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Periodontal tissues-the supporting framework of teeth, which encompass the alveolar bone, periodontal ligament (PDL), cementum, and gingiva-play a pivotal role in tooth stability, act as a barrier to microbial invasion, and support oral and overall health. However, these tissues are susceptible to periodontitis. Periodontitis is a disease in which inflammation of the periodontal tissues results in periodontal pocket formation, alveolar bone loss, and-ultimately-tooth loss.1 It affects a substantial portion of the population, with an estimated 42% of US adults over the age of 30 (64.7 million Americans) having some form of periodontitis, and the most severe forms of the disease impacting approximately 11% of individuals globally.2 Although conventional treatments, which include plaque removal, nonsurgical periodontal therapy, and resective periodontal surgery, can manage symptoms and potentially arrest disease progress, they often fall short in restoring the original integrity of periodontal tissues.
Periodontal regeneration is defined as the regrowth of a functionally oriented periodontal ligament, cementum, and alveolar bone proper on a previously diseased root surface.3 In current practice, periodontal regeneration is most often achieved through the use of guided tissue regeneration (GTR) with or without additional bone replacement grafts. GTR employs the strategic placement of a biocompatible barrier membrane to segregate rapidly proliferating epithelial tissue from the osseous defects. This segregation allows pluripotent stem cells present in the periodontal ligament to populate the defect and differentiate, allowing the reformation of the missing tissues of the periodontium.3 GTR is technique-sensitive, and its success is contingent upon precise surgical technique, optimal membrane selection, appropriate healing processes, and rigorous postoperative management. Given the many variables associated with stem cell recruitment and healing during GTR, enhancing healing during such periodontal regenerative procedures can allow for improved tissue regeneration and enhanced periodontal health and biomechanics.
Traditional regenerative approaches, including GTR and bone grafting, have demonstrated variable and unpredictable outcomes, leaving room for advancements in the field.3 In response to these challenges, this article will explore emerging tissue engineering strategies aimed at recreating the complex microenvironment necessary for successful periodontal regeneration. It will focus on two critical components for periodontal regeneration: the design of scaffolds (biomaterials) and the precise control of drug delivery (bioactive molecules). Against the backdrop of rapid advancements in new biomaterials and technologies for regenerative periodontal treatments over the past decade, this article seeks to provide an updated and comprehensive summary, with a specific focus on biomaterials and drug delivery systems.
Biomaterials and Scaffolding Design for Periodontal Regeneration
Periodontal regeneration can be approached utilizing various materials and/or techniques. The underlying principle of these therapeutic approaches is the occlusion of cells from the periodontal defect that would create repair (ie, healing with tissues that were not present prior to periodontal destruction such as epithelium and/or connective tissue) and recruitment and/or guidance of cells that allow for the formation of new cementum, periodontal ligament, and alveolar bone proper (Figure 1).4-7 Achieving successful outcomes in periodontal regeneration relies heavily on the precision and expertise involved in these techniques. However, the quality of biomaterials used plays a pivotal role in complementing and enhancing these techniques.
To achieve optimal periodontal regeneration, the meticulous application of techniques is essential to create the ideal environment for tissue regrowth. Biomaterials can serve as the foundation of this process, providing the necessary scaffolding and support. The choice of biomaterials is instrumental in mimicking the natural extracellular matrix, promoting cell attachment, proliferation, and differentiation.8
By improving the quality and design of biomaterials, the success rate of periodontal regeneration treatments can be significantly increased. These biomaterials not only provide structural support but also contribute to creating a conducive microenvironment that fosters tissue growth.9
In recent years, tissue engineering has emerged as a promising avenue for periodontal regeneration. It involves the integration of three key components: stem cells, biomaterials, and bioactive molecules. Among these components, biomaterials play a central role in providing structural support, mimicking the extracellular matrix of natural periodontal tissues, and creating a conducive microenvironment for cell proliferation and differentiation.8,10-11 Figure 2 illustrates how the integration of cells, molecular signals, and scaffolds can enhance the regeneration of periodontal tissues when combined with meticulous surgical techniques and postoperative management.
Tissue Engineering Biomaterials
Biomaterial types
Biomaterials used in periodontal tissue engineering can be categorized into two main types-polymeric materials and inorganic materials. Each type serves specific functions in the regeneration process. Polymeric materials include polymers such as collagen, gelatin, and chitosan and are commonly employed for PDL regeneration due to their biocompatibility and ability to support cell adhesion and growth.12 These materials can create nanofibrous matrices that mimic the native extracellular matrix, providing a suitable environment for cell attachment and tissue formation.13 Inorganic materials such as hydroxyapatite and tricalcium phosphate (TCP) are often used in the regeneration of cementum and alveolar bone. These materials closely resemble the mineral composition of natural tissues, making them osteoconductive and capable of supporting mineralization.8
Composite materials
To address the challenge of regenerating the intricate PDL-cementum-alveolar bone complex, composite materials that combine both polymers and inorganic components are used. These composite scaffolds aim to mimic the natural structure and function of periodontal tissues more effectively.
