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  • 1.
    Boisen, Gabriella
    et al.
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD). Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    Enggren, Gabriela
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Dahl, Hanna
    Malmö University, Faculty of Odontology (OD).
    Mkadmi, Cindy
    Malmö University, Faculty of Odontology (OD).
    Davies, Julia R
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Limosilactobacillus reuteri inhibits the acid tolerance response in oral bacteria2023In: Biofilm, E-ISSN 2590-2075, Vol. 6, article id 100136Article in journal (Refereed)
    Abstract [en]

    Probiotic bacteria show promising results in prevention of the biofilm-mediated disease caries, but the mechanisms are not fully understood. The acid tolerance response (ATR) allows biofilm bacteria to survive and metabolize at low pH resulting from microbial carbohydrate fermentation. We have studied the effect of probiotic strains: Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus on ATR induction in common oral bacteria. Communities of L. reuteri ATCC PTA5289 and Streptoccus gordonii, Streptococcus oralis, Streptococcus mutans or Actinomyces naeslundii in the initial stages of biofilm formation were exposed to pH 5.5 to allow ATR induction, followed by a low pH challenge. Acid tolerance was evaluated as viable cells after staining with LIVE/ DEAD & REG;BacLightTM. The presence of L. reuteri ATCC PTA5289 caused a significant reduction in acid tolerance in all strains except S. oralis. When S. mutans was used as a model organism to study the effects of additional probiotic strains (L. reuteri SD2112, L. reuteri DSM17938 or L. rhamnosus GG) as well as L. reuteri ATCC PTA5289 supernatant on ATR development, neither the other probiotic strains nor supernatants showed any effect. The presence of L. reuteri ATCC PTA5289 during ATR induction led to down-regulation of three key genes involved in tolerance of acid stress (luxS, brpA and ldh) in Streptococci. These data suggest that live cells of probiotic L. reuteri ATCC PTA5289 can interfere with ATR development in common oral bacteria and specific strains of L. reuteri may thus have a role in caries prevention by inhibiting development of an acid-tolerant biofilm microbiota.

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  • 2.
    Riaz, Azra
    et al.
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Gidvall, Sanna
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD).
    Hernandez, Aura Rocio
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Ruzgas, Tautgirdas
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Nilsson, Emelie J.
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Davies, Julia R
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Valetti, Sabrina
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies2023In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 5, p. 1513-1513Article in journal (Refereed)
    Abstract [en]

    Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies. We developed both full-thickness (i.e., connective plus epithelial tissue) and split-thickness (i.e., only epithelial tissue) OME using non-tumor-derived human keratinocytes OKF6 TERT-2 obtained from the floor of the mouth. All the OME developed here presented similar transepithelial electrical resistance (TEER) values, comparable to the commercial EpiOral™. Using eletriptan hydrobromide as a model drug, we found that the full-thickness OME had similar drug flux to EpiOral™ (28.8 vs. 29.6 µg/cm2/h), suggesting that the model had the same permeation barrier properties. Furthermore, full-thickness OME showed an increase in ceramide content together with a decrease in phospholipids in comparison to the monolayer culture, indicating that lipid differentiation occurred due to the tissue-engineering protocols. The split-thickness mucosal model resulted in 4–5 cell layers with basal cells still undergoing mitosis. The optimum period at the air–liquid interface for this model was twenty-one days; after longer times, signs of apoptosis appeared. Following the 3R principles, we found that the addition of Ca2+, retinoic acid, linoleic acid, epidermal growth factor and bovine pituitary extract was important but not sufficient to fully replace the fetal bovine serum. Finally, the OME models presented here offer a longer shelf-life than the pre-existing models, which paves the way for the further investigation of broader pharmaceutical applications (i.e., long-term drug exposure, effect on the keratinocytes’ differentiation and inflammatory conditions, etc.).

