Synergistic Efficacy of a Biomimetic Hydroxyapatite-Citrate Complex for Dentin Hypersensitivity: An In Vitro and Clinical Study
A
Xiaobin
Chen
1✉
Emailxiaobin_chen@darlie.com
Han
Jiang
2
Yanxiao
Li
1
Yi
Zhou
1
Decheng
Ye
1
Minquan
Du
2✉
Emailduminquan@whu.edu.cn
1
A
Hawley & Hazel Chemical Co. (Zhongshan) Ltd
Zhongshan
China
2
School & Hospital of Stomatology Wuhan University
Wuhan
China
Xiaobin Chen1*#, Han Jiang2#, Yanxiao Li1, Yi Zhou1, Decheng Ye1, Minquan Du2*
*Correspondence:
Xiaobin Chen xiaobin_chen@darlie.com
Minquan Du duminquan@whu.edu.cn
1Hawley & Hazel Chemical Co. (Zhongshan) Ltd., Zhongshan, China
2School & Hospital of Stomatology Wuhan University, Wuhan, China
#Xiaobin Chen and Han Jiang contributed equally to this work
Abstract
Background
To evaluate the synergistic effect of a novel Hydroxyapatite(HAP)-Citrate complex toothpaste on dentinal tubule occlusion and the relief of dentine hypersensitivity (DH).
Methods
A
A
For the in vitro study, bovine dentin discs were treated with a test toothpaste (HAP, potassium citrate and NaF), a control toothpaste (HAP and NaF), and a placebo toothpaste (NaF only) for 3 and 7 days. Tubule occlusion and mineralized layer formation was assessed using Scanning electron microscopy (SEM). For the clinical study, a 12-week, double-blind, randomized trial involving 129 subjects compared the test toothpaste to a bioactive glass-based positive control toothpaste and a placebo. The severity of DH, indicated by Schiff (air) and Yeaple (tactile), was evaluated at baseline, 2, 6, 8, and 12 weeks, with the last 4 weeks being a washout period.Results
The HAP-Citrate complex toothpaste demonstrated significantly higher surface tubule occlusion rates, deeper intratubular occlusion, and thicker mineralized layer compared to HAP/NaF-only and placebo groups (p < 0.05) in in-vitro studies. In the 12-week clinical study, the HAP/Citrate toothpaste exhibited higher DH relief, with significant improvement in Schiff and Yeaple scores at 6 and 8 weeks compared to placebo (p < 0.05). Its desensitizing performance was comparable to the bioactive glass-based positive control. Notably, the reduction in air-stimulus sensitivity was sustained at the 12-week follow-up, four weeks after the subjects discontinued the product use.
Conclusions
The novel HAP-citrate complex toothpaste can build deep, protective mineral seal on dentin tubules. Its clinically proven performance makes it a superior, science-backed choice for effective sensitivity management.
A
Registry: Chinese Clinical Trial Registry, TRN: ChiCTR2500115399, Registration date: 25 December 2025.Keywords:
Hydroxyapatite
Citrate
Hypersensitivity
Dentine
Remineralization
A
A
1. Background
Dentine hypersensitivity (DH) is characterized by short and sharp pain arising from exposed dentin in response to thermal, tactile, chemical, or osmotic stimuli, and cannot be attributed to dental defects or pathological changes caused by other specific factors [1]. DH is a common and frequently encountered dental problem. According to a published result of random-effects meta-analyses in 2019, the incidence rate of DH is about 33.5% on average, with high heterogeneity ranging from 1.3% to 92.1%, because of differences in population screened, recruitment process, and diagnostic criteria [2]. Although not a major problem for public health, reducing DH is related to improvement in oral health-related quality of life [3]. Brannstrom’s hydrodynamic theory remains the most widely accepted mechanistic explanation for the pathogenesis of DH [4, 5]. This theory posits that fluid movement induced by external stimuli stimulates nerve endings in the dental pulp, thereby resulting in tooth pain [6]. Given this etiology, DH is managed using two primary strategies: nerve desensitization, and dentin tubule occlusion [7, 8]. Potassium ions (K+), typically in the form of potassium nitrate, can depolarize nerve fiber membranes and rendering them less responsive to the stimuli-induced fluid movement [9]. However, no strong evidence is available to support the efficacy of KNO3-containing dentifrices in treating DH [10, 11]. Occlusion of the dentin tubules is a more commonly used strategy. This approach directly addresses the hydrodynamic mechanism, using both chemical or physical methods to block the open orifices of the dentinal tubules, and reducing or eliminating the stimulus-induced fluid flow, thereby preventing the activation of the underlying nerves [11]. There are lots of active ingredients work through this mechanism, including hydroxyapatite (HAP), bioactive glasses (i.e., calcium sodium phosphosilicate), arginine and calcium carbonate technology, and stannous fluoride (SnF2) [11, 12].
