Effect of sustained PDGF nonviral gene delivery on repair of tooth-supporting bone defects.

Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) promotes soft tissue and bone healing, and is Food and Drug Administration-approved for treatment of diabetic ulcers and periodontal defects. The short half-life of topical rhPDGF-BB protein application necessitates bolus, high-dose delivery. Gene therapy enables sustained local growth factor production. A novel gene activated matrix delivering polyplexes of polyethylenimine (PEI)-plasmid DNA encoding PDGF was evaluated for promotion of periodontal wound repair in vivo. PEI-pPDGF-B polyplexes were tested in human periodontal ligament fibroblasts and human gingival fibroblasts for cell viability and transfection efficiency. Collagen scaffolds containing PEI-pPDGF-B polyplexes at two doses, rhPDGF-BB, PEI vector or collagen alone were randomly delivered to experimentally induced tooth-supporting periodontal defects in a rodent model. Mandibulae were collected at 21 days for histologic observation and histomorphometry. PEI-pPDGF-B polyplexes were biocompatible to cells tested and enzyme-linked immunosorbent assay confirmed the functionality of transfection. Significantly greater osteogenesis was observed for collagen alone and rhPDGF-BB versus the PEI-containing groups. Defects treated with sustained PDGF gene delivery demonstrated delayed healing coupled with sustained inflammatory cell infiltrates lateral to the osseous defects. Continuous PDGF-BB production by nonviral gene therapy could have delayed bone healing. This nonviral gene delivery system in this model appeared to prolong inflammatory response, slowing alveolar bone regeneration in vivo.

Local wound healing biomarkers for real-time assessment of periodontal regeneration: pilot study.

BACKGROUND AND OBJECTIVES: Within the same surgical procedure, a great variability on achievement of clinical outcomes exists and may be associated to different molecular factors related to tissue healing. The aim of the present study was to assess the distribution of clinical success separately in regenerative therapy (REG) and open flap debridement (OFD) to evaluate if factors related with healing of epithelium, connective tissue and bone may be associated to the clinical outcome within each surgical procedure. MATERIAL AND METHODS: Sixteen patients underwent periodontal REG and nine patients underwent OFD. Periodontal wound fluid was collected at baseline, 3-5, 7, 14 and 21 d after surgery, and expression of wound healing proteins was assessed. Pocket depth and clinical attachment level were taken at baseline and at 6 mo of follow-up. Percentage pocket depth reduction and percentage clinical attachment level gain were computed. Patients were regarded as better or worse responders depending on their percentage pocket depth reduction or percentage clinical attachment level gain. RESULTS: Higher percentage of better responders was observed in the REG group (68.7%) compared to the OFD group (22.2%). At 21 d, no difference in the profile of most of the proteins emerged, with two exceptions, both regarding REG treatment. Bone morphogenetic protein-7 tended to increase in better responders and to decrease in worse responders. Matrix metalloproteinase-1 increased in worse responders and remained substantially unchanged in better responders. CONCLUSION: Local expression of matrix metalloproteinase-1 and bone morphogenetic protein-7 during wound healing is associated with the clinical performance of periodontal regenerative surgery. The use of local biomarkers offers the potential for real-time assessment of the periodontal healing process.

Bone Marrow Stromal Stem Cells in Tissue Engineering and Regenerative Medicine.

Bone marrow stromal stem cells (BMSCs) are adult multipotent cells, which have the potential to differentiate into cell types of mesodermal origin, namely osteocytes, adipocytes, and chondrocytes. Due to their accessibility and expansion potential, BMSCs have historically held therapeutic promise in tissue engineering and regenerative medicine applications. More recently, it has been demonstrated that not only can bone marrow stromal stem cells directly participate in tissue regeneration, but they also have the capacity to migrate to distant sites of tissue injury, where they can participate in tissue repair either directly through their differentiation or indirectly through paracrine mechanisms. Additionally, they can elicit various immunomodulatory signals, which can attenuate the inflammatory and immune responses. As such, bone marrow stromal stem cells have been explored clinically for treatment of a wide variety of different conditions including bone defects, graft-vs.-host disease, cardiovascular diseases, autoimmune diseases, diabetes, neurological diseases, and liver and kidney diseases. This review provides an overview of current clinical applications of bone marrow stromal stem cells and discusses their therapeutic properties, while also addressing limitations of their use. PubMed, Ovid, and Google Scholar online databases were searched using several keywords, including "stem cells", "tissue engineering", tissue regeneration" and "clinical trials". Additionally, Clinical trials.gov was used to locate completed clinical trials using bone marrow derived stem cells.

