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Our laboratory is exploring the potential of novel methods of growth factor delivery such as gene therapy to stimulate periodontal tissue repair.
William Giannobile, DDS, MS, DMSc
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
734-763-2105 email@example.com
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 100 publications are reported below via PubMed search.
To see all PubMed results go to this complete listing of publications by Dr. Giannobile.
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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]
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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 Mar 4;
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 further symposium was held in March 2015, during the IADR meeting in Boston on March 11th 2015. Involvement is open to editors, associate editors, publishers and others with an interest in scientific publishing.
PMID: 25748020 [PubMed - as supplied by publisher]
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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]
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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]
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Periodontal Health in Women With Early Stage Postmenopausal Breast Cancer Newly on Aromatase Inhibitors: A Pilot Study.
J Periodontol. 2015 Feb 12;:1-14
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 was to assess the prevalence of periodontitis, perceived oral health, and evaluate salivary biomarkers in postmenopausal women who are early stage (I-IIIA) breast cancer (BCa) survivors 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 pocket 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 in mean PD or the number of teeth were found. The AI group had significantly more sites with BOP (27.8 vs. 16.7; p = 0.02), higher worst-site AL (5.2 mm vs. 4.0 mm; p < 0.01) and more sites with dental calculus than did controls (18.2 vs. 6.4; p < 0.001). Linear regression adjusted for income, tobacco use, and dental insurance, and previous radiation and chemotherapy exposure demonstrated AI use increased CAL over 2 mm (95% CI: 0.46 -3.92). Median salivary osteocalcin and Tumor Necrosis Factor levels were significantly higher in the BCa group than the control group. Conclusions: This first investigation of the periodontal status of women initiating adjuvant AI therapy identifies this population as having an increased risk for periodontitis (NCT1272570).
PMID: 25672657 [PubMed - as supplied by publisher]
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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):1206-1216
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 - as supplied by publisher]
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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]
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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]
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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]
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Enhancing periodontal health through regenerative approaches.
J Periodontol. 2015 Feb;86(2 Suppl):S1-3
Authors: Giannobile WV, McClain PK
PMID: 25315020 [PubMed - in process]
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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]
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Authors' response.
J Am Dent Assoc. 2014 Sep;145(9):919, 921
Authors: Gunaratnam NT, Giannobile WV
PMID: 25169998 [PubMed - in process]
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Treatment of periodontitis: destroyed periodontal tissues can be regenerated under certain conditions.
J Periodontol. 2014 Sep;85(9):1151-4
Authors: Giannobile WV
PMID: 25168257 [PubMed - in process]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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Personalized medicine enters dentistry: what might this mean for clinical practice?
J Am Dent Assoc. 2013 Aug;144(8):874-6
Authors: Giannobile WV, Kornman KS, Williams RC
PMID: 23904569 [PubMed - indexed for MEDLINE]
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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]
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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]
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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]
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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]
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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]
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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.
CONCLUSIONS: and
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]
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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]
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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]
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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]
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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]
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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]
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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]
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Sigmund S. Socransky, D.D.S., 1934-2011.
J Clin Periodontol. 2012 May;39(5):415-6
Authors: Giannobile WV, Tonetti MS
PMID: 22486271 [PubMed - indexed for MEDLINE]
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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]
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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]
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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]
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Retraction. A clinical trial of pulpotomy vs. root canal therapy of mature molars. J Dent Res 89:1080-1085.
J Dent Res. 2011 Sep;90(9):1145
Authors: Giannobile WV
PMID: 21844531 [PubMed - indexed for MEDLINE]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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Promotion of oral, dental, and craniofacial research.
J Dent Res. 2010 Oct;89(10):1013-5
Authors: Giannobile WV
PMID: 20876387 [PubMed - indexed for MEDLINE]
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Preclinical methods for the evaluation of periodontal regeneration in vivo.
Methods Mol Biol. 2010;666:285-307
Authors: Seol YJ, Pellegrini G, Franco LM, Chang PC, Park CH, Giannobile WV
For the determination of key factors or devices that promote periodontal regeneration, preclinical investigations using in vivo animal models are critical for evaluating the biological responses before human clinical trial testing. In this chapter, we provide an overview on the commonly used preclinical animals for the study of reconstructive procedures to promote bone and soft tissue repair of tooth-supporting periodontal defects. Steps are provided on the animal management for evaluation of outcome measures using descriptive histology, histomorphometry, three-dimensional imaging, and safety assessments. The use of these key measures of periodontal regeneration should aid investigators in the selection of appropriate surrogate endpoints to be utilized in the clinical arena, which are not practical or ethical in humans. These methods will prepare investigators and assist them in identifying endpoints that can then be adapted to human clinical trial planning.
PMID: 20717791 [PubMed - indexed for MEDLINE]
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Novel antibacterial nanofibrous PLLA scaffolds.
J Control Release. 2010 Sep 15;146(3):363-9
Authors: Feng K, Sun H, Bradley MA, Dupler EJ, Giannobile WV, Ma PX
In order to achieve high local bioactivity and low systemic side effects of antibiotics in the treatment of dental, periodontal and bone infections, a localized and temporally controlled delivery system is crucial. In this study, a three-dimensional (3-D) porous tissue engineering scaffold was developed with the ability to release antibiotics in a controlled fashion for long-term inhibition of bacterial growth. The highly soluble antibiotic drug, doxycycline (DOXY), was successfully incorporated into PLGA nanospheres using a modified water-in-oil-in-oil (w/o/o) emulsion method. The PLGA nanospheres (NS) were then incorporated into prefabricated nanofibrous PLLA scaffolds with a well interconnected macro-porous structure. The release kinetics of DOXY from four different PLGA NS formulations on a PLLA scaffold was investigated. DOXY could be released from the NS-scaffolds in a locally and temporally controlled manner. The DOXY release is controlled by DOXY diffusion out of the NS and is strongly dependent upon the physical and chemical properties of the PLGA. While PLGA50-6.5K, PLGA50-64K, and PLGA75-113K NS-scaffolds discharge DOXY rapidly with a high initial burst release, PLGA85-142K NS-scaffold can extend the release of DOXY to longer than 6weeks with a low initial burst release. Compared to NS alone, the NS incorporated on a 3-D scaffold had significantly reduced the initial burst release. In vitro antibacterial tests of PLGA85 NS-scaffold demonstrated its ability to inhibit common bacterial growth (S. aureus and E. coli) for a prolonged duration. The successful incorporation of DOXY onto 3-D scaffolds and its controlled release from scaffolds extends the usage of nano-fibrous scaffolds from the delivery of large molecules such as growth factors to the delivery of small hydrophilic drugs, allowing for a broader application and a more complex tissue engineering strategy.
PMID: 20570700 [PubMed - indexed for MEDLINE]
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Getting to the root of dental implant tissue engineering.
J Clin Periodontol. 2010 Aug 1;37(8):747-9
Authors: Giannobile WV
PMID: 20546086 [PubMed - indexed for MEDLINE]
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Functional apparent moduli as predictors of oral implant osseointegration dynamics.
J Biomed Mater Res B Appl Biomater. 2010 Jul;94(1):118-26
Authors: Chang PC, Seol YJ, Kikuchi N, Goldstein SA, Giannobile WV
At present, limited functional data exists regarding the application and use of biomechanical and imaging technologies for oral implant osseointegration assessment. The objective of this investigation was to determine the functional apparent moduli (FAMs) that could predict the dynamics of oral implant osseointegration. Using an in vivo dental implant osseous healing model, two FAMs, functional bone apparent modulus (FBAM), and composite tissue apparent modulus (FCAM), of the selected peri-implant structures were calculated via microcomputed tomography (micro-CT) and finite element (FE) simulations in order to support this concept. Results showed significant sensitivity between FAMs and micro-CT parameters, especially between bone mineral density and FBAM, while at extraction defect sites the strongest correlations existed between bone-implant contact and FCAM. Significant enhancement of FCAM indicated progressive functional repair during early osseointegration. Further, the resultant interfacial resistance was predicted by bone mineral content (BMC) and FBAM within a approximately 200 microm peri-implant thickness, while the extraction defects gave zones of approximately 575 microm and 200 microm for BMC and FCAM, respectively. These results suggest that the function of dental implant support can be predicted from a peri-implant structural zone. We conclude that FAMs can be used to predict the dynamics of dental implant osseointegration in vivo.
PMID: 20524185 [PubMed - indexed for MEDLINE]
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Biomimetic hybrid scaffolds for engineering human tooth-ligament interfaces.
Biomaterials. 2010 Aug;31(23):5945-52
Authors: Park CH, Rios HF, Jin Q, Bland ME, Flanagan CL, Hollister SJ, Giannobile WV
A major clinical challenge in the reconstruction of large oral and craniofacial defects is the neogenesis of osseous and ligamentous interfacial structures. Currently, oral regenerative medicine strategies are unpredictable for repair of tooth-supporting tissues destroyed as a consequence of trauma, chronic infection or surgical resection. Here, we demonstrate multi-scale computational design and fabrication of composite hybrid polymeric scaffolds for targeted cell transplantation of genetically modified human cells for the formation of human tooth dentin-ligament-bone complexes in vivo. The newly-formed tissues demonstrate the interfacial generation of parallel- and obliquely-oriented fibers that grow and traverse within the polycaprolactone (PCL)-poly(glycolic acid) (PGA) designed constructs forming tooth cementum-like tissue, ligament, and bone structures. This approach offers potential for the clinical implementation of customized periodontal scaffolds that may enable regeneration of multi-tissue interfaces required for oral, dental and craniofacial engineering applications.
PMID: 20471083 [PubMed - indexed for MEDLINE]
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Angiogenic and osteogenic potential of bone repair cells for craniofacial regeneration.
Tissue Eng Part A. 2010 Sep;16(9):2809-20
Authors: Kaigler D, Pagni G, Park CH, Tarle SA, Bartel RL, Giannobile WV
There has been increased interest in the therapeutic potential of bone marrow derived cells for tissue engineering applications. Bone repair cells (BRCs) represent a unique cell population generated via an ex vivo, closed-system, automated cell expansion process, to drive the propagation of highly osteogenic and angiogenic cells for bone engineering applications. The aims of this study were (1) to evaluate the in vitro osteogenic and angiogenic potential of BRCs, and (2) to evaluate the bone and vascular regenerative potential of BRCs in a craniofacial clinical application. BRCs were produced from bone marrow aspirates and their phenotypes and multipotent potential characterized. Flow cytometry demonstrated that BRCs were enriched for mesenchymal and vascular phenotypes. Alkaline phosphatase and von Kossa staining were performed to assess osteogenic differentiation, and reverse transcriptase-polymerase chain reaction was used to determine the expression levels of bone specific factors. Angiogenic differentiation was determined through in vitro formation of tube-like structures and fluorescent labeling of endothelial cells. Finally, 6 weeks after BRC transplantation into a human jawbone defect, a biopsy of the regenerated site revealed highly vascularized, mineralized bone tissue formation. Taken together, these data provide evidence for the multilineage and clinical potential of BRCs for craniofacial regeneration.
