Spinal epidural fibrosis following hemostatic agent employment.

OBJECTIVE: Failed Back Surgery Syndrome (FBSS) refers to a subset of patients who have new or persistent pain after spinal surgery for back or leg pain. Epidural fibrosis (EF) is a common cause of FBSS. Many agents aiming to prevent EF have been tested. However, hemostatic agents are readily available at hospitals, easy to reach and frequently used. For these reasons, oxidized regenerated cellulose, polysaccharide hemostat, hemostatic thrombin-gelatin matrix and chitosan linear polymer were evaluated for their effects on epidural fibrosis on rats after laminectomy. METHODS: 40 Sprague-Dawley rats were randomly divided into 5 equal groups including the control group where only the laminectomy was performed. The other 4 groups received hemostatic agents after laminectomy. The rats were euthanized 45 days later and were assessed by a blinded observer to grade the fibrosis level. RESULTS: The study revealed that oxidized regenerated cellulose, polysaccharide hemostat and hemostatic thrombin-gelatin matrix lowered the epidural fibrosis grade which was statistically significant (p < 0.001). Although chitosan linear polymer created fibrosis similar to the control group it was not proven to be statistically significant (p = 0.8999). However, when compared with other hemostatic agents it resulted in a higher fibrosis grade (p < 0.001). CONCLUSION: The results obtained from this experimental study revealed that Pahacel, Sealfoam and Surgiflo, were effective in reducing epidural fibrosis after laminectomy in rats.

MicroRNA-29a Mitigates Laminectomy-Induced Spinal Epidural Fibrosis and Gait Dysregulation by Repressing TGF-ß1 and IL-6.

Spinal epidural fibrosis is one of the typical features attributable to failed back surgery syndrome, with excessive scar development in the dura and nerve roots. The microRNA-29 family (miR-29s) has been found to act as a fibrogenesis-inhibitory factor that reduces fibrotic matrix overproduction in various tissues. However, the mechanistic basis of miRNA-29a underlying the overabundant fibrotic matrix synthesis in spinal epidural scars post-laminectomy remained elusive. This study revealed that miR-29a attenuated lumbar laminectomy-induced fibrogenic activity, and epidural fibrotic matrix formation was significantly lessened in the transgenic mice (miR-29aTg) as compared with wild-type mice (WT). Moreover, miR-29aTg limits laminectomy-induced damage and has also been demonstrated to detect walking patterns, footprint distribution, and moving activity. Immunohistochemistry staining of epidural tissue showed that miR-29aTg was a remarkably weak signal of IL-6, TGF-ß1, and DNA methyltransferase marker, Dnmt3b, compared to the wild-type mice. Taken together, these results have further strengthened the evidence that miR-29a epigenetic regulation reduces fibrotic matrix formation and spinal epidural fibrotic activity in surgery scars to preserve the integrity of the spinal cord core. This study elucidates and highlights the molecular mechanisms that reduce the incidence of spinal epidural fibrosis, eliminating the risk of gait abnormalities and pain associated with laminectomy.

The effectiveness of organic vegetable oils with high biocompatibility in preventing epidural fibrosis: An experimental study.

Background and purpose:

Epidural fibrosis after all spinal surgeries is an important surgical issue. Various biological and non-biological materials have been tried to inhibit epidural fibrosis, which is deemed to be the most important cause of pain after spinal surgery. Olive oil, nigella sativa oil and soybean oil employed in oral nutrition in clinics involving liquid fatty acids, palmatic acid, linoleic acid, stearic acid and palmitoleic acid. The effectiveness of olive oil, nigella sativa oil and soybean oil on epidural fibrosis was researched on for the first time in laminectomy model.

Fifty adult male Wistar albino rats weighing between 300 and 400 grams were used in the research. A total of 5 groups were formed: sham (Group I) (n = 10), no application was created; Group II (n = 10) 1 cc saline; Group III (n = 10) 1 cc olive oil; Group IV (n = 10) 1 cc nigella sativa oil; Group V (n = 10); 1 cc soybean oil was applied topically to the epidural region after laminectomy. The total spine of the rats was dissected, histopathological and immuno­chemical measurements were conducted. Neuro-histopathological results were scored semi-quantitatively in terms of vascular modification, neuron degeneration, gliosis and bleeding criteria.

