Moxifloxacin-loaded acrylic intraocular lenses: In vitro and in vivo performance.

PURPOSE: To assess the possibility of using acrylic intraocular lenses (IOLs) to ensure controlled and sustained release of moxifloxacin, an antibiotic commonly used for endophthalmitis prophylaxis after cataract surgery. SETTING: Academic, industrial, and clinical partners from Portugal, Belgium, Iceland, and the United States. DESIGN: Experimental study. METHODS: The physical properties of IOLs loaded with moxifloxacin by soaking were characterized. In vitro drug-release studies were performed under hydrodynamic conditions similar to those of the eye, and the activity of the released drug was tested. In vitro cytotoxicity was evaluated, and the in vivo efficacy of the devices was assessed through rabbit experiments in which the effects of topical moxifloxacin drops (control) and moxifloxacin-loaded IOLs were compared. RESULTS: The presence of moxifloxacin in the IOLs had little effect on the evaluated physical properties and did not induce cytotoxicity. In vitro drug release experiments showed that the IOLs provided controlled release of moxifloxacin for approximately 2 weeks. The drug remained active against the tested microorganisms during that period. Moxifloxacin-loaded IOLs and the control treatment induced similar in vivo behavior in terms of inflammatory reactions, capsular bag opacification scores, and uveal and capsule biocompatibility. The drug concentration in the aqueous humor after 1 week was similar in both groups; however, the concentration with the loaded IOLs was less variable. CONCLUSION: The moxifloxacin-loaded IOLs released the drug in a controlled manner, providing therapeutic levels.

Additive manufacturing of ceramics for dental applications: A review.

OBJECTIVE: The main goal of this review is to provide a detailed and comprehensive description of the published work from the past decade regarding AM of ceramic materials with possible applications in dentistry. The main printable materials and most common technologies are also addressed, underlining their advantages and main drawbacks. METHODS: Online databases (Web of knowledge, Science Direct, PubMed) were consulted on this topic. Published work from 2008 to 2018 was collected, analyzed and the relevant papers were selected for inclusion on this review. RESULTS: Ceramic materials are broadly used in dentistry to restore/replace damaged or missing teeth, due to their biocompatibility, chemical stability and mechanical and aesthetic properties. However, there are several unmet challenges regarding their processing and performance. Due to their brittleness nature, a very tight control of the manufacturing process is needed to obtain dental pieces with adequate mechanical properties. Additive manufacturing (AM) is an emerging technology that constitutes an interesting and viable manufacturing alternative to the conventional subtractive methods. AM enables the production of customized complex 3D parts in a more sustainable and less expensive way. AM of ceramics can be achieved with an extensive variety of methods. SIGNIFICANCE: There is no perfect technology for all materials/applications, capable alone of fulfilling all the specificities and necessities of every patient. Although very promising, AM of ceramic dental materials remains understudied and further work is required to make it a widespread technology in dentistry.

Drug-eluting silicone hydrogel for therapeutic contact lenses: Impact of sterilization methods on the system performance.

Although contact lenses are promising platforms for ocular drug delivery and have been extensively studied for that purpose, the influence of sterilization methods on these systems remains barely investigated. In this work, a silicone-based hydrogel was produced and loaded with different ophthalmic drugs: levofloxacin, chlorhexidine, diclofenac and timolol. The drug release profiles, along with several material properties, were evaluated before and after sterilization by three different methods steam heat, γ-irradiation and ozone gas. Independently of the sterilization method used, the results of the swelling and mechanical properties tests strongly indicate the occurrence of specific drug-polymer interactions promoted by the sterilization. In general, these interactions led to a decrease on the amount of drug released. It is shown that γ-irradiation and ozone led to significant degradation of all of the drugs used in this study. Thus, it was concluded that steam heat is the sterilization method with less impact on the devices. More importantly, the present work shows that the development of efficient and functional drug delivery devices for ophthalmic purposes cannot be done independently of a careful analysis of the influence of the sterilization procedures and methods on the degradation of these polymeric systems as a whole.

Sterilization of hydrogels for biomedical applications: A review.

