Comparative Evaluation of Microneedling With Injectable PRF and Hyaluronic Acid for Papilla Reconstruction: A Randomized Clinical Trial
Phase: EARLY_PHASE1
Conditions: Papilla Reconstruction
Sponsor: King Abdulaziz University

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Cover Letter — Protocol Registration Submission (PRS)                Dec.09.2025 
Comparative Evaluation of Microneedling with Injectable PRF and Hyaluronic Acid for Papilla 
Reconstruction: A Randomized Clinical Trial 
 
This prospective, split-mouth, double-blind, randomized controlled clinical trial investigates two 
minimally invasive interventions—microneedling combined with injectable PRF (i-PRF) versus 
hyaluronic acid (HA) gel injections—for the management of Class I interdental papilla 
deficiency in adult patients. The primary aim is to assess and compare improvements in papillary 
height, width, and soft-tissue thickness during the 12-week follow-up period. 
The study will be conducted at the Department of Periodontology, Faculty of Dentistry, King 
Abdulaziz University, Jeddah, Saudi Arabia. Ethical approval was obtained from the Research 
and Ethics Committee (Reference No. 117-10-24). Written informed consent will be collected 
from all enrolled participants. The study adheres to institutional regulations and the Declaration 
of Helsinki (2013) regarding the protection of human subjects. 
We are registering this protocol in the PRS to ensure transparency, support the dissemination of 
scientifically valid results, and contribute to accessible clinical evidence, all while complying 
with global clinical research standards that prioritize patient safety. 
We appreciate your assistance with processing our registration, and we remain ready to provide 
any further materials or clarifications that may be required. 
Sincerely, 
Dr. Amal Ghazi Jamjoom, BDS, MSc 
Principal Investigator 
Department of Periodontology 
Faculty of Dentistry, King Abdulaziz University 
Jeddah, Saudi Arabia 
Email: agjamjoom@kau.edu.sa 
Phone: [+966-500190435] 
 

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Comparative Evaluation of Microneedling with Injectable 
PRF and Hyaluronic Acid for Papilla Reconstruction: A 
Randomized Clinical Trial  
 
Affiliations: 
1Department of Periodontology, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi 
Arabia 
2Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia 
Corresponding author: Amal Jamjoom, BDS, MS, DABP 
 
 

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Abstract 
Background: Loss of the interdental papilla represents a frequent aesthetic and functional 
challenge in dentistry. Traditional surgical procedures can partially restore papillary form but are 
limited by technical sensitivity, donor-site morbidity, and unpredictable long-term results. 
Consequently, interest has shifted toward minimally invasive, biologically driven strategies for 
papilla reconstruction. Among non-surgical options, hyaluronic acid (HA) injections and the 
injectable form of platelet-rich fibrin (iPRF) have shown considerable promise.  Combining 
microneedling (MN) enhances trans-mucosal delivery of the biologic agent and can boost 
regenerative outcomes. Despite promising results, direct comparisons between HA and MN + 
iPRF remain scarce. Therefore, this clinical trial aims to compare the clinical effectiveness of 
MN + iPRF vs. HA gel injection in the reconstruction of Class I interdental papilla loss.  
 
Methods: This study is conducted as a split-mouth, double-blind, randomized, controlled clinical 
trial to compare the efficacy of MN + iPRF vs. HA injections in the reconstruction of interdental 
papillae. Adult patients with more than one interdental papillary site that need reconstruction will 
be enrolled.  Each site will be randomly assigned to one of two treatment groups: Group MN + 
iPRF, and Group HA.  Clinical parameters measured at baseline, 6 weeks, and 12 weeks will 
include papillary height and papillary width at three levels (base, middle, and tip), and papillary 
thickness.   
 
