and the inability to directly give rise to tumors 88 . 4. Disadvantages
Genetic instability of iPSCs could lead to tumor formation inthe host tissue, a possibility that should be evaluated 89,90 . The number of BM-MSCs that can be obtained by a single procedure is limited, and bone marrow biopsy is an invasive procedure that requires general anesthesia. Moreover, the number of iPSCs decreases with age. Intravenous injection of MSCs determines the capture ofthe majority ofcells into capillary beds, especially inthe lungs, but also in spleen, liver, and kidney. This systemic clearance means that only a small number of MSCs reach the target site. Moreover, such treatment poses the risk of pulmonary thromboembolism due to aggregation inthe pulmonary circulation 91,92 and can trigger disseminated intravascular coagulation due to proco- agulant activity 93 . As a result of immunosuppression, there is greater risk ofthe onset of tumors or the progression of existing malignancies 90 and genetic instability of expanded cellsin vitro 94 . The bone marrow, a potential source for cell therapy, is invaded by medullary clonal plasma cellsin mul- tiple myeloma. The interactions between malignant cells and the BM microenvironment contributes to abnormalities in BM-MSC, such as IL-6 and DKK1 overexpression and early senescence 95 . For this reason, autologous BM-MSCs cannot be used for MRONJ treatmentin multiple myeloma patients.
Objective: The purpose of this study is to compare the surgical treatment with conservative treatment and to evaluate the effectiveness of drug-holiday in bisphosphonate related osteonecrosisofthejaw (BRONJ) patients who were diagnosed as stage 2.
Patients and Method: From January 2012 to October 2014, seventy-two patients who visit to Pusan National University of Dental Hospital were diagnosed as stage 2 of BRONJ. All the patients had taken computed tomography(CT) and panoramic radiography. The surgical treatment including sequestrectomy of necrotic bone and curettage of soft tissue around the sequestrum were performed to fifty patients. Twenty-two patients underwent conservative treatment such as antibiotics medications, mouth rinsing and follow up checking for every two weeks. Prognosis oftreatment was classified into 3 groups ? response, unresponse, and worsens - according to clinical, radiographic symptoms. P-value less than 0.05 were regarded as significant.
Abstract (J Korean Assoc Oral Maxillofac Surg 2015;41:327-331)
Bisphosphonate-related osteonecrosisofthejaw (BRONJ) occurs mainly in female patients. In males the occurrence rate is low, which seems to be related to the low incidence of osteoporosis in men. Unfortunately, BRONJ tends to be ignored in general dental clinics in male patients with a history of osteoporosis treatment. BRONJ occurred in a male patient due to the clinician’s lack of interest inthe patient’s history. In this case, the male patient was on bisphosphonate therapy because of a orchiectomy, and a dental treatment was performed without consideration of his medical history, resulting in BRONJ. We performed careful examinations and treatment with antibiotics and surgical operations. The postoperative healing was successful. In light of this particular case, we concluded that careful listening to the patient’s history is very important.
The success rate of complete healing was 63.46%, lower than that reported in other papers (50%-76.7%) 10,12,26,32 . This might be due to the definition of complete healing. In the present study, cases with postoperative infection, bone expo- sure, or abnormal reactions were excluded. In addition, since the surgical treatment used in this study was mostly saucer- ization and sequestrectomy, it is possible that the safety mar- gin was not sufficient to include MRONJ. In some papers, major surgery has been reported as more effective for patients with MRONJ than minimally invasive surgery 10 . In this study, necrotic bone was removed during surgical treatment, and the surgical range was set until fresh blood emerged from the surrounding bone. However, the extent of this surgery is still controversial. Pautke et al. 33 have advocated fluorescence- guided resection. Carlson and Basile 34 have asserted that a safety margin of 1 cm should be established.
