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Wound healing in spontaneous perforation or myringotomy and middle ear reconstruction.

Concerns have been raised about the potential for ototopical agents to adversely affect middle ear or tympanic wound healing. In general, wound healing takes place in three phases--inflammation, proliferation, and maturation (1):

* The inflammatory phase begins at the moment of injury with an immediate vasoconstriction response. Approximately 10 minutes later, vasodilation begins, and it lasts for up to 3 days. Within minutes of the onset of vasodilation, a cellular response occurs that persists for up to 1 week. The cellular response overlaps with the onset of the proliferative phase.

* The first process in the proliferative phase is re-epithelialization, and it begins on the day of injury. During the next few days, fibroplasia, collagen synthesis, wound contraction, and neovascularization occur. These processes go on for more than 3 weeks.

* Between 2 and 3 weeks following the injury, the maturation phase begins, and it continues for approximately 1 year.

Our knowledge of wound healing is rapidly expanding. Healing of the tympanic membrane is similar to that of other tissues. (2) This article contains a description of the general processes involved in wound healing. The specific mechanisms of healing vary among different species, different organs, and patients of different ages, but the basic principles can be applied to tympanic membrane healing and repair.

Inflammatory phase

Vascular response. Following local vasoconstriction, the coagulation cascade begins, starting with platelet adhesion. (3-6) Platelets contain multiple chemotactic and vasoactive factors that stimulate growth and healing (table). (3) The primary factors that are involved in the healing of tympanic membrane perforations appear to be platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and transforming growth factor.
Table. Chemotactic and vasoactive factors that
stimulate growth and healing (3)

Human growth hormone
Epidermal growth factor
Platelet-derived growth factor
Fibroblast growth factor
Transforming growth factor
Nerve growth factor
Brain-derived neurotrophic factor
Ciliary neurotrophic factor
Insulin-like growth factor 1
Tumor necrosis factor
Interleukins
Interferons
Keratinocyte growth factor


Transforming growth factor has been identified as a contributor to pathologic scarring. It is upregulated in subglottic stenosis, hypertrophic scars, keloids, pulmonary fibrosis, and tympanic membrane perforations. Once bleeding has stopped, histamine release dramatically increases blood flow to the wound bed by vasodilation and elevation of vascular permeability of the wounded tissue. Transforming growth factor, along with other chemotaxins, recruits key effector cells and the proteins they express and induces them to migrate to the edge of the wound.

Cellular response. Granulation tissue serves as a provisional matrix scaffold across which epithelialization occurs. Granulation is initiated by fibronectin followed by the migration of white blood cells and fibroblasts. (7-9) Fibronectin then overtakes the clot, leading to fibroblast proliferation, which in turn produces collagen. This well-orchestrated response occurs along the front and directly behind the leading edge of the injury. In most organs, this proliferation occurs two or three cells behind the leading edge, bringing the edges together. This process changes when the edges come into approximation.

When wound healing occurs in an infected area, granulocytes migrate to the wound, and the regular and orderly process of the healing cascade is significantly altered. (10,11) The macrophages are the main cells of phagocytosis and tissue debridement. Macrophages release chemotactic and growth factors, including transforming growth factor. (12)

Finally, lymphocytes link the immune response to wound repair and further stimulate the fibroblast.

Proliferation phase

There are five stages of the proliferation phase: epithelial regeneration, fibroplasia, collagen formation, wound contraction, and neovascularization.

Epithelial regeneration establishes an environmental barrier by way of active mitosis and the migration of the wound edge. As the wound closes, cell differentiation occurs so that the correct cells are formed to regain the proper histologic cellular stratification of the wounded tissue. After contact inhibition occurs, there is an increase in wound thickness. This increase occurs largely because the fibroblasts manufacture collagen--first collagen III and later, as the scar matures, collagen I. Myofibrils pull the edges of the wound toward each other, and the wound contracts until it completely closes. Macrophages, platelets, lymphocytes, and numerous growth factors combine to promote neovascularization. (13)

Maturation phase

The maturation phase involves remodeling and reorganization. The fibroblasts stop producing collagen III and begin producing collagen I. The fibers reorganize and become stronger. After approximately 1 year, the healed area has regained more than 80% of its tensile strength (it will never regain 100% of its strength).

