Experimental eye in Histology vitreous, · British JournalofOphthalmology, 1979, 63, 312-321...

British Journal of Ophthalmology, 1979, 63, 312-321

Experimental posterior penetrating eye injury in therabbit. II. Histology of wound, vitreous, and retinaPHILIP E. CLEARY AND STEPHEN J. RYANFrom the Department of Ophthalmology, University of Southern California, and Estelle Doheny EyeFoundation, Los Angeles, California, USA

SUMMARY The histological findings of the wound, the vitreous, and the retina in the rabbit eye withexperimental posterior penetrating injury are described. Wound healing had just begun at 3 daysafter injury and was well established by 9 to 12 days. It involved proliferation of cells fromthe episclera and from the choroid. The progression to a fibrous ingrowth from the wound occurredonly in eyes with blood in the vitreous. The intravitreal fibroblastic proliferation had begun at 6days after injury and seemed to be derived from the choroid, the nonpigmented ciliary epitheliumand, posteriorly, from the optic nervehead. During the development of retinal detachment theconfiguration of the peripheral and posterior retina, together with the orientation of vitreousstrands, suggested the presence of vitreous traction. We postulate that the presence of contractilefibroblasts (myofibroblasts) in the vitreous may provide the mechanism for vitreous traction.The retinal detachments were also characterised by epiretinal and subretinal membranes, butthese were not prominent. The end-stage appearance of a soft, shrunken eye with cyclitic membraneformation and retinal detachment resembles the outcome in many human eyes after severepenetrating injuries.

Severe penetrating injuries in human eyes arecharacterised histologically by intraocular fibrosiswith cyclitic membrane formation and tractionretinal detachment (Hogan and Zimmerman, 1962;Coles and Haik, 1972). In fact, traction retinaldetachment is the main reason for loss of vision inthose injuries which are confined to the posteriorsegment (Eagling, 1975).

It has been shown in the preceding paper (Clearyand Ryan, 1979) that the experimental model of aposterior penetrating injury in the rabbit eye resultsin cyclitic membrane formation and in tractionretinal detachment. In the present paper we describethe sequence of histological changes.

Materials and methods

As previously described, rabbit eyes were injuredby a standard wound which was 8 mm long throughthe pars plana, avoiding the lens and the peripheralretina. Prolapsed vitreous was abscissed and thewound carefully closed by microsurgical techniqueswith interrupted sutures of 8-0 silk. After wound

Address for reprints: Mr Philip E. Cleary, FRCS, ArdkeenHospital, Waterford, Ireland

closure the fundus was inspected by indirect ophthal-moscopy and the area of the wound and the peri-pheral retina examined by scleral indentation. Insome eyes autologus blood and in others balancedsalt solution was injected through a 25-gauge needleinserted through the wound and under ophthal-moscopic control into the mid-vitreous, withavoidance of the lens and the retina.The eyes were enucleated at 3-day intervals for

the first 3 weeks after injury as well as at 2 and 3months after injury. Each group consisted of aminimum of 3 eyes. The eyes were fixed in Bouin'sfixative for 24 hours and were then sectionedthrough the optic nerve and midpoint of the woundfor gross examination. Each half eye was examinedunder the dissecting microscope, and drawingsand photographs were made. The eyes werethen slowly dehydrated in alcohol and embedded inparaffin.

Vertical serial sections of 5 Fm thickness weremade through the wound, through the retina, andthrough the optic disc. The sections were stainedwith haematoxylin-eosin, periodic acid Schiff, andtrichrome after Masson.

Controls included 7 normal eyes and 15 eyes witha standard injury but without blood injection.

