Chang Po-Chun
Email Address
dencpc@nus.edu.sg
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Publication Sequential platelet-derived growth factor-simvastatin release promotes dentoalveolar regeneration(2014-01-01) Chang, P.-C.; Chong, L.Y.; Dovban, A.S.M.; Lim, L.P.; Lim, J.C.; Kuo, M.Y.-P.; Wang, C.-H.; DENTISTRY; CHEMICAL & BIOMOLECULAR ENGINEERINGObjectives: Timely augmentation of the physiological events of dentoalveolar repair is a prerequisite for the optimization of the outcome of regeneration. This study aimed to develop a treatment strategy to promote dentoalveolar regeneration by the combined delivery of the early mitogenic factor platelet-derived growth factor (PDGF) and the late osteogenic differentiation factor simvastatin. Materials and Methods: By using the coaxial electrohydrodynamic atomization technique, PDGF and simvastatin were encapsulated in a double-walled poly(d,l-lactide) and poly(d,l-lactide-co- glycolide) (PDLLA-PLGA) microspheres in five different modes: microspheres encapsulating bovine serum albumin (BB), PDGF alone (XP), simvastatin alone (SB), PDGF-in-core and simvastatin-in-shell (PS), and simvastatin-in-core and PDGF-in-shell (SP). The microspheres were characterized using scanning electronic microscopy, and the in vitro release profile was evaluated. Microspheres were delivered to fill large osteotomy sites on rat maxillae for 14 and 28 days, and the outcome of regeneration was evaluated by microcomputed tomography and histological assessments. Results: Uniform 20-μm controlled release microspheres were successfully fabricated. Parallel PDGF-simvastatin release was noted in the PS group, and the fast release of PDGF followed by the slow release of simvastatin was noted in the SP group. The promotion of osteogenesis was observed in XP, PS, and SP groups at day 14, whereas the SP group demonstrated the greatest bone fill, trabecular numbers, and thickest trabeculae. Bone bridging was evident in the PS and SP group, with significantly increased osteoblasts in the SP group, and osteoclastic cell recruitment was promoted in all bioactive molecule-treated groups. At day 28, osteogenesis was promoted in all bioactive molecule-treated groups. Initial corticalization was noted in the XP, PS, and SP groups. Osteoblasts appeared to be decreased in all groups, and significantly, a greater osteoclastic cell recruitment was noted in the SB and SP groups. Conclusions: Both PDGF and simvastatin facilitate dentoalveolar regeneration, and sequential PDGF-simvastatin release (SP group) further accelerated the regeneration process through the enhancement of osteoblastogenesis and the promotion of bone maturation. © Copyright 2014, Mary Ann Liebert, Inc.Publication PDGF-simvastatin delivery stimulates osteogenesis in heat-induced osteonecrosis(2012-06) Chang, P.-C.; Lim, L.P.; Chong, L.Y.; Dovban, A.S.M.; Chien, L.-Y.; Chung, M.-C.; Lei, C.; Kao, M.-J.; Chen, C.-H.; Chiang, H.-C.; Kuo, Y.-P.; Wang, C.-H.; DENTISTRY; CHEMICAL & BIOMOLECULAR ENGINEERINGHeat generated during implant osteotomy might lead to osteonecrosis and delayed bone repair, thus resulting in impaired early osseointegration and fixation of bone-anchoring devices. In this study, we proposed to overcome heat-induced injury to bone by fabricating core-shell polymeric biodegradable microspheres encapsulating a mitogenic factor, platelet-derived growth factor (PDGF), and a differentiation factor, simvastatin, in a simultaneous or sequential release profile. Microspheres encapsulating bovine serum albumin (BSA), PDGF, simvastatin, PDGF-in-core with simvastatin-in-shell, and simvastatin-in-core with PDGF-in-shell were delivered to fill standardized osteotomy sites on edentulous ridges of rat maxillae under irrigated or non-irrigated conditions. In the absence of irrigation, significant reduction of cell viability and increase in inflammation and sequestrum formation without evidence of osteogenesis were observed. Both PDGF and simvastatin deliveries facilitated cell viability and reduced osteonecrosis. Localized osteogenesis was seen under simvastatin treatment, while generalized but primitive osteogenesis was noted in PDGF-treated osteotomy sites. In addition, sequential PDGF-simvastatin delivery further augmented osteogenesis and promoted bone maturation. The results suggested that sequential PDGF-simvastatin delivery was an effective modality to prevent heat-induced complications and facilitate bone apposition after implant osteotomy, potentially favoring the early fixation of bone-anchoring devices and oral implant osseointegration. © 2012 International & American Associations for Dental Research.Publication Interrelationships of periodontitis and diabetes: A review of the current literature(2012) Chang, P.