Despite the beneficial properties and outstanding potential of hydrogels for biomedical applications, several unmet challenges must be overcome, especially regarding to their known sensitivity to conventional sterilization methods. It is crucial for any biomaterial to withstand an efficient sterilization to obtain approval from regulatory organizations and to safely proceed to clinical trials. Sterility assurance minimizes the incidence of medical device-related infections, which still constitute a major concern in health care. In this review, we provide a detailed and comprehensive description of the published work from the past decade regarding the effects of sterilization on different types of hydrogels for biomedical applications. Advances in hydrogel production methods with simultaneous sterilization are also reported. Terminal sterilization methods can induce negative or positive effects on several material properties (e.g., aspect, size, color, chemical structure, mechanical integrity, and biocompatibility). Due to the complexity of factors involved (e.g., material properties, drug stability, sterilization conditions, and parameters), it is important to note the virtual impossibility of predicting the outcome of sterilization methods to determine a set of universal rules. Each system requires case-by-case testing to select the most suitable, effective method that allows for the main properties to remain unaltered. The impact of sterilization methods on the intrinsic properties of these systems is understudied, and further research is needed. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2472-2492, 2018.

Sterilization of silicone-based hydrogels for biomedical application using ozone gas: Comparison with conventional techniques.

Sterilization of hydrogels is challenging due to their often reported sensitivity to conventional methods involving heat or radiation. Although aseptic manufacturing is a possibility, terminal sterilization is safer in biological terms, leading to a higher overall efficiency, and thus should be used whenever it is possible. The main goal of this work was to study the applicability of an innovative ozone gas terminal sterilization method for silicone-based hydrogels and compare its efficacy and effects with those of traditional sterilization methods: steam heat and gamma irradiation. Ozone gas sterilization is a method with potential interest since it is reported as a low cost green method, does not leave toxic residues and can be applied to thermosensitive materials. A hydrogel intended for ophthalmological applications, based on tris(trimethylsiloxy)silyl] propyl methacrylate, was prepared and extensively characterized before and after the sterilization procedures. Alterations regarding transparency, swelling, wettability, ionic permeability, friction coefficient, mechanical properties, topography and morphology and chemical composition were monitored. Efficacy of the ozonation was accessed by performing controlled contaminations and sterility tests. In vitro cytotoxicity testes were also performed. The results show that ozonation may be applied to sterilize the studied material. A treatment with 8 pulses allowed sterilizing the material with bioburdens≤103CFU/mL, preserving all the studied properties within the required known values for contact lenses materials. However, a higher exposure (10 pulses) led to some degradation of the material and induced mild cytotoxicity. Steam heat sterilization led to an increase of swelling capacity and a decrease of the water contact angle. Regarding gamma irradiation, the increase of irradiation dose led to an increase of the friction coefficient. The higher dose (25kGy) originated surface degradation and affected the mechanical properties of the hydrogel by inducing a significant increase of the Young's modulus. Overall, the results show that ozonation may be considered as a valid and promising alternative for the sterilization of silicon-based hydrogels for biomedical applications.

Hydrogel Based Drug Delivery Systems: A Review with Special Emphasis on Challenges Associated with Decontamination of Hydrogels and Biomaterials.

BACKGROUND: Many researches involving the development of new techniques and biomaterials to formulate a suitable drug delivery system and tissue engineering have been conducted. The majority of published literature from these researches emphasizes the production and materials characterization. The safety aspect of hydrogels and biomaterials is a major constraint in their biological applications. OBJECTIVE: The present review article aimed to summarize various literatures that encompass the difficulties encountered with decontamination and sterilization methods in the preparations of biomaterials and especially hydrogels for biological applications. METHOD: We searched for original and review articles from various indexed journals reporting applications of hydrogels and biomaterials in drug delivery systems and the importance of decontamination process for hydrogel containing preparations based on various patents evidences. RESULTS: Despite the vast literature available, limited information regarding the decontamination and sterilization processes related to hydrogels and biomaterials is reported. Sterilization processes to hydrogels are not yet fully explored. Researchers working on hydrogel based systems can consider decontamination of such biomaterial as an important tool to allow for commercialization within the chemical, herbal or pharmaceutical industries. CONCLUSION: Unfortunately, till date, limited papers are available which reported the challenges associated with decontamination methods to prepare hydrogels and biomaterials for biological applications. In conclusion, each case of biomaterial requires individual consideration to decontamination and/or sterilization. This must be submitted to a specific method, but more than one technique can be involved. Physicochemical and biological alterations must be avoided and evaluated by the appropriate assays method. Furthermore, it is also important to consider that each method must be validated depending upon the process variables.