Tympanic membrane healing

While the general principles of wound healing can be applied to the tympanic membrane, there are some variations that occur secondary to the eardrum's unique anatomy and function. Like most healing tissues, tympanic membranes heal more effectively if the local environment is free of infection, if there is a rich blood supply and oxygen level, and if the area is hydrated. (3)

The three levels of the tympanic membrane are the epithelial outer layer, the fibrous middle layer, and the mucosal inner layer. The blood supply is radially arranged along the edges (forming the vascular ring) and the manubrial plexus, which courses down the handle of the malleus.

The pars tensa, which represents the bottom 80% of the eardrum's structure, is composed mainly of collagen II running in parallel sheets, which is unique. (14) The pars flaccida, which is the superior aspect of the drum, is made up primarily of collagen I; it also has multiple three-dimensional areas of collagen.

Basically, a tympanic membrane perforation closes by a process of circumferential epithelial proliferation followed by connective tissue growth. (15) If healing occurs during a time of infection, there is usually poor alignment of the collagen and poor wound strength. (16)

Attempts to promote tympanic membrane perforation healing with various topically applied growth factors and insulin have been met with mixed results. (17-19) As stated earlier, transforming growth factor appears to play a role in the formation of chronic perforations, but this effect may be reversed by epidermal proliferation, fibroblast production, and angiogenesis stimulated by basic fibroblast growth factor. (18, 20)

Myringosclerosis is scarring and calcification of the middle layer of the eardrum, predominantly adjacent to the malleus and annulus, that can hamper the mobility of the tympanic membrane. (21) This pathologic process begins within 9 hours of injury, mediated by the macrophages during the inflammatory portion of healing, depositing calcium in a process that mimics bone remodeling. (22,23) Myringosclerosis is more likely to occur as a result of infection with Streptococcus pneumoniae type 3 than Haemophilus influenzae. Myringosclerosis can be prevented by antioxidant or anti-inflammatory agents. (24-29)

Effects of steroid therapy

Steroids affect all three phases of wound healing. (30) The addition of a steroid to a topical antibiotic has increased the efficacy of the latter in treating a draining ear and in combating granulation tissue. However, granulation tissue, which is an unwanted result of infection, helps the healing of a perforation. The addition of a steroid, then, may impair tympanic membrane healing. However, the possible clinical advantage of shortening the inflammatory phase and diminishing granulocyte activity in a healing tympanic membrane by the judicious use of a topical steroid is still theoretical; no proof has been demonstrated in any known studies.

Steroids reduce the expression of almost all chemotactic and vasoactive proteins involved in wound healing. (31) The negative effect of steroids on healing has been countered by the administration of topical vitamin A, as well as several types of growth factor. (32-34) Several published studies have indicated that local steroid application has no negative effect on the success rate of tympanoplasty when the steroid is used in the wound packing material. (35,36) Recent animal studies of currently available otic drops compared the effects of antibiotic and antibiotic/steroid combinations on the healing process of a membrane perforation. (37,38) These studies have shown that healing with antibiotic/steroid drops may be delayed, but all the membranes will heal. (37) A similar study has shown that myringotomy healing is transiently down-modulated by treatment with antibiotic/ steroid drops, but healing occurs normally after the drops are discontinued. (38) This is fortunate, as topical steroids have enhanced the treatment of both otitis externa and otitis media with drainage. As we better understand the healing mechanisms of the eardrum and the ways that steroids affect those mechanisms, we should be able to use topical steroids to our advantage in helping tympanic membranes heal in a nonpathologic manner.

