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First clinical application of octacalcium phosphate collagen composite on bone regeneration in maxillary sinus floor augmentation: A prospective, single-arm, open-label clinical trial.
Miura, KI, Sumita, Y, Kajii, F, Tanaka, H, Kamakura, S, Asahina, I
Journal of biomedical materials research. Part B, Applied biomaterials. 2020;(1):243-252
Abstract
The overall objective of this study was to assess the safety and efficacy of OCP/Col as a bone substitute material for bone regeneration during sinus floor augmentation. Maxillary sinus floor augmentation was performed thorough lateral window approach. According to the height of host bone, simultaneous approach (≥5 mm) or staged approach (less than 5 mm) was applied. In this research, clinical findings of dental implant treatment after setting the restorations were set as a primary endpoint in both approaches (infection, inflammation around the implant, movement of the implant, pain, sensory disorder, and bone resorption around the implant body on radiological evaluation.). In staged approach, histological evaluation of bone biopsy specimen was also conducted. As secondary endpoints, hounsfield unit (HU) value, vertical bone height, implant stability quotient (ISQ), and adverse events during the research were evaluated. In all cases, as a primary endpoint, clinical findings after setting the restorations were uneventful with no adverse events. Histological structure demonstrated mature bone derived from OCP/Col. In the ossified area, osteogenesis was observed around OCP granules, and osteoblast-like cells were arrayed around OCP granules. Osteocyte encapsulation was recognized in the new bone. HU increased over time with both approaches. Vertical bone height significantly increased at 3 months postoperatively, and maintained during follow-up. ISQ increased with both approaches. In particular, ISQ was significantly increased with the staged approach. This clinical trial demonstrated the safety and efficacy of OCP/Col for bone regeneration in maxillary sinus floor augmentation. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 108B:243-252, 2020.
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Screen-enrich-combine circulating system to prepare MSC/β-TCP for bone repair in fractures with depressed tibial plateau.
Chu, W, Wang, X, Gan, Y, Zhuang, Y, Shi, D, Liu, F, Sun, Y, Zhao, J, Tang, T, Dai, K
Regenerative medicine. 2019;(6):555-569
Abstract
Aim: To evaluate the clinical efficacy of mesenchymal stem cell/β-tricalcium phosphate composites (MSC/β-TCP) prepared with a screen-enrich-combine circulating system (SECCS) in patients with depressed tibial plateau fractures. Materials & methods: Bone defects in depressed tibial plateaus were filled with MSC/β-TCP (n = 16) or with β-TCP only (n = 23). Enrichment efficiency and effect of enrichment on cell viability were evaluated. Clinical results were assessed by imaging examination and Lysholm score. Results: SECCS effectively integrated MSCs with β-TCP. At 18 months postimplantation, new bone ratio was significantly higher in patients treated with MSC/β-TCP than in those treated with β-TCP only (p = 0.000). Patients with MSC/β-TCP implants had better functional recovery (p = 0.028). Conclusion: MSC/β-TCP prepared by SECCS were effective in the treatment of bone defects in patients with depressed tibial plateau fractures, promoted bone regeneration and improved joint function recovery.
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Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.
Gómez-Barrena, E, Rosset, P, Gebhard, F, Hernigou, P, Baldini, N, Rouard, H, Sensebé, L, Gonzalo-Daganzo, RM, Giordano, R, Padilla-Eguiluz, N, et al
Biomaterials. 2019;:100-108
Abstract
BACKGROUND ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).
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Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans.
Kawai, T, Suzuki, O, Matsui, K, Tanuma, Y, Takahashi, T, Kamakura, S
Journal of tissue engineering and regenerative medicine. 2017;(5):1641-1647
Abstract
Recently it was reported that the implantation of octacalcium phosphate (OCP) and collagen composite (OCP-collagen) was effective at promoting bone healing in small bone defects after cystectomy in humans. In addition, OCP-collagen promoted bone regeneration in a critical-sized bone defect of a rodent or canine model. In this study, OCP-collagen was implanted into a human mandibular bone defect with a longer axis of approximately 40 mm, which was diagnosed as a residual cyst with apical periodontitis. The amount of OCP-collagen implanted was about five times greater than the amounts implanted in previous clinical cases. Postoperative wound healing was satisfactory and no infection or allergic reactions occurred. The OCP-collagen-treated lesion was gradually filled with radio-opaque figures, and the alveolar region occupied the whole of the bone defect 12 months after implantation. This study suggests that OCP-collagen could be a useful bone substitute material for repairing large bone defects in humans that might not heal spontaneously. Copyright © 2015 John Wiley & Sons, Ltd.
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Maxillary Sinus Lift with Beta-Tricalcium Phosphate (β-TCP) in Edentulous Patients: A Nanotomographic and Raman Study.