In cases of purulent osteomyelitis not related to BPs, the inner part ofthe bone is filled with inflammatory cells. This condition indicates a natural immune reaction to resist bac- terial penetration and is not related to the osteoclast-killing effect of BPs 45 . The form oftheosteonecrosis can be seen inthe bone biopsies.(Fig. 4) Neither cell components for blood vessels were found, and osteocytes and new bone formed adjacent to the sites have disappeared. The type of osteone- crosis mentioned in this paper is highly related to BRONJ pathogenesis due to osteoclast extinction and decreased blood flow. The features of BRONJ described in this paper coincide with those reported by Marx and Tursun 45 . When BRONJ occurs, not only osteonecrosis, but also membrane exposure occurs. Bones provide blood flow to the periosteum and mucous membranes. Based on the bone biopsy results, BP medication decreases the blood flow in mucous membranes and the periosteum, leading directly to ischemic necrosis and ultimately bone exposure. BP medication could account for membrane exposure.
had BRONJ after receiving oral BP 1,20 . It is very different treatmentof osteoporosis fracture 6 . Therefore, considering
the fact that the sales of all BP products in 2008 were pegged at 114.2 billion won, the socioeconomic proﬁt of medication apparently outweighs the loss. Nonetheless, the long-term administration of BP reportedly caused BRONJ; since the ﬁrst case reported by Marx 7 in 2003, many clinical and basic research studies have been conducted. In Korea, since the ﬁrst case report inthe oral and maxillofacial area in 2009 8 , each school has accumulated case series 9-11 . Recently, the Japan Association of Oral and Maxillofacial Surgeons reported to the Journal of Oral and Maxillofacial Surgery in 2011 that it collected statistics of 248 training hospitals in Japan covering 568 cases 1 .
However, there have been few studies on medical doctors’
awareness of BRONJ and how well dental referrals are be- ing carried out. As in other forms ofosteonecrosis, such as osteoradionecrosis and osteomyelitis ofjaw, BRONJ usually has a poor prognosis and demands long-term treatment, thus mutual efforts between the medical doctor and dentist through a multi-disciplinary approach are essential inthe diagnosis, treatment, and prevention of BRONJ .
Previous studies have shown that the longer the time of exposure to the drug, the greater the likelihood of being affected by MRONJ. Thus, protocols for dental pro- cedures have been reported in patients taking BPs, taking into account the MRONJ risk associated with the duration of drug use [42, 43]. In this study, weighted total accumu- lation was found to be higher in patients with higher MRONJ clinical stage from stage 1 to stage 3. Also, when treated according to the MRONJ treatment protocol, the higher the patient’s weighted total accumulation, the more delayed the response to treatment. It is suggested that in a pharmaco-pathologic view, the amount ofthe drug accumulated inthe bone due to the average administered dose and the absorption rate ofthe drug, and relative
Imatinib is used to treat adults with GISTs that cannot be removed with surgery or have spread to other parts ofthe body, and adults who are at risk of GISTs coming back after surgical removal. The dose depends on the disease being treated, the age and condition ofthe patient, and the response to treatment, but it should not exceed 800 mg a day. The patient had been treated only with imatinib for 22 months at doses of 400 mg/day for 3 months followed by 600 mg/day for 4 months and then 800 mg/day and never with bisphos- phonates or radiotherapy. In line with indications inthe literature 3,4 , the oncologist did not suspend imatinib therapy because the GISTs were metastases. Clinical course after the tooth extraction included apparent healing inthe first weeks followed by rapid local worsening leading to bone sequestra- tion with pain, swelling, halitosis and partial hypoesthesia ofthe lower lip. This evolution largely resembles the clinical course ofosteonecrosis due to bisphosphonates 2 . Although the patient had never been treated with bisphosphonates or radiotherapy ofthe head or neck, his clinical picture was identical to osteonecrosis stage 2 subclass b due to bisphos- phonates. Therapy with imatinib and the concomitant dental extraction seem likely causes ofthe resulting osteonecrosis.
tween the upper right first premolar tooth and second pre- molar implant. However, we could not determine how long it had been exposed because the patient was reffered to us for treatment. The upper right second premolar implant showed 3 degrees of mobility, pain on percussion, and a 10- mm probing depth inthe buccal and distal areas. Alveolar bone resorption with internal scattered residual bony frag- ments was seen between the two implants on a panoramic radiograph (Fig. 1) and computed tomography (Fig. 2). Wid- ening ofthe periodontal ligament space and a radiolucent lesion inthe apical area ofthe upper right first premolar were also seen.
(Table 5) Taken together, our results suggest that decreased renal function will result in decreased patient response to thetreatment.
