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Topical insulin‐liposomal formulation in management of recurrent aphthous ulcers: A randomized placebo‐controlled trial
Abstract
Aim:
To evaluate the effectiveness of topical insulin-liposomal gel in aphthous ulcer treatment.
Methods:
80 participants with minor aphthous ulcers were randomly divided to receive either topical insulin-liposomal gel or placebo gel (once daily) for 6 days. Assessment of outcomes included visual analog scale (VAS) for pain (primary outcome), and secondary outcomes included ulcer duration and impact of treatment on quality of life using the Oral Health Impact Profile 14 (OHIP-14). Testing of the outcomes was carried out at 1, 2, 3, 4 and 6 days after treatment for VAS and at 6 days for OHIP-14.
Results:
For pain scores, the test group showed a significant decrease by time, this was evident from day 1 (P < .001); at day 3, median and interquartile range (IQR) values were 0 (0-1). For the placebo group, a non-significant change by time was reported between baseline and day 1; at day 3, the median value was 7 (IQR, 7-9). The test group showed significantly lower mean duration than the placebo group (P < .001). OHIP-14 scores after 6 days showed that the test group had a significantly lower score than placebo (P < .001).
Conclusions:
Topical insulin-liposomal formulation showed marked effectiveness in management of aphthous ulcers.
... Recurrent Afthous Stomatitis (RAS) is the most common inflammatory process of the oral mucosa. Furthermore, it is painful, multifactorial and generally recurrent (1,2). It is characterized by its periodicity and for being self-limited. ...
... -Inclusion and exclusion criteria The inclusion criteria were: clinical trials, articles written in Spanish or English and no more than 5 years since their publication. The exclusion criteria were: articles which were not available in English or Spanish, which -Studies features (Table 1) All the 17 articles included in this review were written in English and Spanish and were published between 2016 and 2021 (1)(2)(3)5,11,12,14,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Altogether there were 985 patients examined, divided in 505 cases and 480 controls. ...
... Regarding the geographic distribution, 10 of the papers were published in Asia (2 from Iran, 1 from Israel, 1 from Turkey, 4 from China and 1 from India) (1,3,11,12,14,21,(23)(24)(25)(26). 4 published in Europe (2 from Italy, 1 from Denmark and 1 from Liechtenstein) (5,17,19,20). 3 published in Africa (all them from Egypt) (2,18,22). We divided the studies in the kind of treatment used and the patients were distributed in "cases" if they received the experimental treatment, and "controls" if they received a placebo or another treatment in order to compare their efficacy. ...
Background:
Recurrent Aphtous Stomatitis (RAS) is the most common process affecting the oral mucosa. It is painful, multifactorial and generally recurrent. The aim of this systematic review is to know the last treatment approaches and their effectivity.
Material and methods:
we compared the outcome of different kind of treatments in terms of the improvement of the lesions, reduction of the size of those lesions and the time needed for their healing. Inclusion criteria were: clinical trials, articles written in English or Spanish and published less than 5 years ago.
Results:
we used the following keywords: "treatment", "aphtous stomatitis", "canker sores"; combined with Boolean operators AND y OR. We selected 28 articles for reading the whole text, and after applying the eligibility criteria, we selected 17 articles for our revision. Among all the treatments, we emphasize the barrier method based in compound of cellulose rubber and a calcium/sodium copolymer PVM/MA, with which the difference in the 3rd and 7th day was of -6,29 ± 0,14 points in the pain score. The treatment with insulin and chitosan gel, brought a pain suppression on the third day, with no reactivation of the pain during the whole study. The application of a film composed of polyurethane and sesame oil with chitosan, brought a reduction in the size of the lesions of 4,54 ± 2,84mm on the 6th day compared with the situation before the beginning of the treatment. The different kinds of laser, which produced a reduction in the pain score just at the beginning of the treatment up to 8,1 ± 1,6 points, and a reduction of the size of the lesions of 4,42 ± 1,02mm on the 7th day.
Conclusions:
Besides the classic treatments for RAS, we have to take into account other treatment modalities, above all the different kinds of laser.
... Insulin, when applied topically, can enhance the healing process by accelerating re-epithelialization, promoting angiogenesis, and stimulating the secretion of extracellular matrix components in keratinocytes, endothelial cells, and fibroblasts. 65,92 The antibacterial properties are also crucial for treating RAS because open sores on mucosal tissues make it easy for bacteria to colonize, especially Gram-positive bacteria, which can slow down the healing process. 93 Bacterial infections disrupt the regeneration of the oral mucosa. ...
Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause significant discomfort and cannot be attributed to any underlying disease. Different treatments have been used for RAS. This review aims to provide a comprehensive overview of the treatment options over the past decade for recurrent aphthous stomatitis (RAS), encompassing both natural and synthetic treatments. It will utilize clinical efficacy studies conducted in vivo and in vitro, along with a focus on the pharmaceutical approach through advancements in drug delivery development. We conducted a thorough literature search from 2013 to 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of recurrent aphthous stomatitis, and treatment. A total of 53 clinical trials with 3022 patients were included, with 35 using natural materials in their research and a total of 16 articles discussing RAS treatment using synthetic materials. All the clinical trials showed that natural and synthetic medicines seemed to benefit RAS patients by reducing pain score, ulcer size, and number of ulcers and shortening the healing duration.
... There are case reports and publications on the use of topical insulin in many fields including dermatology, surgery, and ophthalmology. In dermatological literature, data exists on its application in diabetic ulcers, aphthous ulcers, pemphigus lesions, diabetic ulcers, and stasis ulcers, and successful treatment results were published in these cases [7,[11][12][13][14]. ...
Leg ulcers are a significant cause of morbidity and mortality and can be caused by vascular, neuropathic, infectious, and traumatic factors, as well as rare metabolic diseases like prolidase deficiency. Despite various wound care methods and systemic treatments, managing ulcers can be challenging.
This case presents a male patient with prolidase deficiency for 35 years whose leg ulcers were resistant to standard treatments such as wound dressings, topical treatments, and hyperbaric oxygen therapy. Considering the ulcers' resistant nature, we applied topical insulin to ulcers as an add-on therapy and observed clinical improvement. In this case, we want to emphasize the potential of insulin as a supplementary treatment agent in prolidase deficiency-induced ulcer treatment.
