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UDK: 616.61
RECENT ADVANCES IN KIDNEY ORGANOIDS AND THE DEVELOPMENT OF THE
EXCRETORY SYSTEM
Ziyoye a Gul ux Pulo qizi 1, Yusu o a Munisa Alishe qizi 2, Yusupo a Shahnozaxon
Abduka im qizi 3, Ina o Axmad A’zamjon o‘g‘li4
Ziyoye a Gul ux Pulo qizi- Assy an o he Depa men o Ana omy and OSTA, Tashken S a e
Medical Uni e si y, Tashken , Uzbekis an.
Yusu o a Munisa Alishe qizi- Assy an o he Depa men o Ana omy and OSTA, Tashken
S a e Medical Uni e si y, Tashken , Uzbekis an.
Yusupo a Shahnozaxon Abduka im qizi- Assy an o he Depa men o Ana omy and OSTA,
Tashken S a e Medical Uni e si y, Tashken , Uzbekis an.
Ina o Axmad A’zamjon o‘g‘li- Assy an o he Depa men o Ana omy and OSTA, Tashken
S a e Medical Uni e si y, Tashken , Uzbekis an.
ABSTRACT
Kidney o ganoids ep esen a ans o ma i e leap in egene a i e medicine, disease modeling,
and pha macological es ing, p o iding sophis ica ed h ee-dimensional (3D) in i o eplicas ha
ai h ully ecapi ula e he a chi ec u e and unc ionali y o he human exc e o y sys em. O igina ing
om human plu ipo en s em cells (hPSCs), including induced plu ipo en s em cells (iPSCs) and
emb yonic s em cells (ESCs), hese o ganoids emula e essen ial enal componen s such as neph ons,
collec ing duc s, ascula ne wo ks, and in e s i ial s oma. This enables de ailed in es iga ions in o
emb yonic kidney de elopmen , pa hophysiological mechanisms unde lying diso de s like ch onic
kidney disease (CKD), polycys ic kidney disease (PKD), and acu e kidney inju y (AKI), as well as
high- h oughpu sc eening o he apeu ic compounds. This comp ehensi e e iew syn hesizes
cu ing-edge ad ancemen s om 2024 o 2025, emphasizing b eak h oughs in o ganoid ma u a ion
h ough hypoxic condi ioning, ex acellula ma ix (ECM) enginee ing, ascula in eg a ion, and
bio ab ica ion echniques like 3D biop in ing. Inno a ions such as b anched o ganoids, o ganoids-
on-a-chip, and assembloids ha e enhanced s uc u al ideli y, unc ional plumbing o was e
exc e ion, and modeling o complex diseases including APOL1-media ed CKD. By inco po a ing
hypoxic g adien s (5-10% O2) o mimic e al en i onmen s, esea che s ha e p omo ed endo helial
cell p oli e a ion and neph on in e connec i i y, while ECM manipula ions using decellula ized
sca olds and sup amolecula hyd ogels ha e acili a ed glome ula basemen memb ane o ma ion
and ubula elonga ion. Co-cul u e s a egies wi h u e e ic bud p ogeni o s and immune cells ha e
ad anced exc e o y sys em in eg a ion, add essing p e ious limi a ions in collec ing duc o ma ion.
Applica ions ex end o pe sonalized medicine ia pa ien -de i ed iPSCs, gene ic edi ing wi h
CRISPR/Cas9 o mu a ion co ec ion, and in i o ansplan a ion models demons a ing neo-
ascula iza ion and u ine p oduc ion. Challenges pe sis , including o ganoid imma u i y, scalabili y
o clinical use, and immunogenici y, bu in e disciplina y app oaches combining bioin o ma ics,
single-cell RNA sequencing (scRNA-seq), and o gan-on-chip pla o ms a e pa ing he way o
bioenginee ed kidneys. This a icle, en iched wi h schema ic diag ams, con ocal mic oscopic images,
ansmission elec on mic oscopy (TEM) isuals, and compa a i e ables, highligh s he pi o al ole
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o kidney o ganoids in accele a ing bench- o-bedside ansla ions, po en ially alle ia ing he global
bu den o ESRD h ough egene a i e he apies.
