Telehealth Utilization in Oral Medicine and Oral and Maxillofacial Surgery.

Objectives: The objectives of this retrospective study were to analyze telehealth utilization for two specialty care practices: oral medicine (OM) and oral and maxillofacial surgery (OMFS) during the first 2 years of the pandemic, its impact as a new treatment modality and on participating providers, as well as identify the type of patient visit that most readily adopted telehealth. Methods: Retrospective study of patients who sought specialty services, OM and OMFS, at an outpatient clinic in a university health system setting between March 1, 2019, and February 28, 2022. Source data were obtained from Epic, an electronic medical record application. Data were graphed using Tableau and Microsoft Excel software. Statistical analysis was performed utilizing chi-squared test and analysis of variance (ANOVA). Results: OMFS utilized telehealth 12% of the time, and OM 8% of the time. The majority (87%) of telehealth visits were for return patients (RPs). Compared with the first year of the pandemic, there was a decrease in the number of telehealth visits in the second year (p = 0.0001). As of August 2022, new patient (NP) telehealth encounters have largely returned to prepandemic levels (0-1.5%), whereas RP telehealth visits remained at an average level of 11.4% (9.4-12.4%). Surveyed providers consider telehealth as an effective complement to in-person care and will continue its use (4.2/5 Likert scale). Conclusions: Telehealth has become a viable pathway of care for OM and OMFS who previously did not utilize the remote platform to deliver healthcare. As a new treatment modality, telehealth is perceived as impactful in increasing access to specialty care by participating providers. NP visits are now almost completely in person, but telehealth continues for RPs. Ongoing demand for telehealth highlights urgency to develop appropriate standards and effective remote diagnostic/monitoring tools to maximize telehealth's capability to leverage finite health care resources and increase access to specialty care.

Established sensitization of ethanol-induced locomotor activity is not reversed by psilocybin or the 5-HT2A receptor agonist TCB-2 in male DBA/2J mice.

RATIONALE: Psychedelic drugs, which share in common 5-HT2A receptor agonist activity, have shown promise in treating alcohol-use disorders (AUDs). Repeated exposure to ethanol (EtOH) induces molecular and behavioural changes reflective of neuroadaptations that may contribute to addiction. Psychedelic drugs can induce neuroplasticity also, raising the possibility that their potential clinical effects in AUD may involve an action to reverse or offset effects of long-term changes induced by EtOH. This possibility was examined by investigating whether psilocybin, or the 5-HT2A receptor agonist TCB-2, counteracted established sensitization of EtOH-induced locomotor activity. METHODS: Male DBA/2J mice received repeated injections of 2.2 g/kg EtOH to induce a sensitized locomotor activity response. In two experiments separate groups of mice were then injected with psilocybin (0, 0.3 and 1 kg/kg) or TCB-2 (0, 1 and 3 mg/kg) on 5 consecutive days. Next, mice were challenged with 1.8 g/kg EtOH and locomotor activity measured for 15 min. RESULTS: Relative to naïve controls, previously sensitized mice showed enhanced locomotor activity to the challenge dose. Despite reducing locomotor activity in their own right psilocybin and TCB-2 did not alter the strength of this sensitized response. CONCLUSION: Psilocybin and TCB-2 at behaviourally effective doses did not reverse sensitization of EtOH-induced activity. This suggests that mechanisms involved in mediating short-term reductions in EtOH intake by psilocybin or TCB-2 may not involve a capacity of these drugs to offset enduring changes in behaviour and any underlying neural adaptations induced by repeated intermittent exposure to EtOH.

Potential Application of Orofacial MSCs in Tissue Engineering Nerve Guidance for Peripheral Nerve Injury Repair.

Injury to the peripheral nerve causes potential loss of sensory and motor functions, and peripheral nerve repair (PNR) remains a challenging endeavor. The current clinical methods of nerve repair, such as direct suture, autografts, and acellular nerve grafts (ANGs), exhibit their respective disadvantages like nerve tension, donor site morbidity, size mismatch, and immunogenicity. Even though commercially available nerve guidance conduits (NGCs) have demonstrated some clinical successes, the overall clinical outcome is still suboptimal, especially for nerve injuries with a large gap (≥ 3 cm) due to the lack of biologics. In the last two decades, the combination of advanced tissue engineering technologies, stem cell biology, and biomaterial science has significantly advanced the generation of a new generation of NGCs incorporated with biological factors or supportive cells, including mesenchymal stem cells (MSCs), which hold great promise to enhance peripheral nerve repair/regeneration (PNR). Orofacial MSCs are emerging as a unique source of MSCs for PNR due to their neural crest-origin and easy accessibility. In this narrative review, we have provided an update on the pathophysiology of peripheral nerve injury and the properties and biological functions of orofacial MSCs. Then we have highlighted the application of orofacial MSCs in tissue engineering nerve guidance for PNR in various preclinical models and the potential challenges and future directions in this field.