How is research publishing going to progress in the next 20 years? Transcription of session for editors, associate editors, publishers and others with an interest in scientific publishing held at IADR meeting in Seattle on Wednesday, 20 March 2013.

On March 20th 2013, a one-hour session for Editors, Associate Editors, Publishers and others with an interest in scientific publishing was held at the IADR International Session in Seattle. Organised by Kenneth Eaton and Chris Lynch (Chair and Secretary, respectively, of the British Dental Editors Forum), the meeting sought to bring together leading international experts in dental publishing, as well as authors, reviewers and students engaged in research. The meeting was an overwhelming success, with more than 100 attendees. A panel involving four leading dental editors led a discussion on anticipated developments in publishing dental research with much involvement and contribution from audience members. This was the third such meeting held at the IADR for Editors, Associate Editors, Publishers and others with an interest in scientific publishing. A follow up session will take place in Cape Town on 25 June 2014 as part of the annual IADR meeting. The transcript of the meeting is reproduced in this article. Where possible speakers are identified by name. At the first time of mention their role/ position is also stated, thereafter only their name appears. We are grateful to Stephen Hancocks Ltd for their generous sponsorship of this event. For those who were not able to attend the authors hope this article gives a flavour of the discussions and will encourage colleagues to attend future events. Involvement is open to Editors, Associate Editors, Publishers and others with an interest in scientific publishing. It is a very open group and all those with an interest will be welcome to join in.

LIM domain protein-3 (LMP3) cooperates with BMP7 to promote tissue regeneration by ligament progenitor cells.

Gene transfer of key regulators of osteogenesis for mesenchymal stem cells represents a promising strategy to regenerate bone. It has been reported that LMP3, a transcription variant of LIM domain mineralization protein (LMP) lacking LIM domains, can induce osteogenesis in vitro and in vivo. As little is known about the effects of LMP3 gene therapy on periodontal ligament (PDL) cell osteogenic differentiation, this study sought to explore whether gene delivery of LMP3 can promote PDL cell mineralization and bone formation. Our results showed that adenoviral mediated gene transfer of LMP3 (AdLMP3) significantly upregulated ALP (Alkaline Phosphatase), BSP (Bone Sialoprotein) and BMP2 gene expression and increased in vitro matrix mineralization in human PDL. Although AdLMP3 gene delivery to PDL cells did not induce ectopic bone formation in vivo, we found that AdLMP3 augments new bone formation, which co-delivered with AdBMP7 gene transfer. Our study provides the evidence that there is a synergistic effect between LMP3 and BMP-7 in vivo, suggesting that LMP3 delivery may be used to augment BMP-mediated osteogenesis. LMP3 and BMP-7 combinatory gene therapy may also have specific applications for oral and periodontal regenerative medicine.

Multicompartmental Scaffolds for Coordinated Periodontal Tissue Engineering.

Successful periodontal repair and regeneration requires the coordinated responses from soft and hard tissues as well as the soft tissue-to-bone interfaces. Inspired by the hierarchical structure of native periodontal tissues, tissue engineering technology provides unique opportunities to coordinate multiple cell types into scaffolds that mimic the natural periodontal structure in vitro. In this study, we designed and fabricated highly ordered multicompartmental scaffolds by melt electrowriting, an advanced 3-dimensional (3D) printing technique. This strategy attempted to mimic the characteristic periodontal microenvironment through multicompartmental constructs comprising 3 tissue-specific regions: 1) a bone compartment with dense mesh structure, 2) a ligament compartment mimicking the highly aligned periodontal ligaments (PDLs), and 3) a transition region that bridges the bone and ligament, a critical feature that differentiates this system from mono- or bicompartmental alternatives. The multicompartmental constructs successfully achieved coordinated proliferation and differentiation of multiple cell types in vitro within short time, including both ligamentous- and bone-derived cells. Long-term 3D coculture of primary human osteoblasts and PDL fibroblasts led to a mineral gradient from calcified to uncalcified regions with PDL-like insertions within the transition region, an effect that is challenging to achieve with mono- or bicompartmental platforms. This process effectively recapitulates the key feature of interfacial tissues in periodontium. Collectively, this tissue-engineered approach offers a fundament for engineering periodontal tissue constructs with characteristic 3D microenvironments similar to native tissues. This multicompartmental 3D printing approach is also highly compatible with the design of next-generation scaffolds, with both highly adjustable compartmentalization properties and patient-specific shapes, for multitissue engineering in complex periodontal defects.