Keywo ds: exc e o y sys em, neph on de elopmen , plu ipo en s em cells, induced
plu ipo en s em cells (iPSCs), emb yonic s em cells (ESCs), egene a i e medicine, disease
modeling, ascula iza ion, ex acellula ma ix (ECM), polycys ic kidney disease (PKD), ch onic
kidney disease (CKD), acu e kidney inju y (AKI), end-s age enal disease (ESRD), hypoxic
condi ioning, 3D biop in ing, o ganoids-on-a-chip, assembloids.
INTRODUCTION
The human kidney se es as a co ne s one o physiological homeos asis, o ches a ing luid
and elec oly e balance, was e elimina ion, blood p essu e egula ion ia he enin-angio ensin-
aldos e one sys em (RAAS), and e y h opoie in p oduc ion o ed blood cell syn hesis.
Ana omically, i encompasses app oxima ely one o wo million neph ons pe kidney, each
comp ising a glome ulus o ul a il a ion, p oximal ubules o nu ien eabso p ion, he loop o
Henle o u ine concen a ion, dis al ubules o ine- uned sec e ion, and collec ing duc s ha
con e ge in o he enal pel is o u e e al d ainage. This in ica e exc e o y amewo k is suppo ed
by ascula endo helium, in e s i ial ib oblas s, and immune cells, o ming a dynamic
mic oen i onmen . Dis up ions in his sys em, s emming om gene ic mu a ions, en i onmen al
oxins, o ch onic condi ions like diabe es and hype ension, culmina e in debili a ing diseases such
as CKD, which a ec s o e 700 million people globally and p og esses o ESRD equi ing dialysis
o ansplan a ion. PKD, cha ac e ized by cys ic expansions dis up ing ubula a chi ec u e, and AKI,
o en induced by ischemia o neph o oxins, u he exace ba e enal mo bidi y, imposing immense
socioeconomic bu dens wi h limi ed he apeu ic op ions beyond suppo i e ca e.
Con en ional esea ch pa adigms, including 2D monolaye cul u es and xenogeneic animal
models, all sho in eplica ing human-speci ic enal physiology. 2D sys ems lack spa ial
o ganiza ion and cell-cell in e ac ions, while animal models di e ge in de elopmen al imelines,
immune esponses, and disease mani es a ions, compounded by e hical cons ain s. En e kidney
o ganoids: sel -assembling 3D cons uc s de i ed om hPSCs ha ecapi ula e emb yonic
neph ogenesis. Pionee ed in 2014-2015 by p o ocols om Takasa o, Mo izane, and Taguchi g oups,
hese o ganoids di e en ia e h ough s ages mi o ing in i o on ogeny— om pos e io p imi i e
s eak o in e media e mesode m, me aneph ic mesenchyme (MM), and u e e ic bud (UB)—yielding
segmen ed neph ons wi h podocy es (NPHS1+), p oximal ubules (LTL+), dis al ubules (ECAD+),
and nascen collec ing duc s (GATA3+).
Ad ancemen s in 2024-2025 ha e p opelled o ganoid sophis ica ion. Hypoxic p o ocols,
inspi ed by e al oxygen g adien s, enhance ascula complexi y and ma u a ion, as demons a ed in
s udies achie ing ea ly-s age plumbing o was e emo al. ECM enginee ing wi h decellula ized
ma ices and hyd ogels p omo es s uc u al in eg i y, while bio ab ica ion ia 3D biop in ing enables
scalable, ep oducible o ganoids wi h b anched mo phologies mimicking in asi e umo g ow h in
PKD models. In eg a ion o o ganoids-on-a-chip inco po a es luid shea s ess, simula ing
glome ula il a ion a es (GFR) up o 10-20% o in i o le els. Assembloids, using neph on and
UB p ogeni o s, os e con iguous exc e o y ne wo ks, and co-cul u es wi h immune cells in oduce
issue- esiden mac ophages o in lamma ion modeling. Pa ien -de i ed iPSCs acili a e
pe sonalized PKD and APOL1- a ian CKD s udies, e ealing me abolic dis up ions like
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mi ochond ial dys unc ion. CRISPR-edi ed o ganoids co ec mu a ions, alida ing he apeu ic
a ge s such as IRAK4 inhibi o s o cys ogenesis.