The lowest level of fibrosis and connective tissue proliferation was observed in the group where nigella sativa oil was used after the operation, followed by the group treated with olive oil and lastly with the group given soybean oil.

Nigella sativa oil and olive oil are very efficient for lowering the degree of epidural fibrosis and adhesions following laminectomy and can be employed as a simple, inexpensive and highly biocompatible material in clinical practice.

Medical ozone treatment on prevention of epidural fibrosis in the rat model.

Background/Aim: Epidural fibrosis is one of the problems that can be seen after spinal surgery. The aim of this study was to investigate the possible preventive role of medical ozone (O) treatment on epidural fibrosis. Materials and Methods: Twenty-four Sprague Dawley rats were randomly split into four groups: control (C), O, laminectomy (L), and L+O groups. Animals in the C group were sacrificed at the beginning of the experiment. The L and L+O groups had L procedure, while O treatment was supplied for the O and O+L groups. After 42 days of follow-up, for histological evaluation and biochemical measurements, the ratio of epidural fibrosis and catalase (CAT) with malondialdehyde (MDA) levels in serum, respectively, were analyzed in terms of statistical differences. Results: Histologically, a distinct difference was o bserved in the epidural space after O treatment. A significant difference in epidural fibrosis areas is found to be between the O, L, and O+L groups (P < 0,0001). There was no statistically significant difference between CAT and MDA levels that were obtained by spectrophotometric analysis. Conclusion: Histological results suggest that medical O treatment after L can be used as an alternative method to prevent epidural fibrosis. Further studies with wide cohorts and interval measures are required to detail the effects of doses.

Six Revision Surgeries for Massive Epidural Fibrosis with Recurrent Pain and Weakness in the Left Lower Extremity.

Epidural fibrosis is a common cause of pain after lumbar surgeries. There are no previous reports documenting profound limb weakness associated with epidural fibrosis. A 43-year-old woman uneventfully underwent microscopic discectomy. However, six additional surgeries were needed due to recurrent pain and weakness episodes, several days after the surgery. Operative findings were severe epidural fibrosis around the thecal sac and nerve roots. Epidural fibrosis excision did not prevent recurrent fibrosis; therefore, we performed a lordotic fusion with posterior column shortening to reduce neural tension and nerve-root stretching. Eventually, she became free from recurrent episodes of deteriorations and repetitive surgeries.

Metformin attenuates post-epidural fibrosis by inhibiting the TGF-ß1/Smad3 and HMGB1/TLR4 signaling pathways.

Excessive post-epidural fibrosis is a common cause of recurrent back pain after spinal surgery. Though various treatment methods have been conducted, the safe and effective drug for alleviating post-epidural fibrosis remains largely unknown. Metformin, a medicine used in the treatment of type 2 diabetes, has been noted to relieve fibrosis in various organs. In the present study, we aimed to explore the roles and mechanisms of metformin in scar formation in a mouse model of laminectomy. Post-epidural fibrosis developed in a mouse model of laminectomy by spinous process and the T12-L2 vertebral plate with a rongeur. With the administration of metformin, post-epidural fibrosis was reduced, accompanied with decreased collagen and fibronectin in the scar tissues. Mechanistically, metformin decreased fibronectin and collagen deposition in fibroblast cells, and this effect was dependent on the HMGB1/TLR4 and TGF-ß1/Smad3 signalling pathways. In addition, metformin influenced the metabolomics of the fibroblast cells. Taken together, our study suggests that metformin may be a potential option to mitigate epidural fibrosis after laminectomy.

Pirfenidone inhibits fibroblast proliferation, migration or adhesion and reduces epidural fibrosis in rats via the PI3K/AKT signaling pathway.