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  • 3.
    Valetti, Sabrina
    et al.
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Riaz, Azra
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Doko, Anemona
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Sultana, Kaiser
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Eskandari, Mahboubeh
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD).
    Feiler, Adam
    Nanologica AB, 151 36 Södertälje, Sweden; Chemistry Department, KTH, Royal Institute of Technology, 100 44 Stockholm, Sweden.
    Rönn, Robert
    Orexo AB, 754 50 Uppsala, Sweden.
    Dahlström, Bengt
    CTC Clinical Trial Consultants AB, 75237 Uppsala, Sweden.
    Engblom, Johan
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Björklund, Sebastian
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Oral transmucosal delivery of eletriptan for neurological diseases.2022In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 627, article id 122222Article in journal (Refereed)
    Abstract [en]

    Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

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  • 4.
    Peruzzi, Niccolò
    et al.
    Lund University.
    Galli, Silvia
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Helmholz, Heike
    Helmholtz-Zentrum hereon GmbH, Germany.
    Kardjilov, Nikolay
    Helmholtz Centre for Materials and Energy, Germany.
    Krüger, Diana
    Helmholtz-Zentrum hereon GmbH, Germany.
    Markötter, Henning
    Bundesanstalt für Materialforschung und-prüfung, Germany.
    Moosmann, Julian
    Helmholtz-Zentrum hereon GmbH, Germany.
    Orlov, Dmytro
    Lund University.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD).
    Willumeit-Römer, Regine
    Helmholtz-Zentrum hereon GmbH, Germany.
    Wennerberg, Ann
    University of Gothenburg.
    Bech, Martin
    Lund University.
    Multimodal ex vivo methods reveal that Gd-rich corrosion byproducts remain at the implant site of biodegradable Mg-Gd screws2021In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 136, p. 582-591Article in journal (Refereed)
    Abstract [en]

    Extensive research is being conducted on magnesium (Mg) alloys for bone implant manufacturing, due to their biocompatibility, biodegradability and mechanical properties. Gadolinium (Gd) is among the most promising alloying elements for property control in Mg alloy implants; however, its toxicity is controversial. Investigating Gd behavior during implant corrosion is thus of utmost importance. In this study, we analyzed the degradation byproducts at the implant site of biodegradable Mg-5Gd and Mg-10Gd implants after 12 weeks healing time, using a combination of different imaging techniques: histology, energy-dispersive x-ray spectroscopy (EDX), x-ray microcomputed tomography (µCT) and neutron µCT. The main finding has been that, at the healing time in exam, the corrosion appears to have involved only the Mg component, which has been substituted by calcium and phosphorus, while the Gd remains localized at the implant site. This was observed in 2D by means of EDX maps and extended to 3D with a novel application of neutron tomography. X-ray fluorescence analysis of the main excretory organs also did not reveal any measurable accumulation of Gd, further reinforcing the conclusion that very limited or no removal at all of Gd-alloy happened during degradation.

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  • 5.
    Davies, Julia R
    et al.
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Kad, Trupti
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Neilands, Jessica
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Kinnby, B
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Bengtsson, Torbjörn
    School of Medical Sciences, Örebro University, Örebro, Sweden..
    Khalaf, Hazem
    School of Medical Sciences, Örebro University, Örebro, Sweden..
    Svensäter, Gunnel
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Polymicrobial synergy stimulates Porphyromonas gingivalis survival and gingipain expression in a multi-species subgingival community.2021In: BMC Oral Health, ISSN 1472-6831, E-ISSN 1472-6831, Vol. 21, no 1, article id 639Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dysbiosis in subgingival microbial communities, resulting from increased inflammatory transudate from the gingival tissues, is an important factor in initiation and development of periodontitis. Dysbiotic communities are characterized by increased numbers of bacteria that exploit the serum-like transudate for nutrients, giving rise to a proteolytic community phenotype. Here we investigate the contribution of interactions between members of a sub-gingival community to survival and development of virulence in a serum environment-modelling that in the subgingival pocket.

    METHODS: Growth and proteolytic activity of three Porphyromonas gingivalis strains in nutrient broth or a serum environment were assessed using A600 and a fluorescent protease substrate, respectively. Adherence of P. gingivalis strains to serum-coated surfaces was studied with confocal microscopy and 2D-gel electrophoresis of bacterial supernatants used to investigate extracellular proteins. A model multi-species sub-gingival community containing Fusobacterium nucleatum, Streptococcus constellatus, Parvimonas micra with wild type or isogenic mutants of P. gingivalis was then created and growth and proteolytic activity in serum assessed as above. Community composition over time was monitored using culture techniques and qPCR.

