{"paper_id":"190f1aec-6cf0-4977-b523-2ea68ca16cfe","body_text":"Toward Opioid-Sparing Oral Surgery: Does Intra-Socket Delivery of a Biodegradable Extended-Release Bupivacaine Hydrogel Enhance Postoperative Analgesia After Impacted Mandibular Third Molar Surgery? | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Toward Opioid-Sparing Oral Surgery: Does Intra-Socket Delivery of a Biodegradable Extended-Release Bupivacaine Hydrogel Enhance Postoperative Analgesia After Impacted Mandibular Third Molar Surgery? Pejman Janbaz, Mahdieh Zarabadipour, Arash Mahboubi, Monirsadat Mirzadeh, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8937175/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 15 You are reading this latest preprint version Abstract Introduction and Aims: Postoperative pain after mandibular third molar extraction often leads to systemic NSAID or opioid use, risking adverse effects and overuse. This study aimed to develop and evaluate a degradable Bupivacaine/Carbopol hydrogel for sustained pain relief after third molar surgery. Methods: A single-center, double-blinded, split-mouth randomized clinical trial was conducted at the Qazvin University of Medical Sciences outpatient clinic. Sixteen adult patients (8 males, 8 females; mean age 24.3 ± 3.1 years) with bilaterally impacted mandibular third molars participated. Intra-socket injections of Bupivacaine/Carbopol hydrogel versus placebo were administered post-operatively. Pain intensity was self-reported on a 10-point visual analog scale (VAS) at 0, 2, 6, 12, 24, and 72 hours post-surgery; daily analgesic (NSAID/opioid) consumption was recorded for three days. Repeated-measures ANOVA using SPSS v24, with α = 0.05, was employed. Results: Significant main effects of time, group, and their interaction on VAS scores were observed (all P < 0.05). Except at 2 hours, the hydrogel group experienced significantly lower pain levels at 6, 12, 24, and 72 hours compared to the placebo. No significant differences in daily analgesic intake between groups over time were found (P > 0.05). Conclusions: The localized, degradable Bupivacaine/Carbopol hydrogel offers sustained postoperative pain relief and could decrease dependence on systemic painkillers in oral surgery. Larger clinical trials are necessary to confirm these findings and optimize the formulation. Trial Registration The study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17). Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Third molars, also known as wisdom teeth, are the most frequent impactions in the human jaw most of which occur in the mandible 1 . Impacted third molars can cause pain, and they have a high likelihood of damaging adjacent teeth, leading to issues such as root resorption and periodontal problems in the adjacent second molars. 2 , 3 Additionally, they can lead to the formation of odontogenic cysts, such as keratocyst odontogenic tumors and dentigerous cysts. 2 , 3 Pericoronitis, an infection causing pain and swelling in the impacted area, is another possible issue. 4 Surgery is recommended if the clinician anticipates any of these complications. 4 Third molar surgery can have a direct impact on people's lives, and although the negative effects are usually short-term and temporary, the treatment process can be unpleasant for the patient. 4 Post-surgery, patients may experience limitations in their diet, speech problems, swelling, inflammation, and pain. 5, 6 Pain following surgery can persist for up to three days and significantly affect the patient's daily life 7 . The most common method of controlling and reducing pain after surgery is through the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, diclofenac, and ketorolac. 8 These drugs play an effective role in reducing pain by inhibiting the cyclooxygenase cycle and the production of prostaglandins, which are the main causes of pain and inflammation. 9 However, there are some complications associated with this category of drugs. The most important side effects of these drugs are gastrointestinal problems, ulcers, and bleeding in the upper parts of the gastrointestinal tract, which can affect up to 25% of patients and sometimes remain asymptomatic for a long time 10 , 11 Efforts in recent years to reduce these side effects have led to changes in the mechanism of action of these drugs in order to design new drugs with the ability to exclusively inhibit COX-2, which has shown fewer digestive problems. However, these changes have also brought uncertainties about cardiovascular complications, which are still being investigated 12 , 13 Opioids and corticosteroids are the next choice for clinicians to reduce inflammation and pain. 8 , 14 Intramuscular dexamethasone post-surgical injection has shown significant results in combination with NSAIDs for pain relief and anti-inflammation. 8 Both of them have their complications. Opioids can cause drug abuse, and over-usage of them has led to a crisis in society, causing more costs and complications that can ultimately lead to death. 14 Steroids also suppress the adrenal system and can lead to a longer recovery due to their effects on the immune system. 15 Another method that can reduce first-stage pain after surgery is the injection of bupivacaine instead of other local anesthetics such as lidocaine. Due to its longer duration of effect and deeper anesthesia, bupivacaine can be more successful than lidocaine in controlling the amount of pain after surgery, and the patient suffers less pain after surgery. 16 – 18 Sometimes a second injection after surgery is suggested to control pain, which has been shown to not make much difference. 19 Liposomal Bupivacaine (LB) is another form of Bupivacaine that is made of multivesicular liposomes with DepoFoam technology and has recently been used in various surgeries, including orthopedics, for pain management because it provides greater stability and anesthesia. 20 Of course, there are different results in trials for this substance, which makes its use doubtful. In a study, it was shown that LB has a reducing effect on the prescription and consumption of opioids after third molar surgery, while in another review, it was concluded that this drug does not show much better pain control. 21 , 22 Also, irrigating the surgical site with Bupivacaine after extraction of the mandibular third molar has shown a positive effect in reducing pain after surgery. 23 Hydrogels, which have a high water content and polymer structure, are suitable for the continuous and local sustained release of drugs and therapeutic agents in specific locations. 24 – 26 Their ability to degrade without reaction makes them a valuable option. 26 , 27 There are several options available for use as a base for hydrogels. Carbopol 934 is a polymer with hydrophilic characteristics, making it a good choice for delivery systems due to its biodegradability, biocompatibility, and stability. It has -COOH groups, among other features, which is crucial as it impacts the swelling of the gel. it shows promise in medicinal carriers, particularly in controlled-release formulations. 27 , 28 In the present study, we aimed to formulate and evaluate the effect of sustained release of Bupivacaine/Carbopol hydrogel on pain after mandibular third molar surgery. Methods and Materials Study Design The current study is a single-center, double-blind, split-moth randomized clinical trial to compare the amount of pain after surgery and the use of painkillers after intra-socket insertion of bupivacaine/carbopol hydrogel and a placebo hydrogel. Patients referred to the Qazvin Dental Faculty outpatient clinic met the following criteria for participation in the clinical trial (Fig. 1 ). The inclusion criteria were having impacted the mesioangular mandibular third molar in classes B and C of the Pell and Gregory classification 7 , Not taking any opioids or NSAIDs continuously for the last 6 months, absence of any systemic disease, and no allergic history to bupivacaine or carbon-based materials. Patients who reported pain before surgery were excluded from the study. Due to the lack of a similar study, based on pilot samples, and considering a ten percent loss of sample volume, 16 samples were calculated for each group (Supplemental Fig. 1). Hydrogels used for the first surgery were allocated to two treatment groups, A and B, using the method of random blocks (balance block randomization); the size of each block was four, and the total number of blocks was four (Supplemental Table 1). Group A was selected as the bupivacaine/carbopol hydrogel, and Group B was chosen as the placebo. Before surgery, the patient’s tooth side was randomly selected using a coin. The participants were informed about the procedure, but they were not aware of the hydrogel used in each surgery. The syringes of the hydrogels were also packed and labeled as 1 and 2 by a person other than the authors, and they did not know which hydrogel was used in each surgery. Finally, the data were provided to the data analyst along with the details of each group. The study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17). Informed consent was obtained from patients who met the inclusion criteria. Data Collection The hydrogel was formulated using carbopol 934, distilled water, 96% ethanol, 0.1% glycerin, 0.04% NaOH, and 0.05% Bupivacaine HCL without epinephrine. The placebo was administered using the same method and materials, but without Bupivacaine HCL. The entire procedure was performed under anti-septic conditions by using sterile materials. After the manufacturing process, the hydrogel was poured into sterile insulin syringes and sterilized using UV radiation. All surgeries were performed by a single surgeon at the same location, using the same steps. The inferior alveolar nerve (IAN) block was administered directly using 3% prilocaine. A long buccal injection of 2% lidocaine was administered. After waiting for 10 min, a pocket-shaped flap was cut from the mesial aspect of the first molar on the buccal side to the beginning of the ramus. The flap was then gently separated from the bone by using a periosteal elevator. If necessary, the tooth was removed using an elevator after removing the bone around the tooth with a round bur and sectioning the tooth using a fissure bur. The socket was curetted and washed with normal saline, followed by the injection of 5 cc of hydrogel (Fig. 2 ). Finally, the tissue was sutured with a 3 − 0 polyglycolic acid (P.G.A) thread. The patient was prescribed Metronidazole 250 mg (1 tablet every 8 h, N = 10) and Amoxicillin 500 mg (1 tablet every 8 h, N = 20). They were also advised to take Ibuprofen 400 mg (with an interval of 8 h) or Acetaminophen 325 mg in case of pain. Self-reported pain of the patients at 2, 6, 12, 24, 48, and 72 hours and the number of painkillers that they used each day for up to 3 days were the outcomes of the present study. Data were collected using a questionnaire designed with a visual analog scale (VAS) for each time point. The VAS consisted of a 10 cm vertical line with \"no Pain\" at the bottom and \"intolerable pain\" at the top. The questionnaire also included a section that recorded the total number of painkillers (ibuprofen and acetaminophen were administered daily). After surgery, the patients were given a questionnaire