Growth Factors and Plastic Surgery

Oct-
19-Or
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P -07
Growth Factors and Plastic Surgery
Bruce A Mast, M.D.
Gregoqy S. Schultz, PhD.
Gainesvillc, FL
INTRODUCTION
Plasric surgcons arc ofren askcd ro man.ge difficult.
corlplcx, or clrronic wounds. Addirionally, since much of
plasric surgcry involves nroving or changing rhc shape of
risruc, rhc specialry is particularly depcndcnr on eppropriarc wound healing. As such, wound hcaling rescarch has
often been wirhin dre rerlm of plasric surgical research.
Advances in rhc undcrsnnding of cissuc rcpair havc providcd inrprovcd ebiliry ro crrc For a vaiiery of discasc
processcs,including chronic wounds. Tlre clucidarion of
growrh facrors as nrediarorsof dssuercpair rcprescnrssuch
an edvanccnrent rlrar is beginning to rransleccinro ncw
trearmcnr regimcns included in rhe cacegoryof "biologic
rhcrapy-" Suclr rhcrapy involvcs dre usc of a biologically
activc strbsrancc thar will srimulate a desired responsc
wirhin risrue. Biologic rhcrapy applicablc ro plastic rurgery
includes the use .rf ropical grorvth facsor,genc rhcrapy, and
arrificial skin or skin subsrirurcs,all of which hrvc seen
gre:rrcsrpotcntial in rhc trcatmenc of chronic wounds. This
erriclc will conccrrrrf,reon thc usc of growth facrors,
GROVTH
EACTORS A}.ID IT/OUND HEALING
The rcpair of injurcd rissucprocecds chrough a scricsof
even$ in which ccllular and exrracellular rnarrix somponen6 acr in conccrr ro resrorc rissuc inrcgriqy. The orderly
inreraction of these componcnrs is largely due ro rhi modularory effccr of growrh hctors. For dcscriprivc purposes,
rhe processcsof wound hcaling cen be dividcd into four
ovcrlapping plrascr; hcnrosrasis,inflanrmation, proliferarion and remodcling (Frg. l) (l). During hemostasis,fibrin is leid down within rhe wound lnd servesas a rcmporary matrix fior rhe influx of subscqucnt cclls. Also,
plarclcs {egranulatc, rcleasing the firsr supply of grcnvrh
facrors thar will help recruir orher wound healing cells inro
thc sicc of injurr', lnflamnration bcgins wirh ncurrophils,
acring as hosr dcfcnse agarnrr concamineting bacteria.
Fig. I . Thgphan of umand kaling and thcir coastittttiac ccllular
and atracclluhr natrix cornportntt.
Macrophagesare prcrcnr wirhin rhc wound for up ro fivc
days, during which rime, they serve as chc primar,v supply
of a varicry of growrh facrors rhar conrrol hcaling. During
prolifcradnn, fibroblascsincrcasein number and then produce collagcn, rhc main srrucrural prorein of skin; cpirhclial cclls migratc and multipl;i; and cndothelial cells partake in angiogencsis. Each of rhcsc cells also produccs
growth faccors rhar conrrol rhcir acriviry, as wdl as surrounding cellular aciviry. Lasrly, rhc remodeling phase
lasrslongcst, during which the rime collagen is organized.
and dcgradcd if too abundanr, cellular dcnsiry dccrcases,
ncovascularizarion recedes,and thc scar fully marurcs.
Regularion of rissuc repair .is largcly due ro an arrav of
ssluble mediators rhat are produccd and/or sccrctcd at the
wound sire ( I )- Thesc cytokincs end polypeptide growth
Facrorsacr lry atmching to spccific rcccprors on chc surfaccs
of target cells.Receptor binding leadsro chenrical reacrions
wirhin thc cyroplasm- Thcse 'sccond signals" subscqucnrly
akcr nuclcar function. genorne rranscriprion and ultimatcly, gell,'l:s bchavior. Cpokincs end growth factors arc
chcmotactic for somc cells, drawing rhcm inro rhe wound
site rhrough induced rnigration: rhcy'stimulae cclls ro proI. FLORIDAU.A- . Jub 2oo0 , Vol.86,No. 2 . 67
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liferare; and/or tynthesisc parricular proreins and enzymes.