    RESULTS: The P. gingivalis strains showed different growth rates in nutrient broth related to the level of proteolytic activity (largely gingipains) in the cultures. Despite being able to adhere to serum-coated surfaces, none of the strains was able to grow alone in a serum environment. Together in the subgingival consortium however, all the included species were able to grow in the serum environment and the community adopted a proteolytic phenotype. Inclusion of P. gingivalis strains lacking gingipains in the consortium revealed that community growth was facilitated by Rgp gingipain from P. gingivalis.

    CONCLUSIONS: In the multi-species consortium, growth was facilitated by the wild-type and Rgp-expressing strains of P. gingivalis, suggesting that Rgp is involved in delivery of nutrients to the whole community through degradation of complex protein substrates in serum. Whereas they are constitutively expressed by P. gingivalis in nutrient broth, gingipain expression in the model periodontal pocket environment (serum) appeared to be orchestrated through signaling to P. gingivalis from other members of the community, a phenomenon which then promoted growth of the whole community.

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  • 6.
    Gustafsson, Anna
    et al.
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD).
    Jankovskaja, Skaidre
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Ruzgas, Tautgirdas
    Malmö University, Biofilms Research Center for Biointerfaces. Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV).
    Engblom, Johan
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Ohlsson, Lars
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Gjörloff Wingren, Anette
    Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
    Effect of IFN-γ on the kynurenine/tryptophan ratio in monolayer-cultured keratinocytes and a 3D reconstructed human epidermis model2020In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 99, no 3, p. 177-184, article id S0923-1811(20)30234-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interferon-gamma (IFN-γ) represents a potent inducer for keratinocyte inflammatory and immune activation in vitro. Since tryptophan (trp) conversion to kynurenine (kyn) is involved in inflammation, the topical kyn/trp ratio may serve as a biomarker of skin inflammation. However, the trp metabolism in keratinocytes exposed to IFN-γ is not yet fully understood.

    OBJECTIVE: The aim of this study was to establish a human epidermis model in order to quantify cytokine and kyn/trp secretion from IFN-γ stimulated cells and tissues. Moreover, to compare the cell response of 2D-cultured keratinocytes and the 3D epidermis model.

    METHODS: Polycarbonate filters were used on which primary keratinocytes could attach and stratify in order to form the typical layers of reconstructed human epidermis (RHE). After IFN-γ treatment, secretion of kyn/trp was measured by high performance liquid chromatography. Gene and protein expression of indoleamine 2,3-dioxygenase 1 (IDO) was analyzed with real-time PCR and immunohistochemistry. The secretion of cytokines was quantified with ELISA.

    RESULTS: Trp catabolism to kyn was significantly increased (P < 0.01) in the 2D culture in response to IFN-γ treatment. Before kyn secretion, IDO was strongly upregulated (P < 0.001). IFN-γ treatment also increased the secretion of IL-6 and IL-8 from the keratinocytes. In the RHE, IDO was upregulated by IFN-γ, and kyn secretion could be detected. Interestingly, IDO expression was only present in the basal cells of the RHE.

    CONCLUSION: Our results suggest that IFN-γ acts as an inducer of trp degradation preferentially in undifferentiated keratinocytes, indicated by the IDO expression in the basal layer of the RHE.

