Penn Dental Medicine
Established in 1878, Penn Dental Medicine is among the oldest university-affiliated dental schools in the nation. The school's mission is to transform global oral health and well-being through exceptional clinical care, innovation, education, and research.
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In Vitro Comparative Study Between Full-Arch Conventional Implant Impressions and Full-Arch Digital Implant Impressions with Snap-on Scan Bodies
Statement of Problem: Digital impression techniques are widely used in everyday cases. There is sufficient evidence to support this technique in partially edentulous patients but the evidence supporting the use of intraoral scanners (IOS) in restorative digital workflows for edentulous patients is still limited. Purpose: The aim of the present in vitro study was to measure and compare the accuracy of full- arch conventional implant impressions with open and closed-trays, full-arch digital implant impressions with intraoral scanners (IOS), and three-dimensional (3D) printed casts from the full-arch digital implant impressions. Material and methods: Six implants were placed into a mandibular model. Snap-on scan bodies were inserted into the implants and scanned with a high-resolution reference scanner and exported in standard tessellation language (.STL) format (Group Control). Splinted open-tray impressions (Group 1, n=5) and closed-tray impressions (Group 2, n=5) were made and stone casts were fabricated. Digital impressions (Group 3, n=5) were made with an intra-oral scanner and the .STL files were exported to fabricate 3D printed casts. Snap-on scan bodies were inserted into analogs in Groups 1, 2, and 3 and scanned with the reference scanner. Using a 3D inspection software, impression techniques were compared to the control. Root mean square (RMS) values were calculated from the control and superimposed digitized casts from different impression techniques. Results: Group 3 had the lowest mean dimensional difference when superimposed with Group Control, then Groups 4, 1, and 2. Significant differences were found in RMS values between Group Control and digitized models fabricated from different techniques (P<0.05). Post Hoc (Tukey) test revealed that Group 3 (P<0.001) was significantly different from other groups while no significant difference was found between Groups 1, 2, and 4 (P>0.001). Conclusions: 3D printed models from full-arch digital impression of Snap-on scan bodies seem to be as accurate as stone models fabricated from full-arch conventional impression techniques. Closed-tray full-arch impression technique using dual-functioning Snap-on scan bodies seem to be as accurate as the splinted open-tray full-arch technique.
Comparison of Bone- and Tooth-Anchored, Bone-Anchored, and Surgically Assisted Bone-Anchored Rapid Palatal Expansion: a Pilot Retrospective CBCT Study
Introduction: The purpose of this retrospective pilot study is to evaluate and compare the transverse dental and skeletal changes in three different approaches to miniscrew-assisted rapid palatal expansion (MARPE) including bone- and tooth-anchored (BTAME), bone-anchored (BAME), and surgically assisted bone-anchored maxillary expansion (SRBAME) maxillary expansion. The secondary purpose is to formulate new research questions and develop methods for future MARPE studies. Materials and Methods: Pre- (T1) and post-expansion (T2) Cone Beam Computed Tomography (CBCT) radiographs from 12 patients treated with BAME (median age = 15.5, 95% CI 14.0-18.1), 7 patients treated with BTAME (median age = 19, 95% CI 14.8-26.9), and 5 patients treated with SRBAME (median age = 38, 95% CI 21.6-56.0) were included in the study. All skeletal, alveolar, and dental changes were standardized using suture opening at first molar for intergroup comparisons. There were seven linear and two angular measurements evaluated at the first premolar, second premolar, first molar, and second molar levels for intra- and intergroup comparisons. Results: BTAME and BAME approaches both resulted in significant changes to transverse skeletal and alveolar transverse dimension with some dental tipping. Alveolar bone tipping at the first molar level in BAME was greater than in BTAME (p0.05) while it was significantly greater in the anterior than posterior in BAME (p Conclusions: Both BTAME and BAME result in significant transverse skeletal, alveolar, and dental expansion. BAME resulted in greater alveolar bone bending while BTAME resulted in greater dental tipping. Among the three groups, BTAME suture opening was closest to parallel from anterior to posterior. Contribution of skeletal expansion to intermolar width increase is more favorable in BAME than BTAME.
Do Buffered Local Anesthetics Provide More Successful Anesthesia Over Non-Buffered Solutions in Patients Requiring Dental Therapy? – A Systematic Review & Meta-Analysis.