Cyrokine is a rcrm rhar reftrs to a sukrance rhat imparrs
some rypc of acrion to a ccll. Ln skin hcaling, rhis rerm is
besr reserved for proinflarnmatory cytokines- Tumor
nccrosis hcror-alpha (TNF- ) arrd the inrerleukins are lhe
most imporrant. Thcsc rytokines ec( to regulare chc
inflamrnarory response to rissuc trautna' Growth facrors
arc rhe cyrokincs that are thc principal rcgularors of hcaling. Thcre is a plethora oFgrowth factors r*'irh tremendous
redundancy in ccllular sourccsand function.
TABLE 1 GROIWTH FACTORS IN WOUND
TGF-bctr
l>lerc{ct<laivql 6rwrh fecru
Treroforming grorrrrhfaror-bcrr
TCF-elphe
Treosforming growth Ectcr-elphr
I'U(;|"
HE{LING
FGF
Fibroblu gowrh fzctor (eridic. besic)
KCFs
Kcntinoc.nc gmh
ECF
EpirJcrmelgrowrh fxror
ICF-l
Inrulin-liLc gowrh fector-l
VECF
Vrculrr cndothcli:I grwth Ecrot
P-OA
skin grafr donor sircsas documcntcd by scrial photography
and biopsy. A similar study by Cohen and co-invescigarors
showcd no diffcrcnce iu wounds treated wirh EGF vcrsus
plecebo control (4). Vcnous scasisulcers also hcal largely b,v
cpi thclialization. A small, randonrized scudy dernonstratcd
thar venous stasisulceru rrea<cdwith EGF showed no sreriscical improvemcnt in hcaling comprrcd to placcbo (J)To dare, no other studies have been shown to demonsrrare
any clinical wound hcaling effect of ECF and there is no
currcnr clinical rolc for icsuse in cutancous wound hcaling.
Howcver EGF has been showing promise as a biologic
thcrapy in fieldr other rhan plasric surgery. Clinical rrids
using EGF have bccn cncouraging in rhe fields of oncology
f<rrncoplastic condirions ((r); ophthalmology for rhc rcpeir
of corncel ulccretions (7); and ocolarvngologyfor rhc treatmenr of chronic perforarions oF rhc rympanic mcmbrane
(8).
fectors
The growrh factors rhat arc mosr importanr for soft tissuc wound hcaling arc listcd io Table l. In tcrms of tissuc
repair, rhe cnd-point of growth factor action can bc consideted ro be stimuladon of conncc[ive rissue dcposition'
promorion of cpithelidizerion or srimularion of angiogenesis. Meny growth faccors havc bcen shown ro stimuhre
such acrion in various cell culture and animal models.
Only a [er+'growrh factors.havcbeen shown to be effecrive
in promoting healing in pcoplc- Epidermal growth factor
(EGF), vascular endothclial growrh tlcror (VEGF) and
placelct derivcd growth fecror (PDGF) hold rhe grcatcst
potcndal as rhcrapeutic agena.
EPIDERMAL GROVTH FACTOR
Epidcrmel growch factor or EGF was thc first growth
frcror ro bc dcscribcd in 1962 (2). ECF is a porcnt kcrarinocyte mitogen, thus inducing epithelializarion. lt is
elicited in rhe *'ound by platelets and mecrophages-F-GF
also sdmulates fibroblasr proliferarion, so that collagenand
counecrivc tissuc dcposition may also be affccted. Bescdon
rhe effecr oF EGF on kerarinocl'tes, this Erowth factor was
studied to dcrcrminc if a clinical cffcct could be garncred
on wounds that hcal primerily by cpithelialization.
