Regenerative dentistry: from science fiction to science !!!

Historically, material and treatment options have provided the dentist with limited ability to replace diseased, infected, traumatized, and lost tissues. Although these materials and therapies have proved effective, they do not exhibit the same mechanical and physical properties as naturally formed oral/dental tissues.

While the regeneration of a lost tissue is known to mankind for several years, it is only in the recent past that research on regenerative medicine/ dentistry has gained momentum. The growing understanding of biological concepts in the regeneration of oral/dental tissues coupled with experiments on stem cells is likely to result in a paradigm shift in the therapeutic armamentarium of dental and oral diseases culminating in an intense search for “biological solutions to biological problems.”.

Dental tissue engineering is a new promising therapeutic approach that merges the principles of engineering and bioscience aiming to develop biological substances for the restoration, conservation and/or improvement of the tissue function. It aims to replace the missing tooth tissue with a bioengineered tooth or to restore the damaged dental tissue by the appliance of stem cells, scaffolds and growth factors, alone or in combination.¹

Studies have demonstrated that dental tissues are a rich source of mesenchymal stem cells (MSCs) that exhibits multipotent differentiation capacity and is drawing worldwide attention because of its potential application in not only dental but also in various medical fields.These include adult tooth pulp tissue (DPSCs), pulp tissue of deciduous teeth (SHED), periodontal ligament (PDLCs), apical papilla (SCAP), and buccal mucosa.^2-6 The process of storing stem cells acquired from patients’ deciduous teeth and wisdom teeth, called dental stem cell banking, is a strategy to realize the potential of dental stem cell-based regenerative therapy. Stem cell-containing tissues are acquired from the patient and can be cryopreserved for many years to retain their regenerative capacity. Whenever required, dental stem cells, which are tolerated by the immune system, can be isolated from the cryopreserved tissue/tooth for future regenerative therapies .⁷

Potential application of dental tissue engineering are as follows .The evidence gathered so far has propelled many elegant studies exploring the role of stem cells and their manifold dental applications.

Regeneration of damaged coronal dentin and pulp: To this date, no restorative material has been able to mimic all physical and mechanical properties of tooth tissue. Furthermore, we have not been successful in providing an ideal solution to certain situations, such as an immature tooth with extensive coronal destruction and reversible pulpitis. If the regeneration of tooth tissue is possible in these situations, it facilitates physiologic dentin deposition that forms an integral part of the tooth thereby restoring structural integrity, minimizing interfacial failure, micro-leakage, and other consequent complications. Similarly, young permanent teeth that require apexogenesis or apexification are the perfect candidates for the regeneration of pulp as they allow completion of both vertical and lateral root development, improving the long-term prognosis.^8,9,10 Pulp tissue regeneration involves either delivery of autologous/allogenic stem cells into the root canals or implantation of the pulp that is grown in the laboratory using stem cells. Both these techniques will have certain advantages and limitations and considerable progress has been made in this area of research.^11,12

Periodontal regeneration: Regenerating the periodontium has always been a high priority in craniofacial regenerative biology. Due to the complex structure of the periodontium (consisting of hard and soft tissues), its complete regeneration has always remained a challenge. All the current regenerative techniques such as autologous bone grafts, allografts, or alloplastic materials have limitations and cannot be used in all clinical situations. Therefore, a cell-mediated bone regeneration technique will be a viable therapeutic alternative. Kawaguchi et al demonstrated that the transplantation of ex vivo expanded autologous MSCs can regenerate new cementum, alveolar bone, and periodontal ligament in class III periodontal defects in dogs.¹³ Going a step further, periodontal ligament cells cultured in vitro were successfully re-implanted into periodontal defects in order to promote periodontal regeneration by Hasegawa et al A subsequent study by the same group reported a similar approach in humans. This study reported firm evidence that stem cells can be used to regenerate a tissue as complex as the periodontium.¹⁴

Repair and regeneration of bone in craniofacial defects: Craniofacial bone grafting procedures rely on autologous bone grafting, devitalized allogenic bone grafting (using bone from bone bank), and natural/synthetic osteoconductive biomaterials. Autologous bone grafting is limited by donor site morbidity and allogenic bone is often destroyed soon. A long-term outcome using biomaterials relies on their ability to encourage local cells to completely regenerate a defect and results are often not encouraging. If stem cells can be harvested in a scaffold and transplanted into a defect to regenerate the lost tissue, it can alleviate a lot of complications associated with the traditional techniques. Abukawa et al used a novel scaffold design with a new fabrication protocol to generate an autologous tissue engineered construct which was used to repair a segmental mandibular defect. The technique promoted osteogenesis and enhanced penetration of bone with blood vessels thereby accelerating tissue regeneration.¹⁵ In a dog model, Yamada et al showed that a mixture of MSCs and platelet-rich plasma improved bone implant contact and bone density in a mandibular defect.¹⁶ The development of new scaffold fabrication technologies has facilitated a successful repair of three dimensionally complex cranial defects.¹⁷ To further enhance the regenerative potential of MSCs, genetic engineering technologies have been utilized to extend the life of stem cells and to enhance osteogenesis.^{18 19 20} In summary, cellderived therapy for the repair of osseous defects has been relatively successful and numerous clinical trials in human craniofacial defects are underway.

Whole tooth regeneration: A therapeutic option that was unthinkable a few years ago seems an achievable goal today. Even to this day, the replacement of missing teeth has limitations. Although, implants are a significant improvement over dentures and bridges, their fundamental limitation is the lack of natural structural relationship with the alveolar bone (absence of periodontal ligament). They rely on direct integration of bone on tooth surface which is indeed an unnatural relationship as compared with the natural tooth. Further, they are also associated with a lot of esthetic, functional, and surgical limitations that affect their prognosis. Ohazama et al reported the reconstruction of murine teeth using cultured stem cells which when transferred into renal capsules resulted in the development of tooth structures and associated bone.²¹ Nakao et al recently engineered teeth ectopically and transplanted them into an anthrotopic site in a mouse jaw.²² Sonayama et al used SCAP and PDLSCs and formed a bioroot in mini pigs. SCAP and PDLSCs were seeded in a scaffold and implanted into the sockets of the lower jaw. Postchannels were pre-created to leave space for postinsertion and 3 months later the bio root was exposed and a porcelain crown was inserted. The bioroot developed, and had a natural relationship with the surrounding bone.²³

In summary, regenerative dentistry holds promise of solution to a number of compelling clinical problems in dentistry that have not been adequately addressed through the use of permanent replacement devices. While Impressive data exist demonstrating the potential for regeneration of enamel, dentin, cementum, bone, and ligaments, there seem to be greater clinical success, with therapies targeted at regeneration of periodontal tissues and craniofacial reconstruction versus enamel, dentin or whole tooth regeneration.

Despite the significant advances made in medicine over the years, replacing the experienced processes perfected by nature is indeed a difficult proposition. There are various challenges and barriers that we have to surmount before translating laboratory results to successful clinical applications.. However, it is certain that the future is going to be exciting for all of us.

‘Regenerative Dentistry has evolved from being Science Fiction to Science’.

The need of the hour is high-quality research engaging the expertise of the molecular biologists, immunologists, biomaterial scientists, cell biologists, matrix biologists, and practicing dental surgeons that is crucial in attaining the desired goal As academicians and researchers let us gear up and contribute our bit to herald the dawn of practice of regenerative dentistry.