Impact of Different Mixing Methods on the Performance of Suspension-Based Transdermal Delivery Systems.

Suspension-based matrix transdermal delivery systems (TDSs) are specialized systems that maintain a continuous driving force for drug delivery over prolonged wear. The pressure-sensitive adhesive (PSA) is the most critical constituent of such systems. Our study aimed to determine the effect of different mixing methods on the performance of silicone PSA-based suspension TDSs. Lidocaine suspension TDSs were prepared using conventional slow rotary mixing, high-speed homogenization, bead-mill homogenization, vortex shaking, and by an unguator. Resultant TDSs were tested for tack, shear, and peel properties and correlated to coat weight, content uniformity, microstructure, and in vitro permeation across dermatomed human skin. Every mixing method tested caused a significant reduction in peel. However, bead-mill homogenization resulted in significant loss of all adhesive properties tested, while unguator-mixed TDSs retained most properties. Good linear correlation (R2 = 1.000) between the shear properties of the TDSs with the average cumulative amount of lidocaine permeated after 24 h was observed, with no significant difference between percutaneous delivery from slow rotary-mixed systems (1334 ± 59.21 µg/cm2) and unguator-mixed systems (1147 ± 108.3 µg/cm2). However, significantly lower delivery from bead-mill homogenized systems (821.1 ± 28.00 µg/cm2) was noted. While many factors affect TDS performance, careful consideration must also be given to the processing parameters during development as they have been shown to affect the resultant system's therapeutic efficacy. Extensive mixing with bead-mill homogenization demonstrated crystallization of drug, loss in adhesive properties, coat weight, and film thickness, with reduced transdermal delivery of lidocaine from the prepared system.

Incisional hernia repair in a high-fidelity silicone model for open retro-muscular mesh implantation with preparation of the fatty triangle: validation and educational impact study.

BACKGROUND: Incisional hernia repair requires detailed anatomic knowledge. Regarding median subxiphoidal hernias, the proper preparation of the fatty triangle is challenging. To foster proficiency-based training, a cost-efficient model for open median retromuscular mesh repair resembling the human body was developed, including the main anatomical structures related to the procedure. The aim is to create and validate a high-fidelity model on open retromuscular mesh repair suitable for "training before doing". MATERIALS AND METHODS: Different types of fabrics for imitation of connective tissue and 2-component silicones were used to construct the incisional hernia model. Sample size for validation of the model was determined by a triangular testing approach. Operations from six beginners and six experts were assessed by three blinded-raters. Reliability and construct-validity were evaluated on a behaviorally anchored rating scale (highest score: 4) for the criteria: "instrument use", "tissue handling", "near misses and errors", and "end-product quality". RESULTS: The model authentically mimicked an open median retromuscular mesh repair. Participants considered the procedure realistic. Reliability was excellent, ranging from 0.811 to 0.974 for "end-product quality", and "tissue handling" respectively. Construct-validity was confirmed with experts significantly outperforming beginners in the "use of instruments" (Mbeg. = 2.33, Mexp. = 3.94, p < 0.001), "tissue handling" (Mbeg. = 2.11, Mexp. = 3.72, p < 0.001), "near misses and errors" (Mbeg. = 2.67, Mexp. = 3.67, p < 0.001), and "end-product quality" (Mbeg. = 2.78, Mexp. = 3.72, p < 0.001). Criterion-validity revealed a paradox effect: beginners performed significantly better than experts (p < 0.05) when preparing the fatty triangle. CONCLUSIONS: The model covers all relevant aspects involved in median-open retromuscular incisional hernia mesh repair. Performance differences between beginners and experts confirm construct-validity and thereby realism of the model. It enables to efficiently improve and practice technical skills of the demanding surgery.

Biological acellular pericardial mesh regulated tissue integration and remodeling in a rat model of breast prosthetic implantation.

