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Healing Processes in Cancellous Bone
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Most of what is known about the biological response during fracture healing comes from numerous animal studies with shaft fractures in the long bone. However, most patients suffer from fractures closer to the ends of the long bones, in the hip, or in the vertebrae. These types of fractures mainly involve cancellous bone, while shaft fractures concern cortical bone. Compared to cortical bone whose structure is dense and compact, cancellous bone is of spongy and porous structure. A growing number of studies point towards that cortical and cancellous bone heal differently. To even this imbalance in knowledge between these two types of bone tissue, further studies in cancellous bone are justified.

In this thesis we delved into the quiet unknown processes behind cancellous bone healing.

In the first study we characterized and compared two models for cancellous bone healing in mice and rats: the first model can be used to analyze the morphology and morphometry of the regenerating bone; the second model can measure the mechanical properties of cancellous bone. The two models correspond in their developing patterns during the first week before they diverge. This suggests that these models can be utilized together to evaluate the initial healing in cancellous bone. Furthermore, we saw in the drill hole model that the bone formation is strictly restricted to the traumatized region, with a distinct interface to the adjacent uninjured tissue.

The second study characterized the cellular response during the initial healing phase in cancellous bone. The focus was to follow the spatial location of inflammatory and osteogenic cells over time in a cancellous bone injury. In contrast to shaft fractures (cortical bone), where healing is described as sequential events where inflammatory cells are the first to arrive to the trauma before osteogenic cells are recruited and initiate healing, we could see how inflammatory and osteogenic cells appeared early, simultaneously after a cancellous bone injury. This study showed that cancellous bone differs from how fracture healing is normally described.

In the third study we explored the role of a subpopulation of lymphocytes (CD8 positive cells), earlier studied in shaft fractures. We wanted to see how their absence would affect the healing in a cancellous bone injury. Without CD8+ cells, cancellous bone healing was impaired as expressed via poorer mechanical properties of the regenerated bone tissue.

The fourth and last study issued the influence of uninjured bone marrow on cortical bone healing. We developed a cortical defect model which blocked uninjured marrow from reaching the defect. Without the presence of marrow, the cortical defects ability to regenerate was significantly impaired. This implies that the marrow is important for cortical bone healing.

In conclusion, cancellous bone healing is different from its cortical counterpart and the general perception of fracture healing. We have briefly discerned healing mechanisms in cancellous bone that might be of clinical importance: the restricted cancellous bone formation is something to take into consideration when performing arthrodeses; and importance of marrow in skeletal defects (e.g. pseudarthroses). With this thesis, we hope to promote that further investigating on cancellous bone healing is necessary.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. , p. 24
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1652
National Category
Orthopaedics Nursing Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:liu:diva-152349DOI: 10.3384/diss.diva-152349ISBN: 9789176851777 (print)OAI: oai:DiVA.org:liu-152349DiVA, id: diva2:1259347
Public defence
2018-12-06, Belladonna, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2018-10-30 Created: 2018-10-29 Last updated: 2019-09-30Bibliographically approved
List of papers
1. Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws
Open this publication in new window or tab >>Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws
2015 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 86, no 6, p. 745-750Article in journal (Refereed) Published
Abstract [en]

Background and purpose - Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods - Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results - The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation - The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123812 (URN)000365484500019 ()26200395 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2031-47-5]; AFA insurance company; EU [279239]; Linkoping University; Eli Lilly and Company

DOI does not work: 10.3109/17453674.2015.1075705

Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2018-10-29
2. Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury
Open this publication in new window or tab >>Osteoblast precursors and inflammatory cells arrive simultaneously to sites of a trabecular-bone injury
2018 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 4, p. 457-461Article in journal (Refereed) Published
Abstract [en]

Background and purpose - Fracture healing in the shaft is usually described as a sequence of events, starting with inflammation, which triggers mesenchymal tissue formation in successive steps. Most clinical fractures engage cancellous bone. We here describe fracture healing in cancellous bone, focusing on the timing of inflammatory and mesenchymal cell type appearance at the site of injury. Material and methods - Rats received a proximal tibial drill hole, A subgroup received clodronate-containing liposomes before or after surgery. The tibiae were analyzed with micro-CT and immunohistochemistry 1 to 7 days after injury. Results - Granulocytes (myeloperoxidase) appeared in moderate numbers within the hole at day 1 and then gradually disappeared. Macrophage expression (CD68) was seen on day 1, increased until day 3, and then decreased. Mesenchymal cells (vimentin) had already accumulated in the periphery of the hole on day 1. Mesenchymal cells dominated in the entire lesion on day 3, now producing extracellular matrix. A modest number of preosteoblasts (RUNX2) were seen on day 1 and peaked on day 4. Osteoid was seen on day 4 in the traumatized region, with a distinct border to the uninjured surrounding marrow. Clodronate liposomes given before the injury reduced the volume of bone formation at day 7, but no reduction in macrophage numbers could be detected. Interpretation - The typical sequence of events in shaft fractures was not seen. Mesenchymal cells appeared simultaneously with granulocyte and macrophage arrival. Clodronate liposomes, known to reduce macrophage numbers, seemed to be associated with the delineation of the volume of tissue to be replaced by bone.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Orthopaedics
Identifiers
urn:nbn:se:liu:diva-150316 (URN)10.1080/17453674.2018.1481682 (DOI)000439704100018 ()29865916 (PubMedID)
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2019-05-02
3. Marrow compartment contribution to cortical defect healing
Open this publication in new window or tab >>Marrow compartment contribution to cortical defect healing
Show others...
2018 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 89, no 1, p. 119-123Article in journal (Refereed) Published
Abstract [en]

Background and purpose - Healing of shaft fractures is commonly described as regards external callus. We wanted to clarify the role of the bone marrow compartment in the healing of stable shaft fractures. Patients and methods - A longitudinal furrow was milled along the longitudinal axis of the femoral shaft in mice. The exposed bone marrow under the furrow was scooped out. The mice were then randomized to no further treatment, or to receiving 2 silicone plugs in the medullary canal distal and proximal to the defect. The plugs isolated the remaining marrow from contact with the defect. Results were studied with histology and flow cytometry. Results - Without silicone plugs, the marrow defect was filled with new bone marrow-like tissue by day 5, and new bone was seen already on day 10. The new bone was seen only at the level of the cortical injury, where it seemed to form simultaneously in the entire region of the removed cortex. The new bone seemed not to invade the marrow compartment, and there was a sharp edge between new bone and marrow. The regenerated marrow was similar to uninjured marrow, but contained considerably more cells. In the specimens with plugs, the marrow compartment was either filled with loose scar tissue, or empty, and there was only minimal bone formation, mainly located around the edges of the cortical injury. Interpretation - Marrow regeneration in the defect seemed to be a prerequisite for normal cortical healing. Shaft fracture treatment should perhaps pay more attention to the local bone marrow.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Orthopaedics
Identifiers
urn:nbn:se:liu:diva-145120 (URN)10.1080/17453674.2017.1382280 (DOI)000423474000020 ()28946782 (PubMedID)
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2019-05-27

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