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  • 7.
    Trindade, Ricardo
    et al.
    Department of Prosthodontics, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Albrektsson, Tomas
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces. Department of Biomaterials, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Galli, Silvia
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Tengvall, Pentti
    Department of Biomaterials, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Wennerberg, Ann
    Department of Prosthodontics, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Bone Immune Response to Materials, Part II: Copper and Polyetheretherketone (PEEK) Compared to Titanium at 10 and 28 Days in Rabbit Tibia2019In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 8, no 6, article id 814Article in journal (Refereed)
    Abstract [en]

    Abstract: Osseointegration is likely the result of an immunologically driven bone reaction to materials such as titanium. Osseointegration has resulted in the clinical possibility to anchor oral implants in jaw bone tissue. However, the mechanisms behind bony anchorage are not fully understood and complications over a longer period of time have been reported. The current study aims at exploring possible differences between copper (Cu) and polyetheretherketone (PEEK) materials that do not osseointegrate, with osseointegrating cp titanium as control. The implants were placed in rabbit tibia and selected immune markers were evaluated at 10 and 28 days of follow-up. Cu and PEEK demonstrated at both time points a higher immune activation than cp titanium. Cu demonstrated distance osteogenesis due to a maintained proinflammatory environment over time, and PEEK failed to osseointegrate due to an immunologically defined preferential adipose tissue formation on its surface. The here presented results suggest the description of two different mechanisms for failed osseointegration, both of which are correlated to the immune system.

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  • 8.
    Trindade, Ricardo
    et al.
    Department of Prosthodontics, Faculty of Odontology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Albrektsson, Tomas
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces. Department of Biomaterials, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Galli, Silvia
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD). Malmö University, Biofilms Research Center for Biointerfaces.
    Tengvall, Pentti
    Department of Biomaterials, Institute of Clinical Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Wennerberg, Ann
    Department of Prosthodontics, Faculty of Odontology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
    Bone Immune Response to Materials, Part I: Titanium, PEEK and Copper in Comparison to Sham at 10 Days in Rabbit Tibia2018In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 7, no 12, article id 526Article in journal (Refereed)
    Abstract [en]

    Bone anchored biomaterials have become an indispensable solution for the restoration of lost dental elements and for skeletal joint replacements. However, a thorough understanding is still lacking in terms of the biological mechanisms leading to osseointegration and its contrast, unwanted peri-implant bone loss. We have previously hypothesized on the participation of immune mechanisms in such processes, and later demonstrated enhanced bone immune activation up to 4 weeks around titanium implants. The current experimental study explored and compared in a rabbit tibia model after 10 days of healing time, the bone inflammation/immunological reaction at mRNA level towards titanium, polyether ether ketone (PEEK) and copper compared to a Sham control. Samples from the test and control sites were, after a healing period, processed for gene expression analysis (polymerase chain reaction, (qPCR)) and decalcified histology tissue analysis. All materials displayed immune activation and suppression of bone resorption, when compared to sham. The M1 (inflammatory)/M2 (reparative) -macrophage phenotype balance was correlated to the proximity and volume of bone growth at the implant vicinity, with titanium demonstrating a M2-phenotype at 10 days, whereas copper and PEEK were still dealing with a mixed M1- and M2-phenotype environment. Titanium was the only material showing adequate bone growth and proximity inside the implant threads. There was a consistent upregulation of (T-cell surface glycoprotein CD4) CD4 and downregulation of (T-cell transmembrane glycoprotein CD8) CD8, indicating a CD4-lymphocyte phenotype driven reaction around all materials at 10 days.

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  • 9.
    Trindade, Ricardo
    et al.
    Malmö University, Faculty of Odontology (OD).
    Albrektsson, Tomas
    Malmö University, Faculty of Odontology (OD). Department of Biomaterials, Institute of Clinical Sciences, Gothenburg University, Gothenburg, Sweden.
    Galli, Silvia
    Malmö University, Faculty of Odontology (OD).
    Prgomet, Zdenka
    Malmö University, Faculty of Odontology (OD).
    Tengvall, Pentti
    Department of Biomaterials, Institute of Clinical Sciences, Gothenburg University, Gothenburg, Sweden.
    Wennerberg, Ann
    Department of Prosthodontics, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
    Osseointegration and foreign body reaction: Titanium implants activate the immune system and suppress bone resorption during the first 4 weeks after implantation2018In: Clinical Implant Dentistry and Related Research, ISSN 1523-0899, E-ISSN 1708-8208, Vol. 20, no 1, p. 82-91Article in journal (Refereed)
    Abstract [en]