Background: The pH of commercially available local anesthetics (LAs) is purposefully low (pH 3–4). Decreasing the pH extends the shelf life of the solution and prevents its early oxidation. However, a low pH may produce a burning sensation on the injection site, a slower onset of anesthesia, and a decrease in its clinical efficacy. Buffering of local anesthetics (alkalinization) by adding sodium bicarbonate has been suggested to achieve better pain control, reduce the pain of injection and produce a faster onset of local anesthetics. The aim of this review is to utilize a systematic review to collate evidence on the use of buffering agents with local anesthetics and its effect on causing profound pulpal anesthesia in patients requiring dental therapy and its side effects. Methods: Electronic searches were conducted in MEDLINE, Scopus, Cochrane Library, and ClinicalTrials.gov, World Health Organization (WHO) International Trials Registry Platform, OpenGrey & Google Scholar beta. Hand searching of two books “Handbook of Local Anesthesia” & “Successful Local Anesthesia for Restorative Dentistry and Endodontics” was conducted. Also, the reference lists of all included and excluded studies were checked to identify any further trials. Weighted anesthesia success rates and 95% confidence intervals (CIs) were estimated and compared by using a random-effects model. Results: 14,011 studies were initially identified from the search; 5 double-blind, randomized clinical trials met the inclusion criteria. For combined studies, buffered local anesthetics were more likely than non-buffered solutions to achieve successful anesthesia (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.11–4.71; P = 0.0232; I2 = 66%). Conclusion: This systematic review of double-blind, randomized clinical trials comparing the use of buffered and non-buffered local anesthetics in patients requiring dental therapy provides level ‘A’ evidence that is based on the criteria given by the Strength of Recommendation Taxonomy (SORT). In conclusion, the present meta-analysis showed that in patients receiving dental therapy, buffered local anesthetics are more effective than non-buffered solutions when used for mandibular or maxillary anesthesia. Buffering local anesthetics has 2.29 times greater likelihood of achieving successful anesthesia.
Novel Endodontic Disinfection Approach Using Nanotechnology
The aim of this in vitro investigation was to use a recently developed Enterococcus faecalis infection model using root canal for evaluating iron oxide (Fe3O4) nanoparticles (NP) with biomimetic (catalytic) properties as a new antimicrobial endodontic treatment. We compared iron oxide NP bioactivity with currently used chemical modalities using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) as analytical tools. We hypothesized that iron oxide NP with enzyme-like (peroxidase) activity catalyzes H2O2 to promote bacterial killing within dentinal tubules (DT) via in situ production of free radicals. We further hypothesized that the NP is more effective than the conventional treatments (irrigants) used in the clinical endodontic practice. Because iron oxides can be used as food additives, and iron oxide NP formulations are low-cost and FDA-approved for human use, it could be a safe and feasible approach to potentiate the effects of a commonly used antiseptic.
Epigenetic Changes in the Innate Response of Gingival Epithelium
In this study we showed TLR2 CpG promoter methylation in periodontitis affected human gingival tissues and in primary human gingival epithelial cells chronically stimulated with P. gingivalis that may instigate epithelial dysbiosis that may create a unique pathogen niche in the gingival crevice and susceptibility to periodontitis.
