Assessing the Efficacy of Self-Assembled Peptide Rada 16-1 As A Direct Pulp Capping Agent for Human Dentin Matrix – A Review

@ 2025 | PUBLISHED BY GJR PUBLICATION, INDIA 68 Global Journal of Research in Dental Sciences ISSN: 2583-2840 (Online) Volume 05 | Issue 05 | Sept. – Oct. | 2025 Journal homepage: https://gjrpublication.com/gjrds/ Review Article Assessing the Efficacy of Self-Assembled Peptide Rada 16-1 As A Direct Pulp Capping Agent for Human Dentin Matrix – A Review Sanskriti Panda 1, Sreelakshmi Girish 2 & *Sihivahanan Dhanasekaran 3 1,2 Undergraduate Student, Department of Conservative Dentistry and Endodontics, SRM Kattankulathur Dental College and Hospital, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamilnadu, India. 3 Professor, Department of Conservative Dentistry and Endodontics, SRM Kattankulathur Dental College and Hospital, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamilnadu, India. *Corresponding author: Sihivahanan Dhanasekaran Professor, Department of Conservative Dentistry and Endodontics, SRM Kattankulathur Dental College and Hospital, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamilnadu, India. ORCID ID: 0000-0001-7672-7511 INTRODUCTION RADA 16-1 is a peptide that can assemble on its own and consists of 16 amino acid residues [1]. It is made up of repeating segments of hydrophobic alanine and hydrophilic arginine, and aspartic acid amino groups [1]. The peptide is characterised by the sequence RADARADARADARADA (ModulusI) [2]. RADA 16-1 contains carboxylic groups that makes the environment more acidic, which can be harmful to both cells and host tissues [2]. However, this problem can be fixed by using neutralization methods [2]. Peptide RADA 16-1 quickly forms gel like scaffolds, which can be modified to support different needs such as osteogenic differentiation, drug delivery or tunable gelation [2]. RADA 16-1 can assemble on its own when the surrounding conditions change, either through pH changes or by adding certain ions to the solution [2]. The self organization of RADA 16-1 is controlled by non-covalent interactions like repulsive and attractive interactions, hydrogen bonds among amide bonds, -COOH, and -OH groups, hydrophobic interactions, π-π stacking interaction among aromatic groups, and ionic interactions between oppositely charged amino acids. RADA 161 peptides self-assemble into a macroscopic hydrogel through essential non-covalent interactions which help fibers connect and form a stable network [3,2]. The resulting hydrogel is safe for biological use and mechanically tunable substance and exhibits low toxicity [3]. Peptide RADA 16-1 is a self-assembling peptide that forms β-sheet structure held together by hydrogen bonds between its amino acid residues [3]. It forms hydrogel when its concentration reaches Abstract Direct pulp capping is a technique that is used to preserve the vitality of pulp of the teeth and saving the tooth from needing a root canal treatment. The pulp capping materials that are used today are less effective and do not always give reliable results. Hence, there is demand for new and better pulp capping agents. RADA 16-1 is a peptide that can assemble on its own and has exhibited promising outcomes in different biomedical applications. This research is about testing RADA 16about the nature of peptide RADA 16-1, direct pulp capping, highlight the challenges of current pulp capping procedures, and the potential advantages of using peptide RADA 16-1 and also, we will compare how peptide RADA 16-1works against traditional materials that are used for pulp capping and explore its potential clinical applications and the rules needed for its use. At last, this paper will address the current gaps in understanding regarding the use of peptide RADA 16-1 as direct pulp capping agent and the potential avenues for further studies. The objective of this study is to contribute to the advancement of pulp capping methods and to enhance clinical outcomes for patients. Keywords: Direct pulp capping, Biomedical applications, Human dentin matrix, Regeneration. Global J Res Dent Sci. 2025; 5(5), 68-73 @ 2025 | PUBLISHED BY GJR PUBLICATION, INDIA 69 specific threshold [3]. Peptide RADA 16-1 can be modified to guide cell behaviour [2]. Peptide RADA 16-1 is a self assembling hydrogel used in tissue engineering that mimics the nano structure of natural ECM, promoting wound healing, cell culture, and formation of synapses [2, 3]. Uses of direct pulp capping in Dentistry Direct pulp capping is a dental procedure in which dental material is applied directly over exposed pulp to promote healing and regeneration. Unlike root canal treatment, it helps to maintain the vitality of pulpal tissue and tooth maturation [1]. This method is particularly valuable in young permanent teeth, where maintaining the vitality of pulp is important [1]. It is used as the first line of treatment for maintaining the vitality of pulp and regenerate the damaged pulp tissue [1]. Comparatively, direct pulp capping has shown promising results in promoting pulp healing and regeneration. Overall, it provides a less invasive and biologically favorable alternative to conventional endodontic treatments. Current challenges in direct pulp capping procedures Direct pulp capping is widely used to help repair damaged or degenerated pulp tissue, but procedures still faces challenges. One of the most important challenge is supporting angiogenesis in regenerated pulp tissues, which is essential for the long-term healing [1]. Research indicates that creating a 3D culture system that mimics natural tissue and provides cell-cell signaling molecules can help us understand role of HUVECs interactions during angiogenesis [1]. Endothelial cells are delicate, if the angiogenesis-related factors are absent, they can undergo apoptosis [1]. Dental pulp stem cells (DPSCs) have been found to promote the formation of blood vessel by releasing vascular endothelial growth factor (VEGF) helping in the migration of HUVECs [1]. These findings highlight the importance of incorporating strategies to stimulate angiogenesis in direct pulp capping procedures with DPSCs showing great promise in making this possible. The Healing Potential of Peptide RADA 161 on Dentin Matrix RADA16-I Peptide hydrogel shows great promise as a material that can be designed to interact with human dentin matrix. By incorporating a dent in derived sequence from a bioactive component of extracellular matrix phosphoglycoprotein, it can support dental tissue regeneration [1]. In vitro studies demonstrated that an injectable self-assembling peptide hydrogel modified with dentin sequence are biocompatible and supports DPSCs proliferation and mineralization [1]. These hydrogels can also anchor themselves to the adhesive -dentin interface, improving integration with tooth structure [4]. Altogether, RADA 16-1 holds significant potential in dental therapies, offering a way to enhance DPSC proliferation and promote regeneration of dental tissues. Potential benefits of using peptide RADA 16-1 as a direct pulp capping agent PuramatrixTM, a self-assembling peptide that forms a biodegradable scaffold of nanofibers when exposed to physiologic pulp stem cells (DPSCs) growth and odontoblastic differentiation. DPSCs exhibited the proliferative and morphological features of healthy cells when cultured with all concentrations of PuramatrixTM [1]. Interestingly, DPSCs expressed DMP-1 and DSPP following 21 days of culturing in dentin slices containing PuramatrixTM [1]. This suggests that PuramatrixTM may have potential. The compatibility of DPSCs with the self-assembling peptide hydrogel PuramatrixTM shows the potential for this material as an effective direct pulp capping agent in dentistry. Further research is necessary to determine the efficacy and safety of PuramatrixTM as a direct pulp capping agent in humans. Key factors that contribute to the healing potential of peptide RADA 16-1 While the text does not directly outline them, studies suggest that RADA16-I hydrogels containing GAG-mimetic and GAG-binding peptides could help in healing [5]. For example, one study showed that the hydrogel could achieve retention and delivery of VEGF, neurite network formation of mouse embryonic stem cells and suggests that the hydrogel helps in promoting nerve tissue regeneration [5]. Peptide RADA16-1 hydrogel can assemble on its own and contains IKVAV, YIGSR, and PDSGR [5]. IKVAV epitopes are added in PA hydrogels which helps in promoting in vitro differentiation of neural progenitor cells and prevent differentiation of astrocytes, which are involved in formation of scar after injury. IKVAV-displaying PAs have been explored to reduce astrocyte-derived scars and aid regeneration of descending motor fibers and ascending sensory fibers in a mouse model [5]. Moreover, RADA16-I hydrogels that RADA16-1 hydrogels have