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The effects of keratinocyte growth factor on healing of tympanic membrane perforations.

Tympanic membrane (TM) perforations heal by reepithelialization and fibrous layer proliferation. The rat TM model may be used to study growth factors that promote epithelialization and fibroblast proliferation, such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). The authors previously evaluated the effects of FGF on tympanic membrane perforations and showed an enhanced rate of wound healing with preservation of normal structure and function. The same model was used to test keratinocyte growth factor (KGF, also called FGF-7). This growth factor has been shown to stimulate the migration and proliferation of keratinocytes. This is the first study investigating KGF in the tympanic membrane perforation model. Our results show that in contrast to FGF and EGF, KGF does not enhance the rate of wound healing, but rather results in a more organized wound repair process.

Animals↗

Embryonic stem cells enhance the healing of tympanic membrane perforations.

OBJECTIVE: Tympanic membrane perforations may cause hearing impairment and otorhea. It is a common indication for ear surgery. The aim of the study was to test whether stem cells may enhance the healing of fresh tympanic membrane perforations. METHODS: In a first assay, the status of the tympanic membrane at 5 days after myringotomy was tested in five Mongolian gerbils that were treated on one side with embryonic stem cells and on the other side with control substance. In a second assay, nine gerbils were treated in the same way, except that fluorescent-labeled embryonic stem cells were used. The integration of the stem cells into the surface layer of the healing tympanic membrane was assessed with fluorescence microscopy, as well as the differentiation of these cells. RESULTS: In the first assay, all perforations in the treated ears were closed, whereas only two of the untreated ears were closed. The strength of the healed perforation was greater in the stem cell treated tympanic membranes (mean rupture pressure 120 daPa in three treated ears compared to 60 daPa in the one control ear). Two stem cell-treated tympanic membranes remained intact throughout the whole sequence of pressures, whereas only one control tympanic membrane remained intact. In three tympanic membranes in the second assay, a group of fluorescence-doped cells was detected in the region of the perforation. CONCLUSION: These findings indicate that stem cells enhance the healing of tympanic membrane perforations, possibly by differentiation and integration into the tympanic membrane tissue.

Animals↗

A hole in the drum. An overview of tympanic membrane perforations.

BACKGROUND: Tympanic membrane perforations are common and can be categorised into either acute or chronic. Acute perforations are usually traumatic or inflammatory in origin and heal spontaneously. Chronic perforations may be associated with underlying progressive disease. OBJECTIVE: To differentiate between safe and unsafe perforations and describe management principles for these conditions. DISCUSSION: The majority of acute tympanic membrane perforations heal spontaneously. Those that do not can be considered for surgical repair. Chronic perforations should be viewed as either safe or unsafe depending on the risk of progression to significant complications. Unsafe perforations are often associated with cholesteatoma (an epidermoid cyst of the middle ear and mastoid air cell system). Cholesteatoma destroys bone and causes serious ear and intracranial complications--surgery is commonly required.

Anti-Infective Agents, Local↗

Tissue-engineered calcium alginate patches in the repair of chronic chinchilla tympanic membrane perforations.

OBJECTIVE: Chronic tympanic membrane perforations are a common problem in the United States. A high number of these cases results from placement of pressure equalization tubes. These perforations may initially be treated with paper patch techniques and although safe and well tolerated, the procedure demonstrates poor efficacy. The ideal treatment for small perforations should be rapid, minimally invasive, and efficacious. Calcium alginate-based tissue engineered tympanic membrane patches represent an attractive option, but in vivo data are required. METHODS: A controlled prospective study of tympanic membrane perforation repair using a well-known chinchilla model of chronic tympanic membrane perforation was performed. Calcium alginate-based tympanic membrane patches were created using computer-aided design techniques. A previously described chinchilla model of chronic tympanic membrane perforations was used to create stable perforations ranging from 2 to 5 mm. Ears with chronic perforations were divided into three groups: control (no patch), paper patch, and calcium alginate plugs. At 10 weeks postimplantation, all animals were killed and inspected both grossly and histologically for healing. RESULTS: In the chinchilla model, the alginate grafts demonstrated significantly improved healing rates over both the untreated control group (spontaneous repair) and the paper patch group; nine of 13 healed in the alginate group versus two of nine healed in the paper patch group (P < .05) versus one of 11 healed in the control group (P < .05). CONCLUSION: Calcium alginate tympanic membrane perforation patches offer a significant advantage in the repair of chronic perforations over traditional techniques in the chinchilla perforation model and may offer attractive opportunities in the clinical setting.