 
Keywords: Papilla reconstructions, Hyaluronic acid, PRF, Microneedling, Gingiva, Plasma 
platelet-rich fibrin 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Introduction  
Mucogingival deformities, including gingival recession and loss of the interdental papilla, 
represent frequent aesthetic and functional challenges in periodontology[1, 2]. These conditions 
are classified under periodontal and peri-implant diseases according to the 2018 World Workshop 
classification[2]. They often result in root exposure, dentin hypersensitivity, plaque accumulation, 
and unaesthetic “black triangles” between teeth[1, 3]. The interdental papilla is a key anatomic 
structure occupying the gingival embrasure between adjacent teeth; its integrity supports 
periodontal health, prevents phonetic and food impaction problems, and contributes to smile 
harmony [4, 5]. When the papilla recedes or is lost, the resultant open gingival embrasure 
compromises both function and appearance. Kokich et al. [6] demonstrated that black triangles 
larger than 3 mm are perceived as unattractive by both clinicians and patients, reflecting the strong 
psychosocial and aesthetic impact of these defects. 
Nordland and Tarnow [5] proposed a simple classification system for the degree of papillary loss 
based on identifiable anatomical landmarks—the contact point, facial CEJ, and interproximal 
CEJ—facilitating clinical assessment and standardized outcome measurement. Traditional 
surgical procedures, including coronally advanced flaps, subepithelial connective tissue grafts, and 
tunneling techniques, can partially restore papillary form but are limited by technical sensitivity, 
donor-site morbidity, and unpredictable long-term results [7, 8]. Consequently, interest has shifted 
toward minimally invasive, biologically driven strategies for papilla reconstruction. 
Among non-surgical options, hyaluronic acid (HA) injections have shown considerable promise. 
HA is a natural glycosaminoglycan abundant in connective tissue and the extracellular matrix, with 
strong hygroscopic and viscoelastic properties that allow volumization and hydration of soft tissue. 

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It also promotes fibroblast proliferation, angiogenesis, and collagen synthesis, contributing to 
wound healing and tissue regeneration[9-11]. Several clinical studies have reported significant 
increases in papilla height and fill, and reductions in the black-triangle area after HA injection[12-
15]. Bal et al. [12] observed that combining HA with plasma rich in growth factors (PRGF) 
enhanced papillary regeneration more effectively than HA alone, emphasizing the potential of 
biologically active adjuncts to prolong HA’s regenerative effects. 
Platelet-rich fibrin (PRF), a second-generation autologous platelet concentrate, provides a 
reservoir of growth factors, including PDGF, VEGF, and TGF-β, that accelerate 
neovascularization and extracellular matrix formation. The injectable form (i-PRF) serves as a 
bioactive scaffold and gradually releases these factors, enhancing soft-tissue healing while 
minimizing immune reactions[16, 17]. 
Microneedling (MN), first introduced in dermatology as percutaneous collagen induction therapy, 
involves controlled micro-perforations that stimulate fibroblast activation, collagen deposition, 
and the release of endogenous growth factors[18, 19]. The technique enhances transmucosal 
delivery of biologic agents and can synergize with materials such as HA or PRF to boost 
regenerative outcomes. In a recent in-vivo study, Fan et al. [20]demonstrated that MN combined 
with HA gel significantly improved periodontal soft-tissue regeneration compared with HA alone. 
Similarly, clinical trials have shown that MN combined with platelet concentrates increases 
papillary height and gingival thickness, outperforming single-agent therapies[21-23]. 
Despite these promising results, direct comparisons between HA and MN + iPRF remain scarce. 
The biological synergy between mechanical collagen induction and autologous growth-factor 
delivery may provide a more durable and natural restoration of interdental papilla than passive 

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fillers alone. This approach could overcome HA's transient effects by stimulating intrinsic tissue 
remodeling and angiogenesis. 
Therefore, this randomized split-mouth clinical trial aims to compare the clinical effectiveness of 
MN combined with iPRF versus HA gel injection in the reconstruction of Class I interdental papilla 
loss. The study hypothesizes that MN + iPRF will yield greater papillary regeneration, offering a 
minimally invasive, biologically active alternative to traditional surgical approaches for soft-tissue 
esthetic rehabilitation. 
 
Materials and Methods  
This study will be a split-mouth, double-blind, randomized, controlled clinical trial comparing the 
efficacy of microneedling combined with injectable platelet-rich fibrin (i-PRF) versus hyaluronic acid 
(HA) injections in the reconstruction of interdental papillae. The study will be carried out at the 
Department of Periodontology, King Abdulaziz University Faculty of Dentistry (KAUFD), Jeddah, 
Saudi Arabia, between November 2025 and March 2026. Ethical approval was obtained from the 
Research and Ethics Committee of the Faculty of Dentistry, King Abdulaziz University (Approval #117-
10-24). Written informed consent will be obtained from all participants before enrollment. The trial 
adhered to CONSORT (2010) guidelines (Figure 1) and the Declaration of Helsinki (2013)[24].  
 The inclusion criteria are age between 18 and 45 years, Plaque index = 0[25], Gingival index = 0[26], 
Class I papillary loss (Nordland and Tarnow classification)[5], probing depth ≤4 mm at the test site, and 
interproximal bone crest distance ≤7 mm from the contact point. Exclusion criteria include pregnancy, 

