| 1. |
- Gilg, Stefan, et al.
(författare)
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The Molecular Adsorbent Recirculating System in Posthepatectomy Liver Failure : Results From a Prospective Phase I Study
- 2018
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Ingår i: HEPATOLOGY COMMUNICATIONS. - : JOHN WILEY & SONS LTD. - 2471-254X. ; 2:4, s. 445-454
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Tidskriftsartikel (refereegranskat)abstract
- Posthepatectomy liver failure (PHLF) represents the single most important cause of postoperative mortality after major liver resection, yet no effective treatment option is available. Extracorporeal liver support devices might be helpful, but systematic studies are lacking. Accordingly, we aimed to assess the safety and feasibility of the Molecular Adsorbent Recirculating System (MARS) in patients with PHLF. Between December 2012 and May 2015, a total of 206 patients underwent major or extended hepatectomy, and 10 consecutive patients with PHLF (according to the Balzan 50: 50 criteria) were enrolled into the study. MARS treatment was initiated on postoperative day 5-7, and five to seven consecutive treatment sessions were completed for each patient. In total, 59 MARS cycles were implemented, and MARS was initiated and completed without major complications in any patient. However, 1 patient developed an immense asymptomatic hyperbilirubinemia (without encephalopathy), 1 had repeated clotting problems in the MARS filter, and 2 patients experienced access problems with the central venous line. Otherwise, no adverse events were observed. In 9 patients, the bilirubin level and international normalized ratio decreased significantly (P < 0.05) during MARS treatment. The 60- and 90-day mortality was 0% and 10%, respectively. Among the 9 survivors, 4 still had liver dysfunction at 90 days postoperatively. Five patients were alive 1 year postoperatively without any signs of liver dysfunction or disease recurrence. Conclusion: The use of MARS in PHLF is feasible and safe and improves liver function in patients with PHLF. In the present study, 60- and 90-day mortality rates were unexpectedly low compared to a historical control group. The impact of MARS treatment on mortality in PHLF should be further evaluated in a randomized controlled clinical trial.
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| 2. |
- Slotte, Christer, 1954, et al.
(författare)
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Four-Millimeter-Long Posterior-Mandible Implants: 5-Year Outcomes of a Prospective Multicenter Study.
- 2015
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Ingår i: Clinical implant dentistry and related research. - : Wiley. - 1708-8208 .- 1523-0899. ; 17:2
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Tidskriftsartikel (refereegranskat)abstract
- There is lack of evidence on long-term success of short dental implants in reduced alveolar bone. Purpose In this prospective 5-year study, survival and marginal bone loss of 4-mm implants, which supported fixed dental prostheses (FDPs) in severely resorbed posterior mandibles, were evaluated. Material and Methods In 28 patients, evaluation of 86 osseointegrated 4-mm-long implants, which supported a 3- or a 4-unit FDP by crown splinting without the use of pontics or cantilevers, was performed over a 5-year period. Results Three subjects dropped out for non-study reasons: one subject had her three implants removed after 1 year and two subjects died (six implants). Five implants in three subjects were lost between 3 and 5 years. Twenty-four subjects and 71 implants were active at the 5-year follow-up (92.2% survival). After 1 year, significant (p<.001) mean (standard error of the mean [SEM]) 0.44-mm (0.05) marginal bone loss occurred. At 2, 3, and 5 years, mean (SEM) bone loss of 0.57mm (0.06), 0.55mm (0.07), and 0.53mm (0.08) occurred, respectively (no significant change after 1 year). At 5 years, average plaque levels were 13.3%; 69% of the implants were plaque free. On average, mucosal bleeding occurred at 8.1% of the implants. During 5 years, two subjects experienced uncomplicated bridge loosening. No other complications occurred during the study. Conclusion Four-millimeter implants can support FDPs in severely resorbed posterior mandibles for 5 years with healthy peri-implant conditions.
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| 3. |
- Birgisson, Helgi, et al.
(författare)
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Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer
- 2015
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Methods: Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Results: Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. Conclusions: The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.
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| 4. |
- Farman, Helen H., 1983, et al.
