Dr. scient Paul
Johan Høl
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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.
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Jeg er medveileder for tre PhD-studenter:
Zouhir
Ekeland Allouni (Dental Biomaterials. UoB).
Prosjekttittel: “Interactions between
Titanium Nanoparticles and Cells: Correlation between Physicochemical
Characteristics and Cellular Parameters.”
Carmen Irina Vamanu (Dental Biomaterials. Centre for International
Health/UoB).
Prosjekttittel: “Biological
effects of Titanium: In vitro studies
on Human Cell Responses and Apoptotic Reactions.”
Rigmor Flatebø (Periodontology/Dental Biomaterials. UoB).
Prosjekttittel: “Histologic
and immunohistochemic evaluation of non-perforated oral mucosa covering
submerged titanium implants.”
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Ferske publikasjoner fra forskningsgruppen:
·
Ellison
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)
s. 1-6.
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.
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Jeg var i perioden 1998 - 2002 universitetsstipendiat ved odontologiske biomaterialer, Universitetet i Bergen.
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."
Last ned pdf-fil av avhandlingen (uten artikler). Pressemelding og omtale i Tidende (Den norske tannlegeforening sitt tidsskrift, nr. 15, 2003).
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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