Esterilização de hidrogéis para aplicações biomédicas / Sterilization of hydrogels for biomedical applications

A esterilidade é um requisito indispensável para a maioria dos biomateriais. Devido à sensibilidade dos hidrogéis, a sua esterilização apresenta-se como um desafio, sobretudo quando estão em causa nanoestruturas ou a presença de fármacos. O objetivo deste trabalho foi estudar os principais efeitos de diversos métodos de esterilização nas propriedades de diferentes tipos de sistemas à base de hidrogel. Além dos métodos convencionais (calor húmido e radiação gama) foi aferida a aplicabilidade da esterilização por ozono, um processo que embora se revele recente e ainda em fase de desenvolvimento, não deixa, no entanto, de ser bastante promissor. Estudou-se uma formulação de hidrogel natural nanoparticulado à base de quitosano (nanogel), com um largo espectro de possíveis aplicações, e duas formulações de hidrogéis sintéticos para aplicações oftálmicas (modelos de lentes de contato convencional e da nova geração de silicone-hidrogel), com e sem fármacos incorporados. Avaliaram-se alterações nas principais propriedades vitais ao bom desempenho e integridade dos materiais. No caso do nanogel: tamanho médio de partícula, potencial zeta, índice de polidispersão, absorvância, morfologia, estrutura química e citotoxicidade. No caso dos hidrogéis sintéticos: intumescimento, propriedades ópticas, permeabilidade iónica, molhabilidade, morfologia e topografia, estrutura química, propriedades mecânicas, citotoxicidade e perfil de libertação dos fármacos. Para garantir a melhor eficácia dos métodos de esterilização, realizaram-se testes de esterilidade após a contaminação intencional das amostras com diferentes cargas dos respetivos indicadores biológicos. A esterilização por calor húmido revelou-se o método mais agressivo, no caso do nanogel, e o menos agressivo para os hidrogéis sintéticos, quer na presença quer na ausência de fármacos. Relativamente à irradiação gama, para o nanogel, verificou-se que a sua resistência à irradiação aumenta consideravelmente na presença de açucares protetores. Já os hidrogéis sintéticos mostram-se resistentes à técnica, apresentando sinais de degradação evidente apenas para a dose mais elevada (25 kGy). Na presença de fármacos, a irradiação gama mostrou-se inadequada devido à sensibilidade dos mesmos. Os resultados obtidos são promissores no que diz respeito à aplicabilidade da esterilização por ozono, tanto para o nanogel como para os hidrogéis sintéticos, sem fármacos incorporados. Os fármacos sofrem, na generalidade, degradação quando expostos a este agente oxidante. Em suma, face à evidente complexidade dos fatores envolvidos (e.g. natureza, composição e propriedades dos materiais, estabilidade dos fármacos, condições e parâmetros dos processos esterilização), torna-se difícil generalizar os efeitos e prever o resultado dos métodos de esterilização. A escolha do processo mais adequado deve, portanto, ser feita caso a caso.

Sterility is mandatory requirement for most biomaterials. Because of their known sensitivity, hydrogel sterilization poses as a challenge, particularly when it comes to nanostructures or when drugs are incorporated. The main goal of this work was to study the key effects of different sterilization methods on the properties of different types of hydrogel-based systems. In addition to the conventional methods (steam heat and gamma radiation) the applicability of a promising new ozone method was assessed. Two formulations of synthetic hydrogels for ophthalmic applications (representing conventional contact lenses and new generation silicone-hydrogel contact lens), unloaded and loaded with ophthalmic drugs, were studied; and a natural chitosan-based nanostructured hydrogel (nanogel), with a broad spectrum of possible applications. Changes in the essential properties were evaluated. For synthetic hydrogels: swelling, optical properties, ionic permeability, wettability, morphology and topography, chemical structure, mechanical properties, cytotoxicity and drug release profile. For the nanogel: average particle size, zeta potential, polydispersity index, absorbance, morphology, chemical structure and cytotoxicity. In order to ensure the effectiveness of the sterilization methods, sterility tests were carried out after purposely contaminating the samples with different loads of biological indicators. Seam heat sterilization proved to be the most aggressive method for the nanogel, while being the least aggressive for the synthetic hydrogels in the presence and absence of drugs. Regarding gamma irradiation, the nanogel resistance to irradiation increased considerably in the presence of protective sugars. The synthetic hydrogels were resistant to this technique, showing signs of severe degradation only at the highest dose (25 kGy). In the presence of drugs, gamma irradiation proved to be inadequate due to drug degradation. The obtained results were encouraging with regard to the applicability of ozone sterilization for both the nanogel and the unloaded synthetic hydrogels. The drugs generally undergo degradation when exposed to this oxidizing agent. In view of the evident complexity of the factors involved (e.g. nature, composition and properties of materials, drug stability, conditions and parameters of sterilization processes), it is difficult to generalize the effects and predict the outcome of the sterilization methods. The selection of the most suitable procedure must be made on a case-by-case basis.

