The Giannobile laboratory explores the potential of novel methods of growth factor delivery such as gene therapy to stimulate periodontal tissue repair. In addition, the lab is involved in clinical research to develop predictive markers of periodontal and peri-implant bone loss.
William V. Giannobile, DDS, MS, DMSc
Najjar Endowed Professor of Dentistry and Biomedical Engineering
Department of Periodontics and Oral Medicine
University of Michigan School of Dentistry
1011 N. University Ave, Rm #3397
Ann Arbor, MI 48109-1078
Dr. Giannobile is the Najjar Endowed Professor of Dentistry and Biomedical Engineering and Chair of the Department of Periodontics and Oral Medicine at the School of Dentistry. He received his DDS and an MS in Oral Biology from the University of Missouri. He later received his certificate in Periodontology and Doctor of Medical Science in Oral Biology from Harvard University. He subsequently completed postdoctoral training in Molecular Biology at the Dana Farber Cancer Institute and Harvard Medical School.
Dr. Giannobile previously served as a faculty member at Harvard and Forsyth Institute in Boston. He has published and lectured extensively in the fields of Regenerative Medicine, Tissue Engineering, and Salivary Diagnostics as it relates to periodontal and peri-implant reconstruction.
Dr. Giannobile is an Editor-in-Chief of the Journal of Dental Research and is on the editorial boards of multiple journals. He is a fellow of the American College of Dentists and a Diplomate of the American Board of Periodontology. Dr. Giannobile currently serves as president of the American Academy of Periodontology Foundation.
Dr. Giannobile also serves as a consultant to the National Institutes of Health. To read more about Dr. Giannobile as an NIDCR investigator, please visit the NIDCR website for an article on the future impact of research on periodontal disease.
The most recent 50 publications are reported below via PubMed search.
To see all PubMed results go to this complete listing of publications by Dr. Giannobile.
TLR4, NOD1 and NOD2 Mediate Immune Recognition of Putative Newly-Identified Periodontal Pathogens.
Mol Oral Microbiol. 2015 Jul 14;
Authors: Marchesan J, Jiao Y, Schaff RA, Hao J, Morelli T, Kinney JS, Gerow E, Sheridan R, Rodrigues V, Paster BJ, Inohara N, Giannobile WV
Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. While the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, 6 being classical pathogens and 4 putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone marrow-derived macrophages (BMDM) from wild-type (WT) and toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. C. concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney (HEK) cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2-stimulatory activity. These studies allowed us to provide important evidence on newly-identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials. gov NCT01154855). This article is protected by copyright. All rights reserved.
PMID: 26177212 [PubMed - as supplied by publisher]
Wound models for periodontal and bone regeneration: the role of biologic research.
Periodontol 2000. 2015 Jun;68(1):7-20
Authors: Sculean A, Chapple IL, Giannobile WV
The ultimate goals of periodontal therapy remain the complete regeneration of those periodontal tissues lost to the destructive inflammatory-immune response, or to trauma, with tissues that possess the same structure and function, and the re-establishment of a sustainable health-promoting biofilm from one characterized by dysbiosis. This volume of Periodontology 2000 discusses the multiple facets of a transition from therapeutic empiricism during the late 1960s, toward regenerative therapies, which is founded on a clearer understanding of the biophysiology of normal structure and function. This introductory article provides an overview on the requirements of appropriate in vitro laboratory models (e.g. cell culture), of preclinical (i.e. animal) models and of human studies for periodontal wound and bone repair. Laboratory studies may provide valuable fundamental insights into basic mechanisms involved in wound repair and regeneration but also suffer from a unidimensional and simplistic approach that does not account for the complexities of the in vivo situation, in which multiple cell types and interactions all contribute to definitive outcomes. Therefore, such laboratory studies require validatory research, employing preclinical models specifically designed to demonstrate proof-of-concept efficacy, preliminary safety and adaptation to human disease scenarios. Small animal models provide the most economic and logistically feasible preliminary approaches but the outcomes do not necessarily translate to larger animal or human models. The advantages and limitations of all periodontal-regeneration models need to be carefully considered when planning investigations to ensure that the optimal design is adopted to answer the specific research question posed. Future challenges lie in the areas of stem cell research, scaffold designs, cell delivery and choice of growth factors, along with research to ensure appropriate gingival coverage in order to prevent gingival recession during the healing phase.
PMID: 25867976 [PubMed - in process]
Improving the quality of papers submitted to dental journals: Transcription of session for editors, associate editors, publishers and others with an interest in scientific publishing held at IADR meeting in Cape Town on Wednesday, 25 June 2014.
J Dent. 2015 Aug;43(8):855-64
Authors: Eaton KA, Giannobile WV, Sourgen DL, Balaji SM, Honkala E, Lynch CD
This satellite symposium was the fourth in a series for editors, publishers, reviewers and all those with an interest in scientific publishing. It was held on Wednesday 25th June 2014 at the IADR International meeting in Cape Town, South Africa. The symposium attracted more than 180 attendees. This symposium placed an emphasis on how the quality of papers submitted to dental journals could be improved. The panel included representation from editors, researchers and publishers from North America, India and the Gulf States. The symposium identified a number of challenges for editors and publishers, including the poor quality of many papers submitted to dental and other scientific journals, plagiarism, attempted duplicate publication and sometimes fraudulent results. Where possible speakers are identified by name. A subsequent symposium was held during the IADR meeting in Boston on March 11th 2015. Involvement open to editors, associate editors, publishers and others with an interest in scientific publishing.
PMID: 25748020 [PubMed - in process]
Counterpoint: Risk factors, including genetic information, add value in stratifying patients for optimal preventive dental care.
J Am Dent Assoc. 2015 Mar;146(3):174-8
Authors: Braun TM, Doucette-Stamm L, Duff GW, Kornman KS, Giannobile WV
BACKGROUND: There is disagreement as to whether patient stratification by a combination of diabetes, smoking, and genetic test results is useful for informing the frequency of dental prophylaxes.
METHODS: The authors appeal to basic tenets of clinical study design and statistical analysis of clinical investigations, and highlight how secondary ad hoc analyses, such as those of Diehl and colleagues, are frequently underpowered and inconclusive. They also provide evidence from numerous studies supporting the use of genetics to identify risk.
RESULTS: The authors believe the conclusions reached from their original analyses are valid and the analyses of Diehl and colleagues serve to simply reinforce the authors' specific intent of avoiding such underpowered analyses altogether with the Michigan Personalized Prevention Study.
CONCLUSIONS: Until full genome sequencing in many people with highly specified disease phenotypes is feasible, experimental approaches based on biological findings and hypothesis testing should not be summarily discounted.
PRACTICAL IMPLICATIONS: Stratification of patients to provide "personalized" treatment remains an important, yet elusive, goal. The current debate serves to highlight the need for large, clinical utility studies that can adequately determine how phenotypic and genotypic data can be best used to improve oral health in the US population.
PMID: 25726344 [PubMed - in process]
Tissue engineering for bone regeneration and osseointegration in the oral cavity.
Dent Mater. 2015 Apr;31(4):317-38
Authors: Pilipchuk SP, Plonka AB, Monje A, Taut AD, Lanis A, Kang B, Giannobile WV
OBJECTIVE: The focus of this review is to summarize recent advances on regenerative technologies (scaffolding matrices, cell/gene therapy and biologic drug delivery) to promote reconstruction of tooth and dental implant-associated bone defects.
METHODS: An overview of scaffolds developed for application in bone regeneration is presented with an emphasis on identifying the primary criteria required for optimized scaffold design for the purpose of regenerating physiologically functional osseous tissues. Growth factors and other biologics with clinical potential for osteogenesis are examined, with a comprehensive assessment of pre-clinical and clinical studies. Potential novel improvements to current matrix-based delivery platforms for increased control of growth factor spatiotemporal release kinetics are highlighting including recent advancements in stem cell and gene therapy.
RESULTS: An analysis of existing scaffold materials, their strategic design for tissue regeneration, and use of growth factors for improved bone formation in oral regenerative therapies results in the identification of current limitations and required improvements to continue moving the field of bone tissue engineering forward into the clinical arena.
