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      Osteoinductive activity of insulin-functionalized cell culture surfaces obtained using diazonium chemistry

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          Polymeric surfaces suitable for cell culture (DR/Pec) were constructed from diazoresin (DR) and pectin (Pec) in a form of ultrathin films using the layer-by-layer (LbL) technique. The surfaces were functionalized with insulin using diazonium chemistry. Such functionalized surfaces were used to culture human mesenchymal stem cells (hMSCs) to assess their suitability for bone tissue engineering and regeneration. The activity of insulin immobilized on the surfaces (DR/Pec/Ins) was compared to that of insulin dissolved in the culture medium. Human MSC grown on insulin-immobilized DR/Pec surfaces displayed increased proliferation and higher osteogenic activity. The latter was determined by means of alkaline phosphatase (ALP) activity, which increases at early stages of osteoblasts differentiation. Insulin dissolved in the culture medium did not stimulate cell proliferation and its osteogenic activity was significantly lower. Addition of recombinant human bone morphogenetic protein 2 (rhBMP-2) to the culture medium further increased ALP activity in hMSCs indicating additive osteogenic action of immobilized insulin and rhBMP-2.

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          A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.

          Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Systematic review. Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Photo-oxidation of proteins.

            Photo-induced damage to proteins occurs via multiple pathways. Direct damage induced by UVB (λ 280-320 nm) and UVA radiation (λ 320-400 nm) is limited to a small number of amino acid residues, principally tryptophan (Trp), tyrosine (Tyr), histidine (His) and disulfide (cystine) residues, with this occurring via both excited state species and radicals. Indirect protein damage can occur via singlet oxygen ((1)O(2)(1)Δ(g)), with this resulting in damage to Trp, Tyr, His, cystine, cysteine (Cys) and methionine (Met) residues. Although initial damage is limited to these residues multiple secondary processes, that occur both during and after radiation exposure, can result in damage to other intra- and inter-molecular sites. Secondary damage can arise via radicals (e.g. Trp, Tyr and Cys radicals), from reactive intermediates generated by (1)O(2) (e.g. Trp, Tyr and His peroxides) and via molecular reactions of photo-products (e.g. reactive carbonyls). These processes can result in protein fragmentation, aggregation, altered physical and chemical properties (e.g. hydrophobicity and charge) and modulated biological turnover. Accumulating evidence implicates these events in cellular and tissue dysfunction (e.g. apoptosis, necrosis and altered cell signaling), and multiple human pathologies. This journal is © The Royal Society of Chemistry and Owner Societies 2012
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              Protect from light: photodegradation and protein biologics.

              The exposure of proteins to light and the ensuing chemical and physical degradation has been studied extensively for many years. The residues in proteins that undergo primary photooxidation include tryptophan, tyrosine, phenylalanine, and cysteine/cystine. While photooxidation has been recognized as a major contributor to protein degradation, the effects of photoinduced damage have not been widely studied for biopharmaceuticals. This is particularly important since photodegradation can lead to changes in primary, secondary, and tertiary structures of protein and these changes, while not definitively established, could lead to differences in long-term stability, bioactivity, or immunogenicity. In this review we briefly describe the major pathways of photodegradation for proteins followed by a description of the limited data on photodegradation of biopharmaceuticals and methods that have been used to reduce or prevent damage. It is our intent to spur additional research in this area for increasing the safety and effectiveness of biopharmaceutical products.

                Author and article information

                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                13 January 2015
                : 2
                1Nanotechnology of Polymers and Biomaterials, Faculty of Chemistry, Jagiellonian University Kraków, Poland
                2Department of Biology and Cell Imaging, Faculty of Biology and Earth Sciences, Jagiellonian University Kraków, Poland
                Author notes

                Edited by: Konstantinos M. Kasiotis, Benaki Phytopathological Institute, Greece

                Reviewed by: Zhenjun Yang, Peking University, China; Hyun Lee, University of Illinois at Chicago, USA

                *Correspondence: Maria Nowakowska and Krzysztof Szczubiałka, Nanotechnology of Polymers and Biomaterials Faculty of Chemistry, Jagiellonian University, Ingardena 3, Kraków, Poland e-mail: nowakows@ 123456chemia.uj.edu.pl ; szczubia@ 123456chemia.uj.edu.pl

                This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry.

                Copyright © 2015 Mikulska, Filipowska, Osyczka, Nowakowska and Szczubiałka.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 29, Pages: 7, Words: 5007
                Original Research Article


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