potential for contributing to tissue regeneration and repair, making them a promising candidate for direct pulp capping in dentistry. Comparison of Peptide RADA 161 with Traditional Pulp Capping Agents The dental pulp is susceptible to damage, but direct and indirect pulp capping techniques have been developed to treat this issue. One such technique is the use of RADA 16-1, a self-assembling synthetic peptide amphiphile. Compared to other techniques, phase display allows for fast assembly of the peptide nanofiber which is more effective than saline or nonfunctionalized RADA 4 [1,6]. Peptides such as CAP-18 and cathelin have also been used for their antimicrobial properties, but the cost of solid phase) residues have shown promise when compared to natural and synthetic hydrogels, as well as traditional polymeric hydrogels [7,8]. Small peptides have advantages as a molecular platform for supramolecular hydrogels, including the ability to act as a template for nanofabrication. RADA-based 3D matrices Global J Res Dent Sci. 2025; 5(5), 68-73 @ 2025 | PUBLISHED BY GJR PUBLICATION, INDIA 70 modified with IKVAV peptide have been shown to be viable options for printable scaffolds for 3D cell culture [9,3]. Biocompatible peptides such as ac-(RADA) 4 have also been synthesized and shown to be effective in comparison to free peptide -adjuvant. However, differences in peptide design can impact efficacy, as seen in the impairment of activity of the RADA peptides when specific residues are altered [10,11]. It is important to note that the efficacy of RADA 16-1 specifically in comparison to traditional pulp capping agents has not been directly studied. Advantages and disadvantages of using peptide RADA 16-1 over traditional agents Peptide RADA 16-1 is a self-assembling synthetic peptide amphiphile that has been studied for potential use in a variety of applications. One area of interest has been its potential use in the treatment of damaged pulp tissue, specifically in direct and indirect pulp capping procedures. Studies have shown that RADA 16-1 is effective in promoting pulp tissue regeneration when compared to untreated dental pulp [1]. Additionally, RADA 16-1 has been compared to other techniques, such as phase display, and has been when compared to other methods of synthesis [7]. Compared to natural and synthetic hydrogels, RADA 16-1 has been found to be an effective self-assembling peptide hydrogel due to its repeating RADARADARADARADA sequence [8]. Moreover, small peptides offer several advantages as a molecular platform for supramolecular hydrogels over traditional polymeric hydrogels, as they are more biocompatible and can serve as 3D cell culture scaffolds with printable properties [9,11]. In terms of local drug delivery, RADA-modified nanoparticles were found to be more effective in breaking down preformed biofilms than free peptide forms [10]. Furthermore, RADA 16-1 when combined with functional peptides of BMP-7 enhance its properties when compared to using RADA alone [12]. While differences in peptide design can translate to varying effects, RADA-based 3D matrices modified with IKVAV peptides have shown promise in nanofabrication and tissue engineering applications [3]. Overall, RADA 16-1 offers benefits over traditional agents due to its self-assembling properties, biocompatibility, tissue regeneration and combat biofilms. Are there any specific scenarios where peptide RADA 16-1 may be more effective than traditional agents? While traditional agents have been used as a first line of treatment for damaged pulp tissue in dentistry, recent studies suggest that peptide RADA 16-1 may be a more effective alternative. RADA 16-1 is a self-assembling synthetic and indirect pulp capping with RADA 16-1 has been shown to be more effective in maintaining pulpal tissue vitality compared to untreated dental pulp [1]. Additionally, RADA peptides have demonstrated advantages over other techniques in terms of speed and efficacy in phase display [6]. The cost of solid-phase peptide synthesis for antimicrobial treatment is also lower than that of other traditional agents [7]. Moreover, designer self-assembling peptide hydrogels, such as RADA-based hydrogels, have been shown to be more effective than traditional polymeric hydrogels in terms of biocompatibility and nanofabrication [8,3]. Small peptides, in general, have been proven to be a prevalent molecular platform for supramolecular peptide to