Yong Oock Kim

Prognosis for craniofacial fibrous dysplasia after incomplete resection: age and serum alkaline phosphatase

Complete resection is usually impossible for fibrous dysplasia (FD) involving the cranial base. Incomplete resection could be followed by regrowth of FD, but there is no method for indicating disease progress. Serum alkaline phosphatase (ALP) is significantly high in patients with FD. The authors investigate the relationship between ALP, progress of FD, and age at surgery. 18 patients with craniofacial FD were separated into 3 groups: Group A, complete resection; Group B, incomplete resection followed by regrowth of FD; and Group C, incomplete resection but no regrowth of FD. Medical records and CT scans were reviewed retrospectively. ALP levels were obtained preoperatively, postoperatively and every year during follow-up. The relation between ALP and regrowth and that between age at surgery and regrowth were investigated. There was no recurrence in Group A (n=4). Regrowth in Group B (n=7) was preceded by an abrupt increase in ALP. In Group C (n=7), no regrowth was observed and ALP was maintained within the normal range. 6 patients (85%) in Group B and 2 (28%) in Group C were under 17 years old. The results revealed that the level of postoperative serum ALP could be a reliable marker for predicting the progress of craniofacial FD.

Outcome analysis of cranial molding therapy in nonsynostotic plagiocephaly.

Background It is known that nonsynostotic plagiocephaly does not spontaneously improve, and the craniofacial deformities that result from it. This study was conducted to analyze the effectiveness of helmet therapy for the nonsynostotic plagiocephaly patient, and to suggest a new treatment strategy based on this analysis. Methods A total of 108 pediatric patients who had undergone helmet therapy after being diagnosed with nonsynostotic plagiocephaly were included in this study. The patients were classified according to the initiation age of the helmet therapy, severity, and helmet wearing time. The treatment effect was compared using cranial vault asymmetry (CVA) and the cranial vault asymmetry index (CVAI), which were obtained from diagonal measurements before and after therapy. Results The discrepancy of CVA and CVAI of all the patients significantly decreased after helmet therapy. According to the initiation time of helmet therapy, the treatment effect was best at 5 months old or less. The helmet wearing time per day was proportional to the treatment effect up to 20 hours. In addition, the rate of the successful treatment (final CVA ≤5 mm) significantly decreased when the initiation age was 9.1 months or older and the treatment period was less than 7.83 months. Conclusions This study showed the effectiveness of the helmet therapy for nonsynostotic plagiocephaly patients. Based on analysis of this study, helmet therapy should be started at the age of 9 months or younger for 7.83 months or more, and the helmet wearing time should be more than 20 hours a day.

Volume and distances of the maxillary sinus in craniofacial deformities with midfacial hypoplasia

Objective: Craniofacial deformities (CFDs) frequently accompany midfacial hypoplasia. The authors evaluated characteristics of maxillary sinuses that had CFDs with variable degrees of midfacial hypoplasia. Study Design: Cross-sectional survey with chart review. Setting: Department of Plastic and Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Subjects and Methods: We investigated 40 patients with CFDs having midfacial hypoplasia. Study group 1 (SG 1) consisted of eight patients with Crouzon syndrome (16 maxillary sinuses). Study group 2 (SG 2) consisted of 10 patients with midfacial hypoplasia after palatoplasty (20 maxillary sinuses). Study group 3 (SG 3) consisted of 22 patients with Pruzansky grade I hemifacial microsomia (22 maxillary sinuses on the affected sides). Data on volume and three-dimensional distances (height, width, and depth) from computed tomography were collected and compared with each corresponding control group. Correlation coefficient between volume and the three distances was also calculated. Results: The volume, height, width, and depth of the maxillary sinus were significantly decreased in SG 1 (P < 0.01). In SG 2, only the depth was significantly decreased (P < 0.05). In SG 3, there were no significant differences in any parameters. A multiple-regression analysis between the volume and the three distances showed a statistically significant relationship for width in SG 1, width and height in SG 2, and all distances in SG 3. Conclusion: There were differences in the structure of the maxillary sinuses among patients with different CFDs.