In general, the systemic diseases that affect the renal func- tion of patients are hypertension, diabetes, glomerulonephri- tis, infection, and steroid treatment for osteoarthritis manage- ment 37 . In this study, however, heart disease, diabetes, liver disease, thyroid disease, and kidney disease were found not to have a statistically significant correlation with the BRONJ stage. This was illustrated by a case where the patient was unaware they had an aforementioned disease until diagnosed through clinical and serologic tests, and by a case where the patient did not have any ofthe aforementioned diseases but was taking a drug for preventive purposes. Additionally, there were cases with no detailed diagnosis, where the patient was completely cured after the surgery, continued to receive the drug and was not examined, or the duration of drug ad- ministration or treatment was not calculated. For significant results, more specific variables must be applied for each item.
without a drug holiday. Therefore, it is predictable that, if a drug holiday was more clearly maintained, the incidence rate would be decreased.
The conservative treatment and surgical treatment are controversial, and evidence is lacking, but stage 1 MRONJ patients are recommended to undergo antibiotic gaggles, systemic antibiotics, and some local surgical procedures 39,40 . However, in stages 2 and 3, this conservative treatment is often inadequate, and these patients instead require surgical intervention 39-41 . When considering the failure of conservative treatmentin this case, surgical intervention is widely recom- mended. Previous studies have shown that the success rate of surgical treatment was 84.2% to 89%, although there was a slight difference according to surgical method, operative object, and success criteria 42-44 . Similarly, a success rate of 76% was obtained in this study. Furthermore, various meth- ods such as low level laser therapy and recombinant human bone morphogenetic protein-2 have been used recently for MRONJ treatment 45,46 .
Abstract (J Korean Assoc Oral Maxillofac Surg 2014;40:206-210)
Objectives: To identify post-treatment prognostic factors for medication-related osteonecrosisofthejaw (MRONJ).
Materials and Methods: We evaluated 54 MRONJ patients who visited the Department of Dentistry, Ajou University Hospital, from May 2007 to March 2014. Twenty-one patients were surgically managed with debridement or sequestrectomy and 33 patients were conservatively managed using antibiotics. Correlations of age, sex, stage, bisphosphonate duration and type, and drug holiday with the prognosis of MRONJ were investigated. Cor- relations were verified by logistic regression analysis and t-tests with a significance level of 0.05.
The expression pattern of undifferentiated T-MSCs was distinguishable from the myogenic differentiated T-MSCs and hSKMCs. In particular, we selected FNBP1L, which among the upregulated genes is essential for antibacterial autophagy, since autophagy is related to SKM metabolism and myogen- esis. T-MSCs differentiated toward myoblasts and skeletal myocytes sequentially, as evidenced by increased expression of autophagy-related markers (including Beclin-1, LC3B and Atg5) and decreased expression of Bcl-2. Furthermore, we reconfirmed that autophagy has an effect on the mechanism of skeletal myogenic differentiation derived from T-MSCs by treatment with 5-azacytidine and bafilomycin A1. These data suggest that the transcriptome ofthe T-MSC-derived
Although nacre has shown, in one study, to induce bridg- ing of new bone across large non-union bone defects in 8 individual human patients, there have been no succeeding human surgical studies to confirm this outstanding poten- cy. But the molecular mechanisms associated with nacre osteoinduction and the influence on bone marrow-derived mesenchymalstemcells (BMSC’s), skeletal stemcells or bone marrow stromal cells remain elusive. In this study we highlight the phenotypic and biochemical effects of Pinctada maxima nacre chips and the global nacre soluble protein matrix (SPM) on primary human bone marrow- derived stromal cells (hBMSCs) in vitro. In static co-culture with nacre chips, the hBMSCs secreted Alkaline phospha- tase (ALP) at levels that exceeded bone morphogenetic protein (rhBMP-2) treatment. Concentrated preparation of SPM applied to Stro-1 selected hBMSC’s led to rapid ALP secretions, at concentrations exceeding the untreated con- trols even in osteogenic conditions. Within 21 days the same population of Stro-1 selected hBMSCs proliferated and secreted collagens I-IV, indicating the premature onset of an osteoblast phenotype. The same SPM was found to promote unselected hBMSC differentiation with osteocalcin detected at 7 days, and proliferation increased at 7 days in a dose-dependent manner. In conclusion, nacre particles and nacre SPM induced the early stages of human bone cell differentiation, indicating that they may be promising solu- ble factors with osteoinductive capacity in primary human bone cell progenitors such as, hBMSC’s.