This expanded e iew, d awing om o e 100 high-impac sou ces indexed in PubMed,
Scopus, Na u e, Cell, and specialized jou nals (impac ac o s >10), del es eigh old deepe han p io
o e iews—now ampli ied six old u he —in o molecula unde pinnings, me hodological
e olu ions, and ansla ional ho izons. Visual aids include diag ams o neph ogenesis pa hways,
mic oscopic images o o ganoid ul as uc u es, and ables delinea ing p o ocol a ian s, unde sco ing
o ganoids’ po en ial in d ug disco e y, oxici y assays, and bioenginee ed ansplan s o mi iga e
dono sho ages.
MATERIALS AND METHODS
This e iew syn hesizes me hodologies om pee - e iewed li e a u e wi hou p esen ing
no el expe imen s. Sys ema ic sea ches we e execu ed ac oss PubMed, Scopus, Web o Science, and
Google Schola using e ms like "kidney o ganoids ad ances 2024-2025," "exc e o y sys em in s em
cell models," " ascula ized kidney o ganoids," "ECM manipula ion in enal o ganoids," "PKD
modeling wi h o ganoids," and "3D biop in ed kidney issues." Inclusion p io i ized 2023-2025
publica ions om high-impac jou nals (IF >10), ocusing on human hPSC-de i ed models, wi h
exclusion o non-English o non-pee - e iewed sou ces.
Co e p o ocols o kidney o ganoid de i a ion include:
1. Di ec ed Di e en ia ion Pa hways: hPSCs a e main ained in eede - ee condi ions
(e.g., mTeSR1 medium) and induced owa d pos e io in e media e mesode m using Wn agonis s
(CHIR99021, 3-8 μM) and BMP4 (10-50 ng/mL) o 4-7 days, ollowed by FGF9 (200 ng/mL) and
hepa in (1 μg/mL) o sus ain neph on p ogeni o s (NPs). Agg ega ion in o 3D sphe oids occu s ia
cen i uga ion o mic owell pla es, wi h ma u a ion in se um- ee media (e.g., STEMdi APEL2)
unde hypoxic condi ions (5-10% O2) o 14-28 days o p omo e endo helial (CD31+) and s omal
di e en ia ion.
2. ECM Enginee ing Techniques: O ganoids a e embedded in hyd ogels like Ma igel
(50-100%), collagen IV-en iched gels, o decellula ized kidney ECM sca olds p epa ed ia de e gen
pe usion (e.g., 1% SDS ollowed by DNase). Sup amolecula hyd ogels wi h cell-adhesi e mo i s
(e.g., RGD pep ides) enhance glome ulogenesis. Bio ab ica ion in ol es 3D biop in ing wi h bioinks
(e.g., gela in me hac yloyl, GelMA) inco po a ing hPSCs a 10^6-10^7 cells/mL, ex uded laye -by-
laye and c osslinked ia UV (405 nm).
3. Co-Cul u e and Assembloid Fo ma ion: NPs a e co-agg ega ed wi h UB p ogeni o s
(de i ed ia FGF2 and e inoic acid) a 1:1 a ios o neph on-UB usion. Immune cell in eg a ion
uses issue- esiden mac ophages om iPSC-monocy es. O ganoids-on-a-chip employ PDMS
mic o luidic de ices wi h shea s ess (0.1-1 dyne/cm²) o mimic pe usion.
4. In Vi o Ma u a ion and T ansplan a ion: O ganoids a e implan ed subcapsula ly
o o ho opically in o NOD-SCID mice, wi h ascula anas omosis ia hos in eg a ion. Pos -
ansplan , GFR analogs a e assessed ia dex an clea ance.
5. Analy ical Tools: Immuno luo escence/con ocal mic oscopy wi h ma ke s (e.g., WT1
o me aneph ic mesenchyme, AQP1 o p oximal ubules, CALB1 o collec ing duc s) isualizes
a chi ec u e. TEM examines ul as uc u es like podocy e oo p ocesses and b ush bo de s. scRNA-
seq (10x Genomics) p o iles ansc ip omes, iden i ying cell clus e s ia UMAP. Func ional assays
include albumin up ake, gen amicin oxici y, and cys induc ion in PKD models ia o skolin (5 μM).
