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[(copy)-431.8(\(TEM,)-425.8(JEM-1011;)-426.6(JEOL\))-429(at)-424(an)-429.6(acceleration)-429.5(voltage)]TJ 0 -1.1116 TD [(of)-560.9(100)-170.3(kV.)-559.4(The)-564.4(N)]TJ 7.3823 0 0 6.5614 391.1243 378.255 Tm (2)Tj 9.843 0 0 9.843 400.3652 379.8991 Tm [(adsorptiondesorption)-567(isotherms)-565.1(and)]TJ -8.8699 -1.1116 TD [(pore)-247.4(size)-248.6(distributions)-244.9(were)-243.7(characterized)-253(by)-244.1(using)-241.6(a)-244.2(specic)]TJ T* [(surface)-483.2(and)-476.8(pore)-483.6(size)-479(distribution)-480.2(analyzer)-480.1(\(Nova)-479.8(4200e;)]TJ 0 -1.1174 TD (Quantachrome\).)Tj /F3 1 Tf 8.9663 0 0 8.9663 323.0361 325.0771 Tm [(Degradation)-295.6(tests)-295(of)-298.8(MSNs.)]TJ /F5 1 Tf 9.843 0 0 9.843 442.8282 325.0771 Tm [(MSNs)-299.6(were)-295.6(resuspended)-303.2(in)]TJ -13.184 -1.1116 TD [(PBS)-286.2(at)-280(a)-284.5(concentration)-290(of)-278.6(1)-168.1(mg/mL.)-283.4(After)-284.1(1,)-286.8(2,)-281(and)-280.9(4)-283.3(weeks)]TJ T* [(of)-267.1(incubation)-261.4(in)-261.5(a)-261.4(humidied)-265.8(incubator)-265.9(at)-262.7(37)]TJ /F11 1 Tf 17.9991 0 TD ()Tj /F5 1 Tf .3974 0 TD [(C,)-259(the)-263.8(samples)]TJ -18.3965 -1.1174 TD [(were)-318.6(centrifuged)-321.1(at)-314.5(16,000)-170.2(rpm)-315.5(to)-313.4(collect)-322.6(the)-315.6(nanoparticles.)]TJ 0 -1.1116 TD [(The)-489.5(resulting)-495.1(nanoparticles)-491.4(were)-491.4(imaged)-488.3(with)-489.3(TEM.)-493.9(Rat)]TJ T* [(bon)14(e)-232.6(mar)11.6(row)-217.2(mes)11.8(enc)11.7(hym)12.8(al)-222.4(ste)12.9(m)-232.7(cel)11.5(ls)-221(\(rB)13(MMS)12.3(Cs\))-223(wer)12(e)-226.9(cul)12.7(-)]TJ 0 -1.1174 TD [(tur)13.9(ed)-348.9(wit)12.8(h)-352.4(1)-162.4(mg/)12.6(mL)-350.2(of)-347.7(MSN)-344.7(in)-347.9(a)-353.6(C)0(O)]TJ 7.3823 0 0 6.5614 465.1652 257.7259 Tm (2)Tj 9.843 0 0 9.843 472.3652 259.3133 Tm [(inc)12.7(uba)18.6(tor)-343.2(\(5%)-344.2(CO)]TJ 7.3823 0 0 6.5614 546.066 257.7259 Tm (2)Tj 9.843 0 0 9.843 549.751 259.3133 Tm (,)Tj -24.0468 -1.1116 TD (37)Tj /F11 1 Tf .9907 0 TD ()Tj /F5 1 Tf .3917 0 TD [(C\))-233.6(for)-227.9(1)-237.2(wee)10.8(k.)-234.9(The)11.6(n,)-229.2(the)-229.2(nan)12.8(opa)12.8(rti)13.8(cle)11.5(s)-237.1(wer)12(e)-238.4(col)12.7(le)13.8(cte)11.5(d)-237.2(and)]TJ -1.3823 -1.1116 TD [(imaged)-327.1(with)-316.6(TEM)-323.4(\(the)-316.7(extraction)-325.9(and)-321.3(culturing)-316.7(methods)-321.1(of)]TJ T* [(rBMMSCs)-339.5(are)-333.9(presented)-341.6(in)-330.6(Supplementary)-335.9(Data\).)]TJ /F3 1 Tf 8.9663 0 0 8.9663 323.0361 204.548 Tm [(Cytotoxicity)-558(of)-558(MSNs.)]TJ /F5 1 Tf 9.843 0 0 9.843 423.0991 204.548 Tm [(The)-535.6(cytotoxicit)-9.3(y)-531(o)0(f)-537.8(the)-540.2(MSNs)]TJ -11.1796 -1.1174 TD [(was)-396.8(determined)-396.1(by)-388.1(cell)-392.9(counting)-396.1(kit-8)-391.6(\(CCK-8\))-396.5(\(Solarbio\))]TJ 0 -1.1116 TD [(assay.)