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Experimental posterior penetrating eye injury in the rabbit. II. Histology of wound, vitreous, and retina 313

Fig. 1 At 3 days after injury.The wound has been artifactuallyseparated during processing(arrow). The striking featuresare the evidence ofproliferationfrom the episcleral tissues intothe wound, and the incarcerationof vitreous with vitreous strandsradiating from the wound (doublearrow) (H and E, x 28)

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Results

STANDARD INCISION AND BLOOD INJECTIONEarly phase (O to 3 days)At 3 days after injury the wound and vitreous inthe inner aspect of the wound were infiltrated withleucocytes and macrophages (Fig. 1). The edges ofthe scleral wound remained clearly defined, andthere was some early evidence of wound healingwith proliferation from the episclera (Fig. 1).Vitreous was incarcerated in the wound, and strandsof vitreous radiated from the wound to the posteriorretina and also to the peripheral retina in the areaof the vitreous base (both directly posterior to thewound and at 180 degrees from the wound). At thisstage intravitreal fibroblastic proliferation was notseen.

In these eyes the retina was attached, and theconfiguration of the peripheral retina resembledthat of the normal control eyes and did not suggestthe presence of vitreous traction.

Intermediate phase (6 to 15 days)From 6 to 15 days after injury cellular proliferationoccurred and became progressively more prominentat the wound and within the vitreous. In most ofthese eyes the retina was detached.During this phase the blood clot became more

diffuse and showed signs of absorption, but itremained loculated within the vitreous. The vitreousdid not separate posteriorly from the retina. Haemo-siderin-containing macrophages were present withinthe vitreous and in the inner retina.Wound healing involved proliferation of cells

from the episclera initially, but in the inner aspect

of the wound fibroblastic proliferation occurredfrom the uvea and also from proliferation of thenonpigmented ciliary epithelium. Even with goodwound apposition fibroblastic ingrowth was alreadypresent at 6 days after injury and was prominentby 12 days (Figs. 2 and 3). The fibroblasts permeatedthe blood clot and lined up along the vitreousstrands, which were incarcerated in the wound(Figs. 2 and 3). Fibroblastic proliferation into thevitreous also occurred posteriorly from the opticnervehead, where the fibroblasts were also lined upalong the vitreous strands (Figs 2 and 3).During the development of retinal detachment

the configuration of the peripheral and posteriorretina, together with the orientation of vitreousstrands, suggested the presence of vitreous traction(Figs. 4, 5, 6). At 6 days after injury, but moreprominently at 9 and 12 days, the peripheral retinaassumed a characteristic appearance of beingdragged or rolled forward on to the pars plana, notonly directly posterior to the wound but also at180 degrees from the wound (Figs. 5 and 6). In fact,this rolling forward of the peripheral retina waspresent throughout its entire circumference.Vitreous strands were attached to these areas ofperipheral retina, and the vitreous was lined upbetween the retina and the wound (Figs. 5 and 6).Detachment of the posterior retina occurredtypically at 12 days after injury, with a similarappearance of lining up of vitreous strands betweenthe wound and the detached posterior retina.

Late phase (18 days to 3 months)Eyes examined between 18 days and 3 months afterinjury showed progression from the initial stages of


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Philip E. Cleary and Stephen J. Ryan

Fig. 2 At 12 days aJter injury.Note the markedfibrousproliferation extending inwardfrom the wound. The ciliaryprocesses are drawn up to thewound. There is a proliferation ofthe nonpigmented ciliaryepithelium (arrow). The fibro-blastic proliferation has invadedthe blood clot and is extendingposteriorly along the vitreouscondensation. In the rabbit eyeafter injury the vitreous does notseparate from the posterior retina,and vitreous becomes condensedand lined up between the woundand the posterior retina. (H andE, x 30)

Fig. 3 The same eye as Fig. 24at 12 days after injury. Thisphotograph shows the attachments S.of the vitreous over the opticnerve head. The blood vesselswhich are normally present on thesurface of the nerve are apparent(arrow). Vitreous strands areattached to the surface of theoptic nerve head, and the ;remarkable feature is theorganisation offibroblasts withtheir long spindle-shaped nucleialong the vitreous strands (doublearrow). (Hand E, x 60)

retinal detachment to the advanced stage of totalretinal detachment, with the retina drawn up intothe wound, with cyclitic membrane formation (Figs.7 and 8), ciliary body and choroidal detachments,and finally the development of an atrophic shrunkeneye.