with instructions on how to fill it out. One week after surgery, a follow-up was conducted, and completed questionnaires were collected. The pain level on the VAS was determined using a ruler to obtain an exact measurement. Data Analysis Data were entered into the computer using SPSS 24 software. Descriptive results were calculated by calculating the frequency, mean, and standard deviation based on the type of variable and were analyzed using an independent t-test to compare the amount of pain and the amount of painkiller consumption between the two groups or its parametric equivalent. A significance level of less than 0.05 was considered. Repeated measurements of analysis of variance (ANOVA) were used to determine the relationships between time and group. Results Sixteen patients who met the inclusion criteria were enrolled in this trial. Of these, 7 were men (44%) and 9 were women (56%). Their ages ranged from 20 to 26 years, with an average age of 23.21. Based on the results of the repeated-measures ANOVA (Table 1 ), the mean reported pain among the patients was significantly different over time and between the groups (P < 0.05). The pattern of pain over time also differed across the groups (P < 0.05). The Bupivacaine/Carbopol group also reported lower pain at all time points (Fig. 3 ). In the first 2 hours, there was no significant difference in pain levels between the groups (P = 0.814). However, at later time points, the Bupivacaine/Carbopol group experienced significantly lower levels of pain (P < 0.05)(Table 2 ). Table 1 Statistical analysis of the effect of each hydrogel on pain in 72 hours post-surgery Time Bupivacaine/ Carbopol Mean ± SD Placebo Mean ± SD Statistical Results Effect F P Partial ƞ 2 2 hours 4.45 ± 2.52 4.70 ± 3.01 Time 26.95 0.01 0.509 6 hours 3.90 ± 2.72 7.17 ± 1.97 12 hours 3.70 ± 2.36 7.04 ± 1.87 Group 18.46 0.01 0.415 24 hours 2.94 ± 2.11 5.38 ± 1.64 48 hours 2.63 ± 1.68 4.01 ± 1.70 Time - Group 4.25 0.01 0.141 72 hours 1.62 ± 0.73 2.32 ± 1.63 Table 2 Independent t-test for pain (VAS) between groups at each time 2 hours F P t df Mean SD 0.28 0.814 0.23 26 2.25 1.049 6 hours 6.36 0.001 3.64 26 3.27 0.89 12 hours 2.31 0.001 4.14 26 3.33 0.80 24 hours 4.43 0.001 4.81 26 3.44 0.71 48 hours 0.04 0.001 3.71 26 2.37 0.64 72 hours 3.10 0.001 3.55 26 1.70 0.47 There was a significant effect of time on painkiller consumption (P < 0.05), but no significant difference between the two groups (P = 0.423), and the time-group effect was also not significant (P = 0.848) (Table 3 ), indicating that the pattern of painkiller consumption over time did not differ across groups, although it was lower in the Bupivacaine/Carbopol group on all three days (Fig. 4 ). Additionally, the number of painkillers used at each time point did not differ significantly between the groups (P = 0.774, 0.452, and 0.389) (Table 4 ). Table 3 Statistical analysis of the effect of each hydrogel on painkiller consumption in 72 hours post-surgery Time Bupivacaine/ Carbopol Mean ± SD Placebo Mean ± SD Statistical Results Effect F P Partial ƞ 2 24 hours 2.28 ± 0.91 2.42 ± 1.60 Time 5.11 0.009 0.164 48 hours 2.92 ± 1.26 3.28 ± 1.20 Group 0.663 0.423 0.025 72 hours 2.21 ± 1.31 2.64 ± 1.27 Time- Group 0.165 0.848 0.006 Table 4 Independent t-test for painkiller consumption between groups at each time 24 hours F P t df Mean SD 1.31 0.774 0.29 26 1.14 0.49 48 hours 0.15 0.452 0.76 26 1.35 0.46 72 hours 0.21 0.389 0.87 26 1.42 0.48 Discussion Hydrogels offer a promising method for drug delivery by localizing the effects of drugs and targeting specific sites. 26 Researchers are exploring their use as scaffolds, adhesive materials, dressings, and biosensors. 26 , 29 To ensure effective performance and stability at the application site, hydrogels must possess specific physical, chemical, and biocompatible properties. Their high water content allows for better integration with the site and reduces the immune response. 30 Solubility and pH are critical factors to ensure gradual degradation over time without triggering an immune response or causing damage to surrounding tissues. 25 Hydrogels can be made from various materials, including natural polymers such as chitosan, hyaluronic acid, gelatin, collagen, and alginate. 31 Some hydrogels made from these polymers have shown therapeutic and anti-inflammatory properties, making them suitable for wound dressing and healing applications. 26 , 31 However, the cost and specific physicochemical limitations remain among the disadvantages. 32 Some hydrogels use synthetic materials such as polyglycolic acid (PGA), polyvinyl alcohol (PVA), and polyhydroxy ethyl methacrylate (PHEMA). 32 Polyacrylic acid, also known as carbopol, is used as a thickener and rheology modifier in the pharmaceutical and food industries. 27 , 33 Studies have often focused on wound healing and dressings using carbopol-based hydrogels for drug delivery. 34 – 36 New research areas, such as ocular, mucosal-oral, and nasal-brain applications, are also being investigated and evaluated. 37 – 39 The null hypothesis of present study, which suggested no significant relationship between the use of bupivacaine-based hydrogel (carbopol) and pain after wisdom tooth surgery, was not confirmed. This study is the first to report the clinical application of bupivacaine/carbopol hydrogel intra-socket injection for long-term release at the surgical site. The results indicated a decrease in the number of painkillers consumed by patients; however, the difference between the intervention and control groups was not statistically significant. Normally, patients use 2–3 painkillers per day as a preventive measure to avoid unbearable pain at the onset of discomfort, which could be a confounding factor. The visual analog scale (VAS) showed that the peak of pain occurred between 6 and 12 hours after surgery, and the increased use of painkillers on the second day was in response to this pain, with some patients taking 5–6 painkillers. The total VAS scores of the intervention group were lower, and the hydrogel had the greatest effect between 6 and 72 hours, leading to a reduction in pain compared to the control group. Numerous studies have been conducted on the use of hydrogels in oral and dental medicine, showing promising results in the areas of oral dressings, drug carriers, and tissue engineering. Hydrogels have been investigated as local drug carriers for the treatment of periodontitis 40 – 42 , TMJ osteoarthritis 43 , 44 and alveolar osteitis (Dry Socket) 45 – 49 . Various drugs such as antibiotics (e.g., metronidazole 42 , 45 , doxycycline 41 and azithromycin 40 ) and other medications (e.g., NSAIDs 44 , 47 , tranexamic acid 46 , lidocaine 45 , 48 , 49 ) have been studied in hydrogel systems based on chitosan 47 , 48 , hyaluronic acid 44 , alginate 46 and poloxamer 40 , 49 . These studies have shown significant results regarding drug effects, release, and the chemical properties of the designed hydrogels, including biocompatibility, rheological properties, absorption, and release. Studies on alveolar steatitis have been similar to present study in terms of the target site. One of the important aspects of a socket is that it does not react as a foreign body, and its absorption and decomposition occur in a short period of time. Supachawaroj et al. in the evaluation of lidocaine hydrogel based on poloxamer expressed positive laboratory results in long-term release and degradability and adhesion and anesthesia effect. 49 Nowak et al. also stated that meloxicam hydrogel based on chitosan showed low cytotoxicity and It does not stimulate the immune system and does not stimulate local inflammation. 47 Bender et al.'s study on hydrogel metronidazole and lidocaine based on Carbopol 934 and Pluronic F-127 in the socket of the extracted tooth also showed a release of more than 24 hours in laboratory tests. It has shown little cytotoxicity and it has the ability to spread and penetrate into silent tissue layers uniformly. 45 Unlike previous studies, present study was conducted as the first phase of a clinical trial, showing good decomposition after two weeks and no signs of inflammation or reactivity. Studies also have been conducted on bupivacaine using different carriers both in vitro and in vivo. Davis et al.'s study involved bupivacaine emulsions in a cross-linked hydrogel, finding that 80 to 100% of the substance is released after 20 to 68 hours, thus enhancing the local anesthetic effect of bupivacaine. 50 Similarly, a study on heat-sensitive graphene oxide/chitosan-based injectable nanocomposite hydrogel reported 55% and 86.43% drug release after 6 and 24 h, respectively. 51 Furthermore, a study on Chitosan-based topical hydrogel of bupivacaine showed that significant local anesthesia without side effects occurred after 15 minutes, providing an alternative to previous methods in dentistry. 52 Another study on a gelatin hydrogel in vitro demonstrated a 72-hour release of bupivacaine ex vivo in the spinal cord. 53 Finally, Sheperd et al. showed in their study on polylactic co-glycolic acid (PLGA) microparticles containing bupivacaine that this drug is more efficient in the first 24 hours 54 . The current study showed the release of the drug and its effect within the first 72 hours. This study is among the first to clinically assess bupivacaine/carbopol hydrogel in third molar surgery. The use of the split-mouth method was an advantage, but the study had limitations such as the small number of patients and the need for additional lab tests, making future studies necessary. Conclusions The importance of selective and localized treatments is now evident. A higher concentration of the drug at a specific site resulted in fewer adverse effects and a faster curing process for the patient. Hydrogels have opened up a wide field of research, allowing us to benefit from localized, extensive, and controlled treatments. The Bupivacaine/Carbopol hydrogel that we developed provides longer pain relief after surgery, which can be beneficial when used alongside other types of medicines and treatments in dentistry. However, further studies are needed to improve these methods. Declarations Ethics approval and consent to participate The study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17). Informed consent was obtained from patients who met the inclusion criteria. Consent for Publication Informed consent was obtained from the patient whose image is used in this article. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution PJ, MZ, and EK contributed substantially to the conceptual design of the study. MM was responsible for data acquisition, analysis, and interpretation. AM developed and formulated the hydrogel. PJ and EK developed the software utilized in this work. MZ and EK drafted the manuscript and critically revised it for important intellectual content. All authors read and approved the final version of the manuscript. Acknowledgement This study was supported by the Vice Chancellor for Research and Technology at Qazvin University of Medical Sciences. The authors sincerely appreciate the officials and staff of the Faculty of Dentistry at Qazvin University of Medical Sciences and the Pharmaceutics Laboratory at Shahid Beheshti University of Medical Sciences for their valuable assistance. The authors also extend their gratitude to Dr. Moein Diarjani, faculty member of Oral and Maxillofacial Surgery at Qazvin University of Medical Sciences, as well as to all individuals who contributed to the successful completion of this study. Data Availability The data that support the findings of this study are available from the corresponding author, EK, upon request. [ [email protected] ](mailto: [email protected] ) References Shaari RB, Nawi MAA, Khaleel AK, AlRifai AS. Prevalence and pattern of third molars impaction: A retrospective radiographic study. J Adv Pharm Tech Res. 2023;14(1):46–50. Carter K, Worthington S. Predictors of third molar impaction: a systematic review and meta-analysis. J Dent Res. 2016;95(3):267–76. Fayad JB, Levy JC, Yazbeck C, Cavezian R, Cabanis E-A. Eruption of third molars: relationship to inclination of adjacent molars. Am J Orthod Dentofac Orthop. 2004;125(2):200–2. Caymaz MG, Buhara O. Association of Oral Hygiene and Periodontal Health with Third Molar Pericoronitis: A Cross-Sectional Study. Biomed Res Int. 2021;2021(1):6664434. Lago-Méndez L, Diniz-Freitas M, Senra-Rivera C, Gude-Sampedro F, Rey JMG, García-García A. Relationships between surgical difficulty and postoperative pain in lower third molar extractions. J Oral Maxillofac Surg. 2007;65(5):979–83. Snyder M, Shugars DA, White RP Jr, Phillips C. Pain medication as an indicator of interference with lifestyle and oral function during recovery after third molar surgery. J Oral Maxillofac Surg. 2005;63(8):1130–7. Hupp JR, Tucker MR, Ellis E. Contemporary Oral and Maxillofacial Surgery-E-Book: Contemporary Oral and Maxillofacial Surgery-E-Book. Seventh ed: Elsevier health sciences; 2013. Akinbade AO, Ndukwe KC, Owotade FJ. Comparative analgesic effects of ibuprofen, celecoxib and tramadol after third molar surgery: a randomized double blind controlled trial. J Contemp Dent Pract. 2018;19(11):1334–40. Sharma V, Mamontov E, Tyagi M. Effects of NSAIDs on the nanoscopic dynamics of lipid membrane. Biochim et Biophys Acta (BBA)-Biomembranes. 2020;1862(2):183100. Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them. Drug Saf. 2006;29(2):119–32. Solomon DH. Nonselective NSAIDs: Overview of adverse effects. UpToDate [internet] UpToDate Inc[updated 0303 2020, cited 0303 2021] Available from: https://www uptodate com. 2020. Marsico F, Paolillo S, Filardi PP. NSAIDs and cardiovascular risk. J Cardiovasc Med. 2017;18:e40–3. Mizushima T. Strategy for development of NSAIDs with lower risk for side effects. Yakugaku zasshi: J Pharm Soc Japan. 2008;128(2):255–61. Han JT, Susarla SM, Dodson TB, Lang MS. Are oral and maxillofacial surgeons prescribing fewer opioids and more non-narcotic analgesics for postoperative pain after third molar removal? J Oral Maxillofac Surg. 2020;78(3):358–65. Rubaia’an B, Alotaibi MA, Alotaibi MK, Alqhtani NM. Cortisol in Oral and Maxillofacial Surgery: A Double-Edged Sword. Int J Dent. 2021;2021(1):7642875. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology. 1985;62(4):396–405. Su N, Wang H, Zhang S, Liao S, Yang S, Huang Y. Efficacy and safety of bupivacaine versus lidocaine in dental treatments: a meta-analysis of randomised controlled trials. Int Dent J. 2014;64(1):34–45. Velioglu O, Calis AS, Koca H, Velioglu E. Bupivacaine vs. lidocaine: a comparison of local anesthetic efficacy in impacted third molar surgery. Clin Oral Invest. 2020;24(10):3539–46. de Souza AMM, Horliana ACRT, Simone JL, Jorge WA, Tortamano IP. Postoperative pain after bupivacaine supplementation in mandibular third molar surgery: splint-mouth randomized double blind controlled clinical trial. Oral maxillofacial Surg. 2014;18(4):387–91. Gangwani P. Evolving Role of Liposomal Bupivacaine in Managing Post-Surgical Analgesia in Oral Surgery. Res Rep Oral Maxillofac Surg. 2019;3:026. Lieblich SE, Misiek D, Olczak J, Fleck H, Waterman F. A Retrospective Cross-Sectional Study of the Effect of Liposomal Bupivacaine on Postoperative Opioid Prescribing After Third Molar Extraction. J Oral Maxillofac Surg. 2021. Ji YD, Harris JA, Gibson LE, McKinley SK, Phitayakorn R. The Efficacy of Liposomal Bupivacaine for Opioid and Pain Reduction: A Systematic Review of Randomized Clinical Trials. J Surg Res. 2021;264:510–33. Khiavi RK, Pourallahverdi M, Pourallahverdi A, Khiavi SG, Oskouei SG, Mokhtari H. Pain control following impacted third molar surgery with bupivacaine irrigation of tooth socket: a prospective study. J Dent Res Dent Clin Dent prospects. 2010;4(4):105. Rizzo F, Kehr NS. Recent advances in injectable hydrogels for controlled and local drug delivery. Adv Healthc Mater. 2021;10(1):2001341. Koehler KC, Anseth KS, Bowman CN. Diels–Alder mediated controlled release from a poly (ethylene glycol) based hydrogel. Biomacromolecules. 2013;14(2):538–47. Thang NH, Chien TB, Cuong DX. Polymer-based hydrogels applied in drug delivery: An overview. Gels. 2023;9(7):523. Mahmood A, Mahmood A, Ibrahim MA, Hussain Z, Ashraf MU, Salem-Bekhit MM, et al. Development and evaluation of sodium alginate/carbopol 934P-Co-poly (methacrylate) hydrogels for localized drug delivery. Polymers. 2023;15(2):311. Suhail M, Wu P-C, Minhas MU. Using carbomer-based hydrogels for control the release rate of diclofenac sodium: Preparation and in vitro evaluation. Pharmaceuticals. 2020;13(11):399. Liu L, Wu D, Tu H, Cao M, Li M, Peng L, et al. Applications of hydrogels in drug delivery for oral and maxillofacial diseases. Gels. 2023;9(2):146. Fraser D, Nguyen T, Kotelsky A, Lee W, Buckley M, Benoit DS. Hydrogel swelling-mediated strain induces cell alignment at dentin interfaces. ACS Biomaterials Sci Eng. 2022;8(8):3568–75. Samiraninezhad N, Asadi K, Rezazadeh H, Gholami A. Using chitosan, hyaluronic acid, alginate, and gelatin-based smart biological hydrogels for drug delivery in oral mucosal lesions: A review. Int J Biol Macromol. 2023:126573. Ghasemiyeh P, Mohammadi-Samani S. Hydrogels as drug delivery systems; pros and cons. Trends Pharm Sci. 2019;5(1):7–24. Barry B, Meyer M. The rheological properties of carbopol gels I. Continuous shear and creep properties of carbopol gels. Int J Pharm. 1979;2(1):1–25. Gavan A, Colobatiu L, Hanganu D, Bogdan C, Olah NK, Achim M, et al. Development and evaluation of hydrogel wound dressings loaded with herbal extracts. Processes. 2022;10(2):242. Sanchez MF, Breda SA, Soria EA, Tártara LI, Manzo RH, Olivera ME. Ciprofloxacin-lidocaine-based hydrogel: development, characterization, and in vivo evaluation in a second-degree burn model. Drug delivery translational Res. 2018;8:1000–13. Wang D, Jin J, Zhang C, Ruan C, Qin Y, Li D, et al. Carbomer Hydrogel Composed of Cu2O and Hematoporphyrin Monomethyl Ether Promotes the Healing of Infected Wounds. ACS omega. 2024;9(4):4974–85. Bandiera G, Talamonti R, Piccolino G, Micaloni A, Raffa S. Evaluation of in vivo adhesiveness of hyaluronic acid combined with xanthan gum and carbomer [Karos® throat lozenges] to the oral cavity mucosa in human healthy subjects: a pilot study. 2019. Mahajan HS, Patil PH. Gel-based delivery of neurotherapeutics via naso-brain pathways. Direct Nose-to-Brain Drug Delivery: Elsevier; 2021. pp. 225–45. Rahbar N, Darvish S, Farrahi F, Kouchak M. Chitosan/carbomer nanoparticles-laden in situ gel for improved ocular delivery of timolol: in vitro, in vivo, and ex vivo study. Drug Delivery Translational Res. 2024:1–11. Kerdmanee K, Phaechamud T, Limsitthichaikoon S. Thermoresponsive azithromycin-loaded niosome gel based on poloxamer 407 and hyaluronic interactions for periodontitis treatment. Pharmaceutics. 2022;14(10):2032. Wang B, Booij-Vrieling HE, Bronkhorst EM, Shao J, Kouwer PH, Jansen JA, et al. Antimicrobial and anti-inflammatory thermo-reversible hydrogel for periodontal delivery. Acta Biomater. 2020;116:259–67. Zussman M, Zilberman M. Injectable metronidazole-eluting gelatin-alginate hydrogels for local treatment of periodontitis. J Biomater Appl. 2022;37(1):166–79. DeJulius CR, Gulati S, Hasty KA, Crofford LJ, Duvall CL. Recent Advances in Clinical Translation of Intra-Articular Osteoarthritis Drug Delivery Systems. Adv Ther. 2021;4(1):2000088. Jung Y-s, Park W, Park H, Lee D-K, Na K. Thermo-sensitive injectable hydrogel based on the physical mixing of hyaluronic acid and Pluronic F-127 for sustained NSAID delivery. Carbohydr Polym. 2017;156:403–8. Bender L, Boostrom HM, Varricchio C, Zuanon M, Celiksoy V, Sloan A, et al. A novel dual action monolithic thermosetting hydrogel loaded with lidocaine and metronidazole as a potential treatment for alveolar osteitis. Eur J Pharm Biopharm. 2020;149:85–94. El Halawany M, Latif R, AbouGhaly MH. Hemostatic Alginate/Nano-Hydroxyapatite Composite Aerogel Loaded with Tranexamic Acid for the Potential Protection against Alveolar Osteitis. Pharmaceutics. 2022;14(10):2255. Nowak KM, Bodek KH, Szterk A, Rudnicka K, Szymborski T, Kosieradzki M, et al. Preclinical assessment of the potential of a 3D chitosan drug delivery system with sodium meloxicam for treating complications following tooth extraction. Int J Biol Macromol. 2019;133:1019–28. Supachawaroj N, Damrongrungruang T, Limsitthichaikoon S. Formulation development and evaluation of lidocaine hydrochloride loaded in chitosan-pectin-hyaluronic acid polyelectrolyte complex for dry socket treatment. Saudi Pharm J. 2021;29(9):1070–81. Supachawaroj N, Limsitthichaikoon S. Lidocaine HCl-Loaded Polyelectrolyte Complex-Poloxamer Thermoresponsive Hydrogel: In Vitro-In Vivo Anesthetic Evaluations for Tooth Socket Wound Delivery. AAPS PharmSciTech. 2024;25(6):182. Davis B, Erickson S, Wojtalewicz S, Simpson A, Metcalf C, Sant H, et al. Entrapping bupivacaine-loaded emulsions in a crosslinked-hydrogel increases anesthetic effect and duration in a rat sciatic nerve block model. Int J Pharm. 2020;588:119703. Eltahir S, Jagal J, Abdelkareem MA, Ghoneim MM, Rawas-Qalaji MM, Greish K, et al. Thermosensitive injectable graphene oxide/chitosan-based nanocomposite hydrogels for controlling the in vivo release of bupivacaine hydrochloride. Int J Pharm. 2022;621:121786. Mihalache C, Rata DM, Cadinoiu AN, Patras X, Sindilar EV, Bacaita SE, et al. Bupivacaine-loaded chitosan hydrogels for topical anesthesia in dentistry. Polym Int. 2020;69(11):1152–60. Steverink JG, van Tol FR, Oosterman BJ, Vermonden T, Verlaan J-J, Malda J, et al. Robust gelatin hydrogels for local sustained release of bupivacaine following spinal surgery. Acta Biomater. 2022;146:145–58. Shepherd SD, O’Buckley SC, Harrington JM, Haines LG, Rothrock GD, Johnson LM, et al. A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain. Sci Rep. 2018;8(1):12172. Additional Declarations No competing interests reported. Supplementary Files Supplement.