-270.1(rBMMSCs)-270.4(were)-272.5(plated)-268.4(in)-267.3(the)-269.5(wells)-266.8(of)-267.1(a)-267.2(96-well)-269.2(plate)]TJ T* [(and)-424.9(allowed)-431.6(to)-422.8(attach)-425(for)-423.7(24)-169.2(h.)-419.2(Culture)-430.6(medium)-425.1(was)-425.6(then)]TJ 0 -1.1174 TD [(removed,)-245.1(and)-240.6(a)-244.2(medium)-240.7(mixed)-244.2(with)-241.7(MSNs)-242(at)-239.6(concentrations)]TJ 0 -1.1116 TD [(of)-336.2(0,)-332.8(0.1,)-331.6(0.5,)-337.4(1,)-332.8(and)-332.8(10)-169.2(mg/mL)-331.8(was)-333.4(added.)-339.6(After)-335.9(coculture)]TJ T* [(for)-291.2(1,)-286.8(4,)-286.8(7,)-286.8(and)-286.7(14)-290.2(days,)-285.3(100)]TJ /F6 1 Tf 11.6288 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(L)-284.5(o)0(f)-290.1(10%)-286.6(CCK-8)-290.6(reagent)-293.5(was)]TJ -12.1818 -1.1116 TD [(added)-353.4(to)-347.9(each)-347.7(well)-346.5(and)-350(incubated)-347.7(for)-348.8(an)-348.9(additional)-347.9(2)-168.1(h)0(.)-344.4(Fi-)]TJ 0 -1.1174 TD [(nally,)-298.3(the)-292.6(absorbance)-297.7(was)-293.1(detected)-301.7(with)-293.5(a)-290.2(microplate)-298.3(reader)]TJ 0 -1.1116 TD [(\(EnSpire;)-340.6(PerkinElmer\))-334.8(at)-337.6(a)-330.6(wavelength)-338.2(of)-336.2(490)-164.6(nm.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 313.0582 83.9622 Tm [(Protein)-336.3(loading)-338.5(and)-329.4(release)-338.7(of)-330.4(MSN-DMEP)]TJ /F5 1 Tf 9.843 0 0 9.843 323.0361 67.5212 Tm [(Cytochrome)-269.1(C)-267.1(\(Cyto-C;)-270.3(Solarbio\),)-268(which)-266.9(has)-269.2(a)-267.2(molecular)]TJ -1.0137 -1.1116 TD [(weight)-440.9(and)-436.4(isoelectric)-443.3(point)-437.7(similar)-436.5(to)-434.3(those)-438.6(of)-439.9(important)]TJ /F8 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (808)Tj 48.7749 0 TD [(MAO)-329.9(ET)-338.7(AL.)]TJ ET endstream endobj 50 0 obj <>stream /GS1 gs BT /F5 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(growth)-600.8(factors)-597.4(in)-595.6(DMEP)-600.5(\(such)-599.7(as)-596.4(TGF-)]TJ /F6 1 Tf 17.9127 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1,)-597.8(IGF-1)-593.6(and)]TJ -18.4656 -1.1174 TD [(bFGF\),)-429.9(was)-425.6(selected)-428.2(as)-429.4(the)-425(model)-422.7(protein)-429.6(for)-423.7(the)-425(evalua-)]TJ 0 -1.1116 TD [(tion)-356(of)-359.3(protein)-354.7(loading)-354.7(and)-361.6(release.)-355.5(The)-357(amount)-360.5(of)-353.5(Cyto-C)]TJ T* [(adsorbed)-690.6(onto)-689.9(MSN)-690.3(and)-684.1(the)-690(concentration)-693.2(of)-687.6(Cyto-C)]TJ T* [(released)-318.6(at)-314.5(different)-317.7(time)-312.3(intervals)-317.7(was)-310.4(analyzed)-318.9(at)-314.5(a)-313.3(wave-)]TJ 0 -1.1174 TD [(length)-532.2(of)-526.3(520)-164.6(nm)-527.6(using)-529.6(a)-526.4(microplate)-528.7(multimodal)-533.5(reader.)]TJ 0 -1.1116 TD [(Excess)-378.4(DMEP)-370.1(was)-373.8(added)-370.7(to)-370.9(1)-168.1(m)0(g)-366.3(o)0(f)-370.8(MSNs)-374.5(and)-373.1(incubated)]TJ T* [(at)-406.7(4)]TJ /F11 1 Tf 1.6358 0 TD ()Tj /F5 1 Tf .3974 0 TD [(C)-405.3(for)-406.4(24)-169.2(h.)