Human Bone Marrow Stromal Cell Exosomes Ameliorate Periodontitis.

Human bone marrow stromal cell (hBMSC)-derived exosomes are promising therapeutics for inflammatory diseases due to their unique microRNA (miRNA) and protein cargos. Periodontal diseases often present with chronicity and corresponding exuberant inflammation, which leads to loss of tooth support. In this study, we explored whether hBMSC exosomes can affect periodontitis progression. hBMSC exosomes were isolated from cell culture medium through sequential ultracentrifugation. miRNAs and proteins that were enriched in hBMSC exosomes were characterized by RNA sequencing and protein array, respectively. hBMSC exosomes significantly suppressed periodontal keystone pathogen Porphyromonas gingivalis-triggered inflammatory response in macrophages in vitro. Transcriptomic analysis suggested that exosomes exerted their effects through regulating cell metabolism, differentiation, and inflammation resolution. In vivo, weekly exosome injection into the gingival tissues reduced the tissue destruction and immune cell infiltration in rat ligature-induced periodontitis model. Collectively, these findings suggest that hBMSC-derived exosomes can potentially be used as a host modulation agent in the management of periodontitis.

Translational and clinical applications of salivary diagnostics.

There have been significant advances in techniques for the detection of biomarker signals in the oral cavity (e.g., ELISAs for proteins, PCR for RNA and DNA) as well as the engineering and development of microfluidic approaches to make oral-based point-of-care (POC) methods for the diagnosis for both local and systemic conditions a reality. In this section, we focus on three such approaches, namely, periodontal disease management, early markers for systemic diseases, and salivary markers useful for pharmacogenomic studies. Novel approaches using non-invasive, salivary samples and user-friendly devices offer results that are as sensitive and specific as laboratory-based analyses using blood or urine.

Recombinant Human Platelet-Derived Growth Factor: A Systematic Review of Clinical Findings in Oral Regenerative Procedures.

AIM: The use of recombinant human platelet-derived growth factor-BB (rhPDGF) has received Food and Drug Administration approval for the treatment of periodontal and orthopedic bone defects and dermal wound healing. Many studies have investigated its regenerative potential in a variety of other oral clinical indications. The aim of this systematic review was to assess the efficacy, safety, and clinical benefit of recombinant human platelet-derived growth factor (rhPDGF) use for alveolar bone and/or soft tissue regeneration. MATERIAL AND METHODS: Comprehensive electronic and manual literature searches according to the PRISMA guidelines were performed to identify interventional and observational studies evaluating the regenerative applications of rhPDGF-BB. The primary outcomes were the safety, efficacy, and overall clinical benefit of rhPDGF use in oral regenerative procedures. RESULTS: Sixty-three human clinical studies (mean ± SD follow-up period of 10.7 ± 3.3 mo) were included in the qualitative analysis. No serious adverse effects were reported in any of the 63 studies, aside from the postoperative complications routinely associated with surgical therapy. Use of rhPDGF was shown to be beneficial when combined with allografts, xenografts, and alloplasts (the latter tricalcium phosphate [ß-TCP]) for the treatment of periodontal defects and gingival recession. The use of rhPDGF also led to favorable clinical outcomes when combined with allografts or xenografts for guided bone regeneration (GBR) and alveolar ridge preservation. While favorable clinical results support the use of the combination of rhPDGF plus allograft or xenograft for GBR, ARP, and sinus floor augmentation, current data support the use of rhPDGF and alloplasts (e.g., ß-TCP) only in periodontal defects and gingival recession. CONCLUSIONS: Based on the clinical evidence, rhPDGF is safe and provides clinical benefits when used in combination with bone allografts, xenograft, or ß-TCP for the treatment of intrabony and furcation periodontal defects and gingival recession or when used with allografts or xenograft for GBR and ARP (PROSPERO CRD42020142446). KNOWLEDGE TRANSFER STATEMENT: Clinicians should be aware that rhPDGF is a safe and effective approach for the treatment of intrabony and furcation periodontal defects and gingival recession or when used with allografts or xenograft for bone regeneration and alveolar ridge preservation. With consideration of cost and patient preference, this result could lead to more appropriate therapeutic decisions.