Accordingly, the donor sitcs for split thickncss skio grafrs
were trcated u'irh EGF or with phccbo in cwo diffcrent
srudies from m'o diffcrenr instirutions- Brown and collcagues(3) found chat EGF causcd a morc rapid hcaling of
88 'J. FLORID.^,r.a. ' hb 2ooo . VoL86,No.2
VASCULAR ENDOTHELIAI- GROWTH FACTOR
Angiogenesisor new blood vesselformation is an inregral part of tissue rcpai,r. Swcral growrh factors stimulate
angiogenesis during wound hcaling including vascular
endothclial growth factor (\{EGF), platcler dcrived growth
factor-(PDGF), transforming growth facror-G and fibroblast growrh facror- Thc mosr imponanr of rhese facrors is
likcly VEGF due to its ebiliry to be secreredby inract cclls,
and irs mitogcnic specificir,vfor endothelium (9). A large
body of data generated fronr aninral experimcnr ha-s
shown VECF ro bc a potcnr inducer of neovascrrlariz;rtion
in ischcmic condidons- lndecd, whert VEGF has b,:cn
adminisrcrcd in the forrn oFgenc therapy, improved vaiculariry has bcen documcnrcd in animal scudiesof myocard i d i s c h c m i a( l o ) a n d l i r n b i s c h c m i a( l l ) ( 1 2 ) - F u r r h c r morc, ropical application of VEGF. aswcll as gcnc thcrapy
epplicrrion has resulrcd in incrtssed survival of ischemic
fleps in animals (13)Managemcnt of chronic wounds oF rhe lower cxtremiry
necesriretesrhe abiliry ro recognizc ulcerations rhar result
from arrcrial insufficicncy. Such wounds arc provided
rreatmen( in conjunction wirh lower cxtremiry revascularization by mcan of bypasssurgcry or angio'plasty. Howeve r'
somc paden$ are not candidatcs for revascularizariondue
ro rhe exren( of their disrd arrerial insufficiency or co-tnotbid mcdical condidons. Many of thcse patienrs undcrgo
ampuurtion. Biologic thcrapy wirh angiogcnic growth facrors is bcing invcstigatedas a mears ro help such Paticnts.
Animal modcls of limb ischemia heve shown VEGF to be
quitc cffccrive in improving limb vasculatity (14) (15).
Oct-19-ot
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This lcd ro a clinical rrial using gen€ rhcrapy ro supply
VEGF co several paricnts with Buerger'sdiseasc(rhromboangiris oblirerans) who had end-strge lower exrrcmiry
ischemia and whose condirions w€re nor amenable ro
angiographic or surgical revascularizerion(16)" Five of che
scven parienrshad hcaling of ischcmic ulccrs or improvement in rcsr pain. Angiography demonsrrared marked
improvement of collareral blood supply, prcsumably due ro
neovasculariation. The marked clinical improvcmcnr in
rhesepaticnts is a dramaric e<ample oFthe porenrial benefit of growth factor thcrapy- It is highly probable ther biologic thcrapy wirh VEGF will find a crue clinical application in rhe near Fucurc.
PI.ATELET DERNIED GROITTH FACTOR
Plarelet dcrived growth facror (PDGF) was nemed for
rhe cell from which rhe growch factor was first isolared.
However, PDGF is supplied wirhin rhc wound sitc by
plarclcrs, nrrcrophages,endochclial cel-lsand smoorh muscle cclls. Broad reachirrg effecrs on woun"il healing resulr
From PDGF, including chenroarrractionof neutroplrils,
macrophagcsand fibroblasrs;stimularion of fibrotrlast proliferation; inducrion of connective rissue deposirion; and
srimulation of angiogenesis.Due ro its far-reachingeffecu,
PDGF has bcen srudied as a porcnrial thcnpeuric agenr for
chronic wounds.
Earlieststudicsdid nor useisolaccdPDGF, bur rarheran
autologous grolvth facror solurion derived as a plarelet
rclcasaterhar is obrained from rhe paricnt'sblood using a
'fhcrc
proprietary merhod.
is extensive expericncc using
this sotution callcd platelcr derivcd wound hcaling fluid
(PD\flHF or Procurcn@)which conrains multiple molccules (growth facrors and cyrokincs), which are normally
releasedfrom plarelcr granulcs. Severalindividual srudies
have bccn perfcrrnred resulring in dau rhar variably supports the efficacyof rhe PDVHF (17). This plarelcrreleasarc has nor bccn subjccced to rhe rigors of FDA required
researchdue ro ir being an aurologous bloodderivbd formuh adminisreredto rhc parient from wbom ir is dcrived.
