RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

Long-term result of guided nerve regeneration with an inert microporous polytetrafluoroethylene conduit

Thedevelopmentinmicrosurgicaltechniqueshasgreatlyimprovednervefunctionalrecovery .However ,owingtotheinabilitytocoaptateandsuturethousandsofnervefiberstotheirfunctionallysimilarnervefibersandinaccuratesutureofthenervestumps ,regeneratednervefiberspartiallylosethechancetoselectivelyregrowintotheirtargetendoneurialtubes,1 4whichresultsinaninevitablemismatchofmotorandsensorynervefibers .Thus,thecontact guidance basedmicrosurgicalnerverepairhasfailedtoachieveconsistentsatisfactoryfunctionalrecover…     

Modifications of the hydrophilicity of heterocyclic methacrylate copolymers for protein release

A series of copolymers comprising ethyl methacrylate (EM) and tetrahydrofurfuryl methacrylate (THFMA) gelled with either THFMA monomer or hydroxyethyl methacrylate (HEMA) monomer have been developed. In this paper, we examine the water uptake characteristics of the polymer systems and address the possibility of increasing the hydrophilicity of the systems by changing the ratios of the copolymers. We have investigated whether protein release from the polymers is related to the composition of the polymer systems. More protein was released from the polymers gelled with the more hydrophilic monomer (HEMA) than with THFMA. This was consistent with the calculated diffusion coefficients, which were 10 times greater for the polymers gelled with HEMA than those gelled with THFMA. Interestingly, the water uptake and protein release profiles were not dependent on the ratio of EM and THFMA in the copolymers. This is probably due to the conflicting roles of THFMA in the copolymer; it is both the more hydrophilic component as well as a cross-linking agent. In addition, it would appear that the structural and surface topography of these polymers had more significant effects on protein release than copolymer composition.     

Hydrogels in endovascular embolization. II. Clinical use of spherical particles

In this study we report the results of clinical experiments, obtained with spherical particles made from poly(2-hydroxyethyl methacrylate) used in the embolization of arteriovenous anastomoses, in the suppression of pulmonary haemorrhage and haemoptysis and in the occlusion of some other arteries. So far we have used these particles in the treatment of 187 patients. It must be stressed that the advantage of spherical particles consists in the simplicity of their introduction into the blood vessel through a catheter, while in the blood vessel itself the particle swells in blood still more, when compared with the particle size in saline. This results in an immediate and permanent haemostatic effect. No revascularization occurs.     

Synthesis of polyetherurethanes containing L-serine dipeptide and their use as materials for biomedical films

Prepolymers, which were produced by the polyaddition reaction of polytetramethylene glycol (PTMG) or polyethylene glycol (PEG) and 4,4'-diphenylmethane diisocyanate (MDI) or hexamethylene diisocyanate (HMDI), were chain-extended with a linear dipeptide of L-serine (Z-Ser-Ser-OMe) or a cyclic dipeptide of L-serine [c-(Ser)2] to yield novel polyetherurethanes containing dipeptide segments. The relationship between the surface morphology and the biomedical properties of the film of the novel polyetherurethanes was investigated. The surface of PU(PTMG,Z-Ser-Ser-OMe,MDI) film was smooth, but fibrous structures were developed in the bulk of the film with increasing molecular weight of the PTMG segment. The antithrombogenicity of the film containing the low molecular weight PTMG segment was better than that of the usual polyetherurethane film without the dipeptide segments. The partial hydrolysis of the ester groups involved in the dipeptide segment improved the antithrombogenicity. In the surface and the bulk of PU[PTMG,c-(Ser)2,MDI] film, spherulite structures were developed when the molecular weight of the PTMG segment was high, while single crystals with a length of 3-4 microns were produced when the molecular weight of the PTMG segment was low. The antithrombogenicity of the film containing the high molecular weight PTMG segment was better than that of the usual polyetherurethane film without the dipeptide segments. PU(PTMG/PEG,Z-Ser-Ser-OMe,MDI) film and PU[PTMG/PEG,c-(Ser)2,MDI] film were permeated by uraemic toxins. The permeation was accelerated with increasing water content of the film and decreasing molecular weight of the solute. The oxygen permeability of the film of the polyetherurethane containing the linear or cyclic dipeptide segments was greater than that of polyetherurethane film which does not contain the dipeptide segments.     