Decorin-expressing adenovirus decreases collagen synthesis and upregulates MMP expression in keloid fibroblasts and keloid spheroids

Decorin is a natural transforming growth factor‐β1 (TGF‐β1) antagonist. Reduced decorin synthesis is associated with dermal scarring, and increased decorin expression appears to reduce scar tissue formation. To investigate the therapeutic potential of decorin for keloids, human dermal fibroblasts (HDFs) and keloid‐derived fibroblasts (KFs) were transduced with decorin‐expressing adenovirus (dE1‐RGD/GFP/DCN), and we examined the therapeutic potential of decorin‐expressing Ad for treating pathologic skin fibrosis. Decorin expression was examined by immunofluorescence assay on keloid tissues. HDFs and KFs were transduced with dE1‐RGD/GFP/DCN or control virus, and protein levels of decorin, epidermal growth factor receptor (EGFR) and secreted TGF‐β1 were assessed by Western blotting and ELISA. And type I and III collagen, and matrix metalloproteinase‐1 (MMP‐1) and matrix metalloproteinase‐3 (MMP‐3) mRNA levels were measured by real‐time RT‐PCR. Additionally, we immunohistochemically investigated the expression levels of the major extracellular matrix (ECM) proteins in keloid spheroids transduced with dE1‐RGD/GFP/DCN. Lower decorin expression was observed in the keloid region compared to adjacent normal tissues. After treatment with dE1‐RGD/GFP/DCN, secreted TGF‐β1 and EGFR protein expressions were decreased in TGF‐β1‐treated HDFs and KFs. Also, type I and III collagen mRNA levels were decreased, and the expression of MMP‐1 and MMP‐3 mRNA was strongly upregulated. In addition, the expression of type I and III collagen, fibronectin and elastin was significantly reduced in dE1‐RGD/GFP/DCN‐transduced keloid spheroids. These results support the utility of decorin‐expressing adenovirus to reduce collagen synthesis in KFs and keloid spheroid, which may be highly beneficial in treating keloids.

Relaxin-expressing adenovirus decreases collagen synthesis and up-regulates matrix metalloproteinase expression in keloid fibroblasts: In vitro experiments

Background: The hormone relaxin has been shown to affect the extracellular matrix by inhibiting collagen synthesis and expression in fibroblasts stimulated with a profibrotic agent. It also increases matrix metalloproteinase (MMP) expression. To investigate its effect on expression of collagen and MMPs in keloid fibroblasts and human dermal fibroblasts, the authors introduced a relaxin-expressing adenovirus (dE1-RGD/lacZ/RLX) into a human dermal fibroblast cell line and keloid fibroblasts. Methods: Both fibroblasts were infected with dE1-RGD/lacZ/RLX or control virus, and protein levels of relaxin and secreted transforming growth factor (TGF)-&bgr;1 were assessed by enzyme-linked immunosorbent assay, and mRNA levels of collagen type I, collagen type III, MMP-1, and MMP-3 were assessed by real-time reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Expression of Smad3 and phosphorylated Smad3 was also examined, and relaxins effect on Smad2/3 complex localization was evaluated. Results: When human dermal fibroblasts and keloid fibroblasts were transduced with dE1-RGD/lacZ/RLX or dE1-RGD/lacZ (control), mRNA expression of type I and type III collagen was markedly decreased by relaxin regardless of TGF-&bgr; (10 ng/ml) treatment. Expression of Smad3 and phosphorylated Smad3 was reduced in keloid fibroblasts and decreased translocation of Smad 2/3 complex from cytosols to the nucleus of the human dermal fibroblasts with TGF-&bgr; after dE1-RGD/lacZ/RLX transduction, suggesting that relaxin reduces collagen synthesis by blocking TGF-&bgr; signaling. Analyses revealed that MMP-1 and MMP-3 expression were significantly increased in human dermal fibroblasts and keloid fibroblasts after dE1-RGD/lacZ/RLX transduction. Conclusion: These results suggest that the antifibrotic effect of relaxin-expressing adenovirus may have therapeutic effects on keloids.

