Håvard Jostein Haugen

• Di Raimondo, Ricardo; Sanz, Javier; Sanz Martin1, Ignacio; Vignoletti, Fabio; Nuñez, Javi; Muñoz, Fernando; Haugen, Håvard Jostein & Sanz, Mariano (2021). Hard tissue volumetric and soft tissue contour linear changes at implants with different surface characteristics after experimentally induced peri-implantitis: an experimental in vivo investigation. Clinical Oral Investigations.  ISSN 1432-6981. . doi: 10.1007/s00784-020-03720-8 Show summary

  Objective To evaluate the hard tissue volumetric and soft tissue contour linear changes in implants with two different implant surface characteristics after a ligature-induced peri-implantitis. Material andmethods In eight beagle dogs, implants with the same size and diameter but distinct surface characteristics were placed in the healed mandibular sites. Test implants had an external monolayer of multi-phosphonate molecules (B+), while control implants were identical but without the phosphonate-rich surface. Once the implants were osseointegrated, oral hygiene was interrupted and peri-implantitis was induced by placing subgingival ligatures. After 16 weeks, the ligatures were removed and peri-implantitis progressed spontaneously. Bone to implant contact (BIC) and bone loss (BL) were assessed three-dimensionally with Micro-Ct (μCT). Dental casts were optically scanned and the obtained digitalized standard tessellation language (STL) images were used to assess the soft tissue vertical and horizontal contour linear changes. Results Reduction of the three-dimensional BIC percentage during the induction and progression phases of the experimental peri-implantitis was similar for both the experimental and control implants, without statistically significant differences between them. Soft tissue analysis revealed for both implant groups an increase in horizontal dimension after the induction of peri-implantitis, followed by a decrease after the spontaneous progression period. In the vertical dimension, a soft tissue dehiscence was observed in both groups, being more pronounced at the buccal aspect. Conclusions The added phosphonate-rich surface did not provide a more resistant environment against experimental periimplantitis, when assessed by the changes in bone volume and soft tissue contours. Clinical relevance Ligature-induced peri-implantitis is a validated model to study the tissue changes occurring during peri-implantitis. It was hypothesized that a stronger osseointegration mediated by the chemical bond of a phosphonaterich implant surface would develop an environment more resistant to the inflammatory changes occurring after experimental peri-implantitis. These results, however, indicate that the hard and soft tissue destructive changes occurring at both the induction and progression phases of experimental peri-implantitis were not influenced by the quality of osseointegration.

• Sukul, Mousumi; Sahariah, Priyanka; Lauzon, Hélène L.; Borges, João; Másson, Már; Mano, Joao F.; Haugen, Håvard Jostein & Reseland, Janne Elin (2021). In vitro biological response of human osteoblasts in 3D chitosan sponges with controlled degree of deacetylation and molecular weight. Carbohydrate Polymers.  ISSN 0144-8617.  254, s 117434 . doi: 10.1016/j.carbpol.2020.117434 Full text in Research Archive. Show summary

  We have studied the effect of chitosan sponges, produced from chitosan batches with distinct degree of deacetylation (DDA) and molecular weight (Mw), on the adhesion, growth and differentiation of primary human osteoblasts with an aim to offer a suitable tool for guided bone regeneration. All the chitosan sponges revealed similar microstructure, irrespective of the DDA (58, 73, 82, 88, and 91 %) and Mw (749, 547, 263, 215, and 170 kDa, respectively). Cell spreading was higher on sponges having a higher DDA. Higher DDA induced a more pronounced increase in alkaline phosphatase activity, osteopontin (OPN), vascular endothelial growth factor-A (VEGF), interleukin-6 (IL-6), and reduction in monocyte chemoattractant protein-1 (MCP-1), sclerostin (SOST) and dickkopf related protein-1 as compared to lower DDA. Lower DDA induced the increased secretion of osteoprotegerin and SOST as compared to higher DDA. The combination of higher DDA and Mw induced an increased secretion of VEGF and IL-6, however reduced the secretion of OPN as compared to chitosan with similar DDA but with lower Mw. In summary, the variations in cellular responses to the different chitosan sponges indicate a potential for individual tailoring of desired responses in guided

• Thieu, Minh Khai Le; Haugen, Håvard Jostein; Esporrin, Javier Sanz; Sanz, Mariano; Lyngstadaas, Ståle Petter & Verket, Anders (2021). Guided bone regeneration of chronic non-contained bone defects using a volume stable porous block TiO2 scaffold: An experimental in vivo study. Clinical Oral Implants Research.  ISSN 0905-7161. . doi: 10.1111/clr.13708 Show summary

  Objectives To evaluate new lateral bone formation and lateral volume augmentation by guided bone regeneration (GBR) in chronic non‐contained bone defects with the use of a non‐resorbable TiO2‐block. Materials and methods Three buccal bone defects were created in each hemimandible of eight beagle dogs and allowed to heal for eight weeks before treatment by GBR. Each hemimandible was randomly allocated to 4 or 12‐week healing time after GBR and three intervention groups were assigned by block randomization: TiO2 block: TiO2‐scaffold and a collagen membrane, DBBM particles: Deproteinized bovine bone mineral (DBBM) and a collagen membrane, Empty control: Collagen membrane only. Microcomputed tomography (microCT) was used to measure the lateral bone formation and width augmentation. Histological outcomes included descriptive analysis and histomorphometric measurements. Results MicroCT analysis demonstrated increasing new bone formation from four to twelve weeks of healing. The greatest width of mineralized bone was seen in the empty controls, and the largest lateral volume augmentation was observed in the TiO2 block sites. The DBBM particles demonstrated more mineralized bone in the grafted area than the TiO2 blocks, but small amounts and less than the empty control sites. Conclusion The TiO2 blocks rendered the largest lateral volume augmentation but also less new bone formation compared to the DBBM particles. The most new lateral bone formation outward from the bone defect margins was observed in the empty controls, indicating that the presence of either graft material leads to slow appositional bone growth.

• Vyas, Cian; Zhang, Jun; Øvrebø, Øystein; Huang, Boyang; Roberts, Iwan; Setty, Mohan; Allardyce, Benjamin J; Haugen, Håvard Jostein; Rajkhowa, Rangam & Bàrtolo, Paulo Jorge da Silva (2021). 3D printing of silk microparticle reinforced polycaprolactone scaffolds for tissue engineering applications. Materials Science and Engineering C: Materials for Biological Applications.  ISSN 0928-4931.  118, s 111433 . doi: 10.1016/j.msec.2020.111433 Full text in Research Archive. Show summary

  Polycaprolactone (PCL) scaffolds have been widely investigated for tissue engineering applications, however, they exhibit poor cell adhesion and mechanical properties. Subsequently, PCL composites have been produced to improve the material properties. This study utilises a natural material, Bombyx mori silk microparticles (SMP) prepared by milling silk fibre, to produce a composite to enhance the scaffolds properties. Silk is biocompatible and biodegradable with excellent mechanical properties. However, there are no studies using SMPs as a reinforcing agent in a 3D printed thermoplastic polymer scaffold. PCL/SMP (10, 20, 30 wt. %) composites were prepared by melt blending. Rheological analysis showed that SMP loading increased the shear thinning and storage modulus of the material. Scaffolds were fabricated using a screw-assisted extrusion-based additive manufacturing system. Scanning electron microscopy and x-ray microtomography was used to determine scaffold morphology. The scaffolds had high interconnectivity with regular printed fibres and pore morphologies within the designed parameters. Compressive mechanical testing showed that the addition of SMP significantly improved the compressive Young’s modulus of the scaffolds. The scaffolds were more hydrophobic with the inclusion of SMP which was linked to a decrease in total protein adsorption. Cell behaviour was assessed using human adipose derived mesenchymal stem cells. A cytotoxic effect was observed at higher particle loading (30 wt. %) after 7 days of culture. By day 21, 10 wt. % loading showed significantly higher cell metabolic activity and proliferation, high cell viability, and cell migration throughout the scaffold. Calcium mineral deposition was observed on the scaffolds during cell culture. Large calcium mineral deposits were observed at 30 wt. % and smaller calcium deposits were observed at 10 wt. %. This study demonstrates that SMPs incorporated into a PCL scaffold provided effective mechanical reinforcement, improved the rate of degradation, and increased cell proliferation, demonstrating potential suitability for bone tissue engineering applications.