The use of biological meshes has proven beneficial in surgical restriction and periprosthetic capsular contracture following breast prosthetic-reconstruction. Three different types (smooth, texturized, and polyurethane) of silicone round mini prostheses were implanted under rat skin with or without two different bovine acellular pericardial biological meshes (APMs, BioRipar, and Tutomesh). One hundred eighty-six female rats were divided into 12 groups, sacrificed after 3, 6, and 24 weeks and tissue samples investigated by histology and immunohistochemistry. Implantation of both APMs, with or without prostheses, reduced capsular α-SMA expression and CD3+ inflammatory cell infiltration, increasing capillary density and cell proliferation, with some differences. In particular, Tutomesh was associated with higher peri-APM CD3+ inflammation, prosthetic capsular dermal α-SMA expression and less CD31+ vessels and cell proliferation compared with BioRipar. None differences were observed in tissue integration and remodeling following the APM + prostheses implantation; the different prostheses did not influence tissue remodeling. The aim of our study was to investigate if/how the use of different APMs, with peculiar intrinsic characteristics, may influence tissue integration. The structure of APMs critically influenced tissue remodeling after implantation. Further studies are needed to develop new APMs able to optimize tissue integration and neoangiogenesis minimizing periprosthetic inflammation and fibrosis.

In vitro measurement of the permeability of endovascular coils deployed in cerebral aneurysms.

BACKGROUND AND PURPOSE: Aneurysm recurrence is the primary limitation of endovascular coiling treatment for cerebral aneurysms. Coiling is currently quantified by a volumetric porosity measure called packing density (pd). Blood flow through a coil mass depends on the permeability of the coil mass, and not just its pd. The permeability of coil masses has not yet been quantified. Here we measure coil permeability with a traditional falling-head permeameter modified to incorporate idealized aneurysms. METHODS: Silicone replicas of idealized aneurysms were manufactured with three different aneurysm diameters (4, 5, and 8 mm). Four different coil types (Codman Trufill Orbit, Covidien Axium, Microvention Microplex 10, and Penumbra 400) were deployed into the aneurysms with a target pd of 35%. Coiled replicas were installed on a falling-head permeameter setup and the time taken for a column of fluid above the aneurysm to drop a certain height was recorded. Permeability of the samples was calculated based on a simple modification of the traditional permeameter equation to incorporate a spherical aneurysm. RESULTS: The targeted 35% pd was achieved for all samples (35%±1%, P=0.91). Coil permeabilities were significantly different from each other (P<0.001) at constant pd. Microplex 10 coils had the lowest permeability of all coil types. Data suggest a trend of increasing permeability with thicker coil wire diameter (not statistically significant). CONCLUSIONS: A simple in vitro setup was developed to measure the permeabilities of coil masses based on traditional permeametry. Coil permeability should be considered when evaluating the hemodynamic efficacy of coiling instead of just packing density. Coils made of thicker wires may be more permeable, and thus less effective, than coils made from thinner wires. Whether aneurysm recurrence is affected by coil wire diameter or permeability needs to be confirmed with clinical trials.

Adherence of Candida albicans to silicone is promoted by the human salivary protein SPLUNC2/PSP/BPIFA2.

Interactions between Candida albicans, saliva and saliva-coated oral surfaces are initial events in the colonization of the oral cavity by this commensal yeast, which can cause oral diseases such as candidiasis and denture stomatitis. Candida albicans also colonizes silicone voice prostheses, and the microbial biofilm formed can impair valve function, necessitating frequent prosthesis replacement. We have previously shown that saliva promoted binding of C. albicans cells to silicone in vitro, and that the selective binding of specific salivary proteins to voice prosthesis silicone mediated attachment of C. albicans cells. The C. albicans cells adhered to a polypeptide (or polypeptides) of ~36 kDa eluted from saliva-treated silicone. We show here that a protein of similar size was identified in replicate blots of the eluate from saliva-treated silicone when the blots were probed with antibodies to human SPLUNC2, a salivary protein with reported microbial agglutination properties. In addition, SPLUNC2 was depleted from saliva that had been incubated with silicone coupons. To determine whether SPLUNC2 is a yeast-binding protein, SPLUNC2 cDNA was expressed in Escherichia coli. Purified recombinant His-tagged protein (SPLUNC2r) bound to silicone as demonstrated by immunoblot analysis of an eluate from SPLUNC2r-treated silicone coupons and (35) S-radiolabelled C. albicans cells adhered in a dose-dependent manner to SPLUNC2r-coated silicone. We conclude that SPLUNC2 binds to silicone and acts as a receptor for C. albicans adherence to, and subsequent colonization of, voice prosthesis silicone.