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 13 Apr, 2026 Reviews received at journal 08 Apr, 2026 Reviews received at journal 04 Apr, 2026 Reviewers agreed at journal 04 Apr, 2026 Reviewers agreed at journal 01 Apr, 2026 Reviews received at journal 31 Mar, 2026 Reviewers agreed at journal 30 Mar, 2026 Reviews received at journal 19 Mar, 2026 Reviews received at journal 18 Mar, 2026 Reviewers agreed at journal 11 Mar, 2026 Reviewers agreed at journal 09 Mar, 2026 Reviewers invited by journal 09 Mar, 2026 Editor assigned by journal 02 Mar, 2026 Submission checks completed at journal 27 Feb, 2026 First submitted to journal 27 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-8937175\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":604632662,\"identity\":\"062a1158-2481-4829-bab2-b03261e7debf\",\"order_by\":0,\"name\":\"Pejman Janbaz\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Qazvin University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Pejman\",\"middleName\":\"\",\"lastName\":\"Janbaz\",\"suffix\":\"\"},{\"id\":604632665,\"identity\":\"26d2f232-d926-4fd4-8267-e1e8f044acfc\",\"order_by\":1,\"name\":\"Mahdieh Zarabadipour\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Qazvin University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mahdieh\",\"middleName\":\"\",\"lastName\":\"Zarabadipour\",\"suffix\":\"\"},{\"id\":604632666,\"identity\":\"9e6efdaa-203f-4953-bb86-b7506e8c6e5a\",\"order_by\":2,\"name\":\"Arash Mahboubi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shahid Beheshti University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Arash\",\"middleName\":\"\",\"lastName\":\"Mahboubi\",\"suffix\":\"\"},{\"id\":604632668,\"identity\":\"735244d4-c59a-4b97-afaa-cfdcfef605f1\",\"order_by\":3,\"name\":\"Monirsadat Mirzadeh\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Qazvin University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Monirsadat\",\"middleName\":\"\",\"lastName\":\"Mirzadeh\",\"suffix\":\"\"},{\"id\":604632671,\"identity\":\"b28d43c2-8477-436c-a581-867e9612f95f\",\"order_by\":4,\"name\":\"Erfan Khorasani\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBElEQVRIiWNgGAWjYFACxgdAIiEBypOQY2DgIaSF2QBFizHJWhgSGwhp4Zc+zPi5gCEtD8h4/OHnDov0DcfPHnzwgcFOTrcBuxbJvmRm6RkMOcWSfWlmkr1nJHI3nMlLNpzBkGxsdgC7FoMz/AekeRgqEjecYTBj4G0DajmQYwYUOZC4DYcW+zPMzL8hWtg/f/zbJpFucP4Nfi0GPMxsQAU5QC08BtJAWxIMbhCwReIMM5s1D0Na4swenjJp2TYJw5k33hgbzjDA7Rf+Hmbm2zwMyYn9POybP75tq5PnO59j+OBDhZ0cLi1gwPgPiaMAVmmARzkGkG8gRfUoGAWjYBSMBAAAhwpV21/dGDAAAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Qazvin University of Medical Sciences\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Erfan\",\"middleName\":\"\",\"lastName\":\"Khorasani\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-02-22 06:08:14\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-8937175/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-8937175/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":104554669,\"identity\":\"947b3706-4f1b-49f0-9085-0b585c04dd20\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:57:36\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":117713,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eConsort 2010 flow diagram\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/62ea7d30618d74ba67a81053.jpg\"},{\"id\":104554679,\"identity\":\"d6f2bca8-5c6b-4c04-aaed-dac35c49d089\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:57:42\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":123037,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHydrogel injection into the socket before the suturing step\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/9ec084d46d8921c6ffdf091c.jpg\"},{\"id\":104554775,\"identity\":\"9008968c-832d-4da9-93d6-bf8e103e0851\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:58:03\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":74321,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePain in 72 hours post-surgery\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/b5df3c09eec2dfb343b7dd05.jpg\"},{\"id\":104554741,\"identity\":\"8f7527af-9c99-48aa-a904-544cb2cc20b7\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:58:01\",\"extension\":\"jpg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":80791,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePainkiller consumption in 72 hours post-surgery in each group\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/ba0624a9536ea1c1f317a97d.jpg\"},{\"id\":104554856,\"identity\":\"1ef64341-8812-405d-b8e0-427f1560e9cd\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:58:14\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1130646,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/f08305c9-5887-4108-90b2-52650aa32ffb.pdf\"},{\"id\":104554682,\"identity\":\"eeeb3c7f-571f-4a98-a5a1-6f4eadcd34cf\",\"added_by\":\"auto\",\"created_at\":\"2026-03-13 08:57:43\",\"extension\":\"docx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":19366,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplement.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8937175/v1/82d08e6bb499a33936fae359.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Toward Opioid-Sparing Oral Surgery: Does Intra-Socket Delivery of a Biodegradable Extended-Release Bupivacaine Hydrogel Enhance Postoperative Analgesia After Impacted Mandibular Third Molar Surgery?\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eThird molars, also known as wisdom teeth, are the most frequent impactions in the human jaw most of which occur in the mandible\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e. Impacted third molars can cause pain, and they have a high likelihood of damaging adjacent teeth, leading to issues such as root resorption and periodontal problems in the adjacent second molars.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e Additionally, they can lead to the formation of odontogenic cysts, such as keratocyst odontogenic tumors and dentigerous cysts.\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003ePericoronitis, an infection causing pain and swelling in the impacted area, is another possible issue.\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e Surgery is recommended if the clinician anticipates any of these complications.\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e Third molar surgery can have a direct impact on people's lives, and although the negative effects are usually short-term and temporary, the treatment process can be unpleasant for the patient.\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e Post-surgery, patients may experience limitations in their diet, speech problems, swelling, inflammation, and pain. \\u003csup\\u003e5, 6\\u003c/sup\\u003e Pain following surgery can persist for up to three days and significantly affect the patient's daily life\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e.\\u003c/p\\u003e \\u003cp\\u003eThe most common method of controlling and reducing pain after surgery is through the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, diclofenac, and ketorolac.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e These drugs play an effective role in reducing pain by inhibiting the cyclooxygenase cycle and the production of prostaglandins, which are the main causes of pain and inflammation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e However, there are some complications associated with this category of drugs. The most important side effects of these drugs are gastrointestinal problems, ulcers, and bleeding in the upper parts of the gastrointestinal tract, which can affect up to 25% of patients and sometimes remain asymptomatic for a long time\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e Efforts in recent years to reduce these side effects have led to changes in the mechanism of action of these drugs in order to design new drugs with the ability to exclusively inhibit COX-2, which has shown fewer digestive problems. However, these changes have also brought uncertainties about cardiovascular complications, which are still being investigated\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e Opioids and corticosteroids are the next choice for clinicians to reduce inflammation and pain.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e Intramuscular dexamethasone post-surgical injection has shown significant results in combination with NSAIDs for pain relief and anti-inflammation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e Both of them have their complications. Opioids can cause drug abuse, and over-usage of them has led to a crisis in society, causing more costs and complications that can ultimately lead to death.\\u003csup\\u003e\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e Steroids also suppress the adrenal system and can lead to a longer recovery due to their effects on the immune system.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eAnother method that can reduce first-stage pain after surgery is the injection of bupivacaine instead of other local anesthetics such as lidocaine. Due to its longer duration of effect and deeper anesthesia, bupivacaine can be more successful than lidocaine in controlling the amount of pain after surgery, and the patient suffers less pain after surgery.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR17\\\" citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e Sometimes a second injection after surgery is suggested to control pain, which has been shown to not make much difference.\\u003csup\\u003e\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u003c/sup\\u003e Liposomal Bupivacaine (LB) is another form of Bupivacaine that is made of multivesicular liposomes with DepoFoam technology and has recently been used in various surgeries, including orthopedics, for pain management because it provides greater stability and anesthesia.\\u003csup\\u003e\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e Of course, there are different results in trials for this substance, which makes its use doubtful. In a study, it was shown that LB has a reducing effect on the prescription and consumption of opioids after third molar surgery, while in another review, it was concluded that this drug does not show much better pain control.\\u003csup\\u003e\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e Also, irrigating the surgical site with Bupivacaine after extraction of the mandibular third molar has shown a positive effect in reducing pain after surgery.\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eHydrogels, which have a high water content and polymer structure, are suitable for the continuous and local sustained release of drugs and therapeutic agents in specific locations.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR25\\\" citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e Their ability to degrade without reaction makes them a valuable option.\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e There are several options available for use as a base for hydrogels. Carbopol 934 is a polymer with hydrophilic characteristics, making it a good choice for delivery systems due to its biodegradability, biocompatibility, and stability. It has -COOH groups, among other features, which is crucial as it impacts the swelling of the gel. it shows promise in medicinal carriers, particularly in controlled-release formulations.\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eIn the present study, we aimed to formulate and evaluate the effect of sustained release of Bupivacaine/Carbopol hydrogel on pain after mandibular third molar surgery.