-C.; Lim, L.P.; DENTISTRYDiabetes and periodontitis are common chronic diseases in the world, and abundant epidemiological evidence implies a bidirectional relationship between the two diseases. It appears that diabetes is a risk factor for greater periodontal destruction, whereas managing periodontitis can also contribute to better glycemic control. The underlying regulatory mechanisms are also bidirectional. The hyperglycemic status may directly alter subgingival microbial compositions, impair cellular function, and change collagen metabolism. The formation of advanced glycation end-products (AGEs) can further modify the extracellular matrix, and establishment of cellular receptor binding can amplify inflammation. Moreover, periodontitis also induces hyperlipidemia and insulin resistance. This cyclical relationship converges via overproduction of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. Thus, this article highlights the importance of maintaining periodontal health to eliminate systemic complications and meticulous metabolic control to prevent further periodontal destruction. From a systemic aspect, targeting proinflammatory cytokines or receptors of AGEs could be a potential modality for treating periodontitis. Copyright © 2012, Association for Dental Sciences of the Republic of China. Published by Elsevier Taiwan LLC. All rights reserved.Publication Erratum: Functional apparent moduli as predictors of oral implant osseointegration dynamics(2010) Chang, P.-C.; Seol, Y.-J.; Kikuchi, N.; Goldstein, S.A.; Giannobile, W.V.; PREVENTIVE DENTISTRYPublication Functional assessment of dental implant osseointegration.(2012) Chang, P.C.; Giannobile, W.V.; DENTISTRYFunctional 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.Publication Glycated matrix up-regulates inflammatory signaling similarly to Porphyromonas gingivalis lipopolysaccharide(2013) Chang, P.-C.; Chien, L.-Y.; Chong, L.Y.; Kuo, Y.-P.; Hsiao, J..-K.; DENTISTRYBackground and Objective: Hyperglycemia and advanced glycation end-products (AGEs) have been hypothesized as the etiologic factors of diabetic periodontitis. The aim of this study was to clarify in greater detail the patterns of AGE-mediated periodontal inflammation under various physiological conditions. Material and Methods: The deposition of AGEs and expression of the receptor for AGEs (RAGE) were identified by immunohistochemistry in Sprague-Dawley rats with experimentally induced periodontitis or diabetes. Human periodontal ligament cells (PDLCs) and mesenchymal stem cells (MSCs) were cultured under simulated conditions of hyperglycemia, Porphyromonas gingivalis lipopolysaccharide (LPS) stimulation and matrix glycation. Cell viability and expression of toll-like receptors (TLRs), Rage, an inflammatory signaling initiator (nuclear factor kappa light chain enhancer of activator β cells), an oxidative stressor (heme oxygenase-1) and collagen synthesis (type I and type IV) genes were evaluated. Results: The deposition of AGEs and the expression of Rage were evident in the inflamed periodontal tissues in all rats and appeared to be enhanced in rats with diabetes. Matrix glycation augmented cytotoxicity, up-regulated RAGE and TLRs in both PDLCs and MSCs, and significantly activated downstream inflammatory signaling in MSCs. Oxidative stress was significantly increased under matrix glycation in both PDLCs and MSCs and was significantly increased at a high-glucose concentration in MSCs. A consistent decrease in expression of type I and type IV collagens was observed in MSCs, but a delayed reduction was noted in PDLCs. Conclusions: Matrix glycation modulated cell behavior to induce inflammation equivalent to that produced by incubation with P. gingivalis LPS. Periodontal inflammation also led to matrix glycation, thus demonstrating a definite interaction between diabetes and periodontitis. © 2012 John Wiley & Sons A/S.Publication Patterns of diabetic periodontal wound repair: A study using micro-computed tomography and immunohistochemistry(2012) Chang, P.