INCIDENCE OF DENTAL IMPLANT FAILURE IN ACADEMIC SETTING - A CLINICAL RETROSPECTIVE STUDY PART ONE: PATIENT LEVEL
Aim: The aim of this retrospective study was to determine the implant failure rate and associated factors in the academic setting by using electronic health records (Axium) and hard copies of patients who received dental implants at in Penn Dental Medicine (PDM) and at Penn Dental Faculty Ppractices (PDFP) ofat the University of Pennsylvania from 06/01/2016 to 08/31/201920. In addition, evaluation of electronic health records and hard copies were reviewed for patients who had implants removed due to bone loss or lack of osseointegration atin PDM and Faculty practicesPDFP of the University of Pennsylvania from 06/01/2016 to 02/29/2020. Secondary objective was to investigate the co-contributing factors for implant failure at the patient level. Method and Material: Electronic health records and hard copies of patients who had implants placed and removed due to bone loss or lack of osseointegration atin PDM and Faculty practicesPDFP of the University of Pennsylvania from 06/01/2016 to 02/29/2020 were analyzed. Results: Data was evaluated at patient count and implant count for this retrospective study. 1609 patients received implants. 883 patients had implant placement at PDM and 726 patients had implant placement at PDFP. Of the total patients, 3180 implants were placed during the study period. 2162 implants were placed at PDM and 1018 implants were placed at PDFP. The total patient failure rate was 4.97% and the failure rate was of 6.0% and 3.7% for PDM and PDFP, respectively. The total implant failure rate was 3.49% and the implant failure rate was 3.7% and 3% for PDM and PDFP, respectively. Based on the chi-square test results, patients with bisphosphonate IV+PO (12%, P-value=0.004) were significantly overrepresented in the failure group. In contrast, patients with no bisphosphonate use (4.60%, P-value=0.004) were significantly underrepresented in the failure group. No overrepresentation (or underrepresentation) of patients with different gender, different age group, diabetes mellitus, history of periodontal disease, current smoking status, penicillin allergy, and recall were noted amongst failures. Based on the chi-square test, implants for bisphosphonate IV variable (11.5%, P-value=0.025) were significantly overrepresented in the failure group. In contrast, implants for no bisphosphonate use (3.20%, P-value<0.001) were significantly underrepresented in the failure group. No overrepresentation (or underrepresentation) of implants for different gender, different age group, diabetes mellitus, history of periodontal disease, current smoking status, penicillin allergy, and recall was noted amongst failures. Based on the multivariate conditional logistic regression, estimated odds of implant failure in participants with multiple implants were about three times than the participants with single implant (Adj OR=2.99, P-value=0.002); estimated odds of implant failure for bisphosphonate use of IV and PO was about four times that of the participants with no bisphosphonate use (Adj. OR=4.09, P-value=0.003). Diabetes and history of failed implants did not show any significant association with implant failure (with P-values>0.05). Conclusion: This study concluded that bisphosphonate use and patients with multiple implants were shown to have a significant contribution to implant failure. There was no difference in the failure rate of patients with different gender, different age group, diabetes mellitus, history of periodontal disease, current smoking status, penicillin allergy, and recallamongst failures. It is important to note that due to limitations and the retrospective nature of this study, only the co-contributing factors were evaluated and not the etiology of the implant failure. To further investigate the etiology, randomized clinical trial should be conducted.
The Role of MRGPRX2/Mrgprb2 in Regulating Mast Cell Function