• Borie, Manon; Lecloux, Geoffrey; Bosshardt, Dieter D.; Barrantes Bautista, Alejandro; Haugen, Håvard Jostein; Lambert, France & Bacevic, Miljana (2020). Peri-Implant Soft Tissue Integration in Humans – Influence of Materials: A study protocol for a randomised controlled trial and a pilot study results. Contemporary Clinical Trials Communications.  ISSN 2451-8654. . doi: 10.1016/j.conctc.2020.100643 Full text in Research Archive. Show summary

  Background : Recently, there has been a growing interest in mucointegration as the formation of an early and long-standing soft tissue barrier seems essential for both the initial healing and long-term implant survival. Aim: To develop an experimental method to characterize the mucointegration of different transgingival materials (titanium (Ti), polyetheretherketone (PEEK), polymethylmethacrylate (PMMA), zirconia (Zi), polymer infiltrated ceramic network (PICN), cobalt-chrome (Co-Cr), and lithium disilicate (LD)) in a human model. Methods / Design : The study is designed as a multi-part randomized controlled clinical trial. Ninety bone level Straumann implants will randomly receive an experimental, custom-made abutment to allow for the removal of the abutment together with the surrounding soft tissues using a punch biopsy device at 8 weeks of healing (10 per material). The specimens will be further processed for non‐decalcified histology, followed by histomorphometric analysis. The same protocol will be used for additional 90 implants-abutments, but during harvesting, soft tissues will be separated from the abutment and processed for immunohistochemistry in order to study tissue inflammation and vascularization, while the abutments will undergo SEM analysis. Additionally, in vitro analyses, including SEM and profilometry, will be performed in order to characterize surface topography of all experimental materials. Conclusion : The limited number of pilot samples presented herein indicate that the use of custommade abutments in humans is a reproducible method to study peri-implant soft tissue integration. This further intensifies the rationale to compare different abutment materials, used as transgingival components in daily practice, under the same conditions.

• Bülbül, Onur; Krockow, Christie & Haugen, Håvard Jostein (2020). Hvilke kjeveortopediske metallkomponenter gir pasientreaksjoner og hvilke reaksjoner er registrert? En oversikt over metall-hypersensitivitet innen kjeveortopedien. Den norske tannlegeforenings tidende.  ISSN 0029-2303.  130, s 212- 217 Show summary

  Kjeveortopedisk behandling innebærer som oftest behandling med apparaturer bestående av metaller og metallegeringer. Studier har vist at lekkasje av metallioner kan føre til allergiske reaksjoner. Målet med denne artikkelen er å gi en oversikt over forekomst av allergi, kliniske tegn og symptomer, hvilke metallioner som er allergifremkallende og behandlingsalternativer. En allergisk reaksjon skyldes en immunrespons, og de kliniske tegn og symptomer kan manifestere seg både intra- og ekstraoralt. Man bør være oppmerksom på at en allergisk pasient kan ha bare ekstraorale symptomer, selv om apparaturene befinner seg intraoralt. Dette skyldes trolig at mukosa og hud har ulike egenskaper. Nikkel forårsaker mest allergiske reaksjoner sammenlignet med andre metaller i kjeveortopedien og kan utgjøre opptil 70% av noen apparaturer. Til tross for den relativt høye prevalensen av nikkelallergi, er synlige bivirkninger på grunn av metalliske kjeveortopediske apparaturer sjeldne og oppdages hos 0,2 til 0,4 % av pasienter. De fleste allergiske pasienter kan behandles med apparaturer av rustfritt stål. Dersom pasienten fortsatt reagerer, finnes nikkelfrie alternativer. Dette kan i midlertid gi endring av behandlingstid og være lite gunstig i noen kasus

• Chahal, Aman S; Schweikle, Manuel; Lian, Aina-Mari; Reseland, Janne Elin; Haugen, Håvard Jostein & Tiainen, Hanna (2020). Osteogenic potential of poly(ethylene glycol)-amorphous calcium phosphate composites on human mesenchymal stem cells. Journal of Tissue Engineering.  ISSN 2041-7314.  11 . doi: 10.1177/2041731420926840 Full text in Research Archive.
• De-Deus, Gustavo; Simões-Carvalho, Marco; Belladonna, Felipe Goncalves; Versiani, Marcio; Silva, Emmanuel João Nogueira Leal; Cavalcante, Daniele Moreira; Souza, Erick Miranda; Johnsen, Gaute Floer; Haugen, Håvard Jostein & Paciornik, S. (2020). Creation of well-balanced experimental groups for comparative endodontic laboratorial studies: a new proposal based on micro-CT and in silico methods. International Endodontic Journal.  ISSN 0143-2885. . doi: 10.1111/iej.13288 Full text in Research Archive. Show summary

  Aim To introduce a new method to select anatomically matched teeth using micro-computed tomographic (micro-CT) technology. Methodology Single-rooted mandibular incisors with a single root canal (n = 60) were selected and distributed into three experimental groups according to the method used for matching 10 pairs of teeth in each group. In group 1, the pairs of mandibular incisors were randomly selected from a pool of teeth. In group 2, teeth were paired based on the measurement of canal width 5 mm from the root apex using radiographs taken from buccolingual and mesiodistal directions. In group 3, teeth were scanned (pixel size of 14.25 μm) and pair-matched based on the anatomical aspects of the root canal, named aspect ratio (AR), volume and three-dimensional canal geometry. After allocating the specimens into groups 1 and 2, the teeth were scanned and the canal morphology evaluated as in group 3. A bivariate Pearson’s regression analysis was performed correlating the individual AR values of each pair and the correlation coefficient was used to estimate the strength of the pair-matching process. One-way ANOVA post hoc Tukey tests were applied for pair-wise comparisons at a significance level of 5%. Results The micro-CT method showed 100% of the samples having strong (80%) or very strong (20%) correlations with respect to AR values. Analysis of the radiographic method revealed strong correlation in two pairs (20%), but most of the samples had weak (30%) or neglectable (30%) correlation coefficients. The randomization method resulted in 3 pairs (30%) with very strong correlations, while 50% had weak or neglectable rates. A significant difference in correlation coefficients was observed in the micro-CT method compared to the other groups (p < 0.05), whilst no difference was detected between radiographic and randomized methods (p > 0.05). Eta squared (η 2 ) calculations demonstrated a very high effect size in the micro-CT group for selecting pairs (0.99), and lower effect sizes in the radiographic (0.67) and randomized (0.66) groups. Conclusions Micro-CT method was able to provide better control of the confounding effect that

• Gross, Karlis Agris; Petzold, Christiane; Pluduma, Liene; Kumermanis, Maris & Haugen, Håvard Jostein (2020). Structural and Chemical Hierarchy in Hydroxyapatite Coatings. Materials.  ISSN 1996-1944.  13(4447), s 1- 15 Full text in Research Archive. Show summary

  Hydroxyapatite coatings need similarly shaped splats as building blocks and then a homogeneous microstructure to unravel the structural and chemical hierarchy for more refined improvements to implant surfaces. Coatings were thermally sprayed with differently sized powders (20-40, 40-63 and 63-80 µm) to produce flattened homogeneous splats. The surface was characterized for splat shape by profilometry and AFM, crystal size by AFM, crystal orientation by X-ray diffraction (XRD) and structural variations by XRD. Chemical composition was assessed by phase analysis, but variations in chemistry were detected by XRD and Raman spectroscopy. The resulting surface electrical potential was measured by Kelvin probe AFM. Five levels of structural hierarchy were suggested: the coating, the splat, oriented crystals, alternate layers of oxyapatite and HAp, and the suggested anion orientation. Chemical hierarchy was present over a lower range of order for smaller splats. Coatings made from smaller splats exhibited a greater electrical potential, inferred to arise from oxyapatite, and supplemented by ordered OH- ions in a rehydroxylated surface layer. A model has been proposed to show the influence of structural hierarchy on the electrical surface potential. Structural hierarchy is proposed as a means to further refine the properties of implant surfaces.