PMID: 20412009 [PubMed - indexed for MEDLINE]
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LMP1 regulates periodontal ligament progenitor cell proliferation and differentiation.
Bone. 2010 Jul;47(1):55-64
Authors: Lin Z, Navarro VP, Kempeinen KM, Franco LM, Jin Q, Sugai JV, Giannobile WV
LMP1 is an intracellular scaffold protein that contains a PDZ domain and three LIM domains. LMP1 has multiple functions including regulating mesenchymal stem cell (MSC) osteogenesis. Gene delivery of LMP1 induces bone formation in vivo in heterotopic and orthotopic sites. However, little is known about the physiological function and gene regulatory mechanisms of LMP1 in MSCs at the molecular level. Periodontal ligament (PDL) cells are a unique progenitor cell population that can differentiate into multiple cell types, including osteoblasts, adipocytes, or chondrocytes. This study sought to determine the physiological function and gene regulatory mechanisms of LMP1 in PDL cells at the molecular level. We show that LMP1 is upregulated in early stage of PDL cell osteogenic differentiation. Stable gene knockdown of LMP1 by shRNA inhibits DNA synthesis and corresponding cell proliferation in PDL cells, and further leads to decreased mineralization in vitro. Overexpression of LMP1 increases cell proliferation, and PDZ and ww-interacting domains are not sufficient to mediate this effect. Further, we found that in PDL cells, LMP1 is a downstream target gene of TGF-beta1 that is an early signal critical in preosteoblast proliferation and differentiation. TGF-beta1 stimulates PDL cell proliferation, however, this effect is compromised when LMP1 is knocked down. We further identified that the activation of TAK1-JNK/p38 kinase cascade is involved in the LMP1 gene regulation by TGF-beta1. We conclude that LMP1 is a downstream gene of TGF-beta1, involved in PDL cell proliferation. Our findings advance the understanding of the physiological function of LMP1 and define a regulatory mechanism of LMP1 in PDL progenitor cells and other MSCs.
PMID: 20348040 [PubMed - indexed for MEDLINE]
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Evaluation of functional dynamics during osseointegration and regeneration associated with oral implants.
Clin Oral Implants Res. 2010 Jan;21(1):1-12
Authors: Chang PC, Lang NP, Giannobile WV
OBJECTIVES: The aim of this paper is to review current investigations on functional assessments of osseointegration and assess correlations to the peri-implant structure.
MATERIAL AND METHODS: The literature was electronically searched for studies of promoting dental implant osseointegration, functional assessments of implant stability, and finite element (FE) analyses in the field of implant dentistry, and any references regarding biological events during osseointegration were also cited as background information.
RESULTS: Osseointegration involves a cascade of protein and cell apposition, vascular invasion, de novo bone formation and maturation to achieve the primary and secondary dental implant stability. This process may be accelerated by alteration of the implant surface roughness, developing a biomimetric interface, or local delivery of growth-promoting factors. The current available pre-clinical and clinical biomechanical assessments demonstrated a variety of correlations to the peri-implant structural parameters, and functionally integrated peri-implant structure through FE optimization can offer strong correlation to the interfacial biomechanics.
CONCLUSIONS: The progression of osseointegration may be accelerated by alteration of the implant interface as well as growth factor applications, and functional integration of peri-implant structure may be feasible to predict the implant function during osseointegration. More research in this field is still needed.
PMID: 20070743 [PubMed - indexed for MEDLINE]
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Platelet-Derived Growth Factor Delivery via Nanofibrous Scaffolds for Soft-Tissue Repair.
Adv Skin Wound Care. 2010 Jan 1;1:375-381
Authors: Jin Q, Ma PX, Giannobile WV
BACKGROUND: Platelet-derived growth factor (PDGF) is a multifunctional growth factor that exerts its biological effects on cellular chemotaxis, proliferation, matrix synthesis, antiapoptosis, and vascularization. PDGF is clinically approved to treat neuropathic diabetic ulcers and osseous defects due to periodontal disease.
THE PROBLEM: The short half-life in vivo of PDGF limits the efficacy of its biological functions. Solving this problem remains a key obstacle for PDGF clinical application. Therefore, the development of an optimized controlled release delivery system offers significant potential.
BASIC/CLINICAL SCIENCE ADVANCES: In this article, we highlight the development of a polymeric delivery system of nanofibrous scaffolds containing PDGF-encapsulated microspheres for tissue engineering. The designed scaffolds were evaluated in a subcutaneous implantation model for tissue neogenesis, vascularization, and chemokine gene expression, as well as soft-tissue repair. PDGF was found to strongly upregulate in vivo gene expression of the CXC chemokine family members such as CXC chemokine ligand CXCL1, CXCL2, and CXCL5 that are important in angiogenesis, inflammation, and wound repair.
CLINICAL CARE RELEVANCE: Recombinant human PDGF is approved by the Food and Drug Administration for patients afflicted with diabetic foot ulcers or compromised periodontal wounds. Challenges related to the transient biological activity of bolus PDGF administration using currently available release systems continue. Thus, it is necessary to explore new delivery systems to optimize biological activity and bioavailability of tissue growth factors.
CONCLUSION: The use of a controlled, "dial-able" delivery system allows for a more tightly regulated release of factors to promote repair of soft- and hard-tissue defects for clinical application.
PMID: 25258592 [PubMed - as supplied by publisher]
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Pro-inflammatory biomarkers during experimental gingivitis in patients with type 1 diabetes mellitus: a proof-of-concept study.
J Clin Periodontol. 2010 Jan;37(1):9-16
Authors: Salvi GE, Franco LM, Braun TM, Lee A, Rutger Persson G, Lang NP, Giannobile WV
AIM: To compare gingival crevicular fluid (GCF) biomarker levels and microbial distribution in plaque biofilm (SP) samples for subjects with type 1 diabetes (T1DM) versus healthy subjects without diabetes during experimental gingivitis (EG).
MATERIALS AND METHODS: A total of nine T1DM patients and nine healthy controls of age and gender similar to the T1DM patients were monitored for 35 days during EG. Hygiene practices were stopped for 3 weeks, and GCF, SP, plaque index (PI) and gingival index were determined. IL-1beta, IL-8, MMP-8 and MMP-9 were quantified by enzyme-linked immunosorbent assay, and SP samples were assessed by DNA-DNA hybridization for a panel of 40 subgingival microbial species.
RESULTS: IL-1beta levels in T1DM patients were elevated compared with healthy individuals, and showed differences between groups at 7-21 days while healthy patients showed IL-1beta increases from baseline to 14-21 days (p<0.05). Differences were observed in MMP-9 levels between patients with and without T1DM at 7-14 days (p<0.05). Orange complex species and PI measurements displayed a superior correlation with biomarker levels when compared with other complexes or clinical measurements during EG.
CONCLUSIONS: The mean GCF biomarker levels for IL-1beta and MMP-8 were most significantly elevated in T1DM subjects compared with healthy individuals during EG, not resulting from differences in the mean PI or microbial composition.
PMID: 19958441 [PubMed - indexed for MEDLINE]
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Immunoglobulin G (IgG) class, but Not IgA or IgM, antibodies to peptides of the Porphyromonas gingivalis chaperone HtpG predict health in subjects with periodontitis by a fluorescence enzyme-linked immunosorbent assay.
Clin Vaccine Immunol. 2009 Dec;16(12):1766-73
Authors: Sweier DG, Shelburne PS, Giannobile WV, Kinney JS, Lopatin DE, Shelburne CE
Chaperones are molecules found in all cells and are critical in stabilization of synthesized proteins, in repair/removal of defective proteins, and as immunodominant antigens in innate and adaptive immunity. Subjects with gingivitis colonized by the oral pathogen Porphyromonas gingivalis previously demonstrated levels of anti-human chaperone Hsp90 that were highest in individuals with the best oral health. We hypothesized that similar antibodies to pathogen chaperones might be protective in periodontitis. This study examined the relationship between antibodies to P. gingivalis HtpG and clinical statuses of healthy and periodontitis-susceptible subjects. We measured the humoral responses (immunoglobulin G [IgG], IgA, and IgM) to peptides of a unique insert (P18) found in Bacteroidaceae HtpG by using a high-throughput, quantitative fluorescence enzyme-linked immunosorbent assay. Indeed, higher levels of IgG class anti-P. gingivalis HtpG P18 peptide (P < 0.05) and P18alpha, consisting of the N-terminal 16 amino acids of P18 (P < 0.05), were associated with better oral health; these results were opposite of those found with anti-P. gingivalis whole-cell antibodies and levels of the bacterium in the subgingival biofilm. When we examined the same sera for IgA and IgM class antibodies, we found no significant relationship to subject clinical status. The relationship between anti-P18 levels and clinical populations and individual subjects was found to be improved when we normalized the anti-P18alpha values to those for anti-P18gamma (the central 16 amino acids of P18). That same ratio correlated with the improvement in tissue attachment gain after treatment (P < 0.05). We suggest that anti-P. gingivalis HtpG P18alpha antibodies are protective in periodontal disease and may have prognostic value for guidance of individual patient treatment.
PMID: 19793900 [PubMed - indexed for MEDLINE]
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Saliva as a diagnostic tool for periodontal disease: current state and future directions.
Periodontol 2000. 2009;50:52-64
Authors: Giannobile WV, Beikler T, Kinney JS, Ramseier CA, Morelli T, Wong DT
PMID: 19388953 [PubMed - indexed for MEDLINE]
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Identification of pathogen and host-response markers correlated with periodontal disease.
J Periodontol. 2009 Mar;80(3):436-46
Authors: Ramseier CA, Kinney JS, Herr AE, Braun T, Sugai JV, Shelburne CA, Rayburn LA, Tran HM, Singh AK, Giannobile WV
BACKGROUND: Periodontitis is the major cause of tooth loss in adults and is linked to systemic illnesses, such as cardiovascular disease and stroke. The development of rapid point-of-care (POC) chairside diagnostics has the potential for the early detection of periodontal infection and progression to identify incipient disease and reduce health care costs. However, validation of effective diagnostics requires the identification and verification of biomarkers correlated with disease progression. This clinical study sought to determine the ability of putative host- and microbially derived biomarkers to identify periodontal disease status from whole saliva and plaque biofilm.
METHODS: One hundred human subjects were equally recruited into a healthy/gingivitis group or a periodontitis population. Whole saliva was collected from all subjects and analyzed using antibody arrays to measure the levels of multiple proinflammatory cytokines and bone resorptive/turnover markers.
