticancer drug 5-fluorouracil. Compared with F127 hydrogel, the FLGO hydrogel showed a linear, slower and stable release pattern within one week. The release rate of FLGO hydrogel could be adjusted by the pH and it was faster under acidic conditions. Therefore, the FLGO hydrogel is expected to be used as a drug release system in the field of biomedicine.

Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy.

Background: Host defense peptides (HDPs) have emerged as a novel therapeutic paradigm for wound management; however, their clinical applications remain a challenge owing to their poor pharmacological properties and lack of suitable pharmaceutical formulations. Nanodefensin (ND), a nanoengineered human α-defensin 5 (HD5), has shown improved pharmacological properties relative to the parent compound. In this study, we engineered a nanodefensin-encased hydrogel (NDEFgel), investigated the effects of NDEFgel on wound healing, and elucidated underlying mechanisms.Method: ND was chemically synthesized and tested functions by in vitro antimicrobial and scratch assays and western blotting. Different NDEFgels were evaluated by in vitro characterizations including degradation, drug release and antimicrobial activity. In full-thickness excisional murine models, the optimal NDEFgel was directly applied onto wound sites, and the efficacy was assessed. Moreover, the underlying mechanisms of pro-regenerative effect developed by NDEFgel were also explored.Results: Apart from bactericidal effects, ND modulated fibroblast behaviors by promoting migration and differentiation. Among the tested hydrogels, the Pluronic F127 (Plu) hydrogel represented the most desirable carrier for ND delivery owing to its favorable controlled release and compatibility with ND. Local treatment of NDEFgel on the wound bed resulted in accelerated wound regeneration and attenuated bacterial burden. We further demonstrated that NDEFgel therapy significantly upregulated genes related to collagen deposition and fibroblasts, and increased the expression of myofibroblasts and Rac1. We therefore found that Rac1 is a critical factor in the ND-induced modulation of fibroblast behaviors in vitro through a Rac1-dependent cytoskeletal rearrangement.Conclusion: Our results indicate that NDEFgel may be a promising dual-action therapeutic option for advanced wound management in the future.

An intrinsically disordered protein in F127 hydrogel: Fluorescence correlation spectroscopy and structural diversity of beta casein

Intrinsically Disordered Proteins (IDPs) switch between diverse structures which prevents them from crystallization. FCS of the IDP beta casein (β-CN), labeled with Alexa488, suggests that in buffer the structure fluctuates between a highly extended state (radius 34.5 ± 7 nm) and a highly collapsed state (radius 1 nm). To understand their behavior in a highly crowded environment, like the cell, β-CN was studied inside a pluronic copolymer (F127) where a 2-times higher rotational and 10–16 times higher translational friction were observed. Fluorescence emissions of Tryptophan indicate that the protein is localized at corona region exposing to the void region of the gel.

Insulin Release from NPH Insulin-Loaded Pluronic® F127 Hydrogel in the Presence of Simulated Tissue Enzyme Activity

Background: Despite the widespread use of newer basal insulins, Natural Protamine Hagedorn (NPH) insulin still represents a well-established basal formulation with its long history of use, featuring the native form of human insulin. However, NPH insulin exhibits an undesirable peak within hours after a single subcutaneous (s.c.) injection, which may lead to hypoglycemia followed by insufficient basal insulin delivery. This may be attributed to the s.c. enzyme activities degrading the protamine in NPH microcrystals. Methods: A thermogelling block copolymer Pluronic® F127 (PF127) was utilized as a protective carrier for NPH microcrystals and as a modulator for insulin release from NPH. NPH insulin-loaded PF127 gel was prepared with varying concentrations of the polymer (15–25%) under mild conditions. The formulations were characterized for their gelling temperature, morphology, gel erosion, and in vitro insulin release, with trypsin concentrations up to 5 U/mL. Results: Scanning electron microscopy (SEM) showed that the integrity of NPH microcrystals was maintained after preparation. The burst release of insulin from NPH was significantly attenuated over the course of ~16h in the presence of PF127 with or without enzyme activity. Conclusion: NPH-PF127 successfully resisted the acceleration of NPH crystal dissolution and insulin release in vitro in the presence of protamine-degrading enzyme activity, warranting further testing.

