PDLSCPeriodontal Tissue Regeneration Using Autologous Periodontal Ligament Stem Cells: Randomized Controlled Clinical Trial

Periodontitis is an inflammatory disease that causes pathological alterations in the tooth-supporting tissues, potentially leading to tooth loss. National surveys have shown that the majority of adults in the population suffer from moderate periodontitis, with up to 15% of the population being affected by severe generalized periodontitis at some stage in their lives. The significant burden of periodontal disease and its impact on general health and patient quality of life point to the clinical need for effective management of this condition. The ultimate goal of periodontal therapy is predictably regeneration of a functional attachment apparatus destroyed by peridontitis, which involves the formation of a new cementum, periodontal ligament (PDL), and alveolar bone. To date, several therapeutic procedures have been attempted to achieve this ambitious purpose, including root surface conditioning, bone graft placement, guided tissue regeneration (GTR) and the use of enamel matrix-derived proteins or growth factors. However, current regenerative techniques that are used either alone or in combination have limitations in attaining complete and predicable regeneration, especially in advanced periodontal defects, where deep intraosseous defects have been shown to be high-risk sites for progression of periodontitis. According to histologic evidence, the GTR technique combined with bone graft is the most predictable regenerative procedure in the treatment of such periodontal defects, although basically, current available GTR-based therapies are still crude and of poor clinical predictability. During periodontal regenerative procedures, the remaining healthy periodontal ligament (PDL) plays a key role in the regeneration of new compartments, and the cells of PDL tissues are the only cells that seem to have the capacity to form new attachment apparatus.. The regenerative capacity of the PDL itself is attributed to a few progenitor cells maintaining their proliferation and differentiation potential in the periodontium. Recent advances in stem cell biology and regenerative medicine have presented opportunities for tissue engineering in periodontal therapy. To date, a large number of studies have reported that stem cells, in conjunction with different physical matrices and growth factors, have the capacity to regenerate periodontal tissues in vivo. It has been demonstrated that PDL-derived progenitors are committed to several developmental lineages, i.e., osteoblastic, fibroblastic and cementoblastic. This property determines the PDL cells as a desirable cell population capable of regenerating a functional periodontal attachment apparatus. It has been shown that PDL cells may prevent ankylosis and root resorption and may possibly also produce a new PDL inserted into the tooth and adjacent bone. Moreover, roots covered with alveolar bone cells induce a cementum-like tissue formation, suggesting that cementoblast and osteoblast precursors commonly originate from the alveolar bone. Thus, PDL-derived cell sources are one of the most promising candidates for cell-based therapies and tissue-engineering-associated periodontal regeneration, and positive pre-clinical results have already been achieved both in vitro and in vivo. Taken together, the results of these investigations demonstrate that PDL cells are capable of preventing epithelial down-growth and root resorption, with the periodontal healing pattern being characterized by connective tissue adaptation involving parallel bundles resting on root dentin. The formation of new bone and cementum varies from a complete absence to coverage of parts of the debrided root surfaces mainly at the borders of the defects, to a thin layer of newly formed cementum with complete new bone formation covering the entire previously denuded root surface. The heterogeneity of results obtained may be explained by the small number of specimens used, the different types of periodontal defects observed and the stability of the carriers utilized to deliver the cells (i.e., hyaluronic acid and blood clots). In addition, one may speculate that PDL cell differentiation is highly sensitive to differences in the microenvironment, resulting in different types of periodontal healing. However, the clinical application of autologous PDL-derived cells are currently lacking. All over the world, periodontitis remains highly prevalent, can lead loss of the affected teeth, and thus threaten quality of life for middle-aged population as far as oral functions are concerned. Unfortunately in clinic, no current periodontal treatments can, at best, heal the scar in the affected region and ever regenerate lost periodontal tissue or normal structure and functionality. Considering that the "mouth" and "teeth" have various aesthetic and functional roles to play, establishing a brand-new treatment that enables the regeneration of periodontal tissue is very important. It is clear that there is both a clinical need for such treatments and a vast patient resource. Interestingly, there is mounting data that demonstrates the induction of periodontal tissue regeneration by PDL stem cells in animal models. In particular, a number of studies show that topical administration of PDL stem cells enhances periodontal tissue regeneration in models of artificial loss of periodontal tissue in beagles and non-human primates. This suggests that PDL stem cells may be safe and effective in the regeneration of periodontal tissues in periodontitis patients. In the phase I clinical trial for 20 healthy male volunteers by local administration of autologous PDL stem cells, neither adverse reactions nor rise of any antibody were observed (unpublished data). Importantly, several groups have commenced small-scale pilot/feasibility studies, leading sufficient information to move cell-based therapy into the clinical arena. It is therefore we established this clinical protocol to further test the efficiency and safety of stem cells in the treatment of periodontal deep intraosseous defects.