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An electrically modulated drug delivery device: I.

A controlled drug delivery device based on the principle of electrophoresis is described. A model system using propranolol HCl and PHEMA films was used to demonstrate how control over the release of a model drug may be achieved using low constant electric currents. It was found that a linear relationship existed between electric current and drug delivery rate. Additionally, two main effects of applying an electric current during the lag period of delivery from the system were identified. First, the drug delivery rate was less when a current was applied before the lag period had expired, and second, the voltage-time profiles were found to be significantly different. The model shows the feasibility of using an electrophoretically controlled drug delivery device to provide truly controllable and predictable release rates.

Cross-Linking Reagents↗

Synthesis and characterisation of poly(2-hydroxyethyl methacrylate) polyelectrolyte complexes.

Copolymerisation of charged and neutral monomers is a well-known methodology to introduce charged moieties in a polymeric chain to obtain polyelectrolytes. New polyelectrolyte complexes have been synthesised by radical copolymerisation of neutral methacrylic monomer 2-hydroxyethyl methacrylate (HEMA) with cationic 2-methacryloyloxyethyltrimethyl ammonium chloride and anionic 2-acrylamido-2-methylpropane-sulphonic acid monomers in 10:1:1 and 10:1:2 stechiometric ratio. Chemical structure of the synthesised terpolymers was confirmed by FT-IR spectroscopy, moreover, X-ray photoelectron spectroscopy showed the presence of a cationic charge excess on the 10:1:2 terpolymer surface with respect to 10:1:1 terpolymer. Swelling studies for 10:1:2 terpolymers showed a high water content in the swollen state and a "smart behaviour" upon changes in external stimuli such as pH, while, 10:1:1 terpolymer presented the behaviour of a neutral polymer. Mechanical and differential scanning calorimetry analysis confirmed that terpolymer networks were stabilised by ionic co-operative interactions. Infact, the inclusion of oppositely ionic charges in the polymeric network of p(HEMA) represent a way to achieve higher elastic modulus as they stabilise the terpolymer networks. Cytotoxicity and cytocompatibility studies demonstrated that all materials were not toxic, moreover, the presence of a cationic charge excess on 10:1:2 terpolymer surface was able to promote fibroblast adhesion.

Absorption↗

True and apparent oxygen permeabilities of contact lenses.

We studied the passage of oxygen through some commercially available contact lenses. Oxygen diffusion coefficients were determined by the time-lag method and a 201T Redher permeometer was used to measure the oxygen permeability and transmissibility by the polarographic method. The measurements were carried out at room temperature with 0.09% sodium chloride physiologic solution. The following types of lenses were tested: (1) 12 lenses of cellulose acetate butyrate (CAB) of a mean thickness of 0.194 mm (observed Dk approximately 6.3 barrers) (1 barrier is equivalent to 10(-11) cm3 of O2 (STP).cm2/cm3.s.mm Hg). (2) 13 lenses of a cross-linked polyhydroxyethyl methacrylate (2-HEMA), manufactured by Lenticon and Bausch & Lomb, with 40 and 38.6% water content, respectively. The mean thicknesses were 0.160 and 0.148 mm, respectively (observed Dk approximately 12 to 13.5 barrers). (3) Finally 10 lenses of a copolymer of 2 HEMA with N-2-vinylpyrrolidone (2-HEMA/VP), manufactured by Bausch & Lomb under the name Hydrocurve II, with 55% water content and a mean thickness of 0.138 mm (observed Dk approximately 24.5 barrers). For a given lens thickness, the transmissibility and permeability of lenses whose main material is 2-HEMA are found to be equivalent. This fact suggests the use of such material as a standard in the study of diffusion processes in contact lenses of low oxygen permeability (Dk approximately 12 to 13.5 barrers). We studied the boundary layer effects and found significant discrepancies between true and apparent oxygen permeabilities. The apparent transmissibility decreased with increasing lens thickness, this effect being more apparent for lenses with low water content. Oxygen permeability is found to be exponentially dependent on water content rather than on the chemical composition of the hydrogel.