Among the numerous occluding agents, HAP stands apart and has been increasingly utilized, primarily owing to its inherent biomimetic properties [13, 14]. As the principal inorganic mineral component of human enamel and dentin, it is considered one of the most biocompatible materials, being widely applied in dentistry for tooth remineralization [15, 16, 17]. The clinical effectiveness of HAP-based products, especially nano-sized, for managing DH is well-supported by a growing body of high-quality evidence [18, 19, 20]. A comprehensive systematic review and meta-analysis of 44 human clinical trials demonstrated that HAP significantly reduced dentin hypersensitivity by 39.5% compared to placebo, 23% compared to fluoride [12].
Strategies to enhance the desensitizing effect of HAP have traditionally focused on physical modifications like nano-sizing or chemical alterations like ion-substitution [21, 22]. However, recent advancements have introduced a novel, bio-inspired strategy using citrate as an active modulator of the mineralization process. Groundbreaking research in bone biology has identified citrate as a key organic molecule that is highly conserved in bone mineral (comprising 1.5-2.0 wt% of bone content) and is essential for normal bone formation [23, 24]. In vitro studies have demonstrated that citrate stabilizes prenucleation calcium phosphate clusters and liquid-like ACP precursors, preventing their premature conversion into crystalline HAP. This stabilization is vital, as it allows a more fluid, amorphous mineral phase to effectively infiltrate the intricate collagen fibril network of bone by reducing ACP-collagen interfacial energy before it solidifies into organized HAP crystals [25, 26]. Dayashankar et al. conducted a randomized controlled trial that compared a citric acid-based nanohydroxyapatite (CA-NHA) composite graft with a nanohydroxyapatite (NHA) graft alone for periodontal regeneration. The study found that while both materials showed significant improvement, the CA-NHA group demonstrated statistically significant better outcomes in all clinical and radiographic parameters at 12 months compared to the NHA-only group [27].
Building on the established role of citrate in bone biology, where amorphous calcium phosphate (ACP) precursors are stabilized to facilitate mineral infiltration, a similar mechanism in dentin remineralization is hypothesized. It is proposed that the efficacy of HAP-based dentinal tubule occlusion will be enhanced by citrate-modulated HAP formation, which promotes a deeper, more integrated mineral seal instead of a simple surface plug. This process is expected to result in the creation of a more durable protective layer on the dentin surface. Therefore, this study aims to validate the superiority of the citrate-HAP complex over HAP alone through in vitro dentinal tubule occlusion assays. Subsequently, a clinical trial will assess its long-term efficacy against a placebo and a commercially available bioactive glass-based toothpaste, which will serve as the positive control. This research seeks to advance the development of more effective and biomimetic treatments for dentin hypersensitivity.
2. Materials and Methods
2.1. In vitro dentinal tubule occluding
An in vitro study assessed dentinal tubule occlusion by toothpastes. Bovine incisors were used as a substrate for the in vitro dentin tubule occlusion model. The teeth were sourced from a commercial slaughterhouse in Bengbu, Anhui province, China. All teeth were collected from animals slaughtered for consumption and were considered by-products of the food industry. Only teeth with intact crowns and no visible cracks or caries were selected for the study. 1 mm thick bovine dentin discs (cervical region), etched with 40% phosphoric acid for 5 min to remove the smear layer, were split longitudinally: one half served as a control (immersed in HEPES-buffered artificial saliva, pH 7.0), while the other half was treated with toothpaste. Three toothpaste groups were tested: group A, test toothpaste (HAP, potassium citrate and NaF), group B, in vitro control toothpaste (HAP and NaF), and group C, placebo toothpaste (NaF only). The 3 formulas shared an identical base formulation (abrasives, humectants, etc.) with the only variables were HAP and citrate.