SIGNIFICANCE: Development of optimized scaffolding matrices for the predictable regeneration of structurally and physiologically functional osseous tissues is still an elusive goal. The introduction of growth factor biologics and cells has the potential to improve the biomimetic properties and regenerative potential of scaffold-based delivery platforms for next-generation patient-specific treatments with greater clinical outcome predictability.
PMID: 25701146 [PubMed - in process]
Periodontal Health in Women With Early-Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study.
J Periodontol. 2015 Jul;86(7):906-16
Authors: Taichman LS, Inglehart MR, Giannobile WV, Braun T, Kolenic G, Van Poznak C
BACKGROUND: Aromatase inhibitor (AI) use results in low estrogen levels, which in turn affect bone mineral density (BMD). Periodontitis, alveolar bone loss, and tooth loss are associated with low BMD. The goal of this study is to assess the prevalence of periodontitis and perceived oral health and evaluate salivary biomarkers in postmenopausal women who are survivors of early-stage (I to IIIA) breast cancer (BCa) and receive adjuvant AI therapy.
METHODS: Participants included 58 postmenopausal women: 29 with BCa on AIs and 29 controls without BCa diagnoses. Baseline periodontal status was assessed with: 1) periodontal probing depth (PD); 2) bleeding on probing (BOP); and 3) attachment loss (AL). Demographic and dental utilization information was gathered by questionnaire. Linear regression modeling was used to analyze the outcomes.
RESULTS: No differences were found in mean PD or number of teeth. The AI group had significantly more sites with BOP (27.8 versus 16.7; P = 0.02), higher worst-site AL (5.2 versus 4.0 mm; P <0.01), and more sites with dental calculus (18.2 versus 6.4; P <0.001) than controls. Linear regression adjusted for income, tobacco use, dental insurance, and previous radiation and chemotherapy exposure demonstrated that AI use increased AL by >2 mm (95% confidence interval, 0.46 to 3.92). Median salivary osteocalcin and tumor necrosis factor-α levels were significantly higher in the AI group than the control group.
CONCLUSION: This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis.
PMID: 25672657 [PubMed - in process]
Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial.
J Bone Miner Res. 2015 Jul;30(7):1206-16
Authors: Kaigler D, Avila-Ortiz G, Travan S, Taut AD, Padial-Molina M, Rudek I, Wang F, Lanis A, Giannobile WV
Bone engineering of localized craniofacial osseous defects or deficiencies by stem cell therapy offers strong prospects to improve treatment predictability for patient care. The aim of this phase 1/2 randomized, controlled clinical trial was to evaluate reconstruction of bone deficiencies of the maxillary sinus with transplantation of autologous cells enriched with CD90+ stem cells and CD14+ monocytes. Thirty human participants requiring bone augmentation of the maxillary sinus were enrolled. Patients presenting with 50% to 80% bone deficiencies of the maxillary sinus were randomized to receive either stem cells delivered onto a β-tricalcium phosphate scaffold or scaffold alone. Four months after treatment, clinical, radiographic, and histologic analyses were performed to evaluate de novo engineered bone. At the time of alveolar bone core harvest, oral implants were installed in the engineered bone and later functionally restored with dental tooth prostheses. Radiographic analyses showed no difference in the total bone volume gained between treatment groups; however, density of the engineered bone was higher in patients receiving stem cells. Bone core biopsies showed that stem cell therapy provided the greatest benefit in the most severe deficiencies, yielding better bone quality than control patients, as evidenced by higher bone volume fraction (BVF; 0.5 versus 0.4; p = 0.04). Assessment of the relation between degree of CD90+ stem cell enrichment and BVF showed that the higher the CD90 composition of transplanted cells, the greater the BVF of regenerated bone (r = 0.56; p = 0.05). Oral implants were placed and restored with functionally loaded dental restorations in all patients and no treatment-related adverse events were reported at the 1-year follow-up. These results provide evidence that cell-based therapy using enriched CD90+ stem cell populations is safe for maxillary sinus floor reconstruction and offers potential to accelerate and enhance tissue engineered bone quality in other craniofacial bone defects and deficiencies (Clinicaltrials.gov NCT00980278). © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.
PMID: 25652112 [PubMed - in process]
Outcomes of regenerative treatment with rhPDGF-BB and rhFGF-2 for periodontal intra-bony defects: a systematic review and meta-analysis.
J Clin Periodontol. 2015 Mar;42(3):272-80
Authors: Khoshkam V, Chan HL, Lin GH, Mailoa J, Giannobile WV, Wang HL, Oh TJ
BACKGROUND: The aim was to evaluate the effects of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and recombinant human fibroblast growth factor-2 (rhFGF-2) on treating periodontal intra-bony defects, compared to the control (carrier alone).
METHODS: Electronic and hand searches were performed to identify eligible studies. The weighed mean differences of linear defect fill (LDF), probing depth (PD) reduction, clinical attachment level (CAL) gain and gingival recession (GR) were calculated using random effect meta-analysis.
RESULTS: The searches yielded 1018 articles, of which seven studies were included. Only one included study was considered at low risk of bias. The outcomes that reached statistical significance in comparison to carriers alone included: LDF (0.95 mm, 95% CI: 0.62-1.28 mm or 20.17%, 95% CI: 11.81-28.54%) and CAL gain (0.34 mm, 95% CI: 0.03-0.65 mm) for PDGF, and LDF (21.22%, 95% CI: 5.82-36.61%) for FGF-2.
CONCLUSIONS: Within the limits of this review, rhPDGF-BB demonstrated significantly more LDF and CAL gain; rhFGF-2 resulted in significantly higher percentage of LDF.
PMID: 25605424 [PubMed - in process]
Epigenetics and its role in periodontal diseases: a state-of-the-art review.
J Periodontol. 2015 Apr;86(4):556-68
Authors: Larsson L, Castilho RM, Giannobile WV
The immune response to oral bacteria and the subsequent activation of inflammatory signaling is not only dependent on genetic factors. The importance of so-called epigenetic mechanisms presents additional regulatory pathways of genes involved in maintaining chronic inflammation, including gingivitis and periodontitis. The term epigenetics relates to changes in gene expression that are not encoded in the DNA sequence itself and include chemical alterations of DNA and its associated proteins. These changes lead to remodeling of the chromatin and subsequent activation or inactivation of a gene. Epigenetic mechanisms have been found to contribute to disease, including cancer and autoimmune or inflammatory diseases. In this state-of-the art review, the authors provide the latest findings on the involvement of epigenetic modifications in the development of periodontal disease and present emerging therapeutic strategies aimed at epigenetic targets (epidrugs) associated with the disruption of tissue homeostasis and the development of periodontitis.
PMID: 25415244 [PubMed - in process]
Cell population kinetics of collagen scaffolds in ex vivo oral wound repair.
PLoS One. 2014;9(11):e112680
Authors: Agis H, Collins A, Taut AD, Jin Q, Kruger L, Görlach C, Giannobile WV
Biodegradable collagen scaffolds are used clinically for oral soft tissue augmentation to support wound healing. This study sought to provide a novel ex vivo model for analyzing healing kinetics and gene expression of primary human gingival fibroblasts (hGF) within collagen scaffolds. Sponge type and gel type scaffolds with and without platelet-derived growth factor-BB (PDGF) were assessed in an hGF containing matrix. Morphology was evaluated with scanning electron microscopy, and hGF metabolic activity using MTT. We quantitated the population kinetics within the scaffolds based on cell density and distance from the scaffold border of DiI-labled hGFs over a two-week observation period. Gene expression was evaluated with gene array and qPCR. The sponge type scaffolds showed a porous morphology. Absolute cell number and distance was higher in sponge type scaffolds when compared to gel type scaffolds, in particular during the first week of observation. PDGF incorporated scaffolds increased cell numbers, distance, and formazan formation in the MTT assay. Gene expression dynamics revealed the induction of key genes associated with the generation of oral tissue. DKK1, CYR61, CTGF, TGFBR1 levels were increased and integrin ITGA2 levels were decreased in the sponge type scaffolds compared to the gel type scaffold. The results suggest that this novel model of oral wound healing provides insights into population kinetics and gene expression dynamics of biodegradable scaffolds.