... In a recent clinical trial, 0.1% triamcinolone acetonide (a corticosteroid) delivery via nano-liposomal carriers for OLP showed significantly higher efficacy of drug when delivered through the nanocarrier which was evident by reduced pain and oral lesion size [220]. In a recent clinical study with 80 patients, the patients with minor recurrent aphthous ulcer randomly received the topical gel treatment with insulin-liposomal gel and placebo gel for 6 days and at the end of study the test group got the significantly lower pain score compared to the placebo group (p < 0.001) [221]. ...
In the growing field of dentistry research, there is significant scope for investigating novel and high performance functional biomaterials for dental care, mainly to combat against oral health diseases. Considering the growing economic burden on dental care, there is an urgent need to investigate affordable and biologically acceptable functional anti-bacterial nanostructures capable of exhibiting desired pharmacological properties. Although a wide range of materials has been investigated for dentistry applications, their acceptability and scaling-up clinical acceptance remain a challenge to cytotoxicity and alterations in cellular function. To address these challenges, nano-lipids are emerging as potential materials to develop the next generation of treatment modalities for dental care and oral
diseases. However, there is a need to cover a knowledge gap between developing good quality nanolipids formulations, their introduction in dental research, establishing a track from laboratory to clinical application, exploring associated risks, and proposing step-by-step systematic research to obtain FDA approval for recommending nano-lipids for next generation system for dentistry applications. This report also summarizes the outcomes of the literature carefully and critically to provide a clear about selecting an appropriate nano-lipid system to manage a targeted dental issue. These programable nano-lipids can be designed and developed using optimized chemistry and pharmacology to perform in a controlled
manner via manipulating their responsiveness according to the demand of targeted diseases management i.e., a programmable system. The future of this research, keeping clinical adaptability as a focus, is also discussed in this review paper, along with possible challenges and possible alternative approaches.
... Data from 46 RCTs [20,25,[28][29][30]38,43,44,46,48,[50][51][52][53]55,[61][62][63][64][65][66][67] with 32 pairwise comparisons among 23 interventions were pooled. Amlexanox, laser and triamcinolone have a significant advantage over placebo (Table 1). ...
Background and objectives: To compare the efficacy and safety of topical interventions used for recurrent aphthous stomatitis. Materials and Methods: This network meta-analysis was conducted in accordance with the PRISMA statement. We searched four electronic databases, PubMed, Web of Science (WOS), Cochrane Central Register of Controlled Trials and Embase, for randomized controlled trials reporting efficacy and safety data on topical interventions for recurrent aphthous stomatitis. We performed a quality evaluation using a methodology based on the Cochrane Handbook. Two authors independently extracted data on healing effect, size reduction effect, symptom reduction effect, recurrence and safety assessment. Network meta-analysis was then performed using ADDIS and RevMan. Results: A total of 72 trials (5272 subjects) involving 29 topical interventions were included. Honey, lnsulin liposome gel, laser, amlexanox, glycyrrhiza and triamcinolone had better efficacy performance. Probiotics and chlorhexidine helped to prolong ulcer intervals and reduce recurrence. Doxycycline and penicillin had a high risk of adverse events. Hematologic evaluation showed no preference. The rank possibility of size-reducing effect and symptom-reducing effect supported the short-term effect of laser and the long-term effect of probiotics. Conclusions: We recommend the use of laser as a short-term intervention during the exacerbation phase of RAS and probiotics as a long-term intervention during the exacerbation and remission phases of RAS.
Recurrent apthous stomatitis (RAS) is associated with small to large ulcers and pain and may cause difficulty in speech and eating. Treatment modalities such as topical applications, mouthwashes, and tablets are available to manage symptoms. The most common pharmacological topical agents are corticosteroids, analgesics, probiotics, and antibiotics. This systematic review and meta-analysis aimed to compare the efficacy of topical triamcinolone with alternative topical treatments for recurrent oral aphthous ulcers, considering factors such as pain reduction, VAS score and ulcer healing time. It was registered in PROSPERO (registration number: CRD420250655772) with the title “Comparative evaluation of pain recovery and healing duration of Triamcinolone with non-steroidal treatment for recurrent oral aphthous ulcers- A systematic review and meta-analysis of Randomized Controlled Trials”. Randomized control trials published in English from March 2014 to March 2025 and available in five electronic databases, viz., Medline, the Cochrane Central Register of Controlled Trials (Central), Embase, Scopus and Web of Science, evaluating treatments for aphthous ulcers and which reported outcomes during follow-up were included. Studies reporting aphthous ulcers with systemic involvement, such as Behcet’s disease, Crohn's disease, and ulcerative colitis and those that included systemic treatment were excluded. A total of 26 studies were included for final qualitative and quantitative review. Risk of bias analysis was performed using the Cochrane ROB version 2 tool. The quantitative analysis and generation of Forest plots were done using the validated web-based tool available at https://metaanalysisonline.com. Natural and synthetic alternatives may provide effective, safer patient options, challenging the traditional reliance on corticosteroids such as triamcinolone. These findings indicate that natural agents such as honey, sage, and pomegranate could be considered first-line treatments for patients with RAS, particularly those who are intolerant to corticosteroids or experiencing frequent recurrences. Laser-based therapies and novel agents such as hyaluronic acid‒microbiome combinations may be effective for severe cases with the same efficacy as corticosteroids but fewer side effects. When evaluating patient satisfaction, natural therapies such as curcumin, aloe vera, Rhus coriaria and cannabidiol were preferred over triamcinolone. However, the current study has limitations, including variations in the study outcomes, ulcer types, and follow-up intervals. This study had no funding.