RESULTS: Salivary biomarker data were correlated to comprehensive clinical, radiographic, and microbial plaque biofilm levels measured by quantitative polymerase chain reaction (qPCR) for the generation of models for periodontal disease identification. Significantly elevated levels of matrix metalloproteinase (MMP)-8 and -9 were found in subjects with advanced periodontitis with Random Forest importance scores of 7.1 and 5.1, respectively. The generation of receiver operating characteristic curves demonstrated that permutations of salivary biomarkers and pathogen biofilm values augmented the prediction of disease category. Multiple combinations of salivary biomarkers (especially MMP-8 and -9 and osteoprotegerin) combined with red-complex anaerobic periodontal pathogens (such as Porphyromonas gingivalis or Treponema denticola) provided highly accurate predictions of periodontal disease category. Elevated salivary MMP-8 and T. denticola biofilm levels displayed robust combinatorial characteristics in predicting periodontal disease severity (area under the curve = 0.88; odds ratio = 24.6; 95% confidence interval: 5.2 to 116.5).
CONCLUSIONS: Using qPCR and sensitive immunoassays, we identified host- and bacterially derived biomarkers correlated with periodontal disease. This approach offers significant potential for the discovery of biomarker signatures useful in the development of rapid POC chairside diagnostics for oral and systemic diseases. Studies are ongoing to apply this approach to the longitudinal predictions of disease activity.
PMID: 19254128 [PubMed - indexed for MEDLINE]
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Systemic MMP inhibition for periodontal wound repair: results of a multi-centre randomized-controlled clinical trial.
J Clin Periodontol. 2009 Feb;36(2):149-56
Authors: Gapski R, Hasturk H, Van Dyke TE, Oringer RJ, Wang S, Braun TM, Giannobile WV
AIM: This multi-centre, prospective, controlled trial was designed to examine the biological response of the matrix metalloproteinase(MMP) inhibitor subantimicrobial dose doxycycline (SDD) combined with access flap surgery on periodontal wound repair in patients with chronic severe periodontitis.
MATERIAL AND METHODS: Seventy subjects were enrolled into a 12-month, randomized, placebo-controlled, double-masked trial to evaluate disease response to 6 months therapy and "wash-out" of either placebo+surgery or SDD (20 mg b.i.d.)+surgery. Primary outcome measure included clinical attachment levels (CAL) and secondary outcomes included probing depth (PD), bleeding on probing (BOP), as well as gingival crevicular fluid bone marker assessment [collagen telopeptides (ICTP)]. These measurements were taken at baseline through 12 months post-surgery and drug administration.
RESULTS: Patients treated with SDD and surgery demonstrated stronger reductions in PD in surgically-treated sites of >or=7 mm as well as gains in CAL (p<0.004). Furthermore, SDD+surgery resulted in short-term reductions in ICTP levels compared with placebo. Rebounds in ICTP levels and clinical parameters occurred when SDD was withdrawn.
CONCLUSIONS: The results from this multi-centre study suggests that SDD in combination with surgery improves the short-term response of periodontal therapy by reducing PD, increasing CAL gain and inhibiting early stage bone resorption.
PMID: 19207891 [PubMed - indexed for MEDLINE]
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Adenovirus encoding human platelet-derived growth factor-B delivered to alveolar bone defects exhibits safety and biodistribution profiles favorable for clinical use.
Hum Gene Ther. 2009 May;20(5):486-96
Authors: Chang PC, Cirelli JA, Jin Q, Seol YJ, Sugai JV, D'Silva NJ, Danciu TE, Chandler LA, Sosnowski BA, Giannobile WV
Platelet-derived growth factor (PDGF) gene therapy offers promise for tissue engineering of tooth-supporting alveolar bone defects. To date, limited information exists regarding the safety profile and systemic biodistribution of PDGF gene therapy vectors when delivered locally to periodontal osseous defects. The aim of this preclinical study was to determine the safety profile of adenovirus encoding the PDGF-B gene (AdPDGF-B) delivered in a collagen matrix to periodontal lesions. Standardized alveolar bone defects were created in rats, followed by delivery of matrix alone or containing AdPDGF-B at 5.5 x 10(8) or 5.5 x 10(9) plaque-forming units/ml. The regenerative response was confirmed histologically. Gross clinical observations, hematology, and blood chemistries were monitored to evaluate systemic involvement. Bioluminescence and quantitative polymerase chain reaction were used to assess vector biodistribution. No significant histopathological changes were noted during the investigation. Minor alterations in specific hematological and blood chemistries were seen; however, most parameters were within the normal range for all groups. Bioluminescence analysis revealed vector distribution at the axillary lymph nodes during the first 2 weeks with subsequent return to baseline levels. AdPDGF-B was well contained within the localized osseous defect area without viremia or distant organ involvement. These results indicate that AdPDGF-B delivered in a collagen matrix exhibits acceptable safety profiles for possible use in human clinical studies.
PMID: 19199824 [PubMed - indexed for MEDLINE]
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Host-response therapeutics for periodontal diseases.
J Periodontol. 2008 Aug;79(8 Suppl):1592-600
Authors: Giannobile WV
Periodontal diseases are initiated by Gram-negative tooth-associated microbial biofilms that elicit a host response, with resultant osseous and soft tissue destruction. In response to endotoxins derived from periodontal pathogens, several osteoclast-related mediators target the destruction of alveolar bone and supporting connective tissues. Major drivers of this aggressive tissue destruction are matrix metalloproteinases (MMPs), cathepsins, and other osteoclast-derived enzymes. This article focuses on the downstream factors of the osteoclast responsible for the degradation of bone and soft tissues around teeth and oral implants. Furthermore, therapeutic approaches that target MMP-2, -8, and -9 inhibition, such as MMP inhibitors, chemically modified tetracyclines, and subantimicrobial formulations of tetracycline analogues, are discussed. The use of rapid, chair-side tests of MMP activity, in particular for MMP-8 and bone collagen fragments, show strong potential as non-invasive measures of tissue health or disease. In addition, studies using other agents for the preservation of bone mass, such as bisphosphonates that inhibit osteoclast recruitment, are highlighted. The application of these bone-preservation strategies to periodontal management and treatment are discussed in the context of high-risk patients susceptible to disease reactivation or disease complications.
PMID: 18673015 [PubMed - indexed for MEDLINE]
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Stromal-derived factor-1alpha (CXCL12) levels increase in periodontal disease.
J Periodontol. 2008 May;79(5):845-53
Authors: Havens AM, Chiu E, Taba M, Wang J, Shiozawa Y, Jung Y, Taichman LS, D'Silva NJ, Gopalakrishnan R, Wang C, Giannobile WV, Taichman RS
BACKGROUND: The CXC chemokine receptor 4 (CXCR4) and its ligand, stromal cell-derived factor-1 (SDF-1alpha or CXC chemokine ligand 12) are involved in the trafficking of leukocytes into and out of extravascular tissues. The purpose of this study was to determine whether SDF-1alpha secreted by host cells plays a role in recruiting inflammatory cells into the periodontia during local inflammation.
METHODS: SDF-1alpha levels were determined by enzyme-linked immunosorbent assay in gingival crevicular fluid (GCF) of 24 individuals with periodontitis versus healthy individuals in tissue biopsies and in a preclinical rat model of Porphyromonas gingivalis lipopolysaccharide-induced experimental bone loss. Neutrophil chemotaxis assays were also used to evaluate whether SDF-1alpha plays a role in the recruitment of host cells at periodontal lesions.
RESULTS: Subjects with periodontal disease had higher levels of SDF-1alpha in their GCF compared to healthy subjects. Subjects with periodontal disease who underwent mechanical therapy demonstrated decreased levels of SDF-1alpha. Immunohistologic staining showed that SDF-1alpha and CXCR4 levels were elevated in samples obtained from periodontally compromised individuals. Similar results were observed in the rodent model. Neutrophil migration was enhanced in the presence of SDF-1alpha, mimicking immune cell migration in periodontal lesions.
CONCLUSIONS: SDF-1alpha may be involved in the immune defense pathway activated during periodontal disease. Upon the development of diseased tissues, SDF-1alpha levels increase and may recruit host defensive cells into sites of inflammation. These studies suggest that SDF-1alpha may be a useful biomarker for the identification of periodontal disease progression.
PMID: 18454663 [PubMed - indexed for MEDLINE]
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Serum antibodies to Porphyromonas gingivalis chaperone HtpG predict health in periodontitis susceptible patients.
PLoS One. 2008;3(4):e1984
Authors: Shelburne CE, Shelburne PS, Dhople VM, Sweier DG, Giannobile WV, Kinney JS, Coulter WA, Mullally BH, Lopatin DE
BACKGROUND: Chaperones are ubiquitous conserved proteins critical in stabilization of new proteins, repair/removal of defective proteins and immunodominant antigens in innate and adaptive immunity. Periodontal disease is a chronic inflammatory infection associated with infection by Porphyromonas gingivalis that culminates in the destruction of the supporting structures of the teeth. We previously reported studies of serum antibodies reactive with the human chaperone Hsp90 in gingivitis, a reversible form of gingival disease confined to the oral soft tissues. In those studies, antibodies were at their highest levels in subjects with the best oral health. We hypothesized that antibodies to the HSP90 homologue of P. gingivalis (HtpG) might be associated with protection/resistance against destructive periodontitis.
METHODOLOGY/PRINCIPAL FINDINGS: ELISA assays using cloned HtpG and peptide antigens confirmed gingivitis subjects colonized with P. gingivalis had higher serum levels of anti-HtpG and, concomitantly, lower levels of attachment loss. Additionally, serum antibody levels to P. gingivalis HtpG protein were higher in healthy subjects compared to patients with either chronic or aggressive periodontitis. We found a negative association between tooth attachment loss and anti-P. gingivalis HtpG (p = 0.043) but not anti-Fusobacterium nucleatum (an oral opportunistic commensal) HtpG levels. Furthermore, response to periodontal therapy was more successful in subjects having higher levels of anti-P. gingivalis HtpG before treatment (p = 0.018). There was no similar relationship to anti-F. nucleatum HtpG levels. Similar results were obtained when these experiments were repeated with a synthetic peptide of a region of P. gingivalis HtpG.
CONCLUSIONS/SIGNIFICANCE: OUR RESULTS SUGGEST: 1) anti-P. gingivalis HtpG antibodies are protective and therefore predict health periodontitis-susceptable patients; 2) may augment the host defence to periodontitis and 3) a unique peptide of P. gingivalis HtpG offers significant potential as an effective diagnostic target and vaccine candidate. These results are compatible with a novel immune control mechanism unrelated to direct binding of bacteria.
PMID: 18431474 [PubMed - indexed for MEDLINE]
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Nanofibrous scaffolds incorporating PDGF-BB microspheres induce chemokine expression and tissue neogenesis in vivo.