A novel three-dimensional model system for keloid study: Organotypic multicellular scar model

We developed a three‐dimensional organotypic multicellular spheroid scar model to mimic the microenvironment of human keloid tissues. Keloid tissues were cultured for 7 days. Changes in total cellularity and apoptotic index in the primary keloid spheroid cultures were evaluated histologically and with a TUNEL assay, respectively. The expression profiles of transforming growth factor‐β (TGF‐β), collagen I, collagen III, elastin, fibronectin, matrix metalloproteinase‐2, and matrix metalloproteinase‐9 were examined with immunohistochemistry. In addition, these expression profiles were investigated after treating primary keloid spheroids with triamcinolone acetonide. Cell viability and morphology of ex vivo cultured keloid spheroids were maintained, and the apoptotic index did not increase for up to 1 week in culture. Keloid spheroids cultivated ex vivo retained the major characteristics of keloids, such as high levels of collagen I and TGF‐β expression for up to 7 days. The biological activity of keloids responding to TGF‐β was also maintained during ex vivo culture. Moreover, ex vivo triamcinolone acetonide treatment of cultivated keloid spheroids significantly reduced collagen I, collagen III, elastin, and fibronectin expression levels, in accordance with clinical observations. The three‐dimensional organotypic multicellular spheroid keloid culture will allow investigators to study keloid pathogenesis and test potential keloid therapeutic agents.

Skull Reconstruction with Custom Made Three-Dimensional Titanium Implant

Background Source material used to fill calvarial defects includes autologous bones and synthetic alternatives. While autologous bone is preferable to synthetic material, autologous reconstruction is not always feasible due to defect size, unacceptable donor-site morbidity, and other issues. Today, advanced three-dimensional (3D) printing techniques allow for fabrication of titanium implants customized to the exact need of individual patients with calvarial defects. In this report, we present three cases of calvarial reconstructions using 3D-printed porous titanium implants. Methods From 2013 through 2014, three calvarial defects were repaired using custommade 3D porous titanium implants. The defects were due either to traumatic subdural hematoma or to meningioma and were located in parieto-occipital, fronto-temporo-parietal, and parieto-temporal areas. The implants were prepared using individual 3D computed tomography (CT) data, Mimics software, and an electron beam melting machine. For each patient, several designs of the implant were evaluated against 3D-printed skull models. All three cases had a custom-made 3D porous titanium implant laid on the defect and rigid fixation was done with 8 mm screws. Results The custom-made 3D implants fit each patients skull defect precisely without any dead space. The operative site healed without any specific complications. Postoperative CTs revealed the implants to be in correct position. Conclusion An autologous graft is not a feasible option in the reconstruction of large calvarial defects. Ideally, synthetic materials for calvarial reconstruction should be easily applicable, durable, and strong. In these aspects, a 3D titanium implant can be an optimal source material in calvarial reconstruction.

Heat Shock Protein 90 Inhibitor Decreases Collagen Synthesis of Keloid Fibroblasts and Attenuates the Extracellular Matrix on the Keloid Spheroid Model.

Background: The 90-kDa heat-shock protein (heat-shock protein 90) is an abundant cytosolic chaperone, and inhibition of heat-shock protein 90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) compromises transforming growth factor (TGF)-&bgr;–mediated transcriptional responses by enhancing TGF-&bgr; receptor I and II degradation, thus preventing Smad2/3 activation. In this study, the authors evaluated whether heat-shock protein 90 regulates TGF-&bgr; signaling in the pathogenesis and treatment of keloids. Methods: Keloid fibroblasts were treated with 17-AAG (10 &mgr;M), and mRNA levels of collagen types I and III were determined by real-time reverse- transcriptase polymerase chain reaction. Also, secreted TGF-&bgr;1 was assessed by enzyme-linked immunosorbent assay. The effect of 17-AAG on protein levels of Smad2/3 complex was determined by Western blot analysis. In addition, in 17-AAG–treated keloid spheroids, the collagen deposition and expression of major extracellular matrix proteins were investigated by means of Masson trichrome staining and immunohistochemistry. Results: The authors found that heat-shock protein 90 is overexpressed in human keloid tissue compared with adjacent normal tissue, and 17-AAG decreased mRNA levels of type I collagen, secreted TGF-ß1, and Smad2/3 complex protein expression in keloid fibroblasts. Masson trichrome staining revealed that collagen deposition was decreased in 17-AAG–treated keloid spheroids, and immunohistochemical analysis showed that expression of collagen types I and III, elastin, and fibronectin was markedly decreased in 17-AAG–treated keloid spheroids. Conclusion: These results suggest that the antifibrotic action of heat-shock protein 90 inhibitors such as 17-AAG may have therapeutic effects on keloids.

Osteoconductivity of porous polyethylene in human skull.