The actud cfficacy of PD\?HF rherapy is nor well dcfincd
due ro the ebscrrccof large prosectivcrandomizedstudics,
Hurnan recombinanr PDGF has been srudied exrensivcly as a thcrapy for chronic wounds- Recombinanr
PDCF-BB has bccn e"aluated by rwo mulricenrer, placebocontrolled, blindcd efficacy srudies for the rrearmenr of
uncomplicatcd diabcric foor ulccrs-Thcsc srudics dcmonsrrate e significanr cnhanccmenr of complete hcaling wirh
P-09
Figprc2
Fig. 2. Healing of diabaic foot ubcrs wat ignifcant$
(p<0.01)
impmacd uttth tht ure oftcombinant human PDGE (adaprcdfom
data connincd in Stccd DL, th Diabaic Lllcer Study Group. Clinical cvaluation of rccombinant human ptau[erdeilucd growth factor for chc tr€dtmcnt of buter cxrrcttirlt diabcic uhen- J Varc Sury
2l :71-81, 199fl.
rcpical use of rhc growrh factor (18) (lg). ln rhe firsr efficary study (Fig. 2), the incidcnce of compicrc hcaling of
norr-ischernicfoot ulccrs was 25o/oin rhc placebo-crcarcd
group and 48i6 in chc PDGF-rrcatcd group (pcO-O I )
(18). Thc sccond efficacy srudy found cher hcaling
occurrcd in 35o/oof placcbo-rcated wounds, compared to
50"/o af'PDGF-rreared wounds, represcnring a 43gb
increasein hceling (p = 0.007) (19). Addirionally, PDGF
rrearcdwounds reduced rhc timc to healing by 6 wcela (p
= 0.013). In both srudies,growrh facror rherapywas combined with cxccllcnt wound care, including moist drcssings, off-loading oF rhc affecrcd foor and aggressive
debridement. Indced rhe pnsirivc cFfecrof debridcmcnt on
hcaling wcs markcdly correlared wich rhe use of PDGF,
whereas fie effeccwas nor nearly as grcxr in rhe placcboIrceted paricna (20). A highcr dose of PDGF was requircd
ro dernonstrarean cffecr on healing in rhe sccond srudy, a
finding arrributed ro che nced for morc growrh facror
whcn wound care is less aggrcssive(wound clinics in rhe
finr srudy v€rsusgeneral ciinics in rhc second srudy). Due
ro rhescsrudics, human recornbinant PDGF (Regranex@)
is approved by rhc FDA fon rrcalrnenr of diabcric foor
ulcers in non-ischemic and noninfected excremities.It is
imporrant to nore charPDGF mu.srbe usedas an adiuncr
ro good wound c:rrc. lr will be incffccrivc if used as solc
therapy.
The heding of pressurc ulcers has also bcen etduared
using PDGF. Early piloc studics suggcsredrher PDGF may
providc somc improvcmenr in rhc rare of closurc of such
wounds (2t1 1271. Rccenrly, a multicenrer, prorpectivc,
/. FLORTDAIvt,A. . Ju$ 2OO0. Vol.86, No.2 . 89
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placcbo conrrolleddouble blinded study evaluatedPDGF
io, ch. trcatment <,Ffull shicknessPrcssureulcers (23)'
Th-rs study used comPlete heir'ling ;.nd 9Uo/ohealing at l6
weeks as ih. trudy cndpoints. PDGF was found to r€sul(
in significantly grearerhcaling for both endpoints: l97o vs'
0olo (placebo) fot completc hcaling: 589o vs' 79o/o
(placcLo) for 9O96healing (Figurc3)- Furthcr studics arc
underway (o trsscrsthe use of PDGF in prcssurculcers'
l'iguru l:
r Ptaccbo
Eroo mcgrml
I t00mcgrml
GomPlele HGaling
90% Heeling
Fig. i. Thc hcaling uf *tgc IJI tnrl IV prctsu'c ulccrs wat signif'