In vitro studies on release and skin permeation of nonivamide from novel oil-in-oil-emulsions.

The purpose of this study was to develop oil-in-oil-emulsions that facilitate long-term treatment for chronic pruritus with capsaicinoids. To this end, oil-in-oil-emulsions, which comprised polydimethyl siloxanes, silicone surfactant and castor oil, were examined. We used nonivamide, a synthetic analogue of capsaicin as the active pharmaceutical ingredient. It was incorporated into castor oil that formed the dispersed phase of the emulsion. We evaluated the influence of formulation variables (nonivamide content, phase volume ratio and viscosity of the silicone oil) on the in vitro release and the permeation of nonivamide. Permeation was found to be controlled by the nonivamide concentration in the dispersed phase and the phase volume ratio. Oil-in-oil-emulsions were found to produce constant permeation rates over a period of 10h. They are thus superior to conventional semisolid formulations as application intervals may be extended.

Quantification of protein deposits on silicone hydrogel materials using stable-isotopic labeling and multiple reaction monitoring.

This study was designed to use multiple reaction monitoring (MRM) for accurate quantification of contact lens protein deposits. Worn lenses used with a multipurpose disinfecting solution were collected after wear. Individual contact lenses were extracted and then digested with trypsin. MRM in conjunction with stable-isotope-labeled peptide standards was used for protein quantification. The results show that lysozyme was the major protein detected from both lens types. The amount of protein extracted from contact lenses was affected by the lens material. Except for keratin-1 (0.83 ± 0.61 vs 0.77 ± 0.20, p = 0.81) or proline rich protein-4 (0.11 ± 0.04 vs 0.15 ± 0.12, p = 0.97), the amounts of lysozyme, lactoferrin, or lipocalin-1 extracted from balafilcon A lenses (12.9 ± 9.01, 0.84 ± 0.50 or 2.06 ± 1.6, respectively) were significantly higher than that extracted from senofilcon A lenses (0.88 ± 0.13, 0.50 ± 0.10 or 0.27 ± 0.23, respectively) (p < 0.05). The amount of protein extracted from contact lenses was dependent on both the individual wearer and the contact lens material. This may have implications for the development of clinical responses during lens wear for different people and with different types of contact lenses. The use of MRM-MS is a powerful analytical tool for the quantification of specific proteins from single contact lenses after wear.

Nano "fly paper" technology for the capture of circulating tumor cells.

Some efficient diagnosis and therapy systems require the isolation and quantification of circulating tumor cells (CTCs), since these species are important "biomarkers" for monitoring cancer metastasis and prognosis. Existing techniques for isolating/counting CTCs include immunomagnetic-bead-based separation and microfluidic capture. However, some of these techniques have low capture efficiency and low specificity. Through the use of a three-dimensional (3D) nanostructured substrate - specifically, a silicon-nanowire (SiNW) array coated with epithelial-cell-adhesion-molecule antibodies (anti-EpCAM) - we show that CTCs can be captured efficiently and specifically. Unlike conventional methods for isolating CTCs that depend on collision frequency and contact duration, nanoscaled local topographic interactions between the CTCs and the substrate increase their binding and markedly enhance capture efficiency.

Bone marrow-derived stem cells contribute skin regeneration in skin and soft tissue expansion.

Skin and soft tissue expansion stimulates the proliferation of skin epidermal basal cells and increase the dermal collagen deposition and angiogenesis. To explore the contribution of bone marrow-derived stem cells (BMSCs) to the generation of "new" skin during the expansion, we used a chimeric mouse model in which the donor C57BL mice were engrafted with the bone marrow of enhanced green fluorescent protein (EGFP) transgenic mice. BMSCs were collected from the tibia and femur of EGFP(+) transgenic mice, and then injected into normal C57BL mice via the tail vein (chimeric mice). Skin was obtained at different times (days 0, 7, 14, 21, 28, and 35). Skin stromal-derived factor-1 (SDF-1) expression was evaluated. The number, distribution, and phenotype changes of EGFP(+) cells in the skin were also evaluated by means of fluorescent microscopy. EGFP(+) cells were present stably in the normal skin. The number of EGFP(+) cells of the Group A mice changed with the tension, and reached the peak on day 21(17.1 ± 6.7%), as compared with either Group B (5.5 ± 1.0%) or Group C (5.1 ± 0.9%). The SDF-1 expression in the expanded skin was significant increased (≈11-fold, P < 0.01) compared to non-expanded skin on day 21. Immunofluorescence showed EGFP(+) cells were converted into vascular endothelial cells, epidermal cells, and spindle-shaped dermal fibroblasts. Strain can promote the expression of SDF-1 and facilitate the differentiation and proliferation of BMSCs in the expanded skin.

