Emerging materials and technologies for advancing bioresorbable surgical meshes.

Surgical meshes play a significant role in the treatment of various medical conditions, such as hernias, pelvic floor issues, guided bone regeneration, and wound healing. To date, commercial surgical meshes are typically made of non-absorbable synthetic polymers, notably polypropylene and polytetrafluoroethylene, which are associated with postoperative complications, such as infections. Biological meshes, based on native tissues, have been employed to overcome such complications, though mechanical strength has been a main disadvantage. The right balance in mechanical and biological performances has been achieved by the advent of bioresorbable meshes. Despite improvements, recurrence of clinical complications associated with surgical meshes raises significant concerns regarding the technical adequacy of current materials and designs, pointing to a crucial need for further development. To this end, current research focuses on the design of meshes capable of biomimicking native tissue and facilitating the healing process without post-operative complications. Researchers are actively investigating advanced bioresorbable materials, both synthetic polymers and natural biopolymers, while also exploring the performance of therapeutic agents, surface modification methods and advanced manufacturing technologies such as 4D printing. This review seeks to evaluate emerging biomaterials and technologies for enhancing the performance and clinical applicability of the next-generation surgical meshes. STATEMENT OF SIGNIFICANCE: In the ever-transforming landscape of regenerative medicine, the embracing of engineered bioabsorbable surgical meshes stands as a key milestone in addressing persistent challenges and complications associated with existing treatments. The urgency to move beyond conventional non-absorbable meshes, fraught with post-surgery complications, emphasises the necessity of using advanced biomaterials for engineered tissue regeneration. This review critically examines the growing field of absorbable surgical meshes, considering their potential to transform clinical practice. By strategically combining mechanical strength with bioresorbable characteristics, these innovative meshes hold the promise of mitigating complications and improving patient outcomes across diverse medical applications. As we navigate the complexities of modern medicine, this exploration of engineered absorbable meshes emerges as a promising approach, offering an overall perspective on biomaterials, technologies, and strategies adopted to redefine the future of surgical meshes.

Bioinspired 3D-printed scaffold embedding DDAB-nano ZnO/nanofibrous microspheres for regenerative diabetic wound healing.

There is a constant demand for novel materials/biomedical devices to accelerate the healing of hard-to-heal wounds. Herein, an innovative 3D-printed bioinspired construct was developed as an antibacterial/regenerative scaffold for diabetic wound healing. Hyaluronic/chitosan (HA/CS) ink was used to fabricate a bilayer scaffold comprising a dense plain hydrogel layer topping an antibacterial/regenerative nanofibrous layer obtained by incorporating the hydrogel with polylactic acid nanofibrous microspheres (MS). These were embedded with nano ZnO (ZNP) or didecyldimethylammonium bromide (DDAB)-treated ZNP (D-ZNP) to generate the antibacterial/healing nano/micro hybrid biomaterials, Z-MS@scaffold and DZ-MS@scaffold. Plain and composite scaffolds incorporating blank MS (blank MS@scaffold) or MS-free ZNP@scaffold and D-ZNP@scaffold were used for comparison. 3D printed bilayer constructs with customizable porosity were obtained as verified by SEM. The DZ-MS@scaffold exhibited the largest total pore area as well as the highest water-uptake capacity andin vitroantibacterial activity. Treatment ofStaphylococcus aureus-infected full thickness diabetic wounds in rats indicated superiority of DZ-MS@scaffold as evidenced by multiple assessments. The scaffold afforded 95% wound-closure, infection suppression, effective regulation of healing-associated biomarkers as well as regeneration of skin structure in 14 d. On the other hand, healing of non-diabetic acute wounds was effectively accelerated by the simpler less porous Z-MS@scaffold. Information is provided for the first-time on the 3D printing of nanofibrous scaffolds using non-electrospun injectable bioactive nano/micro particulate constructs, an innovative ZNP-functionalized 3D-printed formulation and the distinct bioactivity of D-ZNP as a powerful antibacterial/wound healing promotor. In addition, findings underscored the crucial role of nanofibrous-MS carrier in enhancing the physicochemical, antibacterial, and wound regenerative properties of DDAB-nano ZnO. In conclusion, innovative 3D-printed DZ-MS@scaffold merging the MS-boosted multiple functionalities of ZNP and DDAB, the structural characteristics of nanofibrous MS in addition to those of the 3D-printed bilayer scaffold, provide a versatile bioactive material platform for diabetic wound healing and other biomedical applications.