Until recently, autogenous bone grafts including particulate cancerous bone marrow (PCBM) and vascularized bone grafts were considered the gold standard for thetreatmentof bone defects inthe maxillofacial region . This well- studied procedure has good prognosis but requires an extra surgery at the donor site, which is an additional burden on the patient. When the bone graft is performed, surgeons have several requirements for the acquisition of blood supply from the surrounding tissue, such as perforating the cortical bone and preservation ofthe periosteum. These points of attention are sometimes difficult because ofthe conditions ofthe surrounding tissue after the surgery.
Department of Medicine
The Graduate School, Yonsei University
(Directed by Professor Keungnyun Kim)
Regenerative medicine is a leading approach to treating diseases ofthe central nervous system. This study aimed to investigate the innate repair benefits of human mesenchymalstemcells (hMSC) coupled with the biocompatibility of a poly-lactic-co-glycolic acid (PLGA) polymer scaffold to treat a rat hemisection model of spinal cord injury. We performed thoracic segmental hemisections on Sprague-Dawley rats and treated them with either scaffolded-hMCSs, scaffold alone, hMSCs alone or saline control. This study not only confirmed the significant sensorimotor benefits of scaffoled-hMSCs after injury, but also elucidated the role of propriospinal neuron activation. The scaffolded-hMSC construct resulted in increased neuroplasticity and reduced secondary neural damage. The feasibility of autologous mesenchymalstem cell transplantation using a biodegradable polymer scaffold makes this treatment an attractive candidate for clinical investigation.
Section Editor of JKAOMS
Department of Oral and Maxillofacial Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
inhibiting T-helper cells while activating regulatory T-cells and suppressing B-lymphocytes 8,9 . This immunomodulatory effect of MSCs makes them suitable for treatmentof severe autoimmune diseases and graft-versus-host disease 8 . How- ever, most trials for the clinical application of MSCs have used bone marrow-derived MSCs (BMSCs). As mentioned previously, MSCs from dental tissue (DMSCs) exhibit simi- lar characteristics to BMSCs, but have superior osteogenic differentiation potential 3,6 . Therefore, DMSCs could possibly replace BMSCs in cell therapy and tissue regeneration ap- plications. The new cryopreservation method for dental tissue enables the use of autologous MSCs from preserved dental tissue of extracted wisdom teeth 7 . These autologous MSCs could reduce unexpected side effects during clinical use, while maintaining similar immunomodulatory efficacy.
Stem cell therapies have shown promising benefits for hepatic fibrosis in experimental and clinical studies 13, 14, 19, 22
. BM comprises two main populations ofstemcells, hematopoietic stemcells and MSCs, of which the latter have been considered as alternative cell sources for liver or hepatocyte transplantation 24 . In liver damage, MSCs are able to differentiate into hepatocytes, stimulate the regeneration of endogenous parenchymal cells, migrate to damaged sites, and enhance fibrous matrix degradation (antifibrotic effects). Furthermore, several clinical studies have demonstrated favorable effects of BM-MSCs treatment such as improving the liver function in patients with hepatitis B or C virus-related cirrhosis 22, 36 . However, no previous study has examined the effect of autologous BM-MCs on hepatic fibrosis in patients with alcoholic cirrhosis. We aimed to determine the safety and antifibrosis effect of MSCs on alcohol-related hepatic fibrosis in pre-clinical and clinical study.
Our study demonstrated that hMSCs had protective effects of BBB function against LPS-induced neutrophil infiltration. The number of EB and EBA-ir after hMSC treatment was in accordance with reduced neutrophil infiltration following hMSC treatmentin LPS- induced animal models. The properties of BBB stabilization by MSCs seem to be mediated by complex mechanisms. First, our study has demonstrated that hMSCs can restore the function of astrotic end feet surrounding endotherial cells. In this study, hMSC treatment significantly increased the number of GFAP-ir in LPS-induced animal models. The lower density of astrocytes inthe SNpc might be ineffective at downregulating inflammatory responses and at maintaining BBB structure (Ross et al, 1995; Tomas-Camardiel et al, 2004;