Regenerative Dentistry: Harnessing Stem Cells And Growth Factors For Tissue Repair And Reconstruction

Introduction

The field of regenerative medicine and tissue engineering is experiencing rapid growth, driven by recent breakthroughs in biomedical engineering research. It's widely acknowledged that oral and craniofacial tissues have a restricted ability to naturally regenerate and return to their original state after severe damage. By leveraging the regenerative potential inherent in the body's own cellular mechanisms, regenerative dentistry holds promise for addressing a myriad of dental pathologies, from dental pulp necrosis to periodontal disease and bone defects. The advancements of regenerative dentistry have been projected along three key components which are stem cells, bioactive molecules and biomaterials which act as scaffolds to promote cell growth and differentiation.¹ Through precise spatiotemporal control, growth factors modulate the regenerative process, guiding the formation of functional dental tissues. In this review, we explore the multifaceted landscape of regenerative dentistry, delving into the mechanisms underpinning stem cell and growth factor-based therapies.

The potential of human stem cells in regenerative dentistry

Human dental stem cells present a highly promising therapeutic avenue for repairing structural defects, a focus of extensive investigation by numerous researchers.

Dental pulp stem cells:² These are mesenchymal types of stem cells inside dental pulp⁷ have osteogenic and chondrogenic potential and can differentiate into dentin and dentin-pulp-like complexes. Isolation of DPSCs from extracted teeth or pulp tissues offers a minimally invasive approach to obtaining autologous stem cells for therapeutic purposes. 

Stem cells from human exfoliated deciduous teeth:³ Dr. Songtao Shi discovered SHED in 2003. Miura et al.⁸ verified that SHED exhibited a broader differentiation potential compared to DPSCs, encompassing osteoblast-like, odontoblast-like cells, adipocytes, and neural cells. It is used to enhance orofacial bone regeneration, and stem cells derived from exfoliated deciduous teeth (SHED) represent a valuable resource for paediatric dentistry and regenerative endodontics.

Stem cells from apical papilla:⁴ Residing in the apical papilla of permanent teeth with immature roots are,  discovered by Sonoyama et al.⁵ SCAP are capable of forming odontoblast-like cells into dentin. Additionally, it supports apexogenesis, a process that can take place in infected immature permanent teeth affected by periradicular periodontitis or abscess.

Periodontal ligament stem cells (PDLSCs): Seo et al.⁶ described the presence of multipotent postnatal stem cells in the human periodontal ligament (PDLSCs). PDLSCs, derived from the periodontal ligament surrounding teeth, possess regenerative capabilities crucial for periodontal tissue regeneration and alveolar bone repair.

The characterization and isolation of these diverse stem cell populations are essential prerequisites for their clinical translation. 

Role of growth factors in tissue regeneration

Growth factors refer to proteins capable of stimulating cell proliferation, cell differentiation and preventing apoptosis.^9,10 Growth factors function as signal molecules used for communication between cells in an organ, among these their main duty is control of the cell cycle, from cellular quiescence (phase G0) into phase G1 (growth).^11,12,13,14 They also regulate the entry into mitosis, cell survival, cell migration and differentiation. Together with proliferation, they always simultaneously promote differentiation and maturation.  One of the well-known and early attempts in the usage of growth factors in dentistry is the introduction of platelet-rich plasma (PRP), plasma rich in growth factors (PRGF) and plasma rich in fibrin (PRF). 

• Bone Morphogenetic Proteins (BMPs): It is a potent inducer of osteogenesis and bone formation, stimulate the stem cells into osteoblasts, promotes matrix mineralization, and regulates bone remodelling processes.¹⁷ Enhances the augmentation of alveolar bone for dental implant placement, treatment of periodontal defects, and promotion of bone healing in craniofacial reconstructions.
• Platelet-Derived Growth Factor (PDGF): They are key regulators of wound healing and tissue regeneration, stimulates fibroblasts, and endothelial cells to the site of injury, enhancing angiogenesis, collagen synthesis, and tissue remodelling. Enhances periodontal tissue regeneration and reduces pocket depth in patients with periodontal disease.¹⁸
• Transforming Growth Factor-Beta (TGF-β): TGF-β¹⁹ plays a crucial role in regulating immune responses, tissue inflammation, and fibrosis, as well as promoting wound healing following oral surgeries and dental procedures, periodontal tissue regeneration, and dentinogenesis.
• Fibroblast Growth Factor (FGF): FGFs stimulate the proliferation and migration of fibroblasts, endothelial cells, and mesenchymal stem cells, promoting tissue regeneration, vascularization, periodontal regeneration, wound healing in oral mucosal tissues, and angiogenesis in dental titanium implant sites.²⁰
• Insulin-Like Growth Factor (IGF): IGF stimulates cell proliferation, differentiation, and matrix synthesis, contributing to tissue regeneration, bone formation, and wound healing processes. 

Tissue repair and reconstruction in dentistry 

The pursuit of regenerative dentistry has led to remarkable advancements in clinical applications aimed at restoring damaged or lost dental tissues with unprecedented precision and efficacy. A suitable scaffold improves the ability to repair and regenerate the damaged tissues by enhancing the proliferation, differentiation, adhesion and migration of dental stem cells.¹⁵ Biomaterials play a crucial role in scaffold fabrication. Pairing various stem cells with scaffolds, tissue bioengineering shows promising outcomes in regenerating damaged tissues.¹⁶