As many as 48.0% of the global population suffers from disabilities caused by oral conditions. These conditions encompass dental caries, periodontal diseases, oral cancers, and other pathologies affecting the hard and soft tissues of the oral and maxillofacial regions. Topical drug treatments in the oral cavity are often ineffective due to the short contact time, which prevents the drug from reaching optimal concentrations necessary for therapeutic effect. Conventional liposomes have several limitations, including low stability, challenges in long-term storage, and rapid clearance by the reticuloendothelial system (RES). These factors significantly reduce their effectiveness in maintaining sustained drug delivery and achieving desired therapeutic outcomes. To overcome these challenges, advanced drug delivery systems have been developed. Among these systems, liposomes have been extensively explored as nanocarriers in targeted drug delivery systems, particularly in mucosal drug delivery, due to their biocompatibility and degradability, making them promising agents for the treatment of oral diseases. To address these issues, extensive research has been conducted to modify the surface of liposomes, optimizing their efficacy, and understanding their mechanisms of action. This review article discusses the role and recent advancements of liposomes in the treatment of oral diseases, highlighting their potential to revolutionize oral health care through improved drug delivery and therapeutic outcomes.
Aim: This study aimed to develop nanoaggregates of berberine–phospholipid complex incorporated into thiolated chitosan (TCS) hydrogel for the treatment of aphthous stomatitis. Methods: The berberine–phospholipid complex was formulated through the solvent evaporation technique and assembled into nanoaggregates. TCS was synthesized through the attachment of thioglycolic acid to chitosan (CS). Nanoaggregates–TCS was prepared by the incorporation of nanoaggregates into TCS and underwent in vitro and in vivo tests. Results: Nanoaggregates–TCS exhibited prolonged release of berberine. The mucoadhesive strength of nanoaggregates–TCS increased 1.75-fold compared with CS hydrogel. In vivo studies revealed the superior therapeutic efficacy of nanoaggregates–TCS compared with that of other groups. Conclusion: Due to prolonged drug release, appropriate residence time and anti-inflammatory effects, nanoaggregates–TCS is an effective system for the treatment of aphthous stomatitis.
Aim:
To analyze the latest systemic and topical recurrent aphthous stomatitis (RAS) treatment methods that could help patients in their daily lives.
Material and methods:
A systematic literature review was performed of randomized control trials in English identified in MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (Cochrane Library), Researchgate, published between 2018 and 2023. Studies had to be performed in vivo.
Results:
34 randomized clinical trials matched all criterias and were included in systematic literature review. A wide variety of topical and systemic agents are suggested for the treatment of RAS.
Conclusion:
Topical medications can promote the healing time of ulcers and relieve the pain, but most of the time can not decrease the frequency of RAS relapse. However, for continuous RAS, treatment with systemic medication should be considered.
Aphthous stomatitis is a common inflammatory oral disease with challenging management. Crocin is a natural carotenoid that has shown great anti-inflammatory properties. The aim of this study was to develop thiolated chitosan (TCS)-based hydrogels containing niosomes to serve as a mucoadhesive crocin delivery system for aphthous stomatitis. Crocin-loaded niosomes were prepared and the impact of surfactant type, cholesterol content, and lipid to drug ratio on the characteristics of niosomes was evaluated. TCS was synthesized and the success of thiolation was investigated. The optimum niosomal formulation was loaded into the hydrogel and the hybrid system was characterized regarding the morphology, mucoadhesive properties, viscosity, chemical structure, in vitro drug release, and in vivo efficacy. The optimized niosome formulation showed 77% crocin entrapment, a particle diameter of 59 nm, and a zeta potential of -18 mV. The niosome-containing hydrogel exhibited pseudoplastic rheological behavior, mucoadhesive properties, suitable swelling, and sustained release of crocin. In vivo study revealed that the niosome-containing hydrogel improved ulcer healing and decreased the expression of tumor necrosis factor-alpha (TNF-α) and p53 while increasing the expression of vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA). Collectively, TCS hydrogel-embedded crocin-loaded niosomes is a promising therapeutic option for aphthous stomatitis. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Crocin (PubChem CID: 5281233) Chitosan (PubChem CID: 71853) Thioglycolic acid (PubChem CID: 1133) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (PubChem CID: 2723939) 5,5'-dithiobis (2-nitrobenzoic acid) (PubChem CID: 6254) Cholesterol (PubChem CID: 5997).
Peptide drugs have limitations, including low membrane permeability, inability to cross the blood-brain barrier, low stability towards enzymatic degradation, lower plasma half-life, and low oral bioavailability. Nanoparticles can effectively encapsulate various hydrophobic and hydrophilic drugs, protein-based drugs, peptides, and nucleic acids. Entrapment of these drugs can improve their solubility and stability. Nanoparticles can be developed to release the drug at the target site using stimulus trigger release. The different nanoparticles-based system serves this purpose, and they can be broadly classified as dendrimers, micelles, liposomes, carbon nanotubes, and quantum dots. Therapeutic peptides can be incorporated inside the liposomes to enhance stability and better tumor accumulation. Peptide-based liposomes can successfully target the tumor cells and lower the off-target effects of chemotherapeutics. Toxicity to normal cells caused by anticancer therapeutics has been dramatically reduced by the use of peptide-based liposomes. This chapter covers the fundamentals of incorporating peptides in liposomal particles and characterizing them using different methods. Examples of peptide-based liposomal delivery is also discussed.
Recent advances in the field of peptide therapeutics have led to the design and synthesis of many promising peptides. However, research and development to provide safe, stable, efficacious, and patient compliant formulation plays a vital role in bringing peptide therapeutics to market. The conventional parenteral route has made scientific advances to overcome multiple barriers, leading to the approval of many peptide-based products via parenteral route of administration in recent years. In parallel, oral, pulmonary, transdermal, and other delivery routes have been extensively investigated to deliver peptides with improved patient compliance. This includes the use of novel strategies for developing delivery systems that can offer various advantages over conventional dosage forms. This chapter focuses on fundamentals, formulations, and recent advances for successful peptide delivery.KeywordsPeptidesPharmaceutical marketFormulation developmentDelivery systemsParenteralOralPulmonaryTransdermalControlled release parenteralCarrier systems
Purpose
Novel drug delivery systems (DDSs) hold great promise for the treatment of oral cavity diseases. The main objective of this article was to provide a detailed overview regarding recent advances in the use of novel and nanostructured DDSs in alleviating and treating unpleasant conditions of the oral cavity. Strategies to maximize the benefits of these systems in the treatment of oral conditions and future directions to overcome these issues are also discussed.