PLoS One. 2008;3(3):e1729
Authors: Jin Q, Wei G, Lin Z, Sugai JV, Lynch SE, Ma PX, Giannobile WV
Platelet-derived growth factor (PDGF) exerts multiple cellular effects that stimulate wound repair in multiple tissues. However, a major obstacle for its successful clinical application is the delivery system, which ultimately controls the in vivo release rate of PDGF. Polylactic-co-glycolic acid (PLGA) microspheres (MS) in nanofibrous scaffolds (NFS) have been shown to control the release of rhPDGF-BB in vitro. In order to investigate the effects of rhPDGF-BB release from MS in NFS on gene expression and enhancement of soft tissue engineering, rhPDGF-BB was incorporated into differing molecular weight (MW) polymeric MS. By controlling the MW of the MS over a range of 6.5 KDa-64 KDa, release rates of PDGF can be regulated over periods of weeks to months in vitro. The NFS-MS scaffolds were divided into multiple groups based on MS release characteristics and PDGF concentration ranging from 2.5-25.0 microg and evaluated in vivo in a soft tissue wound repair model in the dorsa of rats. At 3, 7, 14 and 21 days post-implantation, the scaffold implants were harvested followed by assessments of cell penetration, vasculogenesis and tissue neogenesis. Gene expression profiles using cDNA microarrays were performed on the PDGF-releasing NFS. The percentage of tissue invasion into MS-containing NFS at 7 days was higher in the PDGF groups when compared to controls. Blood vessel number in the HMW groups containing either 2.5 or 25 microg PDGF was increased above those of other groups at 7d (p<0.01). Results from cDNA array showed that PDGF strongly enhanced in vivo gene expression of the CXC chemokine family members such as CXCL1, CXCL2 and CXCL5. Thus, sustained release of rhPDGF-BB, controlled by slow-releasing MS associated with the NFS delivery system, enhanced cell migration and angiogenesis in vivo, and may be related to an induced expression of chemokine-related genes. This approach offers a technology to accurately control growth factor release to promote soft tissue engineering in vivo.
PMID: 18320048 [PubMed - indexed for MEDLINE]
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Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease.
J Periodontol. 2008 Mar;79(3):440-52
Authors: Preshaw PM, Novak MJ, Mellonig J, Magnusson I, Polson A, Giannobile WV, Rowland RW, Thomas J, Walker C, Dawson DR, Sharkey D, Bradshaw MH
BACKGROUND: Previous studies showed that adjunctive subantimicrobial dose doxycycline (SDD; 20 mg, twice daily) provides significant clinical benefits to scaling and root planing (SRP). A modified-release SDD formulation containing 40 mg doxycycline (SDD-40) to be taken once daily has been developed. The aim of this study was to investigate the efficacy of SDD-40 when used as an adjunct to SRP for the treatment of periodontitis.
METHODS: A 9-month, double-masked, randomized, placebo-controlled, multicenter study was conducted to test the efficacy of adjunctive SDD-40 in 266 subjects with periodontitis. Subjects were treated by SRP and randomized to receive SDD-40 or placebo for 9 months with evaluations at 3, 6, and 9 months.
RESULTS: Adjunctive SDD-40 provided significantly greater clinical benefits than placebo at all time points. At month 9, at sites with baseline probing depths (PD) > or =6 mm, 72% to 76% of sites in the SDD-40 group demonstrated clinically significant PD reductions and clinical attachment level (CAL) gains > or =2 mm compared to 56% to 58% of sites in the placebo group (P <0.0001); 48% to 52% of sites in the SDD-40 group demonstrated PD reductions and CAL gains > or =3 mm compared to 32% of sites in the placebo group (P <0.0001). In moderate sites (baseline PD 4 to 6 mm), adjunctive SDD-40 provided significant clinical benefits compared to placebo for mean CAL (all time points: P <0.05), PD (3 months: P = 0.002; 6 and 9 months: P = 0.001), and bleeding on probing (BOP) (3 months: P <0.01; 6 months: P <0.02; 9 months: P <0.05). In deep sites (baseline PD > or =7 mm), SDD-40 provided significant benefits over control for mean CAL (3 months: P <0.05; 6 and 9 months: P <0.01), PD (all time points: P <0.001), and BOP (3 months: P <0.05; 6 months: not statistically significant; 9 months: P <0.05). Compliance with study medication was high (>92%) with no significant differences in adverse events between groups and no evidence of microbiologically significant changes or development of antibiotic resistance in the subgingival flora in either group.
CONCLUSION: SDD-40 used as an adjunct to SRP resulted in significantly greater clinical benefits than SRP alone in the treatment of periodontitis.
PMID: 18315426 [PubMed - indexed for MEDLINE]
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Effect of adjunctive systemic azithromycin with periodontal surgery in the treatment of chronic periodontitis in smokers: a pilot study.
J Periodontol. 2007 Oct;78(10):1887-96
Authors: Dastoor SF, Travan S, Neiva RF, Rayburn LA, Giannobile WV, Wang HL
BACKGROUND: Along with conventional surgical therapy, systemic antibiotics may provide more effective treatment in smokers by targeting tissue-invasive bacteria. The aim of this randomized, placebo-controlled, double-masked clinical trial was to evaluate the adjunctive effects of systemic azithromycin (AZM) in combination with periodontal pocket reduction surgery in the treatment of chronic periodontitis in smokers.
METHODS: Thirty patients with a greater than one pack/day smoking habit and generalized moderate to severe chronic periodontitis were randomized to the test (surgery plus 3 days of AZM, 500 mg) or control group (surgery plus 3 days of placebo). Full-mouth probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), plaque index, and wound healing indices (WHI) were assessed at baseline and at 2 weeks and 1, 3, and 6 months following surgical intervention. Plaque and gingival crevicular fluid were collected for trypsin-like enzyme activity (benzoyl-dl-arginine naphthylamine) and bone biomarker (crosslinked telopeptide of type I collagen [ICTP]) analyses, respectively, at baseline, 2 weeks, and 1, 3, and 6 months.
RESULTS: Surgical treatment of moderate (PD = 4 to 6 mm) and deep (PD > 6 mm) pockets significantly improved clinical parameters of treated and untreated teeth (CAL gain, PD reduction, and reduction of BOP). The additional use of AZM did not enhance this improvement nor did it promote reduction of ICTP levels. Compared to the control group, the test group had significantly better WHI scores at 1 month, significantly less GI at 2 weeks, and sustained reductions of red-complex bacteria with trypsin-like enzyme activity at 3 months. For non-surgery teeth, only the test group showed significant gains in overall CAL compared to baseline.
CONCLUSIONS: The findings of this pilot study demonstrated that in heavy smokers, adjunctive systemic AZM in combination with pocket reduction surgery did not significantly enhance PD reduction or CAL gain. However, the clinical value of adjunctive AZM may be appreciated by more rapid wound healing, less short-term gingival inflammation, and sustained reductions of periopathogenic bacteria. More expanded studies are recommended to better determine the clinical effects of adjunctive AZM in patients who smoke.
PMID: 17915999 [PubMed - indexed for MEDLINE]
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Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK.
J Biol Chem. 2007 Oct 19;282(42):30938-48
Authors: Chang J, Sonoyama W, Wang Z, Jin Q, Zhang C, Krebsbach PH, Giannobile W, Shi S, Wang CY
Mesenchymal stem cells (MSCs) are multipotent cells that can be differentiated into osteoblasts and provide an excellent cell source for bone regeneration and repair. Recently, the canonical Wnt/beta-catenin signaling pathway has been found to play a critical role in skeletal development and osteogenesis, implying that Wnts can be utilized to improve de novo bone formation mediated by MSCs. However, it is unknown whether noncanonical Wnt signaling regulates osteogenic differentiation. Here, we find that Wnt-4 enhanced in vitro osteogenic differentiation of MSCs isolated from human adult craniofacial tissues and promoted bone formation in vivo. Whereas Wnt-4 did not stabilize beta-catenin, it activated p38 MAPK in a novel noncanonical signaling pathway. The activation of p38 was dependent on Axin and was required for the enhancement of MSC differentiation by Wnt-4. Moreover, using two different models of craniofacial bone injury, we found that MSCs genetically engineered to express Wnt-4 enhanced osteogenesis and improved the repair of craniofacial defects in vivo. Taken together, our results reveal that noncanonical Wnt signaling could also play a role in osteogenic differentiation. Wnt-4 may have a potential use in improving bone regeneration and repair of craniofacial defects.
PMID: 17720811 [PubMed - indexed for MEDLINE]
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RANKL inhibition through osteoprotegerin blocks bone loss in experimental periodontitis.
J Periodontol. 2007 Jul;78(7):1300-8
Authors: Jin Q, Cirelli JA, Park CH, Sugai JV, Taba M, Kostenuik PJ, Giannobile WV
BACKGROUND: Prevention of alveolar bone destruction is a clinical challenge in periodontal disease treatment. The receptor activator of nuclear factor-kappa B ligand (RANKL) inhibitor osteoprotegerin (OPG) inhibits osteoclastogenesis and suppresses bone resorption.
METHODS: To study the effects of RANKL inhibition on alveolar bone loss, an experimental ligature-induced model of periodontitis was used. A total of 32 rats were administered human OPG-Fc fusion protein (10 mg/kg) or vehicle by subcutaneous delivery twice weekly for 6 weeks. Negative or positive controls received no treatment or disease through vehicle delivery, respectively. Biopsies were harvested after 3 and 6 weeks, and mandibulae were evaluated by microcomputed tomography (microCT) and histology. Serum levels of human OPG-Fc and tartrate-resistant acid phosphatase-5b (TRAP-5b) were measured throughout the study by enzyme-linked immunosorbent assay (ELISA). Statistical analyses included analysis of variance (ANOVA) and Tukey tests.
RESULTS: Human OPG-Fc was detected in the sera of OPG-Fc-treated animals by 3 days and throughout the study. Serum TRAP-5b was sharply decreased by OPG-Fc treatment soon after OPG-Fc delivery and remained low for the observation period. Significant preservation of alveolar bone volume was observed among OPG-Fc-treated animals compared to the controls at weeks 3 and 6 (P <0.05). Descriptive histology revealed that OPG-Fc significantly suppressed osteoclast surface area at the alveolar crest.
CONCLUSION: Systemic delivery of OPG-Fc inhibits alveolar bone resorption in experimental periodontitis, suggesting that RANKL inhibition may represent an important therapeutic strategy for the prevention of progressive alveolar bone loss.
PMID: 17608585 [PubMed - indexed for MEDLINE]
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Local delivery of osteoprotegerin inhibits mechanically mediated bone modeling in orthodontic tooth movement.
Bone. 2007 Sep;41(3):446-55
Authors: Dunn MD, Park CH, Kostenuik PJ, Kapila S, Giannobile WV
INTRODUCTION: The RANKL-OPG axis is a key regulator of osteoclastogenesis and bone turnover activity. Its contribution to bone resorption under altered mechanical states, however, has not been fully elucidated. Here we examined the role of OPG in regulating mechanically induced bone modeling in a rat model of orthodontic tooth movement.
METHODS: The maxillary first molars of male Sprague-Dawley rats were moved mesially using a calibrated nickel-titanium spring attached to the maxillary incisor teeth. Two different doses (0.5 mg/kg, 5.0 mg/kg) of a recombinant fusion protein (OPG-Fc), were injected twice weekly mesial to the first molars. Tooth movement was measured using stone casts that were scanned and magnified. Changes in bone quantity were measured using micro-computed tomography and histomorphometric analysis was used to quantify osteoclasts and volumetric parameters. Finally, circulating levels of TRAP-5b (a bone resorption marker) was measured using enzyme-linked immunosorbent assay.