PMID: 25397671 [PubMed - in process]
The multi-center randomized controlled trial (RCT) published by the journal of the American Medical Association (JAMA) on the effect of periodontal therapy on glycated hemoglobin (HbA1c) has fundamental problems.
J Evid Based Dent Pract. 2014 Sep;14(3):127-32
Authors: Borgnakke WS, Chapple IL, Genco RJ, Armitage G, Bartold PM, D'Aiuto F, Eke PI, Giannobile WV, Kocher T, Kornman KS, Lang NP, Madianos PN, Murakami S, Nishimura F, Offenbacher S, Preshaw PM, Rahman AU, Sanz M, Slots J, Tonetti MS, Van Dyke TE
PMID: 25234213 [PubMed - indexed for MEDLINE]
SDF-1 enhances wound healing of critical-sized calvarial defects beyond self-repair capacity.
PLoS One. 2014;9(5):e97035
Authors: Jin Q, Giannobile WV
Host blood circulating stem cells are an important cell source that participates in the repair of damaged tissues. The clinical challenge is how to improve the recruitment of circulating stem cells into the local wound area and enhance tissue regeneration. Stromal-derived factor-1 (SDF-1) has been shown to be a potent chemoattractant of blood circulating stem cells into the local wound microenvironment. In order to investigate effects of SDF-1 on bone development and the repair of a large bone defect beyond host self-repair capacity, the BMP-induced subcutaneous ectopic bone formation and calvarial critical-sized defect murine models were used in this preclinical study. A dose escalation of SDF-1 were loaded into collagen scaffolds containing BMP, VEGF, or PDGF, and implanted into subcutaneous sites at mouse dorsa or calvarial critical-sized bone defects for 2 and 4 weeks. The harvested biopsies were examined by microCT and histology. The results demonstrated that while SDF-1 had no effect in the ectopic bone model in promoting de novo osteogenesis, however, in the orthotopic bone model of the critical-sized defects, SDF-1 enhanced calvarial critical-sized bone defect healing similar to VEGF, and PDGF. These results suggest that SDF-1 plays a role in the repair of large critical-sized defect where more cells are needed while not impacting de novo bone formation, which may be associated with the functions of SDF-1 on circulating stem cell recruitment and angiogenesis.
PMID: 24800841 [PubMed - indexed for MEDLINE]
Swallowed and aspirated dental prostheses and instruments in clinical dental practice: a report of five cases and a proposed management algorithm.
J Am Dent Assoc. 2014 May;145(5):459-63
Authors: Abusamaan M, Giannobile WV, Jhawar P, Gunaratnam NT
BACKGROUND: Accidental swallowing or aspiration of dental instruments and prostheses is a complication of dental procedures. Failure to manage these complications appropriately can lead to significant morbidity and possibly death.
CASE DESCRIPTION: The authors present three cases of accidental swallowing of dental instruments during procedures and two cases of aspiration, one during a procedure and one long after the procedure. Although three of these five cases of foreign-body aspiration or ingestion were caught early and the patients were referred for endoscopic retrieval, two patients experienced prolonged symptoms that affected their quality of life before intervention occurred. Practical Implications The authors reviewed the literature and propose an evidence-based algorithm for management of such complications. Adherence to the proposed algorithm may decrease morbidity and mortality and improve patient outcomes.
PMID: 24789239 [PubMed - in process]
Surgical periodontal therapy with and without initial scaling and root planing in the management of chronic periodontitis: a randomized clinical trial.
J Clin Periodontol. 2014 Jul;41(7):693-700
Authors: Aljateeli M, Koticha T, Bashutski J, Sugai JV, Braun TM, Giannobile WV, Wang HL
AIM: To compare the outcomes of surgical periodontal therapy with and without initial scaling and root planing.
METHODS: Twenty-four patients with severe chronic periodontitis were enrolled in this pilot, randomized controlled clinical trial. Patients were equally allocated into two treatment groups: Control group was treated with scaling and root planing, re-evaluation, followed by Modified Widman Flap surgery and test group received similar surgery without scaling and root planing. Clinical attachment level, probing depth and bleeding on probing were recorded. Standardized radiographs were analysed for linear bone change from baseline to 6 months. Wound fluid inflammatory biomarkers were also assessed.
RESULTS: Both groups exhibited statistically significant improvement in clinical attachment level and probing depth at 3 and 6 months compared to baseline. A statistically significant difference in probing depth reduction was found between the two groups at 3 and 6 months in favour of the control group. No statistically significant differences in biomarkers were detected between the groups.
CONCLUSIONS: Combined scaling and root planing and surgery yielded greater probing depth reduction as compared to periodontal surgery without initial scaling and root planing.
PMID: 24730621 [PubMed - indexed for MEDLINE]
HMGB1 localization during experimental periodontitis.
Mediators Inflamm. 2014;2014:816320
Authors: Nogueira AV, de Souza JA, de Molon RS, Pereira Eda S, de Aquino SG, Giannobile WV, Cirelli JA
AIM: This study sought to investigate the in vitro expression profile of high mobility group box 1 (HMGB1) in murine periodontal ligament fibroblasts (mPDL) stimulated with LPS or IL-1β and in vivo during ligature- or LPS-induced periodontitis in rats.
MATERIAL AND METHODS: For the in vivo study, 36 rats were divided into experimental and control groups, and biopsies were harvested at 7-30 d following disease induction. Bone loss and inflammation were evaluated. HMGB1 expression was assessed by immunohistochemistry, qPCR, and Western blot.
RESULTS: Significant increases in mPDL HMGB1 mRNA occurred at 4, 8, and 12 h with protein expression elevated by 24 h. HMGB1 mRNA expression in gingival tissues was significantly increased at 15 d in the LPS-PD model and at 7 and 15 d in the ligature model. Immunohistochemical staining revealed a significant increase in the number of HMGB1-positive cells during the experimental periods.
CONCLUSION: The results show that PDL cells produce HMGB1, which is increased and secreted extracellularly after inflammatory stimuli. In conclusion, this study demonstrates that HMGB1 may be associated with the onset and progression of periodontitis, suggesting that further studies should investigate the potential role of HMGB1 on periodontal tissue destruction.
PMID: 24692854 [PubMed - indexed for MEDLINE]
Biology of soft tissue wound healing and regeneration--consensus report of Group 1 of the 10th European Workshop on Periodontology.
J Clin Periodontol. 2014 Apr;41 Suppl 15:S1-5
Authors: Hämmerle CH, Giannobile WV, Working Group 1 of the European Workshop on Periodontology
BACKGROUND: The scope of this consensus was to review the biological processes of soft tissue wound healing in the oral cavity and to histologically evaluate soft tissue healing in clinical and pre-clinical models.
AIMS: To review the current knowledge regarding the biological processes of soft tissue wound healing at teeth, implants and on the edentulous ridge. Furthermore, to review soft tissue wound healing at these sites, when using barrier membranes, growth and differentiation factors and soft tissue substitutes.
COLLECTION OF DATA: Searches of the literature with respect to recessions at teeth and soft tissue deficiencies at implants, augmentation of the area of keratinized tissue and soft tissue volume were conducted. The available evidence was collected, categorized and summarized.
FUNDAMENTAL PRINCIPLES OF ORAL SOFT TISSUE WOUND HEALING: Oral mucosal and skin wound healing follow a similar pattern of the four phases of haemostasis, inflammation, proliferation and maturation/matrix remodelling. The soft connective tissue determines the characteristics of the overlaying oral epithelium. Within 7-14 days, epithelial healing of surgical wounds at teeth is completed. Soft tissue healing following surgery at implants requires 6-8 weeks for maturation. The resulting tissue resembles scar tissue. Well-designed pre-clinical studies providing histological data have been reported describing soft tissue wound healing, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Few controlled clinical studies with low numbers of patients are available for some of the treatments reviewed at teeth. Whereas, histological new attachment has been demonstrated in pre-clinical studies resulting from some of the treatments reviewed, human histological data commonly report a lack of new attachment but rather long junctional epithelial attachment and connective tissue adhesion. Regarding soft tissue healing at implants human data are very scarce.