OBJECTIVE: This present study aims to assess the effect of pirfenidone (PFD) on inhibiting fibroblast proliferation, migration or adhesion in vitro and reducing laminectomy-induced epidural fibrosis in vivo. METHODS: The effect of PFD on proliferation inhibition was evaluated with flow cytometry, CCK-8, EdU and western-blotting assays. Altered properties in migration and adhesion were confirmed by wound-scratch, transwell, immunofluorescence (IF), cell adhesion and western-blotting assays. Additionally, fifty male healthy Sprague-Dawley rats were subjected to laminectomy and then treated with various concentrations of PFD. After 4 weeks, the degree of epidural fibrosis was evaluated by histological analysis. RESULTS: In vitro, the results of flow cytometry, CCK-8, EdU and western-blotting assays showed that PFD reduced fibroblast proliferation by a dose-dependent manner. And the results of wound-scratch, transwell, IF, cell adhesion and western-blotting assays showed that the migration and adhesion of fibroblasts could be inhibited and the cytoskeleton could also be altered in a dose-dependent manner. And the inhibitory effect of PFD could be partially reversed in the PI3K overexpression experiment, which indicated that the capability of PFD to inhibit fibroblast proliferation, migration and adhesion might be through the PI3K/AKT signaling pathway. In vivo, an obvious reduction in epidural fibrosis was observed in groups topically treated with PFD. CONCLUSIONS: Topical PFD application obviously suppressed laminectomy-induced epidural fibrosis, possibly by inhibiting fibroblast proliferation, migration and adhesion via the PI3K/AKT signaling pathway. PFD may be a safe and effective pharmaceutical to reduce clinical epidural fibrosis.

Comparison of the effect of bipolar coagulation and fibrillar structured oxidized cellulose on formation epidural fibrosis in rats

Background/aim: Epidural fibrosis (EF) is a common cause of failed back surgery syndrome seen after spinal surgeries. The most frequent reason for the formation of EF is accumulated blood and its products in the operation zone. On the development of EF, the effect of bipolar coagulation and fibrillar oxidized cellulose, which are used frequently to control bleeding, was investigated. Materials and methods: In the study, 45 male Sprague Dawley rats were divided into three groups (control, fibrillar, and bipolar). Lumbar laminectomy was applied to all rats under sterile conditions. In the control group, the epidural area was washed with saline solution. Bleeding was controlled with fibrillar oxidized cellulose in the fibrillar group, with bipolar coagulation in the bipolar group. The area to which laminectomy had been applied was removed as a block 6 weeks later and evaluated histopathologically and genetically in terms of EF development. Fibrosis degree was determined histopathologically by counting fibroblasts using the modified Lubina and EF He grading systems. Interleukin-6 (IL-6), transforming growth factor beta-1 (TGFß-1), and mRNA levels were measured by the droplet digital polymerase chain reaction method. Results: The number of epidural fibroblasts, percentage of modified Lubina, amount of IL-6, and He grading rates were significantly lower in the fibrillar group than in the bipolar and control groups (p ˂ 0.05). On the other hand, there was no significant difference among the control, fibrillar, and bipolar groups in terms of TGFß-1 values (p= 0.525). Conclusion: The use of fibrillar oxidized cellulose was more effective for hemostasis than bipolar coagulation in reducing the development of EF.

The histopathological effects of reabsorbable polyethylene glycol hydrogel (Coseal) on epidural fibrosis in an experimental postlaminectomy model in rats

Background/aim: To investigate the histopathological effects of reabsorbable polyethylene glycol hydrogel (RPGH, Coseal) on epidural fibrosis (EF) following laminectomy in rats. Materials and methods: A total of 24 rats were equally divided into three groups. In the first group, no treatment was applied after laminectomy (control group, Group 1). In the second group, hemostasis was achieved after laminectomy, and 2 mm absorbable gelatin sponge soaked in saline was placed over the epidural space and the wound was closed (Group 2). In the third group, hemostasis was achieved following laminectomy, and 0.5 mL RPGH (Coseal, Group 3) was squeezed over the dura mater, and the wound was closed. A histopathological examination was undertaken to evaluate arachnoidal invasion and EF. Results: The results of EF in the Group 2 and Group 3 were significantly lower compared to the Group 1 (p = 0.023 and p = 0.002, respectively). No statistically significant difference was found between the Group 2 and Group 3 in terms of EF (p = 0.957). There was also no statistically significant difference between the mean arachnoidal invasion of the three groups (p > 0.171). However, the rate of arachnoidal invasion was the lowest in the Group 3. Conclusion: Intraoperative Coseal, a polyethylene glycol polymer, tends to reduce the risk of epidural fibrosis, although this is not statistically significant.

Differentiating epidural fibrosis from disc herniation on contrast-enhanced and unenhanced MRI in the postoperative lumbar spine.

