Congenital Mandibular Hypoplasia: Patient-Specific Total Joint Replacement as a Line Extension in the Treatment of Complex Craniofacial Anomalies.

Introduction: Congenital mandibular hypoplasia (CMH) remains challenging because of the underlying combined hard and soft tissue deficiency. Treatment options include craniofacial distraction, orthognathic surgery, and autologous grafts, although the latter produces inadequate results after distraction and autologous grafting. Unsatisfactory long-term stability may cause relapse, necessitating reoperation. Material and Methods: We investigated the feasibility of using alloplastic total joint replacement (TJR) in growing and young adult CMH patients. The primary outcome was long-term reconstruction stability, without implant failure. Secondary outcomes were TMJ function and pain, and jaw movements achieved during surgery. Results: Three patients (age: 9-22 years) were treated by the same surgeon at one institution during 2018-2021. Anamnesis and clinical parameters were obtained from patient records. Preoperative 3D-scans were superimposed with postoperative 3D-scans and preoperative plans, including TJR-implant STL files, to measure jaw movement. All patients underwent prior reconstructive surgery. Mandibular movement of 16.4-20.1 mm in the sagittal direction was achieved. Post-TJR follow-up ranged from 24 to 42 months. No long-term complications occurred. At the latest follow-up, the maximal interincisal opening was between 21 and 40 mm, and all implants were functioning, without failure. Conclusion: In selected CMH cases, alloplastic TJR can deliver satisfactory medium-term results with predictable and stable outcomes, even in growing patients.

No Significant Bone Resorption after Open Treatment of Mandibular Condylar Head Fractures in the Medium-Term.

Open treatment of condylar head fractures (CHF) is considered controversial. In this retrospective cohort study our primary objective was therefore to assess bone resorption and remodeling as well as patients function after open treatment of CHF in a medium-term follow-up (15.1 ± 2.2 months). We included 18 patients with 25 CHF who underwent open reduction and internal fixation, between 2016 and 2021, in our analysis. The clinical data and cone-beam computed tomography (CBCT) datasets were analyzed. The condylar processes were segmented in the postoperative (T1) and follow-up (T2) CBCT scans. Volumetric and linear bone changes were the primary outcome variables, measured by using a sophisticated 3D-algorithm. The mean condylar head volume decreased non-significantly from 3022.01 ± 825.77 mm3 (T1) to 2878.8 ± 735.60 mm3 (T2; p = 0.52). Morphological alterations indicated remodeling and resorption. The pre-operative maximal interincisal opening (MIO) was 19.75 ± 3.07 mm and significantly improved to 40.47 ± 1.7 mm during follow-up (p = 0.0005). Low rates of postoperative complications were observed. Open reduction of CHF leads to good clinical outcomes and low rates of medium-term complications. This study underlines the feasibility and importance of open treatment of CHF and may help to spread its acceptance as the preferred treatment option.

Referencing for intraoperative navigation: Evaluation of human bias.

Navigation-assisted surgery is the gold standard for complex reconstructive procedures of the midface and facial skeleton, and artificial and anatomical landmarks are often used for reference. The correct identification of these landmarks before surgery is crucial for the accuracy of the navigation system. This study aimed to investigate the human errors in reference point placement. This retrospective study investigated 228 reference-point positions in 51 cases where navigation was utilized. The discrepancies between the actual reference point-position and manually planned preoperative reference points were quantified using Brainlab iPlanCMF 3.0.6. The referencing methods used in these cases included dental registration splints, osteosynthesis materials, anatomical landmarks, and combinations of these methods. The average discrepancy in the actual and manually planned reference points was 0.29 ± 0.41 mm. The use of anatomical landmarks demonstrated a significantly lower deviation (p < 0.05), although the differences between the errors in reference-point placement using dental registration splints, osteosynthesis materials, or combinations of these methods were not statistically significant. The frequency of misplacement of reference points was significantly higher than expected. These errors might have been caused by human bias during manual placement of the points or intraoperative difficulties caused by extensive metal artifacts. Thus, we postulate that the surgical personnel involved in planning navigation-assisted surgery should undergo intensive training. The development of new referencing methods that are less susceptible to these causes of error might help overcome human bias.

