Dr. scient Paul Johan Høl
Jeg er for tiden forsker ved Inst. for kirurgiske fag (UiB) og tilhører forskningsgruppen BioMatLab og Ortopediske biomaterialer. Stillingen er finansiert av Bergen medisinske forskningsstiftelse og varer til oktober 2013.
Nyhetssak om BioMatLab: “På Høyden”.
Jeg arbeider nå på et prosjekt med arbeidstittel:
Clinical biomaterials: Contributing to performance and safety of implants
Korrosjon og slitasje bidrar til å redusere levetiden til kunstige ledd og bruddimplantater. Nyere studier har vist at store mengder slitasjepartikler blir frigjort fra disse ortopediske implantatene. Dette kan føre til en kaskade av hendelser som kan føre til tap av bein rundt implantatet, også kalt osteolyse. Dette kan i verste fall føre til løsning av implantatet og havari av det kunstige leddet. Den utstrakte bruken av metallimplantater innen medisin fordrer også at man overvåker forekomsten av hypersensitivitet mot metaller.
Hovedmålet med denne studien er å påvise nedbrytningsprodukter i biologiske prøver fra pasienter med forskjellige typer havarerte implantater og om disse har ført til biologiske reaksjoner, som for eksempel osteolyse og metallallergi. Vi håper at resultatene fra denne studien kan hjelpe ortopedikirurgen til å velge de biomaterialene som er best tilpasset pasienten, både ved revisjon og første gangs innsetting.
Jeg er medveileder for tre PhD-studenter:
Zouhir Ekeland Allouni (Dental Biomaterials. UoB).
Carmen Irina Vamanu (Dental Biomaterials. Centre for International Health/UoB).
Rigmor Flatebø (Periodontology/Dental Biomaterials. UoB).
Ferske publikasjoner fra forskningsgruppen:
P, Hallan G, Høl, PJ, Gjerdet NR, Havelin LI. Coordinating retrieval
and register studies improves postmarket
surveillance. Clinical Orthopaedics and Related
Research 2012 Nov;470(11):2995-3002. doi: 10.1007/s11999-012-2430-4.
Abstract: BACKGROUND: The relative risk of revision of the Titan((R)) femoral stem due to aseptic loosening increased after 2000; however, the reasons for this have not been established. A retrieval analysis was initiated with the aim of delineating the failure mechanism. QUESTIONS/PURPOSES: We asked whether aseptic loosening in stems after 2000 was associated with (1) appearance of osteolytic lesions, (2) wear particle exposure, (3) stem damage, or (4) changes to the implant or surgical instrumentation. METHODS: Femoral stems, cement, tissue, and radiographs were collected from 28 patients. We assessed the development of osteolytic lesions in 17 patients. Exposure to wear particles was quantified in 18 patients. Stem damage was assessed in 15 patients. We observed differences in the implants by examination of 24 retrieved stems. Information concerning changes to instrumentation was requested from the manufacturer. RESULTS: We found osteolysis in all patients receiving implants after 2000, which was associated with a median dose of cement and stem particles of 14,726/mm(2). Abrasion covered 59% of the surface of stems implanted from 1999. We identified geometric changes to the stem, the percent weight of aluminum in the stem's oxide layer decreased from 25% to 14% after 1997 and the rasp used to prepare the femoral cavity changed to a broach in 1999. CONCLUSIONS: Stems implanted from 2000 failed through osteolysis induced by particles released from the cement and implant. Changes to implant geometry, surface oxide layer, and surgical tools occurred in the same time frame as the reduction in survivorship.