Interaction of antithrombin III with preadsorbed albumin-heparin conjugates

The adsorption of antithrombin III (AT III) onto polystyrene surfaces preadsorbed with albumin or albuminheparin conjugates was studied using a two step enzyme immuno assay. When AT III-buffer solutions were used, the highest adsorption values were measured on high affinity albumin-heparin conjugate pretreated surfaces. Less AT III adsorption was found on nonfractionated albumin-heparin conjugate preadsorbed surfaces. AT III adsorption could also be detected on low affinity conjugate and albumin coated surfaces. When AT III was adsorbed from plasma or plasma dilutions with buffer, only AT III on surfaces preadsorbed with high affinity or nonfractionated albumin-heparin conjugate was found. These results demonstrate that the heparin moiety of the conjugate is directed to the solution phase whereas the albumin moiety contacts the polystyrene surfaca     

Influence of natural weathering on colour stability of materials used for facial prosthesis

Colour stability of resin and silicone is an important factor for longevity of facial prostheses. The aim of this study was to evaluate the colour stability of resins and silicone for facial prostheses. Three brands of acrylic resin and one of facial silicone were evaluated considering pigment incorporation for the colourless materials. Ten samples of each material were fabricated and submitted to measurements of chromatic alteration initially and after 90 and 180 days of weathering natural through visual analysis and spectrophotometry. Data were evaluated by ANOVA and Tukey test (p < 0.05). Statistically significant colour alteration was observed among some materials regardless of the period. The materials did not present a statistical difference between 90 and 180 days except for the pigmented heat-polymerized resin. The colour difference between pigmented Silastic MDX4-4210 and colourless Silastic was statistically significant (p < 0.01) in both periods as well as between pigmented and colourless heat-polymerized resin, and between the resins Rapidaflex and Lentaflex. The visual method demonstrated colour alteration in all materials evaluated during the first 90 days of ageing. All materials exhibited colour alteration due to exposure to environment.     

Hydrogels in ophthalmic applications

More and more people worldwide are affected by severe eye diseases eventually leading to visual impairment or blindness. In most cases, the treatment involves the application of ophthalmic dosage forms such as eye drops, suspensions or ointments. Unfortunately, some of the therapeutic approaches have major shortcomings, especially in the treatment of the posterior segment of the eye, where many vision-threatening diseases originate. Therefore, research focuses on the development of new materials (e.g., for vitreous substitution) and more advanced drug delivery systems. Hydrogels are an extremely versatile class of materials with many potential applications in ophthalmology. They found widespread application as soft contact lenses, foldable intraocular lenses, in situ gelling formulations for ophthalmic drug delivery and ocular adhesives for wound repair; their use as vitreous substitutes and intravitreal drug delivery systems is currently under investigation. In this article, we review the different applications of hydrogels in ophthalmology with special emphasis placed on the used polymers and their suitability as ocular drug delivery systems.     

Titanium dioxide nanotubes with triazine-methacrylate monomer to improve physicochemical and biological properties of adhesives

