Black Phosphorus Hydrogel Scaffolds Enhance Bone Regeneration via a Sustained Supply of Calcium-Free Phosphorus.

Effective bone regeneration remains a challenge for bone-tissue engineering. In this study, we propose a new strategy to accelerate bone regeneration via a sustained supply of phosphorus without providing foreign calcium. Herein, a black phosphorus nanosheet (BPN)-based hydrogel platform was developed, and the BPNs were used to stably and mildly provide phosphorus. The hydrogel was fabricated by photo-crosslinking of gelatin methacrylamide, BPNs, and cationic arginine-based unsaturated poly(ester amide)s. This platform combines the following advantages: the hydrogel scaffold would keep BPNs inside, and the encapsulated BPNs can degrade into phosphorus ions and capture calcium ions to accelerate biomineralization in a bone defect. The introduction of BPNs helped to enhance the mechanical performance of hydrogels, photoresponsively release phosphate, and accelerate mineralization in vitro. Moreover, BPN-containing hydrogels improved osteogenic differentiation of human dental pulp stem cells via the bone morphogenic protein-runt-related transcription factor 2 pathway. In vivo results from a rabbit model of bone defects revealed that the BPNs helped to accelerate bone regeneration. All these results strongly suggest that the strategy of a sustained supply of calcium-free phosphorus and this BPN-containing hydrogel platform hold promise for effective bone regeneration.

Oxythiamine improves antifungal activity of ketoconazole evaluated in canine Malassezia pachydermatis strains.

BACKGROUND: Malassezia pachydermatis is an opportunistic yeast involved in skin and ear canal infections of dogs and cats. Reports suggest that strains of M. pachydermatis resistant to commonly used antifungal agents may be emerging. Therefore, new therapeutic strategies should be explored. OBJECTIVES: The synergistic effect of oxythiamine (OT) and ketoconazole (KTC) was analysed using a reference strain and field isolates (n = 66) of M. pachydermatis. Hydrogel formulations containing these components also were evaluated. METHODS AND MATERIALS: The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of OT, KTC and their mixtures were determined by a broth macrodilution method. The antifungal effects of hydrogel formulations were determined by a plate diffusion method. RESULTS: The MIC and MFC values of OT were in the range 0.08 × 103 to 10 × 103  mg/L. All M. pachydermatis strains showed higher susceptibility to KTC (MICs and MFCs in the range 0.04-0.32 mg/L). Formulations that combined OT and KTC showed a synergistic effect for all tested isolates (n = 66). Hydrogels that contained OT at a concentration of 10 × 103 or 20 × 103  mg/L and KTC at the concentration of 0.1 × 103  mg/L showed a stronger effect than a commercially available product with KTC alone (20 × 103  mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Synergy of these drugs may allow for successful topical treatment which utilizes lower doses of KTC without changing its therapeutic effectiveness. Hydrogel formulations proved to be attractive drug carriers for potential topical use.

Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimized Hydrogel Loaded Liposomal Formulation with In Vivo Evaluation in Wistar Rats.

Aspasomes of methotrexate with antioxidant, ascorbyl palmitate, were developed and optimized using factorial design by varying parameters such as lipid molar ratio, drug to lipid molar ratio, and type of hydration buffer for transdermal delivery for disease modifying activity in rheumatoid arthritis (RA). Aspasomes were characterized by drug-excipients interaction, particle size analysis, determination of zeta potential, entrapment efficiency, and surface properties. The best formulation was loaded into hydrogel for evaluation of in vitro drug release and tested in vivo against adjuvant induced arthritis model in wistar rats, by assessing various physiological, biochemical, hematological, and histopathological parameters. Optimized aspasome formulation exhibited smooth surface with particle size 386.8 nm, high drug loading (19.41%), negative surface potential, and controlled drug release in vitro over 24 h with a steady permeation rate. Transdermal application of methotrexate-loaded aspasome hydrogel for 12 days reduced rat paw diameter (21.25%), SGOT (40.43%), SGPT (54.75%), TNFα (33.99%), IL ß (34.79%), cartilage damage (84.41%), inflammation (82.37%), panus formation (84.38%), and bone resorption (80.52%) as compared to arthritic control rats. Free methotrexate-treated group showed intermediate effects. However, drug-free aspasome treatment did not show any effect. The experimental results indicate a positive outcome in development of drug-loaded therapeutically active carrier system which presents a non-invasive controlled release transdermal formulation with good drug loading, drug permeation rate, and having better disease modifications against RA than the free drug, thereby providing a more attractive therapeutic strategy for rheumatoid disease management.

