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Larsson, Sune
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Publications (10 of 108) Show all publications
Hulsart Billström, G., Stelzl, C., Procter, P., Pujari-Palmer, M., Insley, G., Engqvist, H. & Larsson, S. (2020). In vivo safety assessment of a bio-inspired bone adhesive. Journal of materials science. Materials in medicine, 31(2), Article ID 24.
Open this publication in new window or tab >>In vivo safety assessment of a bio-inspired bone adhesive
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2020 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 31, no 2, article id 24Article in journal (Refereed) Published
Abstract [en]

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the alpha-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue. 

Place, publisher, year, edition, pages
SPRINGER, 2020
National Category
Medical Materials
Identifiers
urn:nbn:se:uu:diva-407133 (URN)10.1007/s10856-020-6362-3 (DOI)000511787900001 ()32036502 (PubMedID)
Funder
Swedish Research Council, RMA15-390 0110
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2020-03-20Bibliographically approved
Lind, T., Lejonklou, M. H., Dunder, L., Kushnir, M. M., Öhman-Mägi, C., Larsson, S., . . . Lind, P. M. (2019). Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only. Environmental Research, 177, Article ID 108584.
Open this publication in new window or tab >>Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 177, article id 108584Article in journal (Refereed) Published
Abstract [en]

Background: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size.

Objective: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development.

Methods: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 mu g/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 mu g/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination.

Results: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone man ow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timpl (in BPA50) were increased exclusively in female offspring.

Conclusions: Developmental BPA exposure at an environmentally relevant concentration resulted in female specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 mu g/kg BW/day, appeared to induce bone stiffness reduction, bone man ow fibrosis and chronic inflammation in female rat offspring later in life.

Keywords
Bisphenol A, Female offspring, P1NP, Fibrosis, Bone
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-394951 (URN)10.1016/j.envres.2019.108584 (DOI)000484645500056 ()31326715 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Procter, P., Pujari-Palmer, M., Hulsart Billström, G., Insley, G., Larsson, S. & Engqvist, H. (2018). A new ex-vivo murine model for evaluation of adhesiveness of a novel biomimetic bone glue. In: : . Paper presented at 34th Annual Meeting of Orthopaedic Trauma association, October 17 – 20, 2018, Kissimmee (Orlando), FL, USA.
Open this publication in new window or tab >>A new ex-vivo murine model for evaluation of adhesiveness of a novel biomimetic bone glue
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2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Keywords
Tissue adhesive, biomaterial, calcium phosphate
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-366372 (URN)
Conference
34th Annual Meeting of Orthopaedic Trauma association, October 17 – 20, 2018, Kissimmee (Orlando), FL, USA
Funder
Swedish Foundation for Strategic Research , RMA15-0110
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-03-06Bibliographically approved
Larsson, S. (2018). Clavicula fractures: considerations when plating. Injury, 49(suppl. 1), S24-S28
Open this publication in new window or tab >>Clavicula fractures: considerations when plating
2018 (English)In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 49, no suppl. 1, p. S24-S28Article in journal (Refereed) Published
Abstract [en]

The preferred treatment of clavicula midshaft fractures in adults has gone from being very conservative into surgery being frequently recommended. However, based on recent meta-analysis favorable outcome with internal fixation is not as consistent as previously reported. Probably due to a combination of indications for surgery becoming too wide and surgery being performed by a wider group of surgeons. When using plating for clavicula fractures there are several considerations to consider to improve outcome while reducing the risk for complications. Traditionally a horizontal approach along the clavicula is used as it provides good exposure. However, this incision is associated with a high risk for permanent anterior chest wall numbness that might be very disturbing for patients. A vertical incision can instead be used. Plates are traditionally placed in a superior position. An alternative can be an anterior-inferior position that allows better soft tissue coverage, less risk for hardware protrusion, longer screws can be used and the risk for damaging the underlying neurovascular bundle is reduced. Angle-stable screw-plate systems has not in a convincing way shown any benefit in clavicula fractures. In part because most patients have good bone quality where conventional screws will be sufficient.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
Keywords
Clavicula fractures, Internal fixation, Plate fixation, Complications, Adults
National Category
Orthopaedics Surgery
Identifiers
urn:nbn:se:uu:diva-360547 (URN)10.1016/S0020-1383(18)30298-5 (DOI)000437774800006 ()29929688 (PubMedID)
Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved
Christersson, A., Larsson, S. & Sandén, B. (2018). Clinical outcome after plaster cast fixation for 10 days versus 1 month in reduced distal radius fractures: A prospective randomized study. Scandinavian Journal of Surgery, 107(1), 82-90
Open this publication in new window or tab >>Clinical outcome after plaster cast fixation for 10 days versus 1 month in reduced distal radius fractures: A prospective randomized study
2018 (English)In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 107, no 1, p. 82-90Article in journal (Refereed) Published
Abstract [en]