Carbon dots labeled Lactiplantibacillus plantarum: a fluorescent multifunctional biocarrier for anticancer drug delivery.

A carbon dots (CDs)-biolabeled heat-inactivated Lactiplantibacillus plantarum (HILP) hybrid was investigated as a multifunctional probiotic drug carrier with bioimaging properties using prodigiosin (PG) as anticancer agent. HILP, CDs and PG were prepared and characterized using standard methods. CDs-labeled HILP (CDs/HILP) and PG loaded CDs/HILP were characterized by transmission electron microscopy (TEM), laser scanning confocal microscopy (LSCM) and for entrapment efficiency (EE%) of CDs and PG, respectively. PG-CDs/HILP was examined for stability and PG release. the anticancer activity of PG-CDs/HILP was assessed using different methods. CDs imparted green fluorescence to HILP cells and induced their aggregation. HILP internalized CDs via membrane proteins, forming a biostructure with retained fluorescence in PBS for 3 months at 4°C. Loading PG into CDs/HILP generated a stable green/red bicolor fluorescent combination permitting tracking of both drug carrier and cargo. Cytotoxicity assay using Caco-2 and A549 cells revealed enhanced PG activity by CDs/HILP. LCSM imaging of PG-CDs/HILP-treated Caco-2 cells demonstrated improved cytoplasmic and nuclear distribution of PG and nuclear delivery of CDs. CDs/HILP promoted PG-induced late apoptosis of Caco-2 cells and reduced their migratory ability as affirmed by flow cytometry and scratch assay, respectively. Molecular docking indicated PG interaction with mitogenic molecules involved in cell proliferation and growth regulation. Thus, CDs/HILP offers great promise as an innovative multifunctional nanobiotechnological biocarrier for anticancer drug delivery. This hybrid delivery vehicle merges the physiological activity, cytocompatibility, biotargetability and sustainability of probiotics and the bioimaging and therapeutic potential of CDs.

Itraconazole for Topical Treatment of Skin Carcinogenesis: Efficacy Enhancement by Lipid Nanocapsule Formulations.

Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.

Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules.

Itraconazole (ITC), a well-tolerated antifungal drug, exerts multiple anticancer effects which justified its preclinical and clinical investigation as potential anti-cancer agent with reduced side effects. Enhancement of ITC anti-cancer efficacy would bring valuable benefits to patients. We propose herein lipid nanocapsules (LNCs) modified with a subtherapeutic dose of miltefosine (MFS) as a membrane bioactive amphiphilic additive (M-ITC-LNC) for the development of an ITC nanoformulation with enhanced anticancer activity compared with ITC solution (ITC-sol) and unmodified ITC-LNC. Both LNC formulations showed a relatively small size (43-46 nm) and high entrapment efficiency (>97%), though ITC release was more sustained by M-ITC-LNC. Cytotoxicity studies revealed significantly greater anticancer activity and selectivity of M-ITC-LNC for MCF-7 breast cancer cells compared with ITC-sol and ITC-LNC. This trend was substantiated by in vivo findings following a 14 day-treatment of murine mammary pad Ehrlich tumors. M-ITC-LNC showed the greatest enhancement of the ITC-induced tumor growth inhibition, proliferation, and necrosis. At the molecular level, the tumor content of Gli 1, caspase-3, and vascular endothelial growth factor verified superiority of M-ITC-LNC in enhancing the ITC antiangiogenic, apoptotic, and Hedgehog pathway inhibitory effects. Finally, histopathological and biochemical analysis indicated greater reduction of ITC systemic toxicity by M-ITC-LNC. Superior performance of M-ITC-LNC was attributed to the effect of MFS on the structural and release properties of LNC coupled with its distinct bioactivities. In conclusion, MFS-modified LNC provides a simple nanoplatform integrating the potentials of LNC and MFS for enhancing the chemotherapeutic efficacy of ITC and possibly other oncology drugs.