Contact Lenses↗

A remotely interrogatable sensor for chemical monitoring.

A new type of continuously operating, in-situ, remotely monitored sensor is presented. The sensor is comprised of a thin film array of magnetostatically coupled, magnetically soft ferromagnetic thin film structures, adhered to or encased within a thin polymer layer. The polymer is made so that it swells or shrinks in response to the chemical analyte of interest, which in this case is pH. As the polymer swells or shrinks, the magnetostatic coupling between the magnetic elements changes, resulting in changes in the magnetic switching characteristics of the sensor. Placed within a sinusoidal magnetic field the magnetization vector of the coupled sensor elements periodically reverses directions, generating magnetic flux that can be remotely detected as a series of voltage spikes in appropriately placed pickup coils. one preliminary sensor design consists of four triangles, initially spaced approximately 50 micrometers apart, arranged to form a 12 mm x 12 mm square with the triangle tips centered at a common origin. Our preliminary work has focused on monitoring of pH using a lightly crosslinked pH sensitive polymer layer of hydroxyethylmethacrylate and 2-(dimethylamino) ethylmethacrylate. As the polymer swells or shrinks the magnetostatic coupling between the triangles changes, resulting in measurable changes in the amplitude of the detected voltage spirits.

Biosensing Techniques↗

Impact of manufacturing technology and material composition on the surface characteristics of hydrogel contact lenses.

BACKGROUND: Our aim was to investigate the impact of manufacturing method and material composition on the surface characteristics of hydrogel contact lenses. METHODS: Five lens types were examined; three polyhydroxyethyl methacrylate (pHEMA) lenses, each manufactured by a different technique, namely, lathing, spin-casting and cast-moulding, a HEMA/methacrylic acid cast-moulded lens and a HEMA/glycerol methacrylate cast-moulded lens. Six lenses of each type were examined (front and back) using scanning electron microscopy (SEM). Additionally, both surfaces of three lenses from each of the pHEMA lens groups were examined, partially hydrated, using an atomic force microscope (AFM). Qualitative data were gathered for both SEM and AFM studies in addition to root-mean-square (RMS) roughness values for the lenses investigated with AFM. RESULTS: The surfaces of the lathed lenses were covered in lathing/polishing marks. RMS roughness values for the anterior surface (10.9 +/- 4.3 nm) were significantly greater (p = 0.02) than those of the posterior surface (9.3 +/- 0.8 nm). The two surfaces of the spun-cast lens appeared similar by SEM but AFM RMS roughness values were greater (p = 0.02) for the anterior (12.3 +/- 1.8 nm) than the posterior (5.8 +/- 1.9 nm) surface. Both SEM and AFM showed similar topographic appearances for the surfaces of the cast-moulded pHEMA lens, although RMS roughness values were greater (p = 0.02) for the anterior (5.8 +/- 0.9 nm) than the posterior (3.9 +/- 0.3 nm) surface. All three cast-moulded lenses had more processing debris than the lathed and spun-cast pHEMA lenses. Overall, the surfaces of the lathed lens were 'rougher' than those of the cast-moulded lens (p = 0.01). CONCLUSION: The surface topographies of the hydrogel contact lenses are dependent on the method of manufacture. Cast-moulded lenses are associated with apparently 'stickier' surfaces, which may be indicative of surface degradation during the manufacturing process.

Biomedical Technology↗

Impact of manufacturing technology and material composition on the mechanical properties of hydrogel contact lenses.