Limitations
While traditional biomaterials have been adapted for periodontal tissue regeneration, they have limitations. These materials, while valuable, often cannot fully replicate the fine structures found in natural periodontal tissues, such as Sharpey's fibers, which anchor the PDL to alveolar bone and cementum. Consequently, there is a growing need for novel biomaterials that can more accurately mimic the complex microarchitecture of periodontal tissues at the micro and nanoscale levels.9
Scaffold Design
The design of scaffolds used in periodontal regeneration is a critical aspect of tissue engineering. Effective scaffold design should consider several factors, including composition, structure, architecture, and ease of use. The goal is to create scaffolds that closely resemble the native extracellular matrix of periodontal tissues.
Material choices
Biomaterials selected for scaffold design should align with the specific tissue being targeted. Inorganic biomaterials, such as calcium phosphate, can enhance biomineralization and are suitable for alveolar bone and cementum regeneration. On the other hand, polymeric biomaterials are preferred for PDL regeneration due to their flexibility and ability to support cell adhesion.14
Advanced techniques
Emerging technologies like 3D printing hold promise in creating highly customized scaffolds. However, improvements in resolution are needed to achieve the intricate extracellular matrix architecture at a nanoscale level. Researchers are actively exploring ways to enhance 3D printing techniques for periodontal tissue engineering applications.
Effective scaffolding design is pivotal to providing the structural support necessary for cell attachment, proliferation, and differentiation in periodontal regeneration. It also plays a crucial role in ensuring the long-term stability of the regenerated tissues.15
Controlled Delivery Systems in Periodontal Regeneration
Bioactive Molecules
Bioactive molecules encompass a diverse array of substances, including growth factors, cytokines, antibiotics, and signaling molecules. These molecules serve as orchestration tools, directing cellular responses, modulating inflammation, and facilitating tissue remodeling-essential facets of periodontal regeneration.16
Monodrug vs. Multidrug Systems
Controlled delivery systems can be categorized into monodrug and multidrug systems. Monodrug systems focus on the controlled release of a single bioactive molecule. In contrast, multidrug systems offer the flexibility to release multiple agents in a precisely controlled sequential manner. The selection between these systems hinges on the specific regenerative demands of the targeted periodontal tissues.9 GTR membranes using controlled delivery systems have been engineered for periodontal regeneration. To ascertain the safety and efficacy of these GTR membranes, an expanded focus on in vivo studies and clinical trials is needed. In the current landscape of periodontal treatment, controlled delivery systems have shown promising improvements in regeneration outcomes, including enhanced tissue repair and reduced inflammation.
Temporal Control Methods
The ability to control the release of bioactive molecules over time can allow clinicians to more closely mimic the dynamic processes involved in periodontal tissue regeneration. Several techniques may be employed to achieve these goals, such as direct presentation, multiphase loading, and particulate-based delivery. In some instances, bioactive molecules are directly presented within or proximal to the defect site, affording immediate, localized effects.9 Alternatively, certain controlled delivery systems incorporate multiple phases, each releasing bioactive molecules at distinct time intervals. This approach aligns with the temporal sequence of events observed in natural tissue repair.9 In addition, bioactive molecules can be encapsulated within biodegradable micro- or nanoparticles, facilitating controlled release over extended durations. This particulate-based delivery method offers versatile temporal control capabilities.9
Applications of Biomaterial and Controlled Delivery Systems in Periodontal Regeneration
Controlled delivery systems find application in the regeneration of a myriad of periodontal tissues.
PDL Regeneration
The regeneration of the PDL often involves employing nanofibrous matrices to replicate the extracellular matrix of the PDL.17 Advanced techniques, including electrospinning, yield scaffolds with aligned fibers, promoting cell attachment and directional growth. Additionally, mechanical stress models are explored to replicate the in vivo conditions necessary for functional PDL regeneration.10
Alveolar Bone and Cementum Regeneration
In hard tissue regeneration, including alveolar bone and cementum regeneration, a combination of inorganic materials (eg, calcium phosphate) with natural or synthetic polymers is commonly employed to create scaffolds. Bioactive molecules such as bone morphogenetic proteins (BMPs) and amelogenin are frequently utilized to stimulate tissue growth in these areas.18 For cementum regeneration, thin, cell-rich constructs known as cell sheets are employed. A study performed by Iwata and colleagues demonstrated promising results with the use of autologous PDL-derived cell sheets combined with β-TCP bone fillers for periodontal regeneration. In 10 out of 12 patients, the cell sheets were successfully created and met all safety and quality standards. These cell sheets, which exhibited high viability and the desired response to osteoinductive mediums, retained a PDL-like phenotype crucial for effective periodontal regeneration. Clinically, the combined use of these cell sheets and β-TCP showed improved outcomes, including enhanced bone regeneration and stable bone levels, without any serious complications over a mid-long-term follow-up. Although the study faced limitations due to the small sample size and challenges in cell cultivation, the overall findings indicate that PDL-derived cell sheets are a viable and effective option for treating severe periodontal defects, potentially revolutionizing periodontal therapy. Further research, however, is needed to refine the materials and techniques used to optimize the regenerative potential of this approach.19
Complex Regeneration (Alveolar Bone- PDL-Cementum)
The intricate task of restoring the cementum- ligament-bone complex necessitates a multi-layered approach to promote the functional regeneration of the entire periodontium. However, the intricate nature of Sharpey's fibers, which establish connections between the PDL, alveolar bone, and cementum, presents an ongoing challenge in achieving comprehensive and functional restoration.3
Long-Term Stability
Ensuring the sustained stability of regenerated periodontal tissues is a pivotal component of successful periodontal regeneration. It is imperative to maintain a harmonious mineralization balance within these tissues. Future research may explore methodologies involving mechanical stimulation and controlled delivery of mineralization regulators to attain this objective.