\\u003c/p\\u003e\"},{\"header\":\"Methods and Materials\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy Design\\u003c/h2\\u003e \\u003cp\\u003eThe current study is a single-center, double-blind, split-moth randomized clinical trial to compare the amount of pain after surgery and the use of painkillers after intra-socket insertion of bupivacaine/carbopol hydrogel and a placebo hydrogel. Patients referred to the Qazvin Dental Faculty outpatient clinic met the following criteria for participation in the clinical trial (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The inclusion criteria were having impacted the mesioangular mandibular third molar in classes B and C of the Pell and Gregory classification\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e, Not taking any opioids or NSAIDs continuously for the last 6 months, absence of any systemic disease, and no allergic history to bupivacaine or carbon-based materials. Patients who reported pain before surgery were excluded from the study.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eDue to the lack of a similar study, based on pilot samples, and considering a ten percent loss of sample volume, 16 samples were calculated for each group (Supplemental Fig.\\u0026nbsp;1).\\u003c/p\\u003e \\u003cp\\u003eHydrogels used for the first surgery were allocated to two treatment groups, A and B, using the method of random blocks (balance block randomization); the size of each block was four, and the total number of blocks was four (Supplemental Table\\u0026nbsp;1). Group A was selected as the bupivacaine/carbopol hydrogel, and Group B was chosen as the placebo. Before surgery, the patient\\u0026rsquo;s tooth side was randomly selected using a coin.\\u003c/p\\u003e \\u003cp\\u003eThe participants were informed about the procedure, but they were not aware of the hydrogel used in each surgery. The syringes of the hydrogels were also packed and labeled as 1 and 2 by a person other than the authors, and they did not know which hydrogel was used in each surgery. Finally, the data were provided to the data analyst along with the details of each group.\\u003c/p\\u003e \\u003cp\\u003eThe study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17). Informed consent was obtained from patients who met the inclusion criteria.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eData Collection\\u003c/h3\\u003e\\n\\u003cp\\u003eThe hydrogel was formulated using carbopol 934, distilled water, 96% ethanol, 0.1% glycerin, 0.04% NaOH, and 0.05% Bupivacaine HCL without epinephrine. The placebo was administered using the same method and materials, but without Bupivacaine HCL. The entire procedure was performed under anti-septic conditions by using sterile materials. After the manufacturing process, the hydrogel was poured into sterile insulin syringes and sterilized using UV radiation.\\u003c/p\\u003e \\u003cp\\u003eAll surgeries were performed by a single surgeon at the same location, using the same steps. The inferior alveolar nerve (IAN) block was administered directly using 3% prilocaine. A long buccal injection of 2% lidocaine was administered. After waiting for 10 min, a pocket-shaped flap was cut from the mesial aspect of the first molar on the buccal side to the beginning of the ramus. The flap was then gently separated from the bone by using a periosteal elevator. If necessary, the tooth was removed using an elevator after removing the bone around the tooth with a round bur and sectioning the tooth using a fissure bur. The socket was curetted and washed with normal saline, followed by the injection of 5 cc of hydrogel (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Finally, the tissue was sutured with a 3\\u0026thinsp;\\u0026minus;\\u0026thinsp;0 polyglycolic acid (P.G.A) thread. The patient was prescribed Metronidazole 250 mg (1 tablet every 8 h, N\\u0026thinsp;=\\u0026thinsp;10) and Amoxicillin 500 mg (1 tablet every 8 h, N\\u0026thinsp;=\\u0026thinsp;20). They were also advised to take Ibuprofen 400 mg (with an interval of 8 h) or Acetaminophen 325 mg in case of pain.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eSelf-reported pain of the patients at 2, 6, 12, 24, 48, and 72 hours and the number of painkillers that they used each day for up to 3 days were the outcomes of the present study. Data were collected using a questionnaire designed with a visual analog scale (VAS) for each time point. The VAS consisted of a 10 cm vertical line with \\\"no Pain\\\" at the bottom and \\\"intolerable pain\\\" at the top. The questionnaire also included a section that recorded the total number of painkillers (ibuprofen and acetaminophen were administered daily). After surgery, the patients were given a questionnaire with instructions on how to fill it out. One week after surgery, a follow-up was conducted, and completed questionnaires were collected. The pain level on the VAS was determined using a ruler to obtain an exact measurement.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData Analysis\\u003c/h2\\u003e \\u003cp\\u003eData were entered into the computer using SPSS 24 software. Descriptive results were calculated by calculating the frequency, mean, and standard deviation based on the type of variable and were analyzed using an independent t-test to compare the amount of pain and the amount of painkiller consumption between the two groups or its parametric equivalent. A significance level of less than 0.05 was considered. Repeated measurements of analysis of variance (ANOVA) were used to determine the relationships between time and group.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eSixteen patients who met the inclusion criteria were enrolled in this trial. Of these, 7 were men (44%) and 9 were women (56%). Their ages ranged from 20 to 26 years, with an average age of 23.21.\\u003c/p\\u003e \\u003cp\\u003eBased on the results of the repeated-measures ANOVA (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e), the mean reported pain among the patients was significantly different over time and between the groups (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). The pattern of pain over time also differed across the groups (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). The Bupivacaine/Carbopol group also reported lower pain at all time points (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). In the first 2 hours, there was no significant difference in pain levels between the groups (P\\u0026thinsp;=\\u0026thinsp;0.814). However, at later time points, the Bupivacaine/Carbopol group experienced significantly lower levels of pain (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05)(Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eStatistical analysis of the effect of each hydrogel on pain in 72 hours post-surgery\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"8\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTime\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eBupivacaine/ Carbopol\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ePlacebo\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"5\\\" nameend=\\\"c8\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eStatistical Results\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEffect\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003ePartial ƞ\\u003csup\\u003e2\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4.45\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4.70\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eTime\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e26.95\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.509\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e6 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3.90\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.72\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.17\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.97\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e12 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3.70\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.04\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.87\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e18.46\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.415\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e24 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.94\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5.38\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e48 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.68\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4.01\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.70\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eTime - Group\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e4.25\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e0.141\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e72 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.62\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.73\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.32\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.63\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"1\\\" nameend=\\\"c8\\\" namest=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eIndependent t-test for pain (VAS) between groups at each time\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e2 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003et\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003edf\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMean\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eSD\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.28\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.814\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.23\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.25\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1.049\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e6 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.89\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e12 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.33\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.80\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e24 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4.43\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4.81\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.44\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.71\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e48 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.04\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.71\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.37\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.64\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e72 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3.10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3.55\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.70\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.47\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThere was a significant effect of time on painkiller consumption (P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), but no significant difference between the two groups (P\\u0026thinsp;=\\u0026thinsp;0.423), and the time-group effect was also not significant (P\\u0026thinsp;=\\u0026thinsp;0.848) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e), indicating that the pattern of painkiller consumption over time did not differ across groups, although it was lower in the Bupivacaine/Carbopol group on all three days (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e). Additionally, the number of painkillers used at each time point did not differ significantly between the groups (P\\u0026thinsp;=\\u0026thinsp;0.774, 0.452, and 0.389) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eStatistical analysis of the effect of each hydrogel on painkiller consumption in 72 hours post-surgery\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eTime\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eBupivacaine/ Carbopol\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003ePlacebo\\u003c/p\\u003e \\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"4\\\" nameend=\\\"c7\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eStatistical Results\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eEffect\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003ePartial ƞ\\u003csup\\u003e2\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e24 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.28\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.91\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.42\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTime\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.009\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.164\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e48 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.92\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3.28\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.20\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eGroup\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.663\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.423\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.025\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e72 hours\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2.21\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.31\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.64\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.27\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eTime- Group\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.165\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.848\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.006\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eIndependent t-test for painkiller consumption between groups at each time\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e24 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eF\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eP\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003et\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003edf\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eMean\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eSD\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.31\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.774\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.29\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.14\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.49\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e48 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.452\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.76\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.46\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e72 hours\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.21\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0.389\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.87\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e26\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.42\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0.48\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eHydrogels offer a promising method for drug delivery by localizing the effects of drugs and targeting specific sites.\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e Researchers are exploring their use as scaffolds, adhesive materials, dressings, and biosensors.\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u003c/sup\\u003e To ensure effective performance and stability at the application site, hydrogels must possess specific physical, chemical, and biocompatible properties. Their high water content allows for better integration with the site and reduces the immune response.\\u003csup\\u003e\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e Solubility and pH are critical factors to ensure gradual degradation over time without triggering an immune response or causing damage to surrounding tissues.\\u003csup\\u003e\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e Hydrogels can be made from various materials, including natural polymers such as chitosan, hyaluronic acid, gelatin, collagen, and alginate.\\u003csup\\u003e\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e\\u003c/sup\\u003e Some hydrogels made from these polymers have shown therapeutic and anti-inflammatory properties, making them suitable for wound dressing and healing applications.\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e\\u003c/sup\\u003e However, the cost and specific physicochemical limitations remain among the disadvantages.\\u003csup\\u003e\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e Some hydrogels use synthetic materials such as polyglycolic acid (PGA), polyvinyl alcohol (PVA), and polyhydroxy ethyl methacrylate (PHEMA).\\u003csup\\u003e\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e Polyacrylic acid, also known as carbopol, is used as a thickener and rheology modifier in the pharmaceutical and food industries.\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e\\u003c/sup\\u003e Studies have often focused on wound healing and dressings using carbopol-based hydrogels for drug delivery.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR35\\\" citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u003c/sup\\u003e New research areas, such as ocular, mucosal-oral, and nasal-brain applications, are also being investigated and evaluated.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR38\\\" citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eThe null hypothesis of present study, which suggested no significant relationship between the use of bupivacaine-based hydrogel (carbopol) and pain after wisdom tooth surgery, was not confirmed.\\u003c/p\\u003e \\u003cp\\u003eThis study is the first to report the clinical application of bupivacaine/carbopol hydrogel intra-socket injection for long-term release at the surgical site. The results indicated a decrease in the number of painkillers consumed by patients; however, the difference between the intervention and control groups was not statistically significant. Normally, patients use 2\\u0026ndash;3 painkillers per day as a preventive measure to avoid unbearable pain at the onset of discomfort, which could be a confounding factor. The visual analog scale (VAS) showed that the peak of pain occurred between 6 and 12 hours after surgery, and the increased use of painkillers on the second day was in response to this pain, with some patients taking 5\\u0026ndash;6 painkillers. The total VAS scores of the intervention group were lower, and the hydrogel had the greatest effect between 6 and 72 hours, leading to a reduction in pain compared to the control group.\\u003c/p\\u003e \\u003cp\\u003eNumerous studies have been conducted on the use of hydrogels in oral and dental medicine, showing promising results in the areas of oral dressings, drug carriers, and tissue engineering. Hydrogels have been investigated as local drug carriers for the treatment of periodontitis \\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR41\\\" citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e\\u003c/sup\\u003e, TMJ osteoarthritis\\u003csup\\u003e\\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e\\u003c/sup\\u003e and alveolar osteitis (Dry Socket)\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR46 CR47 CR48\\\" citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e\\u003c/sup\\u003e. Various drugs such as antibiotics (e.g., metronidazole\\u003csup\\u003e\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e\\u003c/sup\\u003e, doxycycline\\u003csup\\u003e\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e\\u003c/sup\\u003e and azithromycin\\u003csup\\u003e\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e\\u003c/sup\\u003e) and other medications (e.g., NSAIDs \\u003csup\\u003e\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e\\u003c/sup\\u003e, tranexamic acid\\u003csup\\u003e\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e\\u003c/sup\\u003e, lidocaine\\u003csup\\u003e\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e\\u003c/sup\\u003e) have been studied in hydrogel systems based on chitosan\\u003csup\\u003e\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e\\u003c/sup\\u003e, hyaluronic acid\\u003csup\\u003e\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e\\u003c/sup\\u003e, alginate\\u003csup\\u003e\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e\\u003c/sup\\u003e and poloxamer\\u003csup\\u003e\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e\\u003c/sup\\u003e. These studies have shown significant results regarding drug effects, release, and the chemical properties of the designed hydrogels, including biocompatibility, rheological properties, absorption, and release. Studies on alveolar steatitis have been similar to present study in terms of the target site. One of the important aspects of a socket is that it does not react as a foreign body, and its absorption and decomposition occur in a short period of time. Supachawaroj et al. in the evaluation of lidocaine hydrogel based on poloxamer expressed positive laboratory results in long-term release and degradability and adhesion and anesthesia effect.\\u003csup\\u003e\\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e\\u003c/sup\\u003e Nowak et al. also stated that meloxicam hydrogel based on chitosan showed low cytotoxicity and It does not stimulate the immune system and does not stimulate local inflammation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e\\u003c/sup\\u003e Bender et al.'s study on hydrogel metronidazole and lidocaine based on Carbopol 934 and Pluronic F-127 in the socket of the extracted tooth also showed a release of more than 24 hours in laboratory tests. It has shown little cytotoxicity and it has the ability to spread and penetrate into silent tissue layers uniformly.\\u003csup\\u003e\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e\\u003c/sup\\u003e Unlike previous studies, present study was conducted as the first phase of a clinical trial, showing good decomposition after two weeks and no signs of inflammation or reactivity.\\u003c/p\\u003e \\u003cp\\u003eStudies also have been conducted on bupivacaine using different carriers both in vitro and in vivo. Davis et al.'s study involved bupivacaine emulsions in a cross-linked hydrogel, finding that 80 to 100% of the substance is released after 20 to 68 hours, thus enhancing the local anesthetic effect of bupivacaine.\\u003csup\\u003e\\u003cspan citationid=\\\"CR50\\\" class=\\\"CitationRef\\\"\\u003e50\\u003c/span\\u003e\\u003c/sup\\u003e Similarly, a study on heat-sensitive graphene oxide/chitosan-based injectable nanocomposite hydrogel reported 55% and 86.43% drug release after 6 and 24 h, respectively.