AO CMF Start-up Grants

There is a large number of cephalometric analyzes, based on the analysis of facial points or based on radiology analyzes. Nowadays new technologies allow us to catch and analyze patients’ faces (thanks to 3D photography) and to get simple access to head CT-scans. Under those circumstances, our cephalometric analyzes should evolve in order to adapt to these features.
There has already been attempts to create 3D cephalometric analyzes based on CT-scans, but none of them were based on a dedicated software. Therefore results were impossible to reproduce. We propose to create a 3D cephalometric analysis free software for research based on CT-scans DICOM files, easy to use and available for everyone.
Our first step after the creation of the software is to plan a comparative study between “classic” radiography analysis and 3D analysis, on a cohort of 100 to 150 patients with a point to point comparison, to show that the 3D analysis is theoriticaly at least as good as the classical radiographic one.
The advantages of this new technology would be a greater precision in cephalometric outline, and so in the analysis of the patient facial lines. By analyzing a 3D volume we also intend to answer some multi-dimensional questions about the chin position, mandibular asymmetry and other complex facial skull movements.

The aim of the proposed clinical study is to change the conventional CT-based 3D virtual planning workflow for CMF tumors by developing a method for MRI-based tumor resection as well as free flap reconstructive planning. In addition the MRI-based workflow is complemented with the quantification of vascular flow in both donor and recipient site, as well as the 3D visualization of perforators. Project description: Multiple types of MRI sequences will be studied for visualizing bone and vascularization. Several MRI- sequences are known to be suitable for segmenting bone for 3D planning, these will be explored within this project. Also MR-Angiogram with flow measurements will be selected for visualizing arteries and to quantify the arterial flow, thereby determining suitability for transplantation. A workflow for MRI-based 3D surgical planning with bone cutting guides will be developed using a four-step approach. Key MRI parameters are defined (phase 1), followed by an application of selected bone and Phase Contrast-MRI sequences on healthy volunteers (phase 2).The most suitable (bone and Phase Contrast) MRI sequences will be chosen for phase 3. These protocols are validated by applying them on patients (n=10) and comparison to corresponding patients CT data, which is the gold standard. The mean deviation values between the MRI- and the CT-based models are determined by 3D comparison analysis as a primary outcome measure.Already for validation of Black Bone sequences approval has been obtained from the local medicalethical board (file number M16.198347).
Phase 4 entails examination of the clinical value during surgery and in pre-op clinical decision making,using bone cutting guides (for mandible/maxilla and fibula) designed from MRI-based models, inpatients with oral cancer who will undergo surgical treatment with free flap reconstruction. Secondary outcome measures are 1) the deviation of the actual bone cutting planes in the CMF region as well asat the bone-free flap, compared to the 3D planning and 2) the fit of the guides to the bone surface. The final result of this project is aimed to be a complete MRI based 3D virtual planning workflow including resection of the tumor and free flap reconstruction planning.

Published articles

Optimisation of three-dimensional lower jaw resection margin planning using a novel Black Bone magnetic resonance imaging protocol.
PLoS One. 2018 Apr 20;13(4):e0196059. doi: 10.1371/journal.pone.0196059. eCollection 2018.

Facial trauma is a common occurrence worldwide which can lead to a plethora of functional, cosmetic, and emotional sequelae. Proper diagnosis of the direction, extent, and displacement of facial fractures by oral surgeons using the gold standard high-resolution CT scanning is imperative to improve patient outcomes and avoid unnecessary complications. Despite the importance of accurate diagnosis, oral surgery residents often receive a variable level of CT interpretation training from a senior resident or staff in an unstructured manner. To address this inconsistency in training, this project aims to create a standardized, scalable training module called CTRead for new residents in oral and maxillofacial surgery everywhere so that they can become competent and confident when interpreting scans and presenting them to their senior residents and staff. CTRead will be a web based training module which will take a student, resident, or even staff member through the reading of a CT Facial Bones scan one step at a time. Users will be shown normal CT scans, taught how to interpret anatomy, and then taught how to identify common fractures in facial trauma patients. To test the effectiveness of CTRead, participants’ confidence level and actual interpretation skill will be assessed via a mandatory short but comprehensive survey and marked CT interpretation quiz at the beginning and end of the training module. This will allow us to gather key information users’ confidence in interpreting CT scans, and their ability to accurately diagnose traumatic fractures as they progress through the module. It is hoped that completion of CTRead will lead to a significant increase in both confidence level and actual interpretation skill level of oral surgery residents when it comes to reading CT Facial Bones scans for trauma patients.