other formulations, nanoparticle (NP) formulations of RADA peptides have demonstrated higher local doses and increased disruption of preformed biofilms [10]. Additionally, RADA-based matrices modified with functional peptides have shown increased properties compared to RADA alone [12]. Finally, a biocompatible peptide called ac-(RADA)4has been synthesized and shown to outperform free peptide vaccines or aluminum-adjuvant hydrogels for a printable scaffold in 3D cell culture [11]. Research suggests that RADA peptides may be more effective than traditional agents in some cases, such as in regenerating damaged pulp tissue or creating biocompatible scaffolds for 3D cell culture. Clinical Applications and Considerations for Peptide RADA 161 in Dentistry Peptide RADA 16-1, a self-assembling peptide hydrogel, shows potential for use in various dental applications. One such application is the ability to promote hydroxyapatite (HAp) nucleation, which is essential for tooth remineralization and repair. Studies have shown that peptide hydrogels can effectively promote HAp formation, making them a potentially valuable tool in dentistry [4]. Furthermore, the peptide hydrogel has been found to be cytocompatible with dental pulp stem cells and fibroblasts, making it an attractive candidate for dental tissue regeneration [4]. Its self-assembling nature enables it to self-anchor to the adhesive/dentin interface, helping restorative treatments last longer. The use of RADA 161 in dentistry has the potential to revolutionize the way dental procedures are carried out leading to improved clinical outcomes for patients. With further research, it could become a valuable asset in the field of dentistry [4]. How can peptide RADA 16-1 be integrated into existing dental treatment protocols? Peptide RADA 16-1 has immense potential in the realm of dental treatment protocols. In a study, the peptide was combined with RADA SAP to repair dental lesions and enhance the production of peptides [13]. Moreover, selfassembled peptide hydrogels are being developed for dental tissue and bone repair, with RADA peptides being considered promising candidates due to their functionalization properties [4]. Although alternative medical practitioners theorize that inadequate peptide transfer from the intestine to the bloodstream can inhibit the healing process, RADA peptides have been observed to promote healing in dental applications [14]. Peptide RADA 16-1 is also being investigated for use in intraoperative hemostatic applications, endoscopic uses, and the treatment of endodontic infections in the root canal space [15,7]. It has been observed that when RADA peptide is coupled with a BMP-7 mimetic peptide, Global J Res Dent Sci. 2025; 5(5), 68-73 @ 2025 | PUBLISHED BY GJR PUBLICATION, INDIA 71 it enhances osteogenic induction of dental pulp stem cells [6]. Furthermore, incorporating dual VEGF and BDNF mimetic peptide epitopes into found to be more sensitive in releasing MSC integrins than traditional hydrogels [17]. Finally, the use of a variety of peptides in stem cell research is being assessed, with challenges related to their application being discussed [18]. The integration of RADA peptide into existing dental treatment protocols is likely to enhance their ability to repair and regenerate tissues. Safety and regulatory considerations for using peptide RADA 16-1 in clinical practice The clinical use of peptide RADA 16-1 comes with several safety and regulatory points. A key concern is making sure peptide is formed under strict quality controls so as to remain free from potential contamination or impurities. Additionally, any modification of RADA peptides should be carefully checked to make sure that they do not negatively impact their efficacy or safety in clinical use [4]. In dentistry, there is evidence to suggest that RADA peptides may help repair dental lesions and promoting tissue regeneration, but further research is needed to fully understand their benefits and risks [13]. Moreover, as there are chances of endodontic infections and other complications, it is important to carefully monitor the patient undergoing treatment with RADA peptides and make sure that they are not experiencing adverse effects. Finally, it is important that the pH range of RADA peptides may limit their applications, alternative selfassembling peptides or bio-inspired nanofibrous microspheres may serve as suitable for certain therapeutic