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Trinitroglycerin (TNG) with remarkable angiogenic, antibacterial, and antioxidative activity is a promising candidate to govern wound healing capacity. However, its clinical administration is limited due to associated complications and NO short half-life. In the current study, TNG-loaded chitosan nanogels (TNG-Ngs) were examined in-vitro and in-vivo to gain insight into their clinical application. We prepared TNG-Ngs and characterized their physiochemical properties. The potential of TNG-Ngs was assessed using biocompatibility, scratch assay, and a full-thickness skin wounds model, followed by histopathological and immunohistochemistry examinations. TNG-Ngs particle size 96 ± 18 and definite size distribution histogram. The loading capacity (LC) and encapsulation efficiency (EE) of prepared TNG-Ngs were 70.2 % and 2.1 %, respectively. The TNG-Ngs samples showed enhanced migration of HUVECs with no apparent cytotoxicity. The topical use of TNG-Ngs 200 on the wounds revealed a complete wound closure ratio, skin component formation, less scar width, remarkable granulation tissue, promoted collagen deposition, and enhanced the relative mean density of α-SMA and CD 31 . TNG-Ngs accelerated wound healing by promoting collagen deposition and angiogenic activity, as well as reducing inflammation. The findings indicated that TNG-Ngs is expected to be well vascularized in the wound area and to be more effective in topical therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Femoral head necrosis is a debilitating disorder that typically caused by impaired blood supply to the hip joint. In this study, a novel injectable hydrogel based on Oxidized Carboxymethyl Cellulose (OCMC)-Carboxymethyl Chitosan (CMCS) polymers containing an angiogenesis stimulator peptide (QK) with a non-toxic crosslinking interaction (Schiff based reaction) was synthesized to enhance angiogenesis following femoral head necrosis in an animal model. The physicochemical features of fabricated injectable hydrogel were analyzed by FTIR, swelling and degradation rate, rheometry, and peptide release. Also, the safety and efficacy were evaluated following an in vitro hydrogel injection study and an avascular necrosis (AVN) animal model. According to the results, the hydrogel exhibited an appropriate swelling ratio and water uptake (>90 %, 24 h) as well as a suitable degradation rate over 21 days accompanied by a continuous peptide release. Also, data showed that hydrogels containing QK peptide boosted the proliferation, differentiation, angiogenesis, and osteogenic potential of both Bone Marrow mesenchymal Stem Cells (BM-MSCs) and human umbilical vein endothelial cells (HUVECs) (****p < 0.0001 and ***p < 0.001, respectively). Furthermore, molecular and histological evaluations significantly demonstrated the overexpression of Runx2, Osteocalcin, Collagen I, VEGF and CD34 genes (**p < 0.01 and ***p < 0.001, respectively), and also femoral head necrosis was effectively prohibited, and more blood vessels were detected in defect area by OCMC-CMCS hydrogel containing QK peptide (bone trabeculae >9000, ***p < 0.001). In conclusion, the findings demonstrate that OCMC-CMCS-QK injectable hydrogel could be considered as an impressive therapeutic construct for femoral head AVN healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim and Background: Trinitroglycerin (TNG) is a remarkable NO-releasing agent. Here, we synthesized TNG based on chitosan Nanogels (Ngs) for ameliorating complications associated with high-dose TNG administration., Method: TNG-Ngs fabricated through ionic-gelation technique. Fourier-transformed infrared (FT-IR), zeta-potential, dynamic light scattering (DLS), and electron microscopy techniques evaluated the physicochemical properties of TNG-Ngs. MTT was used to assess the biocompatibility of TNG-Ngs, as the antioxidative properties were determined via lactate dehydrogenase (LDH), reactive oxygen species (ROS), and lipid peroxide (LPO) assays. The antibacterial activity was evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE)., Results: Physicochemical characterization reveals that TNG-Ngs with size diameter (96.2 ± 29 nm), polydispersity index (PDI, 0.732), and negative zeta potential (-1.1 mv) were fabricated. The encapsulation efficacy (EE) and loading capacity (LC) were obtained at 71.1 % and 2.3 %, respectively, with no considerable effect on particle size and morphology. The cytotoxicity assay demonstrated that HepG2 cells exposed to TNG-Ngs showed relative cell viability (RCV) of >80 % for 70 μg/ml compared to the TNG-free drug at the same concentration (P < 0.05). TNG-Ngs showed significant differences with the TNG-free drug for LDH, LPO, and ROS formation at the same concentration (P < 0.001). The antibacterial activity of the TNG-Ngs against S. aureus, E. coli, VRE, and MRSA was higher than the TNG-free drug and Ngs (P < 0.05)., Conclusion: TNG-Ngs with enhanced antibacterial and antioxidative activity and no obvious cytotoxicity might be afforded as novel nanoformulation for promoting NO-dependent diseases., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fungal exopolysaccharides (EPSs) are natural biopolymers with diverse potential applications in the biomedical, packaging, cosmetic, and food industries. Fungal EPSs are easy to extract and purify polysaccharides that are biodegradable, biocompatible, with low immunogenicity, bioadhesion ability, antibacterial activity, and contain different reactive groups such as hydroxyl, carboxyl, and amine for chemical modifications. Despite fast progress in identifying and characterization fungal EPSs for biomedical applications, i.e., wound healing, drug, and gene delivery, only a few products have been commercialized based on fungal EPSs. This review critically discusses potential biomedical applications of fungi sourced EPSs in tissue engineering (TE), drug and gene delivery., (Copyright © 2021. Published by Elsevier Ltd.)