-C.; Chung, M.-C.; Wang, Y.-P.; Chien, L.-Y.; Lim, J.C.; Liang, K.; Chong, L.Y.; Kuo, Y.-P.; Chen, C.-H.; Chiang, H.-C.; DENTISTRYBackground: Diabetes is known to impair wound healing and deteriorate the periodontal condition. There is limited information about the patterns and events associated with periodontal wound repair. In this study, we evaluate the dynamics of periodontal wound repair using micro-computed tomography (microCT) and immunohistochemistry. Methods: Thirty-six male rats were used, and diabetes was induced by streptozotocin. The maxillary first molars were extracted, and a tooth-associated osseous defect was created in the extraction area. Animals were sacrificed after 7, 14, and 21 days. Volumetry and distribution of bone trabeculae were evaluated by microCT imaging. The patterns of healing and collagen alignment were evaluated by histology. Advanced glycation end-product (AGE) deposition and expression of the receptor for AGEs (RAGE), tartrate-resistant acid phosphatase, and proliferating cell nuclear antigen were evaluated by histochemical and immunohistochemical staining. Results: Diabetic animals demonstrated a significantly reduced bone volume and trabecular number as well as thinner trabeculae and more trabecular separation in osseous defects. The early stage was characterized by significantly reduced cellular proliferation and prolonged active inflammation without evident bone resorption, whereas delayed recovery of collagen realignment, matrix deposition, and bone turnover was noted in later stages. Although AGEs and RAGE were present during healing in diabetes and controls, a stronger and more persistent level of expression was observed in the group with diabetes Conclusions: Diabetes significantly delayed osseous defect healing by augmenting inflammation, impairing proliferation, and delaying bone resorption. The AGE-RAGE axis can be activated under metabolic disturbance and inflammation. © 2012 American Academy of Periodontology. All rights reserved.Publication Controlling the proliferation and differentiation stages to initiate periodontal regeneration(2013) Chong, L.Y.; Chien, L.-Y.; Chung, M.-C.; Liang, K.; Lim, J.C.-S.; Fu, J.H.; Wang, C.-H.; Chang, P.-C.; DENTISTRYThe success of periodontal regeneration depends on the coordination of early cell proliferation and late cell differentiation. The aim of this study was to investigate whether the proliferation or differentiation stage predominantly promotes the initiation of periodontal regeneration. Critical-sized periodontal defects were surgically created on rat maxillae and filled with poly-(d,l-lactide-co-glycolide)-poly-d,l-lactide hybrid microspheres encapsulating platelet-derived growth factor (PDGF, a promoter of mitogenesis), simvastatin (a promoter of osteogenic differentiation), or bovine serum albumin (a control). The encapsulation efficiency and in vitro release profiles of the microspheres were determined by high-performance liquid chromatography and enzyme-linked immunosorbent assay. The maxillae were harvested after 10 or 14 days and assessed by micro-computed tomography, histology, and immunohistochemistry for regeneration efficacy and cell viability. The rapid release of PDGF was observed within the first week, whereas a slow release profile was noted for simvastatin. The PDGF-treated specimens demonstrated a significantly higher bone volume fraction compared with bovine serum albumin- (p < 0.05) or simvastatin-treated (p < 0.05) specimens at day 14. Histologically, active bone formation originating from the defect borders was noted in both the PDGF- and the simvastatin-treated specimens, and functionally aligned periodontal ligament fiber insertion was only observed in the PDGF-treated specimens. The significant promotion of mitogenesis by PDGF treatment was also noted at day 14 (p < 0.05). In conclusion, increased mitogenesis or osteogenic differentiation may stimulate osteogenesis, and the upregulation of mitogenesis by PDGF appears to play a role in the initiation of periodontal regeneration. © 2013 Informa Healthcare USA, Inc.Publication Irradiation by light-emitting diode light as an adjunct to facilitate healing of experimental periodontitis in vivo(2013) Chang, P.