OBJECTIVE: To determine diagnostic confidence and inter-observer/intra-observer agreement in differentiating epidural fibrosis from disc herniation and lumbar spinal stenosis parameters on magnetic resonance images (MRI) in postoperative lumbar spines with (Gad-MRI) and without (unenhanced MRI) intravenous gadolinium-based contrast agent. SUBJECTS AND METHODS: N = 124 lumbar spine MRI examinations of four groups were included: 1-6 months, 7-18 months, 19-36 months, more than 37 months between lumbar spine surgery and imaging. Two radiologists evaluated Gad-MRI and unenhanced MRI: diagnostic confidence was determined as confident or unconfident. Inter-observer and intra-observer agreement were assessed in differentiating epidural fibrosis from disc herniation and for lumbar spinal stenosis parameters on MRI. Fisher's exact test and Cohen's kappa served for statistics. RESULTS: Diagnostic confidence in differentiating epidural fibrosis from disc herniation was significantly higher on Gad-MR images compared with unenhanced MRI at 1-18 months for observer 1 and at 1-6 months postoperatively for observer 2 (p values: 0.01-0.025). Inter-observer agreement at 1-6 months postoperatively for identification of epidural fibrosis was higher on Gad-MRI (kappa values: 0.53 versus 0.24). Inter-observer and intra-observer agreement for identification of disc herniation and for assessment of lumbar spinal stenosis parameters revealed inconsistent data, without a trend for higher inter-observer or intra-observer agreement on Gad-MRI compared with unenhanced MRI (kappa values: 0.17-0.75). CONCLUSION: Gad-MR images compared with unenhanced MRI improved diagnostic confidence and agreement in differentiating epidural fibrosis from disc herniation for both observers in the first 6 months and for one observer in the first 18 months after lumbar spine surgery. After 18 months, Gad-MR images compared with unenhanced MRI did neither improve confidence nor agreement.

Schisandrin B attenuates epidural fibrosis in postlaminectomy rats by inhibiting proliferation and extracellular matrix production of fibroblasts.

Laminectomy has been widely considered one of the most common treatments for lumbar disorders. Epidural fibrosis (EF) is a common complication after laminectomy, causing recurrent postoperative pain. Schisandrin B (Sch.B), the active ingredient extracted from Schisandra chinensis Fructus, has been found to have potent antiproliferative and antifibrotic effects on several cells. This study aimed to investigate the effects of Sch.B on the prevention of postlaminectomy EF formation. In vitro, we studied the effects of Sch.B on transforming growth factor beta 1 (TGF-ß1)-induced proliferation and extracellular matrix (ECM) production of primary fibroblasts, as well as its underlying mechanism. We found that Sch.B not only inhibited the proliferation of fibroblasts but also reduced ECM production, including that of connective tissue growth factor, fibronectin, and type I collagen, in a dose-dependent manner. Mechanistically, we found that Sch.B suppressed TGF-ß1-stimulated activation of the Smad2/3 and mitogen-activated protein kinase pathways. Moreover, the in vivo study demonstrated that Sch.B treatment attenuated the progression of EF in a postlaminectomy rat model via reducing the cell number and ECM production of scar tissue. Taken together, these data suggested that Sch.B possesses great potential value as a preventative agent for EF.

Preventative effect of diclofenac sodium and/or diltiazem in rats with epidural fibrosis.

OBJECTIVE: Spinal epidural fibrosis is commonly seen after laminectomy. There is not yet proven any agent preventing fibrosis in clinical usage. We used diclofenac sodium and diltiazem, which are fibrosis inhibitors. METHODS AND MATERIALS: 40 rats were divided into four groups of equal numbers: control, diclofenac sodium, diltiazem, and diclofenac sodium + diltiazem. Laminectomies were performed at L5 and L6. After a 4 week period, the rats were decapitated and the vertebral column blocks were removed for histopathologic examination. Fibrosis percentage, spread of fibrous regions, and fibroblast numbers were evaluated in each group and compared between the groups. RESULTS: The distribution of epidural fibrosis density, percentage of fibrosis, and distribution of fibroblasts in the diclofenac sodium + diltiazem group were significantly lower than in the other groups. The fibroblast numbers of the diltiazem, and diclofenac sodium + diltiazem groups were significantly lower than in the other groups. CONCLUSION: Diclofenac sodium + diltiazem used together provided better outcomes because each of them prevented fibrosis via different ways, probably through synergistic action (Tab. 5, Fig. 3, Ref. 43).

Tamoxifen inhibits fibroblast proliferation and prevents epidural fibrosis by regulating the AKT pathway in rats.

