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Kuchepetsa kwa ma fibrous hydrogels kuti achepetse ma capillaries ndikofunikira kwambiri mu biological and biomedical system.Kupanikizika ndi kupsinjika kwa uniaxial kwa ma fibrous hydrogels akhala akuphunziridwa mozama, koma kuyankha kwawo pakusungidwa kwa biaxial mu capillaries sikunadziwikebe.Apa, timasonyeza experimentally ndi theoretically kuti gel osakaniza filamentous amayankha qualitatively mosiyana kuletsa kuposa flexible unyolo gels chifukwa cha asymmetry mu mechanical katundu wa constituent filaments, amene ali ofewa psinjika ndi owuma mu kukangana.Posungidwa mwamphamvu, gel osakaniza amawonetsa kutalika pang'ono komanso kuchepa kwapang'onopang'ono kwa chiŵerengero cha biaxial Poisson kufika pa ziro, zomwe zimapangitsa kuti gel osakaniza aziphatikizana komanso kusayenda bwino kwamadzimadzi kudzera mu gel.Zotsatira izi zikusonyeza kukana anatambasula occlusive thrombi kuti lysis ndi achire wothandizila ndi kulimbikitsa chitukuko cha ogwira endovascular embolization kuchokera fibrous gel osakaniza kusiya mtima magazi kapena ziletsa magazi zotupa.
Ma fibrous network ndiye maziko omangira komanso magwiridwe antchito a minofu ndi ma cell amoyo.Actin ndi gawo lalikulu la cytoskeleton1;fibrin ndi chinthu chofunikira kwambiri pakuchiritsa mabala ndi mapangidwe a thrombus2, ndipo collagen, elastin ndi fibronectin ndi zigawo za matrix a extracellular mu nyama3.Maukonde obwezeretsedwa a fibrous biopolymers akhala zida zogwiritsidwa ntchito kwambiri mu engineering ya minofu4.
Ma filamentous network amayimira gulu losiyana la zinthu zofewa zamoyo zomwe zimakhala ndi makina osiyanasiyana ndi ma netiweki osinthika a maselo5.Zina mwazinthuzi zidasintha panthawi yachisinthiko kuti ziwongolere kuyankha kwa biological matter to deformation6.Mwachitsanzo, maukonde a fibrous amawonetsa kukhazikika kwa mzere pazovuta zazing'ono7,8 pomwe pazovuta zazikulu amawonetsa kuuma kowonjezereka9,10, potero amasunga umphumphu wa minofu.Zomwe zimachitika pamakina ena amagetsi a ulusi, monga kupsinjika kwanthawi zonse poyankha kumeta ubweya wa ubweya11,12, sizinadziwikebe.
Zomwe zimapangidwira za semi-flexible fibrous hydrogels zaphunziridwa pansi pa uniaxial tension13,14 ndi compression8,15, koma kuponderezedwa kwawo kwaufulu kwa biaxial mu capillaries yopapatiza kapena machubu sikunaphunzire.Apa timapereka lipoti lazoyeserera ndipo timapereka lingaliro laukadaulo wamachitidwe a fibrous hydrogels pansi pa biaxial retention mu microfluidic channels.
Fibrin microgels ndi ma ratios osiyanasiyana a fibrinogen ndi thrombin concentrations ndi D0 diameter kuyambira 150 mpaka 220 µm adapangidwa pogwiritsa ntchito njira ya microfluidic (Supplementary Figure 1).Pa mkuyu.1a ikuwonetsa zithunzi za fluorochrome zolembedwa ndi ma microgel opezeka pogwiritsa ntchito confocal fluorescence microscopy (CFM).Ma microgels ndi ozungulira, ali ndi polydispersity yocheperapo 5%, ndipo ali ofanana mwadongosolo kudutsa masikelo oyesedwa ndi CFM (Supplementary Information and Movies S1 ndi S2).Kuchuluka kwa pore kwa microgels (kutsimikiziridwa ndi kuyeza kwa Darcy permeability16) kunatsika kuchokera ku 2280 mpaka 60 nm, kuchuluka kwa fibrin kumawonjezeka kuchokera ku 5.25 mpaka 37.9 mg / mL, ndipo chiwerengero cha thrombin chinatsika kuchokera ku 2.56 mpaka 0.27 mayunitsi / mL, motero.(Zina Zowonjezera).Mpunga.2), 3 ndi tebulo lowonjezera 1).Kuuma kofanana kwa microgel kumawonjezeka kuchokera ku 0,85 mpaka 3.6 kPa (Supplementary Fig. 4).Monga zitsanzo za ma gels opangidwa kuchokera ku maunyolo osinthika, ma agarose microgels a stiffnesses zosiyanasiyana amagwiritsidwa ntchito.