Published articles

Mascarenhas W, Richmond D, Chiasson G. CTRead-A Revolutionary Approach to Training Residents in Computed Tomography Facial Bone Interpretation.
J Oral Maxillofac Surg. 2019 Apr 23. pii: S0278-2391(19)30447-1. doi: 10.1016/j.joms.2019.04.016. [Epub ahead of print]

The treatment of large bone defects remains a major challenge for craniomaxillofacial (CMF) surgeons. Critical-sized bone defects are generally reconstructed with autologous bone grafts, but the procedure suffers from several disadvantages including limited tissue availability, donor-site morbidity and prolonged patient hospitalisation. This project aims to develop an effective strategy using mesenchymal stem cells (MSCs) enhanced by RNA therapy for the regeneration of large bone defects.

Cell therapy strategies using MSCs hold a great deal of promise for bone regeneration, but they have yet to become common clinical practice. A key factor contributing to this lack of progression is the inadequate vascularisation of MSC-based grafts, which can lead to necrosis of the constructs. There is increasing evidence that this challenge may be overcome by implanting chondrogenically-primed MSCs to induce endochondral ossification, the natural pathway of bone formation via a cartilage template. During this process, the MSC-derived cartilage induces the infiltration of blood vessels and remodelling into mature bone. Unfortunately, the chondrogenic priming of the cells requires extensive in vitro handling which severely hinders possible translation to the patient. In this project we will devise a new approach that will remove the need for prolonged in vitro pre-differentiation steps to induce MSC-mediated endochondral ossification in vivo. MSC commitment to the endochondral pathway will be achieved by blocking the activity of inhibitory non-coding RNAs (ncRNAs), regulatory molecules that can repress MSC differentiation. In the first phase of the project we will perform RNA-sequencing studies to unravel the changes in ncRNAs that occur in MSCs during the chondrogenic priming phase of endochondral ossification. This will lead us to identify key inhibitors of the process that can be targeted as molecular switches to trigger chondrogenesis and bone formation. Finally, we will establish a scaffold-based system to induce MSC-mediated endochondral ossification via delivery of anti-ncRNAs in situ, replacing the step of in vitro pre-differentiation. Ultimately, our study will provide proof-of-concept that blocking inhibitory ncRNAs in MSCs upon implantation removes the need for chondrogenic priming and leads to endochondral bone formation. This will bring tissue engineering strategies using MSCs and endochondral ossification closer to clinical application.

microRNA (miRNA) therapeutics have emerged as a promising strategy for a broad range of diseases, yet their use for craniomaxillofacial applications remains largely unexplored. Modulation of miRNA levels in Mesenchymal Stem/Stromal Cells (MSC) is a novel approach to enhance their pro-regenerative properties and accelerate bone repair. We and others have shown that modulation of miRNAs can induce osteogenic differentiation and neovascularization, two crucial mechanisms for bone repair and regeneration. Also, we showed that cell construct priming in vitro promotes better in vivo outcomes.

miR4CMF aims to explore miRNA-engineered MSCs to modulate extracellular matrix (ECM) properties into a pro-regenerative, pro-osteogenic and pro-angiogenic profile, as an innovative solution to repair craniomaxillofacial fractures and defects. Specifically, it will: i) develop a 3D in vitro culture of miRNA-engineered MSC and ii) characterize the MSC newly synthetized pro-regenerative ECM, which in combination with the miRNA-induced MSC will work as seeding centers for new bone formation; iii) perform an in vivo proof-of-concept for the synergistic impact of miRNA-engineered MSC and their ECM in new bone formation, using the calvarial bone defect model.

miR4CMF will respond to the following scientific questions:

1. Are miRNAs useful tools to promote the synthesis and deposition of a pro-osteogenic and a pro-angiogenic bone ECM?
2. Can miRNA-engineered MSC and their synthetized ECM act synergistically to repair craniomaxillofacial fractures and defects?