References

(1.) Fisher E, Frodel JL Jr. Wound healing. In: Papel ID, ed. Facial Plastic and Reconstructive Surgery. 2nd ed. New York: Thieme; 15-25.

(2.) Reijnen CJ, Kuijpers W. The healing pattern of the drum membrane. Acta Otolaryngol Suppl 1971;287:1-74.

(3.) Terris DJ. Dynamics of wound healing. In: Bailey BJ, ed. Head and Neck Surgery-Otolaryngology. Philadelphia: Lippincott-Raven; 1998.

(4.) Saski GH, Krizek TJ. Biology of tissue injury and repair. In: Georglade NG, ed. Essentials of Plastic Maxillofacial and Reconstructive Surgery. Baltimore: Lippincott Williams & Wilkins; 1987.

(5.) Diegelmann RF. Cellular and biochemical aspects of normal and abnormal wound healing: An overview. J Urol 1997;157(1):298302.

(6.) Goslen JB. Wound healing for the dermatologic surgeon. J Dermatol Surg Oncol 1988;14(9):959-72.

(7.) Grinnell F, Billingham RE, Burgess L. Distribution of fibronectin during wound healing in vivo. J Invest Dermatol 1981;76(3): 181-9.

(8.) Simpson DM, Ross R. The neutrophilic leukocyte in wound repair: A study with antineutrophil serum. J Clin Invest 1972;51(8): 2009-23.

(9.) Diegelmann RF, Cohen IK, Kaplan AM. The role of macrophages in wound repair: A review. Plast Reconstr Surg 1981;68(1):107-13.

(10.) Pierce GF. Macrophages: Important physiologic and pathologic sources of polypeptide growth factors. Am J Respir Cell Mol Biol 1990;2(3):233-4.

(11.) Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975;78(1):71-100.

(12.) Bryant WM. Would healing. Clin Symp 1977;29(3):1-36.

(13.) Katz MH, Alvarez AF, Kirsner RS, et al. Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth. J Am Acad Dermatol 1991;25(6 Pt 1): 1054-8.

(14.) Stenfeldt K, Johansson C, Hellstrom S. The collagen structure of the tympanic membrane. Collagen types I, II, and III in the healthy tympanic membrane, during healing of a perforation, and during infection. Arch Otolaryngol Head Neck Surg 2006;132(3):293-8.

(15.) Mondain M, Ryan A. Histological study of the healing of traumatic tympanic membrane perforation after basic fibroblast growth factor application. Laryngoscope 1993; 103(3):312-18.

(16.) Magnuson K, Hermansson A, Hellstrom S. Healing of tympanic membrane after myringotomy during Streptococcus pneumoniae otitis media. An otomicroscopic and histologic study in the rat. Ann Otol Rhinol Laryngol 1996;105(5):397-404.

(17.) Ma Y, Zhao H, Zhou X. Topical treatment with growth factors for tympanic membrane perforations: Progress towards clinical application. Acta Otolaryngol 2002; 122(6):586-99.

(18.) Somers T, Goovaerts G, Schelfhout L, et al. Growth factors in tympanic membrane perforations. Am J Otol 1998;19(4):428-34.

(19.) Eken M, Ates G, Sanli A, et al. The effect of topical insulin application on the healing of acute tympanic membrane perforations: A histopathologic study. Eur Arch Otorhinolaryngol 2007;264(9): 999-1002.

(20.) Ozkaptan Y, Gerek M, Simsek S, Deveci S. Effects of fibroblast growth factor on the healing process of tympanic membrane perforations in an animal model. Eur Arch Otorhinolaryngol 1997; 254(Suppl 1):S2-5.

(21.) Kazikdas KC, Serbetcioglu B, Boyraz I, et al. Tympanometric changes in an experimental myringosclerosis model after myringotomy. Otol Neurotol 2006;27(3):303-7.