CONCLUSIONS: Oral soft tissue healing at teeth, implants and the edentulous ridge follows the same phases as skin wound healing. Histological studies in humans have not reported new attachment formation at teeth for the indications studied. Human histological data of soft tissue wound healing at implants are limited.
CLINICAL RECOMMENDATIONS: The use of barriers membranes, growth and differentiation factors and soft tissue substitutes for the treatment of localized gingival/mucosal recessions, insufficient amount of keratinized tissue and insufficient soft tissue volume is at a developing stage.
PMID: 24640995 [PubMed - indexed for MEDLINE]
Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis.
Arthritis Res Ther. 2013;15(6):R186
Authors: Marchesan JT, Gerow EA, Schaff R, Taut AD, Shin SY, Sugai J, Brand D, Burberry A, Jorns J, Lundy SK, Nuñez G, Fox DA, Giannobile WV
INTRODUCTION: Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model.
METHODS: DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression.
RESULTS: Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA/CII group and IL-1β, tumor necrosis factor-α, transforming growth factor-β, IL-6 and IL-23 in the IFA/CII group.
CONCLUSIONS: Chronic P. gingivalis oral infection prior to arthritis induction increases the immune system activation favoring Th17 cell responses, and ultimately accelerating arthritis development. These results suggest that chronic oral infection may influence RA development mainly through activation of Th17-related pathways.
PMID: 24456966 [PubMed - indexed for MEDLINE]
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.
J Dent. 2014 Mar;42(3):219-28
Authors: Eaton KA, Rex Holland G, Giannobile WV, Hancocks S, Robinson PG, Lynch CD
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 Christopher 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 Seattle 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.
PMID: 24440711 [PubMed - in process]
Crevicular fluid biomarkers and periodontal disease progression.
J Clin Periodontol. 2014 Feb;41(2):113-20
Authors: Kinney JS, Morelli T, Oh M, Braun TM, Ramseier CA, Sugai JV, Giannobile WV
AIM: Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP).
MATERIALS AND METHODS: In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6 months, patients received periodontal therapy and continued participation from 6 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p = 0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing.
RESULTS: Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61, 86).
CONCLUSIONS: Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745).
PMID: 24303954 [PubMed - indexed for MEDLINE]
Image-based, fiber guiding scaffolds: a platform for regenerating tissue interfaces.
Tissue Eng Part C Methods. 2014 Jul;20(7):533-42
Authors: Park CH, Rios HF, Taut AD, Padial-Molina M, Flanagan CL, Pilipchuk SP, Hollister SJ, Giannobile WV
In the oral and craniofacial complex, tooth loss is the most commonly acquired disfiguring injury. Among the most formidable challenges of reconstructing tooth-supporting osseous defects in the oral cavity is the regeneration of functional multi-tissue complexes involving bone, ligament, and tooth cementum. Furthermore, periodontal multi-tissue engineering with spatiotemporal orientation of the periodontal ligament (PDL) remains the most challenging obstacle for restoration of physiological loading and homeostasis. We report on the ability of a hybrid computer-designed scaffold--developed utilizing computed tomography--to predictably facilitate the regeneration and integration of dental supporting tissues. Here, we provide the protocol for rapid prototyping, manufacture, surgical implantation, and evaluation of dual-architecture scaffolds for controlling fiber orientation and facilitating morphogenesis of bone-ligament complexes. In contrast to conventional single-system methods of fibrous tissue formation, our protocol supports rigorous control of multi-compartmental scaffold architecture using computational scaffold design and manufacturing by 3D printing, as well as the evaluation of newly regenerated tissue physiology for clinical implementation.
PMID: 24188695 [PubMed - indexed for MEDLINE]
Generation of site-appropriate tissue by a living cellular sheet in the treatment of mucogingival defects.
J Periodontol. 2014 Apr;85(4):e57-64
Authors: Scheyer ET, Nevins ML, Neiva R, Cochran DL, Giannobile WV, Woo SB, King WN, Spitznagel JK, Bates D, McGuire MK
BACKGROUND: Generation of site-appropriate tissue in the oral cavity includes the restoration of the correct anatomic type, amount, and distribution of the tissue. This study is a post hoc analysis of data collected during previously published results from two randomized clinical trials of a living cellular sheet (LCS; allogenic cultured keratinocytes and fibroblasts in bovine collagen) versus a free gingival graft (FGG), evaluating their ability to augment keratinized tissue or gingiva.
METHODS: Post hoc histologic and clinical (photographic) comparisons of the outcomes of treatment were performed on histologic and photographic data gathered in the two randomized clinical trials.
RESULTS: Histologic findings showed that LCS-treated sites resembled gingiva rather than alveolar mucosa. Photographic analysis indicated that LCS treatment resulted in more site-appropriate tissue than FGG in terms of tissue color, with adjacent untreated tissue, absence of scar formation or keloid-like appearance, and mucogingival junction alignment.
CONCLUSION: Treatment of mucogingival defects with LCS resulted in the generation of tissue that is more site appropriate than tissue transplanted from the palate.
PMID: 24070401 [PubMed - indexed for MEDLINE]
Locally-delivered antibiotics for management of periodontitis: current understanding.
J Mich Dent Assoc. 2013 Jul;95(7):42-7
Authors: Aljateeli M, Giannobile WV, Wang HL
The primary etiology of periodontitis is bacterial plaque in a susceptible host. In an attempt to eradicate or reduce periopathogenic bacterial levels, locally-delivered antibiotic (LDA) agents have been suggested and have shown promising results. By applying the antibiotics locally, clinicians are able to overcome some of the disadvantages of systemic antibiotics in the management of periodontal patients. However, selecting a specific LDA to treat periodontitis out of the many available agents is not an easy task. Furthermore, timing of when to apply these agents can also be challenging. This literature review discusses the current understanding of the use of LDA in the management of periodontitis. A decision tree was developed in an attempt to guide the clinician in understanding the indications for the use of controlled delivery antimicrobial agents as an adjunct or alternative to traditional treatment modalities.
PMID: 23980405 [PubMed - indexed for MEDLINE]
Sclerostin antibody stimulates bone regeneration after experimental periodontitis.
J Bone Miner Res. 2013 Nov;28(11):2347-56
Authors: Taut AD, Jin Q, Chung JH, Galindo-Moreno P, Yi ES, Sugai JV, Ke HZ, Liu M, Giannobile WV
The reconstruction of large osseous defects due to periodontitis is a challenge in regenerative therapy. Sclerostin, secreted by osteocytes, is a key physiological inhibitor of osteogenesis. Pharmacologic inhibition of sclerostin using sclerostin-neutralizing monoclonal antibody (Scl-Ab) thus increases bone formation, bone mass and bone strength in models of osteopenia and fracture repair. This study assessed the therapeutic potential of Scl-Ab to stimulate alveolar bone regeneration following experimental periodontitis (EP). Ligature-induced EP was induced in rats to generate localized alveolar bone defects. Following 4 weeks of disease induction, Scl-Ab (+EP) or vehicle (+/- EP) were systemically delivered, twice weekly for up to 6 wks to determine the ability of Scl-Ab to regenerate bone around tooth-supporting osseous defects. 3 and 6 wks after the initiation of Scl-Ab or vehicle treatment, femur and maxillary jawbones were harvested for histology, histomorphometry, and micro-computed tomography (micro-CT) of linear alveolar bone loss (ABL) and volumetric measures of bone support, including bone volume fraction (BVF) and tissue mineral density (TMD). Serum was analyzed to examine bone turnover markers during disease and regenerative therapy. Vehicle + EP animals exhibited maxillary bone loss (BVF, TMD and ABL) at ligature removal and thereafter. 6 weeks of Scl-Ab significantly improved maxillary bone healing, as measured by BVF, TMD and ABL, when compared to vehicle + EP. After 6 weeks of treatment, BVF and TMD values in the Scl-Ab + EP group were similar to those of healthy controls. Serum analysis demonstrated higher levels of bone formation markers osteocalcin and PINP in Scl-Ab treatment groups. Scl-Ab restored alveolar bone mass following experimental periodontitis. These findings warrant further exploration of Scl-Ab therapy in this and other oral bone defect disease scenarios.