Controlling cellular activity by manipulating silicone surface roughness.

Silicone elastomers exhibit a broad range of beneficial properties that are exploited in biomaterials. In some cases, however, problems can arise at silicone elastomer interfaces. With breast implants, for example, the fibrous capsule that forms at the silicone interface can undergo contracture, which can lead to the need for revision surgery. The relationship between surface topography and wound healing--which could impact on the degree of contracture--has not been examined in detail. To address this, we prepared silicone elastomer samples with rms surface roughnesses varying from 88 to 650 nm and examined the growth of 3T3 fibroblasts on these surfaces. The PicoGreen assay demonstrated that fibroblast growth decreased with increases in surface roughness. Relatively smooth (approximately 88 nm) PDMS samples had ca. twice as much fibroblast DNA per unit area than the 'bumpy' (approximately 378 nm) and very rough (approximately 604 and approximately 650 nm) PDMS samples. While the PDMS sample with roughness of approximately 650 nm had significantly fewer fibroblasts at 24h than the TCP control, fibroblasts on the smooth silicone surprisingly reached confluence much more rapidly than on TCP, the gold standard for cell culture. Thus, increasing the surface roughness at the sub-micron scale could be a strategy worthy of consideration to help mitigate fibroblast growth and control fibrous capsule formation on silicone elastomer implants.

The biology of facial fillers.

The biologic behavior of a facial filler determines its advantages and disadvantages. The purpose of this article is to look at the relevant biology as part of a logical basis for making treatment decisions. Historical perspectives and biologic characteristics such as local tissue reaction (including phagocytosis and granulomatous inflammation) cross-linking, particle concentration, immunogenicity, biofilm formation, gel hardness, and collagen neogenesis are considered. Bovine collagen is the most immunogenic facial filler. Porcine and bioengineered human collagen implants have very low immunogenicity, but allergic reactions and elevations of IgG are possible. Cross-linking and concentration affect the longevity of collagen and hyaluronic acid fillers. Gel hardness affects how a hyaluronic acid filler flows through the syringe and needle. Calcium hydroxylapatite, poly-L-lactic acid, and polymethylmethacrylate fillers have been shown to stimulate collagen neogenesis. It appears that any facial filler can form a granuloma. Bacterial biofilms may play a role in the activation of quiescent granulomas. Various authors interpret the definition and significance of a granuloma differently.

Liquid injectable silicone: history, mechanism of action, indications, technique, and complications.

Medical grade liquid injectable silicone can be used for soft tissue augmentation to correct and replace lost volumes of the subcutaneous tissue. It is potentially a permanent tissue augmentation agent and is the most effective filler for certain indications. This article presents the history, mechanism of action, indications and contraindications, technique, and the possible complications of silicone and their treatment.

Reactive oxygen species inhibited by titanium oxide coatings.

Titanium is a successful biomaterial that possesses good biocompatibility. It is covered by a surface layer of titanium dioxide, and this oxide may play a critical role in inhibiting reactive oxygen species, such as peroxynitrite, produced during the inflammatory response. In the present study, titanium dioxide was coated onto silicone substrates by radio-frequency sputtering. Silicone coating with titanium dioxide enhanced the breakdown of peroxynitrite by 79%. At physiologic pH, the peroxynitrite donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) was used to nitrate 4-hydroxyphenylacetic acid (4-HPA) to form 4-hydroxy-3-nitrophenyl acetic acid (NHPA). Titanium dioxide-coated silicone inhibited the nitration of 4-HPA by 61% compared to aluminum oxide-coated silicone and 55% compared to uncoated silicone. J774A.1 mouse macrophages were plated on oxide-coated silicone and polystyrene and stimulated to produce superoxide and interleukin-6. Superoxide production was measured by the chemiluminescent reaction with 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA). Titanium dioxide-coated silicone exhibited a 55% decrease in superoxide compared to uncoated silicone and a 165% decrease in superoxide compared to uncoated polystyrene. Titanium dioxide-coated silicone inhibited IL-6 production by 77% compared to uncoated silicone. These results show that the anti-inflammatory properties of titanium dioxide can be transferred to the surfaces of silicone substrates.