RESULTS: The 5.0 mg/kg OPG-Fc dose showed a potent reduction in mesial molar movement and osteoclast numbers compared to controls (p<0.01). The molar movement was inhibited by 45.7%, 70.6%, and 78.7% compared to controls at days 7, 14, and 21 respectively, with the high dose of OPG. The 0.5 mg dose also significantly (p<0.05) inhibited molar movement at days 7 (43.8%) and 14 (31.8%). While incisor retraction was also decreased by OPG-Fc, the ratio of incisor to molar tooth movement was markedly better in the high-dose OPG group (5.2:1, p<0.001) compared to the control group (2.3:1) and the low-dose OPG group (2.0:1).
CONCLUSIONS: Local delivery of OPG-Fc inhibits osteoclastogenesis and tooth movement at targeted dental sites.
PMID: 17588510 [PubMed - indexed for MEDLINE]
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Integrated microfluidic platform for oral diagnostics.
Ann N Y Acad Sci. 2007 Mar;1098:362-74
Authors: Herr AE, Hatch AV, Giannobile WV, Throckmorton DJ, Tran HM, Brennan JS, Singh AK
While many point-of-care (POC) diagnostic methods have been developed for blood-borne analytes, development of saliva-based POC diagnostics is in its infancy. We have developed a portable microfluidic device for detection of potential biomarkers of periodontal disease in saliva. The device performs rapid microfluidic chip-based immunoassays (<3-10 min) with low sample volume requirements (10 microL) and appreciable sensitivity (nM-pM). Our microfluidic method facilitates hands-free saliva analysis by integrating sample pretreatment (filtering, enrichment, mixing) with electrophoretic immunoassays to quickly measure analyte concentrations in minimally pretreated saliva samples. The microfluidic chip has been integrated with miniaturized electronics, optical elements, such as diode lasers, fluid-handling components, and data acquisition software to develop a portable, self-contained device. The device and methods are being tested by detecting potential biomarkers in saliva samples from patients diagnosed with periodontal disease. Our microchip-based analysis can readily be extended to detection of biomarkers of other diseases, both oral and systemic, in saliva and other oral fluids.
PMID: 17435142 [PubMed - indexed for MEDLINE]
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Oral fluid-based biomarkers of alveolar bone loss in periodontitis.
Ann N Y Acad Sci. 2007 Mar;1098:230-51
Authors: Kinney JS, Ramseier CA, Giannobile WV
Periodontal disease is a bacteria-induced chronic inflammatory disease affecting the soft and hard supporting structures encompassing the teeth. When left untreated, the ultimate outcome is alveolar bone loss and exfoliation of the involved teeth. Traditional periodontal diagnostic methods include assessment of clinical parameters and radiographs. Though efficient, these conventional techniques are inherently limited in that only a historical perspective, not current appraisal, of disease status can be determined. Advances in the use of oral fluids as possible biological samples for objective measures of current disease state, treatment monitoring, and prognostic indicators have boosted saliva and other oral-based fluids to the forefront of technology. Oral fluids contain locally and systemically derived mediators of periodontal disease, including microbial, host-response, and bone-specific resorptive markers. Although most biomarkers in oral fluids represent inflammatory mediators, several specific collagen degradation and bone turnover-related molecules have emerged as possible measures of periodontal disease activity. Pyridinoline cross-linked carboxyterminal telopeptide (ICTP), for example, has been highly correlated with clinical features of the disease and decreases in response to intervention therapies, and has been shown to possess predictive properties for possible future disease activity. One foreseeable benefit of an oral fluid-based periodontal diagnostic would be identification of highly susceptible individuals prior to overt disease. Timely detection and diagnosis of disease may significantly affect the clinical management of periodontal patients by offering earlier, less invasive, and more cost-effective treatment therapies.
PMID: 17435132 [PubMed - indexed for MEDLINE]
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Microfluidic immunoassays as rapid saliva-based clinical diagnostics.
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5268-73
Authors: Herr AE, Hatch AV, Throckmorton DJ, Tran HM, Brennan JS, Giannobile WV, Singh AK
At present, point-of-care (POC) diagnostics typically provide a binary indication of health status (e.g., home pregnancy test strip). Before anticipatory use of diagnostics for assessment of complex diseases becomes widespread, development of sophisticated bioassays capable of quantitatively measuring disease biomarkers is necessary. Successful translation of new bioassays into clinical settings demands the ability to monitor both the onset and progression of disease. Here we report on a clinical POC diagnostic that enables rapid quantitation of an oral disease biomarker in human saliva by using a monolithic disposable cartridge designed to operate in a compact analytical instrument. Our microfluidic method facilitates hands-free saliva analysis by integrating sample pretreatment (filtering, enrichment, mixing) with electrophoretic immunoassays to quickly measure analyte concentrations in minimally pretreated saliva samples. Using 20 microl of saliva, we demonstrate rapid (<10 min) measurement of the collagen-cleaving enzyme matrix metalloproteinase-8 (MMP-8) in saliva from healthy and periodontally diseased subjects. In addition to physiologically measurable indicators of periodontal disease, conventional measurements of salivary MMP-8 were used to validate the microfluidic assays described in this proof-of-principle study. The microchip-based POC diagnostic demonstrated is applicable to rapid, reliable measurement of proteinaceous disease biomarkers in biological fluids.
PMID: 17374724 [PubMed - indexed for MEDLINE]
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Actinobacillus actinomycetemcomitans lipopolysaccharide-mediated experimental bone loss model for aggressive periodontitis.
J Periodontol. 2007 Mar;78(3):550-8
Authors: Rogers JE, Li F, Coatney DD, Rossa C, Bronson P, Krieder JM, Giannobile WV, Kirkwood KL
BACKGROUND: Bacterial constituents, such as Gram-negative derived lipopolysaccharide (LPS), can initiate inflammatory bone loss through induction of host-derived inflammatory cytokines. The aim of this study was to establish a model of aggressive inflammatory alveolar bone loss in rats using LPS derived from the periodontal pathogen Actinobacillus actinomycetemcomitans.
METHODS: Eighteen female Sprague-Dawley rats were divided into LPS test (N = 12) and saline control (N = 6) groups. All animals received injections to the palatal molar gingiva three times per week for 8 weeks. At 8 weeks, linear and volumetric alveolar bone loss was measured by micro-computed tomography (microCT). The prevalence of inflammatory infiltrate, proinflammatory cytokines, and osteoclasts was assessed from hematoxylin and eosin, immunohistochemical, or tartrate-resistant acid phosphatase (TRAP)-stained sections. Statistical analysis was performed.
RESULTS: A. actinomycetemcomitans LPS induced severe bone loss over 8 weeks, whereas control groups were unchanged. Linear and volumetric analysis of maxillae by microCT indicated significant loss of bone with LPS administration. Histologic examination revealed increased inflammatory infiltrate, significantly increased immunostaining for interleukin IL-6 and -1beta and tumor necrosis factor-alpha, and more TRAP-positive osteoclasts in the LPS group compared to controls.
CONCLUSION: Oral injections of LPS derived from the periodontal pathogen A. actinomycetemcomitans can induce severe alveolar bone loss and proinflammatory cytokine production in rats by 8 weeks.
PMID: 17335380 [PubMed - indexed for MEDLINE]
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A randomized-controlled trial of low-dose doxycycline for periodontitis in smokers.
J Clin Periodontol. 2007 Apr;34(4):325-33
Authors: Needleman I, Suvan J, Gilthorpe MS, Tucker R, St George G, Giannobile W, Tonetti M, Jarvis M
BACKGROUND/AIM: Tobacco use reduces the effect of non-surgical periodontal therapy. Host-modulation with low-dose doxycycline (LDD) might favour repair and promote an improved treatment response. The aim of this study was to investigate the effect of LDD in smokers on non-surgical periodontal therapy.
MATERIAL AND METHODS: This was a parallel arm, randomized, identical placebo-controlled trial with masking of examiner, care-giver, participant and statistician and 6 months of follow-up. Patients received non-surgical therapy and 3 months of test or control drug. Statistical analysis used both conventional methods and multilevel modelling.
RESULTS: Eighteen control and 16 test patients completed the study. The velocity of change was statistically greater for the test group for clinical attachment level -0.19 mm/month (95% CI=-0.34, 0.04; p=0.012) and probing depth 0.30 mm/month (95% CI=-0.42, -0.17; p<0.001). However, no differences were observed for absolute change in clinical or biochemical markers at 6 months.
CONCLUSIONS: This study does not provide evidence of a benefit of using LDD as an adjunct to non-surgical periodontal therapy in smokers.
PMID: 17324155 [PubMed - indexed for MEDLINE]
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Three-dimensional micro-computed tomographic imaging of alveolar bone in experimental bone loss or repair.
J Periodontol. 2007 Feb;78(2):273-81
Authors: Park CH, Abramson ZR, Taba M, Jin Q, Chang J, Kreider JM, Goldstein SA, Giannobile WV
BACKGROUND: Micro-computed tomography (micro-CT) offers significant potential for identifying mineralized structures. However, three-dimensional (3-D) micro-CT of alveolar bone has not been adapted readily for quantification. Moreover, conventional methods are not highly sensitive for analyzing bone loss or bone gain following periodontal disease or reconstructive therapy. The objective of this investigation was to develop a micro-CT methodology for quantifying tooth-supporting alveolar bone in 3-D following experimental preclinical situations of periodontitis or reconstructive therapy.
METHODS: Experimental in vivo bone loss or regeneration situations were developed to validate the micro-CT imaging techniques. Twenty mature Sprague-Dawley rats were divided into two groups: bone loss (Porphyromonas gingivalis lipopolysaccharide-mediated bone resorption) and regenerative therapy. Micro-CT and software digitized specimens were reconstructed three-dimensionally for linear and volumetric parameter assessment of alveolar bone (linear bone height, bone volume, bone volume fraction, bone mineral content, and bone mineral density). Intra- and interexaminer reproducibility and reliability were compared for methodology validation.
RESULTS: The results demonstrated high examiner reproducibility for linear and volumetric parameters with high intraclass correlation coefficient (ICC) and coefficient of variation (CV). The ICC showed that the methodology was highly reliable and reproducible (ICC >0.99; 95% confidence interval, 0.937 to 1.000; CV <1.5%), suggesting that 3-D measurements may provide better alveolar bone analysis than conventional 2-D methods.
CONCLUSIONS: The developed methods allow for highly accurate and reproducible static measurements of tooth-supporting alveolar bone following preclinical situations of bone destruction or regeneration. Future investigations should focus on using in vivo micro-CT imaging for real-time assessments of alveolar bone changes.
PMID: 17274716 [PubMed - indexed for MEDLINE]
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The enhancement of osteogenesis by nano-fibrous scaffolds incorporating rhBMP-7 nanospheres.