(författare)
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Female Mice Lacking Estrogen Receptor-alpha in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:8, s. 3242-3252
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor(ER)alpha. Central ER alpha exerts an inhibitory role on bone mass. ER alpha is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ER alpha in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ER alpha expression specifically in POMC neurons (POMC-ER alpha(-/-)). Female POMC-ER alpha(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 mu g/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ER alpha(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+ 126 +/- 34%, P < .01) and mechanical strength (+ 193 +/- 38%, P <.01). To test whether ER alpha in VMN is involved in the regulation of bone mass, ER alpha was silenced using an adeno-associated viral vector. Silencing of ER alpha in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ER alpha in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ER alpha activity in hypothalamic POMC neuronsin ARC and stimulatory peripheral ER alpha-mediated effects in bone determines cortical bone mass in female mice.
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| 5. |
- Fischer Grönlund, Catarina, 1962-, et al.
(författare)
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Development, validity and reliability testing the Swedish Ethical Climate Questionnaire
- 2019
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Ingår i: Nursing Ethics. - : SAGE Publications. - 0969-7330 .- 1477-0989. ; 26:7-8, s. 2482-2493
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: An ethical climate has been described as a working climate embracing shared perceptions about morally correct behaviour concerning ethical issues. Various ethical climate questionnaires have been developed and validated for different contexts, but no questionnaire has been found concerning the ethical climate from an inter-professional perspective in a healthcare context. The Swedish Ethical Climate Questionnaire, based on Habermas' four requirements for a democratic dialogue, attempts to assess and measure the ethical climate at various inter-professional workplaces. This study aimed to present the construction of and to test the psychometric properties of the Swedish Ethical Climate Questionnaire.METHOD:: An expert group of six researchers, skilled in ethics, evaluated the content validity. The questionnaire was tested among 355 healthcare workers at three hospitals in Sweden. A parallel analysis (PA), an exploratory factor analysis and confirmatory factor analysis were performed.ETHICAL CONSIDERATIONS:: The participants included in the psychometric analysis were informed about the study, asked to participate in person and informed that they could withdraw at any time without giving any reason. They were also assured of confidentiality in the reporting of the results.FINDINGS:: The parallel analysis (PA) recommended one factor as a solution. The initial exploratory factor analysis with a four-factor solution showed low concordance with a four-factor model. Cronbach's alpha varied from 0.75 to 0.82; however, since two factors only consisted of one item, alpha could not be reported. Cronbach's alpha for the entire scale showed good homogeneity (α = 0.86). A confirmatory factory analysis was carried out based on the four requirements and showed a goodness-of-fit after deleting two items. After deletion of these items, Cronbach's alpha was 0.82.DISCUSSION:: Based on the exploratory factor analysis, we suggest that the scale should be treated as a one-factor model. The result indicates that the instrument is unidimensional and assesses ethical climate as a whole.CONCLUSION:: After testing the Swedish Ethical Climate Questionnaire, we found support for the validity and reliability of the instrument. We found the 10-item version of Swedish Ethical Climate Questionnaire satisfactory. However, we found no support for measuring different dimensions and, therefore, this instrument should be seen as assessing ethical climate as of whole.
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| 6. |
- Horstmann, Peter Frederik, et al.
(författare)
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Composite biomaterial as a carrier for bone-Active substances for metaphyseal tibial bone defect reconstruction in rats
- 2017
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Ingår i: Tissue Engineering - Part A. - : Mary Ann Liebert Inc. - 1937-3341 .- 1937-335X. ; 23:23-24, s. 1403-1412
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Tidskriftsartikel (refereegranskat)abstract
- Restoring lost bone is a major challenge in orthopedic surgery. Currently available treatment strategies have shortcomings, such as risk of infection, nonunion, and excessive resorption. Our primary aim was to study if a commercially available gentamicin-containing composite calcium sulfate/hydroxyapatite biomaterial (GBM) could serve as a carrier for local delivery of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) in a tibia defect model in rats. Empty and allograft-filled defects were used as controls. A 3 × 4-mm metaphyseal bone defect was created in the proximal tibia, and the rats were grouped according to defect filling: (1) Empty, (2) Allograft, (3) GBM, (4) GBM + ZA, and (5) GBM + ZA + BMP-2. In vivo microcomputed tomography (micro-CT) images at 4 weeks showed significantly higher mineralized tissue volume (MV) in the intramedullary defect region and the neocortical/callus region in all GBM-Treated groups. After euthanization at 8 weeks, ex vivo micro-CT showed that addition of ZA (GBM + ZA) and BMP-2 (GBM + ZA + BMP-2) mainly increased the neocortical and callus formation, with the highest MV in the combined ZA and BMP-2-Treated group. Qualitative histological analysis, verifying the increased neocortical/callus thickness and finding of trabecular bone in all GBM-Treated groups, supported that the differences in MV measured with micro-CT in fact represented bone tissue. In conclusion, GBM can serve as a carrier for ZA and BMP-2 leading to increased MV in the neocortex and callus of a metaphyseal bone defect in rats.