Chithunzi cha Fluorescence microscopy cha fluorescein isothiocyanate (FITC) chotchedwa PM choimitsidwa mu TBS.Mlingo wa bar ndi 500 µm.b Zithunzi za SEM za SM (pamwamba) ndi RM (pansi).Scale bar 500 nm.c Chithunzi chojambula cha kanjira kakang'ono kamene kamakhala ndi kanjira kakang'ono (m'mimba mwake dl) ndi dera locheperako lokhala ndi ngodya yolowera α ya 15 ° ndi mainchesi a dc = 65 µm.d Kumanzere kupita kumanja: Zithunzi zowonera maikulosikopu za RM (m'mimba mwake D0) m'matchanelo akulu, zone yowongoka ndi kutsekeka (kuchepetsa kutalika kwa gel Dz).Mlingo wa bar ndi 100 µm.e, f zithunzi za TEM za RM yosasinthika (e) ndi RM yotsekedwa (f), yokhazikika kwa ola limodzi ndi constriction 1/λr = 2.7, kutsatiridwa ndi kumasulidwa ndi kukonza 5% ya misa.glutaraldehyde mu TBS.The awiri a undeformed CO ndi 176 μm.Sikelo ya bar ndi 100 nm.
Tidayang'ana kwambiri ma microgels a fibrin okhala ndi kuuma kwa 0.85, 1.87 ndi 3.6 kPa (pambuyo pake amatchedwa ma microgel ofewa (SM), ma microgel olimba (MM) ndi ma microgel olimba (RM), motsatana).Mtundu uwu wa kuuma kwa gel osakaniza wa fibrin uli ndi dongosolo lofanana la kukula kwa magazi18,19 ndipo motero ma gel opangidwa ndi fibrin omwe amaphunzira mu ntchito yathu amagwirizana mwachindunji ndi machitidwe enieni achilengedwe.Pa mkuyu.1b ikuwonetsa zithunzi zapamwamba ndi zapansi zamapangidwe a SM ndi RM omwe amapezedwa pogwiritsa ntchito makina owonera ma electron microscope (SEM), motsatana.Poyerekeza ndi mapangidwe a RM, maukonde a SM amapangidwa ndi ulusi wokulirapo ndi mfundo zochepa za nthambi, zogwirizana ndi malipoti akale 20, 21 (Supplementary Fig. 5).Kusiyana kwa kapangidwe ka hydrogel kumayenderana ndi momwe zimakhalira: kuchuluka kwa gel osakaniza kumachepa ndi kuchepa kwa pore kuchokera ku SM kupita ku MM ndi RM (Supplementary Table 1), ndi kuuma kwa gel osakaniza.Palibe kusintha kwa kapangidwe ka microgel komwe kunadziwika pambuyo posungira pa 4 ° C kwa masiku 30 (Supplementary Fig. 6).
Pa mkuyu.1c ikuwonetsa chithunzi cha kanjira kakang'ono kamene kamakhala ndi gawo lozungulira lomwe lili ndi (kuchokera kumanzere kupita kumanja): njira yayikulu yokhala ndi mainchesi dl momwe microgel imakhala yosasinthika, gawo lokhala ngati koni yokhala ndi m'mimba mwake dc
Pa mkuyu.1e, 1f imawonetsa ma electron microscopy (TEM) zithunzi za RM zosasinthika komanso zocheperako.Pambuyo pa kuponderezedwa kwa RM, kukula kwa pore ya microgel kunachepa kwambiri ndipo mawonekedwe awo anakhala anisotropic ndi kukula kwazing'ono kumbali ya kupanikizika, zomwe zimagwirizana ndi lipoti lapitalo 23.
Kuponderezana kwa Biaxial panthawi yapakati kumapangitsa kuti microgel italikike mopanda malire ndi coefficient λz = \({D}_{{{{{{\rm{z}}}}}}}}/\({D }_ { 0}\) , kumene \({D}_{{{{({(\rm{z}}}}}}}}\) kuli kutalika kwa microgel yotsekedwa Chithunzi 2a chikuwonetsa kusintha kwa λzvs .1/ λr Chodabwitsa, pansi pa kukanikiza kwakukulu kwa 2.4 ≤ 1/λr ≤ 4.2, ma fibrin microgels amawonetsa kutalika kosawerengeka kwa 1.12 +/- 0.03 λz, komwe kumakhudzidwa pang'ono ndi mtengo wa 1/λr. ma agarose microgels ochepa, omwe amawonedwa ngakhale pakuponderezedwa kocheperako 1/λr = 2.6 mpaka kukulitsa kwakukulu λz = 1.3.