Hydrogel materials are not only different as a result of different co-monomer compositions but also as a result of the manufacturing method used to produce them. Hydrogel contact lenses fabricated by different methods are subjected to markedly different processing steps, which are likely to affect the resultant material network structure of a lens. The mechanical performance of five soft contact lens types was investigated using one conventional technique (tensile test) and three novel techniques (probe, tear and ball milling tests). The five lens groups consisted of three polyhydroxyethyl methacrylate (pHEMA) lenses which were each manufactured by a different technique: lathing, spin-casting and cast-moulding, a HEMA/methacrylic acid (HEMA/MAA) cast-moulded lens and a HEMA/glycerol methacrylate (HEMA/GMA) cast-moulded lens. Overall, the results show that the best mechanical performance is obtained for the pHEMA lenses, with some differences occurring between the lenses. The HEMA/GMA lens showed the worst performance.

Biomechanical Phenomena↗

Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials.

AIM: Published clinical series suggest the osteoodontokeratoprosthesis (OOKP) may have a lower extrusion rate than current synthetic keratoprostheses. The OOKP is anchored in the eye wall by autologous tooth. The authors' aim was to compare adhesion, proliferation, and morphology for telomerase transformed keratocytes seeded on calcium hydroxyapatite (the principal mineral constituent of tooth) and materials used in the anchoring elements of commercially available synthetic keratoprostheses. METHODS: Test materials were hydroxyapatite, polytetrafluoroethylene (PTFE), polyhydroxyethyl methacrylate (HEMA), and glass (control). Cell adhesion and viability were quantified at 4 hours, 24 hours, and 1 week using a calcein-AM/EthD-1 viability/cytotoxicity assay. Focal contact expression and cytoskeletal organisation were studied at 24 hours by confocal microscopy with immunoflourescent labelling. Further studies of cell morphology were performed using light and scanning electron microscopy. RESULTS: Live cell counts were significantly greater on hydroxyapatite surfaces at each time point (p<0.04). Dead cell counts were significantly higher for PTFE at 7 days (p<0.002). ss(1) integrin expression was highest on hydroxyapatite. Adhesion structures were well expressed in flat, spread out keratocytes on both HA and glass. Keratocytes tended to be thinner and spindle shaped on PTFE. The relatively few keratocytes visible on HEMA test surfaces were rounded and poorly adherent. CONCLUSIONS: Keratocyte adhesion, spreading, and viability on hydroxyapatite test surfaces is superior to that seen on PTFE and HEMA. Improving the initial cell adhesion environment in the skirt element of keratoprostheses may enhance tissue integration and reduce device failure rates.

Biocompatible Materials↗

Novel materials to enhance keratoprosthesis integration.

BACKGROUND: The successful integration of keratoprostheses (KPros) within the cornea depends in part on peripheral host keratocyte adhesion to anchor the implant in place and prevent epithelial downgrowth. The following study incorporated different acrylate co-monomers with poly(hydroxyethyl methacrylate) (p(HEMA)) and measured the suitability of these materials as potential skirt materials in terms of their ability to enhance keratocyte adhesion to p(HEMA). METHODS: p(HEMA) hydrogels incorporating varying amounts of the acrylate co-monomers methacrylic acid (MA), 2-(dimethylamino)ethyl methacrylate (DEM), or phenoxyethyl methacrylate (PEM) were formed by free radical polymerisation. Keratocytes were seeded onto discs of each material and incubated at 37 degrees C for 72 hours. Assays for viable cell adhesion were carried out. A viability/cytotoxicity assay using solutions of calcein-AM (0.5 mM) and ethidium homodimer-1 (EthD-1) (0.5 microM) were used to measure viable and non-viable cell adhesion, respectively. An ATP assay was also used to quantify cell adhesion in terms of the amount of ATP present following lysis of adherent cells. RESULTS: The viability/cytotoxicity assays indicated that the incorporation of 15 mol% of the co-monomer PEM or of 20 mol% DEM increased cell adhesion to p(HEMA) by at least four times. The ATP assays confirmed the results for PEM but absorption of ATP to the DEM containing hydrogel indicated that the assay was not a suitable measure of cell adhesion to this material. CONCLUSIONS: The properties of p(HEMA) may be moderated to enhance keratocyte adhesion by the incorporation of PEM or DEM suggesting that these may be suitable materials for use in the further development of a novel KPro skirt material.