• Haugen, Håvard Jostein; Basu, Poulami; Sukul, Mousumi & Reseland, Janne Elin (2020). Injectable biomaterials for Dental Tissue Regeneration. International Journal of Molecular Sciences.  ISSN 1422-0067.  21, s 3442 . doi: 10.3390/ijms21103442 Full text in Research Archive. Show summary

  Injectable biomaterials scaffolds play a pivotal role for dental tissue regeneration, as such materials are more applicable in the dental field, particularly when compared to pre-formed scaffolds. The defects in maxilla-oral area are normally small, confined and sometimes hard to access. This narrative review described different types of biomaterials for dental tissue regeneration, also discussing the potential use of nanofibres for dental tissues. Various studies suggest that the tissue engineering approaches involving the use of injectable biomaterials have the potential of restoring not only dental tissue function but also their biological purposes

• Haugen, Håvard Jostein; Marovic, Danijela; Par, Matej; Thieu, Minh Khai Le; Reseland, Janne Elin & Johnsen, Gaute Floer (2020). Bulk Fill Composites Have Similar Performance to Conventional Dental Composites. International Journal of Molecular Sciences.  ISSN 1422-0067.  21(15), s 5136 . doi: 10.3390/ijms21145136 Full text in Research Archive. Show summary

  The aim of the study was to perform comprehensive characterization of two commonly used bulk fill composite materials (SDR Flow (SDR) and Filtek™ Bulk Fill Flowable Restorative (FBF) and one conventional composite material (Tetric EvoCeram; TEC). Eleven parameters were examined: flexural strength (FS), flexural modulus (FM), degree of conversion, depth of cure, polymerisation shrinkage (PS), filler particle morphology, filler mass fraction, Vickers hardness, surface roughness following simulated toothbrush abrasion, monomer elution, and cytotoxic reaction of human gingival fibroblasts, osteoblasts, and cancer cells. The degree of conversion and depth of cure were the highest for SDR, followed by FBF and TEC, but there was no difference in PS between them. FS was higher for bulk fill materials, while their FM and hardness were lower than those of TEC. Surface roughness decreased in the order TEC→SDR→FBF. Bisphenol A-glycidyl methacrylate (BisGMA) and urethane dimethacrylate were found in TEC and FBF eluates, while SDR released BisGMA and triethylene glycol dimethacrylate. Conditioned media accumulated for 24h from FBF and TEC were cytotoxic to primary human osteoblasts. Compared to the conventional composite, the tested bulk fill materials performed equally or better in most of the tests, except for their hardness, elastic modulus, and biocompatibility with osteoblasts.

• Haugen, Håvard Jostein; Qasim, Syed Saad Bin; Matinlinna, Jukka P; Vallittu, Pekka K. & Nogueira, Liebert Parreiras (2020). Nano-CT as tool for characterization of dental resin composites. Scientific Reports.  ISSN 2045-2322.  10 . doi: 10.1038/s41598-020-72599-y Full text in Research Archive. Show summary

  Technological advances have made it possible to examine dental resin composites using 3D nanometer resolution. This investigation aims to characterize existing dental nano-hybrid and micro-hybrid resin composites through comparing and contrasting nano-computed tomography (nano-CT) with micro-CT and high-resolution SEM images. Eight commercially available and widely used dental resin composites, 2 micro-hybrid and 6 nano-hybrid were researched. Cured samples were examined and characterized using nano-CT (resolution 450 nm) and compared with micro-CT images (resolution 2 µm). Acquired images were reconstructed and image analysis was carried out to determine porosity and pore morphology. A comprehensive comparison of scanning micrograph images unsurprisingly revealed that the nano-CT images displayed greater detail of the ultrastructure of cured dental resin composites. Filler particle diameters and its volumes were lower when measured using nano-CT, porosity being higher where analysed at higher resolution. There were large variations between the examined materials. Fewer voids were found in Tetric EvoCeram and IPS Empress Direct, the smallest pores being found in Universal XTE and Tetric EvoCeram. Nano-CT was successfully used to investigate the morphology of dental resin composites and showed that micro-CT gives a lower porosity and pore size but overestimates filler particle size. There were large discrepancies between the tested composites. Evidence of porosities and pores within a specimen is a critical finding and it might have a detrimental effect on a material’s clinical performance.

• Haugen, Håvard Jostein; Soltvedt, Brandon Michael; Nguyen, Peter N; Rønold, Hans Jacob & Johnsen, Gaute Floer (2020). Discrepancy in alloy composition of imported and non-imported porcelain-fused-to-metal (PFM) crowns produced by Norwegian dental laboratories. Biomaterial Investigations in Dentistry. . doi: 10.1080/26415275.2020.1724512 Full text in Research Archive. Show summary

  Even though the use of full ceramic crowns have become a well-established practice in dental clinics compare to the last decade, the use of imported casted porcelain-fused-to-metal (PFMs) crowns is still prevalent. The use of imported PFMs is often economically driven; however, when dentists order PFMs, they do not have capabilities to examine its true alloy content. Therefore, we raise the questions whether cheaper imported PFMs have more discrepancies in alloy content compared to domestically produced PFMs? This study included 62 porcelain-fused-to-metal crowns: 41 produced in Norway and 21 imported. Their alloy-composition was determined non-destructively by EDX and SEM. Imported PFMs demonstrated larger deviations compared with non-imported PFMs. Significant deviation was found in key metallic elements in the different alloys (W, In, Pd, Ag). The detected deviations in key element such as Wolfram and Indium could influence the PFMs service time. These finding may be of international concern.

• Kallas, Pawel; Haugen, Håvard Jostein; Gadegaard, Nikolaj; Stormonth-Darling, John; Hulander, Mats; Andersson, Martin & Valen, Håkon (2020). Adhesion of Escherichia Coli to Nanostructured Surfaces and the Role of Type 1 Fimbriae. Nanomaterials.  ISSN 2079-4991.  11(11), s 2247 . doi: 10.3390/nano10112247 Full text in Research Archive. Show summary

  Bacterial fimbriae are an important virulence factor mediating adhesion to both biotic and abiotic surfaces and facilitating biofilm formation. The expression of type 1 fimbriae of Escherichia coli is a key virulence factor for urinary tract infections and catheter-associated urinary tract infections, which represent the most common nosocomial infections. New strategies to reduce adhesion of bacteria to surfaces is therefore warranted. The aim of the present study was to investigate how surfaces with different nanotopography-influenced fimbriae-mediated adhesion. Surfaces with three different nanopattern surface coverages made in polycarbonate were fabricated by injection molding from electron beam lithography nanopatterned templates. The surfaces were constructed with features of approximately 40 nm width and 25 nm height with 100 nm, 250 nm, and 500 nm interspace distance, respectively. The role of fimbriae type 1-mediated adhesion was investigated using the E. coli wild type BW25113 and ΔfimA (with a knockout of major pilus protein FimA) and ΔfimH (with a knockout of minor protein FimH) mutants. For the surfaces with nanotopography, all strains adhered least to areas with the largest interpillar distance (500 nm). For the E. coli wild type, no difference in adhesion between surfaces without pillars and the largest interpillar distance was observed. For the deletion mutants, increased adhesion was observed for surfaces without pillars compared to surfaces with the largest interpillar distance. The presence of a fully functional type 1 fimbria decreased the bacterial adhesion to the nanopatterned surfaces in comparison to the mutants.