Hydrogel microfluidic-based liver-on-a-chip: Mimicking the mass transfer and structural features of liver.

Liver is fed by nutrition via diffusion across the vascular wall from blood flow. However, hepatocytes in liver models are directly exposed to the perfusion culture medium, where the shear stress reduces the cell viability and liver-specific functions. By mimicking the mass transfer and structural features of hepatic lobule, we designed a microfluidic liver-on-a-chip based on the di-acrylated pluronic F127 hydrogel. In the hydrogel chip, hepatocellular carcinoma HepG2 and human hepatic stellate cell LX-2 were statically cultured inside the microwells on the outer channel. These hepatic cells were fed by the diffused medium from the adjacent but separated inner channel with endothelial cell monolayers, which was perfused by the medium with physiologically relevant shear stress. As found, the hepatic cells in the liver-on-a-chip rapidly formed spheroids within 1-dayincubation and expressed about one to two-fold higher viability/liver-specific functions than the corresponding static culture for at least 8 days. Moreover, the presence of endothelial cells also contributed to the expression of liver-specific functions in the liver-on-a-chip. Therefore, the proposed liver-on-a-chip provides a new concept for construction of 3D liver models in vitro, and shows the potential value for a variety of applications including bio-artificial livers and drug toxicity screening.

Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes Combined Pluronic F127 Hydrogel Promote Chronic Diabetic Wound Healing and Complete Skin Regeneration.

PurposeChronic refractory wounds are a multifactorial comorbidity of diabetes mellitus with the characteristic of impaired vascular networks. Currently, there is a lack of effective treatments for such wounds. Various types of mesenchymal stem cell-derived exosomes (MSC-exos) have been shown to exert multiple therapeutic effects on skin regeneration. We aimed to determine whether a constructed combination of human umbilical cord MSC (hUCMSC)-derived exosomes (hUCMSC-exos) and Pluronic F-127 (PF-127) hydrogel could improve wound healing.Materials and MethodsWe topically applied human umbilical cord-derived MSC (hUCMSC)-derived exosomes (hUCMSC-exos) encapsulated in a thermosensitive PF-127 hydrogel to a full-thickness cutaneous wound in a streptozotocin-induced diabetic rat model. The material properties and wound healing ability of the hydrogel and cellular responses were analyzed.ResultsCompared with hUCMSC-exos, PF-127-only or control treatment, the combination of PF-127 and hUCMSC-exos resulted in a significantly accelerated wound closure rate, increased expression of CD31 and Ki67, enhanced regeneration of granulation tissue and upregulated expression of vascular endothelial growth factor (VEGF) and factor transforming growth factor beta-1 (TGFβ-1).ConclusionThe efficient delivery of hUCMSC-exos in PF-127 gel and improved exosome ability could promote diabetic wound healing. Thus, this biomaterial-based exosome therapy may represent a new therapeutic approach for cutaneous regeneration of chronic wounds.

Structural and therapeutic properties of curcumin solubilized pluronic F127 micellar solutions and hydrogels

Curcumin, the principle active constituent of turmeric, is known to have broad range of therapeutic properties. Its poor aqueous solubility and low bioavailability however, act as constraints for its biomedical applications. Recent studies have shown that incorporation of curcumin in nano-carriers like micelles, vesicles, polymeric nanoparticles etc. can help in overcoming these issues and improve its therapeutic abilities quite significantly. In this manuscript, we report preparation of curcumin solubilized pluronic F127 micellar solutions and hydrogels, along with their structural and therapeutic properties as obtained from SANS, rheological, anti-cancer and wound healing studies. Pluronic F127 being approved by FDA has been used quite extensively as excipient for drug delivery applications. Curcumin solubilization in the aqueous pluronic F127 system was carried out by briefly heating the copolymer solutions with curcumin at 90 °C. The concentrations of curcumin thus obtained were found to be comparable to those obtained by conventional methods of solubilization like thin film hydration or solvent evaporation method, and three orders of magnitude higher than that in pure water. SANS and rheological studies show that curcumin solubilization does not bring about any significant change in the structural and rheological properties of F127 micellar solutions and hydrogels. Curcumin solubilized F127 micellar solutions can be reconstituted after lyophilization, suggesting that curcumin remains nano-dispersed in lyophilized state. Micellar encapsulated curcumin exhibits very good stability in solution state in ambient condition but fails to show cytotoxicity against MCF7 cancer cells, presumably due to shielding of curcumin by large corona region of F127 micelles. Micellar curcumin containing F127 hydrogels on the other hand, exhibit wound healing abilities in mice model upon topical application. The results give an account of how some of the therapeutic properties of curcumin are manifested under micellar encapsulation and the role of pluronic F127 as excipient in those therapeutic applications.