Kuyesa kwa Agarose microgel yokhala ndi ma moduli osiyanasiyana otanuka (2.6 kPa, diamondi yobiriwira yotseguka; 8.3 kPa, bwalo lotseguka lofiirira; 12.5 kPa, masikweya otseguka alalanje; 20.2 kPa, magenta otsegulira makona atatu) ndi SM (ofiira olimba) Sinthani kutalika kwake λz ( mabwalo), MM (mabwalo olimba akuda) ndi RM (makona atatu olimba a buluu).Mizere yolimba imasonyeza λz yonenedweratu ya agarose (mzere wobiriwira) ndi ma fibrin microgels (mizere ndi zizindikiro za mtundu womwewo).b.Pansi: Mawonekedwe a netiweki yofananira isanayambe komanso itatha kusintha.Mayendedwe a x ndi y amawonetsedwa ndi mivi ya magenta ndi bulauni, motsatana.Pachithunzi pamwambapa, maunyolo a maukonde olunjika mu mayendedwe a x ndi y awa akuwonetsedwa ndi mizere yofananira ya magenta ndi bulauni, ndipo maunyolo olowera motsatira z amaimiridwa ndi mizere yobiriwira.Mu fibrin gel (c), mizere yofiirira ndi yofiirira munjira za x ndi y imapindika kuposa momwe ilili yosasinthika, ndipo mizere yobiriwira yolowera ku z imapindika ndi kutambasula.Kulimbana pakati pa mayendedwe a psinjika ndi kukangana kumafalikira kudzera mu ulusi wokhala ndi njira zapakatikati.Mu ma gels a agarose, maunyolo kumbali zonse amatsimikizira kuthamanga kwa osmotic, komwe kumathandizira kwambiri pakuwonongeka kwa gel.d Kusintha kwanenedweratu mu chiŵerengero cha biaxial Poisson, } }^{{{{{\rm{eff}}}}}}}} =-{{{{\rm{ln}}}}}}}{\lambda }_{ z}/{{{{{{{{ \rm{ln}}}}}}}{\lambda }_{r}\ ), pakupondereza kwa equibiaxial kwa ma gels a agarose (green line) ndi fibrin (red line).Zolembapo zikuwonetsa kusinthika kwa biaxial kwa gel.e Translocation pressure change ΔPtr, yokhazikika ku gel stiffness S, imayikidwa ngati ntchito ya compression ratio ya agarose ndi fibrin microgels.Mitundu yachizindikiro imagwirizana ndi mitundu mu (a).Mizere yobiriwira ndi yofiyira ikuwonetsa ubale wamalingaliro pakati pa ΔPtr/S ndi 1/λr wa agarose ndi ma fibrin gels, motsatana.Gawo lophwanyidwa la mzere wofiira limasonyeza kuwonjezeka kwa ΔPtr pansi pa kuponderezedwa kwakukulu chifukwa cha kuyanjana kwa interfiber.
Kusiyanaku kumalumikizidwa ndi njira zosiyanasiyana zosinthira ma fibrin ndi ma agarose microgel network, omwe amakhala ndi ulusi wosinthika24 ndi rigid25, motsatana.Kuphatikizika kwa Biaxial kwa ma gels osinthika kumabweretsa kuchepa kwa voliyumu yawo komanso kuwonjezereka kolumikizana ndi kupanikizika kwa osmotic, zomwe zimatsogolera kukulitsidwa kwa gel osakaniza mopanda malire.Kukula komaliza kwa gel osakaniza kumadalira kuchuluka kwa kuchuluka kwa mphamvu yaulere ya entropic ya unyolo wotambasulidwa komanso kuchepa kwa mphamvu yaulere ya osmosis chifukwa cha kutsika kwa polima mu gel otambasulidwa.Pansi pa kuponderezedwa kwamphamvu kwa biaxial, kukweza kwa gel kumawonjezeka ndi λz ≈ 0.6 \ ({{\ lambda}_{{{\rm{r}}}}^{-2/3}}\) (onani mkuyu 2a mu kukambirana gawo 5.3.3).Kusintha kwa conformational mu unyolo wosinthika ndi mawonekedwe a maukonde ofananira kale ndi pambuyo posungirako biaxial akuwonetsedwa mu Fig.2b .