• Kallas, Pawel; Valen, Håkon; Haugen, Håvard Jostein; Andersson, Martin & Hulander, Mats (2020). Effect of silica nano-spheres on adhesion of oral bacteria and human fibroblasts. Biomaterial Investigations in Dentistry.  7(1), s 134- 145 . doi: 10.1080/26415275.2020.1816175 Full text in Research Archive. Show summary

  Objective This study investigated the effect of surface nano-patterning on adhesion of an oral early commensal colonizer, Streptococcus mitis and the opportunistic pathogen Staphylococcus aureus and human fibroblasts (HDFa) in a laminar flow cell. Methods Nanostructured surfaces were made by functionalizing glass substrates with 40 nm SiO2 nanoparticles. Gradients in nanoparticle surface coverage were fabricated to study the effect of nanoparticle spacing within a single experiment. Bacterial adhesion was investigated after 5 min of contact time by subjecting surfaces to a flow in a laminar flow cell. In addition, to examine the particles effect on human cells, the establishment of focal adhesion and spreading of primary human dermal fibroblasts (HDFa) were investigated after 4 and 24 h. Results Adhesion of both S. aureus and S. mitis decreased on surfaces functionalized with nanoparticles and coincided with higher nanoparticle surface coverage on the surface. Both strains were tested on three separate surfaces. The regression analysis showed that S. mitis was influenced more by surface modification than S. aureus. The establishment of focal adhesions in HDFa cells was delayed on the nanostructured part of the surfaces after both 4 and 24 h of culturing. Significance In the current manuscript, we have used a flow cell to investigate the effect of nanotopographies on S. aureus and S. mitis adhesion. The present findings are of relevance for design of future implant and prostheses surfaces in order to reduce adhesion of bacteria.

• Mengjun, Xue; Sampath, Janani; Gebart, Rachel; Haugen, Håvard Jostein; Lyngstadaas, Ståle Petter; Pfaendtner, Jim & Drobny, Gary (2020). Studies of dynamic binding of amino acids to TiO2 nanoparticle surfaces by Solution NMR and Molecular Dynamics Simulations. Langmuir.  ISSN 0743-7463. . doi: 10.1021/acs.langmuir.0c01256 Full text in Research Archive. Show summary

  Adsorption of biomolecules onto material surfaces involves a potentially complex mechanism where molecular species interact to varying degrees with a heterogeneous material surface. Surface adsorption studies by atomic force microscopy (AFM), Sum Frequency Generation (SFG) spectroscopy, and solid state NMR (ssNMR), detect the structures and interactions of biomolecular species that are bound to material surfaces and which, in the absence of a solid liquid interface, do not exchange rapidly between surface-bound forms and free molecular species in bulk solution. Solution NMR has the potential to complement these techniques by detecting and studying transiently bound biomolecules at the liquid-solid interface. Herein we show that dark-state exchange saturation transfer (DEST) NMR experiments on gel-stabilized TiO2 nanoparticle (NP) samples detect several forms of biomolecular adsorption onto titanium (IV) oxide surfaces. Specifically, we use the DEST approach to study the interaction of amino acids arginine (Arg), lysine (Lys), leucine (Leu), alanine (Ala), and aspartic acid (Asp) with TiO2 rutile nanoparticle surfaces. Whereas Leu, Ala, and Asp display only a single weakly interacting form in the presence of TiO2 nanoparticles , Arg and Lys displayed at least two distinct bound forms: a species that is surface bound and retains a degree of reorientational motion, and a second more tightly bound form characterized by broadened DEST profiles upon addition of TiO2 nanoparticles. Molecular Dynamics simulations indicate different surface bound states for both Lys and Arg depending on the degree of TiO2 surface hydroxylation, but only a single bound state for Asp regardless of the degree of surface hydroxylation, in agreement with results obtained from analysis of DEST profiles.

• Pham, Thi Ngoc Maria Huong; Haugen, Håvard Jostein & Reseland, Janne Elin (2020). Fluoride Modification of Titanium Surfaces Enhance Complement Activation. Materials.  ISSN 1996-1944.  13(3), s 684 . doi: 10.3390/ma13030684 Full text in Research Archive. Show summary

  Immediately after dental implant insertion, blood will be in direct contact and interact with the implant surface and activates inflammatory responses and complement cascades within seconds. The aim of the present study was to determine the ability of fluoride-modified titanium surfaces to activate complement cascades using the human buffy coat as model. The buffy coats were exposed to hydrofluoric acid-modified surfaces for a short time and its responses were compared to controls. Identification and quantification of complement cascade biomarkers were conducted using ELISA kits and multianalyte profiling using Luminex. A lower level of C3 at 30 min and increased levels of C4, MIP-4, CRP, and pigment epithelium-derived factor at 360 min were found on modified surfaces as compared to controls. We found no significant differences in the levels of C3a, C5a, C Factor H, α2M, ApoA1, ApoC3, ApoE, Prealbumin, α1AT, and SAP in modified surfaces in the buffy coats. We conclude that titanium surfaces treated with hydrofluoric acid modify the levels of specific biomarkers related to the complement cascade and angiogenesis and, thus, tissue growth, remodeling and repair, as this may play a role in the enhanced clinical performance of fluoride-modified Ti dental implants.

• Rahmati, Maryam; Blaker, Jonathan James; Lyngstadaas, Ståle Petter; Mano, Joao F. & Haugen, Håvard Jostein (2020). Designing multigradient biomaterials for skin regeneration. Materials Today Advances.  5 . doi: https://doi.org/10.1016/j.mtadv.2019.100051 Full text in Research Archive. Show summary

  Skin defects are amongst the main causes of morbidity and mortality worldwide, which account for significantly high socioeconomic costs. Today, much attention is being paid to tissue engineering and biomaterials strategies for skin regeneration, and among them, there is increasing interest in using multigradient biomaterials. Gradient-based approaches are an emerging trend in tissue engineering for the homogeneous delivery of therapeutic agents by using biomaterials. Several studies have acknowledged that wound repair mechanisms could be enhanced through biomimicking physicochemical properties of different skin layers. In addition, in different layers of skin tissue, cells experience various physicochemical gradients, which potentially regulate their behaviors. Therefore, interface tissue engineering and biomaterials approaches are gaining increasing attention for skin regeneration through the incorporation of physicochemical gradients within the engineered constructs. This review first presents a necessary overview of the biological properties of skin tissue and its changes during repair in different tissue injuries. Fundamental issues and necessities of using different types of gradient scaffolds and interface tissue engineering strategies for skin regeneration are addressed. The focus of this review is on describing current progress in designing gradient scaffolds for controlling and directing cellular and molecular responses in skin tissue. The main used fabrication approaches, including both traditional and advanced methods for designing multigradient scaffolds, are also discussed.

• Rahmati, Maryam; Frank, Matthias Johannes; Walter, Martin Sebastian; Monjo Cabrer, Marta; Satué, María; Reseland, Janne Elin; Lyngstadaas, Ståle Petter & Haugen, Håvard Jostein (2020). Osteoimmunomodulatory effects of enamel matrix derivate and strontium coating layers: A short- and long-term in vivo study. ACS Applied Bio Materials (AABM).  ISSN 2576-6422.  3, s 5169- 5181 . doi: 10.1021/acsabm.0c00608 Full text in Research Archive. Show summary

  Over the past few years, surface modification of implant surface has gained substantial attention as a promising solution to avoid the failure of biomaterials after implantation. Although researchers suggest several strategies for surface functionalization of titanium based implants, only few studies have compared the osteoimmunomodulatory effects of ionic nanostructure and biofunctionalization in the same biological model. Enamel matrix derivate (EMD) and strontium are both known for their positive influences on bone cell responses. In this study, we functionalized the titanium-zirconium implant surface with EMD and strontium using an electrochemical cathodic polarization method. Afterwards, we evaluated the osteoimmunomodulatory effects of EMD or strontium coated titanium zirconium implants in the tibia of eight Grey Bastard Chinchillas rabbits. We performed 2&3D micro-CT, wound fluid, histologic, and histomorphometric analyses on bone tissues after 4- and 8-weeks implantation. Although the results could indicate some differences between groups regarding the bone quality, there was no difference in bone amount or volume. EMD stimulated higher ALP activity and lower cytotoxicity in wound fluid, as well as a lower expression of inflammatory markers after 8 weeks indicating its osteoimmunomodulatory effects after implantation. Overall, the results suggested that ionic nanostructure modification and biofunctionalization might be useful in regulating the immune responses to implants.

