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.
PublicationCrosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration(2021-07-21) Jassim, Assraa Hassan; Inman, Denise M.; Mitchell, Claire H.Mitochondrial dysfunction and excessive inflammatory responses are both sufficient to induce pathology in age-dependent neurodegenerations. However, emerging evidence indicates crosstalk between damaged mitochondrial and inflammatory signaling can exacerbate issues in chronic neurodegenerations. This review discusses evidence for the interaction between mitochondrial damage and inflammation, with a focus on glaucomatous neurodegeneration, and proposes that positive feedback resulting from this crosstalk drives pathology. Mitochondrial dysfunction exacerbates inflammatory signaling in multiple ways. Damaged mitochondrial DNA is a damage-associated molecular pattern, which activates the NLRP3 inflammasome; priming and activation of the NLRP3 inflammasome, and the resulting liberation of IL-1β and IL-18 via the gasdermin D pore, is a major pathway to enhance inflammatory responses. The rise in reactive oxygen species induced by mitochondrial damage also activates inflammatory pathways, while blockage of Complex enzymes is sufficient to increase inflammatory signaling. Impaired mitophagy contributes to inflammation as the inability to turnover mitochondria in a timely manner increases levels of ROS and damaged mtDNA, with the latter likely to stimulate the cGAS-STING pathway to increase interferon signaling. Mitochondrial associated ER membrane contacts and the mitochondria-associated adaptor molecule MAVS can activate NLRP3 inflammasome signaling. In addition to dysfunctional mitochondria increasing inflammation, the corollary also occurs, with inflammation reducing mitochondrial function and ATP production; the resulting downward spiral accelerates degeneration. Evidence from several preclinical models including the DBA/2J mouse, microbead injection and transient elevation of IOP, in addition to patient data, implicates both mitochondrial damage and inflammation in glaucomatous neurodegeneration. The pressure-dependent hypoxia and the resulting metabolic vulnerability is associated with mitochondrial damage and IL-1β release. Links between mitochondrial dysfunction and inflammation can occur in retinal ganglion cells, microglia cells and astrocytes. In summary, crosstalk between damaged mitochondria and increased inflammatory signaling enhances pathology in glaucomatous neurodegeneration, with implications for other complex age-dependent neurodegenerations like Alzheimer’s and Parkinson’s disease. © Copyright © 2021 Jassim, Inman and Mitchell. PublicationOptical Diagnostics in the Oral Cavity: An Overview(2010-11-01) Wilder-Smith, P; Holtzman, J; Epstein, J; Le, AAs the emphasis shifts from damage mitigation to disease prevention or reversal of early disease in the oral cavity, the need for sensitive and accurate detection and diagnostic tools become more important. Many novel and emergent optical diagnostic modalities for the oral cavity are becoming available to clinicians with a variety of desirable attributes including: (i) non-invasiveness, (ii) absence of ionizing radiation, (iii) patient-friendliness, (iv) real-time information (v) repeatability, and (vi) high-resolution surface and subsurface images. In this article, the principles behind optical diagnostic approaches, their feasibility and applicability for imaging soft and hard tissues, and their potential usefulness as a tool in the diagnosis of oral mucosal lesions, dental pathologies, and other dental applications will be reviewed. The clinical applications of light-based imaging technologies in the oral cavity and of their derivative devices will be discussed to provide the reader with a comprehensive understanding of emergent diagnostic modalities. © 2010 John Wiley & Sons A/S. PublicationGenes and Pathways Associated with Skeletal Sagittal Malocclusions: A Systematic Review(2021-12-01) Gershater, Elizabeth; Li, Chenshuang; Ha, Pin; Chung, Chun-Hsi; Tanna, Nipul; Zou, Min; Zheng, ZhongSkeletal class II and III malocclusions are craniofacial disorders that negatively impact people’s quality of life worldwide. Unfortunately, the growth patterns of skeletal malocclusions and their clinical correction prognoses are difficult to predict largely due to lack of knowledge of their precise etiology. Inspired by the strong inheritance pattern of a specific type of skeletal malocclusion, previous genome-wide association studies (GWAS) were reanalyzed, resulting in the identification of 19 skeletal class II malocclusion-associated and 53 skeletal class III malocclusion-associated genes. Functional enrichment of these genes created a signal pathway atlas in which most of the genes were associated with bone and cartilage growth and development, as expected, while some were characterized by functions related to skeletal muscle maturation and construction. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development. There is no doubt that further investigation is necessary to validate these recognized genes’ and pathways’ specific function(s) related to maxillary and mandibular development. In summary, this systematic review provides initial insight on developing novel gene-based treatment strategies for skeletal malocclusions and paves the path for precision medicine where dental care providers can make an accurate prediction of the craniofacial growth of an individual patient based on his/her genetic profile. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. PublicationDeep Margin Elevation: A Literature Review(2022-03-01) Samartzi, Theodora Kalliopi; Papalexopoulos, Dimokritos; Ntovas, Panagiotis; Rahiotis, Christos; Blatz, MarkusA conservative approach for restoring deep proximal lesions is to apply an increment of composite resin over the preexisting cervical margin to relocate it coronally, the so-called “deep margin elevation” (DME). A literature search for research articles referring to DME published from January 1998 until November 2021 was conducted using MEDLINE (PubMed), Ovid, Scopus, Cochrane Library and Semantic Scholar databases applying preset inclusion and exclusion criteria. Elevation material and adhesive system employed for luting seem to be significant factors concerning the marginal adaptation of the restoration. This technique does not affect bond strength, fatigue behavior, fracture resistance, failure pattern or repairability. DME and subgingival restorations are compatible with periodontal health, given that they are well-polished and refined. The available literature is limited mainly to in vitro studies. Therefore, randomized clinical trials with extended follow-up periods are necessary to clarify all aspects of the technique and ascertain its validity in clinical practice. For the time being, DME should be applied with caution respecting three criteria: capability of field isolation, the perfect seal of the cervical margin provided by the matrix, and no invasion of the connective compartment of biological width. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. PublicationGingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review(2021-04-16) Kim, Dane; Lee, Alisa E; Xu, Qilin; Zhang, Qunshou; Le, Anh DA 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. © Copyright © 2021 Kim, Lee, Xu, Zhang and Le. PublicationPolymeric Scaffolds for Dental Pulp Tissue Engineering: A Review(2020-02-01) Jazayeri, Hossein E.; Lee, Su-Min; Kuhn, Lauren; Fahimipour, Farahnaz; Tahriri, Mohammadreza; Tayebi, LobatObjectives: The purpose of this review is to describe recent developments in pulp tissue engineering using scaffolds and/or stem cells. It is crucial to understand how this approach can revitalize damaged dentin-pulp tissue. Widespread scaffold materials, both natural and synthetic, and their fabrication methods, and stem-progenitor cells with the potential of pulp regeneration will be discussed. Data and Sources: A review of literature was conducted through online databases, including MEDLINE by using the PubMed search engine, Scopus, and the Cochrane Library. Study Selection: Studies were selected based on relevance, with a preference given to recent research, particularly from the past decade. Conclusions: The use of biomaterial scaffolds and stem cells can be safe and potent for the regeneration of pulp tissue and re-establishment of tooth vitality. Natural and synthetic polymers have distinct advantages and limitations and in vitro and in vivo testing have produced positive results for cell attachment, proliferation, and angiogenesis. The type of biomaterial used for scaffold fabrication also facilitates stem cell differentiation into odontoblasts and the resulting biochemistry of tissue repair for each polymer and cell type was discussed. Multiple methods of scaffold design exist for pulp tissue engineering, which demonstrates the variability in tissue engineering applications in endodontics. This review explains the potential of evidence-based tissue engineering strategies and outcomes in pulp regeneration. © 2019 The Academy of Dental Materials PublicationClinical Considerations in Orthodontically Forced Eruption for Restorative Purposes(2021-12-02) Huang, Grace; Yang, Min; Qali, Mohannad; Wang, Tun-Jan; Li, Chenshuang; Chang, Yu-ChengFor restorations on teeth involving invasion of the supracrestal tissue attachment (biological width), as well as for lack of ferrule effect, crown lengthening is required for long-term periodontal health and success of the restoration. In the same fashion, site development is often necessary prior to implant placement in order to provide optimal peri-implant soft and hard tissue architecture conducive to future esthetics and function. Orthodontic extrusion, also known as forced eruption, has been developed and employed clinically to serve the purposes of increasing the clinical crown length, correcting the periodontal defect, and developing the implant site. In order to provide comprehensive guidance on the clinical usage of this technique and maximize the outcome for patients who receive the dental restoration, the currently available literatures were summarized and discussed in the current review. Compared to traditional crown lengthening surgery, forced eruption holds advantages of preserving supporting bone, providing improved esthetics, limiting the involvement of adjacent teeth, and decreasing the negative impact on crown-to-root ratio compared to the traditional resective approach. As a non-invasive and natural technique capable of increasing the available volume of bone and soft tissue, forced eruption is also an attractive and promising option for implant site development. Both fixed and removable appliances can be used to achieve the desired extrusion, but patient compliance is a primary limiting factor for the utilization of removable appliances. In summary, forced eruption is a valuable treatment adjunct for patients requiring crown lengthening or implant restorations. Nonetheless, comprehensive evaluation and treatment planning are required for appropriate case selection based upon the known indications and contraindications for each purpose; major contraindications include inflammation, ankylosis, hypercementosis, vertical root fracture, and root proximity. Further studies are necessary to elucidate the long-term stability of orthodontically extruded teeth and the supporting bone and soft tissue that followed them. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. PublicationThe P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis(2021-03-15) Campagno, Keith E.; Mitchell, Claire H.Microglial cells regulate neural homeostasis by coordinating both immune responses and clearance of debris, and the P2X7 receptor for extracellular ATP plays a central role in both functions. The P2X7 receptor is primarily known in microglial cells for its immune signaling and NLRP3 inflammasome activation. However, the receptor also affects the clearance of extracellular and intracellular debris through modifications of lysosomal function, phagocytosis, and autophagy. In the absence of an agonist, the P2X7 receptor acts as a scavenger receptor to phagocytose material. Transient receptor stimulation induces autophagy and increases LC3-II levels, likely through calcium-dependent phosphorylation of AMPK, and activates microglia to an M1 or mixed M1/M2 state. We show an increased expression of Nos2 and Tnfa and a decreased expression of Chil3 (YM1) from primary cultures of brain microglia exposed to high levels of ATP. Sustained stimulation can reduce lysosomal function in microglia by increasing lysosomal pH and slowing autophagosome-lysosome fusion. P2X7 receptor stimulation can also cause lysosomal leakage, and the subsequent rise in cytoplasmic cathepsin B activates the NLRP3 inflammasome leading to caspase-1 cleavage and IL-1β maturation and release. Support for P2X7 receptor activation of the inflammasome following lysosomal leakage comes from data on primary microglia showing IL-1β release following receptor stimulation is inhibited by cathepsin B blocker CA-074. This pathway bridges endolysosomal and inflammatory roles and may provide a key mechanism for the increased inflammation found in age-dependent neurodegenerations characterized by excessive lysosomal accumulations. Regardless of whether the inflammasome is activated via this lysosomal leakage or the better-known K+-efflux pathway, the inflammatory impact of P2X7 receptor stimulation is balanced between the autophagic reduction of inflammasome components and their increase following P2X7-mediated priming. In summary, the P2X7 receptor modulates clearance of extracellular debris by microglial cells and mediates lysosomal damage that can activate the NLRP3 inflammasome. A better understanding of how the P2X7 receptor alters phagocytosis, lysosomal health, inflammation, and autophagy can lead to therapies that balance the inflammatory and clearance roles of microglial cells. © Copyright © 2021 Campagno and Mitchell. PublicationNovel Cell Sources for Bone Regeneration(2021-06-01) Li, Chenshuang; Mills, Zane; Zheng, ZhongA plethora of both acute and chronic conditions, including traumatic, degenerative, malignant, or congenital disorders, commonly induce bone disorders often associated with severe persisting pain and limited mobility. Over 1 million surgical procedures involving bone excision, bone grafting, and fracture repair are performed each year in the U.S. alone, resulting in immense levels of public health challenges and corresponding financial burdens. Unfortunately, the innate self-healing capacity of bone is often inadequate for larger defects over a critical size. Moreover, as direct transplantation of committed osteoblasts is hindered by deficient cell availability, limited cell spreading, and poor survivability, an urgent need for novel cell sources for bone regeneration is concurrent. Thanks to the development in stem cell biology and cell reprogramming technology, many multipotent and pluripotent cells that manifest promising osteogenic potential are considered the regenerative remedy for bone defects. Considering these cells' investigation is still in its relative infancy, each of them offers their own particular challenges that must be conquered before the large-scale clinical application. © 2021 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd. PublicationThe Impact of Dental Implant Surface Modifications on Osseointegration and Biofilm Formation(2021-04-02) Kligman, Stefanie; Ren, Zhi; Chung, Chun-Hsi; Perillo, Michael Angelo; Chang, Yu-Cheng; Koo, Hyun; Zheng, Zhong; Li, ChenshuangImplant surface design has evolved to meet oral rehabilitation challenges in both healthy and compromised bone. For example, to conquer the most common dental implant-related complications, peri-implantitis, and subsequent implant loss, implant surfaces have been modified to introduce desired properties to a dental implant and thus increase the implant success rate and expand their indications. Until now, a diversity of implant surface modifications, including different physical, chemical, and biological techniques, have been applied to a broad range of materials, such as titanium, zirconia, and polyether ether ketone, to achieve these goals. Ideal modifications enhance the interaction between the implant’s surface and its surrounding bone which will facilitate osseointegration while minimizing the bacterial colonization to reduce the risk of biofilm formation. This review article aims to comprehensively discuss currently available implant surface modifications commonly used in implantology in terms of their impact on osseointegration and biofilm formation, which is critical for clinicians to choose the most suitable materials to improve the success and survival of implantation. © 2021 by the author. Licensee MDPI, Basel, Switzerland.