Insight into the Molecule Impact of Critical-Sized UHMWPE-ALN Wear Particles on Cells by the Alginate-Encapsulated Cell Reactor.

Wear particles of ultra-high molecular weight polyethylene (UHMWPE) are inevitable during service as joint prosthesis, and particles ≤ 10 µm with critical size could cause serious osteolysis and aseptic loosening of joint prosthesis. The aim of this study is to adopt the alginate-encapsulated cell reactor to investigate the molecular impact of critical-sized wear particles of UHMWPE loaded with alendronate sodium (UHMWPE-ALN) on cells. Results showed that compared with UHMWPE wear particles, UHMWPE-ALN wear particles inhibited the proliferation of macrophages significantly after being co-cultured for 1, 4, 7, and 14 d. Furthermore, the released ALN promoted early apoptosis, suppressed the secretion of TNF-α and IL-6 of macrophages, and down-regulated relative gene expressions of TNF-α, IL-6, and IL-1ß and RANK. In addition, compared with UHMWPE wear particles, UHMWPE-ALN wear particles promoted the ALP activity of osteoblasts, down-regulated the gene expression of RANKL, and up-regulated gene expression of osteoprotegerin. There were mainly two approaches of the effects of critical-sized UHMWPE-ALN wear particles on cells, one of which was cytology and the other was cytokine signal pathway. The former mainly affected the proliferation and activity of macrophages and osteoblasts. The latter would inhibit osteoclasts via cytokine and RANKL/RANK signal pathway. Thus, UHMWPE-ALN had the potential application in clinics to treat osteolysis induced by wear particles.

Thymoquinone loaded calcium alginate and polyvinyl alcohol carrier inhibits the 7,12-dimethylbenz[a]anthracene-induced hamster oral cancer via the down-regulation of PI3K/AKT/mTOR signaling pathways.

Oral cancer is a multifactorial cancer that affects millions of peoples worldwide. The current exploration aimed to evaluate the mechanisms that thymoquinone nanoencapsulated carrier and its effects on 7,12-Dimethylbenz[a]anthracene (DMBA) stimulated hamster buccal pouch cancer in Syrian hamster model. Nanocarrier was characterized by SEM, TEM, FTIR analysis. The incidence of tumor, and biochemicals makers was studied through standard methods. The mRNA expression level of inflammatory markers NF-κBp50, NF-κBp65, and PI3K/AKT/mTOR markers in the buccal tissues of control and experimental animals were investigated through RT-PCR analysis. In thymoquinone (TQ) loaded calcium alginate and polyvinyl alcohol carrier (TQ/Ca-alg-PVA) no squamous cell carcinogenesis developed and others moderate dysplasia revealed differentiated form of hyperplasia and keratosis. In biochemical analyses with DMBA + TQ/Ca-alg-PVA (20 mg/kg bw) orally administered hamsters showed restored the antioxidants, detoxification, xenobiotic metabolising enzymes in DMBA induced plasma and oral tissues of hamsters. Further, mRNA expression level of NF-κBp50/p65 and PI3K/AKT/mTOR were upregulated in the DMBA alone painted hamster. In contrast, these expressions were down regulated in orally TQ/Ca-alg-PVA treated experimental animals. This ability more eligible to deregulate the inflammatory and PI3K/AKT/mTOR signaling pathway that proved it suppresses anti-invasion/metastasis activity during hamster buccal pouch carcinogenesis. From this study, we recommended that TQ/Ca-alg-PVA has documented as effective chemopreventive agents, in further many molecular machineries need to study.

Drug-Loadable Calcium Alginate Hydrogel System for Use in Oral Bone Tissue Repair.

This study developed a drug-loadable hydrogel system with high plasticity and favorable biological properties to enhance oral bone tissue regeneration. Hydrogels of different calcium alginate concentrations were prepared. Their swelling ratio, degradation time, and bovine serum albumin (BSA) release rate were measured. Human periodontal ligament cells (hPDLCs) and bone marrow stromal cells (BMSCs) were cultured with both calcium alginate hydrogels and polylactic acid (PLA), and then we examined the proliferation of cells. Inflammatory-related factor gene expressions of hPDLCs and osteogenesis-related gene expressions of BMSCs were observed. Materials were implanted into the subcutaneous tissue of rabbits to determine the biosecurity properties of the materials. The materials were also implanted in mandibular bone defects and then scanned using micro-CT. The calcium alginate hydrogels caused less inflammation than the PLA. The number of mineralized nodules and the expression of osteoblast-related genes were significantly higher in the hydrogel group compared with the control group. When the materials were implanted in subcutaneous tissue, materials showed favorable biocompatibility. The calcium alginate hydrogels had superior osteoinductive bone ability to the PLA. The drug-loadable calcium alginate hydrogel system is a potential bone defect reparation material for clinical dental application.