• Rahmati, Maryam; Lyngstadaas, Ståle Petter; Reseland, Janne Elin; Andersbakken, Ingrid; Haugland, Heidi Straume; López-peña, Mónica; Cantalapiedra, Antonio gonzalez; Muñoz, Fernando maria guzon & Haugen, Håvard Jostein (2020). Coating doxycycline on titanium-based implants: two in vivo studies. Bioactive Materials.  ISSN 2452-199X.  5(4), s 787- 797 . doi: 10.1016/j.bioactmat.2020.05.007 Full text in Research Archive. Show summary

  Regardless of the substantial progress in designing titanium-based dental implants and aseptic techniques, infection remains as the most common complication after implantation surgeries. Although, having a weakened immune system or systematic diseases is not seen as contraindicated for dental implants anymore, controlling the immune system is required to avoid surgical site infections after implantation. These patients have to control the surgical site infections by taking a high daily dose of oral antibiotics after dental implantation. The antibiotics oral administration has many side effects such as gastrointestinal symptoms, skin rashes and thrush. Coating antibiotics on the biomaterials surface could be a promising solution to reduce these disadvantages through locally releasing antibiotics in a controlled manner. The aim of this study was to investigate the effects of doxycycline coating layer on titanium-zirconium alloy surfaces in vitro and in vivo. In our previous studies, we demonstrated the chemical presence of doxycycline layer in vitro. In this study, we examined its physical presence using field emission scanning electron microscope and confocal microscope. We also analyzed its controlled released manner using Nano-Drop UV Vis spectrometer. After in vitro characterization of the coating layer, we evaluated its effects on the implant osseointegration in dogs and rabbits. The histological and histomorphometrical results exhibited no significant difference between doxycycline coated and uncoated groups regarding the implants osseointegration and biocompatibility for dental applications. Therefore, coating a doxycycline layer on TiZr implants could be favorable for reducing or removing the antibiotics oral administration after the implantation surgery.

• Rahmati, Maryam; silva, eduardo a.; Reseland, Janne Elin; Heyward, Catherine Anne & Haugen, Håvard Jostein (2020). Biological responses to physicochemical properties of biomaterial surface. Chemical Society Reviews.  ISSN 0306-0012.  49(15), s 5178 . doi: 10.1039/D0CS00103A Full text in Research Archive. Show summary

  Biomedical scientists use chemistry-driven processes found in nature as an inspiration to design biomaterials as promising diagnostic tools, therapeutic solutions, or tissue substitutes. While substantial consideration is devoted to the design and validation of biomaterials, the nature of their interactions with the surrounding biological microenvironment is commonly neglected. This gap of knowledge could be owing to our poor understanding of biochemical signaling pathways, lack of reliable techniques for designing biomaterials with optimal physicochemical properties, and/or poor stability of biomaterial properties after implantation. The success of host responses to biomaterials, known as biocompatibility, depends on chemical principles as the root of both cell signaling pathways in the body and how the biomaterial surface is designed. Most of the current review papers have discussed chemical engineering and biological principles of designing biomaterials as separate topics, which has resulted in neglecting the main role of chemistry in this field. In this review, we discuss biocompatibility in the context of chemistry, what it is and how to assess it, while describing contributions from both biochemical cues and biomaterials as well as the means of harmonizing them. We address both biochemical signal-transduction pathways and engineering principles of designing a biomaterial with an emphasis on its surface physicochemistry. As we aim to show the role of chemistry in the crosstalk between the surface physicochemical properties and body responses, we concisely highlight the main biochemical signal-transduction pathways involved in the biocompatibility complex. Finally, we discuss the progress and challenges associated with the current strategies used for improving the chemical and physical interactions between cells and biomaterial surface.

• Rumian, Lucja; Wolf-Brandstetter, Cornelia; Rößler, Sina; Reczyńska, Katarzyna; Tiainen, Hanna; Haugen, Håvard Jostein; Scharnweber, Dieter & Pamuła, Elżbieta (2020). Sodium alendronate loaded poly(L-lactide-co-glycolide) microparticles immobilized on ceramic scaffolds for local treatment of bone defects. Regenerative Biomaterials.  ISSN 2056-3426.  s 1- 10 . doi: 10.1093/rb/rbaa012 Full text in Research Archive. Show summary

  Bone tissue regeneration in critical-size defects is possible after implantation of a three-dimensional scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing. Sodium alendronate (Aln), a widely used anti-osteoporosis drug, exhibits strong inhibitory effect on bone resorption performed by osteoclasts. Thus we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide (TiO2) scaffolds and poly(L-lactide-co-glycolide) (PLGA) microparticles (MPs) loaded with Aln. The MPs were effectively immobilized on the surface of the scaffolds’ pore walls by human recombinant collagen. Drug release from the scaffolds was characterised by initial burst (24 ± 6% of the drug released within first 24 h) followed by a sustained release phase (on average 5 µg of Aln released per day from day 3 to day 18). In vitro tests showed that Aln in concentrations of 5 µg/mL and 2.5 µg/mL was not cytotoxic for MG-63 osteoblast-like cells (viability between 81 ± 6% to 98 ± 3% of control) but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells (PBMCs), as shown by reduced fusion capability and decreased TRAP 5b activity (56 ± 5% reduction in comparison control after 8 days of culture). Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis, reducing osteoclast activity, but not affecting osteoblast functions, which may be beneficial in the treatment of critical-size bone tissue defects.

• Sukul, Mousumi; Cama, Giuseppe; Dubruel, Peter; Reseland, Janne Elin & Haugen, Håvard Jostein (2020). Methacrylation increase growth and differentiation of primary human osteoblasts for gelatin hydrogels. Emergent Materials.  ISSN 2522-5731.  3, s 559- 566 . doi: 10.1007/s42247-020-00101-5 Full text in Research Archive. Show summary

  The role of gelatin methacrylate hydrogels with varying degree of methacrylation (69% and 84%) was accessed with FTIR, NMR, microCT and subsequently exposure to human osteoblasts. The cells responded positively to the degree of methacrylation and showed attachment, growth and proliferated on both hydrogels. The cell reacted differently to the degree of methacrylation with higher proliferation on higher substitution; however, cell differentiation behavior was improved for less substitution. The secretion of late osteogenic markers (Osteoprotegerin (OPG), Osteopontin (OPN) and Osteocalcein (OCN)) and angiogenic factor Vascular endothelial growth factor (VEGF) was increased for gelatin methacrylate hydrogels with 69% degree of methacrylation and thus would be the better candidate for future bone regenerative applications amongst the three tested hydrogels

• Zhu, Hao; Blahnová, Veronika Hefka; Perale, Giuseppe; Xiao, Jun; Betge, Felice; Boniolo, Fabio; Filová, Eva; Lyngstadaas, Ståle Petter & Haugen, Håvard Jostein (2020). Xeno-Hybrid Bone Graft Releasing Biomimetic Proteins Promotes Osteogenic Differentiation of hMSCs. Frontiers in Cell and Developmental Biology.  ISSN 2296-634X. . doi: 10.3389/fcell.2020.619111
• Haugen, Håvard Jostein; Lyngstadaas, Ståle Petter; Rossi, Filippo & Perale, Giuseppe (2019). Bone grafts: which is the ideal biomaterial?. Journal of Clinical Periodontology.  ISSN 0303-6979.  46(21), s 92- 102 . doi: 10.1111/jcpe.13058 Full text in Research Archive. Show summary

  Abstract Bovine xenograft materials, followed by synthetic biomaterials, which unfortunately still lack documented predictability and clinical performance, dominate the market for the cranio‐maxillofacial area. In Europe, new stringent regulations are expected to further limit the allograft market in the future Aim Within this narrative review, we discuss possible future biomaterials for bone replacement. Scientific Rationale for Study Although the bone graft (BG) literature is overflooded, only a handful of new BG substitutes are clinically available. Laboratory studies tend to focus on advanced production methods and novel biomaterial features, which can be costly to produce. Practical Implications In this review, we ask why such a limited number of BGs are clinically available when compared to extensive laboratory studies. We also discuss what features are needed for an ideal BG. Results We have identified the key properties of current bone substitutes and have provided important information to guide clinical decision‐making and generate new perspectives on bone substitutes. Our results indicated that different mechanical and biological properties are needed despite each having a broad spectrum of variations. Conclusions We foresee bone replacement composite materials with higher levels of bioactivity, providing an appropriate balance between bioabsorption and volume maintenance for achieving ideal bone remodelling.