Targeted inhibition of eIF5Ahpu suppresses tumor growth and polarization of M2-like tumor-associated macrophages in oral cancer.

Eukaryotic initiation factor 5A2 (eIF5A2) is overexpressed in many types of cancer, and spermidine-mediated eIF5A hypusination (eIF5Ahpu) appears to be essential to most of eIF5A's biological functions, including its important role in regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties as well as immune cell functions. Here we investigated the role of eIF5Ahpu in the growth of oral squamous cell carcinoma cells (OSCCs) and OSCC-induced polarization of M2-like tumor-associated macrophages (TAMs). TCGA dataset analysis revealed an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in polyamine (PA) metabolism in HNSCC, which was confirmed by Western blot and IHC studies. Blocking eIF5Ahpu by GC-7 but not the upstream key enzyme activities of PA metabolism, remarkably inhibited cell proliferation and the expression of EMT- and CSC-related genes in OSCC cells. In addition, blocking eIF5Ahpu robustly inhibited OSCC-induced M2-like TAM polarization in vitro. More Importantly, blocking eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like TAM in a syngeneic orthotopic murine tongue SCC model. Thus, eIF5Ahpu plays dual functions in regulating tumor cell growth and polarization of M2-TAMs in OSCC.

Sagittal and Vertical Changes of the Maxilla after Surgically Assisted Rapid Palatal Expansion: A Systematic Review and Meta-Analysis.

Surgically assisted rapid palatal expansion (SARPE) is often performed to correct the transverse deficiency in the maxilla for skeletally mature patients. However, there is little consensus on the sagittal and vertical displacement of the maxilla after SARPE. This systematic review aims to analyze the position changes of the maxilla in the sagittal and vertical dimensions after the completion of SARPE. Registered with PROSPERO (registration number: CRD42022312103), this study complied with the 2020 PRISMA guideline and was conducted on 21 January 2023. Original studies were screened from MEDLINE (PubMed), Elsevier (SCOPUS), and Cochrane, and supplemented by hand-searching. Cephalometric changes of skeletal vertical and sagittal measurements were the focus. A fixed-effects model was applied in R for meta-analysis. After applying inclusion and exclusion criteria, seven articles were included in the final review. Four studies had a high risk of bias, and the other three had a medium risk of bias. Meta-analysis revealed that the SNA angle increased by 0.50° ± 0.08° (95% confidence interval, 0.33° to 0.66°), and the SN-PP angle increased by 0.60° ± 0.09° (95% confidence interval, 0.41° to 0.79°) after SARPE. In summary, the maxilla displayed statistically significant forward and clockwise downward movement after SARPE. However, the amounts were small and might not be clinically significant. Due to the high risk of bias of included studies, our results must be taken cautiously. Future studies are needed to discern the effects of direction and angulation of the osteotomies of SARPE on the displacement of the maxilla.

Quality of life in patients with oral potentially malignant disorders: oral lichen planus and oral epithelial dysplasia.

OBJECTIVE: The aim of this study was to evaluate and compare quality of life (QoL) parameters in patients with oral potential malignant disorders (OPMDs), namely, oral lichen planus (OLP) and oral epithelial dysplasia (OED). STUDY DESIGN: A cross-sectional study was completed at the oral maxillofacial surgery/oral medicine practices at University of Pennsylvania. Patients with clinical and histopathologic confirmation of OLP or OED from January to June 2021 were included in the study. The primary predictor variable was the OPMD type. The primary outcome variable was the score of 3 separate surveys: the Chronic Oral Mucosal Disease Questionnaire-26 (COMDQ-26), Oral Potential Malignant Disorder QoL Questionnaire (OPMDQoL), and Hospital Anxiety and Depression Scale. Multiple linear regression was used to determine independent predictors of increased/decreased questionnaire scores. RESULTS: The final study sample consisted of 100 patients:53 patients had OLP (53.0%), 39 patients had OED (39.0%), and 8 patients had OLP with OED (8.0%). Relative to OED, OLP added 15.7 points to the COMDQ-26 survey score (P < .001). Relative to OED, OLP added 8.9 points to the OPMDQoL survey score (P = .003). CONCLUSIONS: Oral lichen planus shows significantly poorer QoL specifically within the COMD-26 and OPMDQoL questionnaires, compared with OED. Additionally, patients with OPMDs aged 40 to 64 years were independently associated with higher COMD-26 scores compared with older patients (>65 years).

