Concise Review: Periodontal Tissue Regeneration Using Stem Cells: Strategies and Translational Considerations

Abstract

Periodontitis is a widespread disease characterized by inflammation-induced progressive damage to the tooth-supporting structures until tooth loss occurs. The regeneration of lost/damaged support tissue in the periodontium, including the alveolar bone, periodontal ligament, and cementum, is an ambitious purpose of periodontal regenerative therapy and might effectively reduce periodontitis-caused tooth loss. The use of stem cells for periodontal regeneration is a hot field in translational research and an emerging potential treatment for periodontitis. This concise review summarizes the regenerative approaches using either culture-expanded or host-mobilized stem cells that are currently being investigated in the laboratory and with preclinical models for periodontal tissue regeneration and highlights the most recent evidence supporting their translational potential toward a widespread use in the clinic for combating highly prevalent periodontal disease. We conclude that in addition to in vitro cell-biomaterial design and transplantation, the engineering of biomaterial devices to encourage the innate regenerative capabilities of the periodontium warrants further investigation. In comparison to cell-based therapies, the use of biomaterials is comparatively simple and sufficiently reliable to support high levels of endogenous tissue regeneration. Thus, endogenous regenerative technology is a more economical and effective as well as safer method for the treatment of clinical patients. Stem Cells Translational Medicine 2019;8:392-403.

Keywords: Biomaterials; Cell homing; Cell transplantation; Endogenous regeneration; Periodontal regeneration; Tissue engineering.

Figure 1

Periodontal regeneration can potentially be achieved via either in vitro designed cell‐material constructs for transplantation to the area of damage, where the transplants undergo remodeling and revascularization to integrate with the host tissue, or in vivo manipulation of the cell‐material interplay at the target site, where biomaterials and molecules coax the recruitment of endogenous stem cells to regrow new tissues.

Figure 2

Schematic representation of the periodontium containing the intact periodontal complex (i.e., bone‐PDL‐cementum apparatus). As a result of disease (e.g., periodontitis), damage to the periodontium leads to the loss of multiple periodontal tissues surrounding and supporting the tooth. Abbreviation: PDL, periodontal ligament.

Figure 3

Overlaying cell sheets and biomaterials to mimic multiple periodontal tissues. (A): Three‐layered cell sheets together with woven PGA and porous β‐TCP were used to repair three‐wall infrabony defects in dogs 53 (please refer to the original source for more information). (B): Schematic representation of a generated sandwich complex including (i) an engineered membrane (Bio‐Gide collagen membrane seeded with cells on both sides and cultured without the addition of mineralization‐induction medium) and (ii) two mineralized membranes (a cellular small intestinal submucosa in which cells are seeded on one side and cultured in mineralization‐induction medium for 8 days); (iii and iv) a sandwich structure was obtained by placing a cell‐seeded periodontal membrane between the two cell‐seeded/mineralized membranes 54 (please refer to the original source for more details). Abbreviations: PGA, polyglycolic acid; β‐TCP, β‐tricalcium phosphate.

Figure 4

Engineering of biomimetic materials and architectures to reconstruct the periodontal complex. (A): Graphical illustration of the fabrication of a biphasic scaffold mimicking the tooth‐ligament‐bone complex using multiscale computational design and polymeric architecture manufacturing 56 (please refer to the original source for fabrication details). (B): Schematic representation of the fabrication (i) of a biphasic scaffold (ii) composed of the bone compartment (left side, a FDM scaffold) and periodontal compartment (right side, a membrane with electrospun fibers); this scaffold can be applied for the simultaneous regeneration of the bone‐ligament complex when combined with stem cell sheets 58 (please refer to the original source for more information). Abbreviations: 3D, three‐dimensional; FDM, fused deposition modeling; PCL, polycaprolactone; PGA, polyglycolic acid; PDL, periodontal ligament.

Figure 5

Schematic representation of the formation of a trilayered nanocomposite hydrogel scaffold (each layer incorporates different growth factors or preparation‐containing growth factors) for the simultaneous regeneration of multiple periodontal tissues 87 (please refer to the original source for more information). Abbreviations: CEMP1, cementum protein‐1; FGF‐2, fibroblast growth factor‐2; PDL, periodontal ligament; PLGA, poly(lactic‐co‐glycolic acid); PRP, platelet‐rich plasma; nBGC, nanobioactive glass ceramic; rhCEMP1, recombinant human cementum protein‐1; rhFGF, recombinant human fibroblast growth factor.

Figure 6

Schematic representation of the mobilization of stem cells from their niche (e.g., bone marrow) using cell mobilizing factors such as substance P, directed cell movement with the aid of blood flow, and cell homing factors such as SDF‐1α and SCF and the regulation of stem cell fate (e.g., cell proliferation and differentiation) once they reach the site of injury, normally via the design of materials such as the generation of ECM‐mimicking biomaterials and the presentation of a wide variety of growth factors, such as FGF‐2, GDF‐5, and PDGF‐BB and immunomodulatory cytokines, such as IL‐4. Abbreviations: BMMSCs, mesenchymal stem cells derived from bone marrow; ECM, extracellular matrix; FGF‐2, fibroblast growth factor‐2; GDF‐5, growth/differentiation factor‐5; IL‐4, interleukin‐4; PDGF‐BB, platelet‐derived growth factor‐BB; SCF, stem cell factor; SDF‐1α, stromal‐derived factor‐1α.