• Klemm, Anne; Gomez-Florit, Manuel; Almeida Carvalho, Patricia; Wachendörfer, Mattis; Gomes, Manuela E.; Haugen, Håvard Jostein & Tiainen, Hanna (2019). Grain boundary corrosion in TiO2 bone scaffolds doped with group II cations. Journal of the European Ceramic Society.  ISSN 0955-2219.  39, s 1577- 1585 . doi: 10.1016/j.jeurceramsoc.2018.12.055 Full text in Research Archive.
• Pham, Thi Ngoc Maria Huong; Haugen, Håvard Jostein; Rinna, Alessandra; Ellingsen, Jan Eirik & Reseland, Janne Elin (2019). Hydrofluoric acid treatment of titanium surfaces enhance the proliferation of human gingival fibroblasts. Journal of Tissue Engineering.  ISSN 2041-7314.  10 . doi: 10.1177/2041731419828950 Full text in Research Archive. Show summary

  The attachment of implants rely on bone and soft tissue biocompatibility. The aim was to investigate the effect of fluoride modified metallic titanium (Ti) surfaces (Ti-F) on proliferation and differentiation of human gingival fibroblasts (HGF). HGF cells were exposed to hydrofluoric acid (HF) modified Ti coins (Ti-F) for 1, 3, 7, 14 and 21d, and untreated coins were used as controls. A 5-6 fold increase in the proliferation of HGF on Ti-F compared to Ti surfaces was observed. Enhanced gene expression of IL-6 and OPG was found at 7 d. Increased levels of sclerostin, IL- 6 and OPG in the media from HGF cultured on Ti-F coins were found compared to controls. Our results confirm that HF modified surface may indirectly enhance the firm attachment of implant surface to junction epithelium, soft tissue epithelium, which would give protection for underlying osseous structures making osseointegration of the dental implant possible.

• Sanz, Mariano; Dahlin, Christer; Apatzidou, Danae; Artzi, Zvi; Bozic, Darco; Calciolari, Elena; De Bruyn, Hugo; Dommisch, Henrik; Donos, Nicos; Eickholz, Peter; Ellingsen, Jan Eirik; Haugen, Håvard Jostein; Herrera, David; Lambert, France; Layrolle, Pierre; Montero, Eduardo; Mustafa, Kamal Babikeir Eln; Omar, Omar & Schliephake, Henning (2019). Biomaterials and regenerative technologies used in bone regeneration in the craniomaxillofacial region: Consensus report of group 2 of the 15th European Workshop on Periodontology on Bone Regeneration. Journal of Clinical Periodontology.  ISSN 0303-6979.  46(21), s 82- 91 . doi: 10.1111/jcpe.13123 Full text in Research Archive.
• Schweikle, Manuel; Bjørnøy, Sindre Hove; Van Helvoort, Antonius; Haugen, Håvard Jostein; Sikorski, Pawel & Tiainen, Hanna (2019). Stabilisation of amorphous calcium phosphate in polyethylene glycol hydrogels. Acta Biomaterialia.  ISSN 1742-7061.  90, s 132- 145 . doi: 10.1016/j.actbio.2019.03.044 Full text in Research Archive. Show summary

  Acellular polymer-calcium phosphate composites are promising bone graft materials. Hydrogels are suitable for providing a temporary matrix, while calcium phosphate minerals serve as ion depots for calcium and phosphate required for de novo bone formation. Crystalline calcium phosphates are stable under biological conditions and are commonly used in such scaffolds. However, the low solubility of these phases reduces the availability of free ions and potentially obstructs the remodelling necessary for the formation of mineralised tissue. Here, we investigate two different strategies to stabilise amorphous calcium phosphates in a synthetic polyethylene glycol-based hydrogel matrix. In vitro experiments mimicking an injectable application showed that amorphous calcium phosphate (ACP) of variable stability was formed in the hydrogel matrices. In additive-free composites, ACP transformed into brushite within minutes. Citrate or zinc additives were found to stabilise the formed ACP phase to different degrees. In the presence of citrate, ACP was stable for at least 2 h before it transformed into hydroxyapatite within 3–20 days. Partial calcium substitution with zinc (Zn/Ca = 10%) produced zinc-doped ACP of high stability that did not show signs of crystallisation for at least 20 days. The presented methods and findings open new possibilities for the design of novel injectable synthetic bone graft materials. The possibility to produce ACP with tailorable stability promises great potential for creating temporary scaffolds with good osteogenic properties. Statement of significance Synthetic hydrogel-calcium phosphate (CaP) composites are promising biomaterials to replace human- and animal-derived bone scaffolds. Most reported hydrogel-CaP composite materials employ crystalline CaP phases that lack the osteoinductive properties of autograft. Stabilising amorphous calcium phosphates (ACP) could overcome this limitation, readily delivering calcium and phosphate ions and facilitating remodelling into new bone tissue. The design of synthetic hydrogel-ACP scaffolds, however, requires more understanding of the mineralisation processes in such matrices. This study presents a model system to characterise the complex mineral formation and transformation processes within a hydrogel matrix. We demonstrate a facile route to produce self-mineralising injectable synthetic hydrogels and prove two different strategies to stabilise ACP for different periods within the formed composites.

• Tanzi, Maria Cristina; Gantz, Daniel; Bertoldi, Serena; negrini, Nicola Contessi & Haugen, Håvard Jostein (2019). Polymers and Scaffolds with Improved Blood Compatibility and Enhanced Cellular Response with Focus on Polyurethane Foams Functionalized with Amino-Amide Groups. Journal of Advanced Biotechnology and Bioengineering.  ISSN 2311-1755.  7, s 18- 29 . doi: 10.12970/2311-1755.2019.07.03 Show summary

  Biofunctionalization of biomaterial substrates has gained increasing interest in Tissue Engineering (TE) to create functional scaffolds with improved performances and capable of directing cellular behaviour. This work takes into account the functionalization of polyurethane (PU) foams with an active molecule, the diamino-diamide diol PIME, purposely designed to be inserted in the structure of linear PUs and previously found to be able to improve hemo-, cytocompatibility and bacterial resistance of these biomaterials. Here, for the first time, the gas foaming process previously set up for biocompatible PU foams was modified, and different methods were tested to obtain structurally stable foams containing PIME. The obtained foams and respective controls showed appropriate porosity (Ø = 407 ÷ 589 ± 30 m; > 90% open porosity), similar density ( 0.14 g/cm3) and hydrophilicity (water uptake  300%) and adequate compressive properties (E = 0.058 ÷ 0.170 Mpa; Hysteresis Area = 2.07 ÷ 5.59 x 10-3 J/cm3, < 5% residual deformation). PU foams containing PIME exhibited a more spherical pore geometry; the foam obtained by applying a higher stirring speed during synthesis (PU-3kP) exhibited a lower mean pore size and an elastic modulus higher than that of the other foams. FT-IR spectroscopy indicated the presence of new absorption bands and structural changes attributable to the presence of PIME. Cytotoxicity tests performed with the cell line L929 verified the absence of cytotoxic effects. All foams were able to support L929 fibroblasts proliferation and vitality for seven days; PIME-containing foams showed higher values of cell proliferation (p<0.05) that the respective controls. Keywords: Polyurethane foams, scaffold, functionalization, bioactive molecule, PIME, open porosity, compressive properties, cell interactions, L929, fibroblasts.