,o)rty i^prnrrd utith ,cco,nthinant human PDGE but highcr /osct
did iot kad n farthcr improucmcnt in healing' (ad'aptcd fon dzta
contained i" Rnt RS. Robsn MC, Snicll JM, Perry BH' o a['
Bccaphrnir gcl in thc tnE/tttttnt of prcrutc ulret: a that II ran'
lom'izcd, doubbblinl. pkcebo-convollcd study Vtound fup Rrycn'
P-10
CONCLUSIONS
Crowth fact.rrs arc powcrFul rcgulattrry nrolccul,nsthat
control tissue rcpair. To datc, only PDGF ha^sbeen shown
condusively to be cffcctive as a thcrapy for clrronic
wounds. Orher growrh Factors,such as VEGF show signif'
icanr promisc as potcntial inter.,enriortsfor parienu with
problemaric wounds, or failing rcconstructive flaps- Prcs.nr orrd fururc rcsearch will bc conccnrratcd otr finding
more applicedons for growrh frctors, as well as dcvcloping
bertcr dclivcry sysrems,whcther it is gene rhcrepp special
drcssings,or tissuc cnginccred wound coveringp- Indccd,
tissuc engineering has brought to merket e composite skin
cquivalcnt cotrtainirrg:r bileycr ,rf livirrg kcnrrirrrrcvtc;trvcr
fiL.oblasrs wirhin a bovinc collagcn metrix (ApligraFil)
(24). Thcse living cclls produce various growrh facrorsand
cyrokines and it is postula<edthrt the skin substitute mav
be affectivc by mcans of dclivery of rhcse rcgulatory prorcins. Orher similar prodtrcts lrc untlcr investigation'
Thcrepy wir} other cyokincs may dso be forrhconring' A
largc body of data cxisu from enirnal modcls looking at
boie .,r,rrphogcnic protcins (growch factors for bone hcaling) as a tncans of :rugmcnting bone rcpair (25)' Studies
lrli.c shown sysrcmic adrrrinisuatit,n of grooth hormone
in burrrcd childrcn ceuscdeccclcratcdheeling trf sl<ingraFt
donor Sites'(26) (27). Another pilot srudv dcmonstrated
rcduction in hyperrophic btrrn scars ftrllowing systemk
rhcrapy wi<h inrcrferon* 2b' an effbcr postulatcd ro resulr
fronl'io,t,l regularion of trausfrrrming growth factor-|328
t 999).
Biotogic thcrapy with growth flcrors will certainly havc
gr*o,.ppliotions to mcdicine in thc future' Ics usc in plasii. turg.1u, as well as othcr fields is sdll in ics infinc.v' As
researchconrinuel and greater exPcricnceis accumulated'
growth ficrors rvill ccrrainly bc a powcrful tool ftrr I v:rricry of dinicel entirics-
9x . J. FLORIDA1,t.,1. -luk 2O0A'Vol. 86' No.2
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16. IsncrJM, lJrrunrg;rrrrrcrl. llrulr (i, Sclrlirrfchl R. Uleir ll. M:nor o,
Raz'i S. Synres JF- Trratrhent of rhromboangiitir oblitcrzns (Bucryer!
discasc) by inrranuscular gcne tr;rnsftr of "":cuter cndothcliel gtowrh
factor; Prelirninary clinicel nsule. J Vasc Surg !8:964-975, 1998
REFERENCES
7
P- 1 1
SYSTEMS
l. Mryr BA, Schuhz GS. Inrcr*tions of cytokincs, growth Ftctors rnd
prorerser in rctrrc and chrorric *'.unds. !?orrnd Rcp Rcgen 20:41|
420, t9<x>.
l- Colrelr 5. lsolrtillr of I suhrnuillary gllnrJ protrin lecclcrrtitrg
incisor crrrprion and cyciiC opening in the ncwborn aninral' J Drol
Cbcrn 237: l55l ' 1161of wound
J. Broun GL, Nrnnev LB, Griffen J, et el' Enhenccrncnt
L"aling by topicrl lrcrimcnt with cpidcrnral growrh f;rctor' N Engl J
Med 321:76, 1989.