Future Perspectives on Periodontal Regeneration
The evolution of periodontal regeneration holds promise for enhancing clinical outcomes through the utilization of specific biomaterials and techniques. Future directions in research and clinical practice aim to harness these advancements for improved therapeutic efficacy.
Biologically Inspired Materials for Enhanced Biomimicry
Biomaterials that closely emulate the intricate architecture of natural periodontal tissues at micro and nanoscale levels are on the horizon to enhance periodontal regenerative outcomes.20 These advanced scaffold materials will offer a more accurate replica of the extracellular matrix, promoting superior cell attachment, proliferation, and differentiation.14 Examples of materials that can be used in advanced scaffolds include hydroxyapatite, TCP, and composite materials containing both polymers and inorganic components. These materials will enhance tissue integration and functional regeneration, ultimately leading to improved clinical outcomes. The recent advent of 3D printed periodontium patches exemplifies this progression, offering a biomimetic construction that effectively regenerates the complete periodontium, including the alveolar bone-PDL-cementum complex. This technique leverages the precision of digital light processing bioprinting to create scaffolds that guide the differentiated and functionally graded integration of the periodontal components, overcoming the limitations of traditional bioengineering methods. Furthermore, these printed scaffolds could be populated with mesenchymal stem cells capable of recreating the lost tissues of the periodontium. These advanced scaffold materials, in conjunction with cell-based therapies, are poised to revolutionize the treatment of periodontal defects, providing a new direction for periodontal regenerative medicine with promising clinical prospects.21
Targeted Drug Delivery Systems
Although numerous multidrug delivery systems have been designed, none have yet attained the precise control necessary to direct periodontal tissue regeneration optimally. Because the specific growth factors that drive periodontal tissue formation and the optimal timing of their delivery remain unclear, clinicians and researchers are currently not able to produce ideal regenerative results. In addition, the appropriate dosages of bioactive molecules remain uncertain, and bioactive molecules often have a complex dose-response curve. In these cases, both excessive and insufficient use of drugs/growth factors can negatively impact the outcomes. As a result, a comprehensive understanding of basic biology is crucial to inform the development of biomimetic materials, ensuring they are tailored to effectively support and guide tissue regeneration.9
Conclusion
Current periodontal regeneration strategies predominantly utilize techniques like GTR and bone grafting, which, while effective, present limitations in predictability and functional tissue integration. Biomaterials innovations such as the use of nano-hydroxyapatite, as highlighted by Ma and colleagues, offer a promising alternative.21 These nanomaterials, alongside biodegradable polymers, are instrumental in emulating the natural extracellular matrix, thereby enhancing cell attachment and proliferation.
Despite these advancements, the journey toward optimized periodontal regeneration is fraught with challenges. The complexity of the periodontal structure, particularly the intricate nature of Sharpey's fibers and their connections within the PDL-alveolar bone-cementum complex, remains a significant hurdle. While 3D bioprinting technologies offer a ray of hope in scaffold design, achieving the precise microarchitecture of natural periodontal tissues is still a daunting task. The controlled delivery systems, although promising in providing a sequential release of bioactive molecules, struggle with maintaining exact dosages and temporal control, as elucidated by Liang et al.9 These gaps underscore the critical need for an in-depth understanding of periodontal biology and the development of materials that can accurately mimic the complex periodontal environment.
Looking forward, the field of periodontal regeneration is poised for transformative advancements. Future strategies will likely focus on enhancing biomimicry through bio-inspired materials and 3D bioprinting technologies. So-called "smart biomaterials" are capable of adjusting properties in response to environmental stimuli. These developments represent a significant leap toward dynamic and responsive regeneration.22,23 These advanced materials, in conjunction with targeted drug delivery systems, hold the promise of achieving a harmonious balance of mineralization and mechanical stability over time. However, the realization of these future strategies hinges on continuous research, interdisciplinary collaboration, and clinical validation to overcome current limitations and unlock the full potential of these innovative approaches in periodontal regenerative medicine.
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