Autologous stem cells as a promising therapeutic approach for augmentation of alveolar bone

The current gold standard for reconstructive bone surgery is based on autologous bone grafts. However, the risk of complications at both the donor and recipient sites is considerable. There is therefore a need to explore alternative methods of bone regeneration which will restore a defect to full functionality and meet esthetic demands. Nowhere is this a greater challenge than in reconstruction of defects in the orofacial region. Preliminary data, from limited in vitro and in vivo studies, indicate that bone marrow-derived MSC have potential application in bone tissue regeneration. However, interpretation of these studies is complicated by lack of conformity with respect to cell type (expanded or native), culture medium, source of growth factors, expansion time, cell dose and other variables. Moreover, biopsies are required to confirm the osteogenic capacity of the implanted cells and this has not been done routinely. In most studies to date, follow-up has been limited to radiographs, which do not allow differentiation between bone tissue formed by the implanted cells and by the native cells from the border of the osseous defect. The question also remains as to whether the presence of any new bone should qualify as clinical success, or whether a successful outcome requires evidence of new bone formation at the center of the regenerated area. With respect to culture and expansion of MSC for bone tissue engineering, a further issue has arisen, namely the exclusion of animal-derived products from culture medium, requiring a human-derived source of growth factors to replace FBS. The work presented in this thesis was undertaken in order to develop and validate each step in a standardized protocol for expanding autologous MSC in vitro in a GMP-compliant facility (Study II). The expanded MSC produced by this protocol were then applied in a phase I/II clinical trial of restoration of the mandibular alveolar ridge in 11 patients. The surgery was carried out by one experienced oral surgeon (Study III). The same surgeon also undertook the post-operative follow-up, with standardized patient evaluations at each appointment. Bone regeneration was confirmed in all 11 patients, as evidenced by radiographs and biopsies taken at installation of all 21 dental implants. All the implants osseo-integrated. All patients considered the outcomes to be satisfactory, with minimum pain and no morbidity. In a retrospective study of 59 patients who had undergone advanced alveolar ridge reconstruction in accordance with the current gold standard procedure, using autologous bone grafts (Study I), patient satisfaction and OHRQoL among participants was favorable. Despite their overall satisfaction with the outcome, these patients reported significant pain and morbidity. Furthermore, procedures based on autologous grafts from the iliac crest require substantial resources including hospitalization and sick leave. The following conclusions are drawn from this series of studies. Firstly, a standard protocol has been established for GMP expansion of autologous human MSC, using PL as a source of growth factors instead of FBS. Secondly, fresh autologous MSC can be manufactured, expanded and applied in bone regeneration, despite considerable geographic distance between the cell production facility and the clinical center. Thirdly, this protocol was successfully applied for alveolar ridge bone regeneration in 11 patients, with clinical outcomes comparable to those achieved using grafted autologous bone, recovered surgically from a second site. Although patient satisfaction with the new protocol was no different from the standard approach, those treated according to the new protocol reported low pain and morbidity. The results of the comprehensive trial confirm that bone marrow mesenchymal stem cells can successfully promote bone regeneration, with no unexpected adverse events and minimal pain. Hence, this novel augmentation procedure warrants further investigation. It has the potential to form the basis of a new therapeutic approach which may challenge the current gold standard

Omdømmebygging på Facebook: Effekter av kommunikasjon av samfunnsansvar, sett i lys av flyktningkrisen i Europa