S-nitrosothiol-terminated Pluronic F127: Influence of microstructure on nitric oxide release

Hypothesis: Nitric oxide (NO)-releasing Pluronic F127 hydrogels (F127) containing dissolved S-nitrosothiols or pendant N-diazeniumdiolate (NONOate) groups have been described. The NO charging of these hydrogels is usually limited by their low stability or disruption of the micellar packing. S-nitrosothiol-terminated F127 may emerge as a new strategy for allowing NO delivery at different rates in biomedical applications.Experiments: Terminal hydroxyl groups of F127 were esterified and reduced to produce F127-mercaptopropionate (HS-F127-SH), which was subsequently S-nitrosated to generate S-nitrosothiol-terminated F127 (ONS-F127-SNO). Micro-differential scanning calorimetry, 1H NMR spin-spin relaxation (T2), temperature-dependent small-angle X-ray scattering, and cryo-transmission electron microscopy, were used to determine the micellar packing structure, while real-time chemiluminescence NO detection and UV–Vis spectrophotometry were used to evaluate the kinetics of NO release.Findings: HS-F127-SH micellization and gelation processes were analogous to native F127, however, with a decreased short-range ordering of the micelles. ONS-F127-SNO hydrogels released NO thorough a preferentially intramicellar SNO dimerization reaction. Increasing ONS-F127-SNO concentration reduces the rate of SNO dimerization and increases the overall rate of NO release to the gas phase, opening up new possibilities for tailoring NO delivery from F127-based hydrogels.

Dual dynamically crosslinked thermosensitive hydrogel with self-fixing as a postoperative anti-adhesion barrier

Tissue adhesion is a severe postoperative complication. Various strategies have been developed to minimize postoperative adhesion, but the clinical efficacy is still far from satisfactory. Herein, we present a dual dynamically crosslinked hydrogel to serve as a physical postoperative anti-adhesion barrier. The hydrogel was generated by dynamic chemical oxime bonding from alkoxyamine-terminated Pluronic F127 (AOP127) and oxidized hyaluronic acid (OHA), as well as hydrophobic association of AOP127. Rheological analysis demonstrated that the hydrogel exhibits temperature sensitivity. At 37 °C, it shows much higher modulus and higher stability than the Pluronic F127 hydrogel. Hemolytic assays suggested that the hydrogel undergoes low hemolysis. In addition, it exhibited anti-adhesion to blood cells in blood cell adhesion tests. It also showed an anti-attachment effect to fibroblasts and biocompatibility in vitro cell studies. Macroscopic evaluation and lap-shear tests revealed that the hydrogel has a moderate adhesive capacity to tissue, which is important for self-fixation. A rat model of sidewall defect-bowel abrasion was established to evaluate the anti-adhesion effect in vivo. The gross observation and pathological analysis revealed a significant reduction in postoperative peritoneal adhesion in the AOP127/OHA hydrogel-treated group than those treated with normal saline or Pluronic F127 hydrogel. Hence, the dual dynamically crosslinked hydrogel with self-fixable capacity may be suitable as a physical barrier for postoperative adhesion prevention. Statement of SignificanceDespite the development of numerous postoperative anti-adhesion barriers, their anti-adhesion efficacy is still limited in clinical trials due to poor tissue adhesion and rapid clearance from injured areas. Herein, we have developed a dual dynamic crosslinked hydrogel, generated by dynamic oxime bonds and hydrophobic interactions. The hydrogel is temperature-sensitive and demonstrates moderate tissue adhesion capacity, which allows for self-fixation when applied to defects. The introduction of dynamic covalent bonds improves the stability of the hydrogel. Moreover, the hydrogel not only displays appropriate hemocompatibility, cytocompatibility and anti-adhesion of blood cells and fibroblasts, but it also effectively contributes to preventing postoperative peritoneal adhesions in vivo. Hence, this dual dynamic crosslinked hydrogel may have potential applications as a physical barrier in clinical practice.