Local treatment of experimental mandibular osteomyelitis with an injectable biomimetic gentamicin hydrogel using a new rabbit model.

Mandibular osteomyelitis (OM) is a challenging disease. Our objective was to assess a new OM model in rabbits induced by arsenic trioxide and to assess the efficacy of local treatment of OM using injectable gentamicin-collagen hydrogels (GNT-COLL). OM was induced unilaterally by controlled confinement of arsenic trioxide paste to the root canal of lower incisors of rabbits, while OM progression was characterized for 16 weeks. On the other hand, two injectable COLL hydrogels functionalized with GNT were prepared and characterized for physicochemical properties; a simple GNT-COLL and a nanohydroxyapatite (nHA)- loaded hydrogel (GNT-COLL/nHA). The two hydrogels were evaluated to treat OM model, while a multidose intramuscular GNT solution served as positive control. Outcomes were assessed by standard methods at 4 and 12 weeks post-surgery. The clinical, radiographical, and histopathological findings provided evidence for the validity of the arsenic-induced OM. The results demonstrated that a single intra-lesional injection of the two hydrogels was more suppressive to OM compared to multidose systemic GNT. The composite GNT-COLL/nHA hydrogel proved to induce early preservation of alveolar bone (ridge) length and higher amount of bone area\total area at 4 weeks (40.53% ± 2.34) followed by GNT-COLL (32.21% ± 0.72). On the other hand, the positive control group revealed the least ridge length and bone area\total area (26.22% ± 1.32) at 4 weeks. Both hydrogels successfully arrested OM with no signs of recurrence for up to 12 weeks. Therefore, results support the greater advantages of the composite hydrogel as an osteogenic/antibiotic delivery system in OM treatment.

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni.

BACKGROUND: The control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy. METHODS: Two nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukey's post-hoc test for pairwise comparisons. RESULTS: Lipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures. CONCLUSIONS: The therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.

Evaluation of prophylactic efficacy and safety of praziquantel-miltefosine nanocombination in experimental Schistosomiasis mansoni.

The control of schistosomiasis depends exclusively on praziquantel (PZQ) monotherapy with treatment failure due to minor activity against the juvenile stage, re-infection and emerging drug resistance. Improving the antischistosomal therapeutic/prophylactic profile of PZQ is a sensible option to save the clinical benefits of the drug if achieved effectively and safely via a single oral dose. Recently, we developed praziquantel-miltefosine lipid nanocapsules (PZQ 250 mg/kg-MFS 20 mg/kg LNCs) as a nanotechnology-enabled novel drug combination with significant multistage activity against Schistosoma mansoni (S. mansoni) in a murine model. The present study aimed at providing a proof of concept of the chemoprophylactic effect of this nanocombination. A single oral dose of the nanocombination was administered to mice one and seven days before challenge infection with S. mansoni. The protective effect of the nanocombination was assessed parasitologically and histopathologically relative to LNCs singly-loaded with PZQ or MFS and non-treated infected controls. In addition, the safety of the nanocombination was assessed biochemically and histopathologically. Administration of the nanocombination one or seven days pre-infection resulted in a statistically significant reduction in mean worm burden and granulomas size associated with amelioration of hepatic pathology compared to infected non-treated control. Although, the prophylactic effect was significantly reduced upon administration seven days pre-infection compared to administration one day pre-infection, yet, it still exists. Results were explained based on the spectrum of activity of PZQ and MFS and their complementary pharmacokinetic (PK) profiles in addition to the effect of nanoencapsulation on these factors. The novel PZQ-MFS nanocombination offers valuable potentials in PZQ-based mass drug administration programmes by granting radical cure, preventing re-infection, and delaying development of resistance to the component drugs.