Mosiyana ndi izi, ma gels a fibrous monga fibrin mwachibadwa amayankha mosiyana ndi biaxial retention.Ma filaments omwe amawongoka kwambiri amafanana ndi njira ya compression flex (potero amachepetsa mtunda pakati pa maulalo), pomwe ma filaments omwe amakhala okhazikika pakuwongolera amawongoka ndikuwoloka pansi pa mphamvu zotanuka, zomwe zimapangitsa kuti gel osakaniza azitalikira. Chithunzi 1).2c) Mapangidwe a SM, MM ndi RM osasinthika adadziwika ndi kusanthula zithunzi zawo za SEM ndi CFM (Supplementary Discussion Gawo IV ndi Supplementary Figure 9).Pozindikira zotanuka modulus (E), m'mimba mwake (d), kutalika kwa mbiri (R0), mtunda pakati pa malekezero (L0 ≈ R0) ndi ngodya yapakati (ψ0) ya zingwe mu undeformed fibrin microgels (Supplementary Table 2) - 4), tapeza kuti ulusi wopindika modulus \({k}_{{{{{{\rm{b))))))))))}=\frac{9\pi E{d}^{4} } {4 {\psi } _{0}^{2}{L}_{0}}\) ndiyocheperako kuposa makoma ake\({k}_{{{{{{\rm{s}}}}} }} }}=E\frac{\pi {d}^{2}{R}_{0}}{4}\), kotero kb/ks ≈ 0.1 (Zowonjezera 4).Chifukwa chake, pansi pa kusungidwa kwa biaxial gel, zingwe za fibrin zimapindika mosavuta, koma zimakana kutambasula.Kutalikira kwa netiweki ya filamentous yomwe ili ndi kuponderezedwa kwa biaxial ikuwonetsedwa mu Supplementary Fig. 17.
Timapanga chitsanzo chogwirizana (Chigawo Chakukambitsirana Chowonjezera 10-16) momwe kutalika kwa gel osakaniza kumatsimikiziridwa kuchokera ku mgwirizano wam'deralo wa mphamvu zotanuka zomwe zimagwira ntchito mu gel ndikulosera kuti mu mphamvu yamphamvu ya biaxial λz - 1 pansi pazovuta
Equation (1) ikuwonetsa kuti ngakhale pansi pa kupanikizana kwamphamvu (\({\lambda }_{{{\mbox{r))))\,\to \,0\)) pali kukulitsa pang'ono kwa gel ndi kupindika kotsatira. kuchuluka λz–1 = 0.15 ± 0.05.Khalidweli likugwirizana ndi (i) \({\left({k}_{{{{({\rm{b}}}}}}}}}}}/{k}_{{{{{{\rm} {s }}}}}}}\ kumanja)}^{1/2}\) ≈ 0.15−0.4 ndi (ii) mawu omwe ali m'mabulaketi apakati molingana ndi asymptotically \(1{{\mbox{/}}} \sqrt {3 }\) pa ma biaxial bond amphamvu. Ndikofunikira kudziwa kuti prefactor \({\left({k}_{({\mbox{b)))))/{k}_{({\mbox{ s))))\ kumanja)}^{1/ 2 }\) ilibe chochita ndi kuuma kwa ulusi E, koma zimatsimikiziridwa ndi gawo la chiŵerengero cha ulusi d/L0 ndi ngodya yapakati ya arc. ψ0, yomwe ili yofanana ndi SM, MM ndi RM (Supplementary Table 4).
Kuti tiwonetsetsenso kusiyana kwa kupsyinjika komwe kumapangitsa ufulu pakati pa ma gels osinthika ndi ma filamentous, timayambitsa chiŵerengero cha biaxial Poisson \({\nu }_{{{({\rm{b)))))))} {{\ mbox { =}}}\,\mathop{{\lim}}\malire_{{\lambda}_{{{{({(\rm{r}}}}}}}}\to 1}\ frac{{\ lambda } _{ {{{{\rm{z}}}}}}-1}{1-{\lambda }_{{({\rm{r}}}}}}}}}, \) ikufotokoza zopanda malire mayendedwe a gel osakaniza poyankha kupsinjika kofanana m'njira ziwiri zozungulira, ndikukulitsa izi ku mitundu yayikulu \ rm{b}}}}}}}}}}^{{{{\rm{eff}}}}}}} }}=-{{{{{\rm{ln}}}}}}} { \lambda } _{z} /{{{({\rm{ln))))))))}{\lambda }_{{{({\rm{r))))))))}\) .Pa mkuyu.2d ziwonetsero \({{{{\rm{\nu }}}}}}}}_{{{({\rm{b}}}}}}}}}^{{{{{\rm {eff }}}}}}}}\) kwa yunifolomu biaxial compression of flexible (monga agarose) ndi rigid (monga fibrin) gels (Zokambirana zowonjezera, Gawo 5.3.4), ndikuwonetsa mgwirizano pakati pa kusiyana kwakukulu kwa mayankho omangidwa. Kwa ma gels a agarose omwe ali pansi pa zoletsa zamphamvu {\rm{eff}}}}}}}}\) amawonjezeka kufika pa mtengo wa asymptotic 2/3, ndipo kwa ma gels a fibrin amatsika mpaka ziro, popeza lnλz/lnλr → 0, popeza λz amawonjezeka ndi kukhutitsidwa pamene λr ikuwonjezeka.Onani kuti mu zatsopano, chatsekedwa ozungulira microgels deform inhomogeneously, ndi gawo lapakati zinachitikira wamphamvu psinjika;komabe, extrapolation ku mtengo waukulu wa 1/λr kumapangitsa kufananiza kuyesera ndi chiphunzitso cha gels opunduka uniformly.