Allouni, ZE, Høl PJ, Cauqui, MA, Gjerdet NR, Cimpan MR. Role of physicochemical characteristics in the
Uptake of TiO2 nanoparticles by fibroblasts. Toxicology in Vitro 2012 ;Volum 26.(3) s. 469-479
Abstract: The relation between the physico-chemical properties of nanoparticles (NPs) and the degree of cellular uptake is incompletely elucidated. In this study, we investigated the influence on the cellular uptake of a wide range of fully characterized TiO(2) NPs. L929 fibroblasts were exposed for 24h to clinically relevant concentrations of nano-TiO(2) and the degree of their association was assessed by ultrahigh resolution imaging microscopy (URI), scanning (SEM) and transmission (TEM) electron microscopy, as well as inductivity coupled plasma-mass spectroscopy (ICP-MS). The role of actin polymerization, a central feature of active internalization, was also studied and the results indicated that the internalization of TiO(2) NPs involves a combination of actin-dependent uptake of large agglomerates as well as non actin-dependent uptake of small agglomerates. SEM and TEM revealed that the agglomerates of all NPs types were attached to the cellular membrane as well as internalized and confined inside cytoplasmic vesicles. URI and ICP-MS demonstrated that the particle association with cells was dose-dependent. The highest association was observed for spherical particles having mixed anatase-rutile crystallographic phase and the lowest for spindle-shaped rutile particles. ICP-MS revealed that the association was size-dependent in the order 5>10>40nm for anatase spherical nanoparticles.
Hallan G, Espehaug B, Furnes O, Wangen H, Høl PJ, Ellison P, Havelin LI.
Is there still a place for the cemented titanium femoral stem? 10,108 cases
from the Norwegian Arthroplasty Register. Acta Orthopaedica 2012 ;Volum 83.(1)
Abstract: Background and purpose: Despite the fact that there have been some reports on poor performance, titanium femoral stems intended for cemented fixation are still used at some centers in Europe. In this population-based registry study, we examined the results of the most frequently used cemented titanium stem in Norway. Patients and methods: 11,876 cases implanted with the cemented Titan stem were identified for the period 1987-2008. Hybrid arthroplasties were excluded, leaving 10,108 cases for this study. Stem survival and the influence of age, sex, stem offset and size, and femoral head size were evaluated using Cox regression analyses. Questionnaires were sent to the hospitals to determine the surgical technique used. Results: Male sex, high stem offset, and small stem size were found to be risk factors for stem revision, (adjusted RR = 2.5 (1.9-3.4), 3.3 (2.3-4.8), and 2.2 (1.4-3.5), respectively). Patients operated in the period 2001-2008 had an adjusted relative risk (RR) of 4.7 (95% CI: 3.0-7.4) for stem revision due to aseptic stem loosening compared to the period 1996-2000. Changes in broaching technique and cementing technique coincided with deterioration of the results in some hospitals. Interpretation: The increased use of small stem sizes and high-offset stems could only explain the deterioration of results to a certain degree since the year 2000. The influence of discrete changes in surgical technique over time could not be fully evaluated in this registry study. We suggest that this cemented titanium stem should be abandoned. The results of similar implants should be carefully evaluated.
· Flatebø RS, Høl PJ, Leknes KN, Kosler J, Lie SA, Gjerdet NR. Mapping of titanium particles in peri-implant oral mucosa by Laser Ablation Inductively Coupled Plasma Mass Spectrometry and high-resolution optical darkfield microscopy. J Oral Pathol Med 2010 Oct 24.
Abstrakt: The present study examines the quantity, size, element signatures and distribution of titanium particles in normal oral mucosal tissue and in oral mucosa exposed to a titanium implant. Tissue samples from six healthy patients were obtained by a full thickness biopsy taken from the edge of the oral mucosa when inserting a titanium dental implant. At the abutment insertion 6 months later, a punch test biopsy of oral mucosa was taken over the implant site. Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) is a sensitive and specific multi-element microanalytical technique that demonstrated the presence of Ti particles in the tissue adjacent to implant cover-screws. The epithelial part of the control samples revealed more particles than the corresponding area of the test samples, consisting partly of newly formed scar tissue. High-Resolution Optical Darkfield Microscope (HR-ODM) confirmed the presence of particles in both the control and the test samples. The combination of LA-ICP-MS and HR-ODM appears to be a powerful combination for detection of particles in oral tissues; optical microscopy provides an overview with histological references, whereas LA-ICP-MS identifies the chemical composition.