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| 7. |
- Isaksson, Jenny, et al.
(författare)
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Comparison of species identification of endocarditis associated viridans streptococci using rnpB genotyping and 2 MALDI-TOF systems
- 2015
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Ingår i: Diagnostic Microbiology and Infectious Disease. - : Elsevier BV. - 0732-8893 .- 1879-0070. ; 81:4, s. 240-245
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus spp. are important causes of infective endocarditis but challenging in species identification. This study compared identification based on sequence determination of the rnpB gene with 2 systems of matrix-assisted laser desorption ionization-time of flight mass spectrometry, MALDI Biotyper (Bruker) and VITEK MS IVD (bioMerieux). Blood culture isolates of viridans streptococci from 63 patients with infective endocarditis were tested. The 3 methods showed full agreement for all 36 isolates identified in the Anginosus, Bovis, and Mutans groups or identified as Streptococcus cristatus, Streptococcus gordonii, or Streptococcus sanguinis. None of the methods could reliably identify the 23 isolates to the species level when designated as Streptococcus mitis, Streptococcus oralis, or Streptococcus tigurinus. In 7 isolates classified to the Mitis group, the rnpB sequences deviated strikingly from all reference sequences, and additional analysis of sodA and groEL genes indicated the occurrence of yet unidentified Streptococcus spp. (C) 2015 Elsevier Inc. All rights reserved.
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| 8. |
- Isaksson, Johan, et al.
(författare)
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Exploring possible association between D beta H genotype (C1021T), early onset of conduct disorder and psychopathic traits in juvenile delinquents
- 2016
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 266:8, s. 771-773
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Tidskriftsartikel (refereegranskat)abstract
- Early onset of conduct disorder (CD) with callous-unemotional traits has been linked to low levels of dopamine β-hydroxylase (DβH), an enzyme involved in dopamine turnover. The C1021T polymorphism in the DβH gene is a major quantitative-trait locus, regulating the level of DβH. In this study of juvenile delinquents from Northern Russia (n = 180), the polymorphism at -1021 was associated neither with early-onset CD nor with psychopathic traits. Association was found between psychopathic traits and early-onset CD, ADHD and mania.
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| 9. |
- Isaksson, Johan, et al.
(författare)
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Exploring possible association between DβH genotype (C1021T), early onset of conduct disorder and psychopathic traits in juvenile delinquents.
- 2016
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 266:8, s. 771-773
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Tidskriftsartikel (refereegranskat)abstract
- Early onset of conduct disorder (CD) with callous-unemotional traits has been linked to low levels of dopamine β-hydroxylase (DβH), an enzyme involved in dopamine turnover. The C1021T polymorphism in the DβH gene is a major quantitative-trait locus, regulating the level of DβH. In this study of juvenile delinquents from Northern Russia (n = 180), the polymorphism at -1021 was associated neither with early-onset CD nor with psychopathic traits. Association was found between psychopathic traits and early-onset CD, ADHD and mania.
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| 10. |
- Isaksson, Karolin, et al.
(författare)
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A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with Stage III Cutaneous Malignant Melanoma in Sweden.
- 2019
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Ingår i: Annals of surgical oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 26:9, s. 2839-2845
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous melanoma is steadily increasing worldwide. The new AJCC 8th edition was recently launched and introduced several changes in melanoma staging, particularly for stage III. We conducted a population-based registry study with the purpose to evaluate the impact and prognostic accuracy of the new classification in Sweden.Consecutive patients diagnosed with stage III melanoma between January 2005 and September 2017 were identified by the Swedish Melanoma Registry (SMR) and included for analyses. Patients with multiple primary melanomas were excluded. Patients were classified according to the AJCC 7th as well as the 8th edition. Melanoma-specific survival (MSS) was retrieved from the Swedish Cause of Death Registry.A total of 2067 eligible patients were identified from the SMR; 1150 patients (57%) changed stage III subgroup when reclassified according to the AJCC 8th edition. The median 5- and 10-year MSS for the whole cohort of stage III melanoma patients was 59% and 51% respectively. The MSS for substage IIIA, B, and C were all improved when patients were reclassified by using to the AJCC 8th edition. The newly defined substage IIID had the worst prognosis with a 10-year MSS of 16%.A high proportion of patients diagnosed with stage III melanoma in Sweden between 2005 and 2017 was restaged to another subgroup, when they were reclassified according to the AJCC 8th of staging manual. We established an improved MSS for all substages compared with the former AJCC 7th edition. This may have implications on decisions about adjuvant treatment.