Methods
Publications from the last 10 years investigating novel and nanostructured DDSs for pathologic oral conditions were browsed in a systematic search using the PubMed/MEDLINE, Web of Science, and Scopus databases. Research on applications of novel DDSs for periodontitis, oral carcinomas, oral candidiasis, xerostomia, lichen planus, aphthous stomatitis, and oral mucositis is summarized. A narrative exploratory review of the most recent literature was undertaken.
Findings
Conventional systemic administration of therapeutic agents could exhibit high clearance of drugs from the bloodstream and low accumulation at the target site. In contrast, conventional topical systems face problems such as short residence time in the affected region and low patient compliance. Novel and nanostructured DDSs are among the most effective and commonly used methods for overcoming the problems of conventional DDSs. The main advantages of these systems are that they possess the ability to protect active agents from systemic and local clearance, enhance bioavailability and cellular uptake, and provide immediate or modified release of therapeutic agents after administration. In the design of local drug delivery devices such as nanofiber mats, films, and patches, components and excipients can significantly affect factors such as drug release rate, residence time in the oral cavity, and taste in the mouth. Choosing appropriate additives is therefore essential.
Implications
Local drug delivery devices such as nanofiber mats, nanoparticles, liposomes, hydrogels, films, and patches for oral conditions can significantly affect drug efficacy and safety. However, more precise clinical studies should be designed and conducted to confirm promising in vitro and in vivo results. In recent years, novel and nanostructured DDSs increasingly attracted the attention of researchers as a means of treatment and alleviation of oral diseases and unpleasant conditions. However, more clinical studies should be performed to confirm promising in vitro and in vivo results. To transform a successful laboratory model into a marketable product, the long-term stability of prepared formulations is essential. Also, proper scale-up methods with optimum preparation costs should be addressed.
Introduction:
Recurrent aphthous stomatitis (RAS) is a distressing symptom. There are many ways to treat RAS, such as pudilan anti-inflammatory oral liquid and doxycycline and laser therapy, but these take a long time to produce positive effects and compliance is low. Previous reviews of acupuncture treatment for RAS has been growing, but a systematic review is not available. To assess the efficacy and safety of acupuncture for the management of RAS.
Methods and analysis:
The following databases will be searched from their inception to 1 February 2020: PubMed, Embase, Cochrane Library, CINAHL, Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure and Wanfang. The randomised controlled trials in English or Chinese associated with acupuncture for patients with RAS will be included. Eligible study conference abstracts and reference lists of manuscripts will also be searched. Two reviewers will select the studies, extract data independently. The Cochrane risk of bias tool will be used to assess the risk of bias for the studies. According to heterogeneity testing, data will be synthesised using a random-effects model. A meta-analysis will be performed using Rev Man V.5.3.5 statistical software for each outcome. Subgroup analysis and sensitivity analysis are planned according to clinical evidence. Mean difference or standardised mean difference for continuous data and risk ratio for dichotomous data will be calculated.
Ethics and dissemination:
No ethical approval is required. This protocol will not involve individual patient information and endangering participant rights. The results will be reported in a peer-reviewed journal or disseminated in relevant conferences.
Osf registration number:
DOI 10.17605/OSF.IO/QASUY.
Bioactive peptides and proteins have attracted great attention in the
cosmetic industry for the development of new cosmetic products to reverse the
signs of ageing (anti-ageing treatment). These have also led to new therapeutic
agents for clinical applications associated with wound healing; fibrosis,
excessive scarring, and inflammation. One of the mostly used administration
routes is by topical delivery. However, the skin is an intrinsic barrier to peptide/
protein transportation across the stratum corneum. Therefore the key function
of a topical delivery system is to enhance the dermal permeability of the
peptide/protein enabling it to cross the epidermis and retain in the dermis.
The development of pharmaceutical strategies that employ sophisticated
carrier systems such as elastic vesicles (such as liposome’s, and noisome),
nano fibers, micro-emulsions and conjugation with cell-penetrating peptides
may hold the key to enhancing peptide/protein dermal delivery. The aim of this
paper is to review noninvasive topical delivery systems that promote dermal
delivery of peptides/proteins for either cosmetic purposes or clinical therapeutic
applications.
Purpose
To assess 1) patient satisfaction of a mucoadhesive biopatch with citrus essential oil and 2) the change in pain severity and the oral health-related quality of life in patients with recurrent aphthous stomatitis.
Patients and methods
Thirty-seven patients with recurrent aphthous stomatitis participated in the study. Baseline records of personal data, ulcer assessment, visual analog scale, and Oral Health Impact Profile-14 were documented. A mucoadhesive patch was applied over the ulcer. Patients were recommended more applications if pain continued. On the fifth day, a post-therapy assessment was made.
Results
The mean visual analog scale scores at baseline and posttreatment were significantly different (7.3±2.11 and 4.9±2.6, respectively; P=0.001). The mean duration of pain reduced after patch application. The mean total Oral Health Impact Profile-14 scores before and after treatment showed a statistically significant difference (P=0.001). In total, 78.4% of patients reported a considerable improvement in oral functions after treatment (P=0.008).
Conclusion
The mucoadhesive biopatch containing citrus essential oil resulted in satisfying pain alleviation and restoration of oral functions with a significant improvement in the oral health-related quality of life.
Skin is a complex tissue, which comprises multiple layers. An injury to this stratified structure is considered to be the beginning of a sequence of events designed to restore skin integrity. Depending on the diameter and severity of a wound, deleterious physiological and metabolic changes can occur, leading to impaired wound healing and increased morbidity and mortality. While wound dressings provide some form of protection and remedy, the main challenge is to restore local metabolic pathways to normality, especially in the comprised patient suffering from chronic illness, such as diabetes. The implications of this disease in particular have prompted investigations into topical insulin as a potential and promising therapeutic intervention. This mini-review describes the possible mechanisms of insulin that are responsible for stimulating the cellular and molecular pathways, thereby enhancing the wound healing process. Examples of systemic and topical insulin applications are mentioned, together with an evaluation of the critical role played by insulin in tissue regeneration.