Purpose Recently, biomaterials have been generally used in reconstruction of a bony defect or augmentation of the facial skeleton. Medpor implants in vivo in animal models showed both soft tissue and bony ingrowth into its pores and have been widely accepted to have an osteoconduction activity. However, in an in vivo study in humans, there was no definite evidence of bony ingrowth into the pores of Medpor. This study examined the osteoconductivity of Medpor in human vivo. Methods We gained a total of 24 Medpor blocks when removing a distraction device in 11 patients with craniosynostosis. The Medpor blocks were used for secure placement of the distraction device. The blocks were taken out after distraction and consolidation periods. The surface of Medpor in contact with the bone was histologically examined to confirm the osteogenic activity. Results There was no evidence of osteoconduction in all 24 specimens. The mean total duration of implantation was 2.5 months. Conclusions In human vivo, implantation of a porous polyethylene implant is thought to have no osteogenetic effect through osteoconductive activity even in young children.

Transport disc distraction osteogenesis for the reconstruction of a calvarial defect.

PURPOSE According to previous reports about the experimental study of transport disk distraction osteogenesis (TDDO) for the reconstruction of bone defects, TDDO showed great feasibility of successful bone regeneration. However, those studies had some limitations in their design and analysis of the results, either. In this report, we intended to verify the effect of TDDO in the reconstruction of skull defects with a combined result of distraction osteogenesis and bone graft of transported disk (TD). METHODS Six female dogs were operated on and were given a 35×15-mm bilateral skull defect. In the experimental group, TDDO with internal distractors (7×14-mm TD) was performed. On the other side, in the control group, the bone defects were left to heal naturally. The distraction was performed from the postoperative fifth day at a rate of 1 mm/d. The distraction progressed for 14 days, and then the TD was maintained in the middle of the bone defect area. The 40% of the original bone defect area was left the same as the control side. The TD was expected to be survived as a bone graft during the consolidation period. After 3½ months of a consolidation period, the remained bone defects were measured by three-dimensional computed tomography. The solidity of the new bone was compared with the bone tissue of the normal skull bone. RESULTS In the study group, the new bone formation was estimated to be 62.3% (SD, 25.1%) of the defect area, and in the control group, it was 44.8% (SD, 27.3%). The difference between the 2 groups was significant (P=0.04). The solidity of the newly generated bone by TDDO was not different from the normal skull (P=0.74). CONCLUSIONS In this study, the concept of TDDO and bone graft seemed to promote new bone formation. The role of the TD could include bone regeneration from distraction osteogenesis as well as autogenous bone graft, although it needs more investigation. The relationship between the duration of distraction and the positive role of the TD as an autogenous bone graft in TDDO for better clinical application may be investigated.Purpose: According to previous reports about the experimental study of transport disk distraction osteogenesis (TDDO) for the reconstruction of bone defects, TDDO showed great feasibility of successful bone regeneration. However, those studies had some limitations in their design and analysis of the results, either. In this report, we intended to verify the effect of TDDO in the reconstruction of skull defects with a combined result of distraction osteogenesis and bone graft of transported disk (TD). Methods: Six female dogs were operated on and were given a 35 × 15-mm bilateral skull defect. In the experimental group, TDDO with internal distractors (7 × 14-mm TD) was performed. On the other side, in the control group, the bone defects were left to heal naturally. The distraction was performed from the postoperative fifth day at a rate of 1 mm/d. The distraction progressed for 14 days, and then the TD was maintained in the middle of the bone defect area. The 40% of the original bone defect area was left the same as the control side. The TD was expected to be survived as a bone graft during the consolidation period. After 3½ months of a consolidation period, the remained bone defects were measured by three-dimensional computed tomography. The solidity of the new bone was compared with the bone tissue of the normal skull bone. Results: In the study group, the new bone formation was estimated to be 62.3% (SD, 25.1%) of the defect area, and in the control group, it was 44.8% (SD, 27.3%). The difference between the 2 groups was significant (P = 0.04). The solidity of the newly generated bone by TDDO was not different from the normal skull (P = 0.74). Conclusions: In this study, the concept of TDDO and bone graft seemed to promote new bone formation. The role of the TD could include bone regeneration from distraction osteogenesis as well as autogenous bone graft, although it needs more investigation. The relationship between the duration of distraction and the positive role of the TD as an autogenous bone graft in TDDO for better clinical application may be investigated.