\\u003csup\\u003e\\u003cspan citationid=\\\"CR51\\\" class=\\\"CitationRef\\\"\\u003e51\\u003c/span\\u003e\\u003c/sup\\u003e Furthermore, a study on Chitosan-based topical hydrogel of bupivacaine showed that significant local anesthesia without side effects occurred after 15 minutes, providing an alternative to previous methods in dentistry.\\u003csup\\u003e\\u003cspan citationid=\\\"CR52\\\" class=\\\"CitationRef\\\"\\u003e52\\u003c/span\\u003e\\u003c/sup\\u003e Another study on a gelatin hydrogel in vitro demonstrated a 72-hour release of bupivacaine ex vivo in the spinal cord.\\u003csup\\u003e\\u003cspan citationid=\\\"CR53\\\" class=\\\"CitationRef\\\"\\u003e53\\u003c/span\\u003e\\u003c/sup\\u003e Finally, Sheperd et al. showed in their study on polylactic co-glycolic acid (PLGA) microparticles containing bupivacaine that this drug is more efficient in the first 24 hours\\u003csup\\u003e\\u003cspan citationid=\\\"CR54\\\" class=\\\"CitationRef\\\"\\u003e54\\u003c/span\\u003e\\u003c/sup\\u003e. The current study showed the release of the drug and its effect within the first 72 hours. This study is among the first to clinically assess bupivacaine/carbopol hydrogel in third molar surgery. The use of the split-mouth method was an advantage, but the study had limitations such as the small number of patients and the need for additional lab tests, making future studies necessary.\\u003c/p\\u003e\"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eThe importance of selective and localized treatments is now evident. A higher concentration of the drug at a specific site resulted in fewer adverse effects and a faster curing process for the patient. Hydrogels have opened up a wide field of research, allowing us to benefit from localized, extensive, and controlled treatments. The Bupivacaine/Carbopol hydrogel that we developed provides longer pain relief after surgery, which can be beneficial when used alongside other types of medicines and treatments in dentistry. However, further studies are needed to improve these methods.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e \\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e \\u003cp\\u003eThe study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17). Informed consent was obtained from patients who met the inclusion criteria.\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eConsent for Publication\\u003c/strong\\u003e \\u003cp\\u003e Informed consent was obtained from the patient whose image is used in this article.\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.\\u003c/p\\u003e \\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e \\u003cp\\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003ePJ, MZ, and EK contributed substantially to the conceptual design of the study. MM was responsible for data acquisition, analysis, and interpretation. AM developed and formulated the hydrogel. PJ and EK developed the software utilized in this work. MZ and EK drafted the manuscript and critically revised it for important intellectual content. All authors read and approved the final version of the manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgement\\u003c/h2\\u003e\\u003cp\\u003eThis study was supported by the Vice Chancellor for Research and Technology at Qazvin University of Medical Sciences. The authors sincerely appreciate the officials and staff of the Faculty of Dentistry at Qazvin University of Medical Sciences and the Pharmaceutics Laboratory at Shahid Beheshti University of Medical Sciences for their valuable assistance. The authors also extend their gratitude to Dr. Moein Diarjani, faculty member of Oral and Maxillofacial Surgery at Qazvin University of Medical Sciences, as well as to all individuals who contributed to the successful completion of this study.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eThe data that support the findings of this study are available from the corresponding author, EK, upon request. [erfan_khorasani@yahoo.com](mailto:erfan_khorasani@yahoo.com)\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eShaari RB, Nawi MAA, Khaleel AK, AlRifai AS. Prevalence and pattern of third molars impaction: A retrospective radiographic study. J Adv Pharm Tech Res. 2023;14(1):46\\u0026ndash;50.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCarter K, Worthington S. Predictors of third molar impaction: a systematic review and meta-analysis. J Dent Res. 2016;95(3):267\\u0026ndash;76.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFayad JB, Levy JC, Yazbeck C, Cavezian R, Cabanis E-A. Eruption of third molars: relationship to inclination of adjacent molars. Am J Orthod Dentofac Orthop. 2004;125(2):200\\u0026ndash;2.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCaymaz MG, Buhara O. Association of Oral Hygiene and Periodontal Health with Third Molar Pericoronitis: A Cross-Sectional Study. Biomed Res Int. 2021;2021(1):6664434.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLago-M\\u0026eacute;ndez L, Diniz-Freitas M, Senra-Rivera C, Gude-Sampedro F, Rey JMG, Garc\\u0026iacute;a-Garc\\u0026iacute;a A. Relationships between surgical difficulty and postoperative pain in lower third molar extractions. J Oral Maxillofac Surg. 2007;65(5):979\\u0026ndash;83.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSnyder M, Shugars DA, White RP Jr, Phillips C. Pain medication as an indicator of interference with lifestyle and oral function during recovery after third molar surgery. J Oral Maxillofac Surg. 2005;63(8):1130\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHupp JR, Tucker MR, Ellis E. Contemporary Oral and Maxillofacial Surgery-E-Book: Contemporary Oral and Maxillofacial Surgery-E-Book. Seventh ed: Elsevier health sciences; 2013.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAkinbade AO, Ndukwe KC, Owotade FJ. Comparative analgesic effects of ibuprofen, celecoxib and tramadol after third molar surgery: a randomized double blind controlled trial. J Contemp Dent Pract. 2018;19(11):1334\\u0026ndash;40.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSharma V, Mamontov E, Tyagi M. Effects of NSAIDs on the nanoscopic dynamics of lipid membrane. Biochim et Biophys Acta (BBA)-Biomembranes. 2020;1862(2):183100.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNaesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them. Drug Saf. 2006;29(2):119\\u0026ndash;32.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSolomon DH. Nonselective NSAIDs: Overview of adverse effects. UpToDate [internet] UpToDate Inc[updated 0303 2020, cited 0303 2021] Available from: https://www uptodate com. 2020.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMarsico F, Paolillo S, Filardi PP. NSAIDs and cardiovascular risk. J Cardiovasc Med. 2017;18:e40\\u0026ndash;3.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMizushima T. Strategy for development of NSAIDs with lower risk for side effects. Yakugaku zasshi: J Pharm Soc Japan. 2008;128(2):255\\u0026ndash;61.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHan JT, Susarla SM, Dodson TB, Lang MS. Are oral and maxillofacial surgeons prescribing fewer opioids and more non-narcotic analgesics for postoperative pain after third molar removal? J Oral Maxillofac Surg. 2020;78(3):358\\u0026ndash;65.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRubaia\\u0026rsquo;an B, Alotaibi MA, Alotaibi MK, Alqhtani NM. Cortisol in Oral and Maxillofacial Surgery: A Double-Edged Sword. Int J Dent. 2021;2021(1):7642875.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eClarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology. 1985;62(4):396\\u0026ndash;405.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSu N, Wang H, Zhang S, Liao S, Yang S, Huang Y. Efficacy and safety of bupivacaine versus lidocaine in dental treatments: a meta-analysis of randomised controlled trials. Int Dent J. 2014;64(1):34\\u0026ndash;45.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVelioglu O, Calis AS, Koca H, Velioglu E. Bupivacaine vs. lidocaine: a comparison of local anesthetic efficacy in impacted third molar surgery. Clin Oral Invest. 2020;24(10):3539\\u0026ndash;46.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ede Souza AMM, Horliana ACRT, Simone JL, Jorge WA, Tortamano IP. Postoperative pain after bupivacaine supplementation in mandibular third molar surgery: splint-mouth randomized double blind controlled clinical trial. Oral maxillofacial Surg. 2014;18(4):387\\u0026ndash;91.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGangwani P. Evolving Role of Liposomal Bupivacaine in Managing Post-Surgical Analgesia in Oral Surgery. Res Rep Oral Maxillofac Surg. 2019;3:026.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLieblich SE, Misiek D, Olczak J, Fleck H, Waterman F. A Retrospective Cross-Sectional Study of the Effect of Liposomal Bupivacaine on Postoperative Opioid Prescribing After Third Molar Extraction. J Oral Maxillofac Surg. 2021.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJi YD, Harris JA, Gibson LE, McKinley SK, Phitayakorn R. The Efficacy of Liposomal Bupivacaine for Opioid and Pain Reduction: A Systematic Review of Randomized Clinical Trials. J Surg Res. 2021;264:510\\u0026ndash;33.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKhiavi RK, Pourallahverdi M, Pourallahverdi A, Khiavi SG, Oskouei SG, Mokhtari H. Pain control following impacted third molar surgery with bupivacaine irrigation of tooth socket: a prospective study. J Dent Res Dent Clin Dent prospects. 2010;4(4):105.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRizzo F, Kehr NS. Recent advances in injectable hydrogels for controlled and local drug delivery. Adv Healthc Mater. 2021;10(1):2001341.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKoehler KC, Anseth KS, Bowman CN. Diels\\u0026ndash;Alder mediated controlled release from a poly (ethylene glycol) based hydrogel. Biomacromolecules. 2013;14(2):538\\u0026ndash;47.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eThang NH, Chien TB, Cuong DX. Polymer-based hydrogels applied in drug delivery: An overview. Gels. 2023;9(7):523.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMahmood A, Mahmood A, Ibrahim MA, Hussain Z, Ashraf MU, Salem-Bekhit MM, et al. Development and evaluation of sodium alginate/carbopol 934P-Co-poly (methacrylate) hydrogels for localized drug delivery. Polymers. 2023;15(2):311.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSuhail M, Wu P-C, Minhas MU. Using carbomer-based hydrogels for control the release rate of diclofenac sodium: Preparation and in vitro evaluation. Pharmaceuticals. 2020;13(11):399.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLiu L, Wu D, Tu H, Cao M, Li M, Peng L, et al. Applications of hydrogels in drug delivery for oral and maxillofacial diseases. Gels. 2023;9(2):146.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFraser D, Nguyen T, Kotelsky A, Lee W, Buckley M, Benoit DS. Hydrogel swelling-mediated strain induces cell alignment at dentin interfaces. ACS Biomaterials Sci Eng. 2022;8(8):3568\\u0026ndash;75.