The dentin discs were placed in a specially designed fixture used to hold the electric toothbrush, and a sensor for standardized brushing pressure was prepared. 0.5g of toothpaste was applied to the dentin surface. The toothbrush bristles were positioned at a 90-degree angle to the specimen and maintained in contact with the dentin surface. Brushing pressure was set to 200g. The dentin discs were brushed with toothpaste every morning and evening for 2 min each time, and were kept in an artificial saliva (20mM HEPES, 16mM KCl, 1mM CaCl2.2H2O, 4mM KH2PO4, 4.5mM NH4Cl, 0.2mM MgCl2.6H2O, pH = 7.0) incubator at 37°C for the rest of the time.
Post-treatment, samples were dried, gold-sputtered, and analyzed by SEM (HITACHI S4800). Tubule occlusion percentage was calculated from 1000x SEM images using the formula: [(n0 - n1)/n0] X100%, where n0 was the number of fully patent dentinal tubules in the untreated half dentin discs, and n1 was the number of fully patent dentinal tubules in the treated half dentin discs. Statistical analysis was performed using a one-way analysis of variance (ANOVA), with a p-value of < 0.05 considered statistically significant.
2.2. Clinical Study
A
This was a 12-week, double-blind, randomized, parallel design study. The study included three toothpaste groups: the test toothpaste (Group A: HAP, potassium citrate, and NaF), a placebo (Group C: NaF only), and a positive control (Group D: a commercial bioglass-based anti-sensitivity toothpaste). Evaporative (air) stimulus (Schiff) and tactile stimulus (Yeaple) were used as evaluation indices. The study was conducted at the School & Hospital of Stomatology Wuhan University. A
The WUHAN University Institutional Review Board (IRB) approved the study ([2016] Ethics Review No. (01)). The trial was registered on Chinese Clinical Trial Registry (No. ChiCTR2500115399, Date: 25/12/2025). Male and female subjects in good general health condition aged 20–55 were accepted onto the study. Subjects must have symptoms of dentin hypersensitivity, with at least two teeth (in different quadrants and not adjacent) having exposed root dentin. When tested by Schiff cold air sensitivity scale, at least two teeth should have a score of 2 or higher, a VAS score of 4 or higher, and a sensitivity threshold of less than 20 grams when tested with the Yeaple probe. Subjects meeting any of the following criteria will be excluded: severe oral diseases, chronic conditions, or allergies to the test product; progressive periodontal disease or periodontal treatment (including surgery) within the past year; sensitive tooth mobility greater than 1; extensive dental restorations, suspected pulpitis, dental caries, enamel crazing, or removable partial denture abutments; use of anticonvulsants, antihistamines, antidepressants, sedatives, tranquilizers, anti - inflammatory agents, or analgesics within the past month or currently; intermittent pain (e.g., back pain, arthritis); or participation in desensitizing toothpaste studies or regular use of other desensitizing toothpastes within the past three months. Informed consent from subjects was obtained.A
There were totally of six examination visits to complete the study (Fig. 1). Subjects who met enrollment criteria would undergo a two-week washout period by using a standard fluoride toothpaste and designated soft-bristled toothbrush. They were assigned different test toothpastes after baseline examination, and continued to use it for 8 weeks and then changed to the washout standard fluoride toothpaste for another 4 weeks. The subjects were required to brush their teeth twice a day, filling the entire toothbrush head with toothpaste each time, and brushing their teeth for 2 minutes. At each examination visit, Yeaple and Schiff index were evaluated. For the Schiff test, a dental chair air gun (60 ± 5 p.s.i., 19–21℃) blows air for 1 second at 1 cm from the sensitive tooth (with a finger pressing the adjacent tooth to control variables), scored via the Schiff cold air sensitivity scale; for the Yeaple test, a calibrated electronic probe contacts exposed buccal dentin at the enamel-dentin junction, starting at 10 g and increasing by 10 g increments until discomfort (forces > 50 g are recorded as 60 g). One-way analysis of variance (ANOVA) was used to compare the differences between groups at different time points and within groups at the 5% significance level.