• Zhang, Xianbin; Tiainen, Hanna & Haugen, Håvard Jostein (2019). Comparison of titanium dioxide scaffold with commercial bone graft materials through micro-finite element modelling in flow perfusion. Medical and Biological Engineering and Computing.  ISSN 0140-0118.  57(1), s 311- 324 . doi: 10.1007/s11517-018-1884-2 Full text in Research Archive. Show summary

  TiO2 scaffolds have previously shown to have promising osteoconductive properties in previous in vivo experiments. Appropriate mechanical stimuli can further promote this osteoconductive behaviour. However, the complex mechanical environment and the mechanical stimuli enhancing bone regeneration for porous bioceramics have not yet been fully elucidated. This paper aims to compare and evaluate mechanical environment of TiO2 scaffold with three commercial CaP biomaterials, i.e. Bio-Oss, Cerabone and Maxresorb under simulated perfusion culture conditions. The solid phase and fluid phase were modelled as linear elastic material and Newtonian fluid, respectively. The mechanical stimulus was analysed within these porous scaffolds quantitatively. The results showed that the TiO2 had nearly heterogeneous stress distributions, however lower effective Young’s modulus than Cerabone and Maxresorb. The permeability and wall shear stress (WSS) for the TiO2 scaffold was significantly higher than other commercial bone substitute materials. Maxresorb and Bio-Oss showed lowest permeability and local areas of very high WSS. The detailed description of the mechanical performance of these scaffolds could help researchers to predict cell behaviour and to select the most appropriate scaffold for different in vitro and in vivo performances.

• Zhu, Hao; Xiongfa, Ji; Hanfeng, Guan; Liming, Zhao; Libo, Zhao; Changyu, Liu; Cong, Cai; Weijing, Li; Tenghui, Tao; Reseland, Janne Elin; Haugen, Håvard Jostein & Xiao, Jun (2019). Tantalum Nanoparticles Reinforced Polyetheretherketone Shows Enhanced Bone Formation. Materials Science and Engineering C: Materials for Biological Applications.  ISSN 0928-4931.  101, s 232- 242 . doi: 10.1016/j.msec.2019.03.091 Full text in Research Archive. Show summary

  Polyetheretherketone (PEEK) has been used in orthopedic surgery for several decades. Numerous methods were invented to alter the property of PEEK. By adding nanoparticles, fibers, elastic modulus and strength of PEEK can be changed to meet certain demand. In this study, tantalum (Ta), a promising metal, was introduced to modify the properties of PEEK, in which PEEK was reinforced with different contents of tantalum nanoparticles (from 1%wt to 9%wt). Mechanical properties and biological functions (both in vitro and in vivo) were then investigated. The highest elastic modulus and compressive strength were observed in 3%Ta-PEEK. Cell experiments as cell adhesion, collagen secretion, biomineralization and osteogenesis related gene expression showed preferable results in 3%Ta-PEEK and 5%Ta-PEEK. Improved bone integration was shown in 3%Ta-PEEK and 5%Ta-PEEK in vivo. Above all, enhanced mechanical properties and promoted bone formation were proved for 3%Ta-PEEK and 5%Ta-PEEK compared to others groups both in vivo and in vitro, suggesting that the addition of tantalum nanoparticles modified the osseointegration ability of PEEK. This composite of tantalum and PEEK could have a clinical potential for orthopedic implants.

• Johnsen, Gaute Floer; Sunde, Pia Titterud & Haugen, Håvard Jostein (2018). Validation of contralateral premolars as the substrate for endodontic comparison studies. International Endodontic Journal.  ISSN 0143-2885.  51(8), s 942- 951 . doi: 10.1111/iej.12902 Full text in Research Archive. Show summary

  AIM: To use micro-CT technology and metrology software to validate the use of contralateral premolars as samples in endodontic comparison studies by comparing them before and after canal instrumentation with one instrumentation system. Furthermore, to determine if contralateral premolar roots will yield non-significantly different outcomes regarding shaping ability (volume), degree of twisting, and three-dimensional shape changes. The null-hypothesis (H0 ) is that there are no differences between the contralateral premolar roots pre- or post-instrumentation. METHODOLOGY: Twenty-eight extracted human contralateral premolars (n=44 contralateral roots) from 12 donor patients were scanned with microcomputed tomography before and after instrumentation. Root canal lengths (RCL) were measured visually using a dental operating microscope, electronic apex locator, and micro-CT scans. Data were analyzed statistically for differences between pre- and post-instrumentation. RESULTS: Instrumentation increased the volume of the canals significantly (P<0.05). Degree of twisting for a majority (83%) of the contralateral roots pairs did not change significantly (P>0.05). There was no significant difference (P>0.05) in the shape deviation analysis between contralateral pairs. There was no significant difference (P>0.05) for root canal length between the contralateral pairs for any of the three endometric methods. CONCLUSION: Contralateral premolar root canals were associated with similar changes in terms of volume, three-dimensional shape, and degree of twisting from pre- to post-instrumentation. There was no difference between the contralateral premolar root pairs pre- and post-instrumentation, and the study validates contralateral premolars as samples for root canal comparison studies. The null-hypothesis (H0 ) could not be rejected. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

• Kamyar, Negin; Greenhalgh, Ryan; Nascimentoa, Tatiana R. L; Medeiros, Eliton S; Matthews, Peter D; Nogueira, Liebert Parreiras; Haugen, Håvard Jostein; Lewis, David J. & Blaker, Jonny j (2018). Exploiting Inherent Instability of 2D Black Phosphorus for Controlled Phosphate Release from Blow-Spun PLGA Nanofibers. ACS Applied Nano Materials.  ISSN 2574-0970.  1, s 4190- 4197 . doi: 10.1021/acsanm.8b00938 Show summary

  Efforts have been made to stabilize black phosphorus (BP) to utilize its tunable band gap and anisotropic mechanical properties. Here, the intrinsic instability of BP is exploited for controlled therapeutic ion release, namely phosphate. BP was incorporated into degradable poly (lactide-co-glycolide) fibers via solution blow spinning. Raman spectroscopy confirmed the incorporation of 2D-BP into the nanocomposite along with ICP-AES. It was also demonstrated that modifying the initial loading of 2D-BP in the PLGA fibers permitted tunable release rates of phosphate ions over an 8 weeks in vitro study.

• Virto, Leire; Haugen, Håvard Jostein; Fernández-mateos, Pilar; Cano, Pilar; González, Jerián; Jiménez-ortega, Vanesa; Esquifino, Ana isabel & Sanz Alonso, Mariano (2018). Melatonin expression in periodontitis and obesity: An experimental in-vivo investigation. Journal of Periodontal Research.  ISSN 0022-3484.  53(5), s 825- 831 . doi: 10.1111/jre.12571 Full text in Research Archive. Show summary

  Background and Objective: Melatonin deficiency has been associated with obesity and systemic inflammation. This study aims to evaluate whether melatonin could interfere with the mechanisms of co-morbidity linking obesity and periodontitis. Material and Methods: Twenty-eight male Wistar rats were randomly divided in 4 groups: control group (Con) (fed with standard diet); high-fat diet group (HFD) (fed with a diet containing 35.2% fat); Con group with induced periodontitis (Con-Perio) and HFD group with induced periodontitis (HFD-Perio). To induce periodontitis, the method of oral gavages with Porphyromonas gingivalis ATCC W83K1 and Fusobacterium nucleatum DMSZ 20482 was used. Circulating melatonin levels were analyzed by multiplex immunoassays. Periodontitis was assessed by alveolar bone loss (microcomputed tomography and histology) and by surrogate inflammatory outcomes (periodontal pocket depth, modified gingival index and plaque dental index). Results: Plasma melatonin levels were significantly decreased (P < .05) in the obese rats with periodontitis when compared with controls or with either obese or periodontitis rats. Alveolar bone loss increased 27.71% (2.28 µm) in HFD-Perio group compared with the Con group. The histological analysis showed marked periodontal tissue destruction with osteoclast activity, particularly in the HFD-Perio group. A significant negative correlation (P < .05) was found between periodontal pocket depth, modified gingival index and circulating melatonin levels. Conclusion: Obese and periodontitis demonstrated significantly lower melatonin concentrations when compared with controls, but in obese rats with periodontitis these concentrations were even significantly lower when compared with either periodontitis or obese rats. These results may indicate that melatonin deficiency could be a key mechanism explaining the co-morbidity effect in the association between obesity and periodontitis.