Accuracy of Guided Surgery and Real-Time Navigation in Temporomandibular Joint Replacement Surgery.

BACKGROUND: Sophisticated guided surgery has not been implemented into total joint replacement-surgery (TJR) of the temporomandibular joint (TMJ) so far. Design and in-house manufacturing of a new advanced drilling guide with vector and length control for a typical TJR fossa component are described in this in vitro study, and its accuracy/utilization was evaluated and compared with those of intraoperative real-time navigation and already available standard drilling guides. METHODS: Skull base segmentations of five CT-datasets from different patients were used to design drilling guides with vector and length control according to virtual surgical planning (VSP) for the TJR of the TMJ. Stereolithographic models of the skull bases were printed three times for each case. Three groups were formed to compare our newly designed advanced drilling guide with a standard drilling guide and drill-tracking by real-time navigation. The deviation of screw head position, screw length and vector in the lateral skull base have been evaluated (n = 72). RESULTS: There was no difference in the screw head position between all three groups. The deviation of vector and length was significantly lower with the use of the advanced drilling guide compared with standard guide and navigation. However, no benefit in terms of accuracy on the lateral skull base by the use of real-time navigation could be observed. CONCLUSION: Since guided surgery is standard in implant dentistry and other CMF reconstructions, this new approach can be introduced into clinical practice soon, in order to increase accuracy and patient safety.

CAD/CAM-based referencing aids to reduce preoperative radiation exposure for intraoperative navigation.

BACKGROUND: All intraoperative navigation systems need a referencing procedure prior to utilization, usually requiring an additional computed tomography (CT) or cone beam computed tomograph (CBCT) scan. As new techniques in the field of Computer-aided design / Computer-aided manufacturing (CAD/CAM) have evolved, it seemed favourable to develop a new referencing method not relying on additional CT or CBCT scans. METHODS: A digital maxillary dental scan was used to create a referencing splint by CAD/CAM containing four reference points. By matching scanned dental model and initial trauma-CT, the splints position and thus the reference points were digitally simulated. These splints data were imported into the navigation system in Standard Tessellation Language (STL) format. These data were also 3D printed and the resulting piece was placed on the anatomical models' teeth. The methods accuracy was then assessed in vitro. CONCLUSION: Our method for referencing of intraoperative navigation can be feasible to avoid an additional CT or CBCT prior to navigation.

Self-centering second-generation patient-specific functionalized implants for deep orbital reconstruction.

Deep and complete reconstruction of the orbital cavity has been shown to be essential for preventing enophthalmos and hypoglobus in patients with orbital defects or deformities. Additively manufactured patient-specific titanium implants provide unlimited options in design. However, implant malpositioning can still occur, even when intraoperative imaging and navigation are used. In this study, we investigated novel orbital implants containing features facilitating self-centering. Accuracy of implant placement and reconstruction of the orbital dimensions were compared retrospectively between self-centering second-generation patient-specific functionalized orbital implants (study group) and CAD-based individualized implants (control group). Design features of implants in the study group included functionalization with navigation tracks, a preventive design, and flanges - so called stabilizers - towards opposite orbital walls. Implant position was evaluated by fusion of preoperative virtual plans and the post-therapeutic imaging. Aberrances were quantified by 3D heatmap analysis. 31 patients were assigned to the study group and 50 to the control group, respectively. In the study group, most implants were designed with either one (n = 18, 58.06%) or two (n = 10, 32.26%) stabilizers. Twice (6.45%), one stabilizer had to be shortened intraoperatively. Implant fit analysis revealed a significantly more precise (p < 0.001) positioning in the study group (n = 22/31) than in the control group (n = 42/50). Self-centering second-generation patient-specific functionalized orbital implants showed significantly more accurate implant positioning, facilitating the transformation of virtual plans into patient's anatomy. The presented design provides an additional instrument for intraoperative quality control besides intraoperative imaging and navigation.