    Background: Osseointegration mechanisms are still not entirely understood. PurposeThe present pilot study aims at demonstrating the involvement of the immune system in the process of osseointegration around titanium implants, comparing bone healing in the presence and absence of a titanium implant. Materials and Methods: Fifteen New Zealand White rabbits had one osteotomy performed at each of the distal femurs; on one side, no implant was placed (sham) and on the other side a titanium implant was introduced. Subjects were sacrificed at 10 and 28 days for gene expression analysis (three subjects each time point) and for decalcified qualitative histology (six subjects each time point). At 10 days, the three subjects for gene expression analysis were part of the six subjects for histology. Results: Gene expression analysis: at 10 days, ARG1 was significantly up-regulated around titanium, indicating an activation of M2-macrophages. At 28 days CD11b, ARG1, NCF-1, and C5aR1 were significantly up-regulated, indicating activation of the innate immune system, respectively M1-macrophages, M2-macrophages and group 2-innate lymphoid cells, neutrophils, and the complement system; on the other hand, the bone resorption markers RANKL, OPG, cathepsin K, and TRAP were significantly down-regulated around titanium. Histology: at 10 days new bone formation is seen around both sham and titanium sites, separating bone marrow from the osteotomy/implant site; at 28 days no bone trabeculae is seen on the sham site, which is healing at the original cortical level, whereas around titanium implants, bone continues into organization of more mature cortical-like bone, forming a layer between the implant and the bone marrow. Conclusions: The presence of a titanium implant during bone healing activates the immune system and displays type 2 inflammation, which is likely to guide the host-biomaterial relationship. At the same time, bone resorption is suppressed around titanium sites compared to sham sites after 4 weeks of implantation, suggesting a shift to a more pronounced bone forming environment. This suggests two important steps in osseointegration: identification of the titanium foreign body by the immune system and the development of a bone forming environment, that at tissue level translates into bone build-up on the titanium surface and can be perceived as an attempt to isolate the foreign body from the bone marrow space.

  • 10.
    Prgomet, Zdenka
    et al.
    Malmö högskola, Faculty of Odontology (OD). Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
    Andersson, Tommy
    Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
    Lindberg, Pia
    Malmö högskola, Faculty of Odontology (OD).
    Higher expression of WNT5A protein in oral squamous cell carcinoma compared with dysplasia and oral mucosa with a normal appearance2017In: European Journal of Oral Sciences, ISSN 0909-8836, E-ISSN 1600-0722, Vol. 125, no 4, p. 237-246Article in journal (Refereed)
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  • 11.
    Prgomet, Zdenka
    et al.
    Malmö högskola, Faculty of Odontology (OD). Cell and Experimental Pathology, Department of Translational Medicine, Lund University , Clinical Research Centre, Skåne University Hospital , Malmö , Sweden.
    Andersson, Tommy
    Cell and Experimental Pathology, Department of Translational Medicine, Lund University , Clinical Research Centre, Skane University Hospital , Malmo , Sweden.
    Lindberg, Pia
    Malmö högskola, Faculty of Odontology (OD).
    Optimization, validation, and identification of two reliable antibodies for immunodetection of WNT5A2017In: Biotechnic & Histochemistry, ISSN 1052-0295, E-ISSN 1473-7760, Vol. 92, no 1, p. 46-58Article in journal (Refereed)
    Abstract [en]

    WNT5A is a secreted, noncanonical WNT signaling protein that has been reported to promote progression of several types of cancer, including oral squamous cell carcinoma. Many WNT5A antibodies are available commercially for immunohistochemistry (IHC) and western blot analysis. Validation of the primary antibodies, however, is often neglected. We characterized antibodies for detecting WNT5A by IHC and western blot analysis. We evaluated one polyclonal and three monoclonal commercially available WNT5A antibodies. After optimization of the IHC assay, all four antibodies showed cytoplasmic WNT5A expression in tissue samples; in contrast, only one antibody detected WNT5A in western blots. A pre-absorption test with recombinant WNT5A showed that AF645 and 3A4 antibodies specifically detected WNT5A in different assays. We suggest that the monoclonal 3A4 antibody is the most appropriate for use with IHC, while the polyclonal AF645 antibody is the best for western blot analysis.