· Allouni ZE, Cimpan MR, Høl PJ, Skodvin T, Gjerdet NR. Agglomeration and sedimentation of TiO2 nanoparticles in cell culture medium. Colloids and surfaces B: Biointerfaces 2009 Jan 1;68(1):83-7. Epub 2008 Sep 25.
Abstrakt: The physicochemical characterization of nanoparticles in suspension is a prerequisite for the adequate assessment of their potential biological effect. Little is known to date about the colloidal stability of TiO2 nanoparticles in cell culture medium. This study investigates the effect of particle concentration, ionic strength, pH, and the presence of fetal bovine serum (FBS) and human serum albumin (HSA) on the colloidal stability of TiO2 nanoparticles in RPMI cell culture medium, by sedimentation measurements, dynamic light scattering, and electrokinetic measurements (zeta-potential). TEM revealed that the particles were polydisperse, with diameters ranging from approximately 15 to approximately 350 nm. The agglomeration rate and sedimentation rate increased with particles' concentration. The size of the agglomerates at 100 mg/L TiO2 was significantly reduced, from 1620+/-160 to 348+/-13 and 378+/-15 nm, upon the addition of 10% (v/v) FBS and 1% (w/w) HSA, respectively. The isoelectric point of TiO2 in water was 2.9 and the measured zeta-potential in RPMI was -16+/-2 mV at pH 7.4. A slight increase in the zeta-potential of TiO2 in RPMI was observed upon the addition of FBS and HSA. The addition of FBS and HSA prevented high agglomeration, leading to a stable dispersion of TiO2 nanoparticles for at least 24 h, possibly due to steric stabilization of the particles.
· Vamanu CI, Høl PJ, Ekeland Allouni Z, Elsayed S, Gjerdet NR. Formation of potential antigens based on protein binding to titanium dioxide nanoparticles. International Journal of Nanomedicine 2008; 3(1):69-74.
Dette er første ledd i arbeidet med å utvikle en allergitest for titan, men inngår også i prosjektene våre innen nanotoksikologi.
Abstrakt: Degradation products of titanium implants include free ions, organo-metallic complexes, and particles, ranging from nano to macro sizes. The biological effects, especially of nanoparticles, is yet unknown. The main objective of this study was to develop Ti-protein antigens in physiological solutions that can be used in testing of cellular responses. For this purpose, 0.1% TiO2 nanoparticles less than 100 nm were mixed with human serum albumin (HSA), 0.1% and 1%, in cell culture medium (DMEM, pH 7.2). The Ti concentrations in the resulting solutions were analyzed by inductively coupled plasma mass spectrometry. The stability of the nanoparticles in suspension was analyzed by UV-vis spectrophotometer and Dynamic Light Scattering. The concentration of Ti in suspension was dependent on the presence and concentration of HSA. Albumin prevented high aggregation rate of TiO2 nanoparticles in cell culture medium. It is shown that nano TiO2-protein stable aggregates can be produced under physiological conditions at high concentrations, and are candidates for use in cellular tests.
· Høl PJ, Mølster A, Gjerdet NR. Should the galvanic combination of titanium and stainless steel surgical implants be avoided? Injury 2008; 39(2):161-9.
Abstrakt: It is recommended that one should not combine different metals in orthopaedic devices. The least noble metal in such a galvanic coupling is more likely to corrode. However, some studies have failed to show increased corrosion when titanium and stainless steel are combined. The aim of this study was to determine the fretting corrosion of the contact areas between screws and plates made of these dissimilar metals used for internal fixation of bone fractures. The plates were fixed to a bone-simulating material and subjected to tensile and compressive forces in both human serum and Hank's solution. The outcome variables included in the analyses were weight loss, and release of Ti, Cr, Ni and Mo to the different media. Results from the multiple combinations were subjected to multivariate statistics. Principal component analysis visualised our findings and allowed classification of similar samples and separation of discrepant groups of samples. We found a significant effect of the test medium, but no dramatic effect due to mixing of metals. The titanium screws and plates corroded more in serum than in saline, while the opposite was true for stainless steel. Combination of dissimilar screws and plates did not cause higher weight loss or metal release than the single-material constructions, indicating comparable clinical safety.