-407.7(After)-405(encapsulation)-410.8(of)-411.1(DMEP,)-408.1(the)-407.8(MSNs)]TJ -2.0332 -1.1174 TD [(were)-376.2(centrifuged)-372.9(and)-373.1(washed)-372.5(three)-370.8(times.)-374.3(All)-373.1(supernatants)]TJ 0 -1.1116 TD [(and)-338.5(wash)-334.5(solutions)-332.5(were)-335.9(collected.)-340.9(The)-334(MSNs)-334.1(fully)-334(loaded)]TJ T* [(with)-345.4(nDMEP)-342.4(\()-81.7(MSN-nDMEP\))-343.7(and)-344.3(MSNs)-339.9(fully)-345.6(loaded)-343.1(with)]TJ 0 -1.1174 TD [(bDMEP)-653.4(\()-81.7(MSN-bDMEP\))-654.7(were)-646.9(used)-650.5(for)-648.3(the)-649.7(subsequent)]TJ /F9 1 Tf 0 -1.1116 TD [(in)-238.5(vitro)]TJ /F5 1 Tf 3.1506 0 TD (and)Tj /F9 1 Tf 1.6818 0 TD [(in)-238.5(vivo)]TJ /F5 1 Tf 2.9317 0 TD [(experiments.)-239.2(For)-233.5(the)-235(quantication)-242.8(of)-232.6(the)]TJ -7.7641 -1.1116 TD [(encapsulated)-284(protein)-279.8(and)-280.9(TGF-)]TJ /F6 1 Tf 12.5331 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1,)-275.2(a)-278.7(BCA)-282.7(kit)-280(and)-275.2(an)-279.8(ELISA)]TJ -13.0861 -1.1116 TD [(kit)-337.6(against)-332.6(human)-336.2(TGF-)]TJ /F6 1 Tf 9.8549 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1)-335.2(were)-335.9(used)-333.7(as)-337.2(described)-335.8(above.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 549.8077 Tm [(Cell)-336.3(viability)-334.4(of)-336.7(rBMMSCs)-332.3(cultured)-336(with)-336.5(MSN-DMEP)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 533.3668 Tm [(rBMMSCs)-305(were)-301.3(seeded)-297.9(at)-303(a)-296(density)-302.7(of)-295.9(5000)-298.2(cells/well)-303.8(in)]TJ -1.0137 -1.1174 TD (200)Tj /F6 1 Tf 1.6703 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(L)-451.5(o)0(f)-445.7(mesenchym)-9.9(al)-447(stem)-456(cell)-450.5(medium)-453.9(\()-81.7(MSCM\))-457.4(into)]TJ -2.2232 -1.1116 TD [(96-well)-211.6(plates.)-214(After)-209.2(24)-169.2(h,)-206.1(the)-211.9(medium)-206.2(was)-212.5(completely)-212(remo-)]TJ T* [(ved)-344.3(from)-339.6(each)-342(well.)-338.4(Then,)-344.3(1)-162.4(mg/mL)-343.4(of)-336.2(MSNs,)-343.3(1)-168.1(mg/mL)-337.6(of)]TJ 0 -1.1174 TD [(MSN-nDMEP,)-386.4(and)-378.8(1)-162.4(mg/mL)-383.7(of)-376.5(MSN-bDMEP)-382.9(were)-382(added)]TJ 0 -1.1116 TD [(and)-378.8(incubated)-376.5(at)-372.1(37)]TJ /F11 1 Tf 8.2076 0 TD ()Tj /F5 1 Tf .3917 0 TD [(C)-376.5(and)-373.1(5%)-377.6(CO)]TJ 7.3823 0 0 6.5614 203.0173 476.9007 Tm (2)Tj 9.843 0 0 9.843 206.7023 478.5447 Tm [(.)