Introduction: this study aimed to evaluate clinical results after plaster cast fixation for 10 days versus 1 month of moderately displaced and reduced distal radius fractures.Material and Methods: in a prospective randomized study, 109 patients with moderately displaced and conservatively treated distal radius fractures (age ≥50 years) were randomized 10 days after reduction to either removal of the plaster cast and immediate mobilization (active group) or to continued plaster cast fixation for another 3 weeks (control group). Grip strength, pincer strength, range of motion, and pain were assessed at 1, 4, and 12 months after reduction. Clinical outcome was evaluated using three functional assessment scores at 12 months.Results: treatment failed in 3/54 (6%) patients in the active group. one of these patients had the plaster cast reinstituted because of feelings of instability. the fractures in the other two patients displaced severely after mobilization and were therefore treated surgically. for the remaining 51 patients in the active group, the range of wrist motion was slightly better at 1 month compared with the controls, but there were no differences in grip or pincer strength or pain at the 1-month follow-up. there were no differences between the active and control group in any outcome at 4 or 12 months, including functional assessment scores at 12 months.Conclusion: treatment with mobilization 10 days after reduction of moderately displaced distal radius fractures resulted in a few treatment failures compared with none among controls. the only functional benefit for the remaining patients was a small and transient increase in range of motion at the 1-month follow-up. plaster cast removal 10 days after reduction in moderately displaced distal radius fractures is therefore not recommended.

National Category
Orthopaedics Surgery
Research subject
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-334618 (URN)10.1177/1457496917731184 (DOI)000429935400013 ()
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2018-07-18Bibliographically approved
Procter, P., Pujari-Palmer, M., Hulsart Billström, G., Larsson, S., Insley, G. & Engqvist, H. (2018). Designing A Commercial Biomaterial For A Specific Unmet Clinical Need –: An Adhesive Odyssey. In: : . Paper presented at 26th EORS Annual Meeting 25th – 28th September 2018, Galway, Ireland.
Open this publication in new window or tab >>Designing A Commercial Biomaterial For A Specific Unmet Clinical Need –: An Adhesive Odyssey
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2018 (English)Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

There are clinical situations in fracture repair, e.g. osteochondral fragments, where current implant hardware is insufficient. The proposition of an adhesive enabling fixation and healing has been considered but no successful candidate has emerged thus far. The many preclinical and few clinical attempts include fibrin glue, mussel adhesive and even “Kryptonite” (US bone void filler). The most promising recent attempts are based on phosphorylating amino acids, part of a common cellular adhesion mechanism linking mussels, caddis fly larvae, and mammals. Rapid high bond strength development in the wetted fatty environment of fractured bone, that is sustained during biological healing, is challenging to prove both safety and efficacy. Additionally, there are no “predicate” preclinical animal and human models which led the authors to develop novel evaluations for an adhesive candidate “OsStictm” based on calcium salts and amino acids. Adhesive formulations were evaluated in both soft (6/12 weeks) and hard tissue (3,7,10,14 & 42 days) safety studies in murine models. The feasibility of a novel adhesiveness test, initially proven in murine cadaver femoral bone, is being assessed in-vivo (3,7,10,14 & 42 days) in bilateral implantations with a standard tissue glue as the control. In parallel an ex-vivo human bone model using freshly harvested human donor bone is under development to underwrite the eventual clinical application of such an adhesive. This is part of a risk mitigation project bridging between laboratory biomaterial characterisation and a commercial biomaterial development where safety and effectiveness have to meet today´s new medical device requirements.

Keywords
Tissue adhesive, biomaterial, calcium phosphate
National Category
Medical Materials Composite Science and Engineering Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-366369 (URN)
Conference
26th EORS Annual Meeting 25th – 28th September 2018, Galway, Ireland
Funder
Swedish Foundation for Strategic Research , RMA15-0110
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-03-06Bibliographically approved
Lindahl, K., Astrom, E., Dragomir, A., Symoens, S., Coucke, P., Larsson, S., . . . Kindmark, A. (2018). Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy. Bone, 114, 268-277
Open this publication in new window or tab >>Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy
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2018 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 114, p. 268-277Article in journal (Refereed) Published
Abstract [en]

Background: Mutations of the endoplasmic reticulum (ER) stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS(-/-) mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected.

Methods: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by |mu CT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy.

Results: The proband, a boy with severe OI, had blue sclera and tooth agenesis A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%), however, collagen I levels were only reduced in hOBs (5-10%) Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to lifelong bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures.

Conclusions: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.