Translating Dental, Oral, and Craniofacial Regenerative Medicine Innovations to the Clinic through Interdisciplinary Commercial Translation Architecture.

Few university-based regenerative medicine innovations in the dental, oral, and craniofacial (DOC) space have been commercialized and affected clinical practice in the United States. An analysis of the commercial translation literature and National Institute for Dental and Craniofacial Research's (NIDCR's) portfolio identified barriers to commercial translation of university-based DOC innovations. To overcome these barriers, the NIDCR established the Dental Oral Craniofacial Tissue Regeneration Consortium. We provide generalized strategies to inform readers how to bridge the "valley of death" and more effectively translate DOC technologies from the research laboratory or early stage company environment to clinical trials and bring needed innovations to the clinic. Three valleys of death are covered: 1) from basic science to translational development, 2) from translational technology validation to new company formation (or licensing to an existing company), and 3) from new company formation to scaling toward commercialization. An adapted phase-gate model is presented to inform DOC regenerative medicine teams how to involve regulatory, manufacturability, intellectual property, competitive assessments, business models, and commercially oriented funding mechanisms earlier in the translational development process. An Industrial Partners Program describes how to conduct market assessments, industry maps, business development processes, and industry relationship management methods to sustain commercial translation through the later-stage valley of death. Paramount to successfully implementing these methods is the coordination and collaboration of interdisciplinary teams around specific commercial translation goals and objectives. We also provide several case studies for translational projects with an emphasis on how they addressed DOC biomaterials for tissue regeneration within a rigorous commercial translation development environment. These generalized strategies and methods support innovations within a university-based and early stage company-based translational development process, traversing the many funding gaps in dental, oral, and craniofacial regenerative medicine innovations. Although the focus is on shepherding technologies through the US Food and Drug Administration, the approaches are applicable worldwide.

PDGF-B gene therapy accelerates bone engineering and oral implant osseointegration.

Platelet-derived growth factor-BB (PDGF-BB) stimulates repair of healing-impaired chronic wounds such as diabetic ulcers and periodontal lesions. However, limitations in predictability of tissue regeneration occur due, in part, to transient growth factor bioavailability in vivo. Here, we report that gene delivery of PDGF-B stimulates repair of oral implant extraction socket defects. Alveolar ridge defects were created in rats and were treated at the time of titanium implant installation with a collagen matrix containing an adenoviral (Ad) vector encoding PDGF-B (5.5 x 10(8) or 5.5 x 10(9) pfu ml(-1)), Ad encoding luciferase (Ad-Luc; 5.5 x 10(9) pfu ml(-1); control) or recombinant human PDGF-BB protein (rhPDGF-BB, 0.3 mg ml(-1)). Bone repair and osseointegration were measured through backscattered scanning electron microscopy, histomorphometry, micro-computed tomography and biomechanical assessments. Furthermore, a panel of local and systemic safety assessments was performed. Results indicated that bone repair was accelerated by Ad-PDGF-B and rhPDGF-BB delivery compared with Ad-Luc, with the high dose of Ad-PDGF-B more effective than the low dose. No significant dissemination of the vector construct or alteration of systemic parameters was noted. In summary, gene delivery of Ad-PDGF-B shows regenerative and safety capabilities for bone tissue engineering and osseointegration in alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo.

Maresin 1 Promotes Wound Healing and Socket Bone Regeneration for Alveolar Ridge Preservation.