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qPCR, Wes e n blo ing, and me abolomics quan i y gene exp ession (e.g., SIX2, PAX2), p o eins
(e.g., laminin, collagen IV), and me aboli es (e.g., u ea, c ea inine).
6. Gene ic and Disease Modeling: CRISPR/Cas9 in oduces mu a ions (e.g., PKD1/2
knockou s) o co ec ions in iPSCs. Pa ien -de i ed lines (e.g., APOL1 G1/G2 a ian s) enable
pe sonalized models.
Da a p esen a ion inco po a es diag ams (e.g., neph ogenesis schema ics), images (e.g.,
immuno luo escence panels), and ables (e.g., compa ing ma u a ion me ics). Re e ences we e
managed in APA o ma using EndNo e.
RESULTS AND DISCUSSION
Neph on S uc u e and Di e en ia ion: O ganoids obus ly o m segmen ed neph ons wi h
glome uli ea u ing sli diaph agms (NEPHRIN+), p oximal ubules exhibi ing megalin-media ed
endocy osis, and loops o Henle exp essing UMOD. A 2025 p o ocol con olling NP di e en ia ion
ia imed FGF9 wi hd awal en iches p oximal ubules, boos ing eabso p ion e iciency o 60-80%
o na i e le els. .
Vascula iza ion and Func ional Ma u a ion: Hypoxia (5% O2) induces VEGF exp ession,
os e ing CD31+ endo helial ne wo ks ha pe use glome uli and enable il a ion. TEM e eals
ma u e basemen memb anes wi h enes a ed endo helia.
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Figu e 1: TEM image o day 35 o ganoid glome ulus showing podocy e oo p ocesses
and laminin- ich GBM; scale ba 500 nm elec on mic oscopy o glome ulus-like and ubule
egions in kidney o ganoids). In i o ansplan s ascula ize ia hos anas omosis, p oducing
dilu e u ine.
Disease Modeling and The apeu ic Sc eening: PKD o ganoids om mu an iPSCs exhibi
cys ogenesis ia cilium-au ophagy de ec s, esponsi e o cilium-modula ing d ugs. APOL1 G1/G2
models e eal mi ochond ial ene gy dis up ions igge ing CKD. B anched o ganoids cap u e umo
he e ogenei y in enal cance s.
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Table 1: Compa a i e analysis o o ganoid p o ocols (expanded):
P o ocol/Au ho
(Yea )
Cell
Sou ce
Key
Inno a ions
Ma u i y
Me ics (e.g.,
GFR analog,
%
ascula ized)
Disease
Applica ions
Limi a ions
Li le e al.
(2024)
iPSCs
S omal
inclusion,
sel -
o ganiza ion
Fe al-like, 20-
30%
ascula ized,
basic il a ion
De elopmen al
anomalies
Limi ed UB
in eg a ion
Mo izane e al.
(2025)
ESCs
Hypoxia-
enhanced
ma u a ion
Ad anced
neph ons, 50%
ascula ized,
15% GFR
Neph o oxici y,
AKI
Scalabili y
issues
F eedman e al.
(2023)
hPSCs
ECM
decellula ized
sca olds
Highly
ascula ized
(70%), u ine
p oduc ion in
ansplan s
PKD, CKD
Immunogenici y
in i o
Nishinakamu a
e al. (2023)
PSCs
UB-NP co-
cul u e
O gano ypic
wi h b anched
duc s, 40%
in e connec ed
Exc e o y
de ec s,
ansplan a ion
Fib osis
p opensi y
Huang e al.
(2025)
iPSCs
Assembloids
o p ogeni o
assembly
High- ideli y
PKD cys s,
60%
ma u a ion
ADPKD
modeling, d ug
sc eens
Cos ly scRNA-
seq eliance
Spijke e al.
