Mandibular Reconstruction Using Tissue Regeneration With Axially Vascularised Bone Substitutes

Background:

Mandibular reconstruction is necessary following tumour resections, infections or trauma resulting in severe defects of mandibular arch continuity and sacrifice of teeth. Basic reconstruction involves the use of non-vascularized bone grafts together with restoration of lost teeth by means of dental implants and implant-supported prostheses. Smaller bony defects (<6 cm) are commonly treated with nonvascularized corticocancellous grafts harvested from the anterior or posterior iliac crest. (Goh et al. 2008) For reconstructing larger and recurrent defects, currently the vascularized free flaps are regarded as the "gold standard". The use of these flaps, however, presents several major inconveniences. Harvesting of autologous tissue may result in a significant donor site morbidity, the extent of which may vary, according to the donor site and possibly according to the intervention technique. The problems include bleeding, pain, infections, donor site fractures and prolonged hospital stay. (Hartman et al. 2002; Rogers et al. 2003) The field of Regenerative Medicine promises new alternatives to surgical reconstruction through harnessing the regenerative capacity of the human body to repair itself. In the last few decades the rapid expansion of knowledge about the biological basis of wound healing and the role of cells, signals, and biological scaffolds has drawn the attention from ''tissue reconstruction'' to ''tissue regeneration''. New strategies started to emerge aiming at mimicking the normal healing process in regenerating lost or damaged tissues. The term "tissue engineering" was officially coined at a National Science Foundation workshop in 1988 to mean "the application of principles and methods of engineering and life sciences toward fundamental understanding of structure-function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore, maintain or improve tissue function".

Tissue engineering and Regenerative medicine depend on the presence of a biomaterial promoting cell growth and proliferation. In order to populate this biomaterial (scaffold) with new tissue, the body must effectively interact with this biomaterial. This necessitates the establishment of an early and reliable angiogenic response leading to the development of an adequate blood supply for the restoration of structure and function. (Hodde 2002) The three main components required for regeneration are the cells, scaffolds, and induction molecules. When growing tissues in vitro (Tissue Engineering), all three components should exist, however, when referring to Regenerative Medicine, any of these can be provided to the body in an attempt to optimize its capacity for regenerating its own tissues. Adding cells or growth factors to the biomaterials can reinforce tissue regeneration (Pellegrini et al. 2009), but the vascularization, and thus the integration, of theses biomaterials is still considered the determining issue in the success of any critical size defect regeneration. (Novosel et al. 2011) Applying principles of regenerative medicine in the field of cranio-maxillofacial reconstruction has now become a daily practice. The wide spectrum of applications ranges from simple addition of bioactive bone fillers to much more sophisticated techniques for bone replacement and reconstruction. The indications included reconstruction after minor developmental defects, trauma, infections, benign cysts or tumours but seldom following malignant tumour excision. (Clokie and Sandor 2008; Schuckert et al. 2009; Trautvetter et al. 2011) Warnke et al (Warnke et al. 2004), who used a completely different technique than those used in the previous case reports, reported the only case of regeneration after cancer ablation. The main technical difference was related to vascularization of the regenerated tissue. While all the reported cases for mandibular regeneration used the conventional extrinsic vascularization strategy, where the constructs were left to acquire a parasitic blood supply form the recipient site of implantation, Warnke et al (Warnke et al. 2004) used an axial vascularization strategy through a prelamination procedure in the Latissimus dorsi (LD) muscle followed by free tissue transfer of the regenerated mandible. Although this technique avoided bony donor site morbidities, the need to harvest the LD muscle represented a major drawback of this prelamination technique. This single case report highlighted the need for an efficiently vascularized construct if the regenerative therapy is to be applied for larger and recurrent defects.

Axial vascularization of scaffolds aims at providing the construct with blood supply through a defined and dedicated vascular axis. In this context, the blood supply of the construct is not randomly acquired from the implantation site, and thus the implantation in an area of low vascularization potential, as in irradiated or fibrosed surgical sites could be possible (Kneser et al. 2006). The two major techniques for axial vascularization are prelamination and prefabrication.

Prefabrication of a tissue construct is simply done by implanting an arterio-venous fistula or loop (AVL) or a vascular pedicle underneath or within the construct. This results in spontaneous sprouting of vessels from the loop or pedicle and subsequent revascularization of the whole tissue construct (Erol and Spira 1979; Guo and Pribaz 2009). Prelamination is another technique introduced by Pribaz and Fine (Pribaz and Fine 1994) in 1994 where the implantation of a construct into a vascularized territory (flap) is performed to create a customized vascularized unit. The end result of both techniques is an axially vascularized unit that depends for its nourishment upon a defined vascular axis.