Many factors contribute to epidural fibrosis after lumbar laminectomy, particularly the excessive proliferation of fibroblasts. Many studies have shown that tamoxifen (TAM) inhibits fibroblast proliferation and reduces fibrosis, but the detailed effect and mechanism of TAM on preventing epidural fibrosis are unknown. To investigate the effect of TAM on fibroblast proliferation and epidural fibrosis, fibroblasts were cultured and treated with different concentrations of TAM. Cell Counting Kit-8(CCK-8) detection, cell cycle analysis and western blot analysis were used to detect the roles of TAM in regulating fibroblast proliferation. Lumbar laminectomies were performed in rats, and various concentrations of TAM were administered by gavage. Histological and immunohistochemical analyses were used to evaluate the effects of TAM on preventing epidural fibrosis. CCK-8 detection showed that TAM could inhibit fibroblast viability; western blot analysis showed that TAM could decrease the expression of proliferative proteins p-AKT and cyclinD1 and increase the expression of antiproliferative proteins P21 and P27. Histological analysis showed that TAM could reduce epidural fibrosis. Immunohistochemical analysis showed that the p-ATK expression in epidural scar tissue was decreased after TAM treatment. The present study demonstrated that TAM could inhibit fibroblast proliferation and prevent epidural fibrosis, potentially through the regulation of the AKT pathway.

Tacrolimus induces fibroblasts apoptosis and reduces epidural fibrosis by regulating miR-429 and its target of RhoE.

Tacrolimus (FK506) has been demonstrated to reduce epidural fibrosis. However, the detailed mechanism of action has not been elucidated. Aberrant miR-429 is involved in many diseases. The aim of this study was to describe the exact mechanism of FK506 induced apoptosis in fibroblasts and the prevention of epidural fibrosis. FK506 induced fibroblast apoptosis was evaluated using CCK-8 assays, flow cytometry, and western blotting. The expression of miR-429 in fibroblasts treated with FK506 was determined by RT-qPCR. Additionally, luciferase activity assays were used to determine the target relationship between miR-429 and RhoE. Flow cytometry and western blot analysis were used to determine the effects of FK506 and miR-429 on fibroblast apoptosis. The effects of FK506 and RhoE on fibroblast apoptosis were determined by CCK-8 assay, flow cytometry, and western blotting. We also evaluate the effects of FK506 and miR-429 on epidural fibrosis in rats by using histological analysis and TUNEL-staining. The results revealed FK506 induces fibroblast apoptosis and significantly downregulates miR-429 expression in fibroblasts. Additionally, miR-429 downregulation caused the apoptosis of fibroblasts. The luciferase activity assay confirmed that RhoE is a direct target of miR-429 and RhoE promotes fibroblast apoptosis. The rat model demonstrated miR-429 inhibition promotes fibroblast apoptosis and epidural fibrosis, which is consistent with the results of FK506 treatment. Our study demonstrates that FK506 induces fibroblast apoptosis and reduces epidural fibrosis by regulating miR-429 expression and its target of RhoE.

The role of pegaptanib sodium in the suppression of epidural fibrosis in a postlaminectomy rat model.

OBJECTIVE: Spinal epidural fibrosis is a clinical condition that develops after laminectomy and can compress the spine. Many agents have been tried for the treatment, but none has entered clinical use at present. Pegaptanib sodium is an antiangiogenetic drug that prevents the development of new vessels and thus adhesion by inhibiting the effect of VEGF. MATERIAL AND METHOD: 20 Wistar rats were used in this study. The rats were divided into 2 different groups as the control and pegaptanib sodium group. Three levels of laminectomy were performed. Only laminectomy was performed in the control group. A cotton ball soaked with 3 mg/kg Pegaptanib sodium diluted 1: 10 with 0.9 % NaCl was topically applied to the dura in the surgical field for 5 minutes in the pegaptanib sodium group. The rats were sacrificed 3 weeks later and histopathologically examined. The epidural fibrosis was graded. RESULTS: The epidural fibrosis grade in the pegaptanib sodium was significantly lower than in the control group c2 = 11,65; (p = 0.004)CONCLUSION: Pegaptanib sodium blocked the VEGF through its anti-VEGF effect and decreased spinal epidural fibrosis in rats that had undergone laminectomy (Tab. 2, Fig. 3, Ref. 53).