Gjennom et eksperimentelt undersøkelsesdesign (eksperiment) ble det utformet to eksperimentgrupper som ble utsatt for ulike manipulasjoner. De to gruppene mottok informasjon om en bedrifts CSR aktivitet gjennom et Facebookinnlegg hvor den ene manipulasjonen innebar at bedriften selv informerte om initiativet, mens den andre manipulasjonen omhandlet en tredjeparts kommunikasjon av aktiviteten. Basert på tidligere forskning og teori var vi interessert i å undersøke i hvilken grad avsender av CSR kommunikasjon hadde en effekt på bedriftens omdømme. Oppgavens problemstilling lyder: ”I hvilken grad påvirkes omdømmet til en bedrifter når de kommuniserer Corporate Social Responsibility (samfunnsansvar) via Facebook av a) avsender av budskap og b) holdning til budskap?” For å besvare problemstillingen ble det utformet tre ulike hypoteser. Resultatene fra analysen gav signifikante tallverdier som gir støtte til alle våre tre hypoteser. Kort oppsummert viste analysen av eksperimentet at effekten av CSR vil være mest positiv på en bedrifts omdømme dersom andre forteller om bedriftens samfunnsansvar og forbrukeren har en positiv holdning til CSR aktiviteten. Resultatene fra undersøkelsen samsvarte med problemstillingen noe som tilsier at eksperimentet har høy grad av validitet

Talegjenkjenning : hvilke erfaringer har leger med bruk av talegjenkjenning?

Masteroppgave i helse- og sosialinformatikk HSI500 2012 – Universitetet i Agder, GrimstadInnføring av talegjenkjenning i helsevesenet har medført store endringer i legens arbeidsoppgaver, knyttet til utarbeidelse og godkjenning av notater i den elektroniske pasientjournalen. Erfaringer med bruk av talegjenkjenning har i stor grad vært negativt fremstilt i media, og en ønsket derfor i denne studien å kartlegge legers erfaringer med bruk av talegjenkjenning. Problemstillingen har vært: Hvilke erfaringer har leger i den somatiske spesialisthelsetjenesten med bruk av talegjenkjenning som dokumentasjonsstøtte i elektronisk pasientjournal? For å besvare problemstillingen har en brukt en kvantitativ metode med et webbasert spørreskjema. Det ble distribuert til leger i fem helseforetak fordelt på fjorten sykehus i Helse Sør-Øst. Svar fra 381 leger ble inkludert og det ga en svarprosent på 37 %. Funnene i studien viste at legene erfarte at talegjenkjenning ga en redusert kvalitet på dokumentasjonen grunnet feil og at det ikke var tidsbesparende. De var fornøyde med opplæringen, men opplevde at ordbøkene ikke ble oppdatert ofte nok, og at systemet ikke lærte. De mente at talegjenkjenning var nyttig da det førte til oppdaterte journaler som igjen kunne øke pasientsikkerheten. Mange leger var fornøyde med talegjenkjenning, men halvparten mente at pasientsikkerheten ikke ble ivaretatt med bruk av talegjenkjenning. En mener helseforetakene bør sikre en bedre brukerstøtte, få bedre vedlikehold av ordbøker og større fokus på bruk av standardtekster. Dersom dette følges opp, vil en kunne oppleve at flere leger vil ta i bruk talegjenkjenning, samt at talegjenkjenning oppleves tidsbesparende og gir bedret pasientsikkerhet. Nøkkelord: talegjenkjenning, elektronisk pasientjournal (EPJ), leger, erfaringer, kvalitet, nytte, pasientsikkerhet

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke – A Systematic Review and Meta-Analysis

Background: Mesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS). Methods: A systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model. Findings: Of 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively. Interpretation: MSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.publishedVersio

Translation of a standardized manufacturing protocol for mesenchymal stromal cells: A systematic comparison of validation and manufacturing data