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| 11. |
- Kok, Joeri, et al.
(författare)
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Fracture strength of the proximal femur injected with a calcium sulfate/hydroxyapatite bone substitute
- 2019
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Ingår i: Clinical Biomechanics. - : Elsevier BV. - 0268-0033. ; 63, s. 172-178
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Tidskriftsartikel (refereegranskat)abstract
- Background: Available interventions for preventing fragility hip fractures show limited efficacy. Injection of a biomaterial as bone substitute could increase the fracture strength of the hip. This study aimed to show the feasibility of injecting a calcium sulfate/hydroxyapatite based biomaterial in the femoral neck and to calculate the consequent change in strength using the finite element method. Methods: Five patients were injected with 10 ml calcium sulfate/hydroxyapatite in their femoral neck. Quantitative CT scans were taken before and after injection. Five additional patients with fragility hip fractures were also scanned and the images from the non-fractured contralateral sides were used. Finite element models were created for all proximal femora with and without injection and the models were tested under stance and sideways fall loading until fracture. The change in fracture strength caused by the injection was calculated. Additionally, perturbations in volume, location, and stiffness of the injected material were created to investigate their contribution to the fracture strength increase. Findings: The 10 ml injection succeeded in all patients. Baseline simulations showed theoretical fracture strength increases of 0–9%. Volume increase, change in location and increase in stiffness of the material led to increases in fracture strength of 1–27%, −8-26% and 0–17%, respectively. Altering the location of the injection to a more lateral position and increasing the stiffness of the material led to increases in fracture strength of up to 42%. Interpretation: This study shows that an injection of calcium sulfate/hydroxyapatite is feasible and can theoretically increase the hip's fracture strength.
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| 12. |
- Raaholt, Birgitta, et al.
(författare)
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Continuous tubular microwave heating of homogeneous foods: evaluation of heating uniformity
- 2016
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Ingår i: The Journal of microwave power and electromagnetic energy. - London : Taylor & Francis Group. - 0832-7823. ; 50:1, s. 43-65
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Tidskriftsartikel (refereegranskat)abstract
- A pilot-scale process for continuous in-flow microwave processing of foods, designed and implemented at SP Food and Bioscience, was evaluated for heat treatment of a homogeneous model food for high-temperature short-time (HTST) conditions, at constant total input microwave power, at 2450 MHz. The microwave system has three consecutive cavities, one excited by the TM020 microwave mode that heats primarily in the tube centre, and two TM120 mode cavities that heat primarily in the tube periphery. The temperature uniformity of the homogeneous model food after microwave heating is here evaluated in terms of spatial distribution, for different set-ups of input microwave power in each cavity and for different order of the placement of the cavities, while maintaining the total input microwave power. The microwave heating uniformity is evaluated, based on measured and calculated radial temperature profiles. Combined TM020 and TM120 heating was found to result in more uniform heating by means of spatial temperature uniformity over the tube cross section. Furthermore, appropriately selected microwave power distribution between the centre and periphery heating cavities results in a stable heating profile in the studied food, that differs only about 10 °C or less between highest and lowest average values directly after microwave heating.
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| 13. |
- Raaholt, Birgitta, et al.