Kusiyana kwina kwa khalidwe la ma gel osinthasintha ndi ma filamentous gels kunapezeka chifukwa cha kayendedwe kawo pakadutsa.Kuthamanga kwa translocation ΔPtr, komwe kumapangidwira kuuma kwa gel S, kumawonjezeka ndi kuwonjezereka kowonjezereka (mkuyu 2e), koma pa 2.0 ≤ 1 / λr ≤ 3.5, ma microgels a fibrin adawonetsa zotsika kwambiri za ΔPtr / S pansi panthawi ya shrinkage.Kusungidwa kwa agarose microgel kumabweretsa kuwonjezeka kwa kuthamanga kwa osmotic, komwe kumayambitsa kutambasula kwa gel mu njira yotalikirapo pamene mamolekyu a polima amatambasulidwa (mkuyu 2b, kumanzere) ndi kuwonjezeka kwa kupanikizika kwa translocation ndi ΔPtr / S ~( 1/λr)14/317.M'malo mwake, mawonekedwe a ma microgel otsekedwa a fibrin amatsimikiziridwa ndi mphamvu ya mphamvu ya ulusi wa kuponderezedwa kwa radial ndi kugwedezeka kwautali, zomwe zimatsogolera ku kusinthika kwakukulu kwautali λz ~\(\sqrt{{k}_{{{{{{{{{ \rm{ b))))))))} /{k}_{{{{{{{\rm{s}}}}}}}}}}\).Kwa 1/λr ≫ 1, kusintha kwa kuthamanga kwapaulendo kumayesedwa ngati 1 {{({\rm{ln)))))))\left({{\lambda }}_{{{{{{\rm} {r}}}}}}}}}^{{-} 1} \ kumanja)\) (Zokambirana Zowonjezera, Gawo 5.4), monga momwe zasonyezedwera ndi mzere wofiira wolimba mu Chithunzi 2e.Choncho, ΔPtr imakhala yochepa kwambiri kusiyana ndi ma gels a agarose.Pakuti psinjika ndi 1/λr> 3.5, kwambiri kuwonjezeka voliyumu kagawo kakang'ono filaments ndi kugwirizana filaments oyandikana malire kupitirira mapindikidwe gel osakaniza ndi kumabweretsa kupatuka kwa zoyeserera zolosera (red madontho mzere mkuyu. 2e).Timamaliza kuti 1/λr yemweyo ndi Δ\({P}_{{{{{{{\rm{tr}}}}}}}}}}_{{{\rm{fibrin}}}} )) } }}}\) < ΔP < Δ\({P}_{{{{{{{\rm{tr)))))))}}_{{{{\rm{agarose}}}}}} } }}}}\) gel agarose adzatengedwa ndi microchannel, ndipo gel osakaniza fibrin ndi kuuma komweko adzadutsamo.Za ΔP <Δ\({P}_{{{{{{\rm{tr))))))))))_{{{{{\rm{fibrin))))))))))}\ ), Awiri Ma gels onse awiri adzatsekereza njira, koma gel osakaniza a fibrin adzakankhira mozama ndikupanikiza bwino, kutsekereza kutuluka kwamadzimadzi bwino.Zotsatira zomwe zikuwonetsedwa mu Chithunzi 2 zikuwonetsa kuti gel osakaniza amatha kukhala ngati pulagi yothandiza kuchepetsa magazi kapena kuletsa kutuluka kwa magazi ku zotupa.
Kumbali ina, fibrin imapanga chiwombankhanga chomwe chimatsogolera ku thromboembolism, matenda omwe thrombus amatsekereza chotengera pa ΔP <ΔPtr, monga mitundu ina ya ischemic stroke (Mkuyu 3a).Kutalikirako kocheperako komwe kumachititsa kuti ma fibrin ma microgel achuluke kwambiri kunapangitsa kuti ma fibrin azichulukirachulukira a C/C fibrinogen poyerekeza ndi ma gel osinthasintha, pomwe C ndi C fibrinogen amakhala oletsedwa komanso osasinthika ma microgel, motsatana.Polima ndende mu gel osakaniza.Chithunzi cha 3b chimasonyeza kuti fibrinogen C / C mu SM, MM, ndi RM inawonjezeka kuposa kasanu ndi kawiri pa 1 / λr ≈ 4.0, yoyendetsedwa ndi kuletsa ndi kutaya madzi m'thupi (Supplementary Fig. 16).