Itraconazole lipid nanocapsules gel for dermatological applications: In vitro characteristics and treatment of induced cutaneous candidiasis.

There is a growing clinical demand for topical itraconazole (ITC) delivery systems because of the expanding potential of the drug for topical fungal and non-fungal applications. Lipid-based nanocarriers offer great promise in this respect. In the present study, a new topical ITC gel based on lipid nanocapsules (LNC) was developed. ITC-LNC were compared to ITC-loaded nanostructured lipid carriers (ITC-NLC) with more established benefits as topical vectors. Both nanocarriers showed high entrapment efficiency (EE > 98%). Compared to ITC-NLC, the ITC-LNC showed a significantly smaller particle size (∼50 vs 155 nm), narrower size distribution (0.09 vs 0.38), faster initial release rate under sink conditions and greater in vitro antifungal activity against Candida albicans (C. albicans) (inhibition zone 29.4 vs 26.4 mm). ITC-LNC and ITC-NLC-based gels significantly enhanced the dermal retention of ITC in excised human skin relative to a conventional ITC gel. Histopathological assessment of a 14-day treatment of induced cutaneous candidiasis in a rat model indicated efficacy of the gel preparations. Fungal elements developed in the superficial epidermal skin layer were cleared by the end of treatment. Equally important, no histopathological changes in the epidermal and dermal layers of rat skin were observed. Findings of this study verified efficacy of topical ITC in the treatment of superficial fungal infections as well as effectiveness of LNC as biomimetic nanocarrier for dermal drug delivery. Combining ITC and LNC would present a bioactive nanocarrier system with good potentials for fungal infections and other skin applications.

Protective effect of surface-modified berberine nanoparticles against LPS-induced neurodegenerative changes: a preclinical study.

Berberine (BBR) exerts documented protection against neurodegenerative disorders. However, data on the effect of nano-encapsulation on the neuroprotective effect of BBR are lacking. We investigated the effect of BBR loading into chitosan (CS) nanoparticles (NPs) and their surface modification with Tween 80 (T80), polyethylene glycol 4000 (PEG), and miltefosine (MFS) against lipopolysaccharide (LPS)-induced neurodegenerative changes in addition to hepatotoxicity in rats. BBR-NPs were prepared by ionic gelation and characterized for morphology by transmission electron microscopy (TEM), colloidal properties, and entrapment efficiency (EE%). The neuroprotective and hepatoprotective effects of a 14-day pretreatment with four BBR-NPs formulations (4 mg/kg BBR/day) by intraperitoneal (i.p.) injection were challenged by a single i.p. 4 mg/kg dose of LPS on the fifteenth day. Neuroprotective efficacy and potential toxicity of BBR-NPs relative to BBR solution were assessed biochemically and histopathologically. One-way ANOVA followed by Tukey's comparison test was used for statistical analysis. CS nano-encapsulation and surface modification of BBR-NPs altered the neuroprotective and hepatoprotective effects of BBR depending on the physicochemical and/or biological effects of BBR, CS, coating materials, and NP-related features. Similar to the prophylactic and treatment efficacy of NPs for brain delivery, safety of these nanostructures and their individual formulation components warrants due research attention.

Praziquantel-lipid nanocapsules: an oral nanotherapeutic with potential Schistosoma mansoni tegumental targeting.