PMID: 23712325 [PubMed - indexed for MEDLINE]
Induction of bone loss by pathobiont-mediated Nod1 signaling in the oral cavity.
Cell Host Microbe. 2013 May 15;13(5):595-601
Authors: Jiao Y, Darzi Y, Tawaratsumida K, Marchesan JT, Hasegawa M, Moon H, Chen GY, Núñez G, Giannobile WV, Raes J, Inohara N
Periodontitis is a common disease that is characterized by resorption of the alveolar bone and mediated by commensal bacteria that trigger host immune responses and bone destruction through unidentified mechanisms. We report that Nod1, an innate intracellular host receptor for bacterial peptidoglycan-related molecules, is critical for commensal-induced periodontitis in a mouse model. Mice lacking Nod1 exhibit reduced bone resorption as well as impaired recruitment of neutrophils to gingival tissues and osteoclasts to the alveolar bone, which mediate tissue and bone destruction. Further analysis showed that accumulation of a Nod1-stimulating commensal bacterium, NI1060, at gingival sites was sufficient to induce neutrophil recruitment and bone resorption. Genomic sequencing revealed that NI1060 is a mouse-specific bacterium that is related to bacteria associated with the development of aggressive periodontitis in humans. These findings provide insight into commensal-host interactions contributing to periodontitis and identify a potential target for preventing this common oral disease.
PMID: 23684310 [PubMed - indexed for MEDLINE]
Characterization of periodontal structures of enamelin-null mice.
J Periodontol. 2014 Jan;85(1):195-203
Authors: Chan HL, Giannobile WV, Eber RM, Simmer JP, Hu JC
BACKGROUND: Enamelin-null (ENAM(-/-)) mice have no enamel. When characterizing ENAM(-/-) mice, alveolar bone height reduction was observed, and it was hypothesized that enamel defects combined with diet are associated with the periodontal changes of ENAM(-/-)mice. The aim of the present study is to compare the dimension of interradicular bone of ENAM(-/-) (knock-out [KO]) with wild-type (WT) mice, maintained on hard (HC) or soft (SC) chow.
METHODS: A total of 100 animals divided into four groups were studied at 3, 8, and 24 weeks of age: 1) KO/HC; 2) KO/SC; 3) WT/HC; and 4) WT/SC. Microcomputed tomography was performed, and the following measurements were made between mandibular first (M1) and second (M2) molars: relative alveolar bone height (RBH), crestal bone width (CBW), bone volume (BV), bone mineral content (BMC), and bone mineral density (BMD). The position of M1 and M2 in relation to the inferior border of the mandible was also determined at 24 weeks. All variables were analyzed by one-way analysis of variance and Dunnett test for pairwise comparisons. Morphologic analyses were conducted on hematoxylin and eosin-stained sections.
RESULTS: Radiographically, the enamel layer was absent in ENAM(-/-) mice. Interproximal open contacts were observed exclusively in ENAM(-/-) mice, and the prevalence decreased over time, suggesting that a shifting of tooth position had occurred. Additionally, in the two ENAM(-/-) groups, RBH was significantly lower at 8 and 24 weeks (P <0.02); CBW, BV, and BMC were significantly less (P <0.05) at 24 weeks. No differences in BMD were found among the four groups. The molars migrated to a more coronal position in ENAM(-/-) mice and mice on HC. Histologic findings were consistent with radiographic observations. After eruption, the junctional epithelium was less organized in ENAM(-/-) mice.
CONCLUSION: The interdental bone density was not affected in the absence of enamelin, but its volume was, which is likely a consequence of alternations in tooth position.
PMID: 23646854 [PubMed - indexed for MEDLINE]
Clinical, microbiological, and salivary biomarker profiles of dental implant patients with type 2 diabetes.
Clin Oral Implants Res. 2014 Jul;25(7):803-12
Authors: Tatarakis N, Kinney JS, Inglehart M, Braun TM, Shelburne C, Lang NP, Giannobile WV, Oh TJ
OBJECTIVE: Regulators of peri-implant bone loss in patients with diabetes appear to involve multiple risk factors that have not been clearly elucidated. This study was conducted to explore putative local etiologic factors on implant bone loss in relation to type 2 diabetes mellitus, including clinical, microbial, salivary biomarker, and psychosocial factors.
MATERIALS AND METHODS: Thirty-two subjects (divided into type 2 diabetes mellitus and non-diabetic controls), having at least one functional implant and six teeth, were enrolled in a 1-year longitudinal investigation. Analyses of clinical measurements and standardized intra-oral radiographs, saliva and serum biomarkers (via protein arrays for 20 selected markers), and plaque biofilm (via qPCR for eight periodontal pathogens) were performed at baseline and 1 year. In addition, the subjects were asked to respond to questionnaires to assess behavioral and psychosocial variables.
RESULTS: There was a significant increase from baseline to 1 year in the probing depth of implants in the diabetes group (1.95 mm to 2.35 mm, P = 0.015). The average radiographic bone loss during the study period marginally increased at dental implants compared to natural teeth over the study period (0.08 mm vs. 0.05 mm; P = 0.043). The control group harbored higher levels of Treponema denticola at their teeth at baseline (P = 0.046), and the levels of the pathogen increased significantly over time around the implants of the same group (P = 0.003). Salivary osteoprotegerin (OPG) levels were higher in the diabetes group than the control group at baseline only; in addition, the salivary levels of IL-4, IL-10, and OPG associated with host defense were significantly reduced in the diabetes group (P = 0.010, P = 0.019, and P = 0.024), while controls showed an increase in the salivary OPG levels (P = 0.005). For psychosocial factors, there were not many significant changes over the observation period, except for some findings related to coping behaviors at baseline.
CONCLUSIONS: The study suggests that the clinical, microbiological, salivary biomarker, and psychosocial profiles of dental implant patients with type 2 diabetes who are under good metabolic control and regular maintenance care are very similar to those of non-diabetic individuals. Future studies are warranted to validate the findings in longer-term and larger clinical trials (ClinicalTrials.gov # NCT00933491).
PMID: 23445216 [PubMed - in process]
Determination of the dynamics of healing at the tissue-implant interface by means of microcomputed tomography and functional apparent moduli.
Int J Oral Maxillofac Implants. 2013 Jan-Feb;28(1):68-76
Authors: Chang PC, Seol YJ, Goldstein SA, Giannobile WV
PURPOSE: It is currently a challenge to determine the biomechanical properties of the hard tissue-dental implant interface. Recent advances in intraoral imaging and tomographic methods, such as microcomputed tomography (micro-CT), provide three-dimensional details, offering significant potential to evaluate the bone-implant interface, but yield limited information regarding osseointegration because of physical scattering effects emanating from metallic implant surfaces. In the present study, it was hypothesized that functional apparent moduli (FAM), generated from functional incorporation of the peri-implant structure, would eliminate the radiographic artifact-affected layer and serve as a feasible means to evaluate the biomechanical dynamics of tissue-implant integration in vivo.
MATERIALS AND METHODS: Cylindric titanium mini-implants were placed in osteotomies and osteotomies with defects in rodent maxillae. The layers affected by radiographic artifacts were identified, and the pattern of tissue-implant integration was evaluated from histology and micro-CT images over a 21-day observation period. Analyses of structural information, FAM, and the relationship between FAM and interfacial stiffness (IS) were done before and after eliminating artifacts.
RESULTS: Physical artifacts were present within a zone of about 100 to 150 Μm around the implant in both experimental defect situations (osteotomy alone and osteotomy + defect). All correlations were evaluated before and after eliminating the artifact-affected layers, most notably during the maturation period of osseointegration. A strong correlation existed between functional bone apparent modulus and IS within 300 Μm at the osteotomy defects (r > 0.9) and functional composite tissue apparent modulus in the osteotomy defects (r > 0.75).
CONCLUSION: Micro-CT imaging and FAM were of value in measuring the temporal process of tissue-implant integration in vivo. This approach will be useful to complement imaging technologies for longitudinal monitoring of osseointegration.
PMID: 23377049 [PubMed - indexed for MEDLINE]
Salivary diagnostics for periodontal diseases.