Mast"cells"(MCs)"are"derived"from"bone"marrow"pluripotent"hematopoietic" stem" cells" and" are" located" in" close" proximity" to" the" external" environment." MCs" expresses"several"receptors"on"their"surface"such"as"the"high"affinity"IgE"receptor" (Fc!RI)"and"G"ProteinECoupled"Receptors"(GPCRs)."MRGPRX2"is"a"GPCR,"which" consists"of"seven"transmembrane"domains"and"is"expressed"exclusively"in"MCs" but" no" other" immune" cells." This" receptor" is" activated" by" multiple" amphipathic" ligands" including" neuropeptides," US" Food" and" Drug" Administration" (FDA)E approved"peptidergic"drugs"and"host"defense"peptides"such"as"LL_37."HDPs"also" known" as" antimicrobial" peptides" (AMPs)" have" been" investigated" in" depth" as" an" alternative"to"overcome"antibiotic"resistance"crisis."However,"their"susceptibility"to" degradation,"cytotoxicity"and"high"production"expenses"have"limited"their"use."To" overcome" these" limitations," nonEpeptide" small" molecule" HDP" mimetics" (smHDPMs)" that" structurally" resemble" the" AMPs" properties" but" have" better" stability"and"less"cytotoxicity"have"been"developed."We"utilized"five"smHDPMs"and" found" that" these" compounds" demonstrated" its" ability" to" activate" MCs" via" MRGPRX2."This"raises"an"interesting"possibility"that"its"function"as"antimicrobial" agent"could"be"as"a"result"of"harnessing"MCs"host"defense"functions"beside"their" antimicrobial"activities."" MCs" can" also" participate" in" chronic" inflammatory" diseases" when" innate" immunity" is" dysregulated." Rosacea" is" a" chronic" skin" disease" that" is" common" among"middle"aged"Caucasians."Human"rosacea"skin"samples"exhibited"higher" 3 number"of"MCs"compared"to"normal"subjects."AMP"LL37"and"neuropeptide"(NP)" substance"P"(SP)"are"upregulated"in"rosacea."LL37"and"SP"activate"MCs"through" MRGPRX2"in#vitro.#Utilizing"Mrgprb2"knockout"mice"(Mrgprb2E/E)"we"demonstrated" a" reduction" in" erythema" presentation," inflammatory" cell" recruitment," MMP+9" and" CXCL+2"mRNA"expression"compared"to"WT"mice"following"intradermal"injection" of" LLE37" and" SP" to" rosacea" model." Calcium" signaling" is" essential" for" MC" degranulation" and" function." In" this" dissertation" we" present" an" evidence" that" STIM1/Orai1" plays" an" important" role" in" MRGPRX2" mediated" calcium" influx" and" mediators"release"when"stimulated"with"LLE37"and"SP."" Moreover,"this"dissertation"showed"naturally"occurring"missense"mutations" of" MRGPRX2" both" within" and" outside" the" receptor’s" predicted" ligand" binding" pocket" (G165E," D184H," W243R" and" H259Y)" renders" it" unresponsive" neuropeptides," HDPs" and" peptidergic" drugs" for" MC" degranulation." Thus," individuals" harboring" these" mutations" may" develop" resistance" to" drugEinduced" allergic"reactions"and"rosacea"but"may"display"increased"susceptibility"to"microbial" infection.""
Gingival MSCs Improve Bone Phenotype in Ovariectomy-Induced Osteoporosis via Programmed Cell Death Pathway
Estrogen deficiency-related osteoporosis is a skeletal system disorder that affects women after menopause taking a toll on financial and health institutions. Gingival Mesenchymal Stem cells (GMSCs) are a distinctive population of dental tissue-derived stem cells that possess uniquely high proliferation abilities and are capable of self-maintenance and multipotent differentiation. Their use has been investigated in different disease model applications, including cutaneous wound healing models, colitis, and allergy-related inflammatory disease models, but their effect on the bone phenotype of ovariectomy-induced osteoporosis hasn’t been explored. In our study, we show that a single systemic infusion of GMSCs elevated the bone mass reduction caused by Ovariectomy (OVX)-induced osteoporosis in both the femurs and mandibles of OVX mice, they also successfully rescued the function of the defective endogenous population of Bone Marrow Mesenchymal Stem Cells (BMMSCs). We saw that the systemic infusion of GMSCs exerted an immunomodulatory effect on the host, leading to the elevation of T-regulatory lymphocytes (T-regs) and the downregulation of T helper type 1 lymphocytes (Th1) levels in recipient OVX mice. Mechanistically, PD-1/PD-L1 is a popular cellular death pathway being heavily investigated in multiple research fields, In our study, we found that GMSC expresses PD-L1 and that the improved bone phenotype resulting from the GMSC infusion was via the programmed cell death (PD-1/PD-L1) pathway triggering activated T-cell apoptosis in the OVX mice, eventually resulting in an improvement of the bone phenotype.