Visit 1: Screening
Informed consent
, Medical history, OST examination
A
Sensitivity evaluation, decision on eligibility
Suitable subjects will undergo a two-week washout period
↓
No eating at least 4 hours and no drinking water at least 2 hours prior to test session
↓
Visit 2, 3, 4, 5: baseline, 2 weeks, 6 weeks, 8weeks test session
OST examination and Sensitivity evaluation
↓
Switch to regular fluoride toothpaste and continue using for 4weeks
↓
Visit 6: 12weeks test session
OST examination and Sensitivity evaluation
Figure 1. Protocol design of the clinical study
3. Results
3.1 In vitro study
After treatment with 40% phosphoric acid solution for 5 minutes, all dentinal tubules were open. Cross-section images revealed smooth luminal surfaces within the tubules, with no obstructing particles observed (Fig. 2a and 2b). Following 3-day and 7-day treatments, dentin specimens immersed solely in artificial saliva showed no tubule occlusion (Fig. 3a and 3e). In contrast, all toothpaste-treated groups exhibited tubule occlusion (Fig. 3b-3d, 3f-3h). After 3 days of toothpaste treatment, the dentinal tubule occlusion rates for Group A, Group B, and Group C were 96.0 ± 2.1%, 84.7 ± 4.8%, and 43.5 ± 10.1%, respectively. Significant differences in occlusion rates were observed among the three groups (p < 0.05). After 7 days of treatment, the occlusion rates increased to 99.7 ± 0.7% (Group A), 98.1 ± 1.7% (Group B), and 76.4 ± 7.3% (Group C), with statistically significant intergroup differences (p < 0.05).
Fig. 2
SEM images of the dentin surface and longitudinal section after 5-minute treatment with 40% phosphoric acid. Scale bars: 10 µm.
Fig. 3
SEM images showing the top surfaces after 3 and 7 days treatment: (a) and (e) immersed only in artificial saliva for 3 and 7 days; (b) and (f) treated with group A for 3 and 7 days; (c) and (g) treated with group B for 3 and 7 days; (d) and (h) treated with group C for 3 and 7 days. Scale bars: 10 µm.
Cross-section of the dentin showed that tubules immersed only in artificial saliva solution maintained smooth intratubular surfaces after both 3 and 7 days of treatment (Figs. 4a and 5a). After 3 and 7 days of treatment with test toothpaste (group A), the tubules exhibited intratubular occlusion depths of more than 30 µm and 40 µm, respectively. Additionally, mineralized deposit layers more than 3 µm and 5 µm thick formed on the surface (Figs. 4b and 5b). Figure 4b-1 and Fig. 5b-1 are magnified views inside the dentinal tubules after treatment with group 1 for 3 days and 7 days, respectively. Mineralized particles can be seen within the dentinal tubules in both images. Control toothpaste (group B) treatment resulted in occlusion depths of 10 µm and 13 µm at 3 and 7 days, respectively, with a 1 µm thick mineralized deposit layer forming on the surface only after 7 days (Figs. 4c and 5c). Only sparse particles were visible within the tubules of placebo treatment (group C), and no mineralized deposit layer formed on the surface at either time point (Figs. 4d and 5d). Compared to HAP control, citrate-HAP complex exhibited deeper mineral penetration into the dentinal tubules and a thicker mineral deposition layer on the dentin surface.
Fig. 4
SEM images showing cross-sections of dentin discs after 3 days treatment: (a) immersed only in artificial saliva for 3 days; (b) and (b-1) treated with group A for 3 days; (c) treated with group B for 3 days; (d) treated with group C for 3 days. Scale bars: 1 µm (a, b-1, c, d), 10 µm (b).
Fig. 5
SEM images showing cross-sections of dentin discs after 7 days treatment: (a) immersed only in artificial saliva for 7 days; (b) and (b-1) treated with group A for 7 days; (c) treated with group B for 7 days; (d) treated with group C for 7 days. Scale bars: 1 µm (a, b-1, c, d), 15 µm (b).
