BackgroundPeriodontitis results in the destruction of tooth-supporting periodontal tissues and does not have the ability to heal spontaneously. Various approaches have been introduced to regenerate periodontal tissues; however, these approaches have limited efficacy for treating severe defects. Cytotherapies combine stem cell biology and tissue engineering to form a promising approach for overcoming these limitations. In this study, we isolated periodontal ligament (PDL)-derived cells from patients and created cell sheets with “Cell Sheet Engineering Technology”, using temperature responsive culture dishes, in which all the cultured cells can be harvested as an intact transplantable cell sheet by reducing the temperature of the culture dish. Subsequently, the safety and efficacy of autologous PDL-derived cell sheets were evaluated in a clinical setting.MethodsA single-arm and single-institute clinical study was performed to verify the safety and efficacy of autologous PDL-derived cell sheets in patients with periodontitis. Wisdom teeth were extracted from patients diagnosed with chronic periodontitis, ranging in age from 33 to 63 years (mean [±SD], 46 ± 12), and periodontal tissues were scraped for cell sources. Three-layered PDL-derived cell sheets were constructed using temperature-responsive culture dishes and transplanted in an autologous fashion following standard flap surgeries. Bony defects were filled with beta-tricalcium phosphate granules. Clinical variables were evaluated at baseline, 3 months, and 6 months. Cone-beam computed tomography was performed at baseline and 6 months. Additionally, mid-long-term follow-up has been performed with patients’ agreements.ResultsOur method was found to be safe and no severe adverse events were identified. All the findings, including reduction of periodontal probing depth (mean ± SD, 3.2 ± 1.9 mm), clinical attachment gain (2.5 ± 2.6 mm), and increase of radiographic bone height (2.3 ± 1.8 mm), were improved in all 10 cases at 6 months after the transplantation. These therapeutic effects were sustained during a mean follow-up period of 55 ± 19 months, and there were no serious adverse events.ConclusionsThe results of this study validate the safety and efficacy of autologous PDL-derived cell sheets in severe periodontal defects, and the stability of this efficacy during mid-long-term follow up. This cytotherapeutic approach, based on cell sheet engineering, offers an innovative strategy to treat the recognized unmet need of treating severe periodontal defects.
Periodontitis is a inflammation induced by a bacterial infection that causes the destruction of the attachment apparatus of dental roots. Several materials, such as bone graft materials, barrier membranes and protein products have been developed and used to treat periodontal defects clinically; however, it is difficult to regenerate the complete periodontal tissue structure. Recently, cytotherapeutic approaches have been introduced to overcome the limitation of conventional procedures. The in vitro-expanded autologous cells derived from several kinds of tissues have already been used in several clinical trials. These cytotherapeutic treatments have been shown to be safe and effective for the treatment of periodontitis. Our strategy has been to integrate stem cell biology and cell sheet engineering, in which a temperature-responsive intelligent polymer is grafted onto the surface of cell culture dish to create a 'cell sheet', to achieve a novel treatment method for periodontitis. By simple reduction of the temperature to below 32°C, a contiguous cell sheet, which is capable of keeping extracellular matrix proteins and cell-cell interactions intact, can be harvested for transplantation without the use of scaffolds. This technology has already been employed in clinical trials, confirming the safety and efficacy of the treatment. In this review, we introduce recent progress in the engineering of cell sheets and review the potential of cell sheet technology for periodontal regenerative medicine.
Transplanted PDL cell sheets cultured with osteogenic differentiation medium induced periodontal regeneration containing an obvious cementum layer and Sharpey's fibres. Thus, the method could be feasible as a new therapeutic approach for periodontal regeneration.
Periodontal-ligament-derived cells (PDL cells) have stem-cell-like properties and, when implanted into periodontal defects in vivo, can induce periodontal regeneration including the formation of new bone, cementum, and periodontal ligament. We have previously demonstrated that PDL cell sheets, harvested from temperature-responsive cell culture dishes, have a great potential for periodontal regeneration. The purpose of this study has been to validate the safety and efficacy of human PDL (hPDL) cell sheets for use in clinical trials. hPDL tissues from three donors were enzymatically digested, and the obtained cells were cultured with media containing autologous serum in a cell-processing center (CPC). The safety and efficacy of hPDL cell sheets were evaluated both in vitro and in vivo. In vitro studies showed that the hPDL cell sheets had high alkaline phosphatase activity and periostin expression (known PDL markers) and no contamination with microorganisms. In vivo studies revealed that hPDL cell sheets, implanted with dentin blocks, induced the formation of cementum and PDL-like tissue in immunodeficient mice. The hPDL cells presented no evidence of malignant transformation. Thus, hPDL cell sheets created in CPCs are safe products and possess the potential to regenerate periodontal tissues.
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