A new, easy-to-make pectin-honey hydrogel enhances wound healing in rats.

BACKGROUND: Honey, alone or in combination, has been used for wound healing since ancient times and has reemerged as a topic of interest in the last decade. Pectin has recently been investigated for its use in various biomedical applications such as drug delivery, skin protection, and scaffolding for cells. The aim of the present study was to develop and evaluate a pectin-honey hydrogel (PHH) as a wound healing membrane and to compare this dressing to liquid honey. METHODS: Thirty-six adult male Sprague-Dawley rats were anesthetized and a 2 × 2 cm excisional wound was created on the dorsum. Animals were randomly assigned to four groups (PHH, LH, Pec, and C): in the PHH group, the pectin-honey hydrogel was applied under a bandage on the wound; in the LH group, liquid Manuka honey was applied; in the Pec group, pectin hydrogel was applied (Pec); and in the C group, only bandage was applied to the wound. Images of the wound were taken at defined time points, and the wound area reduction rate was calculated and compared between groups. RESULTS: The wound area reduction rate was faster in the PHH, LH, and Pec groups compared to the control group and was significantly faster in the PHH group. Surprisingly, the Pec group exhibited faster wound healing than the LH group, but this effect was not statistically significant. CONCLUSION: This is the first study using pectin in combination with honey to produce biomedical hydrogels for wound treatment. The results indicate that the use of PHH is effective for promoting and accelerating wound healing.

Injectable and responsively degradable hydrogel for personalized photothermal therapy.

Near infrared-absorbing hydrogels are used for the repeated photothermal treatments of cancer. However, a long-term retention of hydrogel in the body leads to increased risk of toxicity. Here we developed an injectable and on-demand degradable hydrogel to conduct the repeated photothermal therapies (PTTs). Alginate-calcium hydrogel immobilized dendrimer-encapsulated platinum nanoparticles (DEPts) in its matrix represented excellent biocompatibility, and was degraded upon injecting chelates. Results from the in vivo studies reveal that the hydrogel/DEPts-mediated repeated PTTs suppressed tumor growth efficiently, and the hydrogel was degraded on-demand to allow renal secretion of DEPts out of the body. Furthermore, coating hydrogel/DEPts on the tumor instead of intratumoral injection could still ablate tumor efficiently. Our investigation provides a smart and safe hydrogel for photothermal cancer therapy.

Dual-functional transdermal drug delivery system with controllable drug loading based on thermosensitive poloxamer hydrogel for atopic dermatitis treatment.

The treatment of atopic dermatitis (AD) has long been viewed as a problematic issue by the medical profession. Although a wide variety of complementary therapies have been introduced, they fail to combine the skin moisturizing and drug supply for AD patients. This study reports the development of a thermo-sensitive Poloxamer 407/Carboxymethyl cellulose sodium (P407/CMCs) composite hydrogel formulation with twin functions of moisture and drug supply for AD treatment. It was found that the presence of CMCs can appreciably improve the physical properties of P407 hydrogel, which makes it more suitable for tailored drug loading. The fabricated P407/CMCs composite hydrogel was also characterized in terms of surface morphology by field emission scanning electron microscopy (FE-SEM), rheological properties by a rheometer, release profile in vitro by dialysis method and cytotoxicity test. More importantly, the findings from transdermal drug delivery behavior revealed that P407/CMCs showed desirable percutaneous performance. Additionally, analysis of cytotoxicity test suggested that P407/CMCs composite hydrogel is a high-security therapy for clinical trials and thus exhibits a promising way to treat AD with skin moisturizing and medication.