Burns are wounds caused by exposure to an agent from thermal, electric, radioactive or chemistry origin which presents attenuated inflammatory response, becoming even more compromised when associated to diabetes mellitus. Despite the fact from experimental evidences demonstrating tissue healing and reconstruction acceleration due to topical insulin used in diabetic and control rats with incised wounds and burn wounds in diabetic rats, however there is no information regarding molecular and cellular mechanism of topical insulin upon burn wounds. Objective Our aim was to investigate the chemical mediators involved in inflammation and proliferation of topical insulin on wound healing following 2nd degree burns in diabetic rats. Materials and methods Rats were divided into two groups: diabetic rats treated with placebo (DP), and diabetic rats treated with topical insulin (DI). We induced second-degree cutaneous burn wound in streptozotocin-induced diabetic rats with a 1.0-cm diameter circular mold, 120°C, during 20 seconds. Burned rats received either placebo cream or topical insulin (PI 0705370-3), once a day. At 7th and 14th days after the wound induction, anesthetized animals had seen extraction of skin wound sites for Elisa, immunohistochemistry, imunoblotting analysis and Weigert staining. Results Treatment with topical insulin induced early enhancement of macrophages infiltration in the wound surroundings detected by MCP-1 and F4/80 antibodies at day 7 and increased in KGF expression (p<0.05), when compared to DP. At 14th day after burn induction accompanied by enhanced angiogenesis, detected with VEGF and TGF-β1 antibodies; increased expression of alpha smooth muscle actin, present in mature blood vessels; increased cell proliferation, detected with Ki67 antibody on groups treated with topical insulin (DI), when compared to DP. Conclusion There was also increased elastic fibers deposition along the granulation area. Herein we demonstrated that cutaneous treatment with topical insulin accelerated wound healing in the diabetic group by increases the activity of macrophages, promoting angiogenesis and elastic fibers deposition.
Recurrent aphthous stomatitis (RAS) is the most common chronic disease of the oral cavity, affecting 5-25% of the population. The underlying etiology remains unclear, and no curative treatment is available.
The present review examines the existing treatments for RAS with the purpose of answering a number of questions: How should these patients be treated in the dental clinic? What topical drugs are available and when should they be used? What systemic drugs are available and when should they be used?
A literature search was made of the PubMed, Cochrane and Scopus databases, limited to articles published between 2008-2012, with scientific levels of evidence 1 and 2 (metaanalyses, systematic reviews, phase I and II randomized clinical trials, cohort studies and case-control studies), and conducted in humans.
The results obtained indicate that the management of RAS should be based on identification and control of the possible predisposing factors, with the exclusion of possible underlying systemic causes, and the use of a detailed clinical history along with complementary procedures such as laboratory tests, where required.
Only in the case of continuous outbreaks and symptoms should drug treatment be prescribed, with the initial application of local treatments in all cases. A broad range of topical medications are available, including antiseptics (chlorhexidine), antiinflammatory drugs (amlexanox), antibiotics (tetracyclines) and corticosteroids (triamcinolone acetonide).
In patients with constant and aggressive outbreaks (major aphthae), pain is intense and topical treatment is unable to afford symptoms relief. Systemic therapy is indicated in such situations, in the form of corticosteroids (prednisone) or thalidomide, among other drugs.
Key words:Recurrent aphthous stomatitis, treatment, clinical management.
Clinical trials have shown the effectiveness of systemic and local insulin therapy in improving wound healing. Diabetic wounds remain a challenge for healthcare providers. Impaired angiogenesis and reduced granulation tissue formation contribute to inadequate wound healing. The aim of this study was to investigate the effect of local insulin administration in acute and chronic diabetic wounds.
Eight diabetic patients presenting with full-thickness wounds, of different causes, were included in this study. Five wounds were due to necrobiosis, one to trauma, and two to postneoplasm resection. All wounds were treated with regular bedside treatment. In addition, half of the wound surface was treated with insulin and the other half did not receive insulin. Thermographic and biopsy specimens of the two sides were obtained on days 0 and 14. The presence of fibrosis, change in temperature, and amount of blood were evaluated.
Significant differences in the number of vessels were observed on the insulin-treated side (96 ± 47) when compared with the no-insulin side (32.88 ± 45) (p < 0.026). The percentage of fibrosis (insulin: 44.42 ± 30.42 percent versus no insulin: 12.38 ± 36.17 percent; p < 0.047) and the mean temperature (insulin: 1.27 ± 1.12°C versus no-insulin: 0.13 ± 1.22°C; p < 0.001) were also significantly different between sides. No adverse events related to the study occurred.
The use of local insulin improves the formation of new blood vessels, increases fibrosis, and correlates with increased temperature.
Therapeutic, II.
Inflammation, the initiating stage of wound healing, is characterized by increased endothelial permeability, infiltration of inflammatory cells, and secretion of numerous growth factors and chemokines. By controlling wound contamination and infection, as well as inducing the repairing process, inflammatory response plays an irreplaceable role during wound healing. We utilized a variety of approaches to observe the effect of insulin on wound inflammatory response, specifically the effect of insulin on the function of wound macrophages. We also investigated whether insulin-regulated inflammatory response contributed to insulin-induced healing. Mice excisional wounds treated with insulin showed advanced infiltration and resolution of macrophages, which correlated with the expression of monocyte chemotactic protein-1, a potent chemotactic factor for macrophages. Blockage of monocyte chemotactic protein-1 resulted in reduced macrophages infiltration and impaired wound healing despite the presence of insulin. In vitro studies showed insulin-facilitated monocytes/macrophages chemotaxis, pinocytosis/phagocytosis, and secretion of inflammatory mediators as well. Our study strongly suggests that insulin is a potent healing accelerant. Regulating wound inflammatory response, especially the quantity and function of macrophages, is one of the mechanisms explaining insulin-induced accelerated wound healing.
The generic and oral health-related quality of life (QoL) has provided opportunity for investigation of the interrelations among generic health, oral health, and related outcomes. The purpose of this study was to identify the generic and oral QoL in the patients with oral mucosal disease (OMD).