Regenerative endodontics

Regenerative endodontics offers a conservative alternative to traditional root canal therapy, preserving tooth vitality and function while promoting continued root maturation and apical closure. Combining the signal molecules and growth factors with scaffolds can increase the regeneration of pulp tissues inside the canal by enhancing dentin formation, mineralization, neovascularization, and innervation.²¹ For example, the stromal cell-derived factor, TGF-β1, and bone morphogenic proteins, loaded on scaffolds such as collagen, gelatin hydrogels, and alginate hydrogels, enhance endodontic regeneration.²² A study by Yang et al.‘s notes that the transplantation of dental stem cells with scaffold of silk fibrin tooth with SDF-1 resulted in the formation of pulp with vascularity, organised fibrous matrix, and dentin in the nude mice.²³ 

Periodontal and alveolar bone regeneration

Guided tissue regeneration (GTR) and guided bone regeneration (GBR)²⁴ techniques utilise barrier membranes, growth factors, and bone grafts to promote periodontal tissue and osteoconductive scaffolds to facilitate successful implant placement and osseointegration. Numerous studies have explored bone regeneration, revealing that the ossification potential of DSCs varies based on their source (e.g., dental pulp, tooth follicle, gingival tissue, and periodontal ligament), influencing their ability to ossify depending on the biomaterial scaffolds used. Hernández-Monjaraz et al. demonstrated that in individuals with periodontal issues, dental stem cells implanted on collagen-polyvinylpyrrolidone sponge scaffold increased bone density while reducing tooth mobility and periodontal pocket depth within the bone defect area.²⁵ The clinical studies report improvements in clinical parameters, including reductions in probing depth, gains in clinical attachment level, and radiographic evidence of bone fill in periodontal defects. 

Nerve regeneration

Dental stem cells exhibit the ability to differentiate into neuron-like cells, Schwann cells, glia, and oligodendrocytes. Utilising a combination of DSCs with various scaffolds such as chitosan, heparin poloxamer, silicone tubes, and poly-ε-caprolactone/poly-lactide-co-glycolic acid enhances the functionality of injured nerve tissues and mitigates inflammatory reactions, offering potential benefits for inferior alveolar nerve injuries.

The clinical applications and outcomes of dental tissue regeneration represent a paradigm shift in dental care, offering personalised and biologically driven solutions for a myriad of dental pathologies. By harnessing the regenerative potential inherent in dental tissues and leveraging innovative therapeutic modalities, clinicians can optimise patient outcomes, preserve natural dentition, and enhance oral health and quality of life for individuals worldwide.

Transformative advancements in regenerative dentistry and its novel approaches  

In the realm of regenerative dentistry, the advent of 3D printing technology has ushered in a new era of precision and customization in scaffold fabrication. 3D printing, also known as additive manufacturing, enables the layer-by-layer deposition of biomaterials to create intricately designed scaffolds with tailored properties, mimicking the complexity and functionality of native tissues within the oral cavity. Nanotechnology has emerged as a game-changing paradigm in drug delivery, offering precise control over therapeutic payloads, enhanced bioavailability, protecting fragile biomolecules and targeted delivery to specific sites within the oral cavity. Nanotechnology enables the design of targeted delivery systems that selectively deliver therapeutic agents to desired sites within the oral cavity, minimising off-target effects and maximising therapeutic efficacy. Gene editing technologies, such as CRISPR-Cas9, have emerged as powerful tools for precisely modifying the genome, offering unprecedented opportunities to enhance the regenerative potential of cells and tissues within the oral cavity. 

Challenges and opportunities in stem cell therapies

Stem cell-based therapies hold immense promise for revolutionising regenerative medicine, offering novel approaches for tissue repair and regeneration across a spectrum of medical specialties. However, despite their therapeutic potential, stem cell-based interventions are not without challenges and limitations. Variability in donor characteristics, tissue sources, and isolation methods can further contribute to the diversity of stem cell populations, posing challenges in standardisation and reproducibility of therapeutic outcomes. Stem cells may elicit immune responses upon transplantation, leading to rejection, inflammation, and graft-versus-host reactions. Allogeneic stem cell transplantation carries a higher risk of immune rejection compared to autologous transplantation, necessitating immunosuppressive regimens that may compromise patient safety and long-term outcomes. Poor cell survival, limited retention, and inadequate homing to target sites can compromise the therapeutic efficacy of stem cell interventions, necessitating optimization of delivery methods and biomaterial scaffolds.

By embracing these key points and taking collective action, we can accelerate progress in regenerative dentistry and ultimately improve oral health outcomes for patients worldwide.

FAQ's:

What are the applications of stem cells in dentistry?

The dental stem cells have the capacity to regenerate damaged or missing tissues in oral and maxillofacial regions. In future, it may have the potential to treat mandibular nerve injuries, TMJ pain and dysfunction and implantation of teeth. 

Can platelet rich plasma regrow gum tissues?

PRP therapy employs platelets to naturally trigger the growth of healthy tissues, promoting the regeneration of periodontal tissues in instances of periodontal disease.

Why do teeth not regenerate?

Unlike bones, which have abundant blood vessels for oxygen and nutrient supply, tooth enamel lacks such provisions. As of now, once damaged, your tooth cannot self-repair like other bodily tissues.

Can teeth be regrown with stem cells?

The stem cells may have the potential to grow new teeth to replace missing teeth! When this method becomes commercially available, it will revolutionise dental treatments.  

What is the common platelet-derived growth factor used in dentistry?

PRP has been employed in dental implantology to promote the formation of new bone or facilitate peripheral nerve regeneration. 

Summary

This literature review covers the topic of regenerative dentistry, exploring the importance of stem cells, growth factors, and biomaterials in tissue repair and reconstruction. Also, it points out the various dental stem cells and their applications in regenerative endodontics, periodontal repair, and alveolar bone regeneration. It examines the role of growth factors in promoting tissue regeneration and highlights transformative technologies such as 3D printing and nanotechnology. Finally, it addresses challenges in stem cell-based therapies and emphasises the need for collective action to overcome these obstacles and improve oral health outcomes.