Chithunzi chojambula cha kutsekeka kwa mtsempha wapakati waubongo muubongo.b Kuchulukitsa kwachibale kwa fibrin mu obstructive SM (zozungulira zofiira zolimba), MM (mabwalo olimba akuda), ndi RM (makona atatu olimba a buluu).c Mapangidwe oyesera omwe amagwiritsidwa ntchito pofufuza kung'ambika kwa ma gels a fibrin oletsedwa.Yankho la fluorescently lolembedwa tPA mu TBS linabadwira pa mlingo wothamanga wa 5.6 × 107 µm3/s ndi kutsika kowonjezereka kwa 0.7 Pa kwa mayendedwe omwe ali perpendicular kumtunda wautali wa microchannel yaikulu.d Chifaniziro cha microscopic chophatikizidwa cha MM (D0 = 200 µm) pa Xf = 28 µm, ΔP = 700 Pa komanso panthawi yogawanika.Mizere yokhala ndi madontho oima imasonyeza malo oyambirira a m'mphepete mwa kutsogolo ndi kumbuyo kwa MM pa tlys = 0. Mitundu yobiriwira ndi yapinki imagwirizana ndi FITC-dextran (70 kDa) ndi tPA yolembedwa ndi AlexaFluor633, motsatira.e Kusiyanasiyana kwa nthawi ya ma RM otsekedwa ndi D0 ya 174 µm (makona atatu otseguka abuluu), 199 µm (makona atatu otseguka abuluu), ndi 218 µm (makona atatu otseguka abuluu), motsatana, munjira yaying'ono yokhala ndi Xf = 28 ± 1 µm.zigawozo zili ndi ΔP 1200, 1800, ndi 3000 Pa, motsatira, ndi Q = 1860 ± 70 µm3/s.Choyikapo chikuwonetsa RM (D0 = 218 µm) ndikutsegula kanjira kakang'ono.f Kusiyanasiyana kwa nthawi ya kuchuluka kwa SM, MM kapena RM yoyikidwa pa Xf = 32 ± 12 µm, pa ΔP 400, 750 ndi 1800 Pa ndi ΔP 12300 Pa ndi Q 12300 m'chigawo chokhazikika cha microchannel, motsatira 23600 ndi 1m800 µ /s.Xf imayimira malo akutsogolo kwa microgel ndikuzindikira mtunda wake kuyambira koyambira kwa shrinkage.V (tlys) ndi V0 ndi kuchuluka kwakanthawi kwa lysed microgel ndi voliyumu ya microgel yosasokoneza, motsatana.Mitundu ya zilembo imagwirizana ndi mitundu ya b.Mivi yakuda pa e, f imagwirizana ndi mphindi yomaliza isanadutse ma microgel kudzera munjira yaying'ono.Sikelo mu d, e ndi 100 µm.
Kuti tifufuze zotsatira za kuletsa kuchepetsa kutuluka kwa madzimadzi kudutsa ma gel otsekereza a fibrin, tidaphunzira za lysis ya SM, MM, ndi RM yolowetsedwa ndi thrombolytic agent tissue plasminogen activator (tPA).Chithunzi 3c chikuwonetsa mawonekedwe oyesera omwe amagwiritsidwa ntchito pazoyeserera za lysis. Pa ΔP = 700 Pa (<ΔPtr) ndi mlingo wotuluka, Q = 2400 μm3/s, wa Tris-buffered saline (TBS) wosakanikirana ndi 0.1 mg/mL wa (fluorescein isothiocyanate) FITC-Dextran, microgel inatseketsa microchannel ya tapered dera. Pa ΔP = 700 Pa (<ΔPtr) ndi mlingo wotuluka, Q = 2400 μm3/s, wa Tris-buffered saline (TBS) wosakanikirana ndi 0.1 mg/mL wa (fluorescein isothiocyanate) FITC-Dextran, microgel inatseketsa microchannel ya tapered dera. При ΔP = 700 Па (<ΔPtr) ndi скорости потока, Q = 2400 мкм3/с, трис-буферного солевого раствора (TBS), смешанного с 0,1 мг/млл (флицанца), микрогель перекрывал сужающийся микроканал. Pa ΔP = 700 Pa (<ΔPtr) ndi mlingo wotuluka, Q = 2400 µm3/s, wa Tris buffered saline (TBS) wosakanikirana ndi 0.1 mg/mL (fluorescein isothiocyanate) FITC-dextran, microgel inatsekereza microchannel yotembenuka.dera.在ΔP = 700 Pa (<ΔPtr) 和流速Q = 2400 μm3/s 的Tris 缓冲盐水(TBS) 与0.1 mg/mL微凝胶堵塞了锥形微通道地区。在ΔP = 700 Pa (<ΔPtr) 和流速Q = 2400 μm3/s了锥形微通道地区. Микрогели закупориваются при смешивании трис-буферного солевого раствора (TBS) с 0,1 мг/мл (флуоресцеинизотиоцианат) FITC-декстра = FITC-декстра = сти потока Q = 2400 мкм3/с Конические области микроканалов. Ma Microgels adalumikizidwa pomwe Tris buffered saline (TBS) idasakanizidwa ndi 0.1mg/mL (fluorescein isothiocyanate) FITC-dextran pa ΔP = 700 Pa (<ΔPtr) ndi kuthamanga kwa Q = 2400 µm3/s Magawo a Conical a ma microchannel.Malo akutsogolo Xf a microgel amatsimikizira mtunda wake kuchokera pagawo loyambira la X0.Kuti apangitse lysis, yankho la fluorescently lolembedwa kuti tPA mu TBS linabayidwa kuchokera ku njira yomwe ili ndi orthogonally kupita kumtunda wautali wa microchannel yayikulu.