Sustained release of magnesium ions mediated by injectable self-healing adhesive hydrogel promotes fibrocartilaginous interface regeneration in the rabbit rotator cuff tear model

The fibrocartilaginous enthesis regeneration after rotator repair is still a major challenge. Although magnesium-based alloy orthopedic implant is effective to promote fibrocartilage formation at the tendon-bone interface in the anterior cruciate ligament reconstruction model, it was limited in the rotator cuff repair for its special anatomical structure. Herein, we developed a multifunctional self-healing magnesium ions-quaternized chitosan/Pluronic® F127 (Mg-QCS/PF) hydrogels to achieve in-situ and customized release of Mg2+, and demonstrated the sustained release of Mg2+ from the hydrogel to significantly promote the rotator cuff repair in the rabbit rotator cuff tear model. The obtained hydrogels showed excellent self-healing and anti-compressive performance. Additionally, the good injectability and adhesive properties of the hydrogels make it easier and stable to deliver Mg2+ at the tendon-bone interface with irregular shapes. The release of Mg2+ from Mg-QCS/PF hydrogels improved the adhesion, proliferation and migration of bone mesenchymal stem cells (BMSCs) and MC3T3 cells in vitro compared with QCS/PF without Mg2+. Furthermore, the composite hydrogels significantly enhanced the fibrocartilaginous interface regeneration in the rabbit rotator cuff tear model in terms of repaired tendon mature scores, fibrocartilage regeneration, collagen remodeling and biomechanical properties. This is the first study to demonstrate the positive effects of Mg2+ for the rotator cuff healing in the rabbit preclinical model, and the results indicate that the acellular injectable self-healing Mg-doped hydrogels are candidates to effectively promote in situ regeneration of rotator cuff.

Therapeutic efficacy of thermosensitive Pluronic hydrogel for codelivery of resveratrol microspheres and cisplatin in the treatment of liver cancer ascites.

Ascites constitutes the most frequent decompensating event in patients with advanced liver cancer and is associated with poor quality of life and high mortality. Intraperitoneal chemotherapy appears to be a reliable treatment strategy for advanced liver cancer ascites. However, the rapid metabolism of drugs and ascites dilution limits the efficacy of chemotherapeutics. Therefore, the present study aimed to develop a novel thermosensitive hydrogel drug system for targeted therapy of advanced hepatocellular carcinoma (HCC) ascites through intraperitoneal administration. The system was prepared by blending resveratrol (RES) microspheres and cisplatin (DDP) into thermosensitive Pluronic F127 hydrogel. The in vitro anti-tumor activity against H22 cells indicated that the prepared drug system could initiate apoptosis and induce cell cycle arrest at the G1 phase. The mice model of ascites with advanced HCC was established to validate the therapeutic potential of the F127 hydrogel drug system in vivo. The results revealed that intraperitoneal administration of F127 hydrogel drug could significantly inhibit the number of ascites, the proliferation of tumor cells, micro-angiogenesis, and prolong the survival of mice, thus, augmenting the efficacy of intraperitoneal chemotherapy. Moreover, immunohistochemical staining revealed that the F127 hydrogel drug system was safe and presented low toxicity to major vital organs. Collectively, this study highlights the clinical application potential of the F127 hydrogel drug delivery system.