Alginates↗

Outcomes in children with perforated tympanic membranes after tympanostomy tube placement: results using a pilot treatment algorithm.

PURPOSE: The objective of this study was to examine the success of a pilot treatment algorithm for tympanic membrane perforations in children after tympanostomy tube placement. MATERIALS AND METHODS: A retrospective chart review of children with diagnosed tympanic membrane perforations after tympanostomy tube placement from 1998 to 2003 at a tertiary care children's hospital was performed. The patients had been treated according to an algorithm used by 2 pediatric otolaryngologists for management of tympanic membrane perforations: observation vs myringoplasty. Success rates were examined. RESULTS: Ninety-five children were identified, 27% of whom had nonhealing perforations after tube extrusion; 73% of the perforations were caused by a retained tube. The median duration of tube retention was 48 months, ranging from 13 to 120 months. After the treatment protocol, 76% of the patients underwent gelatin film or paper patch myringoplasty, 23% had adipose myringoplasty, and 1% were observed. Overall, 91% had healed perforations after the first intervention. Among those requiring a second intervention, the sizes of initial perforations were between 15% and 40%, with postrepair perforation sizes between 5% and 40%. In addition, 75% of those requiring a second intervention underwent tympanoplasty repair and 25% had fat patch myringoplasty. None required a third intervention. CONCLUSIONS: Our treatment algorithm for children with tympanic membrane perforations after tympanostomy tube placement appears to be successful and is an excellent model for other clinicians.

Algorithms↗

An alternative treatment for the reduction of tympanic membrane perforations: sodium hyaluronate. A double blind study.

Topical treatment with 1% sterile sodium hyaluronate solution applied on the tympanic perforation membrane has been suggested as an alternative to surgical treatment in one study only. To further investigate the effects of such a treatment, we designed a double blind study comparing topical administration of 1% sodium hyaluronate with that of 2% methylcellulose solution (placebo). After treatment the degree of perforation healing was evaluated and expressed in percentage of reduction area. The reduced area turned out to be significantly different in the group treated with sodium hyaluronate solution as compared to the placebo group. We believe that sodium hyaluronate is an alternative to myringoplasty for selected tympanic membrane perforations.

Adolescent↗

Histological study of the thin replacement membrane of human tympanic membrane perforations.

A histological study was done on the thin, nearly transparent replacement membrane of tympanic membrane perforations. Human tympanic membranes that were rejected for transplantation, were studied by light and electron microscopy. The abrupt reduction in thickness at the margin of the covered perforation, is entirely due to the reduction of the lamina propria. Even in the thinnest parts of the replacement membrane, a lamina propria is present, separated by continuous basement membranes from the epithelium and mucosa, and measuring no more than some 2-3 microns in thickness. This lamina propria consists of fibrils and interfibrillar matrix, but fibroblasts appear to be lacking. The epithelial layer does not contain basal cells, confirming the thesis that the upper layers are not generated by in situ proliferation, but that they have migrated from the periphery.

Humans↗

[Postoperative result for tympanic membrane perforation].

Ears with tympanic membrane perforation show a wide range of pathophysiology from simple perforation to mobility impairment of the ossicular chain complicated by sclerotic and/or inflammatory lesions of the middle ear. In surgery on such ears, we determine checkpoints and proceed based on the order of procedure. We studied postoperative results for 37 ears of patients undergoing tympanoplasty in the 3 years from June, 1996 to May, 1999. Lesions accountable for mobility impairment of the ossicular chain were confirmed and removed in the order of calcified tympanic membrane, tip of malleus handle, around the anterior tympanic spur, and epitympanum. Success in improving in hearing was 89.2% overall. Conductive impairment (air conduction-bone conduction gap) left on the patch test was found to differ with the site and range of tympanic and middle ear lesions. This can serve as a guide in preoperatively predicting the type of operation required.

Adult↗

Topical ascorbic acid reduces myringosclerosis in perforated tympanic membranes. A study in the rat.