About the Sterilization of Chitosan Hydrogel Nanoparticles.

In the last years, nanostructured biomaterials have raised a great interest as platforms for delivery of drugs, genes, imaging agents and for tissue engineering applications. In particular, hydrogel nanoparticles (HNP) associate the distinctive features of hydrogels (high water uptake capacity, biocompatibility) with the advantages of being possible to tailor its physicochemical properties at nano-scale to increase solubility, immunocompatibility and cellular uptake. In order to be safe, HNP for biomedical applications, such as injectable or ophthalmic formulations, must be sterile. Literature is very scarce with respect to sterilization effects on nanostructured systems, and even more in what concerns HNP. This work aims to evaluate the effect and effectiveness of different sterilization methods on chitosan (CS) hydrogel nanoparticles. In addition to conventional methods (steam autoclave and gamma irradiation), a recent ozone-based method of sterilization was also tested. A model chitosan-tripolyphosphate (TPP) hydrogel nanoparticles (CS-HNP), with a broad spectrum of possible applications was produced and sterilized in the absence and in the presence of protective sugars (glucose and mannitol). Properties like size, zeta potential, absorbance, morphology, chemical structure and cytotoxicity were evaluated. It was found that the CS-HNP degrade by autoclaving and that sugars have no protective effect. Concerning gamma irradiation, the formation of agglomerates was observed, compromising the suspension stability. However, the nanoparticles resistance increases considerably in the presence of the sugars. Ozone sterilization did not lead to significant physical adverse effects, however, slight toxicity signs were observed, contrarily to gamma irradiation where no detectable changes on cells were found. Ozonation in the presence of sugars avoided cytotoxicity. Nevertheless, some chemical alterations were observed in the nanoparticles.

Ozone Gas as a Benign Sterilization Treatment for PLGA Nanofiber Scaffolds.

The use of electrospun nanofibers for tissue engineering and regenerative medicine applications is a growing trend as they provide improved support for cell proliferation and survival due, in part, to their morphology mimicking that of the extracellular matrix. Sterilization is a critical step in the fabrication process of implantable biomaterial scaffolds for clinical use, but many of the existing methods used to date can negatively affect scaffold properties and performance. Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer for 3D scaffolds and can be significantly affected by current sterilization techniques. The aim of this study was to investigate pulsed ozone gas as an alternative method for sterilizing PLGA nanofibers. The morphology, mechanical properties, physicochemical properties, and response of cells to PLGA nanofiber scaffolds were assessed following different degrees of ozone gas sterilization. This treatment killed Geobacillus stearothermophilus spores, the most common biological indicator used for validation of sterilization processes. In addition, the method preserved all of the characteristics of nonsterilized PLGA nanofibers at all degrees of sterilization tested. These findings suggest that ozone gas can be applied as an alternative method for sterilizing electrospun PLGA nanofiber scaffolds without detrimental effects.

Correlation between heavy metal ions (copper, zinc, lead) concentrations and root length of Allium cepa L. in polluted river water

The present work was performed using the common onion (Allium cepa L.) as a bioindicator of toxicity of heavy metals in river water. The test waters were collected at two sampling sites: at the beginning and the end of the Toledo River. The bulbs of A. cepa L. were grown in test water with nine concentration levels of copper, zinc and lead from 0.1 to 50 ppm. In the laboratory, the influence of these test liquids on the root growth was examined during five days. For test liquids containing below 0.03-ppm dissolved Cu the root growth was reduced by 40 percent However, the same reduction occurred for 1-ppm dissolved Zn. For dissolved Pb, results reveal toxicity above 0.1 and 0.6 ppm at the beginning and the end of the Toledo river water, respectively.