Outcome assessment methods of bioactive and biodegradable materials as pulpotomy agents in primary and permanent teeth: a scoping review

Over the past decade, there has been a paradigm shift in the realization that an inflamed pulp may be worth saving. Advancements in the fields of tissue engineering and biomaterials have made preservation and regeneration of the dentin-pulp complex the most sought-after goals of vital pulp therapy strategies. Although the evolution of biomaterials since the discovery of calcium hydroxide has been immense and revolutionary, the unique spatiotemporal nature of the dentin-pulp complex poses multiple challenges. This is further complicated by the inherent anatomical, physiological, and biological differences between the primary and the permanent dental pulps [17]. Furthermore, while the required outcome may be the same, indications and outcome assessment methods for pulpotomy procedures in primary and permanent teeth may be quite different. Indeed, in an era where personalized patient care will represent the future of medicine, bioactive vital pulp therapy agents that aim to regenerate anatomical and functional tissues like the native tissue are continuously being developed. These agents and strategies must therefore be carefully tailored not only to whether the tooth is primary or permanent but also according to the developmental and inflammatory status of the tooth in question [18].

Although pulpotomy procedures for primary teeth have long been practiced, the concept of a pulpotomy for a mature permanent tooth has only recently been addressed. Hence, we aimed to focus more on the last 10 years in which a peak in the publication of these papers was noted. Additionally, the use of bioactive cements and biodegradable scaffolds in randomized clinical trials focusing on pulpotomy is relatively new. Therefore, the goal of this scoping review was to elucidate the present knowledge gap and highlight the need for clear decision-making guidelines regarding outcome assessment methods of pulpotomy procedures utilizing regenerative agents in primary and permanent teeth. It was designed and reported with reference to the recently updated JBI scoping review guidelines [15, 19] and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension (PRISMA-ScR) [2, 20], and was reinforced by the diverse expertise of the authors who include methodologists, analysts, and clinicians sharing an intrigue in evidence-based health care.

While planning this review, the language was restricted to English only to avoid potential confusion in interpretation of data during translation of full text articles. As for exclusion of studies comparing different vital pulp therapy techniques, we wanted to focus the attention of this review on different materials without having the confounding variables of different procedural parameters. Furthermore, we intended to target randomized and non-randomized controlled clinical trials only to provide an overview of the available highest level of clinical evidence to answer the research question, and to determine where further research may be indispensable in this field. We did not set limits for the follow-up periods to include short- and long-term clinical, radiographic, as well as histological and inflammatory assessments. Most of the screened clinical trials (85.8%) comprised 12 months and longer follow-up intervals [18, 21‐127]. As the objective of this review was focused on outcome assessment rather than treatment success, which is highly dependent on the initial inflammatory pulp status, we did not restrict our search according to the type of exposure being carious or traumatic to retrieve as many trials as possible in our search in primary and permanent teeth. Additionally, included studies did not stratify the outcomes according to the type of exposure. Remarkably, the pre-operative pulpal status was mainly distinguished as “reversible pulpitis” for both primary and permanent teeth [18, 21, 22, 26, 28‐36, 39, 40, 43, 44, 47‐56, 58‐60, 62‐71, 75‐123, 125‐127, 135‐139, 150, 151, 155‐157, 167, 168]. On the other hand, teeth categorized with “irreversibly inflamed pulps” were indicated for pulpotomy only for mature permanent teeth [23, 25, 27, 37, 38, 45, 46, 57, 61, 72, 124, 131, 132]. The small percentage of studies performed in mature permanent teeth with irreversible pulpitis highlights this new trend in treatment of the inflamed pulp.

With regards to the total number of studies, the fact that the studies in primary teeth represented almost double those in permanent teeth again clearly reflects that the pulpotomy trend for mature permanent teeth is a new direction in treatment. This is owing to the fact that the pulpotomy procedure is the preferred treatment for preserving the vitality of an asymptomatic cariously exposed primary or immature permanent tooth as dictated by the American Academy of Pediatric Dentistry [128] and is a newly prospective substitute for root canal treatment in managing mature or immature permanent teeth with carious pulp exposures, even with irreversible pulpitis [129]. This was also augmented by the recent position statement from the European Society of Endodontology [130] who recommended minimally invasive vital pulp therapy (VPT) for permanent teeth.