Asymmetric Maxillary Expansion Introduced by Surgically Assisted Rapid Palatal Expansion: A Systematic Review.

PURPOSE: A commonly reported complication of surgically assisted rapid palatal expansion (SARPE) that has not been explored extensively is uneven expansion between left and right sides, which requires secondary surgery for correction. This systematic review aims to analyze the prevalence and potential causes of asymmetric expansion in the transverse dimension after SARPE to guide the clinical practice. METHODS: Electronic databases and manual search were used to search for original articles published on SARPE on March 11, 2022. Original human studies that recorded the number and percentage of asymmetric expansion after two-piece SARPE were included. The 2020 Preferred Reporting Items for Systemic Reviews and Meta-Analyses guideline was implemented for the quality assessment and data analysis of the included articles. The study was registered at the International Prospective Register of Systematic Reviews under the number CRD42022300782. RESULTS: After applying inclusion and exclusion criteria, 13 articles were included in the final review. The risk of bias was high in 8 studies and medium in the other 5 studies. Overall, the prevalence of asymmetric expansion in the transverse dimension (different amount of expansion between left and right sides) was 7.52%, with 12.90% of patients involved receiving a second surgery for correction. Expander design did not significantly affect the rate of asymmetry expansion. Pterygomaxillary fissure release significantly increased the rate of asymmetry expansion (11.02% vs 5.08%, P < .001). In comparison, lateral nasal wall osteotomy (4.26% vs 14.77%, P < .001) and release of the nasal septum (5.22% vs 17.15%, P < .001) significantly lowered the rate of asymmetry expansion, respectively. CONCLUSIONS: Asymmetric dentoskeletal expansion between left and right sides is a common complication of SARPE procedures, mostly caused by variations in surgical cuts. However, the risk of bias in currently available publications is high. Further studies are warranted to fully understand the causes of asymmetric expansion.

Potential application of dental stem cells in regenerative reconstruction of oral and maxillofacial tissues: a narrative review.

Background and Objective: Oral and maxillofacial (OMF) defects caused by congenital conditions, injuries, ablative surgery for benign and malignant head & neck tumor, can often lead to OMF deformities and malfunctions in speech, mastication/chewing, and swallowing as well as have deleterious psychological effects and socioeconomic burdens to patients. Due to the unique complex 3D geometry of the head and neck region, reconstruction and rehabilitation of OMF defects remain a major challenge for OMF surgeons.The purpose of this narrative review is to update the information on the biological properties and functions of mesenchymal stem cells derived from various dental tissues (dental-MSCs) and their potential application in tissue engineering (TE) and regenerative reconstruction of OMF tissues. Methods: A data-based search was performed by using PubMed database whereby articles published between 2000 and 2021 in English were included in the search with the following key words: dental stem cells, OMF reconstruction, OMF TE and regeneration. Key Content and Findings: Currently, the advancement in stem cell biology, biomaterial science, and TE technology has demonstrated the significant potential application of stem cell-based therapy in regenerative reconstruction and rehabilitation of OMF defects. However, no stem cell-based product or device has been translated into clinical application to replace microsurgical free tissue transfer, the current mainstay of care in the reconstruction of OMF defects. Conclusions: Currently, microsurgical free tissue transfer remains the gold standard mainstay of care for the reconstruction of OMF defects due to their abundant blood supply and flexibility for transplantation. However, several major challenges, such as the limited availability, the requirement of a second surgery, donor site morbidity, and the risk of free flap failure, have promoted the development of novel approaches. Due to the advancement in stem cell biology, biomaterial science, and TE technology, stem cell-based regenerative therapy is emerging as a promising therapeutic approach for a variety of diseases, including regenerative reconstruction and rehabilitation of OMF defects. In this narrative review, we update on the characteristics and biological functions of mesenchymal stem cells derived from various dental tissues (dental-MSCs) and their released cell-free products, extracellular vesicles (EVs). We also highlighted their potential application in TE and regenerative reconstruction of OMF defects in animal models and clinical studies and the potential challenges in this field.