An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease.

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.

An insight on human skin penetration of diflunisal: lipogel versus hydrogel microemulsion.

Diflunisal is a NSAID used in acute and long term management of pain and inflammation associated with osteoarthritis, rheumatoid arthritis and symptoms of primary dysmenorrhea. However, its oral use is associated with side effects such as peptic ulceration, dyspepsia, gastrointestinal disturbances and bleeding. The aim of this work was to develop lecithin organogels (LO) transdermal delivery system for diflunisal and to study its human skin penetration ability in comparison with an optimized microemulsion-based hydrogel. Ternary phase diagrams were constructed using butyl lactate as an organic solvent and two commercial grades of lecithin. The formation of gel phase was lecithin concentration dependent with Phosholipion 85 G being capable of forming organogels at lower lecithin concentration than Lipoid S75. The gels prepared using butyl lactate were able to tolerate higher amounts of water than could be incorporated in the lipogels prepared with other organic solvents. All the investigated gels possessed acceptable physical properties and were able to deliver diflunisal through human skin. The lipogels delivered higher total drug amount through the skin than the hydrogel. The composition of lecithin seemed to have some effect on the skin permeability enhancement ability of the lipogel. Lecithin containing higher amount of phosphatidyl ethanolamine could provide better transdermal delivery. The elaborated lecithin organogels are potential carriers that create a good opportunity for transdermal delivery of diflunisal overcoming the side effects associating its oral route.

An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration.

Intervertebral disc (IVD) degeneration is one of the leading causes of lower back pain and a major health problem worldwide. Current surgical treatments include excision or immobilisation, with neither approach resulting in the repair of the degenerative disc. As such, a tissue engineering-based approach in which stem cells, coupled with an advanced delivery system, could overcome this deficiency and lead to a therapy that encourages functional fibrocartilage generation in the IVD. In this study, we have developed an injectable hydrogel system based on enzymatically-crosslinked polyethylene glycol and hyaluronic acid. We examined the effects of adding pentosan polysulphate (PPS), a synthetic glycosaminoglycan-like factor that has previously been shown (in vitro and in vivo) to this gel system in order to induce chondrogenesis in mesenchymal precursor cells (MPCs) when added as a soluble factor, even in the absence of additional growth factors such as TGF-ß. We show that both the gelation rate and mechanical strength of the resulting hydrogels can be tuned in order to optimise the conditions required to produce gels with the desired combination of properties for an IVD scaffold. Human immunoselected STRO-1+ MPCs were then incorporated into the hydrogels. They were shown to retain good viability after both the initial formation of the gel and for longer-term culture periods in vitro. Furthermore, MPC/hydrogel composites formed cartilage-like tissue which was significantly enhanced by the incorporation of PPS into the hydrogels, particularly with respect to the deposition of type-II-collagen. Finally, using a wild-type rat subcutaneous implantation model, we examined the extent of any immune reaction and confirmed that this matrix is well tolerated by the host. Together these data provide evidence that such a system has significant potential as both a delivery vehicle for MPCs and as a matrix for fibrocartilage tissue engineering applications.

Comparison of bone morphogenetic protein-2 and osteoactivin for mesenchymal cell differentiation: effects of bolus and continuous administration.