Alginate (novabel): a new class of injectable filler.

A new class of biodegradable, injectable filler made of alginate, Novabel (Merz Aesthetics, Merz Pharma, UK), was launched in the European market in 2010. This product was supposed to be perfect to fill hollow eye rings and practitioners were immediately enthusiastic. Unfortunately, complications occurred as firm inflammatory nodules after a few months. Histological examinations revealed granulomatous reactions around spheroidal deposits. Treatment by triamcinolone injections was effective in some cases. Because of these complications, the company withdrew the alginate Novabel from the market. This is a didactic example of how a well-meant development with an insufficient test phase can turn into its opposite. Health authorities are exhorted to supervise not only drugs, but also injectables and other medical devices before they are launched, and during their application.

Adverse effects of fillers and their histopathology.

Injectable fillers nowadays represent a pillar in facial rejuvenation and make a significant contribution to the success of the treatment. Despite their obvious benefits, a wide range of possible complications such as immediate, late, delayed, temporary, or irreversible adverse effects have to be respected. Differentiating the various filler materials, these effects are assigned to histopathology findings and currently available treatment options.

[Comparative study of osteoplastic materials based on chitosan, alginate or fibrin with tricalcium phosphate].

The study presents comparative analysis of porous composites made of chitosan, alginate, fibrin with beta-tricalcium phosphate. Histological findings on Wistar rat condyles showed that fibrin-beta-TCP-based composite had the most effective positive biological response.

Early granulomatous foreign body reactions to a novel alginate dermal filler: the system's failure?

BACKGROUND: Cutaneous granulomas after a soft filler injection represent one of the worst scenarios for both patient and injector. OBJECTIVES: To present clinical and histopathological features of granulomatous nodular reactions induced by a new alginate-based dermal filler (Novabel(®)), and put it in context of the process of injectable soft tissue fillers approval and promotion in the EU. METHODS: A case series of four patients injected with Novabel(®) for volume restoration of the face and hands, who developed severe foreign body reactions. RESULTS: Four patients injected with Novabel(®) into tear troughs and/or dorsa of hands developed severe granulomatous reactions within months after injections. As we injected with the new filler into a total of 10 patients, a high incidence of 40% of the disfiguring adverse effect was observed. The inadequate response of manufacturer to our reporting the side-effects along with the available data on registration process of dermal fillers confirmed that the area is not well-regulated. CONCLUSIONS: The status of dermal fillers as class III medical devices, and the process of their approval and marketing in the EU need to be seriously reconsidered to avoid unnecessary and serious adverse reactions.

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.

Granulomatous reaction after injection of a new resorbable filler Novabel.

A new resorbable filler, Novabel, became commercially available in January 2010 in France. A 52-year-old general practitioner injected 0.1 cm3 of a 1 cm3 alginate solution (Novabel) into the deep dermis of her left arm to test it before using it on her patients. Ten days later, she observed a small pink nodule at the injection site forming secondary a bluish papule. A biopsy was performed 2 months after the injection. Histopathology showed a granulomatous reaction involving the deep dermis and the subcutaneous fat. The inflammatory reaction surrounded a nonpolarizing exogenous material consisting of slightly bluish deposits of variable size and shape, some of which were well delineated, others with a blurred or spiky perimeter, frequently showing retraction in a clear vacuole. The papule regressed, resolving completely 5 months after the injection. Novabel is a totally new type of aesthetic injectable resorbable filler consisting of a purified polysaccharide, alginate, which is extracted from crusted brown algae. No side effects have been reported to date and we describe here a first granulomatous reaction after filler injection which has a distinctive appearance in keeping with the histopathological findings.

Safety assessment of thiolated polymers: effect on ciliary beat frequency in human nasal epithelial cells.

