5-FU Weakens Defensive Functions of the Junctional Epithelium.

Aim: To investigate additional factors contributing to the pathophysiology of chemotherapy-induced oral mucositis and periodontitis beyond the systemic immune suppression caused by the chemotherapeutic agent 5-Fluorouracil (5-FU).

Methods: 5-Fluorouracil was topically delivered to the non-keratinized, rapidly proliferating junctional epithelium (JE) surrounding the dentition, and acts as an immunologic and functional barrier to bacterial ingression. Various techniques, including EdU incorporation, quantitative immunohistochemistry (qIHC), histology, enzymatic activity assays, and micro-computed tomographic (μCT) imaging, were employed to analyze the JE at multiple time points following topical 5-FU treatment.

Evaluation of Postoperative Outcomes Following Early and Late Palate Repair: A Preclinical Study.

Objective: To quantitatively assess the impact of early versus late surgical intervention on midfacial growth using a mouse model.

Methods: A full-thickness mucoperiosteal flap surgery was performed on newborn (P17) mice and on neonatal (P30) mice. High-resolution micro-computed tomographic imaging coupled with histomorphometric analyses was used to assess craniomaxillofacial growth.

Dynamic analyses of a soft tissue-implant interface: Biological responses to immediate versus delayed dental implants.

Aim: To qualitatively and quantitatively evaluate the formation and maturation of peri-implant soft tissues around 'immediate' and 'delayed' implants.

Materials And Methods: Miniaturized titanium implants were placed in either maxillary first molar (mxM1) fresh extraction sockets or healed mxM1 sites in mice. Peri-implant soft tissues were evaluated at multiple timepoints to assess the molecular mechanisms of attachment and the efficacy of the soft tissue as a barrier.

The effect of osteocyte-derived RANKL on bone graft remodeling: An in vivo experimental study.

Objectives: Autologous bone is considered the gold standard for grafting, yet it suffers from a tendency to undergo resorption over time. While the exact mechanisms of this resorption remain elusive, osteocytes have been shown to play an important role in stimulating osteoclastic activity through their expression of receptor activator of NF-κB (RANK) ligand (RANKL). The aim of this study was to assess the function of osteocyte-derived RANKL in bone graft remodeling.

Mechanical-induced bone remodeling does not depend on Piezo1 in dentoalveolar hard tissue.

Mechanosensory ion channels are proteins that are sensitive to mechanical forces. They are found in tissues throughout the body and play an important role in bone remodeling by sensing changes in mechanical stress and transmitting signals to bone-forming cells. Orthodontic tooth movement (OTM) is a prime example of mechanically induced bone remodeling.

Wnt/β-Catenin Signaling in Craniomaxillofacial Osteocytes.

Purpose Of Review: There is a growing appreciation within the scientific community that cells exhibit regional variation. Whether the variation is attributable to differences in embryonic origin or anatomical location and mechanical loading has not been elucidated; what is clear, however, is that adult cells carry positional information that ultimately affects their functions. The purpose of this review is to highlight the functions of osteocytes in the craniomaxillofacial (CMF) skeleton as opposed to elsewhere in the body, and in doing so gain mechanistic insights into genetic conditions and chemically-induced diseases that particularly affect this region of our anatomy.

A WNT protein therapeutic accelerates consolidation of a bone graft substitute in a pre-clinical sinus augmentation model.

Aim: Autologous bone grafts consolidate faster than bone graft substitutes (BGSs) but resorb over time, which compromises implant support. We hypothesized that differences in consolidation rates affected the mechanical properties of grafts and implant stability, and tested whether a pro-osteogenic protein, liposomal WNT3A (L-WNT3A), could accelerate graft consolidation.

Materials And Methods: A transgenic mouse model of sinus augmentation with immunohistochemistry, enzymatic assays, and histology were used to quantitatively evaluate the osteogenic properties of autografts and BGSs.

Hormone sensitive lipase ablation promotes bone regeneration.

There is an inverse relationship between the differentiation of mesenchymal stem cells (MSCs) along either an adipocyte or osteoblast lineage, with lineage differentiation known to be mediated by transcription factors PPARγ and Runx2, respectively. Endogenous ligands for PPARγ are generated during the hydrolysis of triacylglycerols to fatty acids through the actions of lipases such as hormone sensitive lipase (HSL). To examine whether reduced production of endogenous PPARγ ligands would influence bone regeneration, we examined the effects of HSL knockout on fracture repair in mice using a tibial mono-cortical defect as a model.

Multiscale analysis of craniomaxillofacial bone repair: A preclinical mini-pig study.

Background: The rate of reparative osteogenesis controls when an implant is sufficiently stable as to allow functional loading. Using a mini pig model, the rate of reparative osteogenesis in two types of implant sites for example, an osteotomy versus a fresh extraction socket were compared.

Methods: Eight adult mini pigs were used for the study.

Clinically relevant preclinical animal models for testing novel cranio-maxillofacial bone 3D-printed biomaterials.