Using miRNA-based molecular engineering to promote an intracellular pro-osteogenic MSC profile, together with the synthesis of a pro-regenerative ECM, this project will offer a novel strategy to accelerate bone craniomaxillofacial regeneration. Importantly, this proposal opens a new line of investigation in the repair/regeneration of craniomaxillofacial fractures and defects.

Computer-aided technologies have revolutionized orthognathic surgery (OS) facilitating cephalometric analysis, surgical simulation, and the fabrication of splints and patient-specific implants. Despite the increasing body of evidence that these techniques are improving accuracy of surgical outcome, wide implementation is limited due to relatively high costs and the time-consuming and complex handling of the software. Alternatively, the application of navigation systems for OS could potentially speed up part of the process through bypassing the necessity of intraoperative surgical guides and splints. So far, navigation has been successfully used for various CMF surgical interventions such as mandibular reconstruction, bony contouring, and maxillary repositioning (2). However, the use of conventional navigation systems for surgery faces three challenges: the depth perception, the hand-eye coordination, and the continuous switch of focus between the navigation screen and the operation site.

Augmented reality (AR) helps in addressing these challenges. This technology brings 3D patient-specific data into the view of the surgeon. By using an AR device, drilling paths, and cutting planes are visualized at the right location, thus eliminating the need to look away from the surgical site. Additionally, AR headsets provide a stereoscopic view of the 3D model which makes it easy to understand the 3D shape of the targeted anatomy. We developed a new augmented reality navigation system with an integrated HoloLens 2 for surgical purposes, that allows an integration of an AR device with a conventional navigation system . The method does not require any adaption of the AR device, and uses a multi-modal marker for aligning the AR device with the navigation system’s coordinate system. The use of this system requires a thorough pre-clinical evaluation. Therefore, four surgeons will use the AR navigation system in a series of phantom trials. The phantoms consist of 3D printed mid-face regions of 20 patients where the drilling trajectories and the cutting planes on each phantom is planned preoperatively. Subsequently, the planning data is imported into the AR system using the HoloLens 2 which projects the 3D virtual models on top of the phantom models. The operators will perform the procedure assisted by the AR visualization, and the comparison between postoperative outcome and preoperative planning will determine the system’s performance.

Background:

 Augmented Reality (AR) is the projection of a computer created image onto the observer’s real environment. AR can allow the projection of medical images such as CT scans onto a patient during surgery. This additional information can help guide surgeons during the procedure, showing the surgeon where to place bone cuts, screws and prostheses. This will allow the surgeon to see patient’s anatomy beyond the surgical incision. Therefore surgery can be performed through a smaller cut. Currently, we use cutting guides on bones which act like stencils. In contrast to AR guides, cutting guides are physical objects. They take weeks to produce and are not re-usable.

Aim:

To compare the accuracy of AR guided bone cuts and cutting-guide guided bone cuts against pre-operative planning.

Method:

30 surgeons in total will be recruited and asked to produce a total of 18 cuts on 3D printed fibula models using a surgical saw and fissure burs. 6 cuts will be made using AR guidance, 6 using cutting guides (control group) and 6 using AR guidance to locate the cutting guide onto the model. The produced bone cuts will undergo CT scan and analysed digitally.

Results:

Dice-coefficient and Hausdorff analysis will be used to compare the cut bone models and the pre-operative planned models. This will allow comparison of the 3 experiment arms.

Conclusion:

If AR is shown to be within acceptable accuracy to guide bone cuts, this experimental model can be used in cadaver studies. AR guided surgery has the benefit of having a short turn-around, it can be modified intra-operatively by the surgeon. It is a much cheaper system and better environmental sustainability profile. This is because the AR Head Mounted Device is reusable.

The same technique can be subsequently applied to other areas of CMF surgery. In CMF trauma, the facial bones are often broken into many small pieces. AR projection of CT scan will allow all the bone fragments to be seen virtually without being fully exposed surgically. It will allow on-table visualisation of hard tissue, minimising surgical access and morbidity.

The current standard procedure to restore mandibular continuity defects involves free tissue transfer with an autologous composite bone flap. Even though success rates are high, several critical drawbacks have been associated with this procedure, including severe donor site morbidity, long hospital stay and recovery process, need for high surgical expertise, insufficient bone graft height, and mechanical failure of the plating system. A systematic approach for the designing and testing of patient-specific implants used as an alternative to the free flap procedure appears to be still lacking.