Vi bruker ulike metoder for in vitro korrosjonstesting av metallimplantater. Målsetningen predikere klinisk korrosjonsutsatthet før implantatene blir satt inn i mennesker. Instrumentene vi bruker er en Parstat 2253 fra Princeton Applied Research (USA) og en egenkonstruert pneumatisk frettingsimulator. Fretting er en form for korrosjon som oppstår når ulike deler av en konstruksjon gnisser mot hverandre. Denne typen korrosjon er veldig vanlig i glideflatene i kne- og hofteproteser, men også i glideskruer for lårhalsbrudd og mellom skruehoder og skruehull i osteosynteseplater.
· Høl PJ, Mølster A, Gjerdet NR, Bell K, Sætersdal C, Gjertsen J-E. Hip fracture implants increase serum metal levels. Scand J Clin Lab Invest. 2006;66 705-716.
Vi undersøkte hvor mye krom, nikkel og molybden to typer vanlige hofteskruer (glideskruer og frittstående skruer) avgir til kroppen. Hovedmålet er å danne et grunnlag for å vurdere evt. skadevirkninger av kroppsfremmede implantater som blir stående i kroppen.
Abstrakt: OBJECTIVE: Hip fractures are disabling accidents in the elderly. The purpose of this prospective study was to investigate systemic exposure to metals from hip implants used for fracture fixation. MATERIAL AND METHODS: Serum levels of Cr, Ni and Mo in patients with compression hip screws (n = 22) or cervical fracture screws (n = 23) were measured by inductively coupled plasma mass spectrometry. Blood samples were collected before surgery and at 3 and 12 months postoperatively. RESULTS: At 3 months, patients with compression hip screws showed higher concentrations of Cr and Ni than did those with cervical screws. Both types of screws led to a 2-fold increase in serum Mo, which was not expected for the freestanding cervical screws. After 12 months, the levels had decreased, but the compression hip screw was still associated with higher values for Cr and Mo. CONCLUSIONS: The difference between the screws is most likely due to the potential for fretting and crevice corrosion between components in the compression hip screws. The apparent short-term systemic elevation of stainless steel elements in patients with hip screws does not support routine removal of asymptomatic hip fracture implants.
· Høl PJ, Bell K, Mølster A, Gjerdet NR. Nickel contamination from an intravenous catheter used for infusion. Scand J Clin Lab Invest 2005;65:221-5.
Abstrakt: At the outset of a clinical research project involving metal analyses on patients receiving metal devices in conjunction with hip fractures, unexpected high concentrations of nickel were discovered in serum samples taken before surgery. The median nickel concentration in 30 patients was 4.6 microg/l (highest 19.5 microg/l), while reference values in non-exposed persons are reported to be 0.05-1.2 microg/l. The sampling and analyzing procedures were scrutinized without positive identification of the source of contamination. A review of all relevant procedures was then undertaken. It was identified that the nickel contamination originated from the intravenous catheter which was always put in place immediately after the patient's admission to the hospital, and thus before the blood sampling. Close inspection of the intravenous catheter revealed that it contained a nickel-plated brass funnel inside the hub of the device which released nickel into the Ringer-acetate passing through the catheter. The present catheter has been the standard device used at Haukeland University Hospital for the past 6 years. Patients have consequently been exposed to small amounts of nickel. The clinical relevance of the exposure cannot be determined. For the patients included in the research project, a metal-free alternative was used. These findings show that the quality and properties of everyday medical devices should be scrutinized, at least before being used for special purposes.
Disputerte for dr. scient-graden 9. mai 2003. Tittelen på avhandlingen er:
"Trace elements in persons with dental amalgam. The role of a chelating agent."
I kjølvannet av doktordisputasen skrev jeg en kronikk i Dagbladet (publ. 22. sept. 2003) med tittelen: "Kunstig stoff i kroppene våre" som omhandler både medisinske implantater og fenomenet piercing.
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