OBJECTIVE: The aim of this study was to investigate the nasal safety of gel formulations of thiolated polymers (thiomers) by assessing their effect on ciliary beat frequency (CBF) in human nasal epithelial cells. METHODS: Poly(acrylic acid) 450 kDa-cysteine (PAA-cys) and alginate-cysteine (alg-cys) were synthesized by covalent attachment of L-cysteine to the polymeric backbone. The cationic polymer chitosan-thiobutylamidine (chito-TBA) was synthesized by attaching iminothiolane to chitosan. CBF using was measured by a photometric system. CBF was measured before incubating the cells with test gels, during incubation and after washing out the polymeric test gels to evaluate reversibility of cilio-inhibition. The influence of viscosity on CBF was determined by using hydroxyethylcellulose (HEC)-gels of various concentrations. RESULTS: Ciliary beating was observed to be affected by viscosity, but cilia were still beating in the presence of a HEC-gel displaying an apparent viscosity of 25 Pa.s. In case of thiolated polymers and their unmodified control, a concentration-dependent decrease in CBF could be observed. PAA-cys, alg-cys, chito-TBA and their corresponding unmodified controls exhibited a moderate cilio-inhibitory effect, followed by a partial recovery of CBF when used at a concentration of 1%. Alg-cys 2% and chito-TBA 2% (m/v) gels exhibited severe cilio-inhibition, which was partially reversible. L-cysteine and reduced glutathione led to mild cilio-inhibition at concentrations of 3% (m/v). CONCLUSIONS: Taking into account that dilution after application and cilio-modifying effects is usually more pronounced under in vitro conditions, thiomers can be considered as suitable excipients for nasal drug delivery systems.

Alginate-amphotericin B nanocomplexes covered by nanocrystals from bacterial cellulose: physico-chemical characterization and in vitro toxicity.

Nanocomplexes systems made up natural poylymers have pharmacotechnical advantages such as increase of water solubility and a decrease of drugs toxicity. Amphotericin B (AmB) is a drug apply as anti-leishmanial and anti-fungal, however it has low water solubility and high toxicity, limiting its therapeutic application. With this in mind, the present study aimed to produce nanocomplexes composed by alginate (Alg), a natural polymer, with AmB covered by nanocrystals from bacterial cellulose (CNC). For this reason, the nanocomplexes were produced utilizing sodium alginate, amphotericin B in a borate buffer (pH 11.0). The CNC was obtained by enzymatic hydrolysis of the bacterial cellulose. To CNC cover the nanocomplexes 1 ml of the nanocomplexes was added into 1 ml of 0.01% CNC suspension. The results showed an ionic adsorption of the CNC into the Alg-AmB nanocomplexes surface. This phenomena was confirmed by an increase in the particle size and PDI decrease. Besides, nanocomplexes samples covered by CNC showed uniformity. The amorphous inclusion of AmB complex into the polysaccharide chain network in both formulations. AmB in the nanocomplexes was in supper-aggregated form and showed good biocompatibility, being significantly less cytotoxic in vitro against kidney cells and significantly less hemolytic compared to the free-drug. The in vitro toxicity results indicated the Alg-AmB nanocomplexes can be considered a non-toxic alternative to improve the AmB therapeutic effect. All process to obtain nanocomplexes and it coat was conduce without organic solvents, can be considered a green process, and allowed to obtain water soluble particles. Furthermore, CNC covering the nanocomplexes brought additional protection to the system can contribut advancement in the pharmaceutical.

Magnetic field assisted preparation of PES-Ni@MWCNTs membrane with enhanced permeability and antifouling performance.

Multiple wall carbon nanotubes (MWCNTs), as an excellent material, have been used in various applications including preparation of polymer-MWCNTs composite membranes. However, few reports have combined the magnetic Ni@MWCNTs with polyether sulfone (PES) membrane to improve its antifouling performance to humic acid (HA), sodium alginate (SA), bovine serum albumin (BSA) and yeast (YE) solutions. In this study, the Ni@MWCNTs was generated by immersing MWCNTs into Ni2+ solution where in-situ reduction reaction was launched by the adsorbed Ag+ on MWCNTs. Since the loaded Ni endowed magnetism to MWCNTs, the Ni@MWCNTs can be easily attracted onto the membrane surface by an external magnetic field during the phase inversion process. The morphology measurements confirmed that the Ni@MWCNTs headed out of the PES-Ni@MWCNTs membrane surface. Because the MWCNTs played a role of free channels for water molecules, the composite membrane water flux reached to threefold flux of the pristine membrane. Moreover, the PES-Ni@MWCNTs membranes displayed the obviously enhanced antifouling ability during all the three alternative filtration cycles of water and BSA, SA, YE and HA solutions. In addition, the optimal PES-Ni@MWCNTs membrane demonstrated a flux recovery rate (FRR) of 67.89%, 85.53%, 60.28 and 90.12% for BSA, SA, YE and HA, respectively, which were not only much higher than that of the pristine membrane, but also exhibited significant improvements comparing with the previous studies. Further results of extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory indicated that the modified membrane possessed advantageous interaction energies with contaminant molecules over the pristine membrane.