17. Srccd Dl-- Modifoing rhc woutrd hcalirrg rcsgrnsc widr exogctrous
growth facrors. Clin Plart Surg 21:)97-405' lgr$
18. Srccd DL. rhc Diabctic Ulccr Study Group. Clinical cvdulrion of
rccombinant human plerclcr-dcrivcd growrh fzcror for thc trcarmcnt of
crrrcmrty diabctic rlc.rr- J Vasc Surg2l:71-81, t995.
4 lrr.rlrrcr
appri- 3;'#l:lIi
RF.-fopicar
A.Dicgcrmann
MC.Garrctr
rK,crossh'd
4.Cohcn
c:rrion o[ cpidermal Ero*'rh frcror onto panial-rhtk"T:
:t""]].:l:
human voluntccrs docs not cnhance rccPithclializ:cion- l'lasr Kcconstr
Surg 1995.96:251-714
5. Felangl V. Growllr
:G61-(t75, r99l .
tacton rnd wound hcaling' Dcrrnrtol
Clin
*::,J'I;ll,]i.Hru:i;:fi:r":;;51?$::;;
(bcczplcrmin] in paricntr wirh nonhcaling diabctic ulccrs: A phasc lll,
placebo-controllcd,.loubl"-biirrrl sru,Jy- Diebercs Carc 2l
,."11-,r.a
:B7Z-8?7, t998.
II
povel cencct vaccinc cotn6. Gonzrhz C, CrombctT' Cerala M. ., "1. 4
growth
factor linked to a carcpidcrmal
poscd of human rccombinant
,i"r proteins, report of a pilot clinic:l rriel' Ann Oncol 9: 4ll' l99E'
*'t'und
7. P"r.or )C, Celongc M' Epidrrrlrrl growth lrctor ihd corncel
h c u l i n g . A n t r r k i < < t r t t r . \ t u J Y (. - - ( ) t n c i I l ; f I l 4 - 3 l 4 ' l 9 i ? - '
8- Remsey HA. Heikkoncn EJ. L-rurila PIC Efftcr of epidcrnral gto*th
hcror oo rvrnpanic mtmcbranes with chronic perforations: a clinical
rria[- Oiofaryngol Hcrd Neck Surg l)3: J75-379, l')9)'
9- trncr JM, Walsh (, -Synrs J et al..{rreriel gene rrlnsfcr for rlrcrepeutic angiogcncsis in 1'aricnts with pcriprlrcr;rl v;rscul;rr Jiscarc l-lurlratr
Gcnr Thcrepv 7:9J9'9Ha' 1"96.
I0. Lopcz JJ, L:ham RJ, Sramler',{, er rl- VEGF administrerion in
c e s l 1 ) 9 8 1{ O : 2 7 2 - Z E l '
c h r o n i c m y < * r r d i r l i s c h c m i ar n p i g s ' C a r d i o ' r ' a s R
I |, Tlurumi Y, Takeshita 5. Chcn f)' cr rl. Direct intnrnuscul;rr gcne
transfcr of nakerj DNA cncodinq vscullr cndothclial rrro*rh lsctdor
r u B r r r e r r r Ac o l l i t L - r r r ld c u c l , t p , r t c n r . r n i l t i s r u c p c r I u s i o r r ' C i r c u l : r t i o n
I 996; 9{:328 I -3290'
i2, Trurumi Y, Kcarncv M. Chen D, ct el. Trcatnrent of acutc limb
ischcmir by inrremusculrr inicction of vasculer cndothclial gro*th facror serrr. Circularion 1997; 96(suPPl ll): lllll2-1136813. Taub PJ, Mrrmur JD, Zhang VX' Scndcrot} D' Nhat P' Phclps R'
Silvcr L, Vcinbcrg H. Locally adnrinisrered.vrsculer
Urken Ml,
endothclial g,rowrh factor rL)NA increilscssurvival oF ischcmic cxpcrinrcnral skin flaps. Ph.rr Reconsrr Srrrg 102:2033-2039' l99E14. Mack CA, Mrgo'crrr Cl. BudcnbcnJcr KT' Patel SR' Sch*'rrr EA'
Z;rnzorrico lt Fcrrir ll, Srndborn T, lstrnr OV, Cryrral RC. Rorcngarr
TIC Salvagc angiogenesi:induccd by adcnoviru-s-mcdiercrlgcnc tr:rnsftr
of ""rc.rLi "ndlthcliel gro*th faaor prorccrs againsr ischcnric vascular
occlusion. J Vasc Surg 27$99-709' 199815. H<;pkins sl', uulgriLr JP, Sinrs RL, B,rwnran B,.Don've.-DL'
Schmidr 5P ConrrollctJ ,lclitcrv of vrscuhr cndothclirl growrh fircror
limb tuncri<ri in a 'bbir
Fromolcs ncov;rscularizario^ anrJ nril''ins
m o d e l o f i s c h c m i a -J V a s cs u r g 2 7 : 6 8 6 - 8 9 5 , 1 9 9 E .