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  • 12.
    Prgomet, Zdenka
    Malmö högskola, Faculty of Odontology (OD).
    The role of WNT5A in oral squamous cell carcinoma2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancer is one of the leading causes of death worldwide and furtherresearch into the cancer biology is required to improve treatment andsurvival. Cancer can start in all sites of the body and is characterizedby uncontrolled cell growth and capability of invading surroundingtissue and spreading to other sites of the body. The most commontype of cancer occurring in the oral cavity is oral squamous cellcarcinoma (OSCC). Tobacco, including the betel quid and othertypes of smokeless tobacco, is the main risk factor for developmentof OSCC. Even though therapeutic treatment of OSCC has beenimproved, the prognosis is still poor, and the 5-year survival remainsaround 50%. The ongoing research have shown that proteins involvedin signaling pathways play an important role in the progression ofcancer, however, no reliable biomarkers have yet been identified aspredictors of OSCC progression.Over the past years, a protein named WNT5A, has been shownto be involved in different types of cancer, either by promoting orsuppressing cancer progression. However, its role in OSCC is stillambiguous. This thesis aimed to provide an insight into the role ofWNT5A signaling in OSCC.We started by investigating the functional role of WNT5A in OSCCcells. Due to the lack of the endogenous WNT5A expression, wetreated the cells with recombinant WNT5A (rWNT5A) and observedactivation of the non-canonical WNT/Ca2+/PKC signaling in OSCCcells. This rWNT5A-induced signaling enhanced migration andinvasion of OSCC cells, which was ascertained by different WNT5Ainhibitors. These inhibitors eliminated the rWNT5A-induced WNT/Ca2+/PKC signaling and migration of OSCC cells indicating apromoting role of WNT5A in OSCC cells.Before investigating the expression of WNT5A in human OSCCtissues, we evaluated four commercially available WNT5A antibodiesfor use in immunohistochemistry (IHC) and western blot analysis(WB). Cytoplasmic WNT5A immunostaining pattern was observedwith all four antibodies but only the polyclonal AF645 antibody wasable to detect WNT5A protein in WNT5A-positive cell lysates. Preabsorptiontests revealed that the polyclonal AF645 antibody is thebest antibody for detection of WNT5A by WB while the monoclonal3A4 antibody is the most suitable for use in IHC. Using the monoclonal 3A4 antibody, we investigated the expressionof WNT5A in human OSCC tissues. No expression of WNT5A wasobserved in normal oral epithelium or in mild grade of dysplasia.However, cytoplasmic WNT5A immunostaining was found in 38%of dysplastic tissues and in 81% of the OSCCs. We also noticedthat WNT5A was more expressed in advanced OSCCs than in earlyinvasive OSCCs. Furthermore, we did not observe any correlationbetween expression of WNT5A and two adhesion-proteins, β-cateninand E-cadherin, either in OSCC tissues or in OSCC cells. Thesefindings suggest that WNT5A does not affect the canonical WNT/β-catenin pathway or downregulation of E-cadherin in OSCC.At last, we investigated if the rWNT5A-induced WNT/Ca2+/PKCsignaling affected secretion and activation of matrix metalloproteinases(MMPs) in OSCC cells. We found that rWNT5A-induced activationof MMP2 is not dependent on activation of either β-catenin, ERK1/2,or p38-MAPK, but could instead be induced by WNT5A/Ca2+/PKCpathway. In conclusion, these findings suggest that WNT5A acts as a cancerpromoter in OSCC by facilitating cell migration and invasion via theWNT5A/Ca2+/PKC signaling and activation of MMP2.