J Am Dent Assoc. 2012 Oct;143(10 Suppl):6S-11S
Authors: Giannobile WV
BACKGROUND: and Overview The use of salivary diagnostics continues to develop and advance the field of risk determination for periodontal diseases. Researchers are investigating genetic, microbial and protein biomarkers with the objective of translating findings to such aspects of clinical care as broad patient screening, monitoring and treatment planning.
METHODS: /st> In this review, the author briefly explores currently available salivary diagnostics used to identify bacteria prevalent in periodontal disease, and focuses on the future development and use of a variety of rapid disease detection platforms, such as lab-on-a-chip, as a point-of-care device for identification of patients' risk.
CLINICAL IMPLICATIONS: /st> Several diagnostic tests are commercially available, and point-of-care tests are under development. However, challenges remain regarding the introduction of these technologies to clinical practice and adoption by dental practitioners for promotion of personalized oral health care.
PMID: 23024320 [PubMed - indexed for MEDLINE]
Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial.
Cell Transplant. 2013;22(5):767-77
Authors: Kaigler D, Pagni G, Park CH, Braun TM, Holman LA, Yi E, Tarle SA, Bartel RL, Giannobile WV
Stem cell therapy offers potential in the regeneration of craniofacial bone defects; however, it has not been studied clinically. Tissue repair cells (TRCs) isolated from bone marrow represent a mixed stem and progenitor population enriched in CD90- and CD14-positive cells. In this phase I/II, randomized, controlled feasibility trial, we investigated TRC cell therapy to reconstruct localized craniofacial bone defects. Twenty-four patients requiring localized reconstruction of jawbone defects participated in this longitudinal trial. For regenerative therapy, patients were randomized to receive either guided bone regeneration (GBR) or TRC transplantation. At 6 or 12 weeks following treatment, clinical and radiographic assessments of bone repair were performed. Bone biopsies were harvested and underwent quantitative micro-computed tomographic (μCT) and bone histomorphometric analyses. Oral implants were installed, subsequently restored, and functionally loaded with tooth restorations. Reconstructed sites were assessed for 1 year following therapy. No study-related, serious adverse events were reported. Following therapy, clinical, radiographic, tomographic, and histological measures demonstrated that TRC therapy accelerated alveolar bone regeneration compared to GBR therapy. Additionally, TRC treatment significantly reduced the need for secondary bone grafting at the time of oral implant placement with a five fold decrease in implant bony dehiscence exposure (residual bone defects) as compared to GBR-treated sites(p < 0.01). Transplantation of TRCs for treatment of alveolar bone defects appears safe and accelerates bone regeneration, enabling jawbone reconstruction with oral implants. The results from this trial support expanded studies of TRC therapy in the treatment of craniofacial deformities (ClinicalTrials.gov number CT00755911).
PMID: 22776413 [PubMed - indexed for MEDLINE]
Functional assessment of dental implant osseointegration.
Int J Periodontics Restorative Dent. 2012 Oct;32(5):e147-53
Authors: Chang PC, Giannobile WV
Functional ankylosis of dental implants in alveolar bone is the current criterion to assess implant osseointegration from a biomechanical standpoint. In this literature review, the clinical significance and current available assessments of implant stability are discussed. However, these assessments demonstrate a variety of correlations to peri-implant structures and as such are difficult to translate to the clinical arena. Calculating the effective stiffness from homogenization of peri-implant tissues appears to be a more reliable approach to predict implant stability in preclinical studies, but the structure-biomechanical relationship remains a clinical challenge. Despite the limitations in functional assessments of dental implant stability and oral implant biomechanics, this review highlights some emerging approaches to adapt these measures to clinical situations.
PMID: 22754907 [PubMed - indexed for MEDLINE]
Postextraction alveolar ridge preservation: biological basis and treatments.
Int J Dent. 2012;2012:151030
Authors: Pagni G, Pellegrini G, Giannobile WV, Rasperini G
Following tooth extraction, the alveolar ridge undergoes an inevitable remodeling process that influences implant therapy of the edentulous area. Socket grafting is a commonly adopted therapy for the preservation of alveolar bone structures in combination or not with immediate implant placement although the biological bases lying behind this treatment modality are not fully understood and often misinterpreted. This review is intended to clarify the literature support to socket grafting in order to provide practitioners with valid tools to make a conscious decision of when and why to recommend this therapy.
PMID: 22737169 [PubMed]
Platelet-derived growth factor promotes periodontal regeneration in localized osseous defects: 36-month extension results from a randomized, controlled, double-masked clinical trial.
J Periodontol. 2013 Apr;84(4):456-64
Authors: Nevins M, Kao RT, McGuire MK, McClain PK, Hinrichs JE, McAllister BS, Reddy MS, Nevins ML, Genco RJ, Lynch SE, Giannobile WV
BACKGROUND: Recombinant human platelet-derived growth factor (rhPDGF) is safe and effective for the treatment of periodontal defects in short-term studies up to 6 months in duration. We now provide results from a 36-month extension study of a multicenter, randomized, controlled clinical trial evaluating the effect and long-term stability of PDGF-BB treatment in patients with localized severe periodontal osseous defects.
METHODS: A total of 135 participants were enrolled from six clinical centers for an extension trial. Eighty-three individuals completed the study at 36 months and were included in the analysis. The study investigated the local application of β-tricalcium phosphate scaffold matrix with or without two different dose levels of PDGF (0.3 or 1.0 mg/mL PDGF-BB) in patients possessing one localized periodontal osseous defect. Composite analysis for clinical and radiographic evidence of treatment success was defined as percentage of cases with clinical attachment level (CAL) ≥2.7 mm and linear bone growth (LBG) ≥1.1 mm.
RESULTS: The participants exceeding this composite outcome benchmark in the 0.3 mg/mL rhPDGF-BB group went from 62.2% at 12 months, 75.9% at 24 months, to 87.0% at 36 months compared with 39.5%, 48.3%, and 53.8%, respectively, in the scaffold control group at these same time points (P <0.05). Although there were no significant increases in CAL and LBG at 36 months among all groups, there were continued increases in CAL gain, LBG, and percentage bone fill over time, suggesting overall stability of the regenerative response.
CONCLUSION: PDGF-BB in a synthetic scaffold matrix promotes long-term stable clinical and radiographic improvements as measured by composite outcomes for CAL gain and LBG for patients possessing localized periodontal defects ( ClinicalTrials.gov no. CT01530126).
PMID: 22612364 [PubMed - indexed for MEDLINE]
Methods to validate tooth-supporting regenerative therapies.
Methods Mol Biol. 2012;887:135-48
Authors: Padial-Molina M, Marchesan JT, Taut AD, Jin Q, Giannobile WV, Rios HF
In humans, microbially induced inflammatory periodontal diseases are the primary initiators that disrupt the functional and structural integrity of the periodontium (i.e., the alveolar bone, the periodontal ligament, and the cementum). The reestablishment of its original structure, properties, and function constitutes a significant challenge in the development of new therapies to regenerate tooth-supporting defects. Preclinical models represent an important in vivo tool to critically evaluate and analyze the key aspects of novel regenerative therapies, including (1) safety, (2) effectiveness, (3) practicality, and (4) functional and structural stability over time. Therefore, these models provide foundational data that supports the clinical validation and the development of novel innovative regenerative periodontal technologies. Steps are provided on the use of the root fenestration animal model for the proper evaluation of periodontal outcome measures using the following parameters: descriptive histology, histomorphometry, immunostaining techniques, three-dimensional imaging, electron microscopy, gene expression analyses, and safety assessments. These methods will prepare investigators and assist them in identifying the key end points that can then be adapted to later stage human clinical trials.
PMID: 22566053 [PubMed - indexed for MEDLINE]
Advanced reconstructive technologies for periodontal tissue repair.