Background Many data are available on expansion protocols for mesenchymal stromal cells (MSCs) for both experimental settings and manufacturing for clinical trials. However, there is a lack of information on translation of established protocols for Good Manufacturing Practice (GMP) from validation to manufacturing for clinical application. We present the validation and translation of a standardized pre-clinical protocol for isolation and expansion of MSCs for a clinical trial for reconstitution of alveolar bone. Methods Key parameters of 22 large-scale expansions of MSCs from bone marrow (BM) for validation were compared with 11 expansions manufactured for the clinical trial “Jaw bone reconstruction using a combination of autologous mesenchymal stromal cells and biomaterial prior to dental implant placement (MAXILLO1)” aimed at reconstruction of alveolar bone. Results Despite variations of the starting material, the robust protocol led to stable performance characteristics of expanded MSCs. Manufacturing of the autologous advanced therapy medicinal product MAXILLO-1-MSC was possible, requiring 21 days for each product. Transport of BM aspirates and MSCs within 24 h was guaranteed. MSCs fulfilled quality criteria requested by the national competent authority. In one case, the delivered MSCs developed a mosaic in chromosomal finding, showing no abnormality in differentiation capacity, growth behavior or surface marker expression during long-term culture. The proportion of cells with the mosaic decreased in long-term culture and cells stopped growth after 38.4 population doublings. Conclusions Clinical use of freshly prepared MSCs, manufactured according to a standardized and validated protocol, is feasible for bone regeneration, even if there was a long local distance between manufacturing center and clinical site. Several parameters, such as colony forming units fibroblasts (CFU-F), percentage of CD34+ cells, cell count of mononuclear cells (MNCs) and white blood cells (WBCs), of the BM may serve as a predictive tool for the yield of MSCs and may help to avoid unnecessary costs for MSC manufacturing due to insufficient cell expansion rates.publishedVersio

Polycrystalline Diamond Coating on Orthopedic Implants: Realization and Role of Surface Topology and Chemistry in Adsorption of Proteins and Cell Proliferation

Polycrystalline diamond has the potential to improve the osseointegration of orthopedic implants compared to conventional materials such as titanium. However, despite the excellent biocompatibility and superior mechanical properties, the major challenge of using diamond for implants, such as those used for hip arthroplasty, is the limitation of microwave plasma chemical vapor deposition (CVD) techniques to synthesize diamond on complex-shaped objects. Here, for the first time, we demonstrate diamond growth on titanium acetabular shells using the surface wave plasma CVD method. Polycrystalline diamond coatings were synthesized at low temperatures (∼400 °C) on three types of acetabular shells with different surface structures and porosities. We achieved the growth of diamond on highly porous surfaces designed to mimic the structure of the trabecular bone and improve osseointegration. Biocompatibility was investigated on nanocrystalline diamond (NCD) and ultrananocrystalline diamond (UNCD) coatings terminated either with hydrogen or oxygen. To understand the role of diamond surface topology and chemistry in the attachment and proliferation of mammalian cells, we investigated the adsorption of extracellular matrix proteins and monitored the metabolic activity of fibroblasts, osteoblasts, and bone-marrow-derived mesenchymal stem cells (MSCs). The interaction of bovine serum albumin and type I collagen with the diamond surfaces was investigated by confocal fluorescence lifetime imaging microscopy (FLIM). We found that the proliferation of osteogenic cells was better on hydrogen-terminated UNCD than on the oxygen-terminated counterpart. These findings correlated with the behavior of collagen on diamond substrates observed by FLIM. Hydrogen-terminated UNCD provided better adhesion and proliferation of osteogenic cells, compared to titanium, while the growth of fibroblasts was poorest on hydrogen-terminated NCD and MSCs behaved similarly on all tested surfaces. These results open new opportunities for application of diamond coatings on orthopedic implants to further improve bone fixation and osseointegration.publishedVersio

Effects of acute substance use and pre-injury substance abuse on traumatic brain injury severity in adults admitted to a trauma centre