3.2 Clinical study
129 subjects completed the trial and no adverse reactions were reported. Both the novel HAP/Citrate toothpaste (group A) and the positive control (group D) showed significant DH reductions in average Schiff and Yeaple indices vs baseline after 6 and 8 weeks (p < 0.05). After 6 weeks of use, the Schiff index of group A and group D was significantly improved compared with the placebo control group (p < 0.05), the improvement was 21.39% and 28.44% for 6 weeks, respectively. After 8 weeks of use, the Yeaple index of the test toothpaste group and the positive control group was significantly improved compared with the placebo control group (p < 0.05), the improvement was 100.85% and 69.17%, respectively. By 8 weeks, Schiff index improvements remained statistically significant (p < 0.05), and even 4 weeks after switching to regular fluoride toothpaste (12-week mark), both groups maintained Schiff index differences from baseline (p < 0.05). For the Yeaple index, while both groups showed significant 8-week changes versus the negative control (p < 0.05), these improvements decreased after switching to regular toothpaste. Group A showed larger average Yeaple index reductions by the 8-week mark, indicating superior late-stage efficacy for tactile stimulus sensitivity.
|
Product
|
Number of subjects
|
Age
|
|||
|---|---|---|---|---|---|
|
Male
|
Female
|
Total
|
Mean
|
Scope
|
|
|
A
|
7
|
35
|
42
|
42
|
21 ~ 54
|
|
C
|
5
|
39
|
44
|
42
|
29 ~ 54
|
|
D
|
6
|
37
|
43
|
41
|
25 ~ 55
|
|
Index
|
Product
|
Baseline
|
2 weeks
|
6 weeks
|
8weeks
|
12 weeks
|
|---|---|---|---|---|---|---|
|
Schiff
|
A
|
2.25(0.37)
|
2.13(0.39)
|
1.75(0.53)^*
|
1.51(0.67)^*
|
1.18(0.73)^*
|
|
C
|
2.32(0.57)
|
2.26(0.39)
|
2.23(0.42)
|
2.15(0.46)
|
2.09(0.5)^
|
|
|
D
|
2.29(0.43)
|
2.13(0.46)
|
1.59(0.63)^*
|
1.38(0.67)^*
|
1.07(0.70)^*
|
|
|
Yeaple
|
A
|
11.48(2.77)
|
10.91(2.23)
|
15.91(8.16)^
|
28.69(13.43)^*
|
23.75(15.29)^
|
|
C
|
11.43(2.54)
|
11.07(2.35)
|
12.62(6.92)
|
14.29(6.95)
|
20.73(13.26)^
|
|
|
D
|
11.28(2.46)
|
11.43(3.71)
|
15.93(9.4)^
|
24.17(13.57)^*
|
20.70(13.52)^
|
|
| Note: ^ means the mean values are significantly different with baseline (p < 0.05); * means the mean values are significantly different with control group C (p < 0.05) | ||||||
|
Index
|
Group
|
2 weeks
|
6 weeks
|
8 weeks
|
12 weeks
|
|---|---|---|---|---|---|
|
Schiff
|
A
|
6.05%
|
21.39%
|
29.86%
|
43.34%
|
|
D
|
5.79%
|
28.44%
|
35.91%
|
48.71%
|
|
|
Yeaple
|
A
|
-1.47%
|
26.07%
|
100.85%
|
14.56%
|
|
D
|
3.23%
|
26.24%
|
69.17%
|
-0.16%
|
^ Improvement rate= (Group A/D-Group C)/ Group C ×100%
4. Discussion
This study demonstrates how the novel hydroxyapatite-citrate complex works better than HAP alone in treating dentin hypersensitivity. In vitro study shows that the HAP-citrate complex significantly enhances dentinal tubule occlusion. It leads to a higher tubule occlusion rate, substantially deeper intratubular mineral penetration and the formation of a thicker mineralized surface layer.
The lab findings provide direct support for the hypothesis that citrate acts as an active modulator of mineralization. Firstly, the multi-carboxylic structure of the citrate ions acts as smart anchors to chelate HAP particles[28], which may help HAP to bind more effectively to the dentine surface and tubule inner surface for targeted deposition. Thereafter, HAP triggers an active remineralization process, providing both crystal nuclei and a sustained supply of calcium and phosphate ions [14]. At this stage, citrate also works to stabilize the ACP precursors [22, 29], allowing a more fluid mineral phase to penetrate deeper into the tubules before solidifying.