Five hundred and thirty-eight OMDs were recruited in this study. The instruments applied were Chinese version of the 36-item short form health survey (SF-36) and the short-form of Oral Health Impact Profile (OHIP-14).
The mean score of sum OHIP-14 was significantly higher in the patients with OMD (10.81 ± 9.01) compared with those in the healthy subjects (HS) (6.55 ± 6.73) (p < 0.001, Mann-Whitney U test). 56.51% of the OMD patients and 12.94% of the HS reported at least one oral negative impact (p < 0.001, Chi-square test). The overall mean score of SF-36 was significantly lower in the patients with OMD (74.54 ± 12.77) compared with those in the HS (77.97 ± 12.39) (p = 0.021, t-test).
Administration of specific and generic questionnaires of QoL can provide us a detailed picture of the impact of OMDs on patients, and both generic and oral QoL were impaired in the patients with OMD.
Although the literature contains evidence demonstrating the beneficial effects of insulin on wound healing, no suitable method for the routine administration of insulin has been reported. A randomized, double-blind, placebo-controlled trial was conducted to determine the safety and efficacy of topical insulin on healing in 45 patients (29 men, mean age for both groups 40.62 years, range 12 to 71 years) with noninfected acute and chronic extremity wounds. Patients were randomly assigned to twice-daily topical application (spray) of 1 cc saline 0.9% for each 10 cm2 of wound with or without 10 units (0.1 cc) of insulin crystal and insulin. The endpoint was complete wound closure. Systemic glucose levels were measured before and 1 hour after treatment application. No patients developed signs or symptoms of hypoglycemia and glucose levels pre- and post-application did not differ significantly. Time to healing did not differ significantly between treatment groups. Healing rates were affected by baseline wound area, patient age, wound type (acute versus chronic), and treatment group. The mean rate of healing rate was 46.09 mm2/day in the treatment and 32.24 mm2/day in the control group (P = 0.029), independent of baseline wound size. In this study, the topical application of insulin was safe and effective. Clinical studies with a larger sample size and that include patients with diabetes mellitus are warranted.
The suitability of surface modified liposomes as drug carriers for brain-specific targeting was investigated using apolipoprotein E fragments as brain-directed vectors. Liposomes coated with polyethylene glycol-2000 (sterically stabilized, PEGylated liposomes) were prepared from hydrogenated egg phosphatidylcholine, cholesterol, and a PEG-derivatized phospholipid. Liposomes were covalently coupled to a peptide of 26 amino acids length, derived from the binding site of human apolipoprotein E4 (ApoE4) and a peptide of random amino acid sequence, respectively. Rhodamine-labeled dipalmitoylphosphatidylethanolamine was incorporated into the lipid bilayer in order to visualize the liposomal interaction with brain capillary endothelial cell monolayers. The interaction of the liposomes with monolayers of porcine brain capillary endothelial cells (BCEC), the rodent cell line RBE4, and freshly isolated porcine brain capillaries was studied by means of confocal laser scanning fluorescence microscopy. In contrast to random peptide coupled liposomes, the ApoE4-fragment coupled liposomes were rapidly taken up by cultured BCECs and RBE4 cells. Uptake could be inhibited by ApoE4, free peptide, and antibodies against the LDL receptor in a concentration-dependent manner. The results indicate that the liposomes are internalized via the LDL receptor, which is expressed at the blood-brain barrier. In conclusion, liposomes coupled to ApoE4 fragments are taken up into brain endothelium via an endocytotic pathway and may therefore be a suitable carrier for drug delivery to the brain.
Regenerative wound repair is a goal of modern medicine. This is important not only for the local repair but also for its beneficial effect to systemic physiological processes. When wounds become chronic, individuals are susceptible to generalized inflammatory cascades that can affect many organs and even lead to death. Skin is the most commonly injured tissue, and its proper repair is important for reestablishment of its barrier function.
We show here that insulin, when topically applied to skin excision wounds, accelerates re-epithelialization and stimulates "maturation" of the healing tissue. These effects are dependent on the insulin receptor but independent of EGF/EGF-R; PI3K-Akt-Rac1 signaling pathways are critically involved, and healing is alpha3 and LN332-dependent.
Insulin has great potential for the treatments of chronic wounds in which re-epthelialization is impaired. Understanding of the pathways induced by insulin is important for the development of analog molecules that function strictly in healing. Because of its long history of safe use in humans for decades, this protein may prove to be a powerful therapy without major adverse effects.
Insulin is proposed as a therapy for suppressing muscle wasting after burn trauma although the long-term effects of this therapy on wound healing are not yet known. The present study was designed to investigate the effect of systemically administered insulin therapy on burn wound healing.
Young rats weighing 80-150 g were subjected to 15-20% total body surface area burn injury on their shaved dorsum. The insulin dosage was increased over the first 3 days in each rat from 0.25 U (Day 1), 0.5 U (Day 2), and 1.0 U (Day 3) per 100 g body wt. The rats were euthanized at the fourth or fifteenth day postinjury. Skin sections were analyzed by histochemistry and quantitative polarization microscopy.
Histology showed a decreased number of inflammatory cells and increased vasodilation in the insulin-treated animals at Day 4 relative to untreated rats; at Day 15 there was increased reepithelialization. Quantitative analysis using polarization microscopy and picrosirius red staining showed an increased collagen deposition in wounds by Day 4 in insulin-treated rats relative to untreated burn controls.
These results indicate that insulin induces accelerated wound healing associated with diminished inflammation and increased collagen deposition.
To determine whether topical application of insulin normalizes delayed corneal wound healing in rats with diabetes mellitus (DB).
Diabetes mellitus was induced with streptozocin. A 5-mm corneal abrasion at 9 or 11 weeks was treated topically for 7 days (4 times daily) with 1, 2, or 5 U of insulin or with sterile vehicle (SV).