Accurate and cost-effective mandibular biomodels: a standardized evaluation of 3D-Printing via fused layer deposition modeling on soluble support structures.

INTRODUCTION: Medical biomodels can be used for illustration of medical conditions, preoperative planning or to facilitate pre-bending of osteosynthesis material. They have been shown to be an effective and efficient method to reduce operating time, blood loss and wound stress in cranio-maxillo-facial surgery. Lately, new time and cost-efficient 3D-printing methods have been introduced into the mass-market. The aim of this study was to establish a standardized method of evaluation and consequently evaluate Fused Layer Deposition Modeling in combination with soluble support structures for fabrication of medical biomodels regarding precision and cost-effectiveness. MATERIALS & METHODS: Twenty-one biomodels of human mandibles equipped with measuring appliances were printed on a FLDM 3D-printers (Ultimaker 3 Extended) using a polyactate filament and a water-soluble Polyvinyl alcohol-based support structures. Precision of these models was compared to commercial, polyamide sintered models and the planning data. Production costs, printing times and post processing procedures were evaluated. RESULTS: Duration of printing of mandibular biomodels was between 6 h 5 min - 15 h 9 min (mean 9 h 12 min, ±2 h 25 min). The average cost of materials was €5.90 (± €1.28) per model. With an average aberrance of 0.29 mm, FLDM printing delivered a high level of accuracy. It was significantly superior to the polyamide reference models in the area of the semilunar incision, yet inferior at the coronoid process. CONCLUSION: FLDM printers are able to provide very precise biomodels at very low costs. The use of using soluble support structures reduces time, costs and equipment needed for post processing procedures close to zero.

CD44(+) tumor cells promote early angiogenesis in head and neck squamous cell carcinoma.

The role of CD44 in progression of head and neck squamous cell carcinoma (HNSCC) has been controversial. The goal of this study was to study the effects of CD44(+) tumor cells on the initial stages of tumor angiogenesis and to evaluate CD44 as a potential marker of tumor angiogenesis. The CD44 gene expression was studied using the Cancer Genome Atlas (TCGA) Head and Neck Cancer data base. Expression levels of CD44 and of microvascular density (MVD) markers were assessed by immunohistochemistry performed with tissue microarrays in a cohort of 49 HNSCC patients, 11 patients with dysplasia and 12 control oral mucosa tissues. The 4-nitroquinoline-1-oxide oral carcinogenesis mouse model was used to study CD44 expression during carcinogenesis. Gelatin sponges seeded with CD44(+), CD44(-) and unsorted cancer cells suspended in Matrigel were implanted in NOD/SCID mice into a dorsal skinfold chamber and compared to non-seeded sponges as controls. Angiogenic response was assessed by intravital microscopy. In the TCGA analysis, CD44 gene expression correlated with various pro-angiogenic genes. In human HNSCC tissues, CD44 expression was upregulated and was associated with blood vessels, although no correlation between MVD and CD44 expression was found. During oral carcinogenesis CD44 expression was upregulated. In dorsal skinfold chambers, CD44(+) cells showed a significantly higher MVD than CD44(-) or unsorted cells (p < 0.001). The results indicate that CD44(+) cells contain pro-angiogenic factors and stimulate tumor angiogenesis in HNSCC. Thus, CD44 might emerge as a potential angiogenic biomarker and a therapeutic target for anti-angiogenic therapies.

Is there more to the clinical outcome in posttraumatic reconstruction of the inferior and medial orbital walls than accuracy of implant placement and implant surface contouring? A prospective multicenter study to identify predictors of clinical outcome.

