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.

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 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.

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.

Capillary electrophoretic method for determination of protease inhibitor indinavir sulfate used in human immunodeficiency virus therapy.

A simple, fast and reliable capillary electrophoresis (CE) method for determination of indinavir sulfate, a potent protease inhibitor used in human immunodeficiency virus (HIV) therapy, in commercial and simulated capsule formulations is described. The analysis was performed in a 75microm i.d. uncoated fused-silica capillary with 27cm length (effective length of 19.4cm) using a 20mmoll-1 phosphate buffer at pH 2.52. Samples were injected hydrodynamically by applying 0.5psi pressure during 2s. The applied voltage was 28kV. Direct UV detection at 214nm led to an adequate sensitivity without interference from sample excipients and known impurities. For quantitative purposes, diazepam was used as internal standard. Under optimized conditions, the migration times for indinavir sulfate and diazepam were 1.06 and 1.66min, respectively. Analytical curve of peak area ratios versus concentration in the range of 20.0-100.0microg/ml gave a coefficient of correlation of 0.9992, establishing the method linearity. The limits of detection and quantitation were 4.61 and 14.0microg/ml, respectively. The within-day precision expressed as relative standard deviation was <1.5% for 10 consecutive sample injections. An average recovery of 100.81+/-0.56% at three concentration levels was obtained. Based on the performance characteristics, the proposed methodology was found suitable for the determination of indinavir sulfate in capsule formulations, presenting additional advantages inherent to the CE technology, such as low consumption of reagents and column endurance.