Implantation of a nerve protector embedded with human GMSC-derived Schwann-like cells accelerates regeneration of crush-injured rat sciatic nerves.

BACKGROUND: Peripheral nerve injuries (PNIs) remain one of the great clinical challenges because of their considerable long-term disability potential. Postnatal neural crest-derived multipotent stem cells, including gingiva-derived mesenchymal stem cells (GMSCs), represent a promising source of seed cells for tissue engineering and regenerative therapy of various disorders, including PNIs. Here, we generated GMSC-repopulated nerve protectors and evaluated their therapeutic effects in a crush injury model of rat sciatic nerves. METHODS: GMSCs were mixed in methacrylated collagen and cultured for 48 h, allowing the conversion of GMSCs into Schwann-like cells (GiSCs). The phenotype of GiSCs was verified by fluorescence studies on the expression of Schwann cell markers. GMSCs encapsulated in the methacrylated 3D-collagen hydrogel were co-cultured with THP-1-derived macrophages, and the secretion of anti-inflammatory cytokine IL-10 or inflammatory cytokines TNF-α and IL-1ß in the supernatant was determined by ELISA. In addition, GMSCs mixed in the methacrylated collagen were filled into a nerve protector made from the decellularized small intestine submucosal extracellular matrix (SIS-ECM) and cultured for 24 h, allowing the generation of functionalized nerve protectors repopulated with GiSCs. We implanted the nerve protector to wrap the injury site of rat sciatic nerves and performed functional and histological assessments 4 weeks post-surgery. RESULTS: GMSCs encapsulated in the methacrylated 3D-collagen hydrogel were directly converted into Schwann-like cells (GiSCs) characterized by the expression of S-100ß, p75NTR, BDNF, and GDNF. In vitro, co-culture of GMSCs encapsulated in the 3D-collagen hydrogel with macrophages remarkably increased the secretion of IL-10, an anti-inflammatory cytokine characteristic of pro-regenerative (M2) macrophages, but robustly reduced LPS-stimulated secretion of TNF-1α and IL-1ß, two cytokines characteristic of pro-inflammatory (M1) macrophages. In addition, our results indicate that implantation of functionalized nerve protectors repopulated with GiSCs significantly accelerated functional recovery and axonal regeneration of crush-injured rat sciatic nerves accompanied by increased infiltration of pro-regenerative (M2) macrophages while a decreased infiltration of pro-inflammatory (M1) macrophages. CONCLUSIONS: Collectively, these findings suggest that Schwann-like cells converted from GMSCs represent a promising source of supportive cells for regenerative therapy of PNI through their dual functions, neurotrophic effects, and immunomodulation of pro-inflammatory (M1)/pro-regenerative (M2) macrophages.

Are Bacteria Just Bystanders in the Pathogenesis of Inflammatory Jaw Conditions?

PURPOSE: It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ. METHODS: This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests. RESULTS: A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1). CONCLUSION: Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.

Harnessing 3D collagen hydrogel-directed conversion of human GMSCs into SCP-like cells to generate functionalized nerve conduits.

Achieving a satisfactory functional recovery after severe peripheral nerve injuries (PNI) remains one of the major clinical challenges despite advances in microsurgical techniques. Nerve autografting is currently the gold standard for the treatment of PNI, but there exist several major limitations. Accumulating evidence has shown that various types of nerve guidance conduits (NGCs) combined with post-natal stem cells as the supportive cells may represent a promising alternative to nerve autografts. In this study, gingiva-derived mesenchymal stem cells (GMSCs) under 3D-culture in soft collagen hydrogel showed significantly increased expression of a panel of genes related to development/differentiation of neural crest stem-like cells (NCSC) and/or Schwann cell precursor-like (SCP) cells and associated with NOTCH3 signaling pathway activation as compared to their 2D-cultured counterparts. The upregulation of NCSC-related genes induced by 3D-collagen hydrogel was abrogated by the presence of a specific NOTCH inhibitor. Further study showed that GMSCs encapsulated in 3D-collagen hydrogel were capable of transmigrating into multilayered extracellular matrix (ECM) wall of natural NGCs and integrating well with the aligned matrix structure, thus leading to biofabrication of functionalized NGCs. In vivo, implantation of functionalized NGCs laden with GMSC-derived NCSC/SCP-like cells (designated as GiSCs), significantly improved the functional recovery and axonal regeneration in the segmental facial nerve defect model in rats. Together, our study has identified an approach for rapid biofabrication of functionalized NGCs through harnessing 3D collagen hydrogel-directed conversion of GMSCs into GiSCs.