Adenosine Triphosphate↗

Controlled release of cytarabine from poly(2-hydroxyethyl methacrylate-co-N-vinyl-2-pyrrolidone) hydrogels.

Controlled release of cytarabine (ara-C) from poly(2-hydroxyethyl methacrylate-co-N-vinyl-2-pyrrolidone) [p(HEMA-co-VP)] hydrogels cross-linked with ethylene glycol dimethacrylate (EGDMA) is reported. Three compositions of copolymer, each one with a different cross-linking degree, have been studied: H50/VP50, H75/VP25, and H80/VP20. Ara-C (5-25 mg by disc) was trapped in the gels by including it in the polymerization feed mixture. The ara-C release time was between 1 day from H50/VP50/E0.5 discs and 16 days from H80/VP20/E15 discs. In all cases there is a time period for which the drug release rate is constant.

Antimetabolites, Antineoplastic↗

Towards an artificial cornea: surface modifications of optically clear, oxygen permeable soft contact lens materials by ammonia plasma modification technique for the enhanced attachment and growth of corneal epithelial cells.

The advent of high water content, oxygen permeable contact lens materials has made the intracorneal implants more feasible. A major obstacle encountered is the regrowth of a stable epithelium over the implant. Therefore, ammonia gaseous plasma modification technique was used to modify the surface chemical properties of soft contact lens material such as poly(2-hydroxyethyl methacrylate and methacrylic acid), PHEMA-MAA copolymer, in an attempt to enhance the cell attachment and growth of rabbit corneal epithelial cells.

Ammonia↗

[A polyvinyl alcohol (PVA) hydrogel as a soft contact lens material].

A transparent polyvinyl alcohol (PVA) hydrogel was prepared from a PVA solution in a mixed solvent consisting of water and a water miscible organic solvent by cooling. The physical properties were evaluated in comparison with commercially available soft contact lens materials, such as polyhydroxyethyl methacrylate (PHEMA) and copolymers of methyl methacrylate (MMA) and N-vinyl pyrrolidone (VP). The PVA hydrogel showed higher tensile strength and elongation at break than the other materials, while it had high water content and oxygen permeability the latter being comparable to those of PMMA/VP copolymers. The protein adsorption of the PVA hydrogel was much less than those of the other materials. The PVA hydrogel soft contact lenses were applied on rabbit eyes for 12 weeks. The influence on the cornea was studied by biomicroscopy, ultrasonic corneal pachymetry and histopathological examination. These examinations revealed no abnormal findings in the cornea. These results suggest that the PVA hydrogel may be promising as a new soft contact lens material.

Adsorption↗

Surface tension measurements on methacrylate monomer solutions, selected solvents, and gel extracts.

The surface tensions of selected methacrylate monomer and solvent solutions were measured, and calibration curves were generated. The curves were then used to deduce the amounts of water soluble extractables in methacrylate hydrogels by measuring the surface tension of the extractant. The detectability limit (parts per 10,000) and the overall sensitivity of the method suggests its possible use as an extraction monitor test for related biomaterials.

Acrylates↗

Effects of long-term heat disinfection on Soflens (polymacon) contact lenses.

Soflens (polymacon) contact lenses were subjected to long-term heat disinfection in a carefully controlled laboratory study and in a patient clinical study. No adverse effects were observed on the physical or chemical properties of the lenses other than the deposition of some tear components in a portion of the patient-worn lenses. This was not unexpected since no enzyme or surfactant cleaners were used.

Acrylates↗

[Methods for the curative treatment of pleural empyema with bronchial fistulae in patients with pulmonary tuberculosis].

