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1.  Osteoblast Maturation and New Bone Formation in Response to Titanium Implant Surface Features are Reduced with Age 
The surface properties of materials contribute to host cellular response and play a significant role in determining the overall success or failure of an implanted biomaterial. Rough titanium (Ti) surface microtopography and high surface free energy have been shown to enhance osteoblast maturation in vitro and increase bone formation in vivo. While the surface properties of Ti are known to affect osteoblast response, host bone quality also plays a significant role in determining successful osseointegration. One factor affecting host bone quality is patient age. We examined both in vitro and in vivo whether response to Ti surface features was affected by animal age. Calvarial osteoblasts isolated from 1-, 3-, and 11-month-old rats all displayed a reduction in cell number and increases in alkaline phosphatase specific activity and osteocalcin in response to increasing Ti surface microtopography and surface energy. Further, osteoblasts from the three ages examined displayed increased production of osteocalcin and local factors osteoprotegerin, VEGF-A, and active TGF-β1 in response to increasing Ti surface roughness and surface energy. Latent TGF-β1 only increased in cultures of osteoblasts from 1- and 3-month-old rats. Treatment with the systemic osteotropic hormone 1α,25(OH)2D3 further enhanced the response of osteoblasts to Ti surface features for all three age groups. However, osteoblasts derived from 11-month-old animals had a reduced response to 1α,25(OH)2D3 as compared to osteoblasts derived from 1-or 3-month-old animals. These results were confirmed in vivo. Ti implants placed in the femoral intramedullary canal of old (9-month) mice yielded lower bone-to-implant contract and neovascularization in response to Ti surface roughness and energy compared to younger (2-month) mice. These results show that rodent osteoblast maturation in vitro as well as new bone formation in vivo is reduced with age. Whether comparable age differences exist in humans needs to be determined.
doi:10.1002/jbmr.1628
PMCID: PMC3835587  PMID: 22492532
2.  Regulation of Angiogenesis during Osseointegration by Titanium Surface Microstructure and Energy 
Biomaterials  2010;31(18):4909-4917.
Rough titanium (Ti) surface microarchitecture and high surface energy have been shown to increase osteoblast differentiation, and this response occurs through signaling via the α2β1 integrin. However, clinical success of implanted materials is dependent not only upon osseointegration but also on neovascularization in the peri-implant bone. Here we tested the hypothesis that Ti surface microtopography and energy interact via α2β1 signaling to regulate the expression of angiogenic growth factors. Primary human osteoblasts (HOB), MG63 cells and MG63 cells silenced for α2 integrin were cultured on Ti disks with different surface microtopographies and energies. Secreted levels of vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (FGF-2), epidermal growth factor (EGF), and angiopoietin-1 (Ang-1) were measured. VEGF-A increased 170% and 250% in MG63 cultures, and 178% and 435% in HOB cultures on SLA and modSLA substrates, respectively. In MG63 cultures, FGF-2 levels increased 20 and 40-fold while EGF increased 4 and 6-fold on SLA and modSLA surfaces. These factors were undetectable in HOB cultures. Ang-1 levels were unchanged on all surfaces. Media from modSLA MG63 cultures induced more rapid differentiation of endothelial cells and this effect was inhibited by anti-VEGF-A antibodies. Treatment of MG63 cells with 1α,25(OH)2D3 enhanced levels of VEGF-A on SLA and modSLA. Silencing the α2 integrin subunit increased VEGF-A levels and decreased FGF-2 levels. These results show that Ti surface microtopography and energy modulate secretion of angiogenic growth factors by osteoblasts and that this regulation is mediated at least partially via α2β1 integrin signaling.
doi:10.1016/j.biomaterials.2010.02.071
PMCID: PMC2896824  PMID: 20356623
Titanium; microstructure; surface energy; osteoblast; angiogenesis; VEGF
3.  Effects of Periodontal Therapy on Rate of Preterm Delivery A Randomized Controlled Trial 
Obstetrics and gynecology  2009;114(3):551-559.
OBJECTIVE
To test the effects of maternal periodontal disease treatment on the incidence of preterm birth (delivery before 37 weeks of gestation).
METHODS
The Maternal Oral Therapy to Reduce Obstetric Risk Study was a randomized, treatment-masked, controlled clinical trial of pregnant women with periodontal disease who were receiving standard obstetric care. Participants were assigned to either a periodontal treatment arm, consisting of scaling and root planing early in the second trimester, or a delayed treatment arm that provided periodontal care after delivery. Pregnancy and maternal periodontal status were followed to delivery and neonatal outcomes until discharge. The primary outcome (gestational age less than 37 weeks) and the secondary outcome (gestational age less than 35 weeks) were analyzed using a χ2 test of equality of two proportions.
RESULTS
The study randomized 1,806 patients at three performance sites and completed 1,760 evaluable patients. At baseline, there were no differences comparing the treatment and control arms for any of the periodontal or obstetric measures. The rate of preterm delivery for the treatment group was 13.1% and 11.5% for the control group (P=.316). There were no significant differences when comparing women in the treatment group with those in the control group with regard to the adverse event rate or the major obstetric and neonatal outcomes.