This formulation offers a dual-action approach to managing hypersensitivity. The K+ from potassium citrate provide the effect of nerve desensitization, offering symptomatic relief by blocking pain signal transmission. At the same time, the HAP-citrate complex tackles the root cause of DH by building a long-lasting tubule occlusion and enhancing the biomimetic remineralization process. This combination of powerful in vitro occlusion and the dual therapeutic action explains the positive clinical results we observed.
In the clinical trial, the HAP-citrate toothpaste delivered significant relief from both air (Schiff) and tactile (Yeaple) stimuli compared to the placebo, with improvements seen as early as 6 weeks. The desensitizing effect of HAP-citrate toothpaste was comparable to the positive control, a commercial bioactive glass toothpaste, showing its strong clinical efficacy. There was an important finding during this clinical process: The reduction in air-stimulus sensitivity not only held steady across the 8-week study duration but, remarkably, persisted even after a 4-week period using a placebo fluoride toothpaste. This finding suggests that the deep, integrated seal created by the citrate-modulated mineralization is effective and long-lasting, solving the problem of tooth sensitivity from the root.
Although these results are highly encouraging, this study has limitations. A primary limitation is the lack of a HAP-only toothpaste as control group in the clinical trial. Future research can set a direct comparison of HAP-citrate and HAP to know the effect of citrate. Additionally, the precise molecular interactions at the citrate-HAP interface still need to be further explored.
This study combines in vitro and clinical research methods, presenting a promising new formulation for the treatment of dentin hypersensitivity. The hydroxyapatite-citrate toothpaste exhibits excellent tubule occlusion efficacy in vitro and effectively provides long-lasting relief from dentin hypersensitivity in the clinical trial. We speculate that citrate stabilizes the calcium phosphate clusters and liquid ACP precursors before nucleation, preventing them from prematurely converting into crystalline HAP, leading to the formation of a highly integrated and robust dentinal seal. It is this biomimetic, depth-percolating mechanism that accounts for the remarkable persistence of the clinical desensitizing effect, especially the sustained reduction of air-stimulus sensitivity observed in the four weeks placebo toothpaste period.
5. Conclusions
The synergistic combination of HAP and citrate effectively occludes dentinal tubules by forming a deep and dense mineralized layer. This principle provides a strong foundation for developing toothpastes that deliver both rapid and sustained clinical relief from dentin hypersensitivity, offering a safe and effective biomimetic treatment strategy.
Abbreviations
HAP
hydroxyapatite
DH
dentine hypersensitivity
Declarations
Ethics approval and consent to participate
For the in vitro portion of this study, bovine teeth were obtained from a commercial slaughterhouse. No animals were sacrificed specifically for this research. As the tissues were by-products of the food industry, formal ethical approval for animal use was not required. The clinical study was conducted at the School & Hospital of Stomatology Wuhan University and was approved by WUHAN University Institutional Review Board (IRB) ([2016] Ethics Review No. (01)).
Consent for publication
All involved subjects agreed to the publication
A
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
A
Competing Interests
Xiaobin Chen, Yanxiao Li, Yi Zhou, Decheng Ye are employees of Hawley & Hazel Chemical Co. (Zhongshan) Ltd. Han Jiang and Minquan Du declare that they have no competing interests.
A
Funding
This study was funded by Hawley & Hazel Chemical Co. (Zhongshan) Ltd.
A
Author Contribution
Xiaobin Chen and Han Jiang contributed equally to this work and are considered co-first authors. Xiaobin Chen and Minquan Du conceived and designed the study. HJ was responsible for the execution of the clinical trial and data collection. Yanxiao Li performed the in vitro experiments and SEM analysis. Yi Zhou and Decheng Ye participated in statistical analysis and clinical coordination. Xiaobin Chen drafted the manuscript, and Minquan Du provided revisions for important intellectual content. All authors read and approved the final manuscript.
Acknowledgements
We would like to thank all the participants of the clinical trial and the staff at the School & Hospital of Stomatology, Wuhan University.
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