An implantable human stem cell-derived tissue-engineered rostral migratory stream for directed neuronal replacement.

The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain's most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine.

Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review.

A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.

The serotonin 2C receptor agonist lorcaserin, alone and in combination with the opioid receptor antagonist naltrexone, attenuates binge-like ethanol drinking.

The serotonin (5-HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5-HT2C receptor agonist, attenuates drug self-administration in animal models. We investigated the effects of lorcaserin on EtOH intake using the drinking-in-the-dark (DID) procedure, an animal model of binge-like drinking. We compared the effects of lorcaserin to those of the Food and Drug Administration (FDA)-approved drug naltrexone and examined the effects of combining lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home-cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with lorcaserin, naltrexone, or a combination of lorcaserin and naltrexone prior to a 4-h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose-dependent fashion over the 2- and 4-h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose-dependent effects being more pronounced over 2 h rather than the full 4-h session. Combining lorcaserin and naltrexone reduced binge-like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that lorcaserin and naltrexone can have additive effects on binge-like EtOH drinking. They also support continued research into the therapeutic potential of lorcaserin for alcohol use disorders.

Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss.

Mesenchymal stem cell (MSC)-derived exosome plays a central role in the cell-free therapeutics involving MSCs and the contents can be customized under disease-associated microenvironments. However, optimal MSC-preconditioning to enhance its therapeutic potential is largely unknown. Here, we show that preconditioning of gingival tissue-derived MSCs (GMSCs) with tumor necrosis factor-alpha (TNF-α) is ideal for the treatment of periodontitis. TNF-α stimulation not only increased the amount of exosome secreted from GMSCs, but also enhanced the exosomal expression of CD73, thereby inducing anti-inflammatory M2 macrophage polarization. The effect of GMSC-derived exosomes on inflammatory bone loss were examined by ligature-induced periodontitis model in mice. Local injection of GMSC-derived exosomes significantly reduced periodontal bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and these effects were further enhanced by preconditioning of GMSCs with TNF-α. Thus, GMSC-derived exosomes also exhibited anti-osteoclastogenic activity. Receptor activator of NF-κB ligand (RANKL) expression was regulated by Wnt5a in periodontal ligament cells (PDLCs), and exosomal miR-1260b was found to target Wnt5a-mediated RANKL pathway and inhibit its osteoclastogenic activity. These results indicate that significant ability of the TNF-α-preconditioned GMSC-derived exosomes to regulate inflammation and osteoclastogenesis paves the way for establishment of a therapeutic approach for periodontitis.

Tissue Engineered Bands of Büngner for Accelerated Motor and Sensory Axonal Outgrowth.

Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration decreases precipitously with increasing gap length. Schwann cells play a key role in driving axon re-growth by forming aligned tubular guidance structures called bands of Büngner, which readily occurs in distal nerve segments as well as within autografts - currently the most reliable clinically-available bridging strategy. However, host Schwann cells generally fail to infiltrate large-gap acellular scaffolds, resulting in markedly inferior outcomes and motivating the development of next-generation bridging strategies capable of fully exploiting the inherent pro-regenerative capability of Schwann cells. We sought to create preformed, implantable Schwann cell-laden microtissue that emulates the anisotropic structure and function of naturally-occurring bands of Büngner. Accordingly, we developed a biofabrication scheme leveraging biomaterial-induced self-assembly of dissociated rat primary Schwann cells into dense, fiber-like three-dimensional bundles of Schwann cells and extracellular matrix within hydrogel micro-columns. This engineered microtissue was found to be biomimetic of morphological and phenotypic features of endogenous bands of Büngner, and also demonstrated 8 and 2× faster rates of axonal extension in vitro from primary rat spinal motor neurons and dorsal root ganglion sensory neurons, respectively, compared to 3D matrix-only controls or planar Schwann cells. To our knowledge, this is the first report of accelerated motor axon outgrowth using aligned Schwann cell constructs. For translational considerations, this microtissue was also fabricated using human gingiva-derived Schwann cells as an easily accessible autologous cell source. These results demonstrate the first tissue engineered bands of Büngner (TE-BoBs) comprised of dense three-dimensional bundles of longitudinally aligned Schwann cells that are readily scalable as implantable grafts to accelerate axon regeneration across long segmental nerve defects.

