The paradigm shifts of periodontal regeneration strategy: From reparative manipulation to developmental engineering.

Ideal periodontal regeneration requires the integration of alveolar bone, periodontal ligament, and cementum, along with Sharpey's fibers for occlusal force resistance. However, physiological regeneration remains rare due to its intricate structure, making clinical regeneration a challenge. Periodontal ligament stem cells (PDLSCs), first isolated in 2004, hold the key to multi-directional differentiation into cementoblasts, fibroblasts, and osteoblasts. While traditional therapies like guided tissue regeneration (GTR) aim to activate PDLSCs, clinical outcomes are inconsistent, suggesting the need for additional strategies to enhance PDLSCs' functions. Advancements in molecular biotechnology have introduced the use of recombinant growth factors for tissue regeneration. However, maintaining their efficacy requires high doses, posing cost and safety issues. Multi-layered scaffolds combined with cell sheet technology offer new insights, but face production, ethical, and survival challenges. Immune regulation plays a crucial role in PDLSC-mediated regeneration. The concept of "coagulo-immunomodulation" has emerged, emphasizing the coupling of blood coagulation and immune responses for periodontal regeneration. Despite its potential, the clinical translation of immune-based strategies remains elusive. The "developmental engineering" approach, which mimics developmental events using embryonic-stage cells and microenvironments, shows promise. Our research group has made initial strides, indicating its potential as a viable solution for periodontal complex regeneration. However, further clinical trials and considerations are needed for successful clinical application. This review aims to summarize the strategic transitions in the development of periodontal regenerative materials and to propose prospective avenues for future development.