-377.8(Biocompatibility)-374.5(was)]TJ -14.9292 -1.1116 TD [(determined)-338.5(by)-336.3(the)-332.9(CCK-8)-336.7(assay)-335.7(as)-331.5(described)-341.6(previously.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 445.6629 Tm [(Chondrogenic)-340.3(induction)-328.9(of)-336.7(rBMMSCs)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 429.2219 Tm [(Chondrogenic)-396.8(differentiation)-400.7(was)-396.8(carried)-397.2(out)-395.1(in)-394(a)-393.9(pellet)]TJ -1.0137 -1.1116 TD [(culture)-361.6(system)-360.1(in)-359.4(a)-353.6(chondrogenic)-362.4(inductive)-358.2(medium)-361.7(\(CIM;)]TJ 0 -1.1174 TD [(detailed)-266.1(information)-262.5(in)-261.5(Supplementary)-266.8(Data\).)-259.9(We)-264.8(separately)]TJ 0 -1.1116 TD [(ad)25.4(d)16.2(e)15(d)-392.8(1)16.2(0)-150.8(n)16.2(g/)26.5(m)15(L)-393.9(o)16.2(f)-392.7(r)16.2(e)15(c)15(o)16.2(mb)25.4(i)16.1(n)16.2(a)15(n)0(t)-376.7(T)15(GF)25.9(-)]TJ /F6 1 Tf 15.5051 0 TD (b)Tj /F5 1 Tf .5357 0 TD [(1)-392.8(\()16.2(No)25.7(v)16.2(o)16.2(p)0(r)26.6(o)16.2(t)16.1(e)15(in)-376.7(Bi)25.4(o)16.2(-)]TJ -16.0408 -1.1116 TD -.0158 Tc [(t)-15.8(e)9.5(ch,)-284.2(S)-15.8(h)11(a)-.8(ngh)-15.8(a)9.6(i).3(,)-284.2(C)-.6(h)-15.8(i)10.7(na\))-287.6(a)-.8(nd)-287.6(1)-166.6(m)-.8(g/)-15.8(m)9.4(L)-283(of)-287.6(MSN)-15.8(,)-274.6(MSN-)-15.8(n)10.8(DMEP)-15.8(,)]TJ 0 -1.1174 TD 0 Tc [(or)-267.1(MSN-bDMEP)-273.5(to)-267.3(the)-269.5(medium)-263.8(of)-267.1(each)-272.8(experimental)-272.9(group)]TJ 0 -1.1116 TD [(and)-304(then)-305.2(formed)-308.4(chondrogenic)-304.8(pellets.)-307.4(Pellets)-303.8(in)-307.6(the)-304.1(TGF-)]TJ /F6 1 Tf 23.7415 0 TD (b)Tj /F5 1 Tf -23.7415 -1.1116 TD [(group)-437.5(were)-433.8(incubated)-434.1(in)-434.3(CIM)-431.4(with)-431.8(10)-169.2(ng/mL)-434.3(of)-434.1(TGF-)]TJ /F6 1 Tf 22.9927 0 TD (b)Tj /F5 1 Tf .5529 0 TD (1,)Tj -23.5457 -1.1174 TD [(while)-295.8(pellets)-298.2(in)-290.3(the)-292.6(other)-294.8(groups)-294.4(were)-295.6(cultured)-299.3(in)-290.3(CIM.)-296.6(The)]TJ 0 -1.1116 TD [(medium)-344.4(was)-345(exchanged)-342.9(every)-347.6(second)-342.8(day)-338.5(over)-345.4(a)-342.1(period)-341.9(of)]TJ T* [(14)-336.3(or)-330.5(21)-336.3(days.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 297.6944 Tm [(Gene)-338.8(expression)-329.5(analysis)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 281.2535 Tm [(After)-376.2(14)-376.6(days)-374(of)-376.5(chondrogenic)-379.7(differentiation)-377.7(induction,)]TJ -1.0137 -1.1116 TD [(total)-341.1(RNA)-334.4(from)-333.9(chondrogenic)-339.4(pellets)-338.5(was)-333.4(isolated)-339.6(with)-333.8(the)]TJ 0 -1.1174 TD [(TRIzol)-517(reagent)-518.2(\(Thermo)-518.1(Fisher)-514.4(Scientic\).)