Keywords
Osteogenesis imperfecta, Recessive, Collagen type 1, Glycosaminoglycan, OASIS, CREB3L1
National Category
Orthopaedics Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-362634 (URN)10.1016/j.bone.2018.06.019 (DOI)000441369000029 ()29936144 (PubMedID)
Available from: 2018-10-09 Created: 2018-10-09 Last updated: 2019-04-02Bibliographically approved
Mei, X., Atturo, F., Wadin, K., Larsson, S., Agrawal, S., Ladak, H. M., . . . Rask-Andersen, H. (2018). Human inner ear blood supply revisited: the Uppsala collection of temporal bone - an international resource of education and collaboration. Upsala Journal of Medical Sciences, 123(3), 131-142
Open this publication in new window or tab >>Human inner ear blood supply revisited: the Uppsala collection of temporal bone - an international resource of education and collaboration
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 3, p. 131-142Article in journal (Refereed) Published
Abstract [en]

Background: The Uppsala collection of human temporal bones and molds is a unique resource for education and international research collaboration. Micro-computerized tomography (micro-CT) and synchrotron imaging are used to investigate the complex anatomy of the inner ear. Impaired microcirculation is etiologically linked to various inner ear disorders, and recent developments in inner ear surgery promote examination of the vascular system. Here, for the first time, we present three-dimensional (3D) data from investigations of the major vascular pathways and corresponding bone channels.

Methods: We used the archival Uppsala collection of temporal bones and molds consisting of 324 inner ear casts and 113 macerated temporal bones. Micro-CT was used to investigate vascular bone channels, and 26 fresh human temporal bones underwent synchrotron radiation phase contrast imaging (SR-PCI). Data were processed by volume-rendering software to create 3D reconstructions allowing orthogonal sectioning, cropping, and soft tissue analyses.

Results: Micro-CT with 3D rendering was superior in reproducing the anatomy of the vascular bone channels, while SR-PCI replicated soft tissues. Arterial bone channels were traced from scala vestibuli (SV) arterioles to the fundus, cochlea, and vestibular apparatus. Drainage routes along the aqueducts were examined.

Conclusion: Human inner ear vessels are difficult to study due to the adjoining hard bone. Micro-CT and SR-PCI with 3D reconstructions revealed large portions of the micro-vascular system in un-decalcified specimens. The results increase our understanding of the organization of the vascular system in humans and how altered microcirculation may relate to inner ear disorders. The findings may also have surgical implications.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
Keywords
Human, micro-computerized tomography, synchrotron phase contrast imaging, temporal bone, Uppsala collection
National Category
Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-368772 (URN)10.1080/03009734.2018.1492654 (DOI)000446977000001 ()30204028 (PubMedID)
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Hulsart Billström, G., Selvaraju, R., Estrada, S., Lubberink, M., Asplund, V., Bergman, K., . . . Antoni, G. (2018). Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept. Journal of Controlled Release, 285, 178-186
Open this publication in new window or tab >>Non-invasive tri-modal visualisation via PET/SPECT/μCT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: A proof of concept
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 285, p. 178-186Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic proteins (BMP's) are vital for bone and cartilage formation, where bone morphogenetic protein-2 (BMP-2) is acknowledged as a growth factor in osteoblast differentiation. However, uncontrolled delivery may result in adverse clinical effects. In this study we investigated the possibility for longitudinal and non-invasive monitoring of implanted [125I]BMP-2 retention and its relation to ossification at the site of implantation. A unilateral critically sized femoral defect was produced in the left limb of rats while the right femur was retained intact as a paired reference control. The defect was filled with a hyaluronan hydrogel with 25% hydroxyapatite alone (carrier control; n = 2) or combined with a mixture of [125I]BMP-2 (150 μg/ml; n = 4). Bone formation was monitored using micro computed tomography (μCT) scans at 1, 3, 5, 7, 9 and 12 weeks. The retention of [125I]BMP-2 was assessed with single photon emission computed tomography (SPECT), and the bone healing process was followed with sodium fluoride (Na18F) using positron emission tomography (PET) at day 3 and at week 2, 4, and 6. A rapid burst release of [125I]BMP-2 was detected via SPECT. This was followed by a progressive increase in uptake levels of [18F]fluoride depicted by PET imaging that was confirmed as bone formation via μCT. We propose that this functional, non-invasive imaging method allows tri-modal visualisation of the release of BMP-2 and the following in vivo response. We suggest that the potential of this novel technique could be considered for preclinical evaluation of novel smart materials on bone regeneration.

Keywords
Bone morphogenetic protein 2, Bone tissue engineering, Hydrogel, Micro computed tomography, Positron emission tomography, Single-photon emission computed tomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356465 (URN)10.1016/j.jconrel.2018.07.012 (DOI)000441737400015 ()30005906 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 262948
Note

G. Hulsart-Billström and R. K. Selvaraju contributed equally to this work and should be regarded as joint first authors.

Available from: 2018-07-28 Created: 2018-07-28 Last updated: 2018-10-10Bibliographically approved
Augat, P. & Larsson, S. (2018). Plating of fractures: current treatments and complications. Injury, 49, S1-S1
Open this publication in new window or tab >>Plating of fractures: current treatments and complications
2018 (English)In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 49, p. S1-S1Article in journal, Editorial material (Other academic) Published
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-365269 (URN)10.1016/S0020-1383(18)30293-6 (DOI)000437774800001 ()29929683 (PubMedID)
Available from: 2018-11-19 Created: 2018-11-19 Last updated: 2018-11-19Bibliographically approved
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