Myringosclerosis, a common finding after myringotomy, has been recently associated with an increased production of oxygen free radicals. Ascorbic acid's proposed actions include collagen synthesis, antioxidation, and free radical scavenging. The effects of topical ascorbic acid on healing tympanic membranes were studied. Particular attention was given to detecting the presence of myringosclerosis. Twelve Sprague-Dawley rats were bilaterally myringotomized. Their ears were randomized into group A, which received topical ascorbic acid in Gelfoam, group B, which received topical saline solution in Gelfoam, and group C, which received no treatment. The tympanic membranes were harvested on day 13, after routine otomicroscopy. Under light microscopy, the connective tissue layer of the untouched side of the pars tensa was distinctly thicker in group A than in group B or group C. At this level, the extent of sclerotic lesions was significantly less in the ascorbic acid-treated group. It is inferred that topical ascorbic acid reduces the occurrence of myringosclerosis following tympanic membrane perforations in the rat.

Administration, Topical↗

Perforated tympanic membrane after blast injury.

The rate of spontaneous healing of tympanic membrane perforations in relation to time after blast injury, size, and location of perforations, was evaluated in 147 patients (210 ears). In 46 patients a paper patch was placed over the perforation. Spontaneous healing was seen in 155 ears (74%), 131 (62%) healed within the first 3 months and 145 ears (69%) healed within 10 months. Large and central kidney-shaped perforations had the least tendency to heal and usually required surgical intervention. Tympanoplasty was performed on 33 ears (15%), ossiculoplasty on 5 and mastoidectomy on 10. Intervention is recommended when the tympanic membrane remains unhealed for at least 10 months.

Adolescent↗

The perforated tympanic membrane.

Tympanic membrane perforations typically result from trauma or acute otitis media. Most perforations do not cause more than a mild conductive hearing loss, aural fullness and mild tinnitus. Blood, purulent secretions and other debris should be carefully suctioned out of the canal and the perforation size and location described. Irrigation and pneumatic otoscopy should be avoided. A history of vertigo, nausea and vomiting and an audiogram showing a conductive hearing loss of more than 30 dB suggest disruption of the ossicular chain. Profound sensorineural loss may signify inner ear nerve damage. Mastoid radiographs and computed tomographic scans may be useful in cases of significant trauma and infection. Most small perforations resolve spontaneously. The affected ear should be kept dry. Oral and topical antibiotics may be prescribed for perforations related to acute otitis media. Otolaryngologic referral may be necessary to evaluate traumatic perforations associated with vertigo or significant hearing loss, perforations from chronic otitis media or perforations from acute otitis media that do not heal within one month.

Ear Diseases↗

[Auricular cartilage palisade technique for repairing tympanic membrane perforation].

OBJECTIVE: To study the auricular cartilage palisade technique for repairing tympanic membrane perforation. METHOD: Sixty-six cases of large tympanic membrane perforation were treated with auricular cartilage. The results were compared with that of temporal fascia repairing in 60 ears. RESULTS: The closure rates of tympanic membrane perforation were 92.4% in cartilage group and 80% in temporal fascia group, respectively. There was no significant difference between two groups in hearing improvement. The cartilage is quite suitable for repairing large perforation of the tympanic membrane and for treating adhesive otitis media. CONCLUSION: The auricular cartilage palisade technique is an ideal method for repairing tympanic membrane perforation.

Adult↗

The effects of hyaluronic acid, epidermal growth factor, and mitomycin in an experimental model of acute traumatic tympanic membrane perforation.