The Role of Specific Integrase Strand Transfer Inhibitors (INSTIs) in the Alteration of Oligodendrocyte Maturation and Myelination in Hand
Currently, thirty-seven million people are infected with human immunodeficiency virus-1 (HIV-1) worldwide. Thankfully, the development of combined antiretroviral therapy (cART) regimens has decreased mortality and significantly improved the overall quality of life for these patients. However, approximately half of all patients clinically manifest with HIV-associated neurocognitive disorder (HAND), a spectrum of cognitive, motor, and behavioral abnormalities which histologically present as non-specific gliosis, synaptodendritc damage and loss of white matter and myelin. Furthermore, the severity of white matter damage correlates with the length of ART duration. However, almost no studies have been performed to determine how the myelin sheath or the oligodendrocytes that synthesize the sheath are damaged. Thus, we hypothesized that the administration of ART contributed in part to the myelin loss in the CNS of HIV-positive patients. Previously, we have reported that the protease inhibitor class of ART drugs hampered the in vitrodifferentiation of oligodendrocytes. Given that the new US guidelines for treating HIV patients recommends anew class of drugs, the integrasestrand transferinhibitors(INSTIs)as front-line therapy, we examined if two specific INSTIs, Elvitegravir (EVG) and raltegravir (RAL), altered the survival and/or maturation of developing oligodendrocytes in vitroand in vivo. We found that treatment of oligodendrocyte precursor cells (OPCs) with EVG, but not RAL, during differentiation reduced the number of cells positive for immature oligodendrocyte marker galactosylceramide (GalC) and mature oligodendrocyte marker myelin basic protein (MBP) in vitro, as well as the synthesis of myelin proteins. However, neither EVG or RAL induced cell loss or apoptosis, as determined by cell counts and TUNEL assays, suggesting that EVG does not affect OPC viability but instead, inhibits differentiation. EVG-induced oligodendrocyte differentiation deficits could be reversed by pre-treating the cells with a drug that pharmacologically inhibits the phosphorylation of eukaryotic initiation factor 2α(eIF2α) throughthe cellular integrated stress response (ISR). Finally, in vivo,mice receiving EVG/COBI failed to remyelinate the corpus callosum during the three week recovery period following demyelination, after cuprizone treatment. Although EVG/COBI treatment by itself did not cause overt white matter loss in this brain region. Our study demonstrates that EVG, but not RAL, inhibits oligodendrocyte precursor cell differentiation both in vitroand in vivo. Furthermore, EVG may be inhibiting oligodendrocyte precursor cell differentiation though activation of the ISR. Also, we found thatthe effects of EVG on oligodendrocyte differentiation could be attenuated in vitroby inhibiting the ISR. These studies suggest that ART may contribute to cognitive impairment by inhibiting renewal and replacement of oligodendrocytes in adults or development of oligodendrocytes in children. Further, our results suggest an ISR inhibitor might attenuate the negative effect of EVG on the maturation of oligodendrocytes. Our findings also suggest that development of less toxic ART compounds and adjunctive therapies are needed to minimize the side effects of ART on the CNS.
MRGPRX2 Signaling on Mast Cell-Mediated Pseudoallergy and Neuroimmune Interaction
In addition to high affinity IgE receptor, human mast cells (MCs) express a newly identified receptor known as Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse ortholog MrgprB2). This receptor is predominantly expressed on only one subtype of MCs and it can be activated by a diverse group of cationic agonists including host defense peptides, Food and Drug Administration (FDA)-approved drugs associated with pseudoallergy and neuropeptides secreted from sensory nerve endings. Not surprisingly, MRGPRX2 has been implicated in several MC-mediated health and disease, ranging from host defense and wound healing to drug-induced pseudoallergic reactions, neurogenic inflammation and pain. However, there is a controversy regarding its role on rocuronium-induced hypersensitivity. Furthermore, the molecular mechanisms underlying MRGPRX2 regulation remain largely unknown. In this dissertation, we first investigated the role of MRGPRX2 on rocuronium-induced hypersensitivity. The effect of MRGPRX2 mutations (M196I, L226P and L237P) identified in a patient with rocuronium hypersensitivity were also tested. We found that rocuronium induced degranulation in murine and human MCs via MrgprB2 and MRGPRX2, respectively, but with different affinities, indicating important functional differences between these receptors. This indicates that mice expressing MrgprB2 may not be a suitable model to study human MRGPRX2 function and highlights the need to develop better animal models. It is now realized that activation of MCs by substance P (SP) via MRGPRX2 contributes to neurogenic inflammation, pain and itch. We sought to identify the mechanisms underlying MRGPRX2 signaling and regulation on SP-activated MC responses. Using pertussis toxin and YM-254890, we demonstrated that SP induces MRGPRX2-mediated Ca2+ mobilization and degranulation via both Gαi and Gαq. Next, we utilized information obtained from both structural modeling and naturally occurring MRGPRX2 missense variants to identify putative G protein coupling regions. In addition, several gain- and loss-of-function missense single nucleotide polymorphisms (SNPs) in MRGPRX2 have been discovered. Finally, we demonstrated that SP can activate β-arrestin recruitment and receptor internalization. A tyrosine residue in the highly conserved NPxxY motif of MRGPRX2 (Tyr279) is crucial for SP-induced β-arrestin recruitment and receptor internalization. This study reveals the novel findings that activation of MRGPRX2/B2 by SP is regulated by β-arrestins and that a highly conserved tyrosine residue is responsible for MRGPRX2 signaling and regulation.