20- Srccd DL. Donohoc D. Wcb.srrr M\U. ct el- Effccr of cxtcn'rivc
dcbridcmcnr lnd rrcatnrcnr rtn the hteling of diabetic foor ulcers"J Anr
Coll Surg l8l:61 -6{' 1996.
21. Robson MC' Phitlips LG' Thonrason A, Robrcn LE, Pcircc GE'
l.'lrrclct-dcrivcd growrlr lecrur BB for rhc rrc:l(lllcnr o[clrronic Prr5surc
ulcrr, L;rtrcet 33\:7J' l!97
22- Mustoe TA, Cutlcr NR, Allmrn RM, Goode PS' Dcucl TF Prerrst
e'elulle rccontJA, Bcar M, .ScnJarCM' Picrce GF. A phesc ll srudy to
of sragcJ antl
ir,
thc
rrcltmcnt
Facrrr
BB
growth
binanr plai6lct-dcrivcd
4 p r c s s u r cr t l c c t s ,A r c h S u r g 1 2 9 : 2 1 1 - J 1 9 , 1 9 9 4
2J. Rers ltS. Robson MC, Snriell Jlvl, Perrv BH, cr al' Bccaplernrin gcl
jn the rrcrtmcnr of pressureulccrs: e phesc ll randomircd. doublc-blind'
plecebo-cuntroilcd srudl'. Vrtxrnd Rcp Regcn, 1999
?4, t)ol1'nchuh K, Hull l', Gucntcr l-. sr rl. Tht rolc of Apligraf in rhc
( r c i r ( n r c r tol f v c n o u s l c g . l c c r t . O s t o n t v / V " o u n d M a n a g e n r c n t4 5 1 4 ^ 4 1 '
l 999.
Rl-'
25. Breirban A5. Grandc DA' Meron JM' Brrcie M. JanrcsT' Granr
Gcnc-cnhrnccd rirsuc cngilccring: rpplicrrions for bonc hcaling using
culturrrl Jrcrkr.*tcelcclls trensdsctd rerrovirelly wirh rhc BMP-7 gcnc'
A|to l'l:ur Srrrg 4.1:4lltt'41)5,l9')9
26. Citpin DA, Berro*'RE, Rutan RL, Brocmcling L, Hcrndon DN'
Recombinent human gro*'th horrrrone accclcratcs wound hcaling in
childrcn with latge cut.ncous burns. Ann Srrrg 210: l9-14' 1994'
--.
l27. Rrnrirrz l{. Volf SE. Berrow Rl'.. l-{crrrrlun DN. Crus'rh Jxrrmonc
trcatnrcn( in pcdiarric burns: a rll-c tlrcrapcuric cpproach' Ann 5rrrg
1998.
2.8:419448.
shtnk'wsky HA' Rrnnu l{' Ncdelcc B' lwashi'a T'
;btranilr'l'
i : ^ I " t t " ' E A'
E ' TJcrum TV' Scort PG''frJrsfbrnrirrg growth facror-bcu in
,l'r.rn',"ily iniurcd paticns wirh hypertrophic scars: cffects of interlcron
c l p h u - 2 b ' I J l u r tR c c o r r s r rs u r g 1 0 2 : l - 1t 9 - 1 3 2 8 ' 1 9 9 8 '
'Jul.l 20O0'Vo['
J. FLORIDA M.A.
86' No' 2'91