PURPOSE: Lipid nanocapsules (LNCs) have shown potential to increase the bioavailability and efficacy of orally administered drugs. However, their intestinal translocation to distal target sites and their implication in pharmacokinetic (PK)-pharmacodynamic (PD) relationships are yet to be elucidated. In this study, the effect of LNCs on the PD activity and pharmacokinetics of praziquantel (PZQ), the mainstay of schistosomiasis chemotherapy, was investigated. MATERIALS AND METHODS: The composition of LNCs was modified to increase PZQ payload and to enhance membrane permeability. PZQ-LNCs were characterized in vitro for colloidal properties, entrapment efficiency (EE%), and drug release. PD activity of the test formulations was assessed in Schistosoma mansoni-infected mice 7 days post-oral administration of a single 250 mg/kg oral dose. Pharmacokinetics of the test formulations and their stability in simulated gastrointestinal (GI) fluids were investigated to substantiate in vivo data. RESULTS: PZQ-LNCs exhibited good pharmaceutical attributes in terms of size (46-62 nm), polydispersity index (0.01-0.08), EE% (>95%), and sustained release profiles. Results indicated significant efficacy enhancement by reduction in worm burden, amelioration of liver pathology, and extensive damage to the fluke suckers and tegument. This was partly explained by PK data determined in rats. In addition, oral targeting of the worms was supported by the stability of PZQ-LNCs in simulated GI fluids and scanning electron microscopy (SEM) visualization of nanostructures on the tegument of worms recovered from mesenteric/hepatic veins. Cytotoxicity data indicated tolerability of PZQ-LNCs. CONCLUSION: Data obtained provide evidence for the ability of oral LNCs to target distal post-absorption sites, leading to enhanced drug efficacy. From a practical standpoint, PZQ-LNCs could be suggested as a potential tolerable single lower dose oral nanomedicine for more effective PZQ mass chemotherapy.

Skin permeability enhancement by Bacillus subtilis alkaline protease: Application to transdermal drug delivery.

Enzymes may offer great potentials in topical pharmaceutical applications provided that treatment conditions are controlled for efficacy and safety. In this study, the effect of alkaline protease produced by recombinant Bacillus subtilis cells on the ex-vivo permeability of rabbit ear skin was investigated under different conditions of enzyme activity (5-60 units) and exposure time (15-60min). Data for transepidermal water loss (TEWL) and permeation of a hydrophilic dye, rhodamine B (Rb), indicated biphasic activity-dependent and exposure time-dependent skin permeability. Maximum effects were obtained at 20 proteolytic units and 30min exposure. Findings proved consistent with histopathological changes indicating progressive stratum corneum (SC) loss and disruption of the dermo-epidermal junction at 20 units and up to 30min exposure time followed by dermal hyalinization at longer exposure. This was associated with progressive loss of skin hair. Applying the identified pretreatment conditions to transdermal delivery of vardenafil in a gel base across dorsal rat skin indicated a significant increase in plasma levels at 30 and 60min with minimal histopathological changes 5days post enzyme treatment. Accordingly, the recombinant B. subtilis alkaline protease offers promise as a pharmaceutical enzyme for transdermal drug delivery bioenhancement and dermatological applications.

Miltefosine lipid nanocapsules: Intersection of drug repurposing and nanotechnology for single dose oral treatment of pre-patent schistosomiasis mansoni.

A dual drug repurposing/nanotechnological approach was used to develop an alternative oral treatment for schistosomiasis mansoni using miltefosine (MFS), an anticancer alkylphosphocholine, and lipid nanocapsules (LNCs) as oral nanovectors. We demonstrated earlier that MFS possesses significant activity against different developmental stages of Schistosoma mansoni in the mouse model using 5 successive 20mg/kg/day oral doses. Moreover, an effective single dose (20mg/kg) oral treatment against the adult stage of S. mansoni in mice was developed using LNCs, particularly modified with CTAB, a positive charge imparting agent (MFS-LNC-CTAB(+)), or oleic acid as membrane permeabilizer (MFS-LNC-OA). Efficacy enhancement involved, at least in part, targeting of the worm tegument with MFS-LNCs as a new therapeutic entity. As the tegument surface charge and composition may differ in pre-patent stages of the parasite, it was of importance in the present study to assess the efficacy of a single oral dose of the two MFS-LNC formulations against invasive and immature stages for potential advantage relative to praziquantel. Results indicated potent schistosomicidal effects against both invasive and immature stages of S. mansoni in infected mice, efficacy being both formulation and developmental stage dependent. This was indicated by the significant reduction in the total worm burden of the invasive stage by 91.6% and 76.8% and the immature stage by 82.7% and 96.7% for MFS-LNC-CTAB+ and MFS-LNC-OA, respectively. Histopathological findings indicated amelioration of hepatic pathology with regression of the granulomatous inflammatory reaction and reduction in granulomas number and size, verifying marked improvement in architecture of hepatic lobules. From a clinical perspective, MFS-LNCs offer potential as an alternative single oral dose nanomedicine with a wide therapeutic profile for the mass chemotherapy of schistosomiasis mansoni.