Synthesis, permeability and biocompatibility of tricomponent membranes containing polyethylene glycol, polydimethylsiloxane and polypentamethylcyclopentasiloxane domains.

The synthesis of "smart" tricomponent amphiphilic membranes containing poly(ethylene glycol) (PEG), polydimethylsiloxane (PDMS) and polypentamethylcyclopentasiloxane (PD(5)) domains is described. Contact angle hysteresis indicates that in air, the surfaces of such PEG/PD(5)/PDMS membranes are enriched by the hydrophobic components, PDMS and PD(5), while in water, the surfaces are rich in the hydrophilic PEG. The oxygen permeability of a series of membranes with varying M(c,hydrophilic) (M(n,PEG)=4600, 10,000 and 20,000 g/mol) and varying PEG/PD(5)/PDMS compositions was studied. Oxygen permeability increased with the amount of PDMS in the membrane. The molecular weight cut-off (MWCO) ranges and permeability coefficients of insulin through a series of PEG/PD(5)/PDMS(=29/14/57) membranes with varying M(c,hydrophilic) were determined. Insulin permeability is directly related to M(c,hydrophilic) of the membrane. MWCO studies show that the membranes are semipermeable to, i.e., allow the transport of smaller proteins such as insulin (M(n)=5733 g/mol, R(s)=1.34 nm) and cytochrome c (M(n)=12,400 g/mol, R(s)=1.63 nm), but are barriers to larger proteins such as albumin (M(n)=66,000 g/mol, R(s)=3.62 nm). Implantation of representative membranes in rats showed them to be biocompatible. According to these studies, PEG/PD(5)/PDMS membranes may be suitable for biological applications, e.g., immunoisolation of cells.

Proposed pathogenesis for the delayed postoperative opacification of the hydroview hydrogel intraocular lens.

PURPOSE: To report the clinical, histopathologic, ultrastructural, and elemental features of 17 opacified Hydroview (Bausch and Lomb Surgical, Rochester, New York, USA) hydrogel intraocular lenses (IOL) necessitating explantation and discuss from a clinicopathologic perspective why these lenses became opacified. Interventional case series with clinicopathologic correlation. METHODS: Seventeen hydrogel lenses were explanted from 17 different patients owing to decreased visual acuity or quality of vision an average of 29 months after uneventful phacoemulsification and IOL implantation and associated with a granular-appearing opacification superficially within the optic. Lenses were examined by light microscopy, transmission electron microscopy (TEM), and energy dispersion x-ray (EDX) spectroscopy. A control IOL was included in our study. RESULTS: All explanted lenses showed positive staining for calcium by light microscopy. Transmission electron microscopy disclosed electron-dense crystalline deposits in the superficial substance of the IOL optic. Energy dispersion x-ray spectra analyses showed the presence of calcium and phosphorus mainly in the electron-dense periphery of the deposits in all of the specimens and the presence of silicon mainly in the electron-lucent center of the deposits in the majority of the specimens. No positive staining or deposits were observed on the IOL control or in the haptics. CONCLUSIONS: Our study is the first to demonstrate that the calcium deposits are associated with silicon, which was presumably derived from the silicone gasket in the Surefold (Bausch and Lomb Surgical, Rochester, New York, USA) packaging system, manufactured specifically for this IOL. Silicon may act as a nidus for calcium deposition within the lens, which is consistent with our findings. There may be other factors involved, and this important clinical problem requires further study.

The clinical spectrum of band erosion following laparoscopic adjustable silicone gastric banding for morbid obesity.

