Wound healing in spontaneous

perforation or myringotomy and

middle ear reconstruction
Billy Giles, MD

Concerns have been rai sed abou t the potential for stenosis, hypertrophic scars, keloids, pulmonary fibro sis,
ototopical agents to adversely affect middle ear or tym- and tympanic membrane perforations. Once bleed ing has
panic wound healing. In ge neral, wo und healing takes stopped, histamine release dr amaticall y increases blood
pla ce in three phases-inflammati on , proliferati on , and flow to the wound bed by vasodilation and ele vation of
maturation ' ; vascular permeability of the wo unded tissue.Transforming
growth fac tor, alon g with other chemotaxin s, recruits key
• Th e inflammatory phase begins at the mom ent of effector ce lls and the protein s they ex press and induces
injury with an immedi ate vas oco nstriction respon se. Ap- them to migrate to the ed ge of the wo und.
proximately 10 minutes later, vasod ilation begins, and Cellular response. Gr anul ation tissue serves as a pro-
it lasts for up to 3 days . Within minutes of the onset of visional matri x scaffold across which epithe lialization
vasodilation , a ce llu lar respon se occurs that per sists for up occurs. Granulation is initi ated by fibronectin followed
to I week . The ce llular response overlaps with the onset by the migra tion of white blood cells and fibroblasts.?:?
of the proliferative phase. Fibronecti n then overtakes the clot, leading to fibroblast
• Th e first proc ess in the proliferative phase is re-epi - proliferati on , which in turn produces co llage n. Th is well -
thelialization , and it begins on the day of injury. Du ring orch estrated response oc curs alon g the front and dir ectl y
the next few days, fibropl asia, coll agen sy nthes is, wo und behind the lead ing edge of the injury. In most organs, this
cont raction , and neovascul arization occ ur. These processes proliferation occurs two or three cell s behind the leading
go on for more than 3 weeks. edge, brin gin g the ed ges together. Thi s process ch anges
• Between 2 and 3 wee ks foll owin g the injury, the when the edges com e int o approx ima tion.
maturation phase begins, and it continues for approxi- Wh en wo und healing occ urs in an infe cted area, granu-
mat ely I year. locytes migrate to the wound , and the reg ular and orderly
process of the hea ling ca scade is significantly altered. IDol I
Our know ledge of wound healing is rapidly expanding. Th e macrophages are the main cells of phagocy tosis and
Healing of the tympanic membrane is similar to that of tissue deb ridement. Ma croph ages rele ase chemotactic and
other tissues.' Thi s article co ntains a description of the gro wth factors, including tran sfo rmin g grow th factor,"
general processes involved in wound healin g. Th e spec ific Finally, lymphocytes lin k the immune respon se to wound
me ch an isms of healin g vary amo ng different species, dif- repair and further stimulate the fibrobl ast.
fer ent organs, and pati ent s of different ages, but the basic
principles can be applied to tymp anic membran e healing Prolif erat ion phase
and rep air. Th ere are five stages of the proliferation phase : epithe-
lia l regen erati on , fibrop lasia , collagen formation , wo und
Inflammatory phase co ntraction, and neovasc ulari zation.
Vascu lar response. Following local vasoconstriction, the Ep ithelial rege neration es tabli shes an env iro nmental
coagulation cascad e begin s, starting with platelet adh e- barri er by way of active mit osis and the migration of the
sion.l" Plat elets cont ain multiple che motactic and vasoac- wo und edge. As the wo und clo ses, ce ll differentiation
tive factors that stimulate growth and healin g (tablej. vT he occ urs so that the correct ce lls are for med to regain the
primary fac tors that are invol ved in the healing oftympanic prop er histologic cellular stra tification of the wo unded
membrane perforation s appea r to be platelet-derived growth tissue . After co ntact inh ibition occ urs, there is an inc rease
fact or, epidermal grow th fac tor, fibrobl ast growth factor, in wo und thickne ss. Thi s inc rease occ urs largel y becau se
and tran sforming grow th factor. the fibrobl asts manufacture collagen -first collagen III
Tr ansforming gro wth factor has been identified as a con- and later, as the scar matures, coll agen I. Myofibril s pull
tributort o patho logic scarring. It is upregul ated in subglottic the edges of the wou nd tow ard eac h oth er, and the wound