Pamene yankho la tPA linafika ku occlusal MM, kumbuyo kwa m'mphepete mwa microgel kunasokonezeka, kusonyeza kuti fibrin cleavage inayamba pa nthawi tlys = 0 (Mkuyu 3d ndi Supplementary Fig. 18).Panthawi ya fibrinolysis, tPA yolembedwa utoto imawunjikana mkati mwa MM ndikumangiriza ku zingwe za fibrin, zomwe zimapangitsa kuti pang'onopang'ono kukula kwa mtundu wa pinki wa ma microgel.Pa tlys = 60 min, MM imapanga mgwirizano chifukwa cha kutha kwa gawo lake lakumbuyo, ndipo malo ake otsogolera Xf amasintha pang'ono.Pambuyo pa 160 min, MM wogwirizana kwambiri adapitirizabe kugwirizanitsa, ndipo pa tlys = 161 min, adadutsa, potero amabwezeretsa kutuluka kwa madzi kudzera mu microchannel (Mkuyu 3d ndi Supplementary Fig. 18, ndime yoyenera).
Pa mkuyu.3e ikuwonetsa kuchepa kwa nthawi ya lysis-mediated kwa voliyumu V (tlys) yokhazikika mpaka voliyumu V0 yamitundu yosiyanasiyana ya fibrin microgel.CO yokhala ndi D0 174, 199, kapena 218 µm inayikidwa mu microchannel ndi ΔP 1200, 1800, kapena 3000 Pa, motero, ndi Q = 1860 ± 70 µm3 / s kuti atseke microchannel (Fig. 3e, inset).zakudya.Ma microgels amachepa pang'onopang'ono mpaka atachepa kwambiri kuti adutse njira.Kutsika kwa voliyumu yovuta ya CO yokhala ndi mainchesi okulirapo kumafuna nthawi yayitali ya lysis.Chifukwa cha kuyenderera kofananako kudzera mu ma RM amitundu yosiyanasiyana, kung'ambika kumachitika pamlingo womwewo, zomwe zimapangitsa kuti tizigawo tating'ono ta ma RM akulu agayidwe ndikuchedwa kusuntha.Pa mkuyu.3f ikuwonetsa kuchepa kwa V (tlys)/V0 chifukwa cha kugawanika kwa SM, MM, ndi RM pa D0 = 197 ± 3 µm yokonzedwa ngati ntchito ya tlys.Kwa SM, MM ndi RM, ikani microgel iliyonse mu microchannel ndi ΔP 400, 750 kapena 1800 Pa ndi Q 12300, 2400 kapena 1860 µm3/s, motsatira.Ngakhale kuti kupanikizika kwa SM kunali kocheperako ka 4.5 kuposa kwa RM, kuthamanga kwa SM kunali kokulirapo kuwirikiza kasanu ndi kamodzi chifukwa cha kuchuluka kwa SM, ndipo kuchepa kwa microgel kunatsika kuchokera ku SM kupita ku MM ndi RM. .Mwachitsanzo, pa tlys = 78 min, SM nthawi zambiri idasungunuka ndikusamutsidwa, pomwe MM ndi PM adapitilizabe kutseka ma microchannel, ngakhale amangosunga 16% ndi 20% ya voliyumu yawo yoyambirira, motsatana.Zotsatirazi zikuwonetsa kufunikira kwa convection-mediated lysis ya constricted fibrous gels ndikulumikizana ndi malipoti ofulumira chigayidwe cha magazi omwe ali ndi fibrin yotsika.
Chifukwa chake, ntchito yathu ikuwonetsa moyesera komanso mwaukadaulo momwe ma gels opangira ma filamentous amayankha kutsekeredwa kwa biaxial.Khalidwe la ma gels a fibrous mu malo ochepa amatsimikiziridwa ndi asymmetry amphamvu a mphamvu ya mphamvu ya filaments (yofewa mu psinjika ndi kupanikizika kolimba) ndipo kokha ndi chiŵerengero cha mawonekedwe ndi kupindika kwa filaments.Izi zimapangitsa kuti ma gels a fibrous atalike pang'ono omwe ali mu capillary yopapatiza, chiŵerengero chawo cha biaxial Poisson chimachepa ndi kupanikizika kochulukira komanso kutsika pang'ono.