-519.1(The)-512.5(isolation)]TJ 0 -1.1116 TD [(was)-494.7(carried)-489.3(out)-487.2(according)-491.6(to)-486.1(the)-494.2(manufacturers)-493.4(manual.)]TJ T* [(Two)-356.7(hundred)-354.4(nanograms)-358.8(of)-353.5(total)-358.4(RNA)-357.4(\(2000)-166.7(ng\))-354.6(was)-356.5(used)]TJ 0 -1.1174 TD [(for)-429.5(a)-428.5(reverse)-431.4(transcription)-431.6(reaction)-427.2(with)-431.8(a)-428.5(complementary)]TJ 0 -1.1116 TD [(DNA)-276.6(\(cD)12(NA\))-275.7(rev)12.8(ers)13(e)-284.5(tra)12.7(nsc)13(rip)13.9(tio)13.7(n)-283.3(k)0(i)15(t)-283.5(\(Ta)11.7(KaR)10.9(a\).)-277.5(Th)13.9(e)-284.5(pri)13.9(m-)]TJ T* [(ers)-430.5(use)13(d)-433.1(t)0(o)-434.3(car)11.7(ry)-428.4(out)-423.9(the)-430.8(qua)12.8(nti)19.5(tat)12.6(ive)-430.8(PCR)-425.7(\(qP)14.2(CR\))-425.8(ana)11.7(ly-)]TJ 0 -1.1174 TD [(sis)-682.7(wer)12(e)-693.4(pre)12.8(de)13.9(sig)14(ned)-684.1(\(Sa)13(ngo)14(n)-686.5(Bio)12.8(tec)11.5(h\))-687.6(\(Su)14.2(ppl)13.8(em)12.7(ent)12.7(ary)]TJ 0 -1.1116 TD [(Tab)11.6(le)-308.8(S1\))14.2(.)-314.5(Qua)17.7(nti)13.7(tat)12.6(ive)-304.1(rea)11.7(l-t)13.8(ime)-305.3(PCR)-304.7(wa)13(s)-317.7(p)0(e)13.9(rfo)14(rme)11.6(d)-312.1(usi)14(ng)]TJ T* [(a)-399.7(Qia)11.8(gen)-390.4(mi)13.7(Scr)13(ipt)-389.5(SYB)12.2(R)-393.8(gre)12.8(en)-395(PCR)-391.1(Ki)14.1(t)-398.6(o)0(n)-393.9(a)0(n)-395(A)0(B)13.2(I)-398.5(750)14(0)]TJ T* [(ins)14(tru)13.9(men)11.6(t)-335.3(\(Ap)13.1(pli)13.7(ed)-331.7(Bio)12.8(sys)14.4(tem)11.5(s\))-330.3(fol)13.9(low)13(ing)-326(the)-332.9(ma)12.7(nuf)14(act)11.5(ur-)]TJ 0 -1.1174 TD [(er)12.9(s)-461.7(ins)14(tru)13.9(cti)12.6(on)15.1(s.)-453.6(The)-449.2(dat)12.7(a)-457.3(wer)12(e)-463(a)0(n)13.9(aly)12.7(zed)-449.1(wit)12.8(h)-461.9(t)0(h)15(e)-463(2)]TJ /F11 1 Tf 7.3823 0 0 6.5614 278.1354 154.0913 Tm (-)Tj /F6 1 Tf .5452 0 TD (DD)Tj /F5 1 Tf 1.3209 0 TD (Ct)Tj 9.843 0 0 9.843 59.7543 138.7842 Tm [(met)11.5(hod)14(.)-326(The)11.6(re)-325.9(wer)12(e)-324.8(thr)13.9(ee)-327.1(rep)12.8(lic)12.6(ate)-316.8(sam)11.8(ple)12.7(s)-329.2(for)-320(ea)12.8(ch)-325.9(gro)14(up.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 116.8441 Tm [(Histological)-339.8(staining)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 100.4031 Tm [(After)-456.9(21)-451.5(days)-460.4(of)-451.4(culture,)-457.2(the)-453.8(pellets)-459.5(were)-456.8(xed)-454.7(in)-451.6(4%)]TJ -1.0137 -1.1116 TD [(paraformaldehyde)-462.5(solution)-452.5(\(Solarbio\),)-453.4(dehydrated)-458.1(with)-449(an)]TJ 0 -1.1174 TD [(ascending)-353.2(ethanol)-355.9(gradient,)-348.9(embedded)-353.4(in)-353.7(parafn,)-347.3(and)-355.8(sec-)]TJ 0 -1.1116 TD [(tioned)-347.9(into)-350.2(5-)]TJ /F6 1 Tf 5.6042 0 TD (m)Tj /F5 1 Tf .5472 0 TD [(m-thick)-350.2(slices.)-352.1(Hematoxylin)-351(and)-344.3(eosin)-352.2(\(HE\))]TJ -6.1514 -1.1116 TD [(staining)-384.5(was)-379.5(performed)-376.2(according)-382.1(to)-376.7(the)-379(standard)-379.7(HE)-378.6(pro-)]TJ 25.5097 67.9242 TD [(tocol)-329.5(\(Solarbio\).)