Pascaretti-Grizon, F, Guillaume, B, Terranova, L, Arbez, B, Libouban, H, Chappard, D
Calcified tissue international. 2017;(3):280-290
Abstract
Sinus lift elevation restores bone mass at the maxilla in edentulate patients before the placement of dental implants. It consists of opening the lateral side of the sinus and grafting beta-tricalcium phosphate granules (β-TCP) under the olfactory membrane. Bone biopsies were obtained in five patients after 60 weeks. They were embedded undecalcified in poly(methyl methacrylate) (pMMA); blocks were analyzed by nanocomputed tomography (nanoCT); specific areas were studied by Raman microspectroscopy. Remnants of β-TCP were osseointegrated and covered with mineralized bone; osteoid tissue was also filling the inner porosity. Macrophages having engulfed numerous β-TCP grains were observed in marrow spaces. β-TCP was identified by nanoCT as osseointegrated particles and as granules in the cytoplasm of macrophages. Raman microspectroscopy permitted to compare the spectra of β-TCP and bone in different areas. The ratio of the ~820 cm-1 band of pMMA (-CH2 groups) on the ν1 phosphate band at 960 cm-1 reflected tissue hydration because water was substituted by MMA during histological processing. In bone, the ratio of the ~960 cm-1 phosphate to the amide 1 band and the ratio ν2 phosphate band by the 1240-1250 amide III band reflect the mineralization degree. Specific bands of β-TCP were found in osseointegrated β-TCP granules and in the grains phagocytized by the macrophages. The hydration degree was maximal for β-TCP phagocytized by macrophages. Raman microspectroscopy associated with nanoCT is a powerful tool in the analysis of the biomaterial degradation and osseointegration.
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Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study.
Sotome, S, Ae, K, Okawa, A, Ishizuki, M, Morioka, H, Matsumoto, S, Nakamura, T, Abe, S, Beppu, Y, Shinomiya, K
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2016;(3):373-80
Abstract
BACKGROUND Porous hydroxyapatite/collagen composite (HAp/Col) is a bioresorbable bone substitute composed of nano-scale HAp and porcine type 1 collagen. In this study, the efficacy and safety were assessed in comparison to commercially available porous β-tricalcium phosphate (β-TCP). METHODS Patients with bone defects caused by benign bone tumors, fractures, or harvesting of autografts were randomly allocated for implantation of porous HAp/Col (n = 63) or porous β-TCP (n = 63). X-ray images were scored and used to evaluate the efficacy of the implantation until 24 weeks after surgery. Blood tests and observation of the surgical site were also performed to evaluate the safety of the implants. In total, 59 and 60 cases were analyzed in the porous HAp/Col and β-TCP groups, respectively. RESULTS At 18 and 24 weeks after surgery, the highest grade of bone regeneration was more frequent in the porous HAp/Col group than in the porous β-TCP group (p = 0.0004 and 0.0254 respectively). Wilcoxon's rank sum test confirmed the superiority of porous HAp/Col from early time points onward (p = 0.0084, 4 w; p = 0.0037, 8 w; p = 0.0030, 12 w; p < 0.0001, 18 w; and p = 0.0316, 24 w). The incidence of adverse effects was higher in the porous HAp/Col group than in the β-TCP group. However, no serious adverse events were reported and no cases needed to drop out of the clinical trial. CONCLUSIONS The superiority of porous HAp/Col for bone regeneration in comparison to an established porous β-TCP was confirmed. Although the incidence of side effects associated with the porous HAp/Col implant was higher than that in the β-TCP group, no serious adverse events occurred that resulted in rejection of the implants.
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Utilizing Autologous Multipotent Mesenchymal Stromal Cells and β-Tricalcium Phosphate Scaffold in Human Bone Defects: A Prospective, Controlled Feasibility Trial.
Šponer, P, Filip, S, Kučera, T, Brtková, J, Urban, K, Palička, V, Kočí, Z, Syka, M, Bezrouk, A, Syková, E
BioMed research international. 2016;:2076061
Abstract
The purpose of this prospective controlled study was to compare healing quality following the implantation of ultraporous β-tricalcium phosphate, containing either expanded autologous mesenchymal stromal cells (trial group, 9 patients) or β-tricalcium phosphate alone (control group, 9 patients), into femoral defects during revision total hip arthroplasty. Both groups were assessed using the Harris Hip Score, radiography, and DEXA scanning at 6 weeks and 3, 6, and 12 months postoperatively. A significant difference in the bone defect healing was observed between both groups of patients (P < 0.05). In the trial group, trabecular remodeling was found in all nine patients and in the control group, in 1 patient only. Whereas, over the 12-month follow-up period, no significant difference was observed between both groups of patients in terms of the resorption of β-tricalcium phosphate, the significant differences were documented in the presence of radiolucency and bone trabeculation through the defect (P < 0.05). Using autologous mesenchymal stromal cells combined with a β-tricalcium phosphate scaffold is a feasible, safe, and effective approach for management of bone defects with compromised microenvironment. The clinical trial was registered at the EU Clinical Trials Register before patient recruitment has begun (EudraCT number 2012-005599-33).