Bone tissue engineering is a rapidly developing field with potential for the regeneration of craniomaxillofacial (CMF) bones, with 3D printing being a suitable fabrication tool for patient-specific implants. The CMF region includes a variety of different bones with distinct functions. The clinical implementation of tissue engineering concepts is currently poor, likely due to multiple reasons including the complexity of the CMF anatomy and biology, and the limited relevance of the currently used preclinical models.

Effects of masticatory loading on bone remodeling around teeth versus implants: Insights from a preclinical model.

Objectives: Teeth connect to bone via a periodontal ligament, whereas implants connect to bone directly. Consequently, masticatory loads are distributed differently to periodontal versus peri-implant bone. Our objective was to determine how masticatory loading of an implant versus a tooth affected peri-implant versus periodontal bone remodeling.

Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity.

Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity.

Biology of sinus floor augmentation with an autograft versus a bone graft substitute in a preclinical in vivo experimental model.

Objectives: Compared to autografts, bone graft substitutes are slower to consolidate. If we understood why, this might open strategies to accelerate new bone formation and thus shorten the time to implant placement. In this study, we aimed at comparing autologous bone graft with a bovine bone graft substitute in a preclinical sinus lift model.

Comparative analyses of the soft tissue interfaces around teeth and implants: Insights from a pre-clinical implant model.

Aim: To evaluate the similarities and differences in barrier function of a peri-implant epithelium (PIE) versus a native junctional epithelium (JE).

Materials And Methods: A mouse model was used wherein titanium implants were placed sub-occlusally in healed extraction sites. The PIE was examined at multiple timepoints after implant placement, to capture and understand the temporal nature of its assembly and homeostatic status.

A novel cryo-embedding method for in-depth analysis of craniofacial mini pig bone specimens.

The disconnect between preclinical and clinical results underscores the imperative for establishing good animal models, then gleaning all available data on efficacy, safety, and potential toxicities associated with a device or drug. Mini pigs are a commonly used animal model for testing orthopedic and dental devices because their skeletons are large enough to accommodate human-sized implants. The challenge comes with the analyses of their hard tissues: current methods are time-consuming, destructive, and largely limited to histological observations made from the analysis of very few tissue sections.

Formation and regeneration of a Wnt-responsive junctional epithelium.

Aim: To identify the molecular mechanisms mediating the persistent defensive functions of the self-renewing junctional epithelium (JE).

Materials And Methods: Two strains of Wnt reporter mice, Axin2 ;R26R and Axin2 , were employed, along with three clinically relevant experimental scenarios where the function of the JE is disrupted: after tooth extraction, after a partial gingivectomy, and after a complete circumferential gingivectomy.

Results: Using transgenic Wnt reporter strains of mice, we established the JE is a Wnt-responsive epithelium beginning at the time of its formation and that it maintains this status into adulthood.

Pro-osteogenic Effects of WNT in a Mouse Model of Bone Formation Around Femoral Implants.

Wnt signaling maintains homeostasis in the bone marrow cavity: if Wnt signaling is inhibited then bone volume and density would decline. In this study, we identified a population of Wnt-responsive cells as osteoprogenitor in the intact trabecular bone region, which were responsible for bone development and turnover. If an implant was placed into the long bone, this Wnt-responsive population and their progeny contributed to osseointegration.

Drill Hole Models to Investigate Bone Repair.

Our understanding of the mechanisms underlying fracture healing is rapidly developing and is contributing to new therapeutic strategies to enhance repair. To gain new insights, animal models must also evolve. From initially imprecise, uncontrolled bone defects we now have precise injury models that still capture all of the stages and phases of bone repair yet do so in a highly reproducible manner.

Mechano-adaptive Responses of Alveolar Bone to Implant Hyper-loading in a pre-clinical in vivo model.

Objectives: Oral implants transmit biting forces to peri-implant bone. In turn, those forces subject peri-implant bone to mechanical stresses and strains. Here, our objective was to understand how peri-implant bone responded to conditions of normal versus hyper-loading in a mouse model.

Bone formation around unstable implants is enhanced by a WNT protein therapeutic in a preclinical in vivo model.

Objectives: Our objective was to test the hypothesis that local delivery of a WNT protein therapeutic would support osseointegration of an unstable implant placed into an oversized osteotomy and subjected to functional loading.

Materials And Methods: Using a split-mouth design in an ovariectomized (OVX) rat model, 50 titanium implants were placed in oversized osteotomies. Implants were subjected to functional loading.

A novel system exploits bone debris for implant osseointegration.

Background: Bone debris generated during site preparation is generally evacuated with irrigation; here, we evaluated whether retention of this autologous material improved the rate of peri-implant bone formation.

Methods: In 25 rats, a miniature implant system composed of an osseo-shaping tool and a tri-oval-shaped implant was compared against a conventional drill and round implant system. A split-mouth design was used, and fresh extraction sockets served as implant sites.

Bioactivating a bone substitute accelerates graft incorporation in a murine model of vertical ridge augmentation.

Objective: Compared to autologous bone grafts, allogeneic bone grafts integrate slowly, which can adversely affect clinical outcomes. Here, our goal was to understand the molecular mechanisms underlying graft incorporation, and then test clinically feasible methods to accelerate this process.

Methods: Wild-type and transgenic Wnt "reporter" mice were used in a vertical ridge augmentation procedure.