Popeza kuti biaxial containment of soft deformable particles imagwiritsidwa ntchito muumisiri wosiyanasiyana, zotsatira zathu zimalimbikitsa kupanga zinthu zatsopano za fibrous.Makamaka, posungira biaxial wa filamentous gels mu yopapatiza capillaries kapena machubu kumabweretsa compaction awo amphamvu ndi kuchepa lakuthwa permeability.Kuletsa kwamphamvu kwa madzi oyenda kudzera mu occlusive fibrous gels kuli ndi ubwino wake pamene amagwiritsidwa ntchito ngati mapulagi kuti ateteze magazi kapena kuchepetsa magazi ku malignancies33,34,35.Kumbali ina, kuchepa kwa madzi othamanga kudzera mu occlusal fibrin gel, motero kulepheretsa convective-mediated thrombus lysis, kumapereka chisonyezero cha pang'onopang'ono lysis ya occlusal clots [27, 36, 37].Dongosolo lathu lachitsanzo ndi gawo loyamba pakumvetsetsa zomwe zimachitika pamakina a fibrous biopolymer hydrogels ku biaxial retention.Kuphatikizira maselo a magazi kapena mapulateleti mu ma fibrin gels oletsa kusokoneza machitidwe awo oletsa 38 ndipo chidzakhala sitepe yotsatira pakuvumbulutsa machitidwe a machitidwe ovuta kwambiri a biologically.
Ma reagents omwe amagwiritsidwa ntchito popanga ma fibrin microgels ndi kupanga zida za MF akufotokozedwa mu Supplementary Information (Njira Zowonjezera Gawo 2 ndi 4).Ma microgels a Fibrin adakonzedwa ndi emulsifying njira yosakanikirana ya fibrinogen, Tris buffer ndi thrombin mukuyenda molunjika pa chipangizo cha MF, ndikutsatiridwa ndi droplet gelation.Bovine fibrinogen solution (60 mg/ml mu TBS), Tris buffer ndi bovine thrombin solution (5 U/ml mu 10 mM CaCl2 solution) ankayendetsedwa pogwiritsa ntchito mapampu a syringe awiri odzilamulira okha (PhD 200 Harvard Apparatus PHD 2000 Syring Pump).kutsekereza MF, USA).Gawo la F-mafuta lopitilira lomwe lili ndi 1 wt.% block copolymer PFPE-P(EO-PO)-PFPE, idayambitsidwa mugawo la MF pogwiritsa ntchito pampu yachitatu ya syringe.Madontho opangidwa mu chipangizo cha MF amasonkhanitsidwa mu chubu cha 15 ml centrifuge chomwe chili ndi F-mafuta.Ikani machubu mu osamba madzi pa 37 °C kwa 1 h kumaliza fibrin gelation.FITC yotchedwa fibrin microgels inakonzedwa posakaniza bovine fibrinogen ndi FITC yotchedwa human fibrinogen mu 33: 1 kulemera kwa chiŵerengero, motsatira.Njirayi ndi yofanana ndi yokonzekera fibrin microgels.
Tumizani ma microgels kuchokera ku mafuta F kupita ku TBS mwa centrifuging kubalalitsidwa pa 185 g kwa 2 min.Tizilombo toyambitsa matenda tinamwazikana mu mafuta F osakaniza ndi 20 wt.% perfluorooctyl mowa, kenako anamwazikana mu hexane munali 0.5 wt.% Span 80, hexane, 0.1 wt.% Triton X m'madzi ndi TBS.Potsirizira pake, ma microgels anabalalitsidwa mu TBS yomwe ili ndi 0.01 wt% Pakati pa 20 ndi kusungidwa pa 4 ° C kwa pafupifupi masabata a 1-2 asanayambe kuyesa.
Kupangidwa kwa chipangizo cha MF kumafotokozedwa mu Supplementary Information (Njira Zowonjezera Gawo 5).Pakuyesa komweko, mtengo wabwino wa ΔP umatsimikiziridwa ndi kutalika kwa malo osungira omwe amalumikizidwa kale ndi pambuyo pa chipangizo cha MF choyambitsa ma microgel okhala ndi mainchesi a 150
Deta yothandizira zotsatira za kafukufukuyu ikupezeka kuchokera kwa olemba omwe afunsidwa.Zithunzi za SEM zaiwisi za ma gels a fibrin, zithunzi za TEM zaiwisi za ma gels a fibrin musanayambe komanso pambuyo pa inoculation, ndi deta yaikulu yolowera pa Zithunzi 1 ndi 2. 2 ndi 3 zimaperekedwa mu fayilo ya data yaiwisi.Nkhaniyi imapereka deta yoyambirira.
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Nthawi yotumiza: Feb-23-2023