Tooth extraction results in alveolar bone resorption and is accompanied by postoperative swelling and pain. Maresin 1 (MaR1) is a proresolving lipid mediator produced by macrophages during the resolution phase of inflammation, bridging healing and tissue regeneration. The aim of this study was to examine the effects of MaR1 on tooth extraction socket wound healing in a preclinical rat model. The maxillary right first molars of Sprague-Dawley rats were extracted, and gelatin scaffolds were placed into the sockets with or without MaR1. Topical application was also given twice a week until complete socket wound closure up to 14 d. Immediate postoperative pain was assessed by 3 scores. Histology and microcomputed tomography were used to assess socket bone fill and alveolar ridge dimensional changes at selected dates. The assessments of coded specimens were performed by masked, calibrated examiners. Local application of MaR1 potently accelerated extraction socket healing. Macroscopic and histologic analysis revealed a reduced soft tissue wound opening and more rapid re-epithelialization with MaR1 delivery versus vehicle on socket healing. Under micro-computed tomography analysis, MaR1 (especially at 0.05 µg/µL) stimulated greater socket bone fill at day 10 as compared with the vehicle-treated animals, resulting in less buccal plate resorption and a wider alveolar ridge by day 21. Interestingly, an increased ratio of CD206+:CD68+ macrophages was identified in the sockets with MaR1 application under immunohistochemistry and immunofluorescence analysis. As compared with the vehicle therapy, local delivery of MaR1 reduced immediate postoperative surrogate pain score panels. In summary, MaR1 accelerated extraction wound healing, promoted socket bone fill, preserved alveolar ridge bone, and reduced postoperative pain in vivo with a rodent preclinical model. Local administration of MaR1 offers clinical potential to accelerate extraction socket wound healing for more predictable dental implant reconstruction.

AAV2/1-TNFR:Fc gene delivery prevents periodontal disease progression.

Periodontal disease is a chronic inflammatory condition induced by tooth-associated microbial biofilms that induce a host immune response. Therapeutic control of progressive tissue destruction in high-risk patients is a significant challenge in therapy. Soluble protein delivery of antagonists to tumor necrosis factor-alpha (TNF-alpha) inhibits alveolar bone resorption due to periodontitis. However, protein therapy raises several concerns, such as recurrence of disease activity after treatment cessation and repeated dosing regimens. In this study, we used pseudotyped adeno-associated virus vector based on serotype 1 (AAV2/1) to deliver the TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene to rats subjected to experimental Porphyromonas gingivalis (Pg)-lipopolysaccharide (LPS)-mediated bone loss. Animals received Pg-LPS delivered to the gingivae thrice weekly for 8 weeks, vehicle alone, Pg-LPS and intramuscular delivery of pseudotyped AAV2/1-TNFR:Fc vector (1 x 10(11) DNase I-resistant particles) or AAV2/1-TNFR:Fc vector delivered to naive animals. AAV2/1-TNFR:Fc therapy led to sustained therapeutic levels of serum TNFR protein and protected against Pg-LPS-mediated loss of bone volume and density. Furthermore, AAV2/1-TNFR:Fc administration reduced local levels of multiple proinflammatory cytokines and osteoclast-like cells at the periodontal lesions. These findings suggest that delivery of AAV2/1-TNFR:Fc may be a viable approach to modulate periodontal disease progression.

Genome Editing: A New Horizon for Oral and Craniofacial Research.

Precise and efficient genetic manipulations have enabled researchers to understand gene functions in disease and development, providing a platform to search for molecular cures. Over the past decade, the unprecedented advancement of genome editing techniques has revolutionized the biological research fields. Early genome editing strategies involved many naturally occurring nucleases, including meganucleases, zinc finger nucleases, and transcription activator-like effector-based nucleases. More recently, the clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated nucleases (CRISPR/Cas) system has greatly enriched genetic manipulation methods in conducting research. Those nucleases generate double-strand breaks in the target gene sequences and then utilize DNA repair mechanisms to permit precise yet versatile genetic manipulations. The oral and craniofacial field harbors a plethora of diseases and developmental defects that require genetic models that can exploit these genome editing techniques. This review provides an overview of the genome editing techniques, particularly the CRISPR/Cas9 technique, for the oral and craniofacial research community. We also discuss the details about the emerging applications of genome editing in oral and craniofacial biology.

Platelet-derived growth factor-B gene delivery sustains gingival fibroblast signal transduction.