(författare)
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Continuous tubular microwave heating of particulate foods at high temperatures
- 2017
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Ingår i: The Journal of microwave power and electromagnetic energy. - : Informa UK Limited. - 0832-7823. ; 51:4, s. 259-285
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Tidskriftsartikel (refereegranskat)abstract
- A pilot-scale process for continuous in-flow microwave processing of particulate pumpable foods, designed and implemented at RISE Agrifood and Bioscience, was evaluated for heat treatment of a particulate, viscous model food at high-temperature conditions at 2450 MHz. The microwave system has three consecutive cavities, one excited by the TM020 microwave mode that heats primarily in the centre of the tube, and two cavities fed by TM120 modes that heat primarily in the tube periphery. In this paper, combined TM020 and TM120 tubular microwave heating is evaluated as an alternative to high-temperature short-time (HTST) processing for a high-concentrated particulate model product. Rapidness in heating of the product was evaluated after tubular microwave heating for different time-temperature conditions, corresponding to the required microbiological inactivation for a model product intended for storage at ambient conditions. Moreover, the effects on product quality of the microwave heated model soup were investigated in terms of texture, piece integrity and colour. Microstructural analysis was used to gain an understanding of the effects of heating at a microscopic scale. It was found that the microwave-assisted HTST system results in large process flexibility. Additionally, it offers advantages in product quality in terms of piece integrity and texture.
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| 14. |
- Raina, Deepak Bushan, et al.
(författare)
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A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay early resorption. In-vitro, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. In-vivo bone formation was studied in an abdominal muscle pouch model in rats (n = 6/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4 ± 5.5 mm3) as compared to rhBMP-2 alone (10.9 ± 2.1 mm3) when analyzed using micro computed tomography (μ-CT) (p 0.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone.
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| 15. |
- Raina, Deepak Bushan, et al.
(författare)
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Biocomposite macroporous cryogels as potential carrier scaffolds for bone active agents augmenting bone regeneration
- 2016
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659. ; 235, s. 365-378
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Tidskriftsartikel (refereegranskat)abstract
- Osteoinduction can be enhanced by combining scaffolds with bone morphogenic protein-2 (BMP-2). However, BMP's are known to also cause bone resorption. This can be controlled using bisphosphonates like zoledronic acid (ZA). In this study, we produced two different scaffolds containing silk-fibroin, chitosan, agarose and hydroxyapatite (HA) with and without bioactive glass. The aims of the study were to fabricate, physico-chemically characterize and evaluate the carrier properties of the scaffolds for recombinant human BMP-2 (rhBMP-2) and ZA. Scaffolds were characterized using various methods to confirm their composition. During cell-material interactions, both scaffolds exhibited gradual but sustained proliferation of both C2C12 and MSCs for a period of 6 weeks with augmentative effects on their phenotype indicated by elevated levels of alkaline phosphatase (ALP) cuing towards osteogenic differentiation. In-vitro effects of rhBMP-2 and ZA contained within both the scaffolds was assessed on MC3T3 preosteoblast cells and the results show a significant increase in the ALP activity of the cells seeded on scaffolds with rhBMP-2. Further, the scaffold with both HA and bioactive glass was considered for the animal study. In-vitro, this scaffold released nearly 25% rhBMP-2 in 21-days and the addition of ZA did not affect the release. In the animal study, the scaffolds were combined with rhBMP-2 and ZA, rhBMP-2 or implanted alone in an ectopic muscle pouch model. Significantly higher bone formation was observed in the scaffold loaded with both rhBMP-2 and ZA as seen from micro-computed tomography, histomorphometry and energy dispersive X-ray spectroscopy.
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| 16. |
- Raina, Deepak Bushan, et al.
(författare)
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Biomodulation of an implant for enhanced bone-implant anchorage
- 2019
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Ingår i: Acta Biomaterialia. - : Elsevier. - 1742-7061 .- 1878-7568. ; 96, s. 619-630
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Tidskriftsartikel (refereegranskat)abstract