Interestingly, while studies on both primary and permanent teeth displayed a high tendency to use bioactive agents, more than 31.7% (13/41) of studies on permanent teeth implemented biodegradable scaffolds [23, 25, 38, 57, 74, 90, 94, 122, 131‐134]versus only 22.1% (19/86) of the studies conducted on primary teeth [18, 22, 40, 53, 55, 56, 70, 71, 77, 84, 97, 102, 108, 110, 135‐139]. This could reflect the recent nature of the use of pulpotomy procedures as a permanent treatment modality in mature permanent teeth, which coincides with the recent boom in the development and optimization of a wide variety of bioactive agents [3, 5, 6]. This could also be attributed to the higher need for retaining the permanent teeth throughout life of the patients. Furthermore, it might highlight the differences in outcome assessment methods and follow up duration required following pulpotomy in primary or permanent teeth.

For primary teeth, the main objective of pulpotomy procedures is to keep the tooth symptom-free until the successor tooth erupts [7]. Hence, it is seldom required to aim to regenerate the damaged tissue but rather sustain the condition of the vital pulp until the time of shedding. Indeed, many studies in primary teeth do not consider minor radiographic changes as a reason for further intervention since the tooth can function and the patient has no signs or symptoms [140‐143]. However, this concept fails to consider the duration of time that this failure may require. Additionally, it has been shown that the inflammatory milieu within the pulp may be influenced by the active conditions of physiologic tooth resorption, and the contrary may also be true [144‐147]. Root resorption is one of the most frequently reported reasons of failure in primary teeth which may again highlight a continued inflammatory trigger even following the pulpotomy procedure [33, 99, 148]. Aiming to regenerate the lost dentin-pulp tissue and restore nociception and immune defense within the pulp may create an inflammation-free environment, allowing the natural process of shedding and eruption. On the other hand, the goal of partial or complete pulpotomy procedures in permanent teeth is to remove the coronally inflamed or infected pulp and preserve the remaining normal or reversibly inflamed radicular pulp. It also aims to promote healing and repair of the remaining vital tissue, not as a temporary treatment but rather as a long-term predictable treatment like conventional root canal treatment [130, 149].

The recent rise in the implementation of biodegradable scaffolds for pulpotomy procedures demonstrates the rapid transition in knowledge and understanding of the dentin-pulp complex from preservation to regeneration. There are also a handful of studies that have used natural derivatives and plant extracts indicating a tendency towards using readily available, naturally healing materials that not only have therapeutic potential but are also cost-effective and environment friendly [35, 50, 93, 116, 125, 137, 150]. Indeed, the use of these extracts in primary teeth has long preceded their use as palliative and healing agents in the permanent dentition.

The evolution of bioactive cements is clearly demonstrated by the results of this study in that most clinical studies utilized either MTA or more recently biodentine [18, 21, 23‐30, 32, 33, 35‐50, 53‐66, 68, 69, 72‐101, 103‐109, 111‐127, 131‐136, 138, 151‐157]. MTA has been advocated as the new gold standard for pulpotomy procedures. Certainly, almost all of the included studies used MTA for one of the control arms [21, 23‐30, 32, 33, 35, 37‐39, 41‐46, 48‐50, 53‐70, 72, 73, 75, 76, 78, 79, 81‐85, 87‐90, 92‐96, 98‐104, 106‐109, 111‐127, 132‐136, 138, 151‐154, 156, 157]. It has excellent potential as a pulpotomy medicament, as it is highly biocompatible, with regenerative potential and effective induction of dentinal bridge formation. Furthermore, a recent study suggested MTA to be a useful material in both infected and uninfected pulp tissue [158] with low toxicity [159] and no adverse effects on permanent successors [160]. The years of clinical experience have revealed some disadvantages of MTA that occur in practice, such as long setting time, potential of discoloration and lengthy procedure. Biodentine seems to have superior properties in that it is more biocompatible, has better handling properties, produces more predictable dentin bridges, and shows comparable treatment outcomes to MTA [59, 82, 98, 161].