-338.2(The)-334(sections)-333.5(were)-335.9(stained)-332.6(with)-333.8(safranin)-339.3(O)]TJ 0 -1.1174 TD [(\(Solarbio\))-323.2(and)-315.5(alcian)-321.4(blue)-322.5(\(Solarbio\))-323.2(according)-318.8(to)-319.1(the)-321.4(man-)]TJ 0 -1.1116 TD [(ufacturers)-338(instructions.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 310.8472 681.2786 Tm [(In)-330.4(vivo)]TJ /F12 1 Tf 3.2689 0 TD (study)Tj /F5 1 Tf 9.843 0 0 9.843 320.8251 664.8376 Tm [(All)-505.5(animal)-511.5(experiments)-512.2(were)-508.7(approved)-506.4(by)-509.1(the)-505.7(Institu-)]TJ -1.0137 -1.1116 TD [(tional)-520.8(Animal)-528.5(Care)-520.3(and)-522.8(Use)-529.3(Committee)-523(of)-520.5(Peking)-526.1(Uni-)]TJ T* [(versity)-481.2(Health)-488.1(Science)-484.6(Center.)-485.8(Articular)-485.7(cartilage)-487.2(defec)-9(ts)]TJ 0 -1.1174 TD [(were)-410.7(created)-409.9(in)-411.3(both)-407.7(knees)-410.8(of)-411.1(New)-409.4(Zealand)-409.9(white)-411(rabbits)]TJ 0 -1.1116 TD [(\(weight:)-472(2.02.5)-167.9(kg;)]TJ /F9 1 Tf 8.7317 0 TD (n)Tj /F11 1 Tf .6681 0 TD (=)Tj /F5 1 Tf .7142 0 TD [(3)-473.4(per)-471(group\).)-470.8(Rabbits)-470.7(were)-474.1(anes-)]TJ -10.114 -1.1116 TD [(thetized)-294.9(with)-293.5(10%)-292.3(chloral)-292.5(hydrate.)-295.8(Defects)-294.2(of)-290.2(3.0)-166.9(mm)-292.6(depth)]TJ 0 -1.1174 TD [(and)-511.3(5.0)-166.9(mm)-517.3(diameter)-514.9(were)-520.2(created)-519.3(in)-509.2(the)-517.2(middle)-516.1(of)-514.8(the)]TJ 0 -1.1116 TD [(articular)-324.8(cartilage)-320.2(of)-318.9(the)-321.4(femoral)-322.4(trochlea.)-321.2(The)-322.4(rabbits)-319.9(were)]TJ T* [(randomly)-322.3(divided)-320.2(into)-321.4(four)-321.1(groups)-323.2(as)-320(follows:)-320.9(blank)-323.6(group,)]TJ 0 -1.1174 TD [(nothing)-301.7(was)-304.6(implanted)-301.8(into)-304.2(the)-304.1(defects;)-306.1(collagen)-306.3(\(C\))-303.8(group,)]TJ 0 -1.1116 TD (60)Tj /F6 1 Tf 1.1635 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(L)-399.7(o)0(f)-405.3(collagen)-404.2(I)-398.5(was)-402.6(implanted)-405.5(into)-396.3(the)-402(defects;)-404(colla-)]TJ -1.7164 -1.1116 TD (gen)Tj /F11 1 Tf 1.4457 0 TD (+)Tj /F5 1 Tf .5529 0 TD [(MSN)-287.1(\(C)]TJ /F11 1 Tf 3.4443 0 TD (+)Tj /F5 1 Tf .5529 0 TD [(S\))-290(group,)-285.4(60)]TJ /F6 1 Tf 5.2125 0 TD (m)Tj /F5 1 Tf .5472 0 TD [(L)-290.3(o)0(f)-290.1(collagen)-289(I)-289.1(with)-287.8(10)-169.2(mg/mL)]TJ -11.7556 -1.1174 TD [(of)-238.3(MSN)-241.1(was)-241.3(implanted)-244.2(into)-240.8(the)-240.7(defects;)-242.7(and)-240.6(collagen)]TJ /F11 1 Tf 21.2476 0 TD (+)Tj /F5 1 Tf .5529 0 TD (MSN-)Tj -21.8005 -1.1116 TD [(bDMEP)-238.7(\(C)]TJ /F11 1 Tf 4.5098 0 TD (+)Tj /F5 1 Tf .5529 0 TD (S)Tj /F11 1 Tf .5529 0 TD (+)Tj /F5 1 Tf .5529 0 TD [(D\))-239.2(group,)-239.3(60)]TJ /F6 1 Tf 5.2759 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(L)-244.2(o)0(f)-238.3(collagen)-243(I)-237.2(with)-241.7(10)-169.2(mg/mL)]TJ -11.9975 -1.1116 TD [(of)-837.3(MSN-bDMEP)-843.7(\()-87.5(MSNs)-841(with)-840.7(maximum)-842.1(loading)-844.3(of)]TJ T* [(bDMEP\))-441.4(was)-437.1(implanted)-445.8(into)-436.6(the)-442.3(defects.)