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to describe the occurrence of substance use at the time of injury and pre-injury substance abuse in patients with moderate-to-severe traumatic brain injury (TBI). Effects of acute substance use and pre-injury substance abuse on TBI severity were also investigated.</p> <p>Methods</p> <p>A prospective study of 111 patients, aged 16-55 years, injured from May 2005 to May 2007 and hospitalised at the Trauma Referral Centre in Eastern Norway with acute TBI (Glasgow Coma Scale 3-12). Based on structural brain damages shown on a computed tomography (CT) scan, TBI severity was defined by modified Marshall classification as less severe (score <3) and more severe (score ≥3). Clinical definition of substance use (alcohol and/or other psychoactive substances) was applied when hospital admission records reflected blood alcohol levels or a positive drug screen, or when a physician verified influence by examining the patient. Pre-injury substance abuse (alcohol and drug problems) was screened by using the CAGE questionnaire.</p> <p>Results</p> <p>Forty-seven percent of patients were positive for substance use on admission to hospital. Significant pre-injury substance abuse was reported by 26% of patients. Substance use at the time of injury was more frequent in the less severe group (p = 0.01). The frequency of pre-injury substance abuse was higher in the more severe group (30% vs. 23%). In a logistic regression model, acute substance use at time of injury tended to decrease the probability of more severe intracranial injury, but the effect was not statistically significant after adjusting for age, gender, education, cause of injury and substance abuse, OR = 0.39; 95% CI 0.11-1.35, p = 0.14. Patients with positive screens for pre-injury substance abuse (CAGE ≥2) were more likely to have more severe TBI in the adjusted regression analyses, OR = 4.05; 95% CI 1.10-15.64, p = 0.04.</p> <p>Conclusions</p> <p>Acute <b>s</b>ubstance use was more frequent in patients with less severe TBI caused by low-energy events such as falls, violence and sport accidents. Pre-injury substance abuse increased the probability of more severe TBI caused by high-energy trauma such as motor vehicle accidents and falls from higher levels. Preventive efforts to reduce substance consumption and abuse in at-risk populations are needed.</p

Autologous stem cells as a promising therapeutic approach for augmentation of alveolar bone

The current gold standard for reconstructive bone surgery is based on autologous bone grafts. However, the risk of complications at both the donor and recipient sites is considerable. There is therefore a need to explore alternative methods of bone regeneration which will restore a defect to full functionality and meet esthetic demands. Nowhere is this a greater challenge than in reconstruction of defects in the orofacial region. Preliminary data, from limited in vitro and in vivo studies, indicate that bone marrow-derived MSC have potential application in bone tissue regeneration. However, interpretation of these studies is complicated by lack of conformity with respect to cell type (expanded or native), culture medium, source of growth factors, expansion time, cell dose and other variables. Moreover, biopsies are required to confirm the osteogenic capacity of the implanted cells and this has not been done routinely. In most studies to date, follow-up has been limited to radiographs, which do not allow differentiation between bone tissue formed by the implanted cells and by the native cells from the border of the osseous defect. The question also remains as to whether the presence of any new bone should qualify as clinical success, or whether a successful outcome requires evidence of new bone formation at the center of the regenerated area. With respect to culture and expansion of MSC for bone tissue engineering, a further issue has arisen, namely the exclusion of animal-derived products from culture medium, requiring a human-derived source of growth factors to replace FBS. The work presented in this thesis was undertaken in order to develop and validate each step in a standardized protocol for expanding autologous MSC in vitro in a GMP-compliant facility (Study II). The expanded MSC produced by this protocol were then applied in a phase I/II clinical trial of restoration of the mandibular alveolar ridge in 11 patients. The surgery was carried out by one experienced oral surgeon (Study III). The same surgeon also undertook the post-operative follow-up, with standardized patient evaluations at each appointment. Bone regeneration was confirmed in all 11 patients, as evidenced by radiographs and biopsies taken at installation of all 21 dental implants. All the implants osseo-integrated. All patients considered the outcomes to be satisfactory, with minimum pain and no morbidity. In a retrospective study of 59 patients who had undergone advanced alveolar ridge reconstruction in accordance with the current gold standard procedure, using autologous bone grafts (Study I), patient satisfaction and OHRQoL among participants was favorable. Despite their overall satisfaction with the outcome, these patients reported significant pain and morbidity. Furthermore, procedures based on autologous grafts from the iliac crest require substantial resources including hospitalization and sick leave. The following conclusions are drawn from this series of studies. Firstly, a standard protocol has been established for GMP expansion of autologous human MSC, using PL as a source of growth factors instead of FBS. Secondly, fresh autologous MSC can be manufactured, expanded and applied in bone regeneration, despite considerable geographic distance between the cell production facility and the clinical center. Thirdly, this protocol was successfully applied for alveolar ridge bone regeneration in 11 patients, with clinical outcomes comparable to those achieved using grafted autologous bone, recovered surgically from a second site. Although patient satisfaction with the new protocol was no different from the standard approach, those treated according to the new protocol reported low pain and morbidity. The results of the comprehensive trial confirm that bone marrow mesenchymal stem cells can successfully promote bone regeneration, with no unexpected adverse events and minimal pain. Hence, this novel augmentation procedure warrants further investigation. It has the potential to form the basis of a new therapeutic approach which may challenge the current gold standard