uses [19]. Overall, while the potential looks very promising, RADA peptides need more evaluation to confirm their safety and efficacy before becoming a regular part of dental care. DISSCUSION Future Research and Development of Peptide RADA 161 in Dentistry The use of self-assembled peptide hydrogels for bone and dental tissue has shown promise in repairing dental lesions and improving However, there are still gaps in knowledge regarding the use of RADA 16-1 in direct pulp capping. One limitation is the relatively low pH range of the peptide, which could affect its effectiveness [19]. Further research is needed to determine the optimal concentration and application of RADA 16-1 in dental interventions. Additionally, the potential use of other defense peptides as part of scaffolds could be explored to enhance the integration of synthetic heart valves, dental implants, and other medical interventions [20,21]. Overall, critical insights from ongoing investigations on peptide nanotechnology will inspire further research and development of peptide-based materials for various applications in dentistry. Potential avenues for further research and development of peptide RADA 16-1 in dentistry Making changes to Peptides, such as the incorporation of RGD, is helpful in antimicrobial performance of biomaterials used for repairing dental tissues. Future research might focus on how peptide hydrogels helps in promoting angiogenesis in dental pulp stem/stromal cells and can also be engineered from ultra-short peptide building blocks to determine their ability to stop microbial growth in dentistry. This could lead to the development of new dental materials that are more effective at preventing bacterial colonization and promoting tissue regeneration. Additionally, further studies could investigate the effects of different peptide amounts and modifications on the strength of peptide hydrogels and their compatibility with different dental applications. Overall, future research and development on peptide RADA 16-1 and other peptide-based materials in dentistry, could bring about more effective and versatile biomaterials for improving oral health and tissue regeneration [21]. How can the findings from this study contribute to the future advancements in dental pulp capping techniques? Hydrogel systems are emerging as a promising option for dental pulp capping. A study showed that these hydrogel systems are safe for use with primary human dental pulp cells, making their potential for use in human clinical settings [21]. The hydrogel groups also have the ability to slow down the growth of Streptococcus mutans and Lactobacillus casei strains which are commonly associated with dental caries [21]. The composite hydrogels can also influence the body’s immune response to bacteria, indicating possible anti -inflammatory feature [21]. These antimicrobial hydrogels help in enhancing dental regeneration, and could contribute to future advancements in dental pulp capping techniques [21]. Furthermore, they offer a multifunctional approach that could be effective in promoting odontogenic differentiation in treated cells, and helps in dental tissue healing [21]. Using self-assembled peptide hydrogels represent promising approach for improving dental pulp capping techniques. In particular, peptide RADA 16-1 shows immense potential for increasing dental regeneration. Peptide RADA 16-1 has the ability to assemble on its own into a β-sheet structure through non-covalent interactions that forms biocompatible and mechanically tunable hydrogels that can interact with human dentin matrix. Global J Res Dent Sci. 2025; 5(5), 68-73 @ 2025 | PUBLISHED BY GJR PUBLICATION, INDIA 72 CONCLUSION However, there is still a lot we don’t know about how RADA 16-1works when used for direct pulp capping and further studies are required to find out the effects of different peptide concentrations and modifications on the mechanical properties of peptide hydrogels and their compatibility with different dental applications. Researchers are also exploring whether adding adding certain bioactive sequences from natural tooth proteins could make the peptide bond even better with dentin. Future research are exploring whether RADA 16-1 hydrogels can help in promoting angiogenesis in dental pulp stem/stromal cells. 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In Global Journal of Research in Dental Sciences (Vol. 5, Number 5, pp. 68–73).