Current osteoinductive protein therapy utilizes bolus administration of large doses of bone morphogenetic proteins (BMPs), which is costly, and may not replicate normal bone healing. The limited in vivo biologic activity of BMPs requires the investigation of growth factors that may enhance this activity. In this study, we utilized the C3H10T1/2 murine mesenchymal stem cell line to test the hypotheses that osteoactivin (OA) has comparable osteoinductive effects to bone morphogenetic protein-2 (BMP-2), and that sustained administration of either growth factor would result in increased osteoblastic differentiation as compared to bolus administration. Sustained release biodegradable hydrogels were designed, and C3H10T1/2 cells were grown on hydrogels loaded with BMP-2 or OA. Controls were grown on unloaded hydrogels, and positive controls were exposed to bolus growth factor administration. Cells were harvested at several time points to assess osteoblastic differentiation. Alkaline phosphatase (ALP) staining and activity, and gene expression of ALP and osteocalcin were assessed. Treatment with OA or BMP-2 resulted in comparable effects on osteoblastic marker expression. However, cells grown on hydrogels demonstrated osteoblastic differentiation that was not as robust as cells treated with bolus administration. This study shows that OA has comparable effects to BMP-2 on osteoblastic differentiation using both bolus administration and continuous release, and that bolus administration of OA has a more profound effect than administration using hydrogels for sustained release. This study will lead to a better understanding of appropriate delivery methods of osteogenic growth factors like OA for repair of fractures and segmental bone defects.

[Treatment of atrophic and irritative vulvovaginal symptoms with an anhydrous lipogel and its complementary effect with vaginal estrogenic therapy: new evidences]. / Trattamento dei disturbi trofici e irritativi vulvovaginali con un lipogel anidro e suo effetto complementare alla terapia estrogenica per via vaginale: nuovi approfondimenti.

It is sometimes difficult to treat vulvovaginal itching and dryness, which represent frustrating symptoms for both patients and doctors. In case that the etiological agent is Candida albicans, effective antimycotic therapies are available; however, itching is often caused by aspecific allergic-irritative factors, which are difficult to be defined. In these cases, patients are invited to limit local irritative factors; nevertheless, this advice is not always taken and sometimes it turns out to be insufficient. Besides behavioral suggestions, a therapeutic support would be useful; medical doctors habitually prescribe local symptomatic treatments which, however, do not target numerous causes of irritative vulvovaginal symptomatology, though they are formulated for vulvovaginal application. If there is estrogenic deficit, the best therapeutic approach is based on topical estrogenic therapy, which is sometimes ineffective on vulvar symptoms. Frequently, it is necessary to choose a complementary therapeutic tool for vaginal application in order to alleviate itching, burning, erythema, dryness. The aim of this study was to evaluate the efficacy of an innovative anhydrous lipogel containing vitamin E and boswellic acids. Results of this study, performed on 34-58-year-old patients, confirmed the efficacy of the lipogel on irritative vulvovaginal symptoms. In postmenopausal women, the lipogel is a useful synergistic complement to topical hormonal therapy.

Injectable thermosensitive hydrogel based on chitosan and quaternized chitosan and the biomedical properties.

A novel injectable thermosensitive hydrogel (CS-HTCC/alpha beta-GP) was successfully designed and prepared using chitosan (CS), quaternized chitosan (HTCC) and alpha,beta-glycerophosphate (alpha,beta-GP) without any additional chemical stimulus. The gelation point of CS-HTCC/alpha beta-GP can be set at a temperature close to normal body temperature or other temperature above 25 degrees C. The transition process can be controlled by adjusting the weight ratio of CS to HTCC, or different final concentration of alpha,beta-GP. The optimum formulation is (CS + HTCC) (2% w/v), CS/HTCC (5/1 w/w) and alpha,beta-GP 8.33% or 9.09% (w/v), where the sol-gel transition time was 3 min at 37 degrees C. The drug released over 3 h from the CS-HTCC/alpha,beta-GP thermosensitive hydrogel in artificial saliva pH 6.8. In addition, CS-HTCC/alpha,beta-GP thermosensitive hydrogel exhibited stronger antibacterial activity towards two periodontal pathogens (Porphyromonas gingivalis, P.g and Prevotella intermedia, P.i). CS-HTCC/alpha, beta-GP thermosensitive hydrogel was a considerable candidate as a local drug delivery system for periodontal treatment.