Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial

Abstract

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher’s exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

Roles of Dental Mesenchymal Stem Cells in the Management of Immature Necrotic Permanent Teeth

“…Thus, this study demonstrates better efficacy and safety of DPSCs implantation in cell-based REPs, in which 3-D dental pulp tissue with vasculature and innervation was regenerated. Besides, the efficacy and safety of allogenic umbilical cord MSCs have been proved in a preclinical trial ( Brizuela et al, 2020 ). Other cell populations, such as SCAP or non-dental cells might also be useful in cell-based REPs.…”

“…The immunomodulatory effects of allogeneic MSCs are suggested to be of importance in inflammatory disorders. Allogenic umbilical cord MSCs have been used for mature permanent teeth with combination of plasma-derived biomaterials, showing acceptable safety and efficacy in a phase 1/2 clinical trial ( Brizuela et al, 2020 ). Although transplantation of allogeneic MSCs in REPs shows promising prospects, more research is needed regarding immunogenicity, long-term outcomes, and safety.…”

Harnessing biomolecules for bioinspired dental biomaterials

“…456 The recent results of the first randomized, controlled phase I/II clinical trial for delivery of mesenchymal stem/stromal cells (MSCs) encapsulated in platelet-poor plasma (PPP) showed that PPP/MSC treatment increased pulp response compared to a non-regenerative endodontic control. 457 A wide array of manufactured, biomolecule-based scaffolds has been used for pulp and dentin-pulp complex regeneration. 458 Indeed, the range of biomolecules used for pulp regeneration encompasses the range of biomolecules highlighted in this review.…”

Prospects of Advanced Therapy Medicinal Products–Based Therapies in Regenerative Dentistry: Current Status, Comparison with Global Trends in Medicine, and Future Perspectives

“…Very few clinical trials have been published on pulp regeneration 23,82,83 . Nakashima et al 23 published studies on the potential of mobilized DPSCs to regenerate pulp in dog pulpectomized teeth, and on this basis, they have initiated a clinical trial, making a reality the standardization and establishment of regulatory guidelines for SC therapy in clinical endodontics.…”

“…It should be mentioned that although the authors supported cell expansion to take place under current GMP conditions, conventional research-grade media and supplements have been used; nevertheless, all patients passed the safety evaluation assessments. In another welldesigned RCT by Brizuela et al 83 they applied umbilical cord-derived MSCs encapsulated in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) (n 5 18), while the control group (n 5 18) received conventional root canal treatment. The results proved the safety of the REP method, while both groups showed 100% efficacy at 12 months, defined as tooth remaining in the mouth with no percussion pain and an apical bone lesion of equal size, decrease, or no more than a 0.1-mm increase.…”