Chitosan-coated miconazole as an effective anti-inflammatory agent for the treatment of postoperative infections in obstetrics and vaginal yeast infection control on in vitro evaluations.

People with immune deficiency are at risk of developing infections caused by several bacterial and fungal species. In this work, chitosan-coated miconazole was developed by a simple sol-gel method. Miconazole is considered an effective drug to treat vaginal infection-causing bacteria and fungi. The coating of chitosan with miconazole nitrate showed the highest drug loading efficiency (62.43%) and mean particle size (2 µm). FTIR spectroscopic analysis confirmed the entrapment of miconazole nitrate into chitosan polymer. The antifungal result demonstrated that MN@CS microgel possessed notable anti-Aspergillus fumigatus and Candida albicans activity in lower doses. Antibacterial activity results revealed excellent bacterial growth inhibition of MN@CS microgel towards human skin infectious pathogens Escherichia coli and Staphylococcus aureus. The biocompatibility studies of In vitro cell viability and Artemia salina lethality assay suggested that MN@CS microgel is more biosafe and suitable for human external applications. In the future, it will be an efficient anti-inflammatory agent for the treatment of vaginal infections.

Charge-reversible and biodegradable chitosan-based microgels for lysozyme-triggered release of vancomycin.

INTRODUCTION: High-dose drug administration for the conventional treatment of inflammatory bowel disease induces cumulative toxicity and serious side effects. Currently, few reports have introduced smart carriers for intestinal inflammation targeting toward the treatment of inflammatory bowel disease. OBJECTIVES: For the unique lysozyme secretory microenvironment of the inflamed intestine, vancomycin-loaded chitosan-polyaniline microgels (CH-PANI MGs) were constructed for lysozyme-triggered VM release. METHODS: Aniline was first grafted to chitosan to form polymers that were crosslinked by glutaraldehyde to achieve CH-PANI MGs using the inverse (water-in-oil) miniemulsion method. Interestingly, CH-PANI MGs exhibit polyampholyte behaviour and display charge-reversible behaviour (positive to negative charges) after treatment with a NaCl solution. RESULTS: The formed negatively charged N-CH-PANI MG aqueous solution is employed to load cationic vancomycin with a satisfactory loading efficiency of 91.3%, which is significantly higher than that of chitosan-based MGs. Moreover, N-CH-PANI MGs present lysozyme-triggered biodegradation and controllable vancomycin release upon the cleavage of glycosidic linkages of chitosan. In the simulated inflammatory intestinal microenvironment, vancomycin is rapidly released, and the cumulative release reaches approximately 76.9%. Remarkably, N-CH-PANI@VM MGs not only exhibit high resistance to harsh gastric acidity but also prevent the premature leakage of vancomycin in the healthy gastrointestinal tract. Encouragingly, the N-CH-PANI@VM MGs show obvious antibacterial activity against Staphylococcus aureus at a relatively low concentration of 20 µg/mL. CONCLUSION: Compared to other pH-responsive carriers used to treat inflammatory bowel disease, the key advantage of lysozyme-responsive MGs is that they further specifically identify healthy and inflammatory intestines, achieving efficient inflammatory bowel disease treatment with few side effects. With this excellent performance, the developed smart MGs might be employed as a potential oral delivery system for inflammatory bowel disease treatment.

Ionically bridged dexamethasone sodium phosphate-zinc-PLGA nanocomplex in alginate microgel for the local treatment of ulcerative colitis.

Colon-targeted oral drug delivery systems comprising nanoparticles and microparticles have emerged as promising tools for the treatment of ulcerative colitis (UC) because they minimize side effects and maximize the local drug concentration. Dexamethasone sodium phosphate (DSP) is a potent anti-inflammatory glucocorticoid used for the treatment of UC. However, it remains a rather short-term treatment option owing to its side effects. In the present study, we developed the alginate gel encapsulating ionically bridged DSP-zinc-poly(lactic-co-glycolic acid) (PLGA) nanocomplex (DZP-NCs-in-microgel) for the oral local treatment of UC. The successful encapsulation of DSP-zinc-PLGA nanocomplex (DZP-NCs) in alginate microgel was confirmed by SEM imaging. The prepared gel released DZP-NCs in the stimulated intestinal fluid and dampened the release of DSP in the upper gastrointestinal tract. Furthermore, DZP-NCs-in-microgel alleviated colonic inflammation in a mouse model of dextran sodium sulfate-induced colitis by relieving clinical symptoms and histological marks. Our results suggest a novel approach for the oral colon-targeted delivery of dexamethasone sodium phosphate for the treatment of UC.

Emulsion-free chitosan-genipin microgels for growth plate cartilage regeneration.

The growth plate is a cartilage tissue near the ends of children's long bones and is responsible for bone growth. Injury to the growth plate can result in the formation of a 'bony bar' which can span the growth plate and result in bone growth abnormalities in children. Biomaterials such as chitosan microgels could be a potential treatment for growth plate injuries due to their chondrogenic properties, which can be enhanced through loading with biologics. They are commonly fabricated via an emulsion method, which involves solvent rinses that are cytotoxic. Here, we present a high throughput, non-cytotoxic, non-emulsion-based method to fabricate chitosan-genipin microgels. Chitosan was crosslinked with genipin to form a hydrogel network, and then pressed through a syringe filter using mesh with various pore sizes to produce a range of microgel particle sizes. The microgels were then loaded with chemokines and growth factors and their release was studied in vitro. To assess the applicability of the microgels for growth plate cartilage regeneration, they were injected into a rat growth plate injury. They led to increased cartilage repair tissue and were fully degraded by 28 days in vivo. This work demonstrates that chitosan microgels can be fabricated without solvent rinses and demonstrates their potential for the treatment of growth plate injuries.