Periodontol 2000. 2012 Jun;59(1):185-202
Authors: Ramseier CA, Rasperini G, Batia S, Giannobile WV
Reconstructive therapies to promote the regeneration of lost periodontal support have been investigated through both preclinical and clinical studies. Advanced regenerative technologies using new barrier-membrane techniques, cell-growth-stimulating proteins or gene-delivery applications have entered the clinical arena. Wound-healing approaches using growth factors to target the restoration of tooth-supporting bone, periodontal ligament and cementum are shown to significantly advance the field of periodontal-regenerative medicine. Topical delivery of growth factors, such as platelet-derived growth factor, fibroblast growth factor or bone morphogenetic proteins, to periodontal wounds has demonstrated promising results. Future directions in the delivery of growth factors or other signaling models involve the development of innovative scaffolding matrices, cell therapy and gene transfer, and these issues are discussed in this paper.
PMID: 22507066 [PubMed - indexed for MEDLINE]
The stimulation of adipose-derived stem cell differentiation and mineralization by ordered rod-like fluorapatite coatings.
Biomaterials. 2012 Jul;33(20):5036-46
Authors: Liu J, Wang X, Jin Q, Jin T, Chang S, Zhang Z, Czajka-Jakubowska A, Giannobile WV, Nör JE, Clarkson BH
In this study, the effect of ordered rod-like FA coatings of metal discs on adipose-derived stem cell (ASC)'s growth, differentiation and mineralization was studied in vitro; and their mineral inductive effects in vivo. After 3 and 7 days, the cell number on the metal surfaces was significantly higher than those on the ordered and disordered FA surfaces. However, after 4 weeks much greater amounts of mineral formation was induced on the two FA surfaces with and even without osteogenesis induction. The osteogenic profiles showed the up regulation of a set of pro-osteogenic transcripts and bone mineralization phenotypic markers when the ASCs were grown on FA surfaces compared to metal surfaces at 7 and 21 days. In addition to BMP and TGFβ signaling pathways, EGF and FGF pathways also appeared to be involved in ASC differentiation and mineralization. In vivo studies showed accelerated and enhanced mineralized tissue formation integrated within ordered FA coatings. After 5 weeks, over 80% of the ordered FA coating was integrated with a mineralized tissue layer covering the implants. Both the intrinsic properties of the FA crystals and the topography of the FA coating appeared to dominate the cell differentiation and mineralization process.
PMID: 22483243 [PubMed - indexed for MEDLINE]
Tissue engineering bone-ligament complexes using fiber-guiding scaffolds.
Biomaterials. 2012 Jan;33(1):137-45
Authors: Park CH, Rios HF, Jin Q, Sugai JV, Padial-Molina M, Taut AD, Flanagan CL, Hollister SJ, Giannobile WV
Regeneration of bone-ligament complexes destroyed due to disease or injury is a clinical challenge due to complex topologies and tissue integration required for functional restoration. Attempts to reconstruct soft-hard tissue interfaces have met with limited clinical success. In this investigation, we manufactured biomimetic fiber-guiding scaffolds using solid free-form fabrication methods that custom fit complex anatomical defects to guide functionally-oriented ligamentous fibers in vivo. Compared to traditional, amorphous or random-porous polymeric scaffolds, the use of perpendicularly oriented micro-channels provides better guidance for cellular processes anchoring ligaments between two distinct mineralized structures. These structures withstood biomechanical loading to restore large osseous defects. Cell transplantation using hybrid scaffolding constructs with guidance channels resulted in predictable oriented fiber architecture, greater control of tissue infiltration, and better organization of ligament interface than random scaffold architectures. These findings demonstrate that fiber-guiding scaffolds drive neogenesis of triphasic bone-ligament integration for a variety of clinical scenarios.
PMID: 21993234 [PubMed - indexed for MEDLINE]
Analysis of tissue neogenesis in extraction sockets treated with guided bone regeneration: clinical, histologic, and micro-CT results.
Int J Periodontics Restorative Dent. 2011 Sep-Oct;31(5):457-69
Authors: Neiva R, Pagni G, Duarte F, Park CH, Yi E, Holman LA, Giannobile WV
The aims of this article were to perform a detailed evaluation of the healing of extraction sockets covered with a resorbable collagen membrane 12 weeks following exodontia and to determine if this device had ossifying properties. Ten consecutive subjects in need of extraction of maxillary premolars were recruited. Each subject had a hopeless maxillary premolar extracted with minimal trauma. Sockets were then covered with a collagen barrier membrane alone. At 12 weeks, reentry surgery was performed, clinical measurements were repeated, and bone core biopsies were obtained prior to dental implant placement for histologic and microcomputed tomography (micro-CT) analysis. Study sites showed mean bone regeneration horizontally of 7.7 mm (buccopalatally) and 4.6 mm (mesiodistally). Vertical bone repair showed a mean gain of 10.9 mm. Subtraction radiography showed a mean apical shift of the crestal bone at the center of the socket of 2.1 mm (range, 0.7 to 4.3 mm). Micro-CT and histology revealed formation of well-mineralized tissue at 12 weeks, with a mean percentage of vital bone of 45.87% ± 12.35%. No signs of membrane ossification were observed. A detailed analysis of tissue neogenesis in extraction sites protected by this barrier membrane has demonstrated that adequate bone formation for implant placement occurs as early as 12 weeks following exodontia, with minimal changes in alveolar ridge dimensions. No evidence of membrane ossification was observed.
PMID: 21845241 [PubMed - indexed for MEDLINE]
Bacterial and salivary biomarkers predict the gingival inflammatory profile.
J Periodontol. 2012 Jan;83(1):79-89
Authors: Lee A, Ghaname CB, Braun TM, Sugai JV, Teles RP, Loesche WJ, Kornman KS, Giannobile WV, Kinney JS
BACKGROUND: The aim of this human investigation is to explore the relationship of gingivitis with salivary biomarkers, periodontal pathogens, and interleukin (IL)-1 polymorphism after a transient inflammatory burden.
METHODS: Thirty healthy human participants were randomized by IL-1 genotype status to control for potential influences of this particular single nucleotide polymorphism on the inflammatory profile. Oral hygiene practices ceased for 21 days to induce gingivitis (induction), after which home care was reinstated until 35 days (resolution). Clinical parameters included plaque (PI) and gingival (GI) indices and papillary bleeding score (PBS). Levels and proportions of 40 subgingival bacteria were determined using checkerboard DNA-DNA hybridization. Saliva was analyzed using a multiplex protein array for 30 biomarkers associated with host defense, inflammation, tissue destruction, and angiogenesis.
RESULTS: Mean PI, GI, and PBS values were significantly increased during induction and decreased during resolution as measured at 35 days (P <0.01), although no differences were observed between IL-1 groups. Participants were stratified as either "high" or "low" responders based on inflammatory response (high: GI >1.5; low: GI ≤1.5). Baseline levels of salivary IL-6 and IL-8 demonstrated the highest ability to discriminate between high and low responders (area under the curve [AUC] of 0.81 and 0.72, respectively). Salivary biomarkers, matrix metalloproteinases (MMPs), and bacterial biofilm were combined to generate receiver operating characteristic curves. High levels of IL-6 and MMP-1 at baseline demonstrated the strongest ability to predict high responders (AUC of 0.89; odds ratio of 17.0; 95% confidence interval, 1.7 to 171.7).
CONCLUSION: In this proof-of-concept investigation, we identified specific biomarker and microbial signatures that are associated with gingival inflammation (ClinicalTrials.gov number NCT00980525).
PMID: 21563952 [PubMed - indexed for MEDLINE]
Living cellular construct for increasing the width of keratinized gingiva: results from a randomized, within-patient, controlled trial.
J Periodontol. 2011 Oct;82(10):1414-23
Authors: McGuire MK, Scheyer ET, Nevins ML, Neiva R, Cochran DL, Mellonig JT, Giannobile WV, Bates D
BACKGROUND: The standard of care for increasing keratinized gingiva adjacent to teeth that do not require root coverage is the free gingival graft (FGG). A pilot study indicated that the use of a living cellular construct (LCC) could be effective in this clinical scenario.
METHODS: A pivotal, multicenter, randomized, within-patient, controlled, open-label trial was conducted (N = 96 patients). After removing the mucosa and keratinized gingiva from the test site, either an LCC or FGG was applied. The primary efficacy endpoint was the ability of the LCC to regenerate ≥2 mm keratinized gingiva at 6 months. Secondary measures were the same color and texture as the adjacent tissue, a 1-mm width of keratinized gingiva at 6 months, patient treatment preference, surgical site sensitivity at 1 week, and patient-reported pain after 3 days. Safety was assessed by reports of adverse events.