Proliferations on the surface of the retina with theformation of epiretinal membranes were identifiedoccasionally at 18 and 21 days after injury. However,when the retinal detachments became total and theretina was convoluted and drawn up into the wound,it was not possible to identify discrete epiretinal orsubretinal membranes.

Hyperplasia of the retinal pigment epithelium wasfrequent, with sheets of flattened pigmented cellsand plaques of spindle-shaped cells (Fig. 9). Inaddition, these eyes were characterised histologicallyby a focal nongranulomatous inflammatory infiltra-tion of the choroid.

STANDARD INCISION AND INJECTION OFBALANCED SALT SOLUTIONThese eyes demonstrated uncomplicated healing ofthe wound, which had started at 3 days after injuryand was well established by 21 days. Proliferationfrom the episclera appeared as the initial response

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Experimental posterior penetrating eye injury in the rabbit. IL Histology of wound, vitreous, and retina 315

Fig. 4 At 12 days after injury.The fibrous proliferation fromthe wound is quite prominent.The fibrous ingrowth appears tobe derived from the uvea and alsofirom the scleral wound. Note thelining up of the condensed vitreousfibrils which extendfrom thewound to the posterior retina(arrows). There are a number ofinflammatory cells in the vitreous,and overlying the vitreous is theblood clot which is in the processof Iysis and organisation. (H andE, x23)

3,Fig. 5 At 12 days after injury.The lens has been lost duringprocessing. The wound in thisanimal illustrates a less luxuriantfibrous proliferation. None the lessthe incarceration of vitreous inthe wound and the proliferationoffibroblasts along the anteriorvitreous are quite apparent(arrow). The vitreous iscondensed in the region of thevitrous base, and strands ofvitreous extend between the woundand the Deripheral retina (doublearrow). The peripheral retinahas rolledforward on to the non-pigmented ciliary epithelium.There is a real retinal detachmentin the periphery as evidenced byserous fluid beneath the sensoryretina (broad arrow). (H and E,x 28)

Fig. 6 The same eye as Fig. Sat 12 days after injury. At 180degrees from the wound theperipheral retina has also rolledforward on to the nonpigmentedciliary epithelium. The condensa-tion of vitreous over the peripheralretina and vitreous base is quitestriking. Note again the lining-upof vitreous fibrils and theorganisation of inflammatory cellswithin this matrix. The non-pigmented ciliary epitheliumshows a suggestion of earlyproliferation (arrow). (H and E,x 37)


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316Philip E. Cleary and Stephen J. Ryan

Fig. 7 At 21 days after injury.The lens has been lost duringprocessing. Fibrous proliferationfrom the wound appears to bederived mainly from the uvealtract. The retina has been throwninto folds and is drawn up to thewound by thisfibrous proliferation.The fibrous tissue in the processofforming a cyclitic membraneextends along the surface of the

Z detached retina. (H and E, ,20)

Fig. 8 Another eye showing the Yend stage appearance at 4 weeks "'uafter injury. The wound isorganised and has blood vessels U-and scattered pigment in the newfibrous tissue (arrows). A markedfibrous proliferation extendsinwards from the wound, and >.,,swirls of fibrous tissue form a "plaque on the surface of theretina. In this animal the entireretina is drawn up into the regionof the wound and fibrousproliferation. (H and E, x 56)

in wound healing, but fibroblastic proliferation fromthe choroid, together with proliferation of the non-pigmented ciliary epithelium, was also present.Some cellular proliferation occurred on the innervitreal aspect of the wound, but it did not showprogression, and fibroblastic proliferation within thevitreous was not seen (Fig. 10).

Vitreous strands were incarcerated in the wound,and they were also attached to the posterior retinaand to the peripheral retina in the region of thevitreous base. The configuration of the retina,however, did not suggest evidence of vitreoustraction (Fig. 10).

Eyes examined at 3 months after injury showed ahealed and remodeled scar, an attached retina, andthe absence of fibrous ingrowth. Some eyes showedproliferation of the nonpigmented ciliary epitheliumjust posterior to the wound.