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSamiraninezhad N, Asadi K, Rezazadeh H, Gholami A. Using chitosan, hyaluronic acid, alginate, and gelatin-based smart biological hydrogels for drug delivery in oral mucosal lesions: A review. Int J Biol Macromol. 2023:126573.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGhasemiyeh P, Mohammadi-Samani S. Hydrogels as drug delivery systems; pros and cons. Trends Pharm Sci. 2019;5(1):7\\u0026ndash;24.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBarry B, Meyer M. The rheological properties of carbopol gels I. Continuous shear and creep properties of carbopol gels. Int J Pharm. 1979;2(1):1\\u0026ndash;25.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGavan A, Colobatiu L, Hanganu D, Bogdan C, Olah NK, Achim M, et al. Development and evaluation of hydrogel wound dressings loaded with herbal extracts. Processes. 2022;10(2):242.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSanchez MF, Breda SA, Soria EA, T\\u0026aacute;rtara LI, Manzo RH, Olivera ME. Ciprofloxacin-lidocaine-based hydrogel: development, characterization, and in vivo evaluation in a second-degree burn model. Drug delivery translational Res. 2018;8:1000\\u0026ndash;13.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang D, Jin J, Zhang C, Ruan C, Qin Y, Li D, et al. Carbomer Hydrogel Composed of Cu2O and Hematoporphyrin Monomethyl Ether Promotes the Healing of Infected Wounds. ACS omega. 2024;9(4):4974\\u0026ndash;85.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBandiera G, Talamonti R, Piccolino G, Micaloni A, Raffa S. Evaluation of in vivo adhesiveness of hyaluronic acid combined with xanthan gum and carbomer [Karos\\u0026reg; throat lozenges] to the oral cavity mucosa in human healthy subjects: a pilot study. 2019.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMahajan HS, Patil PH. Gel-based delivery of neurotherapeutics via naso-brain pathways. Direct Nose-to-Brain Drug Delivery: Elsevier; 2021. pp. 225\\u0026ndash;45.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRahbar N, Darvish S, Farrahi F, Kouchak M. Chitosan/carbomer nanoparticles-laden in situ gel for improved ocular delivery of timolol: in vitro, in vivo, and ex vivo study. Drug Delivery Translational Res. 2024:1\\u0026ndash;11.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKerdmanee K, Phaechamud T, Limsitthichaikoon S. Thermoresponsive azithromycin-loaded niosome gel based on poloxamer 407 and hyaluronic interactions for periodontitis treatment. Pharmaceutics. 2022;14(10):2032.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang B, Booij-Vrieling HE, Bronkhorst EM, Shao J, Kouwer PH, Jansen JA, et al. Antimicrobial and anti-inflammatory thermo-reversible hydrogel for periodontal delivery. Acta Biomater. 2020;116:259\\u0026ndash;67.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZussman M, Zilberman M. Injectable metronidazole-eluting gelatin-alginate hydrogels for local treatment of periodontitis. J Biomater Appl. 2022;37(1):166\\u0026ndash;79.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDeJulius CR, Gulati S, Hasty KA, Crofford LJ, Duvall CL. Recent Advances in Clinical Translation of Intra-Articular Osteoarthritis Drug Delivery Systems. Adv Ther. 2021;4(1):2000088.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJung Y-s, Park W, Park H, Lee D-K, Na K. Thermo-sensitive injectable hydrogel based on the physical mixing of hyaluronic acid and Pluronic F-127 for sustained NSAID delivery. Carbohydr Polym. 2017;156:403\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBender L, Boostrom HM, Varricchio C, Zuanon M, Celiksoy V, Sloan A, et al. A novel dual action monolithic thermosetting hydrogel loaded with lidocaine and metronidazole as a potential treatment for alveolar osteitis. Eur J Pharm Biopharm. 2020;149:85\\u0026ndash;94.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEl Halawany M, Latif R, AbouGhaly MH. Hemostatic Alginate/Nano-Hydroxyapatite Composite Aerogel Loaded with Tranexamic Acid for the Potential Protection against Alveolar Osteitis. Pharmaceutics. 2022;14(10):2255.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNowak KM, Bodek KH, Szterk A, Rudnicka K, Szymborski T, Kosieradzki M, et al. Preclinical assessment of the potential of a 3D chitosan drug delivery system with sodium meloxicam for treating complications following tooth extraction. Int J Biol Macromol. 2019;133:1019\\u0026ndash;28.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSupachawaroj N, Damrongrungruang T, Limsitthichaikoon S. Formulation development and evaluation of lidocaine hydrochloride loaded in chitosan-pectin-hyaluronic acid polyelectrolyte complex for dry socket treatment. Saudi Pharm J. 2021;29(9):1070\\u0026ndash;81.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSupachawaroj N, Limsitthichaikoon S. Lidocaine HCl-Loaded Polyelectrolyte Complex-Poloxamer Thermoresponsive Hydrogel: In Vitro-In Vivo Anesthetic Evaluations for Tooth Socket Wound Delivery. AAPS PharmSciTech. 2024;25(6):182.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDavis B, Erickson S, Wojtalewicz S, Simpson A, Metcalf C, Sant H, et al. Entrapping bupivacaine-loaded emulsions in a crosslinked-hydrogel increases anesthetic effect and duration in a rat sciatic nerve block model. Int J Pharm. 2020;588:119703.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEltahir S, Jagal J, Abdelkareem MA, Ghoneim MM, Rawas-Qalaji MM, Greish K, et al. Thermosensitive injectable graphene oxide/chitosan-based nanocomposite hydrogels for controlling the in vivo release of bupivacaine hydrochloride. Int J Pharm. 2022;621:121786.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMihalache C, Rata DM, Cadinoiu AN, Patras X, Sindilar EV, Bacaita SE, et al. Bupivacaine-loaded chitosan hydrogels for topical anesthesia in dentistry. Polym Int. 2020;69(11):1152\\u0026ndash;60.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSteverink JG, van Tol FR, Oosterman BJ, Vermonden T, Verlaan J-J, Malda J, et al. Robust gelatin hydrogels for local sustained release of bupivacaine following spinal surgery. Acta Biomater. 2022;146:145\\u0026ndash;58.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eShepherd SD, O\\u0026rsquo;Buckley SC, Harrington JM, Haines LG, Rothrock GD, Johnson LM, et al. A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain. Sci Rep. 2018;8(1):12172.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-oral-health\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ohea\",\"sideBox\":\"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/ohea/default.aspx\",\"title\":\"BMC Oral Health\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8937175/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8937175/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eIntroduction and Aims:\\u003c/strong\\u003ePostoperative pain after mandibular third molar extraction often leads to systemic NSAID or opioid use, risking adverse effects and overuse. This study aimed to develop and evaluate a degradable Bupivacaine/Carbopol hydrogel for sustained pain relief after third molar surgery.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e A single-center, double-blinded, split-mouth randomized clinical trial was conducted at the Qazvin University of Medical Sciences outpatient clinic. Sixteen adult patients (8 males, 8 females; mean age 24.3 ± 3.1 years) with bilaterally impacted mandibular third molars participated. Intra-socket injections of Bupivacaine/Carbopol hydrogel versus placebo were administered post-operatively. Pain intensity was self-reported on a 10-point visual analog scale (VAS) at 0, 2, 6, 12, 24, and 72 hours post-surgery; daily analgesic (NSAID/opioid) consumption was recorded for three days. Repeated-measures ANOVA using SPSS v24, with α = 0.05, was employed.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e Significant main effects of time, group, and their interaction on VAS scores were observed (all P \\u0026lt; 0.05). Except at 2 hours, the hydrogel group experienced significantly lower pain levels at 6, 12, 24, and 72 hours compared to the placebo. No significant differences in daily analgesic intake between groups over time were found (P \\u0026gt; 0.05).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions:\\u003c/strong\\u003e The localized, degradable Bupivacaine/Carbopol hydrogel offers sustained postoperative pain relief and could decrease dependence on systemic painkillers in oral surgery. Larger clinical trials are necessary to confirm these findings and optimize the formulation.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTrial Registration\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was conducted in accordance with the WMA Declaration of Helsinki and approved by the Research Ethics Committee of Qazvin University of Medical Sciences (approval ID: IR.QUMS.REC.1402.102) and the Iranian Registry of Clinical Trials (approval ID: IRCT20221201056682N1, 2023-07-17).\\u003c/p\\u003e\",\"manuscriptTitle\":\"Toward Opioid-Sparing Oral Surgery: Does Intra-Socket Delivery of a Biodegradable Extended-Release Bupivacaine Hydrogel Enhance Postoperative Analgesia After Impacted Mandibular Third Molar Surgery?\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-03-13 08:55:47\",\"doi\":\"10.21203/rs.3.rs-8937175/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2026-04-13T07:10:03+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-04-08T13:09:41+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-04-05T02:40:45+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"42092660682656024661769227178603044705\",\"date\":\"2026-04-05T02:15:47+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"83336923537705992698878962110358728204\",\"date\":\"2026-04-01T08:41:52+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-03-31T10:31:14+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"25003448628257683195070518851966797373\",\"date\":\"2026-03-30T09:01:29+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-03-19T22:46:50+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-03-18T18:16:48+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"334048857601790653331361813190016625324\",\"date\":\"2026-03-11T18:21:41+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"6980287606905514771488383130136394012\",\"date\":\"2026-03-09T21:46:21+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2026-03-09T04:04:08+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-03-02T06:49:57+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2026-02-28T00:09:27+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Oral Health\",\"date\":\"2026-02-27T20:42:04+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-oral-health\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ohea\",\"sideBox\":\"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/ohea/default.aspx\",\"title\":\"BMC Oral Health\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"6f0156c5-97e1-4426-a03c-534c90be29df\",\"owner\":[],\"postedDate\":\"March 13th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"in-revision\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-04-13T07:27:50+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-03-13 08:55:47\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8937175\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8937175\",\"identity\":\"rs-8937175\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}