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Bone Regeneration Using the Freshly Isolated Autologous Stromal Vascular Fraction of Adipose Tissue in Combination With Calcium Phosphate Ceramics.
Prins, HJ, Schulten, EA, Ten Bruggenkate, CM, Klein-Nulend, J, Helder, MN
Stem cells translational medicine. 2016;(10):1362-1374
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Abstract
UNLABELLED : In patients undergoing maxillary sinus floor elevation (MSFE) for dental implant placement, bone substitutes are currently evaluated as alternatives for autologous bone. However, bone substitutes have only osteoconductive properties and lack osteoinductive potential. Therefore, this phase I study evaluated the potential additive effect on bone regeneration by the addition of freshly isolated, autologous but heterologous stromal vascular fraction (SVF), which is highly enriched with adipose stromal/stem cells when compared with native adipose tissue. From 10 patients, SVF was procured using automatic processing, seeded on either β-tricalcium phosphate (n = 5) or biphasic calcium phosphate carriers (n = 5), and used for MSFE in a one-step surgical procedure. Primary objectives were feasibility and safety. The secondary objective was efficacy, evaluated by using biopsies of the augmented area taken 6 months postoperatively, concomitant with dental implant placement. Biopsies were assessed for bone, graft, and osteoid volumes. No adverse effects were reported during the procedure or follow-up (≥3 years). Bone and osteoid percentages were higher in study biopsies (SVF supplemented) than in control biopsies (ceramic only on contralateral side), in particular in β-tricalcium phosphate-treated patients. Paired analysis on the six bilaterally treated patients revealed markedly higher bone and osteoid volumes using microcomputed tomography or histomorphometric evaluations, demonstrating an additive effect of SVF supplementation, independent of the bone substitute. This study demonstrated for the first time the feasibility, safety, and potential efficacy of SVF seeded on bone substitutes for MSFE, providing the first step toward a novel treatment concept that might offer broad potential for SVF-based regenerative medicine applications. SIGNIFICANCE This is the first-in-human study using freshly isolated, autologous adipose stem cell preparations (the stromal vascular fraction [SVF] of adipose tissue) applied in a one-step surgical procedure with calcium phosphate ceramics (CaP) to increase maxillary bone height for dental implantations. All 10 patients received CaP plus SVF on one side, whereas bilaterally treated patients (6 of 10) received CaP only on the opposite side. This allowed intrapatient evaluation of the potential added value of SVF supplementation, assessed in biopsies obtained after 6 months. Feasibility, safety, and potential efficacy of SVF for bone regeneration were demonstrated, showing high potential for this novel concept.
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Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer.
Rao, NG, Trotti, A, Kim, J, Schell, MJ, Zhao, X, Amdur, RJ, Brizel, DM, Chambers, MS, Caudell, JJ, Miyamoto, C, et al
Oral oncology. 2014;(8):765-9
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PURPOSE We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer. MATERIALS/METHODS The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis. RESULTS 98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%. CONCLUSION We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading.
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Clinical performance of a highly porous beta-TCP as the grafting material for maxillary sinus augmentation.
Bettach, R, Guillaume, B, Taschieri, S, Del Fabbro, M
Implant dentistry. 2014;(3):357-64
Abstract
BACKGROUND Beta-tricalcium phosphate (β-TCP) is a synthetic bone substitute having high porosity and fast resorption. This retrospective study aimed at evaluating the effectiveness of an highly macroporous β-TCP for maxillary sinus floor augmentation. METHODS Twenty-seven consecutive patients (17 woman/10 men, mean age: 59.7 years) in 2 clinics underwent maxillary sinus augmentation by lateral approach using β-TCP as grafting material. Implant survival, prosthesis success, periimplant bone loss, oral hygiene level, soft tissue condition, complication occurrence, and patient satisfaction were assessed. RESULTS Thirty-one sinuses were successfully augmented. Sixty implants were placed. No sinus membrane perforations occurred. The mean follow-up after grafting was 39.3 ± 8.7 months (range, 22-52 months), and it was 30.5 ± 8.1 months (range, 15-43 months) after implant loading. No implants were lost. After 1 year of loading, marginal bone loss averaged -0.88 ± 0.46 mm (n = 54 implants). Mean full-mouth plaque and bleeding scores were 11.5% ± 4.8% and 3.5% ± 2.8%, respectively. No biological or mechanical complications were recorded. Patient satisfaction was very high. CONCLUSION Despite limited sample size and follow-up duration, highly macroporous β-TCP proved a valuable bone substitute for sinus augmentation, even when used alone.