-440.8(After)-439.6(operation,)]TJ 0 -1.1174 TD [(joints)-335.1(were)-335.9(closed)-337.2(with)-333.8(suture.)]TJ 1.0137 -1.1116 TD [(Rabbits)-442(were)-445.3(sacriced)-446.3(at)-447(12)-439.9(weeks)-446.3(after)-445.6(surgery.)-444(The)]TJ -1.0137 -1.1116 TD [(whole)-405.1(knee)-404.1(joints)-398.5(were)-405(dissected)-410.7(and)-401.9(xed)-402.8(in)-399.7(a)-405.4(4)0(%)-400.7(para-)]TJ 0 -1.1174 TD [(formaldehyde)-478.8(solution)-481.3(for)-475.5(24)-169.2(h.)-476.8(Subsequently,)-479.7(the)-476.9(tissues)]TJ 0 -1.1116 TD [(were)-399.2(decalcied)-402.8(with)-403(10%)-396(\(w/v\))-403.9(EDTA)-400.2(and)-396.1(embedded)-405.2(in)]TJ T* [(parafn.)-301.2(Sections)-299(were)-295.6(cut)-298.3(at)-297.2(a)-301.8(thickness)-300.1(of)-295.9(5)]TJ /F6 1 Tf 18.719 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(m.)-293.7(Then)-300.5(HE)]TJ -19.272 -1.1174 TD [(and)-309.7(alcian)-315.6(blue)-311(staining)-309.7(was)-310.4(performed)-312.9(as)-314.2(described)-312.8(above.)]TJ 0 -1.1116 TD [(Safranin)-535.2(O-fast)-532.7(green)-537.7(staining)-534.3(\(Solarbio\))-536.3(was)-535(performed)]TJ T* [(according)-336(to)-330.6(the)-338.7(manufacturers)-337.9(instructions.)]TJ /F12 1 Tf 8.9663 0 0 8.9663 310.8472 379.8991 Tm [(Statistical)-336.1(analysis)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 363.4582 Tm [(SPSS)-297.5(26.0)-306.2(software)-305.6(\(IBM)-300(Corp.,)-306(Armonk,)-300.1(NY\))-304.5(was)-304.6(used)]TJ -1.0137 -1.1174 TD [(for)-464(data)-461.9(analysis.)-463.7(Measurement)-468.1(data)-467.6(are)-460.6(presented)-468.3(as)-463.9(the)]TJ 0 -1.1116 TD (mean)Tj /F11 1 Tf 2.3442 0 TD ()Tj /F5 1 Tf .72 0 TD [(standard)-327.8(deviation.)-332.8(Data)-336(were)-330.1(analyzed)-336.1(by)-330.5(one-way)]TJ -3.0642 -1.1116 TD [(analysis)-264.4(of)-261.4(variance)-267(and)-263.7(Students)-264.4(unpaired)]TJ /F9 1 Tf 17.7802 0 TD (t)Tj /F5 1 Tf .2765 0 TD [(-test.)-263.6(A)]TJ /F9 1 Tf 3.2254 0 TD (p)Tj /F5 1 Tf .4953 0 TD (-value)Tj /F11 1 Tf -21.7774 -1.1116 TD (<)Tj /F5 1 Tf .5529 0 TD [(0.05)-329.3(was)-339.2(selected)-336.1(as)-337.2(the)-332.9(level)-336.4(of)-330.5(statistical)-338.5(signicance.