Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

Ulrike Rottensteiner-Brandl,Lara F Lingens,Tobias Fey,Ulf Bertram,Andreas Arkudas,Katrin Köhn,Carolin Körner,Luitpold Distel,Raymund E Horch

doi:10.3390/cells10092256

Abstract

Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2.

Highlights

Large bone defects occur in several clinical situations, such as severe trauma, posttraumatic nonunion, tumor resection and osteomyelitis [1,2,3,4]
One unirradiated animal had developed severe respiratory distress two days after the critical-size femoral defect (CSFD) surgery, and two irradiated animals were euthanized during CSFD surgery due to breakage of the femur while handling
A hypertrophic proximal femoral stump was noted in four cases (5.4%; three unirradiated and one irradiated animal), whereas instability of the femur/construct axis was present in seven cases (9.9%; all irradiated animals)

Summary

Introduction

Large bone defects occur in several clinical situations, such as severe trauma, posttraumatic nonunion, tumor resection and osteomyelitis [1,2,3,4]. The current gold standard for treatment consists in filling the defect with autologous bone grafts [5], a method that carries two major drawbacks, namely the limited graft availability and the risk of donor site morbidity [6]. The use of allografts bypasses donor site morbidity if material from dead donors or from femoral heads at primary total hip replacements is used [5]. The transmission of diseases remains a matter of concern in allogenic transplantation [7]. The use of freeze-dried bone material allows for unlimited availability and sterilization by gamma irradiation, carrying the downside of non-vital material and limited osteogenic properties [7]. All allogenic transplants share the risk of inducing an immune reaction in the host [6]. Considering the potential drawbacks of all different therapeutic options, further research is highly needed to develop new treatment modalities

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Results

Conclusion