CONCLUSION
Periodontal therapy did not reduce the incidence of preterm delivery.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, www.clinicaltrials.gov, NCT00097656.
LEVEL OF EVIDENCE
I
doi:10.1097/AOG.0b013e3181b1341f
PMCID: PMC2917914  PMID: 19701034
4.  Cellular Effects of Enamel Matrix Derivative Are Associated With Different Molecular Weight Fractions Following Separation by Size Exclusion Chromatography 
Journal of periodontology  2009;80(4):648-656.
Background
Enamel matrix derivative (EMD) has been shown to enhance both soft tissue healing and regeneration of the periodontium, but the mechanisms of this action are still unknown. It is assumed that amelogenin, the most abundant protein in EMD, is the protein primarily responsible for the effects of EMD. The purpose of this study was to fractionate EMD and associate specific cellular effects of EMD with different molecular weight fractions following size exclusion chromatography.
Methods and Materials
Freshly dissolved EMD was fractionated by gel filtration and forty-five 7ml fractions collected, desalted, lyophilized, and resuspended. These fractions were analyzed for their effects on differentiation of osteoprogenitor cells (C2C12) and proliferation and differentiation of human microvascular endothelial cells (HMVEC). Alkaline phosphatase activity (C2C12) was measured as a marker for osteogenic differentiation before and after pre-incubation of the fractions with the bone morphogenetic protein (BMP) decoy receptor, noggin. Angiogenesis (HMVEC) was evaluated as a marker for endothelial cell differentiation. Enzymographic assays used polyacrylamide gels co-polymerized with denatured type I collagen to determine gelatinolytic activities in each fraction.
Results
EMD fractionated into three major protein peaks following size exclusion chromatography with Sephadex G-100. Peak I was associated with the column void volume, while peak III eluted near the salt volume. Peak II eluted between these two peaks. Proliferation and angiogenic activities were associated with both peak II and peak III for the microvascular cells. Differentiation of osteoprogenitor cells, indicated by alkaline phosphatase activity, was induced by EMD components present in peak I and the leading edge of peak II. The additional observation that this differentiation was inhibited by prior treatment of the fractions with noggin suggested the activity was induced by BMP rather than amelogenin or other unknown proteins. Gelatinolytic activities were detected in the early fractions of peaks 1 and 2 of gel fractionated EMD.
Conclusions
The cellular activities stimulated by EMD are not associated with a single molecular weight species. The fact that noggin abolishes C2C12 alkaline phosphatase activity suggests that effects on osteoprogenitor cell differentiation are the result of a BMP-like protein(s), while effects on proliferation and angiogenesis are associated with lower molecular weight species present in peak II and peak III. Finally, unheated EMD displays gelatinolytic activities that are also detectable following size exclusion separation of EMD constituents. The masses of these activities were consistent with those reported for latent and active MMP-20.
doi:10.1902/jop.2009.070420
PMCID: PMC2866653  PMID: 19335085
EMD; BMP; differentiation; proliferation; angiogenesis; collagenolytic activity
5.  Role of Glutathione Metabolism of Treponema denticola in Bacterial Growth and Virulence Expression 
Infection and Immunity  2002;70(3):1113-1120.
Hydrogen sulfide (H2S) is a major metabolic end product detected in deep periodontal pockets that is produced by resident periodontopathic microbiota associated with the progression of periodontitis. Treponema denticola, a member of the subgingival biofilm at disease sites, produces cystalysin, an enzyme that catabolizes cysteine, releasing H2S. The metabolic pathway leading to H2S formation in periodontal pockets has not been determined. We used a variety of thiol compounds as substrates for T. denticola to produce H2S. Our results indicate that glutathione, a readily available thiol source in periodontal pockets, is a suitable substrate for H2S production by this microorganism. In addition to H2S, glutamate, glycine, ammonia, and pyruvate were metabolic end products of metabolism of glutathione. Cysteinyl glycine (Cys-Gly) was also catabolized by the bacteria, yielding glycine, H2S, ammonia, and pyruvate. However, purified cystalysin could not catalyze glutathione and Cys-Gly degradation in vitro. Moreover, the enzymatic activity(ies) in T. denticola responsible for glutathione breakdown was inactivated by trypsin or proteinase K, by heating (56°C) and freezing (−20°C), by sonication, and by exposure to Nα-p-tosyl-l-lysine chloromethyl ketone (TLCK). These treatments had no effect on degradation of cysteine by the purified enzyme. In this study we delineated an enzymatic pathway for glutathione metabolism in the oral spirochete T. denticola; our results suggest that glutathione metabolism plays a role in bacterial nutrition and potential virulence expression.
doi:10.1128/IAI.70.3.1113-1120.2002
PMCID: PMC127775  PMID: 11854190

Results 1-5 (5)