PF-127 hydrogel plus sodium ascorbyl phosphate improves Wharton\u2019s jelly mesenchymal stem cell-mediated skin wound healing in mice

BackgroundFactors such as poor engraftment, retention, and survival of the transplanted stem cells are deemed to limit their therapeutic efficacy for wound regeneration. Hence, it is necessary to explore these issues in order to resolve them. In this study, we aim to investigate the role of Pluronic F-127 (PF-127) hydrogel plus antioxidant sodium ascorbyl phosphate (SAP) in enhancing Wharton’s jelly mesenchymal stem cell (WJMSC)-mediated effectiveness on full-thickness skin wound healing in mice.MethodsFirst, the cytotoxicity of PF-127 and the biological effect of SAP on the survival of WJMSCs were tested in vitro using cell viability and proliferation assays. Next, a cell suspension containing WJMSCs, PF-127, and SAP was topically administered onto an 8-mm diameter excisional full-thickness wound bed. Eight days after transplantation, the mice were sacrificed and the skin tissue was excised for histological and immunohistochemical analysis. Finally, in vivo distribution of transplanted WJMSCs was traced to investigate cell engraftment and the potential therapeutic mechanism.ResultsPF-127 was found to be cytotoxic to WJMSCs while SAP significantly improved the survival of PF-127-embedded WJMSCs. When this combination was topically transplanted onto the wound bed, wound healing was facilitated and dermis regeneration was achieved on the 8th day after surgery, as evidenced by an increase in dermal thickness, newly developed hair follicles, and collagen fiber deposition accompanied by a reduction in scar width. Further, immunohistochemical analysis demonstrated a higher number of anti-inflammatory M2 macrophages, proliferating cells, and newly formed blood vessels in the WJMSCs/PF-127/SAP group relative to all other groups. In addition, in vivo tracking results revealed a highly enhanced engraftment of WJMSCs accumulated in the dermis in the WJMSCs/PF-127/SAP group.ConclusionsSAP significantly improves the survival of WJMSCs in PF-127 encapsulation. Further, PF-127 plus SAP is an effective combination that enhances WJMSC engraftment in the dermis, which then promotes full-thickness wound healing through potential M2 macrophage formation and angiogenesis.

Direct Ink Writing Glass: A Preliminary Step for Optical Application.

In this paper, we present a preliminary study and conceptual idea concerning 3D printing water-sensitive glass, using a borosilicate glass with high alkali and alkaline oxide contents as an example in direct ink writing. The investigated material was prepared in the form of a glass frit, which was further ground in order to obtain a fine powder of desired particle size distribution. In a following step, inks were prepared by mixing the fine glass powder with Pluoronic F-127 hydrogel. The acquired pastes were rheologically characterized and printed using a Robocasting device. Differential scanning calorimetry (DSC) experiments were performed for base materials and the obtained green bodies. After sintering, scanning electron microscope (SEM) and X-ray diffraction (XRD) analyses were carried out in order to examine microstructure and the eventual presence of crystalline phase inclusions. The results confirmed that the as obtained inks exhibit stable rheological properties despite the propensity of glass to undergo hydrolysis and could be adjusted to desirable values for 3D printing. No additional phase was observed, supporting the suitability of the designed technology for the production of water sensitive glass inks. SEM micrographs of the sintered samples revealed the presence of closed porosity, which may be the main reason of light scattering.

Injectable baicalin/F127 hydrogel with antioxidant activity for enhanced wound healing

Baicalin, extracted from traditional Chinese medicine Scutellaria baicalensis Georg, possesses multiple pharmacological activities and has great potential for chronic skin wound repair. However, the poor solubility and lack of suitable vehicles greatly limit its further application. Herein, we proposed a convenient and robust strategy, employing PBS solution as solvent, to enhance the solubility of baicalin. Furthermore, we constructed injectable baicalin/F127 hydrogels to study their application in skin wound treatment. The composition and temperature sensitivity of baicalin/Pluronic® F-127 hydrogels were confirmed by FTIR and rheological testing, respectively. In vitro release measurement indicated that the first order model was best fitted with the release profile of baicalin from hydrogel matrix. Besides, MTT assay, AO/EO staining assay as well as hemolytic activity test revealed the excellent cytocompatibility of baicalin/F127 hydrogels. Antioxidant activity assay demonstrated the cytoprotective activity of baicalin/F127 hydrogels against reactive oxygen species (ROS). Furthermore, the in vivo experiments exhibited the ability of baicalin/F127 hydrogel to accelerate wound healing. In conclusion, this novel injectable baicalin/F127 hydrogel should have bright application for chronic wound treatment.