Out of the 13 studies that used biodegradable scaffolds in permanent teeth, the majority were conducted using PRF [23, 25, 38, 74, 122, 124, 131‐133, 138]. On the other hand, the 19 studies conducted on primary teeth utilized a variety of scaffolds with 0.5% hyaluronic acid gel being the most implemented [22, 56, 97, 110]. This could be due to the rising concept of using regenerative agents for pulpotomy procedures in primary teeth. The use of PRF as a scaffold for permanent tooth pulpotomy stems from the rise in the use of PRF and other platelet-derived concentrates as scaffolds for regenerative endodontics [162, 163]. Platelet rich fibrin is a second-generation platelet-rich concentrate that relies on the body’s own clotting mechanisms without the addition of extrinsic factors to trigger coagulation. The clinical protocol for producing autologous PRF is relatively simple, cost-effective, and reproducible. In comparison to platelet-rich plasma (PRP) and other platelet-derived concentrates, PRF can provide a more sustained release of growth factors which can aid in stem cell recruitment, angiogenesis, and cell proliferation and differentiation [164, 165]. One drawback which may limit the use of PRF and other concentrates for primary teeth pulpotomy is that its procurement may be considered an invasive procedure from children often requiring withdrawing 5–10 cc of blood [165, 166].

A notable observation in this study was that most pulpotomized primary teeth as well as young permanent teeth, capped with biodegradable scaffolds in the screened studies, were covered with zinc oxide eugenol and/or glass ionomer cement followed by stainless steel crowns. This could be because zinc oxide eugenol is regarded as a preservative material not capable of initiating a reparative process in addition to being the material of choice for standard of care procedures in pulpotomized primary teeth [128]. On the other hand, studies in mature permanent teeth that used biodegradable scaffolds/agents mainly utilized mineral trioxide aggregate, biodentine or other calcium silicate cements for sealing. These materials have also been recommended by recent guidelines as vital pulp capping materials [130]. Undoubtedly, the choice of sealing material may have a profound negative effect on the outcome of healing, further advancing the inflammatory process and eventually contributing to failure of the procedure [18].

Although this review clearly shows that numerous well-conducted clinical studies have evaluated pulpotomy outcomes with bioactive agents both in primary and permanent teeth, more than 90% of the screened trials [18, 21‐101, 103‐115, 125‐127, 131‐139, 150‐153, 155, 156, 167, 168] assessed the pulpotomy treatment outcome via subjective clinical and radiographic parameters.However, recent data has shown that the initial inflammatory status of the pulp is perhaps the only true determining factor that affects the outcome of treatment. Around only 10% of the studies mapped in this review performed histological analysis or attempted to measure inflammatory biomarkers [18, 28, 56, 87, 102, 109, 133, 134, 137, 152, 154, 157]. While histological analysis is of course not possible and, in fact, unwarranted in most clinical trials, it remains the only measure of the actual condition of the pulp [169].

Several recent studies have shown that dentinal fluid and pulpal blood of teeth with inflamed pulps may contain elevated levels of pro-inflammatory markers that can determine the inflammatory status of the pulp [170, 171]. Whilst numerous efforts have been made recently to link biological markers of inflammation (quantitative measure of inflammatory cytokines) to the status of pulp, scarce evidence was identified among the screened trials in this regard. Only one published study [18] and one completed registered clinical trial [87] assessed the relationship between markers of pulp inflammation and the outcome of pulpotomy treatment. Therefore, this review highlighted the gap in the literature with respect to inflammatory assessment of the preoperative pulpal status and its correlation with the pulpotomy outcomes. This has triggered the search for specific pulpal markers and the development of chair-side detection kits that may better help in assessing the eligibility of teeth for pulpotomy procedures and thereby provide the basis for better diagnosis and predictable treatment outcomes.

Another important fact to take into consideration is the duration of follow-up. Pulpotomy procedures have been long practiced in primary teeth, thus providing long term data. However, there are very few studies in permanent teeth with more than 2-4-year follow-up, which is considered moderate-term follow-up at best. Most of the studies were content to hit the 12-month recall [18, 22‐25, 27, 32, 37‐44, 47, 50, 51, 54‐57, 61, 62, 64, 66‐72, 77, 79, 80, 84, 85, 88, 90‐93, 95, 96, 98, 100, 103‐105, 108, 110, 112, 113, 116‐118, 120, 124, 125, 127, 131, 132, 151]. This, however, does not allow ample time to assess important parameters such as incidence of root resorption, pulp canal obliteration, tooth survival or impact on quality of life [10, 11].