BACKGROUND: Morbid obesity is effectively treated by restrictive surgery. A severe complication associated with gastric banding is gastric erosion. We review here our experience over a 5-year period. METHODS: A total of 1496 patients underwent gastric banding. Eighty-five percent of patients were available for follow-up. When band erosion was diagnosed, laparoscopic removal was performed. RESULTS: Band erosion was identified in 17 patients (1.13%). The time from primary operation to diagnosis of band erosion ranged from 3 weeks to 45 months (mean, 19 months). Clinical manifestations included weight gain in 2 (11.6%), band system leak in 1 (5.8%), chronic port-cutaneous fistula in 2 (11.6%), neglected peritonitis in 1 (5.8%), left subphrenic abscess in 2 (11.6%), but most commonly, protracted port-site infection that occurred in 7 patients (40.6%). CONCLUSIONS: Patients were effectively treated by band removal and suturing of the stomach wall. We suggest that different pathologies contribute to the same complication depending upon the time of presentation. We recommend a high index of suspicion in order to diagnose this life-threatening complication.

Continuous selective extraction of secondary metabolites from Catharanthus roseus hairy roots with silicon oil in a two-liquid-phase bioreactor.

A two-liquid-phase bioreactor was designed to extract indole alkaloids from Catharanthus roseus hairy roots with silicon oil. Partition studies between silicon oil and culture medium showed that the silicon oil did not alter the availability of nutrients. The affinity of tabersonine and löchnericine for silicon oil is nine times higher than for the aqueous phase. Cultures were elicited with 25 mg/L of jasmonic acid. The growth of the hairy roots was not significantly modified by the presence of silicon oil. The overall specific yields of tabersonine and löchnericine were increased by 100-400% and 14-200%, respectively, with the use of silicon oil in nonelicited control cultures. In elicited cultures, these values were 10-55% for tabersonine and 20-65% for löchnericine. Serpentine was never found in the silicon oil. All measured alkaloids' specific yields were higher using silicon oil and elicitation, suggesting that the silicon oil, while acting as a metabolic sink for tabersonine and löchnericine, was efficient in increasing metabolic fluxes of the secondary metabolism pathways.

Growth of connective tissue progenitor cells on microtextured polydimethylsiloxane surfaces.

Growth of human connective tissue progenitor cells (CTPs) was characterized on smooth and microtextured polydimethylsiloxane (PDMS) surfaces. Human bone-marrow-derived cells were cultured for 9 days under conditions promoting osteoblastic differentiation on smooth PDMS surfaces and on PDMS post microtextures that were 6 microm high and 5, 10, 20, and 40 microm in diameter, respectively. Glass tissue-culture dishes were used as controls. The number of viable cells was determined, and an alkaline phosphatase stain was used as a marker for osteoblastic phenotype. CTPs attached, proliferated, and differentiated on all surfaces. Cells on the smooth PDMS and control surfaces spread and proliferated as colonies in proximity to other cells and migrated in random directions, with cell process lengths of up to 80 microm. In contrast, cells on the PDMS post microtextures grew as sparsely distributed networks of cells, with processes, occasionally up to 300 microm, that appeared to interact with the posts. Cell counts revealed that there were fewer (50%) CTPs on the smooth PDMS surface than were on the glass control surfaces. However, there were consistently more (>144%) CTPs on the PDMS post textures than on the controls. In particular, the 10-microm-in-diameter posts (268%) exhibited a significantly (p < 0.05) greater cell number than did the smooth PDMS.

Liquid injectable silicone: techniques for soft tissue augmentation.

This article includes a description of the uses and indications of liquid injectable silicone and a discussion of the results obtained. Patient selection, indications, mechanism of action, potential complications, and adjunct procedures are also addressed.

In vitro effectiveness of silicone oil removal.

PURPOSE: To evaluate the effectiveness of silicone oil removal from the human eye under in vitro conditions. METHODS: Six keratoplasty donor eyes were vitrectomized and filled with silicone oil (5000 centistokes). After oil removal, the amount of residual oil was determined by quantifying the silicon content of the eyes. Six control eyes were prepared without oil filling. RESULTS: The six control specimens showed a silicon content of 2.83-10.2 microg (mean 5.06 microg, SD 3.19), the six test specimens a silicon content of 70.54-297.10 microg (mean 163.91 microg, SD 86.89). The difference is significant (p<0.05). The amount of residual oil in the test eyes was 192.0-856.2 microg (0.0037-0.0179% of the applicated oil quantity). CONCLUSION: The low magnitude of residual intraocular oil after oil removal shows that silicone oil could be removed to almost 100% when emulsification and biological mechanisms of oil retention are excluded. This could favour early silicone oil removal.