The goal of this project is to conduct a preliminary clinical study on the reconstruction of a lateral segmental defect following mandibulectomy using a 3D printed patient-specific titanium cage implant. Qualified patients will require reconstruction following segmental resection for a benign defect in the lateral mandible and have no indication for radiotherapy. In these cases, a normal viable and adequately vascularized soft tissue bed is expected. The reconstruction cage will be designed through a semi¬-automatic workflow for designing patient¬ specific mandibular reconstruction implants in the Materialise Mimics® and Materialise 3-Matic® software environment. Comparison of specific implant design variables (e.g. number of screws, screw position, and screw type) will be made prior to clinical application using topology optimization techniques. The biomechanical performance of the different implant designs will be evaluated through validated computational finite element analyses and experimental testing. The porous and cage-shaped design of the implant provides the possibility for the insertion of autografts harvested with minimal donor side morbidity, as well as the subsequent integration of dental implants. Post-operative monitoring using (CB)CT scan imaging following surgery will take place to quantify bone ingrowth and graft healing. Aesthetical and functional outcomes of the reconstructive procedure will be assessed using a patient-perceived quality of life questionnaire. A successful in-house study on the semi-automated implant designing, computational modeling and biomechanical testing of a patient-specific proof-of-concept implant highlights the potential of the proposed framework to yield more cost- and time-effective pre-surgical planning and result in implant designs that can minimize morbidity and maximize aesthetic and functional outcomes.

Bone periosteum is a natural scaffold and a source of regenerative cells and bioactive factors that promote osteogenesis. The areas in which the periosteal cells are subjected to mechanical loading co-localize with the greatest new bone deposition. The regenerative pathways during periosteal distraction osteogenesis (PDO) depend on the duration and magnitude of tensile stress. Our preliminary data indicate that the distraction alternated with relaxation, named “pumping of periosteum” (PP) results in enhanced osteogenic capacity of periosteum. While the histological features associated with PDO have been described, the underlying molecular mechanisms remain unknown. Our objective is to clarify the interaction between the periosteum and the underlying tissues in response to mechanical stimuli, by using a rat model of calvarial regeneration. In parallel, the same studies will be conducted using a mechanical loading bioreactor, a model that allows extension to controlled studies of human bone regeneration. To this end, we intend to: 1. Examine bone formation following PP protocol at different time points (Aim 1), and 2. Analyse the expression of bone-specific genes on the mRNA and protein levels (Aim 2). Following a latency period, the PP protocol alternating relaxation with activation will be systematically compared to the conventional PDO protocol. The amounts of (i) new tissue generated relative to the area confined by the parental bone, (ii) periosteum and (iii) distraction plate, will be determined histomorphometrically and by micro-CT. In both models, molecular differences between the two modes of periosteal elevation will be related to the alterations in the expression of tissue-specific proteins. We expect that the parameters of periosteal manipulation will induce expression of osteogenic differentiation markers and influence the nature and kinetics of bone formation in places that would otherwise never become bone. The osteogenesis and the subsequent early stage bone development shall involve a mechanism, which detects and responds to the level and duration of hydrodynamic shear forces. Consequently, we propose to elucidate the mechanobiological principles governing hard tissue formation during different modes of periosteal elevation. The outcomes of this work would impact our understanding of the role of periosteum in bone augmentation and ultimately, enable a paradigm shift in the field of regenerative medicine.  

Applicants: Benmahdjoub M / Wolvius E / Niessen W / Walsum van T

Abstract:
In the past decades, surgical navigation has shown to be of important assistance to surgeons. This technology allows the localization of instruments with respect to a preoperatively acquired image (e.g., CT, MRI). It also helps with visualizing preoperative planning to avoid critical structures or to reach a specific target during the operation. A crucial step to benefit from these advantages is image to patient registration. This procedure aligns the preoperative image with the real patient. Conventionally, it is a manual process where the surgeon uses a pointer to locate landmarks (anatomical/artificial) on the patient, that have also been annotated on the diagnostic preoperative image. The two sets of points, preoperatively annotated and intraoperatively pointed, are used to compute the alignment matrix [1]. Whereas more advanced approaches, such as scanning the patient skin surface, have been developed, the alignment remains a relatively elaborate part of using navigation. In addition, the use of conventional navigation systems (tracker and 2D screen), is hampered by the hand coordination difficulty, the lack of depth perception, and the switch of focus between the surgical area and the screens [2].