BACKGROUND AND OBJECTIVE: Platelet-derived growth factor-BB is a potent mediator of tooth-supporting periodontal tissue repair and regeneration. A limitation of the effects of topical platelet-derived growth factor-BB application is its short half-life in vivo. Gene therapy has shown strong promise for the long-term delivery of platelet-derived growth factor in both skin ulcer healing and periodontal tissue engineering. However, little is known regarding the extended effects of platelet-derived growth factor-B on cell signaling via gene delivery, especially at the level of phosphorylation of intracellular kinases. This study sought to evaluate the effect of gene transfer by Ad-PDGF-B on human gingival fibroblasts (HGFs) and the subsequent regulation of genes and cell-surface proteins associated with cellular signaling. MATERIAL AND METHODS: HGFs from human subjects were treated by adenoviral PDGF-B, PDGF-1308 (a dominant negative mutant of PDGF) and recombinant human platelet-derived growth factor-BB, and then incubated in serum-free conditions for various time points and harvested at 1, 6, 12, 24, 48, 72 and 96 h. Exogenous PDGF-B was measured by RT-PCR and Western blot. Cell proliferation was evaluated by [methyl-3H]thymidine incorporation assay. We used proteomic arrays to explore phosphorylation patterns of 23 different intracellular kinases after PDGF-B gene transfer. The expression of alpha and beta PDGFR and Akt were measured by Western blot analysis. RESULTS: Sustained in vitro expression of PDGF-B in HGFs by Ad-PDGF-B transduction was seen at both the mRNA and protein levels. Compared to rhPDGF-BB and Ad-PDGF-1308, Ad-PDGF-B maintained cell growth in serum-free conditions, with robust increases in DNA synthesis. Gene delivery of PDGF-B also prolonged downregulation of the growth arrest specific gene (gas) PDGF alpha R. Of the 23 intracellular kinases that we tested in proteomic arrays, Akt revealed the most notable long-term cell signaling effect as a result of the over-expression of Ad-PDGF-B, compared with pulse recombinant human platelet-derived growth factor BB. Prolonged Akt phosphorylation was induced by treatment with Ad-PDGF-B, for at least up to 96 h. CONCLUSION: These findings further demonstrate that gene delivery of PDGF-B displays sustained signal transduction effects in human gingival fibroblasts that are higher than those conveyed by treatment with recombinant human platelet-derived growth factor-BB protein. These data on platelet-derived growth factor gene delivery contribute to an improved understanding of these pathways that are likely to play a role in the control of clinical outcomes of periodontal regenerative therapy.

Periostin is essential for the integrity and function of the periodontal ligament during occlusal loading in mice.

BACKGROUND: The ability of the periodontal ligament (PDL) to absorb and distribute forces is necessary for periodontal homeostasis. This adaptive response may be determined, in part, by a key molecule, periostin, which maintains the integrity of the PDL during occlusal function and inflammation. Periostin is primarily expressed in the PDL and is highly homologous to betaig-H3 (transforming growth factor-beta [TGF-beta] inducible gene). Cementum, alveolar bone, and the PDL of periostin-null mice dramatically deteriorate following tooth eruption. The purpose of this study was to determine the role of periostin in maintaining the functional integrity of the periodontium. METHODS: The periodontia from periostin-null mice were characterized followed by unloading the incisors. The effect of substrate stretching on periostin expression was evaluated using a murine PDL cell line. Real-time reverse transcription-polymerase chain reaction was used to quantify mRNA levels of periostin and TGF-beta. TGF-beta1 neutralizing antibodies were used to determine whether the effects of substrate stretching on periostin expression are mediated through TGF-beta. RESULTS: Severe periodontal defects were observed in the periostin-null mice after tooth eruption. The removal of masticatory forces in periostin-null mice rescue the periodontal defects. Periostin expression was increased in strained PDL cells by 9.2-fold at 48 hours and was preceded by a transient increase in TGF-beta mRNA in vitro. Elevation of periostin in response to mechanical stress was blocked by the addition of 2.5 ng/ml neutralizing antibody to TGF-beta1, suggesting that mechanical strain activates TGF-beta to have potential autocrine effects and to increase periostin expression. CONCLUSION: Mechanical loading maintains sufficient periostin expression to ensure the integrity of the periodontium in response to occlusal load.

Is Metal Particle Release Associated with Peri-implant Bone Destruction? An Emerging Concept.

Peri-implant diseases affecting the surrounding structures of endosseous dental implants include peri-implant mucositis and peri-implantitis. The prevalence of peri-implantitis ranges between 15% and 20% after 10 y, highlighting the major challenge in clinical practice in the rehabilitation of dental implant patients. The widespread nature of peri-implant bone loss poses difficulties in the management of biological complications affecting the long-term success of osseointegrated implant reconstructions. Metal and titanium particles have been detected in peri-implant supporting tissues. However, it remains unclear what mechanisms could be responsible for the elicitation of particle and ion release and whether these released implant-associated materials have a local and/or systemic impact on the peri-implant soft and hard tissues. Metal particle release as a potential etiologic factor has been intensively studied in the field of orthopedics and is known to provoke aseptic loosening around arthroplasties and is associated with implant failures. In dental medicine, emerging information about metal/titanium particle release suggests that the potential impact of biomaterials at the abutment or bone interfaces may have an influence on the pathogenesis of peri-implant bone loss. This mini-review highlights current evidence of metal particle release around dental implants and future areas for research.

