A Preclinical Trial Protocol Using an Ovine Model to Assess Scaffold Implant Biomaterials for Repair of Critical-Sized Mandibular Defects.

The present work describes a preclinical trial (in silico, in vivo and in vitro) protocol to assess the biomechanical performance and osteogenic capability of 3D-printed polymeric scaffolds implants used to repair partial defects in a sheep mandible. The protocol spans multiple steps of the medical device development pipeline, including initial concept design of the scaffold implant, digital twin in silico finite element modeling, manufacturing of the device prototype, in vivo device implantation, and in vitro laboratory mechanical testing. First, a patient-specific one-body scaffold implant used for reconstructing a critical-sized defect along the lower border of the sheep mandible ramus was designed using on computed-tomographic (CT) imagery and computer-aided design software. Next, the biomechanical performance of the implant was predicted numerically by simulating physiological load conditions in a digital twin in silico finite element model of the sheep mandible. This allowed for possible redesigning of the implant prior to commencing in vivo experimentation. Then, two types of polymeric biomaterials were used to manufacture the mandibular scaffold implants: poly ether ether ketone (PEEK) and poly ether ketone (PEK) printed with fused deposition modeling (FDM) and selective laser sintering (SLS), respectively. Then, after being implanted for 13 weeks in vivo, the implant and surrounding bone tissue was harvested and microCT scanned to visualize and quantify neo-tissue formation in the porous space of the scaffold. Finally, the implant and local bone tissue was assessed by in vitro laboratory mechanical testing to quantify the osteointegration. The protocol consists of six component procedures: (i) scaffold design and finite element analysis to predict its biomechanical response, (ii) scaffold fabrication with FDM and SLS 3D printing, (iii) surface treatment of the scaffold with plasma immersion ion implantation (PIII) techniques, (iv) ovine mandibular implantation, (v) postoperative sheep recovery, euthanasia, and harvesting of the scaffold and surrounding host bone, microCT scanning, and (vi) in vitro laboratory mechanical tests of the harvested scaffolds. The results of microCT imagery and 3-point mechanical bend testing demonstrate that PIII-SLS-PEK is a promising biomaterial for the manufacturing of scaffold implants to enhance the bone-scaffold contact and bone ingrowth in porous scaffold implants. MicroCT images of the harvested implant and surrounding bone tissue showed encouraging new bone growth at the scaffold-bone interface and inside the porous network of the lattice structure of the SLS-PEK scaffolds.

Optimal placement of fixation system for scaffold-based mandibular reconstruction.

A current challenge in bone tissue engineering is to create favourable biomechanical conditions conducive to tissue regeneration for a scaffold implanted in a segmental defect. This is particularly the case immediately following surgical implantation when a firm mechanical union between the scaffold and host bone is yet to be established via osseointegration. For mandibular reconstruction of a large segmental defect, the position of the fixation system is shown here to have a profound effect on the mechanical stimulus (for tissue regeneration within the scaffold), structural strength, and structural stiffness of the tissue scaffold-host bone construct under physiological load. This research combines computer tomography (CT)-based finite element (FE) modelling with multiobjective optimisation to determine the optimal height and angle to place a titanium fixation plate on a reconstructed mandible so as to enhance tissue ingrowth, structural strength and structural stiffness of the scaffold-host bone construct. To this end, the respective design criteria for fixation plate placement are to: (i) maximise the volume of the tissue scaffold experiencing levels of mechanical stimulus sufficient to initiate bone apposition, (ii) minimise peak stress in the scaffold so that it remains intact with a diminished risk of failure and, (iii) minimise scaffold ridge displacement so that the reconstructed jawbone resists deformation under physiological load. First, a CT-based FE model of a reconstructed human mandible implanted with a bioceramic tissue scaffold is developed to visualise and quantify changes in the biomechanical responses as the fixation plate's height and/or angle are varied. The volume of the scaffold experiencing appositional mechanical stimulus is observed to increase with the height of the fixation plate. Also, as the principal load-transfer mechanism to the scaffold is via the fixation system, there is a significant ingress of appositional stimulus from the buccal side towards the centre of the scaffold, notably in the region bounded by the screws. Next, surrogate modelling is implemented to generate bivariate cubic polynomial functions of the three biomechanical responses with respect to the two design variables (height and angle). Finally, as the three design objectives are found to be competing, bi- and tri-objective particle swarm optimisation algorithms are invoked to determine the most optimal Pareto solution, which represents the best possible trade-off between the competing design objectives. It is recommended that consideration be given to placing the fixation system along the upper boundary of the mandible with a small clockwise rotation about its posterior end. The methodology developed here forms a useful decision aid for optimal surgical planning.