30· Volume 86 • Suppl 1

contracts unt il it completely closes. Macrophages, platelets, healin g wi th various top ically applied grow th factors and
lymphoc ytes, and num erous gro wth factors combine to insulin have been met with mixed re sults.": " As stated
promote neo vasculariza tio n." earlier, tra nsformi ng grow th fac tor app ears to play a ro le
in the fo rma tion of chro nic perforati on s, but this effect
Maturation phase may be reversed by epide rm al proliferati on , fibrobl ast
Th e maturation phase invo lves remo deling and reorgani za- production, and angioge nes is stimulated by basic fibroblast
tion . Th e fibr obl asts stop producing coll agen III and begin gro wth factor. 18.20
producing coll agen 1. Th e fiber s reorgani ze and becom e
stro nger. After approx imately I year, the healed area has
regained more than 80% of its ten sile strength (it will never Steroids affect all three phases of wound
regain 100% of its stre ng th) .
healing.
Tympanic membrane healing
While the ge neral prin cipl es of wound heali ng can be ap-
plied to the tymp anic membrane , there are so me variations Myr ingosclerosis is scarring and ca lcification of the
that occ ur secondary to the eardru m's unique ana tomy and middle layer of the eardrum, predominantly adj ace nt to
function. Lik e most he alin g tissues, tympanic membranes the malleu s and annulus, that ca n hamper the mob ility of
heal mo re effective ly if the local environme nt is free of the tympan ic membrane." This pathologic process begins
infecti on , if there is a rich blood supply and oxygen level , within 9 hour s of injury, mediated by the macrophages
and if the area is hydrated.' dur ing the inflammatory portion of healing, depo siting
Th e thr ee levels of the tympanic membrane are the epi- calc ium in a process that mim ics bone remodeling.v -"
theli al outer layer, the fibrous middle layer, and the mu cosal Myringoscl erosis is more likel y to oc cur as a res ult of
inner lay er. The blood supply is radially arra nge d along infection with Streptococcus pn eum onia e typ e 3 than Ha e-
the edges (fo rming the vas cular ring) and the manubrial mophilus infi uenzae. Myrin gosclerosis can be prevented
plexus, whic h co urses down the handl e of the malleu s. by antioxi da nt or anti-inflammatory agents ." :"
Th e pars ten sa, which represents the bott om 80 % of
the eardr um's struc ture, is co mposed mainl y of collage n Effects of steroid therapy
II running in parallel shee ts, whic h is unique.' :' T he pa rs Stero ids affect all three phases of wound healing." The
flaccid a, which is the super ior as pec t of the drum, is made additio n of a stero id to a topical antibiotic has increased
up primarily of coll agen I; it also has multiple three- the efficacy of the latter in treating a draining ear and in
dimen sional areas of co llage n. co mbating granulation tissue. Ho we ver, granulation tis-
Basic all y, a tymp anic mem brane perforation closes by a sue, which is an un wanted result of infec tion, help s the
proc ess ofcircumferentia l epith elial proli feration followed heal ing of a perforati on . Th e addition of a stero id , then,
by co nnec tive tissue grow th. 15 If he alin g occurs during a may impair tymp ani c membrane he alin g. However, the
time of infec tion, there is usually poor alignme nt of the possibl e clinical adva ntage of shor tening the inflammatory
co llag en and poor wo und strength. 16 phase and diminishin g granulocyte activity in a healing
Att em pts to prom ote tympanic memb rane perforation tympan ic membrane by the judiciou s use of a topi cal ste-
roid is still the oreti cal; no pro of ha s been demonstrated
in any know n studies.
Table. Chemotactic and vasoactive factors that Stero ids reduce the expression of almost all chemotac tic
stimulate growth and healinq"
and vasoactive proteins involved in wound healin g." The
negative effect of stero ids on healing has been countered by
Human growth hormone
the admi nistra tio n of topical vitami n A, as well as several
Epidermal growth factor
Platelet-derived growth factor types of growth factor.v" Several published studies have
Fibroblast growth factor indi cat ed that local steroi d applica tion has no negat ive ef-
Transforming growth factor fect on the success rate of tympanoplasty when the stero id
Nerve growth factor is used in the wound pac king material. 35.36 Recent animal
Brain-derived neurotrophic factor studies of curre ntly ava ilable otic drops compared the ef-
Ciliary neurotrophic factor fects of antibiotic and antibio tic/s tero id co mbinations on
Insulin-li ke growth factor 1 the healin g process of a membr ane perforation.F " These
Tumor necrosis factor studies have sho wn that he alin g wi th antibiotic/steroid
Interleukins
drops may be delayed, but all the membran es will he al ."
Interferons
Keratinocyte growth factor A simi lar study has sho wn that myrin gotom y healing is
tran sientl y down-m odul ated by treatment with antibi otic/

ENT-Ear, Nose & Throat Journal· Suppl1 • November 2007·31

 WOU ND HEALING IN SPONTAN EO US PERFO RATION OR MYRIN G OTOMY AN D MIDDLE EAR REC ONSTRUCTIO N

stero id drop s, but healing occurs normally after the drops 20. Ozkaptan Y, Gerek M, Simse k S, Deveci S. Effect s of fibroblast
grow th factor on the heal ing process of tymp anic mem brane per-
are discontinued." Thi s is fortunat e, as topic al steroids
forations in an animal model. Eur Arch Oto rhinolary ngol 1997;
have enhanced the treatment of both otitis externa and 254( Suppl I):S2-5.
otiti s media with drainage. As we better understand the 2 1. Kazikdas KC, Serbetcioglu B, Boyra z I, et al. Tym panometric
healing mechani sms of the eardrum and the ways that cha nges in an experi mental myringosclero sis mode l afte r myrin-
gotomy. Oto l NeurotoI2006;27(3) :303-7.
steroids affect those mechanisms, we should be able to
22. Mattsson C, Johansson C, Hellstrom S. Myrin gosclerosis develops
use topical steroids to our advantage in helpin g tymp anic within 9h of myringotomy. ORL J Otorhinolaryngol Relat Spec
membranes heal in a nonpathologic manner. 1999;61( 1):3 1-6.
23. Raustyte G. Caye -Thomasen P, Hennansson A. et al. Ca lciu m
dep osition and exp ressio n of bone modelli ng markers in the
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32 • Volume 86 • Suppl 1