Craniofacial tissue engineering by stem cells.

Craniofacial tissue engineering promises the regeneration or de novo formation of dental, oral, and craniofacial structures lost to congenital anomalies, trauma, and diseases. Virtually all craniofacial structures are derivatives of mesenchymal cells. Mesenchymal stem cells are the offspring of mesenchymal cells following asymmetrical division, and reside in various craniofacial structures in the adult. Cells with characteristics of adult stem cells have been isolated from the dental pulp, the deciduous tooth, and the periodontium. Several craniofacial structures--such as the mandibular condyle, calvarial bone, cranial suture, and subcutaneous adipose tissue--have been engineered from mesenchymal stem cells, growth factor, and/or gene therapy approaches. As a departure from the reliance of current clinical practice on durable materials such as amalgam, composites, and metallic alloys, biological therapies utilize mesenchymal stem cells, delivered or internally recruited, to generate craniofacial structures in temporary scaffolding biomaterials. Craniofacial tissue engineering is likely to be realized in the foreseeable future, and represents an opportunity that dentistry cannot afford to miss.

Detection of activated platelet-derived growth factor receptors in human meningioma.

The beta receptor subunit of platelet-derived growth factor (PDGF) and its corresponding ligand (PDGF-BB) are coordinately expressed in fresh surgical isolates of human meningioma. These observations imply that PDGF autocrine loops are engaged in human meningioma and suggest that activated PDGF-beta receptors might contribute to the pathology of this common brain neoplasm. The study of PDGF autocrine loops and human meningioma has been slowed by the scarcity of meningioma cell culture model systems. Furthermore, in meningioma tumor tissue, the activation state of PDGF receptors is difficult to assess with conventional reagents, because the tumor is intermixed with normal stroma. In fact, there is no evidence that PDGF receptors within the tumor are activated by ligand. We used a synthetic tyrosine phosphopeptide to raise an antibody that reports the phosphorylation state of tyrosine 751 in the human PDGF-beta receptor. Phosphorylated tyrosine 751 is a recognition site for phosphatidylinositol 3'-kinase, a cytoplasmic effector of PDGF-induced mitogenesis, chemotaxis, and membrane ruffling. Immunoblotting and immunostaining analyses with this antibody show that the PDGF-beta receptor is constitutively phosphorylated at tyrosine 751 within multiple fresh surgical isolates of human meningioma. These findings are consistent with a role for activated PDGF receptors in the proliferation of human meningiomas.

Regenerative Medicine for Periodontal and Peri-implant Diseases.

The balance between bone resorption and bone formation is vital for maintenance and regeneration of alveolar bone and supporting structures around teeth and dental implants. Tissue regeneration in the oral cavity is regulated by multiple cell types, signaling mechanisms, and matrix interactions. A goal for periodontal tissue engineering/regenerative medicine is to restore oral soft and hard tissues through cell, scaffold, and/or signaling approaches to functional and aesthetic oral tissues. Bony defects in the oral cavity can vary significantly, ranging from smaller intrabony lesions resulting from periodontal or peri-implant diseases to large osseous defects that extend through the jaws as a result of trauma, tumor resection, or congenital defects. The disparity in size and location of these alveolar defects is compounded further by patient-specific and environmental factors that contribute to the challenges in periodontal regeneration, peri-implant tissue regeneration, and alveolar ridge reconstruction. Efforts have been made over the last few decades to produce reliable and predictable methods to stimulate bone regeneration in alveolar bone defects. Tissue engineering/regenerative medicine provide new avenues to enhance tissue regeneration by introducing bioactive models or constructing patient-specific substitutes. This review presents an overview of therapies (e.g., protein, gene, and cell based) and biomaterials (e.g., resorbable, nonresorbable, and 3-dimensionally printed) used for alveolar bone engineering around teeth and implants and for implant site development, with emphasis on most recent findings and future directions.