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Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing.

ABSTRACT: Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro human organotypic model of physiological loading of a cartilage callus, based on a novel perfused compression bioreactor (PCB) system. We then used the fracture callus model to investigate the regulatory role of dynamic mechanical loading. Our findings provide a proof-of-principle that dynamic mechanical loading applied by the PCB can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix. The PCB provides a promising tool to study fracture healing and for the in vitro assessment of alternative fracture treatments based on engineered tissue grafts or pharmaceutical compounds, allowing for the reduction of animal experiments.

SUBMITTER: Hoffmann W

PROVIDER: S-EPMC4313709 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing.

Hoffmann Waldemar W Feliciano Sandra S Martin Ivan I de Wild Michael M Wendt David D

Frontiers in bioengineering and biotechnology 20150202

Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro h ...[more]

PMID: 25699254

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Project description:BackgroundSclerostin is a secreted glycoprotein that inhibits the intracellular Wnt signaling pathway, which, when inactivated, stimulates bone formation. This has been seen in fracture studies, which have shown larger and stronger calluses with accelerated fracture healing in sclerostin knockout and sclerostin antibody injection models. However, the effects of these two mechanisms have not been compared in the context of fracture healing.Questions/purposesWe sought to determine the degree to which sclerostin inhibition (Scl-Ab injection) and complete sclerostin depletion inhibit fracture healing in a mouse model as evaluated by (1) morphometric trabecular bone measures at the fracture site, and (2) fracture site structural strength.MethodsTen-week-old male sclerostin knockout (n = 20) and wild type (n = 40) mice underwent insertion of a tibial intramedullary pin after which a midshaft tibial osteotomy was performed. The mice were divided in three groups: sclerostin knockout (n = 20), wild type with sclerostin antibody injection (intravenous dose of 100 mg/kg weekly) (n = 20), and wild type with saline injection (n = 20). The mice for each group where subdivided and euthanized at 14, 21, 28, and 35 days after surgery, at which time the fractured tibias were assessed with microCT (to assess morphometric trabecular bone measures: bone volume to total volume (BV/TV), trabecular thickness, trabecular number, and structural model index at the fracture site. Biomechanical testing in the form of three-point bending also was done to assess fracture site structural strength. A difference greater than 3.7% in our primary outcome (BV/TV) would be required to detect a difference between groups with a power of 80%, as per our power analysis.ResultsThe wild type with sclerostin antibody and the sclerostin knockout groups showed increased trabecular BV/TV at the fracture site compared with the wild type group with saline at all times, however no difference was seen between the treatment groups with the numbers available, except at 28 days postoperatively when the sclerostin knockout group showed greater BV/TV than the wild type sclerostin antibody group (47.0 ± 3.5 vs 40.1 ± 2.1; p < 0.05). On biomechanical testing the wild type sclerostin antibody showed increased stiffness at Days 14 and 28 compared with the wild type with saline group (70.9 ± 6.4 vs 14.8 ± 8.1; p = 0.001), (106.8 ± 24.3 vs 74.9 ± 16.0; p = 0.004); respectively. However, with the numbers available, no differences were detected between the wild type with sclerostin antibody and the sclerostin knockout groups in terms of whole-bone structural strength.ConclusionsSclerostin antibody injections showed promising results, which were not different with the numbers available, from results achieved with complete depletion of sclerostin, especially at earlier stages of the healing process, and therefore completed the healing process at an earlier time.Clinical relevanceSclerostin antibody injections appear to enhance fracture healing to a degree that is not different than complete sclerostin depletion, but larger animal studies are required to assess the accurate dosage and timing of administration in the fracture healing process to further evaluate its potential clinical utility to enhance fracture healing.

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Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing.

Publications

Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing.

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