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Bratengeier, Cornelia
Publications (2 of 2) Show all publications
Bratengeier, C. (2019). Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.

In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?

We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.

In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 47
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1696
National Category
Cell and Molecular Biology
urn:nbn:se:liu:diva-159776 (URN)10.3384/diss.diva-159776 (DOI)9789176850145 (ISBN)
Public defence
2019-09-24, Belladonna, Building 511, Campus US, Linköping, 13:00 (English)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-08-21Bibliographically approved
Fahlgren, A., Bratengeier, C., Gelmi, A., Semeins, C. M., Klein-Nulend, J., Jager, E. & Bakker, A. D. (2015). Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants. PLoS ONE, 10(7), Article ID e0134023.
Open this publication in new window or tab >>Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134023Article in journal (Refereed) Published
Abstract [en]

Polypyrrole (PPy) is a conducting polymer that enables controlled drug release upon electrical stimulation. We characterized the biocompatibility of PPy with human primary osteoblasts, and the effect of dopants. We investigated the biocompatibility of PPy comprising various dopants, i.e. p-toluene sulfonate (PPy-pTS), chondroitin sulfate (PPy-CS), or dodecylbenzenesulfonate (PPy-DBS), with human primary osteoblasts. PPy-DBS showed the roughest appearance of all surfaces tested, and its wettability was similar to the gold-coated control. The average number of attached cells was 45% higher on PPy-DBS than on PPyCS or PPy-pTS, although gene expression of the proliferation marker Ki-67 was similar in osteoblasts on all surfaces tested. Osteoblasts seeded on PPy-DBS or gold showed similar vinculin attachment points, vinculin area per cell area, actin filament structure, and Ferets diameter, while cells seeded on PPY-CS or PPY-pTS showed disturbed focal adhesions and were enlarged with disorganized actin filaments. Osteoblasts grown on PPy-DBS or gold showed enhanced alkaline phosphatase activity and osteocalcin gene expression, but reduced osteopontin gene expression compared to cells grown on PPy-pTS and PPy-CS. In conclusion, PPy doped with DBS showed excellent biocompatibility, which resulted in maintaining focal adhesions, cell morphology, cell number, alkaline phosphatase activity, and osteocalcin gene expression. Taken together, conducting polymers doped with DBS are well tolerated by osteoblasts. Our results could provide a basis for the development of novel orthopedic or dental implants with controlled release of antibiotics and pharmaceutics that fight infections or focally enhance bone formation in a tightly controlled manner.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Cell and Molecular Biology
urn:nbn:se:liu:diva-120873 (URN)10.1371/journal.pone.0134023 (DOI)000358837700051 ()26225862 (PubMedID)

Funding Agencies|VINNOVA [2012-04409]; Vetenskapradet [521-2013-2593]; Linkoping Initiative in Life Science Technologies (LIST)

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2018-10-11

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