The pharmacological stressor yohimbine, but not U50,488, increases responding for conditioned reinforcers paired with ethanol or sucrose.

RATIONALE: Environmental stimuli paired with alcohol can function as conditioned reinforcers (CRfs) and trigger relapse to alcohol-seeking. In animal models, pharmacological stressors can enhance alcohol consumption and reinstate alcohol-seeking, but it is unknown whether stress can potentiate the conditioned reinforcing properties of alcohol-paired stimuli. OBJECTIVES: We examined whether the pharmacological stressors, the α-2 adrenoreceptor antagonist yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) and the K-opioid receptor agonist U50,488 (vehicle, 1.25, 2.5 mg/kg; SC), increase responding for conditioned reinforcement, and if their effects interact with the nature of the reward (alcohol vs. sucrose). We subsequently examined the effects of yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) on responding for sensory reinforcement. METHODS: Male Long-Evans underwent Pavlovian conditioning, wherein a tone-light conditioned stimulus (CS) was repeatedly paired with 12% EtOH or 21.7% sucrose. Next, tests of responding for a CRf were conducted. Responding on the CRf lever delivered the CS, whereas responding on the other lever had no consequences. In a separate cohort of rats, the effects of yohimbine on responding just for the sensory reinforcer were examined. RESULTS: Both doses of yohimbine, but not U50,488, increased responding for conditioned reinforcement. This enhancement occurred independently of the nature of the reward used during Pavlovian conditioning. Yohimbine-enhanced responding for a CRf was reproducible and stable over five tests; it even persisted when the CS was omitted. Both doses of yohimbine also increased responding for sensory reinforcement. CONCLUSIONS: Yohimbine increases operant responding for a variety of sensory and conditioned reinforcers. This enhancement may be independent of its stress-like effects.

Considerations in the evaluation and management of oral potentially malignant disorders during the COVID-19 pandemic.

AIM: The COVID-19 pandemic has resulted in society experiencing unprecedented challenges for health care practitioners and facilities serving at the frontlines of this pandemic. With regard to oral cancer, there is a complete absence of literature regarding the long-term impact of pandemics on patients with oral potentially malignant disorders (OPMDs). The objective of this article is to put forth an institutional multidisciplinary approach for the evaluation and management of OPMDs. METHODS: A multidisciplinary approach was put formalized within our institution to risk stratify patients based on need for in-person assessment vs telehealth assessment during the COVID-19 pandemic. RESULTS: With judicious risk stratification of patients based on clinical features of their OPMD and with consideration of ongoing mitigation efforts and regional pandemic impact, providers are able to safely care for their patients. CONCLUSIONS: The COVID-19 pandemic has required health care practitioners to make novel decisions that are new to us with development of creative pathways of care that focused on patient safety, mitigation efforts, and clinical management of disease processes. The care of patients with OPMDs requires special considerations especially as patients at high risk for severe COVID-19 illness are also higher risk for the development of OPMDs.

LGR5+ epithelial tumor stem-like cells generate a 3D-organoid model for ameloblastoma.

Ameloblastoma (AM) is a benign but locally aggressive tumor with high recurrences. Currently, underlying pathophysiology remains elusive, and radical surgery remains the most definitive treatment with severe morbidities. We have recently reported that AM harbors a subpopulation of tumor epithelial stem-like cells (AM-EpiSCs). Herein, we explored whether LGR5+ epithelial cells in AM possess stem-like cell properties and their potential contribution to pathogenesis and recurrence of AM. We found that LGR5 and stem cell-related genes were co-expressed in a subpopulation of AM epithelial cells both in vivo and in vitro, which were enriched under 3D-spheroid culture. As compared to LGR5- counterparts, LGR5+ AM epithelial cells showed increased expression of various EMT- and stemness-related genes, and functionally, exhibited increased capacity to form 3D-spheroids and generate human tumor 3D organoids, which recapitulated the histopathologic features of distinct subtypes of solid AM, thus, contributing a useful human tumor platform for targeted therapeutic screening. Treatment with a selective BRAFV600E inhibitor, vemurafenib, unexpectedly enriched the subpopulation of LGR5+ AM-EpiSCs in tumor 3D organoids, which may have explained therapeutic resistances and recurrences. These findings suggest that LGR5+ AM-EpiSCs play a pivotal role in pathogenesis and progression of AM and targeted inhibition of both BRAF and LGR5 potentially serves a novel nonsurgical adjuvant therapeutic approach for this aggressively benign jaw tumor.