• Virto, Leire; Cano, Pilar; Jiménez-ortega, Vanesa; Fernández-mateos, Pilar; González, Jerián; Haugen, Håvard Jostein; Esquifino, Ana isabel & Sanz Alonso, Mariano (2018). Melatonin as adjunctive therapy in the treatment of periodontitis associated with obesity. Journal of Clinical Periodontology.  ISSN 0303-6979.  45(11), s 1336- 1346 . doi: 10.1111/jcpe.13013 Full text in Research Archive. Show summary

  Aims To study the effect of adjunctive systemic administration of melatonin to standard mechanical periodontal therapy in obese rats with experimental periodontitis. Materials and methods In 42 Wistar rats with an initial body weight of 180 g., half (n=21) were fed with a high‐fat diet to induce obesity. In both obese and normal‐weight groups, experimental periodontitis was subsequently induced through oral gavages with a combination of Porphyromona gingivalis and Fusobacterium nucleatum. Both groups were randomly allocated to either, no treatment or periodontal treatment consisting on standard mechanical debridement, with either adjunctive chlorhexidine or melatonin. Outcomes were evaluated by the changes in clinical parameters (probing depth modified gingival index, plaque dental index and bleeding on probing), in bone resorption and in the levels of biomarkers in plasma and in gingival tissue (inflammatory cytokines, insulin, leptin, osteocalcin, osteopontin, plasminogen activator inhibitor‐1, intercellular adhesion molecule 1, E‐selectin and lipids). Results In the obese‐periodontitis group, adjunctive melatonin administration resulted in reduced gingival inflammation and bleeding on probing, with significant reductions in probing depth and enhanced bone repair demonstrated by Micro‐CT (15% reduction in alveolar bone destruction) when compared with the same group treated with adjunctive CHX or the normal‐weight rats with either melatonin or CHX. In this melatonin‐treated obese‐periodontitis group, a significant impact on biochemical biomarkers was also demonstrated in both gingival and plasma samples, when compared with the other groups, with significant reductions in pro‐inflammatory cytokines. Conclusions Adjunctive melatonin therapy significantly reduced alveolar bone loss and exerted a protective anti‐inflammatory effect mainly in those experimental animals affected by the co‐morbidity of periodontitis and obesity.

• Barrantes Bautista, Alejandro; Wengenroth, Jonas; Arnebrant, Thomas & Haugen, Håvard Jostein (2017). Poly-L-lysine/heparin multilayer coatings prevent blood protein adsorption. Journal of Colloid and Interface Science.  ISSN 0021-9797.  485, s 288- 295 . doi: 10.1016/j.jcis.2016.09.046 Full text in Research Archive.

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• Esporrin, Javier Sanz; Haugen, Håvard Jostein & Sanz, Mariano (2019). Experimental Peri-implantitis around Titanium Implants with a Modified Titanium Surface with a Phosphonic Acid Monolayer. NanoCT Results of an Experimental In-vivo Investigation.
• Haugen, Håvard Jostein (2019). Micro and nano-CT applied to dental research.
• Haugen, Håvard Jostein (2019). Micro-porosities Revealed in Hybrid Dental Composites by Nano X-ray Tomography.
• Haugen, Håvard Jostein (2019). Novel nano-computed tomography techniques applied to dental research.
• Haugen, Håvard Jostein (2019). Structural and Bio-inspired Bioceramic Materials and Implants.
• Pawlik, A; Sulka, G.D. & Haugen, Håvard Jostein (2019). Fabrication and characterization of doxycycline-coated nanoporous TiO2 layers.
• Tanzi, Maria Cristina; gantz, daniel; Bertoldi, Serena; negrini, Nicola Contessi & Haugen, Håvard Jostein (2019). FUNCTIONALIZED POLYURETHANE FOAMS AS TISSUE SCAFFOLDS WITH ENHANCED CELLULAR RESPONSE. Show summary

  Recentadvancementsintissueengineeringrequirethedevelopmentoftailoredscaffoldswithphysicochemicalcuesabletopromotespecificandpositiveresponsesoncellsofthetargettissue • Biomedicalpolyurethanes(PU)exhibitgoodresilienceandfatiguestrength,goodcytoandhemocompatibilityandlowbacteriaadhesion;PUfoamscanbedesignedassuitablescaffoldsintissueengineering[1-3] • The diamino-diamide diolPIME (figure)canform stable complexes with heparin, due to the protonation of its tertiary amino groups at a physiological pH, has excellent cytocompatibility and can promote cells adhesion and proliferation on linear PUs containing

• de Lange, Thomas; Haugen, Håvard Jostein & Møystad, Anne (2018). Digital Prospects of Formative and Summative Assessment in Dental Education: Technological Opportunities and Challenges. Show summary

  Abstract: It is a well-known fact that assessment is an important driver for student learning. In the advancement of digital technologies, the question is how digital resources can be used to improve formative and summative assessment in ways that support student learning as well as ensuring knowledge standards for future dental professionals. Two experimental studies on digital assessment have been conducted at the Faculty of Dentistry, University of Oslo. Firstly, digitized formative assessment based on Multiple Choice questionnaires (MCQ) was implemented in testing students’ knowledge from prior parts of their education. Secondly, a pilot-study of a digitized summative assessment in oral radiology was conducted to identify benefits and challenges in applying entirely digital based exams. Results from these experiments are presented and discussed in relation to research on assessment and student learning.

• Haugen, Håvard Jostein & Ellingsen, Jan Eirik (2018, 30. august). Her skapes fremtidens arbeidsplasser i bioteknologi. [Fagblad].  Apollon. Show summary

  I det nye laboratoriet Sharelab på Blindern møtes forskere, bedriftsutviklere og investorer. De håper å skape hundrevis av kommersielle arbeidsplasser innen bioteknologi.

• Haugen, Håvard Jostein & Reseland, Janne Elin (2018). In vivo performance of a highly porous titanium dioxide bone scaffold and its way to the medical device market.
• Haugen, Håvard Jostein; Reseland, Janne Elin & Gomez-Florit, Manuel (2018). The effect of IDP coated biomaterial.
• Klemm, Anne; Haugen, Håvard Jostein & Tiainen, Hanna (2018). Grain boundary corrosion in Sr and Ca doped TiO2 bone scaffold. Show summary

  Porous TiO2 scaffolds as a bone support structure showed high porosity combined with high compressive strength1. Doping ceramic scaffolds with Ca or Sr leads to even higher compressive strength and formation of impurity rich grain boundaries2. Grain boundary dissolution can occur during bone healing, because of a local pH drop3. To improve the corrosion resistance of cationic doped TiO2 scaffolds, the objective of this study was to investigate the corrosion depending on doping concentration to evaluate corrosion mechanisms.

• Schweikle, Manuel; Bjørnøy, Sindre Hove; Lyngstadaas, Ståle Petter; Haugen, Håvard Jostein; Van Helvoort, Antonius; Sikorski, Pawel & Tiainen, Hanna (2018). Self-mineralising synthetic injectable hydrogels for bone repair.

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