Bone regeneration for spinal fusion - translational studies and the pathway to the patient

D. Delawi

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

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Abstract

Aim of this thesis: The central aim of this thesis is to study the potential of several promising bone grafts substitutes in comparison to iliac crest autograft for spinal fusion. The emphasis will be on posterolateral fusion, since this is one of the most commonly performed techniques, but also one of the most challenging indications for bone grafts, due to the large distance that needs to bridged, limited contact surface and the unfavorable biomechanical environment. This thesis includes several preclinical and clinical studies including a randomized clinical trial. Outline: We started with critically investigating two assumptions that are generally made when discussing the use of autograft: 1) the morbidity of bone graft harvesting and 2) the relevance of viable cells within this graft. Although many severe and major complications are reported from harvesting bone from iliac crest, 6,7,11,12,62–64 the most common complication is enduring pain at the donor site. As mentioned before, the reported incidence of donor site pain varies between 6% to 39%. 10,12,13,15,17,18,63 The close proximity of the primary surgery to the iliac crest, however, could interfere with the reported incidence. In Chapter 2 the incidence of donor site pain was compared between patients who underwent fusion of different spinal levels to evaluate this effect and to determine the ‘true’ importance of donor site pain after posterior iliac crest bone harvesting. In Chapter 3 we investigate the relevance of viable osteogenic cells in autologous bone grafts. This is important as viable cells are a prominent difference between autologous bone graft and most conventional alternatives, which may be a reason for its superiority. On the other hand it is unlikely that these cells survive after transplantation. 65,66 The bone forming capacity between viable and devitalized autologous bone grafts was evaluated in a chamber model mounted on the transverse processes of a goat. In the continuing chapters several bone grafts or enhancers were compared to iliac crest autograft. In Chapter 4 the effect of adding platelet-leukocyte gel to three bone grafts (autologous bone graft, biphasic calcium phosphate and trabecular metal) was evaluated in the same transverse process cassette model that represents the initial phase of bone formation for spinal fusions. The next objective was to determine if a new putatively bioactive tricalcium phosphate was a suitable bone graft substitute for spinal fusions in a large animal model. It was compared to the currently most used grafts: iliac crest autograft and allograft. In Chapter 5 we present the results of an instrumented posterolateral fusion study in goats. The final part of this thesis focuses on bone morphogenetic proteins (BMPs). In Chapter 6 we describe how the sequential converging of the technologies of biochemistry, biomaterial science, imaging, and molecular biology finally resulted in the development of a new regenerative treatment (the use of BMPs) in orthopaedics. In contrast to the decades it took from the discovery of BMPs to becoming commercially available, these proteins are rapidly incorporated in the clinical routine with limited, if any, evidence for most indications. In this thesis, we conducted a European multi-center study comparing OP-1 (BMP-7) to iliac crest autograft in instrumented posterolateral fusions, which is one of the most applied indications of BMPs. We started with a pilot phase to obtain information on safety and feasibility of which the results are shown in Chapter 7. After this pilot, we continued the whole study that is presented in Chapter 8. During the course of this clinical study, the European Union adopted a new Clinical Trials Directive (2001/20/EC) as a framework for good management in trials of medicine. The goal of this directive was simplifying and harmonizing the administrative provisions governing clinical trials in EU countries. In Chapter 9, we discuss the practical consequences of this Clinical Trials Directive. Especially with respect to our situation during the conduction of a European multi-center study. We conclude this thesis with a general summery, which addresses the previously discussed items in Chapter 10, and finish with a general discussion and future perspectives in Chapter 11
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
Supervisors/Advisors
  • Dhert, W.J.A., Primary supervisor, External person
  • Oner, Cumhur, Supervisor
  • Kruijt, Moyo, Co-supervisor
Award date25 Sept 2013
Publisher
Print ISBNs978-90-393-1017-0
Publication statusPublished - 25 Sept 2013

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