-C.; Chien, L.-Y.; Ye, Y.; Kao, M.-J.; DENTISTRYChang P-C, Chien L-Y, Ye Y, Kao M-J. Irradiation by light-emitting diode light as an adjunct to facilitate healing of experimental periodontitis in vivo. J Periodont Res 2013; 48: 135-143. © 2012 John Wiley & Sons A/S Background and Objective: This study evaluated the biostimulatory effect of 660nm light-emitting diode (LED) as an adjunct in the treatment of experimental periodontitis. Material and Methods: Ninety-six Sprague-Dawley rats underwent experimental periodontitis by placement of a silk ligature followed with or without additive Porphyromonasgingivalis lipopolysaccharide (Pg-LPS) injection. Irradiation with LED light was performed at varying energy densities of 5, 10 and 15J/cm2, 1d after debridement and detoxification. Rats were killed at 3, 7 and 14d after irradiation with LED light, and the effect of irradiation was evaluated by descriptive histology and quantitative measurements of periodontal bone loss, inflammatory infiltration and cellular proliferation. Results: Reduction of inflammation, accelerated collagen deposition and realignment was noted following irradiation with LED light at densities of 10 and 15J/cm2, and temporary reduction of periodontal bone loss, as well as bundle bone apposition, was noted at day 3 in rats treated with 10J/cm2 light. The biomodulatory effect was stronger in sites treated with Pg-LPS injection. In sites without Pg-LPS injection, temporary reduction of inflammation was noted in all LED light-irradiated specimens at day 3. No significant change in cellular proliferation was noted in any LED light-treated group. Conclusions: LED light (660nm) with an energy density of 10J/cm2 appeared suitable as an adjunct modality for periodontitis by temporarily reducing inflammation, facilitating collagen realignment and bundle bone deposition. Future studies will aim to amplify the biostimulatory effect of LED light by adding a supplementary medium or repeated irradiation. © 2012 John Wiley & Sons A/S.Publication A comparison of the thresholding strategies of micro-CT for periodontal bone loss: A pilot study(2013) Chang, P.-C.; Liang, K.; Lim, J.C.; Chung, M-C.; Chien, L-Y.; DENTISTRYObjectives: Micro-CT provides three-dimensional details and has been widely used for biomedical assessments. This study aimed to determine the most appropriate threshold method for quantitatively assessing the dynamics of periodontal destruction. Methods: Inflammation was induced by submerging a silk ligature in the sulcus of the maxillary second molars of rats, and the animals were killed prior to ligature placement and after 7 and 21 days. The maxillae were examined for the bone resorptive activities by micro-CT, histology and tartrate-resistant acid phosphatase staining. The imaging threshold was determined by CT phantom, global and local algorithms. A bone fraction measurement from each thresholddetermining technique was compared with histomorphometry. The reliability and reproducibility were examined by the intraclass correlation coefficient (ICC) and the coefficient of variation. Results: Significant reduction of inflammatory infiltration (p,0.01) and active osteoclastic resorption (p,0.05) from Day 7 to Day 21 were noted. High inter- and intraexaminer agreement were demonstrated in both histomorphometric and micro-CT assessments (ICC.0.98). The algorithm-based technique demonstrated stronger correlation to histomorphometry than phantom-based thresholds, and the highest agreement was presented by the local algorithm (ICC.0.96). This, however, was considerably computationally expensive. Conclusions: The local threshold-determining algorithm is suggested for examining inflammation-induced bone loss. Further investigation will be aimed at enhancing computational efficiency. Dentomaxillofacial Radiology (2013) 42, 66925194. © 2013 The British Institute of Radiology.