HYPOTHESIS: The goal of this study was to evaluate the effects of hyaluronic acid, epidermal growth factor, and mitomycin C on the healing of acute experimental traumatic perforations of the tympanic membrane. BACKGROUND: Most acute perforations of the tympanic membrane heal spontaneously. However, some form of surgical treatment (i.e., myringoplasty) is needed for nonhealing perforations. Because the closure occurs by squamous epithelial migration, drugs that stimulate this regenerative process may aid in the closure of the perforation, obviating the need for more extensive treatments. METHODS: Bilateral perforations of the tympanic membrane were created in 30 rats, divided into three groups (A, B, C). The perforations in the right ears were treated with hyaluronic acid, epidermal growth factor, or mitomycin C. Those in the left ears were left untreated for comparison. To examine the healing process in different periods, 5 animals were killed in each group at days 3, 5, 7, 9 and 14. The other 5 animals in each group were observed daily to determine the duration of perforation closures. Thirty surgical specimens (5 right sides from each group and all 15 left sides in all groups) were histopathologically examined for tympanic membrane thickness, fibroblastic reaction, neovascularization, and crust morphology. RESULTS: Hyaluronic acid and epidermal growth factor applications significantly shortened the healing in acute experimental traumatic perforations of the tympanic membrane (p = 0.0432); however, the difference between them was not significant (p = 0.3160). On the other side, tympanic membrane perforations treated with topical mitomycin C showed no evidence of closure. There were no significant differences in the histologic parameters between the treated groups and their contralateral control ears. CONCLUSION: Hyaluronic acid and epidermal growth factor accelerated the closure of acute tympanic membrane perforations in rats. This may make them clinically useful in augmenting the efficiency of conservative treatments of acute perforations of the tympanic membrane.

Adjuvants, Immunologic↗

Repair of chronic tympanic membrane perforations with fibroblast growth factor.

A number of angiogenic growth factors have been shown to accelerate wound healing. Previous work has demonstrated that topical application of epidermal growth factor is effective in healing chronic tympanic membrane perforations in an animal model. Theoretically, fibroblast growth factor may result in a superior healed membrane through preferential stimulation of the fibroblasts within the middle layer of the tympanic membrane. To test this hypothesis, the effects of exogenously applied fibroblast growth factor on the chronically perforated tympanic membrane were evaluated. A buffered solution of fibroblast growth factor (25 microliters of fibroblast growth factor, 0.2 mg/ml) was administered to a Gelfoam pledget placed over chronic tympanic membrane perforations in chinchillas. Control ears were treated with Gelfoam and the buffer solution only. Complete closure of the tympanic membrane perforation was observed in 81% (13 of 16) of the fibroblast growth factor-treated ears, but in only 41% (7 of 17) of the controls (p = 0.05). Heading took place gradually, requiring an average of 4 weeks for the fibroblast growth factor-treated and 6.5 weeks for the control ears that healed. The relatively high healing rate for the control group does not imply that the pretreatment perforations were not chronic, rather there appears to be some efficacy to the control protocol of repeated applications of Gelfoam and buffer. A histologic analysis of the fibroblast growth factor-healed eardrums immediately after closure demonstrated hypertrophy of the squamous and fibrous layers of the tympanic membrane. Over time, the eardrum thinned to reach proportions similar to those of the normal tympanic membrane, including the presence of a substantial middle fibrous layer. A screening ototoxicity study revealed no structural damage to the organ of Corti after growth factor treatment. To assess the potential for systemic toxicity, blood and peripheral tissues were analyzed for radioactivity at time points during a 48-hour period after application of 25 microliters of 125I-fibroblast growth factor to the perforated tympanic membrane. More than 78% of the radioactivity remained at the application site. Given the tiny original dosage, the small fraction absorbed systemically is minuscule and highly unlikely to induce adverse effects in light of published toxicity data. On the basis of these promising safety and efficacy data in the chinchilla model, clinical trials of fibroblast growth factor in repair of chronic tympanic membrane perforations in human beings are being initiated.

Administration, Topical↗

An observational study of the management of traumatic tympanic membrane perforations.

Controversies of how best to treat fresh tympanic membrane perforations have always existed. While some otolaryngologists prefer the paper patch method, others prefer modified myringoplasty. A prospective study is needed to investigate the most effective and least expensive management of this common ear trauma. This study examined prospectively, in three sections, a group of patients with a cellophane patch (n = 6), another group with a gentamicin ointment seal (n = 15) and a control group (n = 9) with a gentamicin plug placed at the distal end of the external auditory cavity. Successful healing of the traumatic tympanic membrane perforations was achieved in 50 per cent of the cellophane seal group, 86.7 per cent of the gentamicin ointment seal group and 77.8 per cent of the control group. This study shows that the management of a fresh tympanic membrane perforation should be limited to cleaning the traumatized ear and preventing infection.

Administration, Topical↗