STANDARD INCISION WITH INJURY TO THERETINA

Typically, wound healing was uncomplicated, and,although vitreous was incarcerated in the wound,neither a fibrous ingrowth from the wound norintravitreal fibrous proliferations were seen.The detached retina showed the usual associated

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Fig. 9 At 2 months after injury.Hyperplasia of the retinal pigmentepithelium has occurred. Notethe tubular proliferation of theretinal pigment epithelium cells(arrow). Note the overlyingplaque ofpartially depigmentedspindle cells (double arrows),presumably laid down by thepigment epithelium during itsproliferation into the subretinalspace. (H and E, x 22)

nlr'~:00, Fig. 10 At 3 months afterinjury and injection of balancedsalt solution. The wound hashealed and is remodelled. There

4 4 ~~is a limited fibrous proliferationat the site of/penetration of'thepars plana and ciliary body(arrow). There has been a slidingforward of the nonpigmentedciliary epithelium in the region ofthe wound. More importantly,the retina is noted to be in anormal position without detach-ment (double arrows). This viewof the peripheral retina is alsonoteworthy in that the samemeans offixation as well ashistopathological techniques wereemployed as for all other eyes.

Thus we can feel confident that the rolling forward of the peripheral retina on to the pars plana ciliary epitheliumobserved in eyes with a standard injury and blood injection is not an artifact due to processing. (H and E, x 26)

degenerative changes, with loss of photoreceptorsand intraretinal cystoid swelling. In some areas theretina was thrown into folds, which could be relatedto the presence of epiretinal membranes. However,the configuration of the retinal detachment remainedfunnel shaped, and the retina was not drawn upinto the wound.As early as 21 days after injury epiretinal mem-

branes were found, which in some eyes were con-nected to the underlying retina by a small bridge of

tissue and which contained cells with abundantcytoplasm and oval-to-spindle-shaped nuclei. Inother eyes the epiretinal membranes may haveoriginated from the prepapillary blood vessels (Fig.11). The epiretinal membranes also contained pig-mented cells which stained positive with Prussianblue for iron. These cells had the appearance ofhaemosiderin-laden macrophages.

Subretinal membranes lying outside the externallimiting membrane could also be found as early as

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Fig. 11 At 2 months afterinjury. Full-thickness retinal foldsare present. The medullated andnerve fibre layers have beenpulled close to each other andapproximated in one region(arrow). The epiretinal membraneconsists of cells with abundantcytoplasm and oval nuclei whichmay be glial in origin, and alsocontains pigmented haemosiderin-laden macrophages. In additionthe epiretinal membrane hascontinuity with the blood vesselswhich are normally present on thesurface of the medullary rays inthe rabbit eye (double arrows).(H and E, x 45)

21 days after injury, but were very uncommon andwere confined to retinal folds (Fig. 12). Withinretinal folds it was more common to observe aproliferation in the outer retina, of irregularlyarranged cells with abundant cytoplasm and oval orspindle-shaped nuclei, but lying within the externallimiting membrane (Fig. 12). These cells had dis-placed the outer retinal layers from the externallimiting membrane to the inner nuclear layer.When the retina was detached, proliferation of

the retinal pigment epithelial cells was common andwas observed as early as 15 days after injury. Bothdiffuse hyperplasia with sheets of flattened pig-mented cells and plaques of partially depigmented,closely packed, spindle-shaped cells were seen(Fig. 9). When the retinal detachment extendedanteriorly to the ora, the pigment epitheliumproliferated in the area of the detached pars planaepithelium, becoming 2 or 3 layers thick withirregularly arranged depigmented cells.Two additional eyes that suffered spontaneous

choroidal and subretinal haemorrhage during theinjury were enucleated immediately after woundclosure. These eyes had a choroidal vascular bedthat was engorged with blood.

Discussion

In experimental posterior penetrating injury in therabbit eye we observed intraocular fibrous prolifera-tion, the formation of cyclitic membranes, and thedevelopment of traction retinal detachment. Humaneyes suffer the same sequelae after severe posteriorpenetrating injuries, although the time course is

quite different (Coles and Haik, 1972; Eagling,1975; Winthrop et al., 1978). The evolution of thepathological process can be conveniently dividedinto 2 stages.