This study prepared a novel three-dimensional nanocomposite scaffold by the surface modification of PCL/chitosan nanofiber/net with alginate hydrogel microlayer, hoping to have the privilege of both nanofibers and hydrogels simultaneously. Bead free randomly oriented nanofiber/net (NFN) structure composed of chitosan and polycaprolactone (PCL) was fabricated by electrospinning method. The low surface roughness, good hydrophilicity, and high porosity were obtained from the NFN structure. Then, the PCL/chitosan nanofiber/net was coated with a microlayer of alginate containing neurotrophin-3 (NT-3) and conjunctiva mesenchymal stem cells (CJMSCs) as a new stem cell source. According to the cross-sectional FESEM, the scaffold shows a two-layer structure with interconnected pores in the range of 20 μm diameter. The finding revealed that the surface modification of nanofiber/net by alginate hydrogel microlayer caused lower inflammatory response and higher proliferation of CJMSCs than the unmodified scaffold. The initial burst release of NT-3 was 69% in 3 days which followed by a sustained release up to 21 days. The RT-PCR analysis showed that the expression of Nestin, MAP-2, and β-tubulin III genes were increased 6, 5.4, and 8.8-fold, respectively. The results revealed that the surface-modified biomimetic scaffold possesses enhanced biocompatibility and could successfully differentiate CJMSCs to the neuron-like cells., (© 2021 Wiley Periodicals LLC.)

Silica plays an effective role in collagen creation; hence, the degradation products of silica-based materials accelerate wound healing. In this regard, chitosan/polyethylene oxide/silica hybrid nanofibers were prepared by the combining the sol-gel method with electrospinning technique to accelerate the wound healing process. Ciprofloxacin, as an antibacterial drug, was then added to the electrospinning mixture. The nanofibers were characterized by SEM, EDX, X-ray mapping, TEM, TGA, FTIR, and XRD analysis. The degradation, swelling ratio, and release of ciprofloxacin were investigated in PBS. The prepared nanofiber could absorb water, maintain its morphological integrity during the degradation process, and gradually release ciprofloxacin. The nanofibers revealed an efficient antibacterial activity against Escherichia coli and Staphylococcus aureus. Cell viability assays showed that the nanofibers had no cytotoxicity against L929 mouse fibroblast and HFFF2 human foreskin fibroblast cell lines. The potential of the chitosan/polyethylene oxide/silica/ciprofloxacin nanofiber for healing full-thickness wound was assessed by applying the scaffold in the dorsal cutaneous wounds of the Balb/C mice. The white blood cell counts of the animals indicated the nanofiber-treated mice compared with the untreated ones had less infection and inflammation. According to the histopathologic data, the prepared nanofiber accelerated and enhanced tissue regeneration by increasing fibroblast cells and angiogenesis as well as decreasing the inflammation phase. The findings suggest that the prepared antibacterial scaffold with drug delivery properties could be an appropriate candidate for many medical and hygienic applications, especially as a bio-compatible and bio-degradable wound dressing., (Copyright © 2021. Published by Elsevier B.V.)

The aim of the present study was to develop modified nanoemulsions to improve the oral bioavailability and pharmacokinetics of a poor water-soluble drug, repaglinide (RPG). The repaglinide-loaded nanoemulsions (RPG-NEs) were prepared from olive oil as internal phase, span 80, tween 80, and poloxamer 188 as emulsifiers, using homogenization technique. The mean droplet size, zeta potential, and entrapment efficiency of RPG-NEs were 86.5 ± 3.4 nm, -33.8 ± 2.1 mV, and 96.3 ± 2.3%, respectively. The chitosan-coated RPG-NEs (Cs-RPG-NEs) showed an average droplet size of 149.3 ± 3.9 nm and a positive zeta-potential of +31.5 ± 2.8 mV. Drug release profile of RPG-NEs was significantly higher than free drug in the simulated gastrointestinal fluids (p < .005). The in vivo study revealed 3.51- and 1.78-fold increase in the AUC 0-12h and C max of the drug, respectively, in RPG-NEs-receiving animals in comparison to the free drug. The pharmacokinetic analysis confirmed that Cs-RPG-NEs were more efficient than uncoated ones for the oral delivery of RPG. Cs-RPG-NEs showed a longer t 1/2 and higher AUC 0-∞ compared to control group. The relative bioavailability of Cs-RPG-NEs was higher than that of uncoated RPG-NEs and free drug. Collectively, these findings suggest that chitosan-coated nanoemulsions are promising carrier for improving the oral bioavailability of RPG., (© 2019 Wiley Periodicals, Inc.)