Biomaterials. 2007 Apr;28(12):2087-96
Authors: Wei G, Jin Q, Giannobile WV, Ma PX
It is advantageous to incorporate controlled growth factor delivery into tissue engineering strategies. The objective of this study was to develop a three-dimensional (3D) porous tissue engineering scaffold with the capability of controlled releasing recombinant human bone morphogenetic protein-7 (rhBMP-7) for enhancement of bone regeneration. RhBMP-7 was first encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanospheres (NS) with an average diameter of 300nm. Poly(l-lactic acid) (PLLA) scaffolds with interconnected macroporous and nano-fibrous architectures were prepared using a combined sugar sphere template leaching and phase separation technique. A post-seeding technique was then utilized to immobilize rhBMP-7 containing PLGA nanospheres onto prefabricated nano-fibrous PLLA scaffolds with well-maintained 3D structures. In vitro release kinetics indicated that nanosphere immobilized scaffold (NS-scaffold) could release rhBMP-7 in a temporally controlled manner, depending on the chemical and degradation properties of the NS which were immobilized onto the scaffold. In vivo, rhBMP-7 delivered from NS-scaffolds induced significant ectopic bone formation throughout the scaffold while passive adsorption of rhBMP-7 into the scaffold resulted in failure of bone induction due to either the loss of rhBMP-7 biological function or insufficient duration within the scaffold. We conclude that the interconnected macroporous architecture and the sustained, prolonged delivery of bioactive rhBMP-7 from NS immobilized nano-fibrous scaffolds actively induced new bone formation throughout the scaffold. The approach offers a new delivery method of BMPs and a novel scaffold design for bone regeneration.
PMID: 17239946 [PubMed - indexed for MEDLINE]
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Novel host response therapeutic approaches to treat periodontal diseases.
Periodontol 2000. 2007;43:294-315
Authors: Kirkwood KL, Cirelli JA, Rogers JE, Giannobile WV
PMID: 17214846 [PubMed - indexed for MEDLINE]
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Growth factor delivery for oral and periodontal tissue engineering.
Expert Opin Drug Deliv. 2006 Sep;3(5):647-62
Authors: Kaigler D, Cirelli JA, Giannobile WV
The treatment of oral and periodontal diseases and associated anomalies accounts for a significant proportion of the healthcare burden, with the manifestations of these conditions being functionally and psychologically debilitating. Growth factors are critical to the development, maturation, maintenance and repair of craniofacial tissues, as they establish an extracellular environment that is conducive to cell and tissue growth. Tissue-engineering principles aim to exploit these properties in the development of biomimetic materials that can provide an appropriate microenvironment for tissue development. These materials have been constructed into devices that can be used as vehicles for delivery of cells, growth factors and DNA. In this review, different mechanisms of drug delivery are addressed in the context of novel approaches to reconstruct and engineer oral- and tooth-supporting structures, namely the periodontium and alveolar bone.
PMID: 16948560 [PubMed - indexed for MEDLINE]
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Effect of rhPDGF-BB delivery on mediators of periodontal wound repair.
Tissue Eng. 2006 Jun;12(6):1441-50
Authors: Cooke JW, Sarment DP, Whitesman LA, Miller SE, Jin Q, Lynch SE, Giannobile WV
Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of tooth-supporting structures. This investigation examined the effect of the local delivery of PDGF-BB when combined with reconstructive periodontal surgery on local wound fluid (WF) levels of PDGF-AB, vascular endothelial growth factor (VEGF), and bone collagen telopeptide (ICTP) in humans with advanced periodontitis. Sixteen patients exhibiting localized periodontal osseous defects were randomized to one of three groups (beta-TCP carrier alone, beta-TCP + 0.3 mg/mL of recombinant human PDGF-BB [rhPDGF-BB], or beta-TCP + 1.0 mg/mL of rhPDGF-BB) and monitored for 6 months. WF was harvested and analyzed for PDGF-AB, VEGF, and ICTP WF levels. Teeth contralateral to the target lesions served as controls. Increased levels of VEGF in the WF was observed for all surgical treatment groups with the 1.0 mg/mL rhPDGF-BB group showing the most pronounced difference at 3 weeks in the AUC analysis versus control (p < 0.0001). PDGF-AB WF levels were increased for the carrier alone group compared to both rhPDGFBB groups. Low-dose rhPDGF-BB application elicited increases in ICTP at days 3-5 in the wound healing process, suggesting a promotion of bone turnover at early stages of the repair process (p < 0.02). These results demonstrate contrasting inducible expression patterns of PDGF-AB, VEGF, and ICTP during periodontal wound healing in humans.
PMID: 16846342 [PubMed - indexed for MEDLINE]
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The impact of primary hyperparathyroidism on the oral cavity.
J Clin Endocrinol Metab. 2006 Sep;91(9):3439-45
Authors: Padbury AD, Tözüm TF, Taba M, Ealba EL, West BT, Burney RE, Gauger PG, Giannobile WV, McCauley LK
CONTEXT: Primary hyperparathyroidism (HPT) is a systemic disease causing bone loss. Periodontal disease is a local inflammatory disease characterized by alveolar bone loss. The older literature records that HPT is associated with loss of radicular lamina dura and brown tumors of the bone, but contemporary studies are lacking.
OBJECTIVE: The objective of the study was to determine the effects of HPT on oral bony structures and periodontal disease in a contemporary population.
DESIGN: This was a cross-sectional, case-controlled study.
SETTING: The study was conducted at the clinics of endocrine surgery and hospital dentistry.
PATIENTS AND OTHER PARTICIPANTS: Fifty-nine patients, 39 with HPT and 20 thyroid controls, were included in the study.
MAIN OUTCOME MEASURES: Periodontal clinical measures and dental radiographic analyses were used in this study.
RESULTS: HPT patients were more likely to have tori and reductions in radicular lamina dura on dental radiographs. Widening of the periodontal ligament space surrounding teeth correlated with serum PTH levels. Panoramic radiographs demonstrated reduced cortical bone thickness at the angle of the mandible in HPT patients but no evidence of brown tumors or other overt pathologies.
CONCLUSIONS: Changes in the oral cavity observed in patients with HPT suggested both decreased cortical density and increased likelihood of oral tori. The contemporary oral manifestations of primary HPT are different from those previously reported, and health care providers should be aware of newer, more subtle findings that may be present when treating patients with HPT.
PMID: 16822829 [PubMed - indexed for MEDLINE]
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Gene therapeutics for periodontal regenerative medicine.
Dent Clin North Am. 2006 Apr;50(2):245-63, ix
Authors: Ramseier CA, Abramson ZR, Jin Q, Giannobile WV
There has been significant advancement in the field of periodontal tissue engineering over the past decade for the repair of tooth-supporting structures. Although encouraging results for periodontal tissue regeneration have been found in numerous clinical investigations using recombinant growth factors, limitations exist with topical protein delivery. Newer approaches seek to develop methodologies that optimize growth factor targeting to maximize the therapeutic outcome of periodontal regenerative procedures. Genetic approaches in periodontal tissue engineering show early progress in achieving delivery of growth factor genes, such as platelet-derived growth factor or bone morphogenetic protein, to periodontal lesions. Ongoing investigations in ex vivo and in vivo gene transfer to periodontia seek to examine the extent of the potential effects in stimulating periodontal tissue engineering.
PMID: 16530061 [PubMed - indexed for MEDLINE]
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The first descriptions of bone morphogenetic protein in the dental literature appeared more than a decade ago, yet there is no commercially viable application for this product. Comment on the likelihood that this material will become available to the general dental community and describe those situations in which you see it providing additional benefits to the currently available treatment modalities.
Int J Oral Maxillofac Implants. 2006 Jan-Feb;21(1):148-53
Authors: Marx RE, Giannobile WV, Koka S, Moy PK
PMID: 16519195 [PubMed - indexed for MEDLINE]
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Nano-fibrous scaffold for controlled delivery of recombinant human PDGF-BB.
J Control Release. 2006 May 1;112(1):103-10
Authors: Wei G, Jin Q, Giannobile WV, Ma PX
The localized and temporally controlled delivery of growth factors is key to achieving optimal clinical efficacy. In sophisticated tissue engineering strategies, the biodegradable scaffold is preferred to serve as both a three-dimensional (3-D) substrate and a growth factor delivery vehicle to promote cellular activity and enhance tissue neogenesis. This study presents a novel approach to fabricate tissue engineering scaffolds capable of controlled growth factor delivery whereby growth factor containing microspheres were incorporated into 3-D scaffolds with good mechanical properties, well-interconnected macroporous and nano-fibrous structures. The microspheres were uniformly distributed throughout the nano-fibrous scaffold and their incorporation did not interfere the macro-, micro-, and nanostructures of the scaffold. The release kinetics of platelet-derived growth factor-BB (PDGF-BB) from microspheres and scaffolds was investigated using poly(lactic-co-glycolic acid) (PLGA50) microspheres with different molecular weights (6.5 and 64kDa, respectively) and microsphere-incorporated poly(l-lactic acid) (PLLA) nano-fibrous scaffolds. Incorporation of microspheres into scaffolds significantly reduced the initial burst release. Sustained release from several days to months was achieved through different microspheres in scaffolds. Released PDGF-BB was demonstrated to possess biological activity as evidenced by stimulation of human gingival fibroblast DNA synthesis in vitro. The successful generation of 3-D nano-fibrous scaffold incorporating controlled-release factors indicates significant potential for more complex tissue regeneration.
PMID: 16516328 [PubMed - indexed for MEDLINE]
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Effect of rhPDGF-BB on bone turnover during periodontal repair.
J Clin Periodontol. 2006 Feb;33(2):135-40
Authors: Sarment DP, Cooke JW, Miller SE, Jin Q, McGuire MK, Kao RT, McClain PK, McAllister BS, Lynch SE, Giannobile WV
PURPOSE: Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of periodontia. Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a well-known biomarker of bone turnover, and as such is a potential indicator of osseous metabolic activity. The objective of this study was to evaluate the release of the ICTP into the periodontal wound fluid (WF) following periodontal reconstructive surgery using local delivery of highly purified recombinant human PDGF (rhPDGF)-BB.
METHODS: Forty-seven human subjects at five treatment centres possessing chronic severe periodontal disease were monitored longitudinally for 24 weeks following PDGF regenerative surgical treatment. Severe periodontal osseous defects were divided into one of three groups and treated at the time of surgery with either: beta-tricalcium phosphate (TCP) osteoconductive scaffold alone (active control), beta-TCP+0.3 mg/ml of rhPDGF-BB, or beta-TCP+1.0 mg/ml of rhPDGF-BB. WF was harvested and analysed for local ICTP levels by radioimmunoassay. Statistical analysis was performed using analysis of variance and an area under the curve analysis (AUC).
RESULTS: The 0.3 and 1.0 mg/ml PDGF-BB treatment groups demonstrated increases in the amount of ICTP released locally for up to 6 weeks. There were statistically significant differences at the week 6 time point between beta-TCP carrier alone group versus 0.3 mg/ml PDGF-BB group (p<0.05) and between beta-TCP alone versus the 1.0 mg/ml PDGF-BB-treated lesions (p<0.03). The AUC analysis revealed no statistical differences amongst groups.