(1) FIBROUS INGROWTH AND INTRAVITREALFIBROUS PROLIFERATIONThe process of wound healing and repair withproliferation from the episclera and choroid hadjust begun at 3 days after injury and was welladvanced by 9 days, which accords with previousobservations (Duke-Elder, 1965). However, thepresence of blood in the vitreous had a major effectin the development of a fibrous ingrowth from thewound. In eyes without blood in the vitreoushealing of the scleral wound was rapid and theresultant scar was inconspicuous. By contrast, inthe eyes with blood in the vitreous, the progressionto an intraocular fibrous ingrowth from the woundwas a constant feature. Other factors are recognisedas important in the development of a fibrousingrowth, such as incarceration of tissues and poorwound apposition (Duke-Elder, 1965). Yet in theseexperiments despite good wound apposition aprominent fibrous ingrowth was typical.During intravitreal fibrous proliferation the cells

appeared to line up along vitreous strands as ascaffolding. Cellular proliferation into the vitreousfrom the wound appeared to be derived not onlyfrom the episclera and choroid, but also from thenon-pigmented ciliary epithelium (Fig. 14). Thesecells hypertrophy and become elongated and mayproliferate along the vitreous strands to which theyare attached. The normal nonpigmented ciliary

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Fig. 12 At 3 months afterinjury. Note the external limitingmembrane delimits the outerretina. An intraretinal glialproliferation has occurred,containing irregularly arrangedcells with abundant cytoplasm andoval-to-spindle-shaped nuclei.Inflammatory cells, macrophages,and polymorphonuclear leucocytesare present in the subretinalspace. (H and E, x 123)

epithelium may give rise to collagen fibrils in thevitreous (Fine and Zimmerman, 1963), and hyper-plasia of these cells is recognised in a variety ofconditions, including injury and inflammation(Hogan and Zimmerman, 1962).

Intravitreal fibrous proliferation from the opticnervehead has been observed previously in rabbiteyes after injection of autogenous blood or sac-charated iron oxide (Cibis and Yamashita, 1959).This proliferation may be derived from epipapillaryglial tissue or, more likely, from the prepapillaryblood vessels.The eyes which contained blood also contained

-..... Fig. 13 At 3 weeks after injury.4 1 Note the absence of the external* > | limiting membrane. There is a

-;a] 2 proliferation ofglial cellsextending from the outer aspect

p ; S,e , S, Iof one retinal fold to another(arrows). These cells contain

s RS R | abundant cytoplasm and longprocesses and oval-to-spindle-shaped nuclei. (H and E, x 154)

monocytes and macrophages; and it is possible thatfibroblasts may be derived from haematogenouscells, particularly monocytes and macrophages(Ailgower and Hullinger, 1960), although most ofthe experimental evidence now supports the viewthat fibroblasts involved in wound healing arederived locally (Grubl, 1964). It is also possible thatcells which originated in the pigment epithelium inthe area of the wound may have contributed to thefibrous ingrowth, and we observed some spindle-shaped cells with pigment other than haemosiderinin their cytoplasm. Certainly, 'fibrous metaplasia' ofpigment epithelium is not uncommon (Hogan and


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Fig. 14 At 21 days after injurythe appearance of the ciliarybody at 180 degrees from thewound in an eye with a subtotalretinal detachment. Thisphotograph shows proliferation ofthe nonpigmented ciliaryepithelium. The appearancecannot be explained on the basisof tangential cutting alone, whichis apparent in I ciliary process.The number of cells and theirnuclei suggest a real proliferationof the nonpigmented ciliaryepithelium cells. (H and E, x 50)

Zimmerman, 1962; Freyer, 1966; Wallow and Tso,1972; Tso, 1973; Machemer and Laqua, 1975), butrecognition of the epithelial characteristics of these'fibrocyte-like' cells can be demonstrated only byelectron microscopy (Wallow and Tso, 1972;Machemer and Laqua, 1975).