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study.

Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases.

Vancomycin-eluting niosomes: a new approach to the inhibition of staphylococcal biofilm on abiotic surfaces.

A new vancomycin (VCM)-eluting mixed bilayer niosome formulation was evaluated for the control of staphylococcal colonization and biofilm formation on abiotic surfaces, a niosome application not explored to date. Cosurfactant niosomes were prepared using a Span 60/Tween 40/cholesterol blend (1: 1: 2). Tween 40, a polyethoxylated amphiphile, was included to enhance VCM entrapment and confer niosomal surface properties precluding bacterial adhesion. VCM-eluting niosomes showed good quality attributes including relatively high entrapment efficiency (∼50%), association of Tween 40 with vesicles in a constant proportion (∼87%), biphasic release profile suitable for inhibiting early bacterial colonization, and long-term stability at 4°C for a 12-month study period. Niosomes significantly enhanced VCM activity against planktonic bacteria of nine staphylococcal strains. Using microtiter plates as abiotic surface, VCM-eluting niosomes proved superior to VCM in inhibiting biofilm formation, eradicating surface-borne biofilms, inhibiting biofilm growth, and interfering with biofilm induction by VCM subminimal inhibitory concentrations. Data suggest dual functionality of cosurfactant VCM-eluting niosomes as passive colonization inhibiting barrier and active antimicrobial-controlled delivery system, two functions recognized in infection control of abiotic surfaces and medical devices.

A quality by design approach to optimization of emulsions for electrospinning using factorial and D-optimal designs.

Emulsion electrospinning is a multifactorial process used to generate nanofibers loaded with hydrophilic drugs or macromolecules for diverse biomedical applications. Emulsion electrospinnability is greatly impacted by the emulsion pharmaceutical attributes. The aim of this study was to apply a quality by design (QbD) approach based on design of experiments as a risk-based proactive approach to achieve predictable critical quality attributes (CQAs) in w/o emulsions for electrospinning. Polycaprolactone (PCL)-thickened w/o emulsions containing doxycycline HCl were formulated using a Span 60/sodium lauryl sulfate (SLS) emulsifier blend. The identified emulsion CQAs (stability, viscosity and conductivity) were linked with electrospinnability using a 3(3) factorial design to optimize emulsion composition for phase stability and a D-optimal design to optimize stable emulsions for viscosity and conductivity after shifting the design space. The three independent variables, emulsifier blend composition, organic:aqueous phase ratio and polymer concentration, had a significant effect (p<0.05) on emulsion CQAs, the emulsifier blend composition exerting prominent main and interaction effects. Scanning electron microscopy (SEM) of emulsion-electrospun NFs and desirability functions allowed modeling of emulsion CQAs to predict electrospinnable formulations. A QbD approach successfully built quality in electrospinnable emulsions, allowing development of hydrophilic drug-loaded nanofibers with desired morphological characteristics.

Microneedle/nanoencapsulation-mediated transdermal delivery: mechanistic insights.

