Tissue regeneration in the dental pulp entails the resolution of acute and chronic inflammation, pulp necrosis and infection, followed by the restoration of damaged dentoalveolar tissues, including the organized pulp–dentin complex. The rationale for endodontic regeneration is to reinstate normal physiologic function in an otherwise necrotic pulp, including the protective mechanisms—e.g., innate pulp immunity, pulp repair through tertiary dentin mineralization, and sensation of occlusal pressure and pain.

Cao et al from the UCLA School of Dentistry, California, conducted a literature search to establish the current state of research and develop a novel regenerative approach that would restore not only pulp vitality but an organized pulp–dentin structure with the full spectrum of normal physiologic functions. In general, tissue engineering encompasses 3 requirements: a scaffold, growth differentiation signals and stem cells.

Because of the root canal system’s unique environment, successful endodontic regeneration requires coordination of infection control, biomaterials and stem cells, the triad of pulp tissue engineering. Elimination of root canal infection is the primary objective in regenerative therapies to resolve apical periodontitis and is achieved by chemo-mechanical debridement and intracanal medicaments.

Such therapies eliminate elements that interfere with the differentiation and maturation of apical papilla cells. In the interest of salvaging the apical papilla cells, canal irrigation is recommended with lower-strength sodium hypo-chlorite solutions at 1.5%, while irrigation with 17% ethylenediaminetetraacetic acid (EDTA) has been shown to promote the release of growth factors, resulting in hard tis-sue formation. Intracanal disinfection is primarily achieved by use of calcium hydroxide (CH) or a mixture of antibi-otics known as triple antibiotic paste (TAP), composed of ciprofloxacin, metronidazole and doxycycline. The American Association of Endodontics recommends placement of CH or low concentrations of TAP during the first appointment of regenerative procedures, although this recommendation is supported only by limited case reports. CH appears to promote pro-liferation of periapical pulpal mes-enchymal stem cells (MSCs); a high concentration of antibiotics, on the other hand, has a detrimental effect.

A dental material suitable for pulp regeneration must satisfy the follow-ing criteria

  • be biocompatible, since it will be in direct contact with the regener-ated dental pulp
  • be hard enough to withstand repeated masticatory pressure
  • provide an excellent seal against the dentinal wall to prevent leak-age of oral microorganisms into the pulp space

Mineral trioxide aggregate (MTA), a calcium silicate cement-based material, has been the preferred material for endodontic regeneration because of its exceptional biocompatibility, hardness and enhanced marginal adaptation against dentin. However, due to its reduced washout strength because of its extended setting period, MTA is less than ideal in the context of pulp tissue engineering. Since pulp—dentin regeneration cases would require direct contact between the restorative material and the intracanal medium in forms of a blood clot, hydrated scaffold and/or cellular suspensions, fast-setting material may be preferred for regenerative endodontics.

MSCs are represented by stromal cell populations demonstrating stem characteristics and multipotent differentiation. They are generally thought to be immunomodulatory and immunosuppressive, supporting the concept of allotransplantation for therapeutic purposes. Some reports indicate the potential for immunogenicity.

While revascularization appears successful in resolving apical periodontitis and revitalization of pulpless teeth in limited cases, the revascularized tissues may not truly represent pulp-dentin regeneration, which requires the formation of an organized odontoblastic layer. Several preclinical and large animal studies have refuted the notion that revascularization is bona fide tissue regeneration. Progress with the cell-based approach for pulp-dentin regeneration has been hampered because of safety and regulatory issues regarding pulpal MSC production and transplantation in patients. Clinical translation of the cell-based approach must also overcome the challenge of MSC exparion in vitro and the regulatory requirements of good manufacturing practice facilities to ensure reliable cell production.

As an alternative, allogeneic pulpal MSCs can be mass produced, enabling a rapid turnaround to generate potent MSCs ready to be used for transplantation. Another alternative, developed at the researchers’ laboratory, generates MSCs from primary normal human epidermal keratinocytes by including epithelial-mesenchymal transition. The authors coined the term induced MSCs (iMSCs) to describe these cells, which are distinct from induced pluripotent stem cells that are generated by the transduction of defined reprogramming factors. These iMSCs may represent an alternative for patients who lack adequate tissue sources for endogenous MSCs.


More studies are needed to determine the potency of these iMSCs and assess their transdifferentiation capacities into functional odontoblasts when transplanted into the root canal microenvironment.

Cao Y, Song M, Kim E, et al. Pulp-dentin regeneration: current state and future prospects. J Dent Res 2015 ;doi:10.1177/00220 34515601658.