Thermosensitive Hydrogel Based on Poly(2-Ethyl-2-Oxazoline)-Poly(D,L-Lactide)-Poly(2-Ethyl-2-Oxazoline) for Sustained Salmon Calcitonin Delivery.

This study developed a thermosensitive hydrogel based on poly(2-ethyl-2-oxazoline)-poly(D,L-lactide)-poly(2-ethyl-2-oxazoline) (PPP) for the delivery of salmon calcitonin to improve the hypocalcemic effect. The tube inversion and rheological tests revealed that the copolymer solution underwent temperature-dependent sol-gel-sol transitions. Observation by scanning electron microscopy (SEM) showed that the hydrogel exhibited a porous three-dimensional network. The swelling test demonstrated that there was a maximum swelling ratio at low temperature (25°C) as compared with the high temperature (37°C). In vitro release revealed that the PPP hydrogel were capable of sustained release of salmon calcitonin (sCT). The in vivo biodegradability study indicated the good degradability of PPP hydrogel. More importantly, the in vivo retention time of the hydrogel in situ was significantly prolonged after subcutaneous injection of the PPP hydrogel compared to the F127 hydrogel. In vivo pharmacodynamics analysis showed that the hypocalcemic effect of both PPP and F127 hydrogel was significantly greater than that of sCT solution, and the mean serum Ca reduction effect could be maintained for 24h of PPP hydrogel, indicating that PPP hydrogel could achieve a significant enhanced hypocalcemic effect. In conclusion, the PPP hydrogel has been shown to be prospective as a controlled release carrier for injection delivery of protein drugs.

Dual responsive oligo(lysine)-modified Pluronic F127 hydrogels for drug release of 5-fluorouracil.

Peptide-containing hydrogels have become a research hotspot due to their unique secondary structure and biocompatibility. Herein, we used amino-terminated F127 as a macroinitiator to initiate the ring-opening polymerization of l-lysine(z)-NCA, and the obtained oligo(lysine)-modified F127 (FL) had degrees of polymerization of lysine of 2, 5, and 8. The results showed that the FL hydrogels had reversible temperature-dependent sol–gel transitions, and the introduction of lysine increased the critical gel temperature. In the dilute solution of FL, the micelle size increased and aggregated as the pH increased; the micelle grew into a rod-like shape under alkaline conditions. Scanning electron micrographs showed that the interior of the FL hydrogel had a more complete porous structure. The FL-2 hydrogel loaded with 5-fluorouracil exhibited an approximately linear release trend within 12 h and has good biocompatibility. Therefore, FL hydrogels have potential applications in the field of biomedicine.

Formulation and Evaluation of Eudragit RL-100 Nanoparticles Loaded In-Situ Forming Gel for Intranasal Delivery of Rivastigmine.

Purpose: Rivastigmine hydrogen tartrate (RHT) is commonly used for the treatment of mild to moderate Alzheimer’s disease (AD). The aim of this work was to formulate in-situ pluronic F-127 (PF-127) hydrogels containing Eudragit RL-100 (EU-RL) nanoparticles (NPs) in order to improve the therapeutic efficacy of RHT through the nasal route. Methods: The NPs were prepared using different polymer to drug ratios and evaluated for their physicochemical characteristics, cellular uptake and in vitro cytotoxicity against lung adenocarcinoma cells (A459). PF-127 nanoformulations were prepared via cold method and analyzed in terms of physicochemical properties and drug release profiles. The nanoformulations and plain drug gel were then assessed by ex vivo permeation studies across the sheep nasal mucosa. Results: The EU-RL NPs exhibited a particle size within the range of 118 to 154 nm and positive zeta potential values of 22.5 to 30 mV with an approximately spherical shape. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) suggested no drug to polymer interaction through the preparation of nanoformulations. The RHT-loaded NPs exhibited an acceptable cytocompatibility with a time- and dose-dependent cellular internalization.Conclusion: Our results clearly indicated the potential of nanoformulations as controlled release systems to improve the therapeutic efficacy of RHT through the intranasal administration