(2) TRACTION RETINAL DETACHMENTIn the rabbit eyes, with experimental posteriorpenetrating injury and blood in the vitreous, wehave suggested that the development of retinaldetachment may be related to vitreous traction.We interpreted the characteristic configuration ofthe peripheral retina and elevation of the posteriorretina, which was confined initially to the medullaryrays, as evidence of vitreoretinal traction (Figs. 4,5, 6). The lining up of vitreous strands between thewound and posterior retina and between the woundand peripheral retina in the region of the vitreousbase suggests a mechanism by which traction iseffected. Certainly in the rabbit eye it is apparentduring vitrectomy that the vitreous is tightly attachednot only over the peripheral retina in the vitreousbase but also over the posterior retina in the regionof the medullary rays.The onset of traction retinal detachment at about

12 days after injury coincides with the presence ofsignificant intravitreal fibroblastic proliferation. Infact fibrous proliferation within the vitreous waspresent at 6 days after injury but showed a significantprogression by 9 to 12 days. Although we haveimplicated vitreous traction in the development ofretinal detachment, the mechanism for traction isobscure but is perhaps related to changes in vitreous

collagen, such as reorientation of collagen fibrils asa result of changes in cross-linkage between thenative vitreous collagen and the new collagen laiddown by fibroblasts.On the other hand it has been shown that wound

contraction occurs independently of collagen forma-tion (Abercrombie et al., 1956) and is mediated byfibroblasts with characteristics typical of smoothmuscle cells-myofibroblasts (Gabbiani et al., 1972).The presence of such contractile fibroblasts in thevitreous could provide a mechanism for vitreoustraction. Furthermore, the development of vitreoustraction leading to traction retinal detachment inthe rabbit eye at about 12 days after injury coincideswith the rapid increase in the percentage of myo-fibroblasts observed at between 1 and 2 weeks inexperimental full-thickness skin wounds (Rudolphet al., 1977). Although we have not performedelectron microscopy on the injured rabbit eyes, wehave observed typical myofibroblasts in rhesusmonkey eyes after an experimental posteriorpenetrating injury.

Epiretinal and subretinal membrane formationcomplicates many posterior penetrating injuries inhuman eyes (Winthrop et al., 1978). In somecontraction of epiretinal membranes at the macularesults in macular pucker, while in others massiveperiretinal proliferation leads to inoperable retinaldetachment (Hutton et al., 1976; Benson andMachemer, 1976; Faulborn et al., 1977; Winthropet al., 1978). In the rabbit eye epiretinal membraneswere not common and were probably glial in origin,as indicated by the bridges connecting the epiretinalfibrous tissue and the retina. In human eyes the

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development of epiretinal fibrosis and surfacewrinkling retinopathy has been linked with detach-ment of the posterior vitreous (Roth and Foos,1971; Wise, 1975; Gass, 1977), though the relation-ship is far from clear (Foos, 1977). It is of interest,therefore, that in the rabbit eye posterior vitreousdetachment does not occur, and we have commentedon the tight attachment between the vitreous andposterior retina over the medullary rays.

It is recognised that subretinal membrane in bothhuman and monkey eyes can have their origin inthe retinal pigment epithelium (Machemer andLaqua, 1975; Machemer et al., 1978). In the rabbitwe noted that proliferation of pigment epithelialcells was common in eyes in which the retina wasdetached. Nonetheless we found subretinal mem-branes infrequently in the rabbit eyes, while theirappearance and continuity with the retina and atotal lack of pigmentation suggested a glial cellrather than pigment epithelium cell origin.The rabbit eyes enucleated at 3 months after a

standard injury and blood injection were soft, theanterior chamber was frequently absent, the lenswas often cataractous, the retina was detached, anda cyclitic membrane was present. This end-stageappearance resembles the atrophy and shrinkageseen in many human eyes enucleated after severeocular trauma (Hogan and Zimmerman, 1962).

We thank Ms K. Borkowski for technical assistance for thispaper.

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Cleary, P. E., and Ryan, S. J. (1979). Experimental posteriorpenetrating eye injury in the rabbit. I. Method of produc-tion and natural history. British Journal of Ophthalmology,63, 306-311.

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Experimental eye in Histology vitreous, · British JournalofOphthalmology, 1979, 63, 312-321...

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