PURPOSE: Reconstruction of orbital wall fractures is demanding and has improved dramatically with the implementation of new technologies. True-to-original accuracy of reconstruction has been deemed essential for good clinical outcome, and reasons for unfavorable clinical outcome have been researched extensively. However, no detailed analysis on the influence of plate position and surface contour on clinical outcome has yet been published. MATERIALS AND METHODS: Data from a previous study were used for an ad-hoc analysis to identify predictors for unfavorable outcome, defined as diplopia or differences in globe height and/or globe projection of >2 mm. Presumed predictors were implant surface contour, aberrant implant dimension or position, accuracy of reconstructed orbital volume, and anatomical fracture topography according to the current AO classification. RESULTS: Neither in univariable nor in multivariable regression models were unfavorable clinical outcomes associated with any of the presumed radiological predictors, and no association of the type of implant, i.e., standard preformed, CAD-based individualized and non-CAD-based individualized with its surface contour could be shown. CONCLUSION: These data suggest that the influence of accurate mechanical reconstruction on clinical outcomes may be less predictable than previously believed, while the role of soft-tissue-related factors may have been underestimated.

A customised digitally engineered solution for fixed dental rehabilitation in severe bone deficiency: A new innovative line extension in implant dentistry.

OBJECTIVES: Numerous procedures including soft and hard tissue reconstructions are necessary to allow for final implant-borne dental rehabilitation in patients with severe alveolar atrophy or resected jaws. In these cases, customised digitally engineered patient solutions for fixed or removable dental rehabilitation provide an innovative line extension to conventional implant dentistry. MATERIAL AND METHODS: A wax-up was performed on plaster models that were scanned by 3D laser. The generated stereolithographic files were then fused with the preoperative 3D imaging data. The individualised "dental" patient solutions were designed digitally and comprised a skeletonised anchorage system and a suprastructure connection system. Insertion of the implants was performed on an outpatient basis. Conventional implant-supported prosthodontic rehabilitation was performed. RESULTS: This digital planning algorithm can be applied to manufacture individualised patient solutions. Similar to conventional implant-supported dentures, these implants can be equipped with individual suprastructure connection systems for internal conical connection, ball-retained attachment, and external conical (telescopic) connection. CONCLUSIONS: In patients with severe atrophy or resected jaws, particularly following ablative tumour surgery, customised digitally engineered solutions allow for an innovative, less invasive line extension to conventional implant dentistry. When conventional implant dentistry reaches its limits, they still offer a strategy for implant-borne dental rehabilitation.

CD24+ tumor-initiating cells from oral squamous cell carcinoma induce initial angiogenesis in vivo.

BACKGROUND: In oral squamous cell carcinoma (OSCC), a minor subset of cancer stem cells has been identified using the surface marker CD24. The CD24+ cell population is involved in initiating, maintaining, and expanding tumor growth, but has not been reported to be involved in angiogenesis to date. METHODS: NOD/SCID mice were equipped with dorsal skinfold chambers and gelatin sponges seeded with CD24+, CD24-, and unsorted cancer cells suspended in Matrigel® were implanted. Following intravital fluorescence microscopy, specimens were examined by immunohistology. RESULTS: Sponges seeded with CD24+ cells showed a significantly higher functional capillary density than those seeded with CD24- cells. The presence of endothelial cells was confirmed by immunohistochemistry for CD31. CONCLUSION: For the first time, CD24+ tumorigenic cells with angiogenic potential, which were isolated from OSCC, were characterized. Our findings provide a promising in vivo model to facilitate the development of therapeutic agents against cancer stem cells and their angiogenic pathways.

A prospective multicenter study to compare the precision of posttraumatic internal orbital reconstruction with standard preformed and individualized orbital implants.

PURPOSE: A variety of implants are available for orbital reconstruction. Titanium orbital mesh plates are available either as standard preformed implants or able to be individualized for the patient. The aim of this study was to analyze whether individualized orbital implants allow a more precise reconstruction of the orbit than standard preformed implants. MATERIALS AND METHODS: A total of 195 patients treated between 2010 and 2014 were followed up to 12 weeks after surgery. Of the patients, 100 had received standardized preformed and 95 individualized implants. The precision of orbital reconstruction with the different implants was determined by comparing the variances in the volume difference between the reconstructed and the contralateral orbit on the postoperative computed tomographic scans. Clinical volume-related parameters including globe position, vision, motility, and diplopia and surgical details including approach, timing and technique of implant modification, use of navigation, duration of surgery, as well as adverse events were documented. RESULTS: Orbital reconstruction was significantly more precise when individualized implants were used. The same was seen with intraoperative navigation. An overlap in the use of individualized implants and navigation makes it difficult to attribute the improved precision to a single factor. CONCLUSION: This study demonstrated that individualization and navigation provide clinical benefit.