Sustained release of dermal papilla-derived extracellular vesicles from injectable microgel promotes hair growth.

Hair regeneration has long captured researchers' attention because alopecia is a common condition and current therapeutic approaches have significant limitations. Dermal papilla (DP) cells serve as a signaling center in hair follicles and regulate hair formation and cycling by paracrine secretion. Secreted EVs are important signaling mediators for intercellular communication, and DP-derived extracellular vesicles (DP-EVs) may play an important role in hair regeneration. However, the instability of EVs in vivo and their low long-term retention after transplantation hinder their use in clinical applications. Methods: Human DP-EVs were encapsulated in partially oxidized sodium alginate (OSA) hydrogels, yielding OSA-encapsulated EVs (OSA-EVs), which act as a sustained-release system to increase the potential therapeutic effect of DP-EVs. The ability of the OSA-EVs to protect protein was assessed. The hair regeneration capacity of OSA-EVs, as well as the underlying mechanism, was explored in hair organ culture and a mouse model of depilation. Results: The OSA-EVs were approximately 100 µm in diameter, and as the hydrogel degraded, DP-EVs were gradually released. In addition, the hydrogel markedly increased the stability of vesicular proteins and increased the retention of EVs in vitro and in vivo. The OSA-EVs significantly facilitated proliferation of hair matrix cells, prolonged anagen phase in cultured human hairs, and accelerated the regrowth of back hair in mice after depilation. These effects may be due to upregulation of hair growth-promoting signaling molecules such as Wnt3a and ß-catenin, and downregulation of inhibitory molecule BMP2. Conclusion: This study demonstrated that OSA hydrogels promote the therapeutic effects of DP-EVs, and indicate that our novel OSA-EVs could be used to treat alopecia.

Microgels: Modular, tunable constructs for tissue regeneration.

Biopolymer microgels are emerging as a versatile tool for aiding in the regeneration of damaged tissues due to their biocompatible nature, tunable microporous structure, ability to encapsulate bioactive factors, and tailorable properties such as stiffness and composition. These properties of microgels, along with their injectability, have allowed for their utilization in a multitude of different tissue engineering applications. Controlled release of growth factors, antibodies, and other bioactive factors from microgels have demonstrated their capabilities as transporters for essential bioactive molecules necessary for guiding tissue reconstruction. Additionally, recent in vitro studies of cellular interaction and proliferation within microgel structures have laid the initial groundwork for regenerative tissue engineering using these materials. Microgels have even been crosslinked together in various ways or 3D printed to form three-dimensional scaffolds to support cell growth. In vivo studies of microgels have pioneered the clinical relevance of these novel and innovative materials for regenerative tissue engineering. This review will cover recent developments and research of microgels as they pertain to bioactive factor release, cellular interaction and proliferation in vitro, and tissue regeneration in vivo. STATEMENT OF SIGNIFICANCE: This review is focused on state-of-the-art microgel technology and innovations within the tissue engineering field, focusing on the use of microgels in bioactive factor delivery and as cell-interactive scaffolds, both in vitro and in vivo. Microgels are hydrogel microparticles that can be tuned based on the biopolymer from which they are derived, the crosslinking chemistry used, and the fabrication method. The emergence of microgels for tissue regeneration applications in recent years illuminates their versatility and applicability in clinical settings.

NIR-responsive ROS generating core and ROS-triggered 5'-Deoxy-5-fluorocytidine releasing shell structured water-swelling microgel for locoregional combination cancer therapy.

Combination chemotherapy now becomes the most standard cancer treatment protocol. Here, we present a core-shell type polymeric microgel (CSPM) which combines photodynamic and chemo therapeutic modalities in one-pot system. CSPM localizes in the malignant lesion after intratumoral injection, releases reactive oxygen species (ROS) and anticancer drug (5'-deoxy-5-fluorocytidine; DFCR) under the near-infrared (NIR) laser treatment. Pheophorbide A (PheoA)-linked poly(hydroxyethyl methacrylate) (poly-HEMA) was designated to a ROS-generating core, and chemically covered with a chitosan shell. In addition, phenylboronic acid was employed in chitosan shells and linked to DFCR to form an ROS cleavable boronic ester. The core-shell structure of CSPM was determined by transmission electron microscopy. NIR-responsive photodynamic ROS generation was confirmed by the oxidative reduction of 9,10-dimethylanthracene (a fluorescent dye), and the cascadic release of DFCR by ROS was confirmed by a release study and a live and dead cell imaging study. Typically, poly-HEMA cored microgel increased its volume by 48.9-fold after absorption of body fluid. This swelling property ensured CSPM was retained in tumor tissues after subtumoral injection and the suitability of CSPM for locoregional phototherapy. The therapeutic effect of CSPM was attributed to the combined, cascadic deliveries of cytotoxic ROS and DFCR and confirmed by growth inhibition studies in in vitro pancreatic cancer cells and in vivo colon cancer mouse model.