In contrast to non-specific pleural empyemas in which closed sanitization is sufficiently beneficial, an early application of thoracostoma is essential for patients with tuberculous pleural empyema with bronchial fistulas. Thoracostoma allows for effective sanitization of the cavity, long-term antituberculous chemotherapy and preparation of patients for radical operations. This has been supported by the comparative analysis of the outcomes of radical operations in 139 patients following closed and open management of the empyemic cavity in pulmonary tuberculosis. The site of thoracostoma is defined depending on the location and volume of an abscess and the forthcoming radical operation. Long-acting antiseptic dressings containing chlorohexidine bigluconate, which are based on the polymer polyhydroxyethyl methacrylate and which have been developed in the clinical setting, and ultraviolet irradiation with a unique-design apparatus are proposed for sanitization of open pleural empyemas.

Bronchial Fistula↗

Temporal evolution of the corneal curvature in contact lens wearers.

In the present work, we have measured the corneal radii in a group of 126 healthy subjects, studying the temporal evolution of these radii after adaptation to contact lenses of polyhydroxyethyl methacrylate with 55% hydration. We measured the horizontal and vertical radii before adaptation, as well as after 3, 6 and 9 months of wearing contact lenses. The decreases were not significant (P < 0.05) in the corneal radii of these subjects; maximum decreases were reached the day after wearing contact lenses, with subsequent recuperation, such that at 9 months the decreases, though persisting, were minimal.

Adolescent↗

Biological response to a supraDescemetic synthetic cornea in rabbits.

OBJECTIVE: To evaluate the biocompatibility of a novel nonpenetrating keratoprosthesis (supraDescemetic synthetic cornea) in a rabbit model. METHODS: Seven rabbits received a supraDescemetic synthetic cornea (7-mm diameter, 350-microm-thick optical zone, 100-microm-thick peripheral flange) in their healthy right eyes. A surgical technique was developed that allowed implantation of the device on top of the bare Descemet membrane. Three rabbits received a supraDescemetic synthetic cornea made of hydroxyethyl methacrylate-methyl methacrylate(26), 1 received a hydroxyethyl methacrylate-N-vinyl pyrrolidone(75) mesoplant, and 3 were implanted with devices made of polymethyl methacrylate. All rabbits were euthanized after 8 weeks; the eyes were enucleated and examined by conventional histological and immunohistochemical evaluations. RESULTS: All eyes became quiet within several days. The Descemet membrane remained transparent during the observation period. Indirect ophthalmoscopy performed through the prosthesis allowed accurate examination of the posterior pole. Histological evaluation of the implanted corneas displayed no signs of an acute or chronic inflammatory reaction to the supraDescemetic synthetic cornea in 5 eyes; a few inflammatory cells were detected in the corneas of 2 rabbits. The interface between the Descemet membrane and the mesoplant displayed ingrowth of very thin (<10-microm) tissues colonized by keratocytes in 3 of the 7 corneas. CONCLUSIONS: This study validates the biocompatibility of this new type of nonpenetrating keratoprosthesis. Because opening of the anterior chamber is not required with the supraDescemetic synthetic cornea, the risk for intraocular infection is minimal, and the implantation procedure is less traumatic compared with a penetrating device.

Animals↗

Physicochemical aspects of the giant multinucleate cell formation.

Process of multinucleate cell formation was studied under two conditions: (1) during the perichondral ossification of the chick embryonal tibia, and (2) in foreign-body reaction against polyhydroxyethylmethacrylate (POLYHEMA) and copolymer of hydroxyethylmethacrylate and methacrylic acid (POLYHEMA-MA) subcutaneously implanted into the rat. Multinucleate cells covered a surface of the substrate with relatively low hydrophylia and with low or without acidic groups (mineralized bone and POLYHEMA). On the other hand, no (POLYHEMA-MA) or only exceptional (nonmineralized resorbed cartilage) multinucleate cells were visible on the substrate rich in water and acidic groups. This similarity is not surprising, since it is accepted that both cell types represent a specialized phagocytic element. These results demonstrate that precursor cells can fuse only under convenient conditions. Forces analogous to hydrophobic and electrostatic interactions probably participate in this process.

Animals↗