Two intriguing findings from the current scoping review are the trend of publications from 2012 to 2023 as well as the global distribution of studies. The increased implementation of vital pulp treatment strategies in the last ten years has started as a result of a global effort to diagnose accurately the pulp status of permanent teeth, to preserve pulp vitality, and to increase pulp survival. Regarding the number of publications, there appear to be two peaks: in 2017 and in 2022. The first peak appears to coincide with the initial surge of clinical trials published deeming pulpotomy as a permanent treatment modality for mature permanent teeth with symptomatic irreversible pulpitis, as evidenced by several studies published in that period (20/127) [24, 29, 30, 33, 42, 64, 79, 85, 109, 114‐116, 118, 120, 134, 138, 139, 152, 154, 167]. The second peak seems to correspond to the immediate post-pandemic phase. During the COVID-19 outbreak, clinical researchers were impaired by reduced access to health care, and clinical trials were suspended and postponed. Scientific research was then resumed as the world was vaccinated and access to health care was restored [172].

At the beginning of the pandemic and later throughout the rest of 2020 to 2021, most clinical recommendations for the emergency treatment of “hot” teeth or teeth with symptomatic irreversible pulpitis were to employ pulpotomy procedures when possible as a permanent treatment [173, 174]. The reduced invasive nature of the procedure and the ability to perform a pulpotomy in one visit, in addition to the reduced operative time, reduced the risks of infection with COVID-19 due to dental exposure. This, coupled with the apparent reduced cost of pulpotomies, seemed to help in convincing more practitioners to attempt this treatment, although it is still new and lacking long-term evidence. This behavior corresponds perfectly with the sharp peak in the number of publications and clinical trials reported in 2022 (20/127) [21, 25, 35, 37, 41, 48, 61, 63, 73, 76, 77, 84, 90, 96, 98, 110, 112, 127, 156]. The other remarkable finding that coincides with the publication trends is the global distribution, where most studies are distributed in low-to-middle-income countries in the middle east and Asia, particularly in Egypt and India. This global distribution again reflects how adopting pulpotomy procedures as permanent treatments, especially in mature permanent teeth, can present multiple benefits especially where resources are limited.

A significant strength of this scoping review is the demonstration of compliance with the recently updated JBI scoping review guidelines [15, 19] and PRISMA-ScR [2, 20]. Moreover, to our knowledge, this is the first scoping review to address the outcome assessment methods of pulpotomy procedures in both primary and permanent teeth using regenerative non-degradable bioactive cements and biodegradable tissue engineering scaffolds. Another point of strength in this review is that it included grey literature, especially registered clinical trials in the National Institute of Health (NIH) database. The inclusion of grey literature allows a more objective perspective on the status of the evolution of new concepts in treatment.

On the other hand, some limitations related to the methodology were encountered while conducting this review. Only primary research (controlled trials, randomized controlled trials) was included while uncontrolled trials, case reports, case series, systematic reviews, position statements, and clinical guidelines were not. Despite our search being guided by an expert librarian, our electronic literature search was bounded to MEDLINE (via Pubmed), Web of Science, Scopus, Proquest, and clinicaltrials.gov in an attempt to limit the number of articles being scanned; however, this might have led to missing some evidence that address the review questions and objectives present in other search engines.

Our review also revealed significant knowledge gaps, including a scarcity of studies conducted on permanent teeth and a dearth of studies establishing a correlation between actual inflammatory status of the pulp and treatment outcomes. Therefore, long term evidence from well-conducted clinical trials is still needed, as well as the development of a set of predictable outcome measures and the interpretation of outcomes in terms of both treatment success and tooth survival. It is also crucial when designing new biodegradable scaffolds, for promoting tissue regeneration following pulpotomy procedures, to tailor their properties according to the inflammatory milieu and whether they will be designed for usage in primary or permanent teeth.