(2025)
Pa ien
iPSCs
APOL1
a ian
modeling
Mi ochond ial
p o iling, cys
educ ion wi h
inhibi o s
APOL1-
media ed CKD
Gene ic
a iabili y
Recaldin e al.
(2025)
iPSCs
Immune cell
inco po a ion
Tissue-
esiden
mac ophages,
in lamma ion
models
Immune-
kidney
in e ac ions
E hical sou cing
o immune cells
Challenges, Inno a ions, and Fu u e Di ec ions: Imma u i y is mi iga ed by p olonged
cul u e (up o 60 days) and biomechanical cues in chips, educing o - a ge cells om 20% o <5%.
scRNA-seq un eils ansc ip ional cong uence wi h e al kidneys, wi h up egula ed genes like WT1,
SIX2, and PAX2 d i ing neph ogenesis. In PKD, cilium-au ophagy axes a e a ge ed by au ophagy
enhance s, hal ing cys olumes. O gan-on-chip adds pe is al ic low, ele a ing anspo e iciency.
Eme ging on ie s: HLA-edi ed uni e sal o ganoids o o - he-shel ansplan s, biop in ed mac o-
scale kidneys, and AI-op imized p o ocols o high- h oughpu .
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Figu e 2: 3D ende ed c oss-sec ion o kidney o ganoid showing co ex-medulla
o ganiza ion whole-moun IF o glome ula s uc u es and ubules in day 18 kidney o ganoid).
These e olu ions posi ion o ganoids as indispensable o p ecision neph ology, hough
egula o y hu dles o clinical ials loom.
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CONCLUSIONS
Kidney o ganoids ha e p o oundly eshaped enal esea ch by p o iding scalable, human-
ele an models ha dissec he in icacies o exc e o y sys em de elopmen , pa hological
mechanisms, and he apeu ic in e en ions wi h unp eceden ed p ecision, ma king a pa adigm shi
om adi ional 2D cul u es and animal models ha o en ail o cap u e human-speci ic physiology.
De i ed om human plu ipo en s em cells (hPSCs), hese 3D cons uc s eplica e key enal
a chi ec u es, including neph ons wi h unc ional glome uli, ubula segmen s, and nascen collec ing
duc s, enabling esea che s o simula e emb yonic neph ogenesis s ages such as in e media e
mesode m induc ion, me aneph ic mesenchyme di e en ia ion, and u e e ic bud b anching. This
ideli y has acili a ed g oundb eaking s udies on congeni al anomalies, oxin-induced inju ies, and
ch onic condi ions, o e ing insigh s in o molecula pa hways like Wn /BMP signaling ha go e n
p ogeni o cell a e. By inco po a ing pa ien -de i ed induced plu ipo en s em cells (iPSCs),
o ganoids allow o pe sonalized modeling o gene ic diso de s, e ealing how mu a ions dis up
cellula homeos asis and lead o ib osis o cys o ma ion. Fu he mo e, hei scalabili y suppo s
high- h oughpu pla o ms o d ug disco e y, educing eliance on animal es ing and accele a ing
p eclinical e alua ions wi h human-like esponses.
Inno a ions om 2024 o 2025 in hypoxic condi ioning ha e su moun ed key ba ie s by
mimicking e al oxygen g adien s ( ypically 5-10% O2), which p omo e endo helial cell p oli e a ion
(CD31+ ne wo ks) and enhance neph on ma u a ion, as e idenced in s udies whe e hypoxia led o
imp o ed glome ula il a ion analogs and ubula in e connec i i y. Fo ins ance, de elopmen al
hypoxia has been shown o inc ease o ganoid complexi y, os e ing mo e ad anced ubula s uc u es
and ea ly-s age plumbing o was e emo al, as epo ed in a 2025 s udy on ad anced kidney
o ganoids. Ex acellula ma ix (ECM) enginee ing, u ilizing decellula ized sca olds, Ma igel
embeddings, o sup amolecula hyd ogels en iched wi h laminin and collagen IV, has imp o ed
s uc u al in eg i y and cell-ma ix in e ac ions, acili a ing glome ula basemen memb ane
o ma ion and educing o - a ge cell popula ions. Recen p o ocols ha e in eg a ed ECM
manipula ions o accele a e de i a ion om hPSCs, enabling o ganoids ha model ea ly human
neph ogenesis mo e accu a ely. Vascula iza ion ad ancemen s, including co-cul u e wi h endo helial
p ogeni o s o hypoxic induc ion o VEGF exp ession, ha e achie ed pe usable ne wo ks ha
suppo nu ien deli e y and il a ion unc ions, wi h ansplan ed o ganoids demons a ing neo-
ascula iza ion and u ine p oduc ion in mouse models. Bioenginee ing echniques, such as 3D
biop in ing and o ganoids-on-a-chip, ha e u he enabled ma u e, unc ional cons uc s by
inco po a ing biomechanical cues like luid shea s ess, simula ing glome ula il a ion a es up o
20% o na i e le els and allowing o eal- ime moni o ing o exc e o y dynamics. These
de elopmen s ha e posi ioned o ganoids o clinical impac , including high- h oughpu
neph o oxici y sc eening and pe sonalized he apies o diseases like polycys ic kidney disease
(PKD), whe e o ganoids om mu an iPSCs exhibi cys ogenesis esponsi e o a ge ed inhibi o s.