Hemostasis vs. epidural fibrosis?: A comparative study on an experimental rat model of laminectomy.

AIM: The aim of this study was to evaluate the histopathological and biochemical impact and effectiveness of two hemostatic agents, Ankaferd blood stopper (ABS) and Microporous Polysaccharide Hemospheres (MPH), on epidural fibrosis in an experimental rat laminectomy model. MATERIAL AND METHODS: Twenty adult Wistar albino rats were divided into MPH-treated (n=6), ABS-treated (n=6) and control (n=8) groups. Laminectomy of the lumbar spine was performed in all animals and treatment groups were exposed to MPH and ABS while closure was applied in control group as per usual. Epidural fibrosis was evaluated in all groups macroscopically, histopathologically, biochemically and with electron microscopy four weeks later. RESULTS: Statistically, it was found that MPH-treated group had significantly less epidural fibrosis compared to ABS-treated and control groups. CONCLUSION: We compared two hemostatic agents for their propensity to cause adhesions in the present study. Our results show that MPH significantly reduces epidural scar formation and dural adhesion in a rat model of laminectomy while ABS increases postoperative fibrosis.

[Prevention and treatment of postoperative epidural scar adhesions]. / Profilaktika i lechenie posleoperatsionnogo rubtsovo-spaechnogo épidurita.

Postoperative epidural scar adhesions remain one of the most frequent late complications of microdiscectomy, which deteriorates the overall outcome in treatment of herniated lumbosacral discs. Despite a large number of conservative and surgical treatment options for epidural scar adhesions, the treatment outcome not always satisfies the patient and doctor. The review's aim was to systematize the available data on this complication and to facilitate the choice of appropriate tactics for its treatment.

ERK2 small interfering RNAs prevent epidural fibrosis via the efficient inhibition of collagen expression and inflammation in laminectomy rats.

Laminectomy is a widely accepted treatment for lumbar disorders. Epidural Fibrosis (EF) is a common post-laminectomy or post-discectomy complication, which is thought to cause recurrent pain. RNA interference (RNAi) is a process by which double-stranded RNA triggers the destruction of mRNAs sharing the same sequence. Previously, extra-cellular signal-regulated kinase (ERK) 2 plays crucial roles in suppressing the collagen expression. To investigate the effects of lentiviral ERK2 siRNA on the prevention of post-laminectomy EF formation in a rat model, a controlled double-blinded study was conducted in 75 healthy adult Wistar rats that underwent laminectomy. They were divided randomly into 3 groups according to the treatment method: (1) control group; (2) ERK scrRNA group; (3) ERK siRNA group. All rats were euthanized humanely 4 weeks post-laminectomy. The hydroxyproline content, Rydell score, vimentin cells density, fibroblasts density, inflammatory cells density and inflammatory factors expressions were performed. The hydroxyproline content, Rydell score, vimentin cells density, fibroblasts density, inflammatory cells density and inflammatory factors expressions all suggested better results in ERK siRNA group than other two groups. None of the rats expired and no obvious adverse effects were observed. Local delivery of a lentiviral siRNA targeting ERK2 can prevent epidural scar adhesion in post-laminectomy rat via inhibiting collagen expression and inflammation.

Cinnamaldehyde has Antifibrotic Effects on Rats with Epidural Fibrosis.

BACKGROUND: Laminectomy is a widely employed surgical procedure for the treatment of spinal stenosis, but it may lead to epidural fibrosis (EF) and failed back surgery syndrome. Cinnamaldehyde, a phenylpropanoid found in cinnamon, has demonstrated antioxidant and anti-inflammatory properties. In the present study, we hypothesized that topical application and systemic administration of cinnamaldehyde could be helpful in the prevention of EF in a rat laminectomy model. METHODS: The rats were randomly assigned to control, local, and systemic Tween-80 and local and systemic cinnamaldehyde experimental groups (n = 6, per group). In the control group, just laminectomy was performed. In local treatment groups, applications were done just after the laminectomy onto dura. In systemic treatment groups, intraperitoneal administrations were performed following skin suturing. The degree of epidural fibrosis was evaluated macroscopically and histopathologically 4 weeks later. RESULTS: Macroscopic assessment revealed decreased EF with both topical and systemic cinnamaldehyde application, whereas microscopic examination results were not significant. CONCLUSIONS: Our findings provide the first experimental evidence of cinnamaldehyde's potential protective effects against EF.