Putative CD133+ melanoma cancer stem cells induce initial angiogenesis in vivo.

Tumor angiogenesis is essential for tumor growth and metastasis, and is regulated by a complex network of various types of cells, chemokines, and stimulating factors. In contrast to sprouting angiogenesis, tumor angiogenesis is also influenced by hypoxia, inflammation, and the attraction of bone-marrow-derived cells. Recently, cancer stem cells have been reported to mimic vascularization by differentiating into endothelial cells and inducing vessel formation. In this study, the influence of cancer stem cells on initial angiogenesis was evaluated for the metastatic melanoma cell line D10. Following flow cytometry, CD133+ and CD133- cells were isolated using magnetic cell separation and different cell fractions were transferred to porcine gelatin sponges, which were implanted into the dorsal skinfold chamber of immunocompromised mice. Angiogenesis was analyzed based on microvessel density over a 10-day period using in vivo fluorescence microscopy, and the results were verified using immunohistology. CD133+ D10 cells showed a significant induction of early angiogenesis in vivo, contrary to CD133- D10 cells, unsorted D10 cells, and negative control. Neovascularization was confirmed by visualizing endothelial cells by immunohistology using an anti-CD31 antibody. Because CD133+ cells are rare in clinical specimens and hardly amenable to functional assays, the D10 cell line provides a suitable model to study the angiogenic potential of putative cancer stem cells and the leukocyte-endothelial cell interaction in the dorsal skinfold chamber in vivo. This cancer stem cell model might be useful in the development and evaluation of therapeutic agents targeting tumors.

Functional features of cancer stem cells in melanoma cell lines.

BACKGROUND: Recent evidence suggests a subset of cells within a tumor with "stem-like" characteristics. These cells are able to transplant tumors in immunodeficient hosts. Distinct from non-malignant stem cells, cancer stem cells (CSC) show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumor cells, and resistance to chemotherapy or radiation. They are often characterized by elevated expression of stem cell surface markers, in particular CD133, and sets of differentially expressed stem cell-associated genes. CSC are usually rare in clinical specimens and hardly amenable to functional studies and gene expression profiling. In this study, a panel of heterogenous melanoma cell lines was screened for typical CSC features. METHODS: Nine heterogeneous metastatic melanoma cell lines including D10 and WM115 were studied. Cell lines were phenotyped using flow cytometry and clonogenic assays were performed by limiting dilution analysis on magnetically sorted cells. Spheroidal growth was investigated in pretreated flasks. Gene expression profiles were assessed by using real-time rt-PCR and DNA microarrays. Magnetically sorted tumor cells were subcutaneously injected into the flanks of immunodeficient mice. Comparative immunohistochemistry was performed on xenografts and primary human melanoma sections. RESULTS: D10 cells expressed CD133 with a significantly higher clonogenic capacity as compared to CD133- cells. Na8, D10, and HBL cells formed spheroids on poly-HEMA-coated flasks. D10, Me39, RE, and WM115 cells expressed at least 2 of the 3 regulatory core transcription factors SOX2, NANOG, and OCT4 involved in the maintenance of stemness in mesenchymal stem cells. Gene expression profiling on CD133+ and CD133- D10 cells revealed 68 up- and 47 downregulated genes (+/-1.3 fold). Two genes, MGP and PROM1 (CD133), were outstandingly upregulated. CD133+ D10 cells formed tumors in NSG mice contrary to CD133- cells and CD133 expression was detected in xenografts and primary human melanoma sections using immunohistochemistry. CONCLUSIONS: Established melanoma cell lines exhibit, to variable extents, the typical features of CSCs. The tumorigenic cell line D10, expressing CD133 and growing in spheroids and might qualify as a potential model of melanoma CSCs.