- Aseptic loosening of implants is the major cause for revision surgery. By modulating the bone-implant interface, early bone-implant anchorage could be improved. Implant surface manipulation by the addition of osteopromotive molecules locally and systemically to promote implant integration has been described with limited success. This study describes a novel approach by making the implant capable of biologically modulating its surroundings. It was hypothesized that the early implant fixation would improve by filling the interior of the implant with a carrier providing spatio-temporal release of bone active drugs with known osteogenic effect. The implant consisted of a threaded polyether ether ketone (PEEK) hollow chamber with holes at the bottom. The implant was filled with a calcium sulphate (CaS)/hydroxyapatite (HA) carrier, delivering two bone active molecules; zoledronic acid (ZA) and bone morphogenic protein-2 (BMP-2). At first, a rat abdominal muscle pouch model indicated a sustained in-vivo release of both I-125-rhBMP-2 (57%) and C-14-ZA (22%) from the CaS/HA carrier over a period of 4-weeks. The biomodulated implant was then inserted in the proximal tibia in rats with the following experimental groups: G1) Empty implant, G2) Implant + CaS/HA, G3) Implant + CaS/HA + ZA and G4) Implant + CaS/HA + ZA + rhBMP-2. Significantly higher bone volume (BV) was seen around the implant in groups G3 (3.3 +/- 0.7 mm(3)) and G4 (3.1 +/- 0.7 mm(3)) compared to the control (1.3 +/- 0.4 mm(3)) using micro-computed tomography and qualitative histology. Group G3, also exhibited significantly higher pull-out force and absorbed energy when compared to the control group G1. These findings indicate that a low dose of ZA alone, released in a controlled manner from within a fenestrated implant is enough to improve implant anchorage without the need of adding rhBMP-2. This simple method of using a fenestrated implant containing a ceramic carrier releasing bone active molecules improved bone anchorage and could clinically reduce prosthetic failure. Statement of Significance Aseptic loosening remains as a major cause for implant revisions and early reaction of surrounding bone to the prosthesis is important for longevity. A novel approach to enhance early bone-implant anchorage is presented. The implant is filled with a carrier providing controlled release of bone active molecules. In an animal model, a calcium sulphate (CaS)/hydroxyapatite (HA) carrier was used to provide a spatio-temporal release of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA). Significantly better bone-implant integration was achieved using ZA alone, thereby eliminating the need for adding BMP-2. The developed method of implant biomodulation holds potential to prevent implant loosening and is an alternative to prosthetic coatings or systemic drug treatment. Importantly, all constituents are approved for clinical use.
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| 17. |
- Raina, Deepak Bushan, et al.
(författare)
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Gelatin- hydroxyapatite- calcium sulphate based biomaterial for long term sustained delivery of bone morphogenic protein-2 and zoledronic acid for increased bone formation : In-vitro and in-vivo carrier properties
- 2018
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 272, s. 83-96
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a novel macroporous composite biomaterial consisting of gelatin-hydroxyapatite-calcium sulphate for delivery of bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) has been developed. The biomaterial scaffold has a porous structure and functionalization of the scaffold with rhBMP-2 induces osteogenic differentiation of MC3T3-e1 cells seen by a significant increase in biochemical and genetic markers of osteoblastic differentiation. In-vivo muscle pouch experiments showed higher mineralization using scaffold + rhBMP-2 when compared to an approved absorbable collagen sponge (ACS) + rhBMP-2 as verified by micro-CT. Co-delivery of rhBMP-2 + ZA via the novel scaffold enabled a reduction in the effective rhBMP-2 doses. The presence of tartrate resistant acid phosphatase staining in the rhBMP-2 group indicates osteoclastic resorption, which could be stalled by adding ZA, which by speculation could explain the net increase in mineralization. The new scaffold allowed for slow release of rhBMP-2 in-vitro (3.3 ± 0.1%) after 4 weeks. Using single photon emission computed tomography (SPECT), the release kinetics of 125I–rhBMP-2 in-vivo was followed for 4 weeks and a total of 65.3 ± 15.2% 125I–rhBMP-2 was released from the scaffolds. In-vitro 14C–ZA release curve shows an initial burst release on day 1 (8.8 ± 0.7%) followed by a slow release during the following 4 weeks (13 ± 0.1%). In-vivo, an initial release of 43.2 ± 7.6% of 14C–ZA was detected after 1 day, after which the scaffold retained the remaining ZA during 4-weeks. Taken together, our results show that the developed biomaterial is an efficient carrier for spatio-temporal delivery of rhBMP-2 and ZA leading to increased bone formation compared to commercially available carrier for rhBMP-2.
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| 18. |
- Raina, Deepak Bushan, et al.