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lactation, uncontrolled systemic diseases (e.g., diabetes), anticoagulant therapy, recent radiotherapy, 
orthodontic treatment, midline diastema, high frenum attachment, and Class II/III papillary loss.  
Adult patients with at least two interdental papillary sites will be enrolled. Each site will be randomly 
assigned to one of two treatment groups: Group MN + iPRF, which will receive microneedling with i-
PRF, and Group HA, which will receive hyaluronic acid injection (Juvéderm Ultra, Allergan). 
Randomization will be achieved using computer-generated random numbers and a sealed opaque 
envelope. The surgeon will draw one envelope to determine which treatment (MN + i-PRF or HA) will 
be applied to each site. The split-mouth design effectively controls for intrasubject variability, 
improving internal validity, while double-blinding minimizes experimenter and response biases. 
Patients will receive standardized oral hygiene instruction and supragingival prophylaxis 1 week before 
baseline measurement. The i-PRF will be prepared by drawing one tube of venous blood from the 
antecubital vein, placing it into anticoagulant-free Choukroun i-PRF 13 ml tubes, and centrifuging at 
700 rpm for 3 minutes using a Process for PRF centrifuge system (Choukroun PRF Duo Quattro 
Centrifuge). The freshly obtained i-PRF (0.2 mL) will be immediately injected into the papilla using a 
0.25 mm x 6 mm sterile insulin syringe (BD Microfine Plus), followed by microneedling with a sterile 
blood lancet to create microchannels (ACCU-CHEKⓇ). This will be performed at baseline and 3 weeks, 
with a standalone microneedling session (no i-PRF) at 1 week. The control site will receive 0.2 mL of 
HA gel, split into 0.1 mL at baseline and 0.1 mL at 3 weeks. All procedures will be performed under 
local anesthesia (2% Mepivacaine with 1:100,000 epinephrine). After the injection, patients will be 
advised to avoid mechanical plaque control in the treated area for the first 24 hours and to use a 0.2% 
chlorhexidine digluconate mouthwash twice daily. After the initial 24 hours, they will be instructed to 
resume gentle brushing with a soft toothbrush, combined with the mouthwash.  

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A blinded, calibrated examiner will perform all clinical assessments. All instruments will be calibrated, 
and measurement procedures will be standardized across all patients to ensure validity and reliability. At 
baseline, pocket depth, bone-to-contact distance, and gingival recession type will be recorded. Clinical 
parameters will be measured at baseline, 6 weeks, and 12 weeks included papillary height (from the 
mucogingival junction to the papilla tip), papillary width at three levels (base, middle, and tip) using a 
University of North Carolina (UNC-15) periodontal probe, and papillary thickness, which will be 
measured using an endodontic K-file size 10 with a silicone stop inserted perpendicularly into the soft 
tissue 2 mm apical to the midbuccal region[21]. Standardized intraoral photographs will be taken with a 
camera, using cheek retractors and occlusal mirrors under consistent lighting conditions. 
Statistical Analysis 
Descriptive statistics (mean ± standard deviation) summarize baseline and follow-up values (6 
weeks and 12 weeks) within each group. Longitudinal and between-groups comparisons will be 
analyzed using linear mixed-effects models. For each outcome, fixed effects will be group (MN + 
iPRF vs HA) and time (baseline, 6 weeks, 12 weeks), with their interaction; random effects will 
be specified as sites nested within subjects. Pairwise contrasts (inter-group differences at each time 
point and intra-group change over time from baseline) will be estimated from marginal means with 
false discovery rate (FDR) adjustment.  Analyses will be performed in R software version (4.5.1) 
within RStudio version (2025.05.1) [27]using the packages lme4, lmerTest, and emmeans.  The 
percent change from baseline to 6 and 12 weeks will be calculated for each clinical parameter, 
with values expressed as percentages relative to baseline, where positive values indicate increases 
and negative values indicate decreases. In addition, correlations among clinical parameters for 
each group will be assessed using the repeated-measures correlation (rmcorr) package, with results 

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reported as the repeated-measures correlation coefficient (rrm),[28].  P-values from (rmcorr) will 
be corrected with FDR. A p-value < 0.05 will be considered statistically significant. 
 
 
 
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