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    Comprehensive summary
  • 13.
    Prgomet, Zdenka
    et al.
    Malmö högskola, Faculty of Odontology (OD).
    Andersson, T
    Lindberg, P
    WNT5A activates MMP2 in oral squamous cell carcinoma2017Manuscript (preprint) (Other academic)
  • 14.
    Prgomet, Zdenka
    et al.
    Malmö högskola, Faculty of Odontology (OD).
    Axelsson, Lena
    Lindberg, Pia
    Malmö högskola, Faculty of Odontology (OD).
    Andersson, Tommy
    Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression2015In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 44, no 10, p. 776-784Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oral squamous cell carcinoma (OSCC) constitutes 90% of all cancers in the oral cavity, and the prognosis for patients diagnosed with OSCC is still poor. The identification of novel therapeutic targets and prognostic markers for OSCC is therefore essential. Previous studies of OSCC revealed an increased expression of WNT5A in the tumor tissue. However, no functional studies of WNT5A-induced effects in OSCC have been performed. METHODS: Two different OSCC cell lines were used for analysis of WNT5A expression by Western blot, whereas WNT5A-induced responses were analyzed by measuring calcium (Ca2+ ) signaling, PKC activation, migration and invasion. RESULTS: Despite the lack of WNT5A expression, both cell lines responded to recombinant WNT5A (rWNT5A) with activation of the non-canonical WNT/Ca2+ /PKC pathway. This effect was ascertained to be mediated by WNT5A by use of the WNT5A antagonist, Box5. To investigate how WNT5A affects tumor progression, rWNT5A-induced alterations in BrdU absorbance (reflecting the number of tumor cells) were analyzed. rWNT5A had no effect on BrdU absorbance but instead promoted tumor cell migration and invasion. These results were confirmed by the use of the WNT5A-mimicking peptide Foxy5, while the rWNT5A-induced migration was blocked by secreted Frizzled-related protein 1 (SFRP1), protein kinase C inhibitors or the intracellular Ca2+ chelator, MAPT. CONCLUSIONS: These novel data clearly show that WNT5A activates the non-canonical WNT/Ca2+ /PKC pathway and increases migration and invasion of OSCC cells. This may indicate how an increased WNT5A expression in the tumor tissue is likely to promote progression of OSCC.

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    FULLTEXT01
  • 15.
    Prgomet, Zdenka
    et al.
    Malmö högskola, Faculty of Odontology (OD).
    Lindberg, Pia
    Malmö högskola, Faculty of Odontology (OD).
    Andersson, Tommy
    Wnt5a stimulates migration and invasion in OSCC2013In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 49, p. S115-S116Article in journal (Other academic)
    Abstract [en]

    Purpose: Wnt5a is the most important Wnt protein activating the non-canonical Wnt pathway. It regulates proliferation, differentiation, migration, adhesion and polarity of the cell. Clinical studies have shown that Wnt5a could act as a prognostic marker in various cancers. It seems that Wnt5a acts both as a tumor suppressor (breast, thyroid, colon and livercancer) and as a tumor promotor (malignant melanoma, pancreatic and gastric cancer). In oral squamous cell carcinoma (OSCC) a number of Wnt and Frizzled genes are expressed, mostly Wnt5a and Frizzled-5 but the role of Wnt5a has not yet been thoroughly elucidated. The aim of this study is to evaluate the role of Wnt5a in oral OSCC and its influence on the cell proliferation, migration and invasion. Material and methods: The protein content of Wnt5a in two OSCC cell lines (SCC25 and SCC9) was determined by Western blotting. The influence of rWnt5a and two Wnt5a-derived hexapeptides: Foxy5 (an agonist that mimics Wnt5a activity) and Box5 (an antagonist that inhibits Wnt5a) on the migration and proliferation in OSCC cell lines was studied by a scratch assay and BrdU. Invasion influenced by rWnt5a was studied using Boyden chambers. Results: Both cell lines express Wnt5a. Dose–response curves of rWnt5a in SCC9 and SCC25 indicate that Wnt5a increases migration with statistically significant effective concentration at 0.4 μg/ml but has no effect on the proliferation of the two cell lines. To confirm this we used Foxy5 and Box5. Foxy5 increases migration with statistically significant effective concentration at 150 μM while Box5 inhibits Wnt5a effect on the migration. Foxy5 and Box5 have no influence on proliferation. Invasion was increased by rWnt5a. Conclusions: The results demonstrate that Wnt5a increases migration and invasion but has no influence on proliferation in OSCC cell lines.

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