(22.) Mattsson C, Johansson C, Hellstrom S. Myringosclerosis develops within 9h of myringotomy. ORL J Otorhinolaryngol Relat Spec 1999;61(1):31-6.

(23.) Raustyte G, Caye-Thomasen P, Hermansson A, et al. Calcium deposition and expression of bone modelling markers in the tympanic membrane following acute otitis media. Int J Pediatr Otorhinolaryngol 2006;70(3):529-39.

(24.) Mattsson C, Carlsson L, Marklund SL, Hellstrom S. Myringotomized mice develop myringosclerosis in the pars flaccida and not in the pars tensa. Laryngoscope 1997; 107(2):200-5.

(25.) Raustyte G, Hermansson A. Development of myringosclerosis during acute otitis media caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae: A clinical otomicroscopical study using the rat model. Medicina (Kaunas) 2005 ;41 (8):661-7.

(26.) Ozcan C, Gorur K, Cinel L, et al. The inhibitory effect of topical N-acetylcysteine application on myringosclerosis in perforated rat tympanic membrane. Int J Pediatr Otorhinolaryngol 2002;63(3): 179-84.

(27.) Spratley JE, Hellstrom SO, Mattsson CK, Pais-Clemente M. Topical ascorbic acid reduces myringosclerosis in perforated tympanic membranes. A study in the rat. Ann Otol Rhinol Laryngol 2001; 110(6):585-91.

(28.) Ozcan C, Polat G, Gorur K, et al. The effect of local administration of N-acetylcysteine in perforated rat tympanic membrane: An experimental study in myringosclerosis. Pharmacol Res 2002;45(1):5-9.

(29.) Akbas Y, Pata YS, Gorur K, et al. The effect of L-carnitine on the prevention of experimentally induced myringosclerosis in rats. Hear Res 2003;184(1-2):107-12.

(30.) Eaglstein WH, Mertz PM. "Inert" vehicles do affect wound healing. J Invest Dermatol 1980;74(2):90-1.

(31.) Ishimoto S, Ishibashi T. Induction of growth factor expression is reduced during healing of tympanic membrane perforations in glucocorticoid-treated rats. Ann Otol Rhinol Laryngol 2002; 111 (10): 947-53.

(32.) Haws M, Brown RE, Suchy H, Roth A. Vitamin A-soaked gelfoam sponges and wound healing in steroid-treated animals. Ann Plast Surg 1994;32(4):418-22.

(33.) Beckert S, Haack S, Hierlemann H, et al. Stimulation of steroid-suppressed cutaneous healing by repeated topical application of IGF-I: Different mechanisms of action based upon the mode of IGF-I delivery. J Surg Res 2007;139(2):217-21.

(34.) Ishimoto S, Ishibashi T, Bottaro DP, Kaga K. Direct application of keratinocyte growth factor, basic fibroblast growth factor and transforming growth factor-alpha during healing of tympanic membrane perforation in glucocorticoid-treated rats. Acta Otolaryngol 2002; 122(5):468-73.

(35.) Anderson O, Takwoingi YM. Tri-adcortyl ointment ear dressing in myringoplasty: An analysis of outcome. EurArch Otorhinolaryngol 2007;264(8):873-7.

(36.) Nakhla V, Takwoingi YM, Sinha A. Myringoplasty: A comparison of bismuth iodoform paraffin paste gauze pack and tri-adcortyl ointment ear dressing. J Laryngol Otol 2007; 121(4):329-32.

(37.) Buyten J, Kaufman G, Ryan M. Effects ofciprofloxacin/dexamethasone and ofloxacin on tympanic membrane perforation healing. Otol Neurotol [in press].

(38.) Hebda PA, Yuksel S, Dohar JE. Effects of ciprofloxacin-dexamethasone on myringotomy wound healing. Laryngoscope 2007; 117(3):522-8.

Billy Giles, MD
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Author:Giles, Billy
Publication:Ear, Nose and Throat Journal
Date:Nov 1, 2007
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