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      Biocompatibility of common implantable sensor materials in a tumor xenograft model

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          Abstract

          Real‐time monitoring of tumor microenvironment parameters using an implanted biosensor could provide valuable information on the dynamic nature of a tumor's biology and its response to treatment. However, following implantation biosensors may lose functionality due to biofouling caused by the foreign body response (FBR). This study developed a novel tumor xenograft model to evaluate the potential of six biomaterials (silicon dioxide, silicon nitride, Parylene‐C, Nafion, biocompatible EPOTEK epoxy resin, and platinum) to trigger a FBR when implanted into a solid tumor. Biomaterials were chosen based on their use in the construction of a novel biosensor, designed to measure spatial and temporal changes in intra‐tumoral O 2, and pH. None of the biomaterials had any detrimental effect on tumor growth or body weight of the murine host. Immunohistochemistry showed no significant changes in tumor necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration, or collagen deposition. The absence of biofouling supports the use of these materials in biosensors; future investigations in preclinical cancer models are required, with a view to eventual applications in humans. To our knowledge this is the first documented investigation of the effects of modern biomaterials, used in the production of implantable sensors, on tumor tissue after implantation. © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1620–1633, 2019.

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          Metals, toxicity and oxidative stress.

          Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link between vanadium and oxidative stress in the etiology of diabetes. The impact of zinc (Zn) on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiology of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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            Radiation oncology in the era of precision medicine.

            Technological advances and clinical research over the past few decades have given radiation oncologists the capability to personalize treatments for accurate delivery of radiation dose based on clinical parameters and anatomical information. Eradication of gross and microscopic tumours with preservation of health-related quality of life can be achieved in many patients. Two major strategies, acting synergistically, will enable further widening of the therapeutic window of radiation oncology in the era of precision medicine: technology-driven improvement of treatment conformity, including advanced image guidance and particle therapy, and novel biological concepts for personalized treatment, including biomarker-guided prescription, combined treatment modalities and adaptation of treatment during its course.
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              Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma.

              Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine-glycine-aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in αvβ3 integrin-expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting.
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                Author and article information

                Contributors
                s9900757@sms.ed.ac.uk
                Journal
                J Biomed Mater Res B Appl Biomater
                J. Biomed. Mater. Res. Part B Appl. Biomater
                10.1002/(ISSN)1552-4981
                JBM
                Journal of Biomedical Materials Research. Part B, Applied Biomaterials
                John Wiley & Sons, Inc. (Hoboken, USA )
                1552-4973
                1552-4981
                27 October 2018
                July 2019
                : 107
                : 5 ( doiID: 10.1002/jbm.b.v107.5 )
                : 1620-1633
                Affiliations
                [ 1 ] The Royal (Dick) School of Veterinary Studies and Roslin Institute University of Edinburgh Edinburgh EH25 9RG UK
                [ 2 ] Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh EH4 2XU UK
                [ 3 ] Institute of Sensors, Signals and Systems, School of Engineering and Physical Sciences Heriot‐Watt University Edinburgh EH14 4AS UK
                [ 4 ] School of Engineering, Faraday Building Edinburgh EH9 3JL UK
                Author notes
                [*] [* ] Correspondence to: M. Gray; e‐mail: s9900757@ 123456sms.ed.ac.uk
                Article
                JBMB34254
                10.1002/jbm.b.34254
                6767110
                30367816
                a886b788-0eba-4146-bc39-382f0c300160
                © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 June 2018
                : 30 August 2018
                : 09 September 2018
                Page count
                Figures: 7, Tables: 2, Pages: 14, Words: 12006
                Funding
                Funded by: UK Engineering and Physical Sciences Research Council
                Award ID: EP/K‐34510/1
                Categories
                Original Research Report
                Original Research Reports
                Custom metadata
                2.0
                jbmb34254
                July 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:30.09.2019

                Biomaterials & Organic materials
                biocompatibility,tumor xenograft model,tumor microenvironment,innate immune response,foreign body response,implantable biosensor

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