(författare)
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Guided tissue engineering for healing of cancellous and cortical bone using a combination of biomaterial based scaffolding and local bone active molecule delivery
- 2019
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 188, s. 38-49
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Tidskriftsartikel (refereegranskat)abstract
- A metaphyseal bone defect due to infection, tumor or fracture leads to loss of cancellous and cortical bone. An animal model separating the cancellous and cortical healing was used with a combination of a macroporous gelatin-calcium sulphate-hydroxyapatite (Gel-CaS-HA) biomaterial as a cancellous defect filler, and a thin collagen membrane (CM) guiding cortical bone regeneration. The membrane was immobilized with bone morphogenic protein-2 (rhBMP-2) to enhance the osteoinductive properties. The Gel-CaS-HA cancellous defect filler contained both rhBMP-2 and a bisphosphonate, (zoledronate = ZA) to prevent premature callus resorption induced by the pro-osteoclast effect of rhBMP-2 alone. In the first part of the study, the CM delivering both rhBMP-2 and ZA was tested in a muscle pouch model in rats and the co-delivery of rhBMP-2 and ZA via the CM resulted in higher amounts of bone compared to rhBMP-2 alone. Secondly, an established tibia defect model in rats was used to study cortical and cancellous bone regeneration. The defect was left empty, filled with Gel-CaS-HA alone, Gel-CaS-HA immobilized with ZA or Gel-CaS-HA immobilized with rhBMP-2+ZA. Functionalization of the Gel-CaS-HA scaffold with bioactive molecules produced significantly more bone in the cancellous defect and its surroundings but cortical defect healing was delayed likely due to the protrusion of the Gel-CaS-HA into the cortical bone. To guide cortical regeneration, the cortical defect was sealed endosteally by a CM with or without rhBMP-2. Subsequently, the cancellous defect was filled with Gel-CaS-HA containing ZA and rhBMP-2+ZA. In the groups where the CM was doped with rhBMP-2, significantly higher number of cortices bridged. The approach to guide cancellous as well as cortical bone regeneration separately in a metaphyseal defect using two bioactive molecule immobilized biomaterials is promising and could improve the clinical care of patients with metaphyseal defects.
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| 19. |
- Raina, Deepak Bushan, et al.
(författare)
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Synthetic hydroxyapatite: a recruiting platform for biologically active molecules
- 2019
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose — Targeted delivery of drugs is important to achieve efficient local concentrations and reduce systemic side effects. We hypothesized that locally implanted synthetic hydroxyapatite (HA) particles can act as a recruiting moiety for systemically administered drugs, leading to targeted drug accretion. Methods — Synthetic HA particles were implanted ectopically in a muscle pouch in rats, and the binding of systemically circulating drugs such as zoledronic acid (ZA), tetracycline and 18F-fluoride (18F) was studied. The local biological effect was verified in an implant integration model in rats, wherein a hollow implant was filled with synthetic HA particles and the animals were given systemic ZA, 2-weeks post-implantation. The effect of HA particle size on drug binding and the possibility of reloading HA particles were also evaluated in the muscle pouch. Results — The systemically administered biomolecules (ZA, tetracycline and 18F) all sought the HA moiety placed in the muscle pouch. Statistically significant higher peri-implant bone volume and peak force were observed in the implant containing HA particles compared with the empty implant. After a single injection of ZA at 2 weeks, micro HA particles showed a tendency to accumulate more 14C-zoledronic acid (14C-ZA) than nano-HA particles in the muscle pouch. HA particles could be reloaded when ZA was given again at 4 weeks, showing increased 14C-ZA accretion by 73% in microparticles and 77% in nanoparticles. Interpretation — We describe a novel method of systemic drug loading resulting in targeted accretion in locally implanted particulate HA, thereby biologically activating the material.
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| 20. |
- Širka, Aurimas, et al.
(författare)
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Calcium Sulphate/Hydroxyapatite Carrier for Bone Formation in the Femoral Neck of Osteoporotic Rats
- 2018
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Ingår i: Tissue Engineering. Part A. - 1937-335X. ; 24:23-24
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated bone regeneration in the femoral neck canal of osteoporotic rats using a novel animal model. A calcium sulphate (CS)/hydroxyapatite (HA) carrier was used to deliver a bisphosphonate, zoledronic acid (ZA), locally, with or without added recombinant human bone morphogenic protein-2 (rhBMP-2). Twenty-eight-week-old ovariectomized Sprague-Dawley rats were used. A 1 mm diameter and 8 mm long defect was created in the femoral neck by drilling from the lateral cortex in the axis of the femoral neck, leaving the surrounding cortex intact. Three treatment groups and one control group were used: (1) CS/HA alone, (2) CS/HA + ZA (10 μg) (3) CS/HA + ZA (10 μg) + rhBMP-2 (4 μg), and (4) empty defect (control). The bone formation was assessed at 4 weeks post surgery using in vivo micro computed tomography (micro-CT). At 8 weeks post surgery, the animals were sacrificed, and both defect and contralateral femurs were subjected to micro-CT, mechanical testing, and histology. Micro-CT results showed that the combination of CS/HA with ZA or ZA + rhBMP-2 increased the bone formation in the defect when compared to the other groups and to the contralateral hips. Evidence of new dense bone formation in CS/HA + ZA and CS/HA + ZA + rhBMP-2 groups was seen histologically. Mechanical testing results showed no differences in the load to fracture between the treatments in either of the treated or contralateral legs. The CS/HA biomaterial can be used as a carrier for ZA and rhBMP-2 to regenerate bone in the femoral neck canal of osteoporotic rats.