Diclofenac sustained release from sterilised soft contact lens materials using an optimised layer-by-layer coating.

A layer-by-layer (LbL) coating was designed using ionic polysaccharides (chitosan, sodium alginate, sodium hyaluronate) and genipin (crosslinker), to sustain the release of diclofenac sodium salt (DCF) from soft contact lens (SCL) materials. The coating was hydrophilic, biocompatible, non-toxic, reduced bacterial growth and had minor effects on the physical properties of the material, such as wettability, ionic permeability, refractive index and transmittance, which remained within the recommended values for SCLs. The coating was applied on a silicone-based hydrogel and on commercial SofLens and Purevision SCLs. The coating attenuated the initial drug burst and extended the therapeutic period for, at least, two weeks. Relevantly, the problems of sterilizing drug loaded SCLs coated with biopolymers, using classic methods that involve high temperature or radiation, were successfully solved through high hydrostatic pressure (HHP) sterilization.

Effect of peroxymonosulfate oxidation activated by powdered activated carbon for mitigating ultrafiltration membrane fouling caused by different natural organic matter fractions.

Powdered activated carbon (PAC) adsorption has been widely applied prior to ultrafiltration membrane for potable water production. However, the impact of PAC adsorption on membrane fouling was still controversial. To solve this problem, combined PAC and peroxymonosulfate (PMS) pretreatment was proposed in this study. The application of PAC/PMS for mitigating membrane fouling by natural organic matter (NOM) has been evaluated, and compared with PMS oxidation or PAC adsorption alone. The influence of NOM fractions on the control efficiency was also investigated using humic acid (HA), bovine serum albumin (BSA), sodium alginate (SA), and their mixture (HA-BSA-SA). The performance was examined through normalized flux decline, fouling resistances analysis, scanning electron microscopy, and model fits. The results indicated that PAC and PMS exhibited a remarkable synergistic effect in the reduction of NOM, with the DOC reduction rates of 53.6%, 24.3%, 27.1% and 31.4% for HA, BSA, SA and HA-BSA-SA, respectively. PAC adsorption exhibited limited influence on mitigating membrane fouling, and the co-existence of PAC and HA even exacerbated fouling due to the synergistic fouling effect between them. By contrast, PAC/PMS pretreatment efficiently reduced both reversible and irreversible fouling resistances. The control efficiency was closely associated with the NOM fractions in the feed water, and followed the order of SA > HA-BSA-SA > BSA > HA. The fouling mitigation by PAC/PMS was attributed to both PAC adsorption and oxidation with SO4- and OH. The experimental results are expected to provide a feasible strategy of PAC/PMS for fouling mitigation, and simultaneously solve the problem faced by PAC adsorption.

Ultraviolet/persulfate (UV/PS) pretreatment of typical natural organic matter (NOM): Variation of characteristics and control of membrane fouling.

The effects of ultraviolet/persulfate (UV/PS) pretreatment on ultrafiltration (UF) membrane fouling caused by typical natural organic matter (NOM) fractions including humic acid (HA), sodium alginate (SA), and bovine serum albumin (BSA) were investigated. UF membrane fouling during the filtration of different NOM fractions after UV/PS pretreatment was compared through the evaluation of normalized membrane flux decline and membrane fouling reversibility. The fouling mitigation mechanisms were investigated through the characterization of ultraviolet absorbance (UV254), dissolved organic matter, zeta potential, particle size distribution, fluorescence excitation-emission matrix spectra, and fitness of four classic fouling models. Furthermore, the fouled membranes were characterized by Fourier-transform infrared spectroscopy and scanning electron microscopy. The results showed that UV/PS pretreatment significantly alleviated membrane fouling caused by HA, SA, and HA-SA-BSA mixture, and the fouling control performance improved at high PS doses. However, either UV alone or UV/PS pretreatment at low PS dose (10 mg/L) significantly aggravated BSA fouling with the normalized flux at the end of first filtration cycle being 8% and 15%, respectively. The increased particle size of BSA after UV/PS pretreatment was attributed to the formation of aggregates, which mainly accumulated in membrane pores and aggravated membrane fouling. Modeling results suggest that the mitigation of membrane fouling derived from SA and mixed organic fractions was primarily ascribed to the control of cake filtration, while the mitigation of HA fouling was attributed to the declined contribution of standard blocking.

Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues.

Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp) related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123) were conducted in the absence (control group) and presence (experimental groups) of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M) increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate) changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies.

In vitro and in vivo evaluation of colon cancer targeted epichlorohydrin crosslinked Portulaca-alginate beads.