ObjectiveFormulate experimental adhesives containing titanium dioxide nanotubes (nt-TiO₂) or titanium dioxide nanotubes with a triazine-methacrylate monomer (nt-TiO₂:TAT) and evaluate the effect of these fillers on the physical, chemical, and biological properties of the adhesives.MethodsFirst, nt-TiO₂ were synthesized via a hydrothermal method. The nt-TiO₂ were mixed with a triazine-methacrylate monomer (TAT) to formulate nt-TiO₂:TAT, which were characterized by transmission electron microscopy (TEM). The nt-TiO₂, TAT, and nt-TiO₂:TAT were evaluated via Fourier Transform Infrared, Ultraviolet–visible, and micro-Raman spectroscopies. An experimental adhesive resin was formulated with bisphenol A glycerolate dimethacrylates, 2-hydroxyethyl methacrylate, and photoinitiator/co-initiator system. nt-TiO₂ or nt-TiO₂:TAT were incorporated at 2.5 wt.% and 5 wt.% in the adhesive. The base resin without nt-TiO₂ or nt-TiO₂:TAT was used as a control group. The adhesives were evaluated for antibacterial activity, cytotoxicity, polymerization kinetics, degree of conversion (DC), Knoop hardness, softening in solvent (ΔKHN%), ultimate tensile strength (UTS), 24 h- and 1 year- microtensile bond strength (μ-TBS).ResultsTEM confirmed the nanotubular morphology of TiO₂. FTIR, UV–vis, and micro-Raman analyses showed the characteristic peaks of each material, indicating the impregnation of TAT in the nt-TiO₂. Adhesives with nt-TiO₂:TAT showed antimicrobial activity against biofilm formation compared to control (p < 0.05), without differences in the viability of planktonic bacteria (p > 0.05). All groups showed high percentages of pulp cell viability. The polymerization kinetics varied among groups, but all presented DC above 50%. The addition of 5 wt.% of nt-TiO₂ and both groups containing nt-TiO₂:TAT showed higher values ??of Knoop hardness compared to the control (p < 0.05). The groups with nt-TiO₂:TAT presented lower ΔKHN% (p < 0.05) and higher UTS (p < 0.05) than the control group. After one year, the group with 5 wt.% of nt-TiO₂, as well as both groups containing nt-TiO₂:TAT, showed higher μ-TBS than the control (p < 0.05).SignificanceThe mixing of a triazine-methacrylate monomer with the nt-TiO₂ generated a filler that improved the physicochemical properties of the adhesive resins and provided antibacterial activity, which could assist in preventing carious lesions around tooth-resin interfaces. The set of physical, chemical, and biological properties of the formulated polymer, together with the greater stability of the bond strength over time, make nt-TiO₂:TAT a promising filler for dental adhesive resins.     

Development and characterization of a new chitosan-based scaffold associated with gelatin,microparticulate dentin and genipin for endodontic regeneration

ObjectiveAn ideal scaffold for endodontic regeneration should allow the predictableness of the new tissue organization and limit the negative impact of residual bacteria. Therefore, composition and functionalization of the scaffold play an important role in tissue bioengineering. The objective of this study was to assess the morphological, physicochemical, biological and antimicrobial properties of a new solid chitosan-based scaffold associated with gelatin, microparticulate dentin and genipin.MethodsScaffolds based on chitosan (Ch); chitosan associated with gelatin and genipin (ChGG); and chitosan associated with gelatin, microparticulate dentin and genipin (ChGDG) were prepared by using the freeze-drying method. The morphology of the scaffolds was analyzed by scanning electron microscopy (SEM). The physicochemical properties were assessed for biodegradation, swelling and total released proteins. The biological aspects of the scaffolds were assessed using human cells from the apical papilla (hCAPs). Cell morphology and adhesion to the scaffolds were evaluated by SEM, cytotoxicity and cell proliferation by MTT reduction-assay. Cell differentiation in scaffolds was assessed by using alizarin red assay. The antimicrobial effect of the scaffolds was evaluated by using the bacterial culture method, and bacterial adhesion to the scaffolds was observed by SEM.ResultsAll the scaffolds presented porous structures. The ChCDG had more protein release, adhesion, proliferation and differentiation of hCAPs, and bacteriostatic effect on Enterococcus faecalis than Ch and ChGG (p < 0.05).SignificanceThe chitosan associated with gelatin, microparticulate dentin and genipin has morphological, physicochemical, biological and antibacterial characteristics suitable for their potential use as scaffold in regenerative endodontics.