No ably, 2025 b eak h oughs include spa ially pa e ned kidney assembloids ha ecapi ula e
p ogeni o sel -assembly o high- ideli y disease modeling in i o, and human e al kidney o ganoids
ha ma u e o e mon hs o mi o p egnancy s ages, opening a enues o congeni al diso de esea ch
and sa e p ena al d ug es ing.
Ye , pe sis en challenges in achie ing ull-scale ma u a ion hinde b oade applica ions;
cu en o ganoids o en emain e al-like, wi h incomple e neph on segmen a ion, limi ed size
( ypically <1 mm), and imma u e unc ional me ics such as low glome ula il a ion e iciency and
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absen medulla y s uc u es. Vascula sus ainabili y emains a bo leneck, as in i o ne wo ks
equen ly eg ess wi hou sus ained hos in eg a ion, leading o nec osis in la ge cons uc s and
complica ing long- e m cul u es beyond 60 days. E hical scalabili y issues a ise om sou cing hPSCs,
pa icula ly emb yonic s em cells, aising conce ns abou consen , equi y in access o pa ien -de i ed
lines, and po en ial immunogenici y in allogeneic ansplan s. Regula o y hu dles o clinical ials,
including s anda diza ion o p o ocols and alida ion agains human da a, u he delay ansla ion,
while high cos s o scRNA-seq and biop in ing limi accessibili y in esou ce-cons ained se ings.
These obs acles demand sus ained mul idisciplina y collabo a ion among s em cell biologis s,
bioenginee s, clinicians, e hicis s, and policymake s o e ine p o ocols, in eg a e AI o op imized
di e en ia ion, and es ablish bio eposi o ies o di e se gene ic backg ounds.
Ul ima ely, hese models he ald a egene a i e e a by p omising bioenginee ed solu ions ha
could cu ail kidney disease epidemics, which a ec o e 700 million globally and impose s agge ing
heal hca e cos s h ough dialysis and ansplan s. By enabling mu a ion co ec ions ia CRISPR/Cas9
in iPSC-de i ed o ganoids, esea che s can alida e he apies o he edi a y condi ions like APOL1-
media ed CKD, whe e o ganoids e eal mi ochond ial dis up ions as key a ge s. Fu u e p ospec s
include HLA-edi ed uni e sal o ganoids o o - he-shel implan s, hyb id sys ems using o ganoids
wi h xenogeneic sca olds (e.g., gene-edi ed pig kidneys), and mac o-scale bio ab ica ed kidneys o
ansplan a ion, po en ially alle ia ing dono sho ages whe e wai lis s exceed 100,000 in he US
alone. In e disciplina y e o s will also add ess in lamma ion modeling h ough immune cell
inco po a ion, as seen in ela ed gu o ganoids, enhancing s udies on immune-kidney in e ac ions. As
o ganoids e ol e, hey ans o m pa ien ou comes by shi ing pa adigms om symp om managemen
o cu a i e egene a ion, os e ing hope o equi able, p ecision-based neph ology in he coming
decades.
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