Periodontal regeneration with autologous periodontal ligament-derived cell sheets – A safety and efficacy study in ten patients

Abstract

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.

Decellularized human corneal stromal cell sheet as a novel matrix for ocular surface reconstruction

“…For example, an autologous myoblast sheet which was generated from skeletal muscle was used and transplanted to the lateral surface of the dilated heart of a patient suffering from dilated cardiomyopathy (DCM;Sawa et al, 2015). It was also used to reconstruct defects of the esophagus (Yamaguchi et al, 2017), middle cavity of the ear (Yamamoto et al, 2017), lung (Kanzaki, Takagi, Washio, Kokubo, & Yamato, 2017), periodontal tissue (Iwata et al, 2018), and the cornea (Nishida et al, 2004). For the cornea, this method has mostly been used for corneal epithelial cell and limbal epithelial stem cell transplantation in patients with unilateral stem cell deficiency (Umemoto, Yamato, Nishida, & Okano, 2013).…”

Three-dimensional periodontal tissue regeneration using a bone-ligament complex cell sheet

“…Cell sheet technology has a great advantage in that it can transplant appropriate stem/progenitor cells for tissue regeneration of target site as a uniform tissue, and can be used clinically for diseases and injuries in various tissues 31,32 . Different types of cell sheets, such as cartilage, esophagus epithelium and myocardium, can be easily made using tissue-derived stem/progenitor cells [39][40][41] , and a current advance in this field can create transplantable cell sheets, including retinal pigment epithelium and corneal epithelium, using the induced pluripotent stem (iPS) cells 42,43 .…”

“…Scaffold-free cell sheet engineering has been applied in regeneration of such tissues as cornea, heart, esophagus, cartilage, liver and periodontal 31 . A PDL cell sheet for the regeneration of periodontal tissue is now at the stage of clinical therapy for periodontal disease 32 . Although this technology contributes to partial tissue repair, a single cell sheet cannot sufficiently regenerate a large-scale tissue injury 33 .…”

Stable cell adhesion affects mesenchymal stem cell sheet fabrication: Effects of fetal bovine serum and human platelet lysate

“…Retained native endogenous cell adhesion proteins provide several strategic advantages for cell sheet engraftment and retention at target tissues. Over 15 years of clinical data support enhanced therapeutic properties for autologous‐sourced cell sheets through increased cell retention at target tissues (Ebihara et al, 2012; Iwata et al, 2018; Kanzaki, Takagi, Washio, Kokubo, & Yamato, 2017; Nishida et al, 2004; Ohki et al, 2012; Sawa et al, 2015; Yamaguchi et al, 2017; Yamamoto et al, 2017). Recently, several preclinical studies have also reported MSC sheet use in wound healing, heart, and pancreas regeneration (Kato et al, 2015; Kim et al, 2018; Miyahara et al, 2006).…”