CONCLUSION: This study corroborates the release of ICTP as a measure of active bone turnover following local delivery of PDGF-BB to periodontal osseous defects. The amount of ICTP released from the WF revealed an early increase for all treatment groups. Data from this study suggests that when PDGF-BB is delivered to promote periodontal tissue engineering of tooth-supporting osseous defects, there is a direct effect on ICTP released from the wound.
PMID: 16441739 [PubMed - indexed for MEDLINE]
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Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial.
J Periodontol. 2005 Dec;76(12):2205-15
Authors: Nevins M, Giannobile WV, McGuire MK, Kao RT, Mellonig JT, Hinrichs JE, McAllister BS, Murphy KS, McClain PK, Nevins ML, Paquette DW, Han TJ, Reddy MS, Lavin PT, Genco RJ, Lynch SE
BACKGROUND: Growth factors are generally accepted to be essential mediators of tissue repair via well-established mechanisms of action that include stimulatory effects on angiogenesis and cellular proliferation, ingrowth, differentiation, and matrix biosynthesis. The aim of this study was to evaluate in a large-scale, prospective, blinded, and randomized controlled clinical trial the safety and effectiveness of purified recombinant human platelet-derived growth factor (rhPDGF-BB) mixed with a synthetic beta-tricalcium phosphate (beta-TCP) matrix for the treatment of advanced periodontal osseous defects at 6 months of healing.
METHODS: Eleven clinical centers enrolled 180 subjects, each requiring surgical treatment of a 4 mm or greater intrabony periodontal defect and meeting all inclusion and exclusion criteria. Subjects were randomized into one of three treatment groups: 1) beta-TCP + 0.3 mg/ml rhPDGF-BB in buffer; 2) beta-TCP + 1.0 mg/ml rhPDGF-BB in buffer; and 3) beta-TCP + buffer (active control). Safety data were assessed by the frequency and severity of adverse events. Effectiveness measurements included clinical attachment levels (CAL) and gingival recession (GR) measured clinically and linear bone growth (LBG) and percent bone fill (% BF) as assessed radiographically by an independent centralized radiology review center. The area under the curve (AUC), an assessment of the rate of healing, was also calculated for CAL measurements. The surgeons, clinical and radiographic evaluators, patients, and study sponsor were all masked with respect to treatment groups.
RESULTS: CAL gain was significantly greater at 3 months for group 1 (rhPDGF 0.3 mg/ml) compared to group 3 (beta-TCP + buffer) (3.8 versus 3.3 mm; P = 0.032), although by 6 months, this finding was not statistically significant (P = 0.11). This early acceleration of CAL gain led to group 1 exhibiting a significantly greater rate of CAL gain between baseline and 6 months than group 3 as assessed by the AUC (68.4- versus 60.1-mm weeks; P = 0.033). rhPDGF (0.3 mg/ml)-treated sites also had significantly greater linear bone gain (2.6 versus 0.9 mm, respectively; P < 0.001) and percent defect fill (57% versus 18%, respectively; P < 0.001) than the sites receiving the bone substitute with buffer at 6 months. There was less GR at 3 months in group 1 compared to group 3 (P = 0.04); at 6 months, GR for group 1 remained unchanged, whereas there was a slight gain in gingival height for group 3 resulting in comparable GR. There were no serious adverse events attributable to any of the treatments.
CONCLUSIONS: To our knowledge, this study is the largest prospective, randomized, triple-blinded, and controlled pivotal clinical trial reported to date assessing a putative periodontal regenerative and wound healing therapy. The study demonstrated that the use of rhPDGF-BB was safe and effective in the treatment of periodontal osseous defects. Treatment with rhPDGF-BB stimulated a significant increase in the rate of CAL gain, reduced gingival recession at 3 months post-surgery, and improved bone fill as compared to a beta-TCP bone substitute at 6 months.
PMID: 16332231 [PubMed - indexed for MEDLINE]
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The effect of platelet-rich plasma on the coronally advanced flap root coverage procedure: a pilot human trial.
J Periodontol. 2005 Oct;76(10):1768-77
Authors: Huang LH, Neiva RE, Soehren SE, Giannobile WV, Wang HL
BACKGROUND: Coronally advanced flap (CAF) has been shown to effectively treat gingival recession. Platelet-rich plasma (PRP), containing autologous growth factors, has been shown to promote soft tissue healing. Therefore, the purpose of this study was to evaluate the effects of PRP in combination with CAF.
METHODS: Twenty-four systemically healthy patients participated in this study. A single Miller's Class I buccal recession defect per patient was treated. These patients were randomly assigned into CAF or PRP + CAF groups. Clinical parameters included recession depth (RD), recession width (RW), gingival thickness (GT), width of keratinized tissue (WKT), clinical attachment level (CAL), probing depth (PD), plaque index (PI), wound healing index (WHI), and gingival index (GI). PRP was prepared from whole blood drawn prior to surgery and applied to root surfaces. Patients were followed at 2, 4, 12, and 24 weeks post-surgery.
RESULTS: Twenty-three patients completed the study. The RD at 24 weeks was significantly reduced from 2.9 +/- 0.5 to 0.5 +/- 0.6 mm in the CAF group (P < 0.05) and from 2.8 +/- 0.2 to 0.5 +/- 0.7 mm in the PRP + CAF group (P < 0.05). The mean root coverage was 83.5% +/- 21.8% in the CAF group and 81.0% +/- 28.7% in the CAF + PRP group (P > 0.05). Fourteen out of 23 patients (60.9%) experienced 100% root coverage at the 24-week postoperative follow-up.
CONCLUSION: Based on the results of this pilot study, the application of PRP in CAF root coverage procedure provides no clinically measurable enhancements on the final therapeutic outcomes of CAF in Miller's Class I recession defects.
PMID: 16253100 [PubMed - indexed for MEDLINE]
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Periodontal regeneration.
J Periodontol. 2005 Sep;76(9):1601-22
Authors: Wang HL, Greenwell H, Fiorellini J, Giannobile W, Offenbacher S, Salkin L, Townsend C, Sheridan P, Genco RJ, Research, Science and Therapy Committee
Untreated periodontal disease leads to tooth loss through destruction of the attachment apparatus and tooth-supporting structures. The goals of periodontal therapy include not only the arrest of periodontal disease progression,but also the regeneration of structures lost to disease where appropriate. Conventional surgical approaches (e.g., flap debridement) continue to offer time-tested and reliable methods to access root surfaces,reduce periodontal pockets, and attain improved periodontal form/architecture. However, these techniques offer only limited potential towards recovering tissues destroyed during earlier disease phases. Recently, surgical procedures aimed at greater and more predictable regeneration of periodontal tissues and functional attachment close to their original level have been developed, analyzed, and employed in clinical practice. This paper provides a review of the current understanding of the mechanisms, cells, and factors required for regeneration of the periodontium and of procedures used to restore periodontal tissues around natural teeth. Targeted audiences for this paper are periodontists and/or researchers with an interest in improving the predictability of regenerative procedures. This paper replaces the version published in 1993.
PMID: 16171453 [PubMed - indexed for MEDLINE]
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Oral reconstructive and corrective considerations in periodontal therapy.
J Periodontol. 2005 Sep;76(9):1588-600
Authors: Greenwell H, Fiorellini J, Giannobile W, Offenbacher S, Salkin L, Townsend C, Sheridan P, Genco R, Research, Science and Therapy Committee
This paper was prepared by the Research, Science and Therapy Committee of the American Academy of Periodontology. It is intended to provide information for the dental profession and other interested parties. The purpose of this paper is to provide a general overview of oral reconstructive and corrective procedures used in periodontal therapy. It is not intended to be a comprehensive review of this subject.
PMID: 16171452 [PubMed - indexed for MEDLINE]
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Diagnostic biomarkers for oral and periodontal diseases.
Dent Clin North Am. 2005 Jul;49(3):551-71, vi
Authors: Taba M, Kinney J, Kim AS, Giannobile WV
This article provides an overview of periodontal disease diagnosis that uses clinical parameters and biomarkers of the disease process.This article discusses the use of biomarkers of disease that can be identified at the tissue, cellular, and molecular levels and that are measurable in oral fluids such as saliva and gingival crevicular fluid. Biomarkers identified from these biologic fluids include microbial, host response, and connective tissue-related molecules that can target specific pathways of local alveolar bone resorption. Future prospects for oral fluid-based diagnostics that use micro-array and microfluidic technologies are presented.
PMID: 15978241 [PubMed - indexed for MEDLINE]
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Tissue engineering: what does it mean? Why is it important?
Compend Contin Educ Dent. 2005 Jan;26(1):54, 56, 58 passim
Authors: Williams RC, Cochran DL, Giannobile WV, Lynch SE
PMID: 15948510 [PubMed - indexed for MEDLINE]
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Clinical response of azithromycin as an adjunct to non-surgical periodontal therapy in smokers.
J Periodontol. 2005 Mar;76(3):426-36
Authors: Mascarenhas P, Gapski R, Al-Shammari K, Hill R, Soehren S, Fenno JC, Giannobile WV, Wang HL
BACKGROUND: Antibiotic therapy can be used in very specific periodontal treatment situations such as in refractory cases of periodontal disease found to be more prevalent in smokers. This study was designed to determine the efficacy of azithromycin (AZM) when combined with scaling and root planing (SRP) for the treatment of moderate to severe chronic periodontitis in smokers.
METHODS: Thirty-one subjects were enrolled into a 6-month randomized, single-masked trial to evaluate clinical, microbial (using benzoyl- DL-arginine naphthylamine [BANA] assay), and gingival crevicular fluid (GCF) pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) levels in response to SRP alone or SRP + AZM. At baseline, patients who smoked > or =1 pack per day of cigarettes who presented with at least five sites with probing depths (PD) of > or =5 mm with bleeding on probing (BOP) were randomized into the test or control groups. At baseline and 3 and 6 months, clinical measurements (probing depth [PD], clinical attachment loss [CAL], and bleeding on probing [BOP]) were performed. GCF bone marker assessment (Ctelopeptide [ICTP] as well as BANA test analyses) were performed at baseline, 14 days, and 3 and 6 months.
RESULTS: The results demonstrated that both groups displayed clinical improvements in PD and CAL that were sustained for 6 months. Using a subject-based analysis, patients treated with SRP + AZM showed enhanced reductions in PD and gains in CAL at moderate (4 to 6 mm) and deep sites (>6 mm) (P <0.05). Furthermore, SRP + AZM resulted in greater reductions in BANA levels compared to SRP alone (P <0.05) while rebounds in BANA levels were noted in control group at the 6-month evaluation. No statistically significant differences between groups on mean BOP and ICTP levels during the course of the study were noted.
CONCLUSIONS: The utilization of AZM in combination with SRP improves the efficacy of non-surgical periodontal therapy in reducing probing depth and improving attachment levels in smokers with moderate to advanced attachment loss.