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| 21. |
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| 22. |
- Teotia, Arun Kumar, et al.
(författare)
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Nano-Hydroxyapatite Bone Substitute Functionalized with Bone Active Molecules for Enhanced Cranial Bone Regeneration
- 2017
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 9:8, s. 6816-6828
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to synthesize and characterize a nano-hydroxyapatite (nHAP) and calcium sulfate bone substitute (NC) for cranioplasty. The NC was functionalized with low concentrations of bone morphogenetic protein-2 (BMP-2) and zoledronic acid (ZA) and characterized both in vitro and in vivo. In vitro studies included MTT, ALP assays, and fluorescent staining of Saos-2 (human osteoblasts) and MC3T3-E1 (murine preosteoblasts) cells cultured on NC. An in vivo study divided 20 male Wistar rats into four groups: control (defect only), NC, NC + ZA, and NC + ZA + rhBMP-2. The materials were implanted in an 8.5 mm critical size defect in the calvarium for 12 weeks. Micro-CT quantitative analysis was carried out in vivo at 8 weeks and ex vivo after 12 weeks. Mineralization was highest in the NC + ZA + rhBMP-2 group (13.0 ± 2.8 mm3) compared to the NC + ZA group (9.0 ± 3.2 mm3), NC group (6.4 ± 1.9 mm3), and control group (3.4 ± 1.0 mm3) after 12 weeks. Histological and spectroscopic analysis of the defect site provided a qualitative confirmation of neo-bone, which was in agreement with the micro-CT results. In conclusion, NC can be used as a carrier for bioactive molecules, and functionalization with rhBMP-2 and ZA in low doses enhances bone regeneration.
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| 23. |
- Wang, Jian Sheng, et al.
(författare)
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Tissue reaction and material biodegradation of a calcium sulfate/apatite biphasic bone substitute in rat muscle
- 2016
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Ingår i: Journal of Orthopaedic Translation. - : Elsevier BV. - 2214-031X. ; 6, s. 10-17
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Tidskriftsartikel (refereegranskat)abstract
- Background/Objective: A biphasic ceramic bone substitute consisting of calcium sulfate and hydroxyapatite has been reported to give good clinical outcome regarding bone regeneration and may serve as a carrier for antibiotics in the treatment of bone infections. Often, the overlying muscle is in direct contact with the synthetic graft. The dissolving bone substitute induces inflammation, which may be harmful to the surrounding soft and muscle tissue. The aim of the present study was to evaluate the surrounding soft tissue reaction and the biodegradation of the biphasic bone substitute. Materials and methods: Rods (3 mm × 6 mm) were cast and implanted in the rat abdominal rectus muscle. The rods were either soaked or not soaked in autologous bone marrow before insertion to induce bone formation. Thirty-two rats underwent bilateral operation. After 6 weeks and 12 weeks, the bone substitute material and the surrounding muscle were harvested. The right rod was evaluated by histology to study tissue reaction and the left rod was analysed with micro-computed tomography and scanning electron microscopy to study bone substitute degradation. Results: The muscle tissue around the material was similar at 6 weeks and 12 weeks, with or without prior treatment with bone marrow. The remaining material showed close contact with the muscle, and blood vessels penetrated the material in both groups. Wide bundles of collagen were embedded around the apatite particles, more at the 12-week time point. No bone formation was found, either at 6 weeks or 12 weeks, and scanning electron microscopy showed that the calcium sulfate phase was resorbed after 6 weeks with the calcium phosphate phase remaining intact. Micro-computed tomography showed significantly more hydroxyapatite at 6 weeks than after 12 weeks. Conclusion: Calcium sulfate hydroxyapatite bone substitute can be used as a carrier for antibiotics or other drugs, without adverse reaction due to the fast resorption of the calcium sulfate. No bone formation was seen despite treating the bone substitute with autologous bone marrow.
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