RESULTS: At 6 months, the LCC regenerated ≥2 mm of keratinized gingiva in 95.3% of patients (81 of 85 patients; P <0.001 versus a 50% predefined standard). As expected, the FGG generated more keratinized gingiva than the LCC (4.57 ± 1.0 mm versus 3.2 ± 1.1 mm, respectively). The gingiva regenerated with the LCC matched the color and texture of the adjacent gingiva. All patients achieved ≥1 mm keratinized gingiva with the LCC treatment by 6 months, and more patients preferred treatment with the LCC than with the FGG. No difference in sensitivity or pain was noted between the treatments. The treatments were well tolerated, and reported adverse events were typical for this type of periodontal surgery.
CONCLUSION: The use of an LCC may provide a safe and effective therapy for augmenting the zone of keratinized gingiva.
PMID: 21513473 [PubMed - indexed for MEDLINE]
Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration.
Expert Opin Biol Ther. 2011 Mar;11(3):375-85
Authors: Kaigler D, Avila G, Wisner-Lynch L, Nevins ML, Nevins M, Rasperini G, Lynch SE, Giannobile WV
INTRODUCTION: Achieving successful tissue regeneration following traditional therapeutic protocols, combining bone grafts and barrier membranes, may be challenging in certain clinical scenarios. A deeper understanding of periodontal and peri-implant wound healing and recent advances in the field of tissue engineering have provided clinicians with novel means to obtain predictable clinical outcomes. The use of growth factors such as recombinant human platelet-derived growth factor-BB (rhPDGF) with biocompatible matrices to promote tissue regeneration represents a promising approach in the disciplines of periodontology and implantology.
AREAS COVERED: This review covers the basic principles of bone and periodontal regeneration, and provides an overview of the biology of PDGF and its potential to predictably and reproducibly promote bone regeneration in regular clinical practice. The results of preclinical and clinical human studies evaluating the effectiveness of growth-factor-enhanced matrices are analyzed and discussed.
EXPERT OPINION: Current available evidence supports the use of rhPDGF-enhanced matrices to promote periodontal and peri-implant bone regeneration.
PMID: 21288185 [PubMed - indexed for MEDLINE]
Cell- and gene-based therapeutic strategies for periodontal regenerative medicine.
J Periodontol. 2011 Sep;82(9):1223-37
Authors: Rios HF, Lin Z, Oh B, Park CH, Giannobile WV
Inflammatory periodontal diseases are a leading cause of tooth loss and are linked to multiple systemic conditions, such as cardiovascular disease and stroke. Reconstruction of the support and function of affected tooth-supporting tissues represents an important therapeutic endpoint for periodontal regenerative medicine. An improved understanding of periodontal biology coupled with current advances in scaffolding matrices has introduced novel treatments that use cell and gene therapy to enhance periodontal tissue reconstruction and its biomechanical integration. Cell and gene delivery technologies have the potential to overcome limitations associated with existing periodontal therapies, and may provide a new direction in sustainable inflammation control and more predictable tissue regeneration of supporting alveolar bone, periodontal ligament, and cementum. This review provides clinicians with the current status of these early-stage and emerging cell- and gene-based therapeutics in periodontal regenerative medicine, and introduces their future application in clinical periodontal treatment. The paper concludes with prospects on the application of cell and gene tissue engineering technologies for reconstructive periodontology.
PMID: 21284553 [PubMed - indexed for MEDLINE]
Salivary biomarkers for periodontal disease diagnostics.
Expert Opin Med Diagn. 2011 Jan;5(1):25-35
Authors: Brinkmann O, Zhang L, Giannobile WV, Wong DT
IMPORTANCE OF THE FIELD: Periodontal disease is one of the most prevalent of all diseases. The chronic inflammatory process causes tooth loss and is associated with negative systemic effects. There are still major challenges when it comes to precise diagnosis, prognosis and appropriate disease therapy. The rapidly emerging field of salivary diagnostics could help to overcome these problems.
AREAS COVERED IN THIS REVIEW: The article covers the last 20 years of periodontal disease biomarker research and gives an overview of the current status of salivary diagnostic techniques.
WHAT THE READER WILL GAIN: The reader will gain insight into the periodontopathic process, associated biomarkers and biomarker detection techniques in the field of saliva-based molecular diagnostics.
TAKE HOME MESSAGE: Salivary diagnostics has great potential for the detection of oral and systemic diseases. Periodontal disease diagnostics, therapy and prognosis could benefit from this emerging diagnostic field.
PMID: 23484474 [PubMed]
Gene expression dynamics during bone healing and osseointegration.
J Periodontol. 2011 Jul;82(7):1007-17
Authors: Lin Z, Rios HF, Volk SL, Sugai JV, Jin Q, Giannobile WV
BACKGROUND: Understanding the molecular features of bone repair and osseointegration may aid in the development of therapeutics to improve implant outcomes. The purpose of this investigation is to determine the gene expression dynamics during alveolar bone repair and implant osseointegration.
METHODS: An implant osseointegration preclinical animal model was used whereby maxillary defects were created at the time of oral implant placement, while a tooth extraction socket healing model was established on the contralateral side of each animal. The surrounding tissues in the zone of the healing defects were harvested during regeneration for temporal evaluation using histology, immunohistochemistry, laser capture microdissection, and quantitative reverse transcription-polymerase chain reaction for the identification of a panel of 17 putative genes associated with wound repair.
RESULTS: In both models, three distinct expression patterns were displayed: 1) genes that are slowly increased during the healing process, such as bone morphogenetic protein 4, runt-related transcription factor 2, and osteocalcin; 2) genes that are upregulated at the early stage of healing and then downregulated at later stages, such as interleukin and chemokine (C-X-C motif) ligands 2 and 5; and 3) genes that are constitutively expressed over time, such as scleraxis. Although some similarities between osseointegration and tooth extraction socket were seen, distinct features developed and triggered a characteristic coordinated expression and orchestration of transcription factors, growth factors, extracellular matrix molecules, and chemokines.
CONCLUSIONS: Characterization of these events contributes to a better understanding of cooperative molecular dynamics in alveolar bone healing, and highlights potential pathways that could be further explored for the enhancement of osseous regenerative strategies.
PMID: 21142982 [PubMed - indexed for MEDLINE]
Teriparatide and osseous regeneration in the oral cavity.
N Engl J Med. 2010 Dec 16;363(25):2396-405
Authors: Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, Giannobile WV, McCauley LK
BACKGROUND: Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking.
METHODS: A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 μg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life.
RESULTS: Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed.
CONCLUSIONS: Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .).
PMID: 20950166 [PubMed - indexed for MEDLINE]
Dr. Giannobile helps pioneer new approach to dental care: M-Dentistry News
DentNEWS: Dr. Giannobile named new JDR editor-in-chief
Gene therapy to treat gum disease: U-M News Service
The future of periodontology: An interview with Dr. William Giannobile and Dr. Pamela Robey
Growth rate of replacement blood vessels, tissues: U-M News Service
Gene therapy promising for growing tooth-supporting bone: U-M News Service
Dr. Salvatore Batia
Dr. Po Chun Chang
Dr. Jong-Hyuk Chung
Kyung Hee University, Seoul, Korea
Dr. Joni Cirelli
Dr. Roberto Farina
Dr. Lukas Furhauser
Dr. Reinhard Gruber
Dr. Zhao Lin
Dr. Andrea Ottonello
Dr. Chan Ho Park
Dr. Gaia Pelligrini
Dr. Christoph Ramsier
Dr. Stefan Schroeckmair, Bernhard Gottlieb University Clinic of Dentistry, Vienna, Austria
Dr. Mario Taba, Jr.
Dr. Valeria Tedeschi
Dr. Kemal Ustun
Dr. Christian Wehner, Bernhard Gottlieb University Clinic of Dentistry, Vienna, Austria
University of Michigan School of Dentistry
Department of Periodontics & Oral Medicine
Room 3310-O Dental Building
1011 N. University Avenue
Ann Arbor, MI 48109