Residual corneal epithelial defects of rats with DB receiving SV (hereafter called DB SV rats or animals) were approximately 35% larger than in healthy animals receiving SV (hereafter called healthy SV rats or animals). Rats with DB receiving topical insulin had wounds ranging from 19% to 60% smaller than DB SV rats, corresponding to wound sizes in healthy SV rats. Topical insulin had no effect on reepithelialization of corneal wounds in healthy SV rats. Insulin did not affect corneal thickness, ocular pressure, or serum glucose level. The corneal sensitivity of DB SV rats was markedly reduced from healthy SV rats, but rats with DB given insulin had corneal sensitivity values comparable to the healthy SV group. DNA synthesis was decreased in DB SV corneal epithelium but was comparable to that in healthy SV rats after they received insulin; apoptosis and necrosis levels were similar in all groups.
Topical insulin normalizes corneal reepithelialization in diabetic rats.
Direct application of insulin may serve as an important strategy for treating diabetic keratopathy.
Aphthous stomatitis is a painful and often recurrent inflammatory process of the oral mucosa that can appear secondary to various well-defined disease processes. Idiopathic recurrent aphthous stomatitis is referred to as recurrent aphthous stomatitis. The differential diagnosis for recurrent aphthous ulcerations is extensive and ranges from idiopathic benign causes to inherited fever syndromes, to connective tissue disease, or even inflammatory bowel diseases. A thorough history and review of systems can assist the clinician in determining whether it is related to a systemic inflammatory process or truly idiopathic. Management of aphthous stomatitis is challenging. For recurrent aphthous stomatitis or recalcitrant aphthous stomatitis from underlying disease, first-line treatment consists of topical medications with use of systemic medications as necessary. Herein, the authors discuss the differential diagnosis and treatment ladder of aphthous stomatitis as described in the literature.
Objective
In recent years, there has been a tendency to search for regulatory substances that can optimize the healing process of perforated tympanic membranes (TMs). The purpose of this study was to determine the effects of using topical insulin on the healing process of traumatic TMs perforations.Study DesignExperimental.Methods
Tympanic membranes of 20 Wistar rats were perforated in two sections, anterior and posterior to the malleus. The rats were divided into two groups: control and insulin. The insulin group was treated with topical regular insulin. The TMs were histologically examined 3, 5, and 7 days after the perforation through a morphometric analysis of the epithelial layer thickness, perforation size, TM cross-sectional area, semiquantitative and qualitative evaluation of the collagen production by polarization microscopy, and immunohistochemical evaluation of epithelial cells and myofibroblasts markers.ResultsInsulin accelerated the healing process of the perforated TMs (P < 0.01); stimulated early thickening of the outer epithelial layer (P < 0.01); contributed to a larger identification of the antipankeratin antibody as epithelial marker (P < 0.05); and increased labeling of smooth muscle anti-alpha-actin antibody (P < 0.05), indicating greater proliferation of myofibroblasts. When the topical insulin was used, it resulted in a greater formation of collagen tissue (P < 0.05), with thicker and better-organized collagen fibers (P < 0.05).Conclusion
Insulin accelerated the healing process of TMs traumatic perforations.Level of EvidenceN/A. Laryngoscope, 2015
Objectives
The role of glucose metabolism disorders in periodontal diseases including recurrent aphthous stomatitis (RAS) is currently attracting attention. The aim of this study is to investigate insulin resistance (IR) in patients with RAS in otherwise healthy individuals.
Materials and methods
The study enrolled 81 patients with RAS and 61 healthy control subjects. Blood glucose, insulin, C-peptide, hemoglobin A1c, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and HOMA-IR were measured in each individual.
Results
Forty-two of the RAS group were in the active, and 39 of the RAS group were in the passive stage. The levels of c-peptide, insulin, and HOMA-IR were remarkably higher in the RAS group (p = 0.015; p
When wounds are treated with regular insulin, they are also being treated with zinc; used in the formula to crystallize insulin molecules. It is not clear if regular insulin-accelerated wound healing is due to insulin, the zinc it contains, or both. Thus, we aimed to compare topical regular crystalline insulin (containing zinc) vs. aqueous zinc chloride solution to controls, on healing of open uncomplicated cutaneous wounds. In this randomized controlled pilot study, 90 nondiabetic patients were randomly assigned to one of three groups depending on the twice daily applications received; group I: regular insulin; group II: aqueous zinc chloride solution, and group III: 0.9% saline (control). A questionnaire was used to determine the effect of wounds on the quality of life. Both topical regular crystalline insulin (containing zinc) and aqueous zinc chloride solution enhanced healing of uncomplicated cutaneous wounds of nondiabetic patients, than control (p < 0.001), and hence improved patients' quality of life. However, regular insulin showed better results than aqueous zinc solution (p = 0.015), probably due to synergistic effect between insulin and zinc of its formulation. Healing rate was significantly higher in acute than chronic wounds (p < 0.001), in those ≤40 years than those >40 (p = 0.004), and in upper body wounds than lower body (p = 0.015).
This study assessed the effects of systemic omega-3 on the treatment of recurrent aphthous stomatitis and on the improvement of quality of life.
Fifty participants were randomly assigned to receive either omega-3 (1 g, 3 times daily) or placebo for 6 months. Assessment of outcome measures including monthly number of new ulcers, average duration of ulcer episodes, and pain level of ulcers was carried out at baseline and monthly for 6 months. Analysis of potential impact on quality of life using the Oral Health Impact Profile 14 was carried out at baseline and 6 months.
Daily omega-3 treatment achieved a significant reduction in number of ulcers, duration of ulcers, and level of pain by 3 months that persisted for 6 months. Mean score on Oral Health Impact Profile 14 also significantly improved by 6 months.
A daily omega-3 regimen shows promise as therapy for treatment and management of patients with recurrent aphthous stomatitis.
Insulin plus glucose, given for 7 days to hypermetabolic burn patients, has been shown to stimulate limb protein anabolism. We hypothesized that insulin plus glucose given to burn patients would also stimulate wound healing.
Six patients with burns >40% total body surface area were randomized to receive insulin or placebo in a crossover study during the healing of their first and second donor sites. Insulin treatment was titrated at 25 to 49 U/h to achieve a plasma insulin level of 400 to 900 microU/mL for 7 days. Patients receiving insulin received dextrose 50 at 20 to 50 mL/h, titrated to maintain euglycemia. Donor-site biopsies were taken at 7 days and evaluated by three observers blinded to the treatment.