Pharmacokinetics of single doses of methadone and buprenorphine in blood and oral fluid in healthy volunteers and correlation with effects on psychomotor and cognitive functions

PURPOSE: We aimed to study the pharmacokinetics of methadone and buprenorphine in blood and oral fluid after single-dose administration and investigate correlations between concentrations in blood and neurocognitive functions. METHODS: A 5-way, double-blind, randomized, placebo-controlled, double-dummy, crossover study was performed to study the pharmacokinetics and neurocognitive effects of methadone (5 and 10 mg per oral) and buprenorphine (0.2 and 0.4 mg sublingual) in 22 healthy volunteers. Blood and oral fluid were collected throughout the test days, and drug concentrations in both matrices were analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. On-road driving testing, neurocognitive computerized tests, and subjective questionnaires were performed. RESULTS: Large individual variations in concentrations of methadone and buprenorphine in blood and oral fluid, and accordingly oral fluid/blood drug concentration ratios, were observed. The mean ratio 6.5 hours after drug administration was 2.0 (range, 0.49-7.39) for methadone after both doses. Buprenorphine was not detected above the limit of quantification in blood after 6.5 hours. No significant correlation between methadone concentration in blood and effect was found. Significant correlations were found between buprenorphine concentration in blood and standard deviation of lateral position in the driving test and some measures of reaction time, divided attention, balance, alertness, contentedness. and sleepiness. CONCLUSIONS: Concentrations of methadone and buprenorphine in blood and oral fluid showed large interindividual variations. No concentration-effect correlations were found for methadone, whereas low to moderate correlations were observed between buprenorphine concentration and driving, psychomotor function, and subjective rating of sleep and alertness

Patient experience following iliac crest alveolar bone gradfting av implant replacement

Background The objective of this study was to assess patient-reported outcomes such as satisfaction and quality of life after advanced alveolar bone augmentation with anterior iliac crest grafting and implant treatment in orally compromised patients. Methods This cross-sectional retrospective cohort study included 59 patients (29 women and 30 men) with major functional problems, who underwent advanced alveolar augmentation with autologous iliac bone grafts during a 10-year period (2002–2012). The self-administered questionnaire included 36 validated questions related to (1) demographics, (2) perceived general and oral health, (3) donor site and hospitalization, (4) status of implants and/or prosthesis, and (5) oral health-related quality of life (OHRQoL). Results Questionnaires were completed by 44 patients: 24 women and 20 men (response rate, 74.6%). Most patients reported good tolerance of the operative iliac bone harvesting (85%) and implant (90%) procedures. Post-operative pain at the donor site was reported by 38%, lasting 18.1 ± 16.1 days. An average of 4.3 ± 3.5 days of hospitalization and 20.2 ± 18.5 days of sick leave was reported. The overall satisfaction with prosthetic reconstruction was 90.5%. OHRQoL was reported with a mean Oral Health Impact Profile-14 (OHIP-14) score of 8.4. Conclusion Favorable OHRQoL and satisfaction were reported after advanced reconstruction of alveolar ridges with iliac crest-derived grafting and implants in severely compromised patients. However, this treatment requires substantial resources including hospitalization and sick leave