Augmented reality has been suggested in the literature as a potential solution to these issues and has been linked to many craniomaxillofacial surgeries [3].In augmented reality (AR) navigation, the AR device sensors may aid in automatic detection of landmarks, and thus it may also help in a more automated alignment of the patient to image in AR-based navigation.

The automated detection of artificial markers (such as sticked to patient) is an important step in facilitating this alignment, and if the AR system is linked to a conventional navigation system, it enables automation of the image to patient registration procedure. Such automated approaches may also permit continuous quality check of the patient-to-image alignment in navigation. Whereas deep learning-based methods likely are a suitable approach to such automated detection of markers, the training of models is hampered by the lack of real data (pictures of patients). It is our hypothesis that such models may also be trainable by synthetic images, generated from photo-realistic rendering engines. Demonstrating that this indeed is possible opens the way for novel AI approaches in surgery, where real patient data for training is lacking.

Therefore, in a first step, we will generate photo-realistic synthetic data, and investigate its use for landmark detection on real images. In a second step, we want to investigate the usability of the trained models for image to patient registration in an augmented reality navigation context.

Applicants: Aello F / Koudstaal M / Helms J

Abstract:
In patients born with cleft lip and palate (CL/P), surgical repairs are typically undertaken in the first years of life. This approach is guided by clinical data demonstrating that early closure of the lip and soft palate improves feeding and speech development 1,2. There is, however, no consensus on the optimal timing for closure of the hard palate because, in this anatomical location, early surgical repair is associated with a subsequent arrest in midfacial growth 3-7. This growth arrest is directly attributable to the surgical intervention since children who undergo similar repairs after their fifth birthday rarely exhibit midfacial growth truncations 3-7. If we understood exactly what aspects of the surgery led to craniomaxillofacial (CMF) growth arrest in younger patients, then we would be in a better position to develop new techniques and strategies that significantly improved overall functional outcomes 8.

Currently, there is a limited understanding of why hard palate repair procedures cause surgically-induced midfacial growth arrest. It has been speculated that general disruptions at the vomero-premaxillary and transverse palatal sutures, scarring in soft tissues, and/or resorption/remodeling of hard tissues are contributing factors 9-11 but at present, these data are insufficient to guide surgical improvements. The purpose of our proposal is to use a validated animal model, coupled with a surgical intervention that mimics hard palate repair and reliably produces midfacial growth arrest, to pinpoint those soft and hard tissue responses that specifically contribute to midfacial growth arrest. With that information in hand, we then propose to test whether modified surgical approaches can minimize growth disturbances and yield better overall outcomes for CLP patients.

Applicants: Hofmann E / Neckel N / Kreutzer K / Koerdt S

Abstract:
The project is designed as a pilot study to demonstrate the clinical feasibility of a modified pull-through approach for the resection of head and neck malignancies, which are localized at the posterior third of the oral cavity and the oropharynx. Current surgical techniques, such as the mandibular lip-split approach and the pull through approach with a lingual release, are associated with morbidities, including difficulties in swallowing and speech. The motivation of this study was to introduce a modified pull-through approach to reduce postoperative morbidities and improve patient’s quality of life.
The modified pull-through technique uses individualized CAD/CAM-designed cutting guides to facilitate a v-shaped, self-retentive osteotomy to maintain the attachment of the geniohyoid und genioglossus muscles. By maintaining the physiological attachment of these muscles, that are considered essential for swallowing and speech, postoperative function will be improved. The v-shaped osteotomy eliminates the need for osteosynthesis to re-fixate the bony segment in contrast to the mandible lip-split approach. Our research group was able to show the feasibility of the modified pull-through technique and the anatomic foundation for its clinical use in a cadaver study.

The aim of this pilot study is to demonstrate the clinical application of the described modified pull-through approach. We hypothesize that the improved postoperative function with regard to speech and swallowing benefits patients and improves their quality of life. By eliminating the need for osteosynthesis material to restore bone continuity, postoperative complications can be reduced.