The mean (+/-SD) donor-site healing time was reduced from 6.5 +/- 1.0 days with placebo to 4.7 +/- 1.2 days during insulin infusion (p < 0.05). Laminin showed intense staining along the basal lamina and blood vessels. Collagen type IV staining also increased after insulin therapy compared with placebo.
Data indicate that high doses of insulin and glucose can be safely administered to massively burned patients to improve wound matrix formation.
Diabetes is a condition known even in its early stages to impair the normal course of wound healing, thus leading to chronic wounds. The role of insulin in the regulation of energy metabolism, protein synthesis, cell differentiation and growth suggests that this hormone could also play an essential role in regulation of wound healing.
To determine the effects of topical insulin administration on wound healing in rats with or without acute diabetes.
This study was conducted using four groups of male Sprague-Dawley rats: (i) nondiabetic rats receiving topical insulin (n = 7), (ii) nondiabetic rats receiving topical sterile water (n = 7), (iii) diabetic rats receiving topical insulin (n = 7) and (iv) diabetic rats receiving topical sterile water (n = 7). Wound healing was assessed by wound contraction rate, complete epithelialization time and histological results.
Topical insulin enhanced wound healing by shortening the time needed for complete epithelialization in both the nondiabetic and acute diabetic groups. The histological observations supported the planimetric results in both groups.
This study revealed that topical insulin application to cutaneous wounds accelerates wound healing in rats with or without acute diabetes.
The objectives of this study were to clinically determine the topical efficacy and safety of amlexanox oral adhesive tablets in the treatment of recurrent minor aphthous ulcerations (MiRAU) in a Chinese cohort.
A randomized, double-blind, vehicle-controlled, unparallel multicenter clinical trial was carried out. The tablets were applied by subjects themselves 4 times a day for 5 days. Four parameters (pain scale, size change, degree of erythema and exudation, and efficacy index) were recorded both before (baseline) and during the trial (on the morning of days 4 and 6).
There were 104 and 108 subjects who fulfilled the trial in the amlexanox group and the vehicle-control group, respectively. Group differences for all parameters but degree of erythema and exudation of day 4 were statistically significant both for the day 4 visit and the day 6 visit (P < .05). No systemic side effects were reported.
Amlexanox oral adhesive tablets are effective and safe in reducing aphthous ulcer pain and lesion size, as well as erythema and exudation in this Chinese cohort.
To translate the original English version of the Oral Health Impact Profile (OHIP) into an Arabic version, and to investigate the psychometric properties of the translated instrument among adults in Saudi Arabia.
The original English version of OHIP with 49 items was translated into Arabic following accepted cultural adaptation technique guidelines using a forward-backward method. After pilot testing, the instrument was administered to 426 adults in Saudi Arabia.
A priori hypothesised associations between the OHIP summary score, self-reported oral health and five oral disorders were confirmed in a convenience sample of the general population (n = 356). These associations were interpreted as support for construct validity. The instrument's responsiveness, as indicated by a mean OHIP summary score change from 62.27 to 14.00, was established in 30 consecutive patients treated for complete and removable partial dentures. Test-retest reliability was demonstrated by intraclass correlation coefficients of 0.75 - 0.90 for dimensions and summary score (n = 40). Internal consistency was high (Cronbach's alpha > 0.74) in the general population sample.
Sufficient psychometric properties of the OHIP-A make the instrument suitable for assessment of oral health-related quality of life in Saudi Arabia.
Systemically administered insulin has been shown to accelerate wound healing. To minimize the hypoglycemic and hypokalemic effects of insulin, we investigated a new route of insulin administration by local injection into skin wounds.
Partial thickness skin donor site wounds were created on the backs of adult rabbits with a dermatome set at 0.015 inch. The wounds were covered by Aquaphor gauze (Smith and Nephew, Largo, FL), and OpSite membrane (Smith and Nephew, Hull, United Kingdom) and protected by rabbit jackets. Long-acting insulin-zinc suspension was selected for local injection. In study 1, insulin was injected into the wound at different doses, and the concentrations of blood glucose and wound insulin were measured to determine the proper dose and injection frequency. In study 2, wound healing days were compared between two groups (n = 7 each) receiving local injection of either insulin-zinc or zinc alone as control. Based on the results from study 1, a dose of 0.25 units of long-acting insulin-zinc suspension was injected into the wound every other day in the insulin group.
After injection, 0.25 units of insulin decreased blood glucose concentration (minimum 60 mg/dL) during the first 3 h, which then returned to the preinjection level (80 mg/dL). One injection maintained wound insulin concentration above 50 muU/mL for more than 24 h. With local injection of 0.25 units insulin-zinc every other day, the wound healing time was 11.2 +/- 2.3 d, which was faster (P = 0.02) than 15.1 +/- 4.1 d in the control group.
Local injection of long-acting insulin-zinc suspension accelerated skin wound healing without major systemic side effects, demonstrating its potential usefulness in burn treatment.
Wound healing is a dynamic and complex biologic process that could be accelerated by growth factors. To investigate the efficacy of topical recombinant human acidic fibroblast growth factor (rh-aFGF) treatment in deep partial-thickness burn or skin graft donor sites, we designed a randomized, multicenter, double-blind, and placebo-controlled clinical trial. The healing rate, fully healed rate, and healing time were evaluated to assess the efficacy of rh-aFGF application. Laboratory examinations and abnormal signs were used to assess the side and toxic effects. The results showed that the healing rate of burn wounds and skin graft donor sites treated by rh-aFGF was significantly higher than that by placebo, and the mean healed time of burn wounds and skin graft donor sites in the rh-aFGF group was significantly the shorter than that in the placebo group. In conclusion, topical administration of rh-aFGF can accelerate the wound healing process and shorten the healed time. It is a potential therapeutic application for promoting healing of deep partial-thickness burns or skin graft donor sites.
Effect of insulin on healing of pressure sore
- Ebrahimifard F