PMID: 15857078 [PubMed - indexed for MEDLINE]
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BMP gene delivery for alveolar bone engineering at dental implant defects.
Mol Ther. 2005 Feb;11(2):294-9
Authors: Dunn CA, Jin Q, Taba M, Franceschi RT, Bruce Rutherford R, Giannobile WV
A challenge in the tissue engineering of alveolar bone surrounding oral or dental implants is achieving the targeted and sustained delivery of growth-promoting molecules at the osteotomy site. Bone morphogenetic protein-7 (BMP-7) has demonstrated the ability to stimulate bone regeneration in multiple skeletal sites, including the craniofacial complex. This study evaluates in vivo gene delivery of BMP-7 for bone tissue engineering around titanium dental implants. The maxillary first molar teeth of 44 Sprague-Dawley rats were extracted and allowed to heal for a period of 1 month. Large osteotomy defects were created in the edentulous ridge areas followed by the placement of dental implant fixtures. Recombinant adenoviral vectors encoding either the BMP-7 or the luciferase gene were delivered to the osseous defects using a collagen matrix. The kinetics of the gene expression was measured using in vivo bioluminescence optical imaging, while bone regeneration was evaluated under light and scanning electron microscopy. The results revealed sustained, targeted transgene expression for up to 10 days at the osteotomy sites with nearly undetectable levels by 35 days. Treatment of dental implant fixtures with Ad/BMP-7 resulted in enhancement of alveolar bone defect fill, coronal new bone formation, and new bone-to-implant contact. In vivo gene therapy of BMP-7 offers potential for alveolar bone engineering applications.
PMID: 15668141 [PubMed - indexed for MEDLINE]
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Engineering of tooth-supporting structures by delivery of PDGF gene therapy vectors.
Mol Ther. 2004 Apr;9(4):519-26
Authors: Jin Q, Anusaksathien O, Webb SA, Printz MA, Giannobile WV
Platelet-derived growth factor (PDGF) exerts potent effects on wound healing including the regeneration of tooth-supporting structures. Limitations of topical protein delivery to periodontal osseous defects include transient biological activity and the bioavailability of PDGF at the wound site. The objective of this investigation was to determine the feasibility of in vivo PDGF-B gene transfer to stimulate periodontal tissue regeneration in large tooth-associated alveolar bone defects in rats. Periodontal lesions (0.3 x 0.2 cm in size) were treated with a 2.6% collagen matrix alone or a matrix containing adenoviruses encoding luciferase (control), a dominant negative mutant of PDGF-A (PDGF-1308), or PDGF-B. Block biopsies were harvested at 3, 7, and 14 days post-gene delivery and descriptive histology and histomorphometric analyses were performed. The defects treated with Ad-PDGF-B demonstrated greater proliferating cell nuclear antigen positively stained cells and strong evidence of bone and cementum regeneration beyond that of Ad-luciferase and Ad-PDGF-1308 groups. Quantitative image analysis showed a nearly fourfold increase in bridging bone and sixfold increase in tooth-lining cemental repair in the Ad-PDGF-B-treated sites compared to lesions treated with Ad-luciferase or collagen matrix alone, which showed limited hard tissue neogenesis. In addition, the Xenogen In Vivo Imaging System revealed sustained and localized gene expression of the luciferase reporter at the periodontal lesions for up to 21 days after gene transfer. These results indicate that in vivo direct gene transfer of PDGF-B stimulates alveolar bone and cementum regeneration in large periodontal defects. Gene therapy utilizing PDGF-B may offer the potential for periodontal tissue engineering applications.
PMID: 15093182 [PubMed - indexed for MEDLINE]
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Effect of sustained gene delivery of platelet-derived growth factor or its antagonist (PDGF-1308) on tissue-engineered cementum.
J Periodontol. 2004 Mar;75(3):429-40
Authors: Anusaksathien O, Jin Q, Zhao M, Somerman MJ, Giannobile WV
BACKGROUND: Cementum, a mineralized tissue lining the tooth root surface, is destroyed during the inflammatory process of periodontitis. Restoration of functional cementum is considered a criterion for successful regeneration of periodontal tissues, including formation of periodontal ligament, cementum, and alveolar bone. Short-term administration of platelet-derived growth factor (PDGF) has been shown to partially regenerate periodontal structures. Nonetheless, the role of PDGF in cementogenesis is not well understood. The aim of the present study was to determine the effect of sustained PDGF gene transfer on cementum formation in an ex vivo ectopic biomineralization model.
METHODS: Osteocalcin (OC) promoter-driven SV40 transgenic mice were used to obtain immortalized cementoblasts (OCCM). The OCCM cells were transduced with adenoviruses (Ad) encoding either PDGF-A, an antagonist of PDGF signaling (PDGF-1308), a control virus (green fluorescent protein, GFP), or no treatment (NT). The transduced cells were incorporated into polymer scaffolds and implanted subcutaneously into severe combined immunodeficient (SCID) mice. The implants were harvested at 3 and 6 weeks for histomorphometric analysis of the newly formed mineralized tissues. Northern blot analysis was performed to determine the expression levels of mineral-associated genes including bone sialoprotein (BSP), OC, and osteopontin (OPN) in the cell-implant specimens at 3 and 6 weeks.
RESULTS: The results indicated mineralization was significantly reduced in both the Ad/PDGF-A and Ad/PDGF-1308 treated specimens when compared to the NT or Ad/GFP groups at 3 and 6 weeks (P<0.01). In addition, the size of the implants treated with Ad/PDGF-A and Ad/PDGF-1308 was significantly reduced compared to implants from Ad/GFP and NT groups at 3 weeks (P<0.05). At 6 weeks, the size of implants and mineral formation increased in NT, Ad/GFP, and Ad/PDGF-A groups, while the Ad/PDGF-1308 treated implants continued to decrease in size and mineral formation (P<0.01). Northern blot analysis revealed that in the Ad/PDGF-A treated implants OPN was increased, whereas OC gene expression was downregulated at 3 weeks. In the Ad/PDGF-1308 treated implants, BSP, OC, and OPN were all downregulated at 3 weeks. At 3 weeks, the Ad/PDGF-A treated implants contained significantly higher multinucleated giant cell (MNGC) density compared to NT, Ad/GFP, and Ad/PDGF-1308 specimens. The MNGC density in NT, Ad/GFP, and Ad/PDGF-A treated groups reduced over time, while the Ad/PDGF-1308 transduced implants continued to exhibit significantly higher MNGC density compared with the other treatment groups at 6 weeks.
CONCLUSIONS: The results showed that continuous exposure to PDGF-A had an inhibitory effect on cementogenesis, possibly via the upregulation of OPN and subsequent enhancement of MNGCs at 3 weeks. On the other hand, Ad/PDGF-1308 inhibited mineralization of tissue-engineered cementum possibly due to the observed downregulation of BSP and OC and a persistence of stimulation of MNGCs. These findings suggest that continuous exogenous delivery of PDGF-A may delay mineral formation induced by cementoblasts, while PDGF is clearly required for mineral neogenesis.
PMID: 15088882 [PubMed - indexed for MEDLINE]
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Cementoblast delivery for periodontal tissue engineering.
J Periodontol. 2004 Jan;75(1):154-61
Authors: Zhao M, Jin Q, Berry JE, Nociti FH, Giannobile WV, Somerman MJ
BACKGROUND: Predictable periodontal regeneration following periodontal disease is a major goal of therapy. The objective of this proof of concept investigation was to evaluate the ability of cementoblasts and dental follicle cells to promote periodontal regeneration in a rodent periodontal fenestration model.
METHODS: The buccal aspect of the distal root of the first mandibular molar was denuded of its periodontal ligament (PDL), cementum, and superficial dentin through a bony window created bilaterally in 12 athymic rats. Treated defects were divided into three groups: 1) carrier alone (PLGA polymer sponges), 2) carrier + follicle cells, and 3) carrier + cementoblasts. Cultured murine primary follicle cells and immortalized cementoblasts were delivered to the defects via biodegradable PLGA polymer sponges, and mandibulae were retrieved 3 weeks and 6 weeks post-surgery for histological evaluation. In situ hybridization, for gene expression of bone sialoprotein (BSP) and osteocalcin (OCN), and histomorphometric analysis were further done on 3-week specimens.
RESULTS: Three weeks after surgery, histology of defects treated with carrier alone indicated PLGA particles, fibrous tissue, and newly formed bone scattered within the defect area. Defects treated with carrier + follicle cells had a similar appearance, but with less formation of bone. In contrast, in defects treated with carrier + cementoblasts, mineralized tissues were noted at the healing site with extension toward the root surface, PDL region, and laterally beyond the buccal plate envelope of bone. No PDL-bone fibrous attachment was observed in any of the groups at this point. In situ hybridization showed that the mineralized tissue formed by cementoblasts gave strong signals for both BSP and OCN genes, confirming its nature as cementum or bone. The changes noted at 3 weeks were also observed at 6 weeks. Cementoblast-treated and carrier alone-treated defects exhibited complete bone bridging and PDL formation, whereas follicle cell-treated defects showed minimal evidence of osteogenesis. No new cementum was formed along the root surface in the above two groups. Cementoblast-treated defects were filled with trabeculated mineralized tissue similar to, but more mature, than that seen at 3 weeks. Furthermore, the PDL region was maintained with well-organized collagen fibers connecting the adjacent bone to a thin layer of cementum-like tissue observed on the root surface. Neoplastic changes were observed at the superficial portions of the implants in two of the 6-week cementoblast-treated specimens, possibly due in part to the SV40-transformed nature of the implanted cell line.
CONCLUSIONS: This pilot study demonstrates that cementoblasts have a marked ability to induce mineralization in periodontal wounds when delivered via polymer sponges, while implanted dental follicle cells seem to inhibit periodontal healing. These results confirm the selective behaviors of different cell types in vivo and support the role of cementoblasts as a tool to better understand periodontal regeneration and cementogen-
PMID: 15025227 [PubMed - indexed for MEDLINE]
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
Hermann Agis
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
Qiming Jin
Dr. Zhao Lin
Julie Marchesan
Dr. Andrea Ottonello
Dr. Chan Ho Park
Dr. Gaia Pelligrini
Dr. Christoph Ramsier
Dr. Stefan Schroeckmair, Bernhard Gottlieb University Clinic of Dentistry, Vienna, Austria
Seung-Yun Shin
Dr. Mario Taba, Jr.
Dr. Valeria Tedeschi
Dr. Kemal Ustun
Dr. Christian Wehner, Bernhard Gottlieb University Clinic of Dentistry, Vienna, Austria
Dr. Andreas Weisbauer
Dr. Yang-Jo Seol
University of Michigan School of Dentistry
Department of Periodontics & Oral Medicine
Room 3310-O Dental Building
1011 N. University Avenue
Ann Arbor, MI 48109
Phone: 734-615-2467
Fax: 734-763-5503

subset: commoncrawl