The aim of this study was to formulate a novel dual crosslinked hydrogel bead using Portulaca mucilage for colon-targeted delivery of 5-fluorouracil (5-FU) and evaluate its safety, specificity and efficacy. The ionotropic gelation technique was employed to prepare the hydrogel beads of Portulaca mucilage. For this, the mucilage was initially crosslinked with alginate and calcium ions. Epichlorohydrin was employed as a crosslinker in the second crosslinking step. The formulation was subjected to in vitro and in vivo studies to evaluate morphology, size, cytotoxicity, and organ distribution. Human HT-29 colon cancer cell-line was used for in vitro assays and in vivo studies were performed in Wistar rats to assess the usefulness and effectiveness of the formulation for colon cancer therapy. Microsphere sizes ranged from 930 to 977µm and possessed a high level of drug encapsulation efficiency (ca. 78% w/w). Compared with 5-FU solution (Tmax = 1.2 h, mean resident time: MRT = 3.3h) the dual crosslinked Portulaca microspheres exhibited sustained drug release after oral administration to rats (Tmax = 16h, MRT = 14h). The relative bioavailability of 5-FU solution and the microspheres were 100 and 93.6% respectively. Tissue distribution studies indicated high concentration of 5-FU in colon. In-vitro anticancer assay demonstrated IC50 value of 11.50 µg/ml against HT-29 colon cancer cell line. The epichlorohydrin cross-linked Portulaca microspheres prepared in this study provided sustained release of 5-FU up to 16h in the colonic region and enhanced the antitumor activity of the neoplastic drug. The formulation is hence an ideal carrier system for colon-targeted drug delivery.

Split-thickness skin graft donor sites: a comparative study of two absorbent dressings.

OBJECTIVE: To identify the optimal dressing for split-thickness skin graft (SSG) donor sites. METHOD: This prospective randomised controlled trial compared two dressings - a new absorbent form of a polyurethane film dressing (Tegaderm Absorbent, 3M) and our standard alginate dressing (Kaltostat, ConvaTec) - on SSG donor sites in 40 patients. Primary outcome measures were: reduced time to full healing; reduced postoperative pain; reduced leakage rates from the dressing. Secondary outcome measures related to acceptability of the dressings to the patient. RESULTS: On removal of the dressings at the first assessment, 79% of the Tegaderm Absorbent donor sites had healed completely, compared with 16% of the Kaltostat ones (p<0.001).A significantly greater median area had healed with Tegaderm Absorbent (100%), when compared with Kaltostat (89%) (p<0.001). Mean time to complete healing was also significantly faster for Tegaderm Absorbent than Kaltostat (14 versus 21 days) (p<0.001). Significantly fewer subjects experienced postoperative pain with Tegaderm Absorbent on both day 1 (21% versus 67%, p=0.006, NNT=3) and day 2 (17% versus 75%, p<0.001, NNT=2). Leakage rates reduced by 48% with Tegaderm Absorbent, with no leakage in the smaller donor sites. Tegaderm Absorbent was significantly easier to apply than Kaltostat (89% versus 27% found it'very easy') as was ease of removal (84% versus 11% found it'very easy') (p<0.0001). Patients found Tegaderm Absorbent dressings significantly more convenient to manage and bathe with. At one month post-surgery, Vancouver scar scores showed thatTegaderm Absorbent donor sites were less red, flatter, softer and less itchy. CONCLUSION: Tegaderm Absorbent provides a significant improvement in terms of donor-site pain, healing and ease of management.

Incorporation of proteins within alginate fibre-based scaffolds using a post-fabrication entrapment method.

In this study, a physical entrapment process was explored for the incorporation of proteins within preformed fibrous alginates and the release profile was tuned by varying the processing parameters. The entrapment process was carried out in a series of aqueous solutions at room temperature and involved pre-swelling of the fibrous alginate within a Na(+)-rich solution, followed by exposure to the protein of choice and entrapping it by re-establishing cross-links of alginate with BaCl2. Entrapment and release of fluorescein isothiocyanate-labelled bovine serum albumin (FITC-BSA), a model protein, was studied. It was found that a sustained release of the incorporated protein in cell culture medium for about 6 days was achieved. The main factors determining the release profile included the NaCl/CaCl2 ratio in the pre-swelling solution, protein concentration, and the exposure time. To retard protein release, alginate fibres with entrapped FITC-BSA were processed together with poly(D, L-lactide) (PDLLA) into porous alginate fibre/PDLLA composites using supercritical CO2. In this manner, release of the protein for up to 3 months was achieved.