This study aimed to evaluate bio-safety of magnetic chitosan nanogels as dual triggered drug carrier for doxorubicin through analysis of mitochondrial function. In the present study, chitosan/TPP nanogels containing magnetite nanoparticles (NPs) were prepared according to the ionotropic gelation method as novel pH-sensitive magnetic nanogels. The NPs showed outstanding entrapment efficiency for doxorubicin (76.6%) with a sustained and high extent of drug release in the acidic media (pH=5-7) compared to the neutral media. Various mitochondrial functional parameters including complex II activity, MDA amount, GSH level, membrane potential collapse, swelling, apoptosis and release of cytochrome c were used to investigate the bio-safety of the nanogels. The findings revealed that the extent of mitochondrial dysfunction of doxorubicin were in the order of free doxorubicin>doxorubicin loaded magnetic nanogels=>doxorubicin loaded Nanogels. The results also revealed that the nanogels and the magnetite nanogels seem to possess promising capability as a safe carrier in comparison of the toxic potential effect of free doxorubicin., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Delivery of the hydrophilic drugs to the brain is still a great challenge for the treatment of many CNS-related diseases. Nanogels loaded by methotrexate (MTX) were prepared using the ionic gelation method. After intravenous administration of surface-modified (SMNs) and unmodified nanogels (UMNs) compared to the free drug, the neuropharmacokinetic evaluations were applied mainly by tissue drug uptake and graphic estimation of the uptake clearance methods. In optimized condition, the particle sizes of UMNs and SMNs were 118.54±15.93 nm and 106.68±7.23 nm, respectively. Drug entrapment efficiency and drug loading capacity were 61.82±6.84%, and 53.68±3.09%, respectively. The brain concentrations of MTX were shown to be higher in the case of both types of the nanogels. There were no significant differences between SMNs and UMNs in terms of the brain concentrations and AUCs of brain concentration-time profiles. Meanwhile, the brain uptake clearance of the drug loaded in SMNs were significantly higher than UMN ones (i.e. about 3- and 1.6-times for the high and low MTX doses, respectively). It can be concluded that, while the drug loading in both forms of nanogels have a significant increasing effect on the brain penetration of MTX, surface treatment of nanogels exerts an additional effect on the plasma volume cleared from MTX via brain tissue in time unit., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

Methotrexate-loaded hydrogel nanoparticles were prepared and after in vitro characterization, their transport across blood-brain barrier was investigated in vivo in intact animals in this study. The ionic gelation method was used for preparation of drug-loaded nanogels, after optimized by a systematic multi-objective optimization approach. After surface-modification with polysorbate 80, nanoparticles with the final particle size, poly-dispersity index (PDI), loading efficiency (LE) and loading capacity (LC) of 118.54 ± 15.93 nm, 0.35 ± 0.05, 61.82 ± 6.84%, and 53.68 ± 3.09% were obtained, respectively. The in vitro drug release study indicated non-Fickian diffusion kinetic, apparently governed by both diffusion of the drug out of the nanoparticles and swelling/disintegration of the polymeric network as characterized by a Weibull model for both surface-treated and untreated nanogels. After intravenous administration of surface-modified and unmodified nanogels compared to the free drug, all with the same dose of 25 mg/kg, remarkably higher brain concentrations of methotrexate were achieved with the nanogel formulations in comparison to the free drug (in some cases, more than 10-fold); but there were no significant differences between the surface-modified and unmodified nanogels in all the time points tested., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: Management of blood coagulation-related diseases is currently limited by the inability to provide an adequate drug concentration in blood circulation for a long term. As a promising way to overcome this problem, the long-acting forms of these drugs have attracted many interests in recent years., Methods: In this study, chitosan-heparin nanoparticles were prepared as a polymeric delivery system intended for the prolonged intravenous delivery of heparin where the drug was used as both the therapeutic agent and a gel-forming counter-ion. The nanoparticle preparation method was optimized using a Taguchi orthogonal array. Critical formulation variables were optimized in this study in terms of their corresponding effects on the target response of particle size. Nanoparticles were characterized by the Fourier transform infrared spectroscopy, transmission electron microscopy and zeta potential., Key Findings: The size, polydispersity index, zeta potential and encapsulation efficiency for the optimized formulation were found to be 61.33 ± 1.53 nm, 0.06, +15.7 mv and 74.16 ± 1.27%, respectively. The sizes of the prepared drug-loaded nanoparticles were stable at least 1 week at room temperature and 3 months in refrigerator., Conclusions: The ex-vivo and in-vivo tests on the heparin-chitosan nanoparticles using activated partial thromboplastin time (aPTT) as the biological index were indicative of a smoother and longer elevation in aPTT in the presence of nanoparticulate drug., (© 2013 Royal Pharmaceutical Society.)