A systematic study was undertaken to gain more insight into the mechanism of transdermal delivery of nanoencapsulated model dyes across microneedle (MN)-treated skin, a complex process not yet explored. Rhodamine B (Rh B) and fluorescein isothiocyanate (FITC) as model hydrophilic and hydrophobic small/medium-size molecules, respectively, were encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and delivered through full thickness porcine skin pretreated with MN array. Permeation through MN-treated skin was affected by physicochemical characteristics of NPs and the encapsulated dyes. Dye flux was enhanced by smaller particle size, hydrophilicity, and negative zeta potential of NPs. Regarding encapsulated dyes, solubility at physiological pH and potential interaction with skin proteins proved to outweigh molecular weight as determinants of skin permeation. Data were verified using confocal laser scanning microscopy imaging. Findings coupled with the literature data are supportive of a mechanism involving influx of NPs, particularly of smaller size, deep into MN-created channels, generating depot dye-rich reservoirs. Molecular diffusion of the released dye across viable skin layers proceeds at a rate determined by its molecular characteristics. Data obtained provide mechanistic information of importance to the development of formulation strategies for more effective intradermal and transdermal MN-mediated delivery of nanoencapsulated therapeutic agents.

Effect of microneedle treatment on the skin permeation of a nanoencapsulated dye.

OBJECTIVES: The aim of the study was to investigate the effect of microneedle (MN) pretreatment on the transdermal delivery of a model drug (Rhodamine B, Rh B) encapsulated in polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) focusing on the MN characteristics and application variables. METHODS: Gantrez MNs were fabricated using laser-engineered silicone micro-mould templates. PLGA NPs were prepared using a modified emulsion-diffusion-evaporation method and characterised in vitro. Permeation of encapsulated Rh B through MN-treated full thickness porcine skin was performed using Franz diffusion cells with appropriate controls. KEY FINDINGS: In-vitro skin permeation of the nanoencapsulated Rh B (6.19 ± 0.77 µg/cm²/h) was significantly higher (P < 0.05) compared with the free solution (1.66 ± 0.53 µg/cm²/h). Mechanistic insights were supportive of preferential and rapid deposition of NPs in the MN-created microconduits, resulting in accelerated dye permeation. Variables such as MN array configuration and application mode were shown to affect transdermal delivery of the nanoencapsulated dye. CONCLUSIONS: This dual MN/NP-mediated approach offers potential for both the dermal and transdermal delivery of therapeutic agents with poor passive diffusion characteristics.

Flux of ionic dyes across microneedle-treated skin: effect of molecular characteristics.

Drug flux across microneedle (MN)-treated skin is influenced by the characteristics of the MN array, formed microconduits and physicochemical properties of the drug molecules in addition to the overall diffusional resistance of microconduits and viable tissue. Relative implication of these factors has not been fully explored. In the present study, the in vitro permeation of a series of six structurally related ionic xanthene dyes with different molecular weights (MW) and chemical substituents, across polymer MN-pretreated porcine skin was investigated in relation of their molecular characteristics. Dyes equilibrium solubility, partition coefficient in both n-octanol or porcine skin/aqueous system, and dissociation constants were determined. Results indicated that for rhodamine dyes, skin permeation of the zwitterionic form which predominates at physiological pH, was significantly reduced by an increase in MW, the skin thickness and by the presence of the chemically reactive isothiocyanate substituent. These factors were generally shown to override the aqueous solubility, an important determinant of drug diffusion in an aqueous milieu. The data obtained provided more insight into the mechanism of drug permeation across MN-treated skin, which is of importance to both the design of MN-based transdermal drug delivery systems and of relevance to skin permeation research.

Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium.

There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multidose therapy with a non- or minimally invasive delivery approach. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly(methylvinylether-co-maleic anhydride) were used for the first time in active transdermal delivery of the LMWH nadroparin calcium (NC). Importantly, an array loading of 630IU of NC was achieved without compromising the array mechanical strength or drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single-step 'poke and release' approach allowed permeation of approximately 10.6% of the total NC load over a 48-h study period. The cumulative amount of NC that permeated DHS at 24h and 48h attained 12.28±4.23IU/cm(2) and 164.84±8.47IU/cm(2), respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offers great potential as a relatively low-cost functional delivery system for enhanced transdermal delivery of LMWH and other macromolecules.