Abstract
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.
Highlights
Medical device related infections are becoming an increasing prevalent area of infectious disease that contribute greatly to the increasing costs on health care systems [1]
It has been reported that several factors, such as pH, molecular weight of chitosan and its deacetylation level, may affect the physical and chemical properties of nanoparticles, and, in last
The formation of CS-hydrogel nanoparticles (HNP) can be confirmed by the appearance of the absorption bands of the P-O groups (1215 cm-1) and of N-H deformations vibrations (1647 cm-1), which in turn are indicative of interaction between CS and TPP [17]
Summary
Medical device related infections are becoming an increasing prevalent area of infectious disease that contribute greatly to the increasing costs on health care systems [1]. The outbreak in the field of nanotechnology, the growing interest that nanomaterials have raised in pharmaceutical and nanomedicine fields and the high complexity that they may assume, triggered the need for developing strategies to guaranty the safety and effectiveness of these structures [2]. A nanosystem designed for biomedical applications (e.g. injectables, ophthalmic solutions) cannot be toxic or irritating and must be sterile [2]. Terminal sterilization is safer in biological terms, leading to a higher overall efficiency, and must be used whenever it is possible [3]. Changes on the physicochemical characteristics of nanosystems can induce toxicity and loss of properties that lead to system failure [2, 4]. Few studies address the sterilization of nanostructured systems [2]. As far as the authors know, no work has been published regarding the sterilization of chitosan (CS) hydrogel nanoparticles (HNP)
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