Applicants: Mirzaali M / Shahriari N / Jonker B

Abstract:
The mandible is the largest bone in the human skull and acts an important role in the body, however, its health and functionality can be affected by diseases such as bone infections, neoplasms, and trauma. These defects can severely cause facial deformity, loss of speech, and reduced masticatory function if left untreated. To restore the functional and esthetical role of the mandible, it is essential to perform reconstructive surgery. The currently involved techniques for mandibular reconstruction comprise the use of traditional vascularized combined soft and bony tissue flaps which encompass several drawbacks such as the limitation in the amount of available bone, increased risk for surgical revisions, and prolonged recovery processes. Therefore, it reveals the importance of developing mandibular implants with (bio)functional properties as well as adjusted shape within which those advanced mandibular implants can provide a faster tissue integration without increasing the risk of implant-associated infections.

Here, we propose an innovative design and manufacturing process for the development of multi-functional patient-specific mandibular implants. In order to promote better cell-implant integration, we propose surface-based lattice patterns in the functionally graded porous structure of the mandibular implants. This will allow us to not only mimic the mechanical and morphological properties of the natural bone but also to increase the contact area between the implant and the remaining bone, thus improving the integration of the implant with the undamaged tissue. In addition, we will develop a localized and spatiotemporal functionalized surface coating using a combination of advance manufacturing processes (i.e., additive manufacturing, AM) and atomic layer deposition (ALD) techniques. Such a combination will enable us to coat the surface of the additively manufactured porous implant and provide on-demand bio-functionality (i.e., revealing anti-bacterial properties over time).
In this project first, the innovative design workflow will be developed. Then, a selective laser melting (SLM) machine will be used to manufacture the developed design with different groups of Ti-6Al-4V powders and antibacterial materials will be deposited on their surface by ALD technique. The outputs of this proposal will go beyond the state-of-the-art and will propose next-generation mandibular implants with multiple bio-functionality necessary for craniomaxillofacial surgeries.

Applicants: Mangione F / Vital S / Salmon B / Bardet C / Jacobs R

Abstract:
INTRODUCTION:
In the oro-facial region, tissue engineering is required to recreate an adequate bone volume for implantology rehabilitation purposes either to treat bone defects resulting from traumas, malformations, or neoplasia.

The assessment of angiogenesis is of primary importance for jawbone tissue engineering since blood vessel formation is crucial for bone regeneration.

In preclinical large animal models of jawbone regeneration, non-destructive and non-invasive methods for the evaluation of tissue regeneration are required, according to 3Rs principles (Replacement, Reduction and Refinement). Cone beam computed tomography (CBCT) angiography can be interestingly implied for characterization of angiogenesis during bone regeneration.

The aim of this study is to validate an innovative method of blood supply morphometric analysis using an adapted CBCT subtraction angiography technique in a porcine model of jawbone regeneration.

MATERIALS AND METHODS:
This study is designed in conformity to the ARRIVE guidelines and approved by the Ethics Committee for animal experiments of French Ministry of Research (APAFIS#12534-2017121118586862). 2 eleven-months-old Yucatan minipigs will be used. A buccal wall bone defect will be surgically created in the premolar-molar area in each hemimandible. Angiogenic process will be monitored during 90 days by CBCT angiographies. Images will be acquired by C-arm CBCT.

Scanned volumes will be imported into MeVisLab (MeVis Research). Vascular net of the region of the defect will be segmented after the subtraction of mineralized tissues.
Segmented blood supply will be quali-quantified by morphometric analysis. Considered parameters will be: number of edges, number of nodes, radius of the edges, length of the edges and number of edges per node.

Histology and immunohistochemistry highlighting angiogenesis (CD31, a-SMA) will be performed and blood vessels will be quali-quantified. Data from histology and imaging morphometric analysis will be statistically compared by Bland-Altman analysis.

CLINICAL RELEVANCE:
CBCT subtraction angiography for angiogenesis assessment in large preclinical models could substantially contribute to the validation of jawbone regeneration procedures. Since the technique allows to perform longitudinal non-destructive follow-up of vascularization, it could be interestingly employed in other pre-clinical studies of dento-maxillo-facial tissue engineering procedures as well as in pathological models such as BRONJ ones.