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 310.8472 297.6944 Tm (Results)Tj /F12 1 Tf 0 -1.8336 TD [(DMEP)-335.4(extracted)-329.4(in)-336.5(basic)-333.6(buffer)-332.3(increased)-336.4(growth)]TJ 0 -1.2266 TD [(factor)-333.7(content)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 253.8141 Tm [(DMEP)-352.8(extracted)-360.4(in)-353.7(neutral)-361.6(and)-355.8(basic)-359.1(solutions)-355.5(was)-356.5(ana-)]TJ -1.0137 -1.1116 TD [(lyzed)-359.3(by)-359.3(BCA)-357.6(and)-361.6(ELISA)-359.9(experiments.)-365.9(There)-360.3(was)-362.2(no)-359.3(sig-)]TJ T* [(nicant)-499.7(difference)-505.3(in)-503.4(the)-499.9(total)-502.4(protein)-498.7(content)-505.6(of)-497.5(DMEP)]TJ 0 -1.1174 TD [(extracted)-314.3(in)-313.3(bDMEP)-313.6(\(0.232)]TJ /F11 1 Tf 11.4273 0 TD ()Tj /F5 1 Tf .72 0 TD [(0.063)-163.3(mg/mL\))-315.6(and)-315.5(in)-307.6(nDMEP)]TJ -12.1472 -1.1116 TD (\(0.194)Tj /F11 1 Tf 2.7474 0 TD ()Tj /F5 1 Tf .72 0 TD [(0.063)-169.1(mg/mL\).)-382.4(Nevertheless,)-384.9(the)-379(concentrations)-388.9(of)]TJ -3.4673 -1.1116 TD (TGF-)Tj /F6 1 Tf 2.2175 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1,)-476.8(bFGF,)-480.7(and)-482.5(IGF-1)-478.4(in)-480.4(bDMEP)-480.6(were)-479.9(signicantly)]TJ -2.7704 -1.1174 TD [(higher)-226.7(than)-230.3(those)-225.5(in)-227(nDMEP.)-230.6(The)-224.5(concentrations)-233.4(of)-226.8(TGF-)]TJ /F6 1 Tf 22.987 0 TD (b)Tj /F5 1 Tf .5529 0 TD (1,)Tj -23.5399 -1.1116 TD [(bFGF,)-486.4(and)-482.5(IGF)-487.8(in)-486.1(bDMEP)-486.4(were)-485.6(4.35)]TJ /F11 1 Tf 16.4497 0 TD ()Tj /F5 1 Tf .72 0 TD [(0.56,)-482.5(4.58)]TJ /F11 1 Tf 4.4004 0 TD ()Tj /F5 1 Tf .72 0 TD (0.92,)Tj -22.2901 -1.1116 TD [(and)-482.5(9.18)]TJ /F11 1 Tf 3.8475 0 TD ()Tj /F5 1 Tf .72 0 TD [(1.36)-162.2(ng/mL,)-483.8(respectively.)-488(In)-486(nDMEP,)-484.1(the)-482.6(con-)]TJ -4.5674 -1.1116 TD [(centrations)-476.5(of)-474.5(TGF-)]TJ /F6 1 Tf 8.4092 0 TD (b)Tj /F5 1 Tf .5472 0 TD [(1,)-476.8(bFGF,)-474.9(and)-476.8(IGF)-476.3(were)-474.1(1.32)]TJ /F11 1 Tf 12.6138 0 TD ()Tj /F5 1 Tf .72 0 TD (0.62,)Tj -22.2901 -1.1174 TD (1.85)Tj /F11 1 Tf 1.918 0 TD ()Tj /F5 1 Tf .7142 0 TD [(0.71,)-344.2(and)-338.5(4.26)]TJ /F11 1 Tf 6.0477 0 TD ()Tj /F5 1 Tf .72 0 TD [(1.64)-168(ng/mL,)-339.8(respectively)-346.3(\(Fig.)-336.1(1\).)-345.4(In)]TJ -9.3998 -1.1116 TD [(nDMEP,)-299.7(the)-298.3(concentrations)-308.2(of)-295.9(BMP-2,)-304.4(VEGF,)-298.6(and)-298.2(TGF-)]TJ /F6 1 Tf 23.2404 0 TD (b)Tj /F5 1 Tf .5472 0 TD (3)Tj -23.7876 -1.1116 TD [(were)-664.2(86.63)]TJ /F11 1 Tf 5.0225 0 TD ()Tj /F5 1 Tf .72 0 TD [(150.05,)-663.2(6.63)]TJ /F11 1 Tf 5.5812 0 TD ()Tj /F5 1 Tf .7142 0 TD [(2.81,)-661(and)-666.8(3.23)]TJ /F11 1 Tf 6.687 0 TD ()Tj /F5 1 Tf .72 0 TD [(5.60)-168(pg/mL,)]TJ -19.4448 -1.1174 TD [(respectively,)-263.4(while)-255.5(in)-261.5(bDMEP,)-259.4(the)-258(concentrations)-262.2(of)-255.6(BMP-2)]TJ 0 -1.1116 TD [(and)-332.8(VEGF)-335.5(were)-335.9(50.27)]TJ /F11 1 Tf 9.4171 0 TD ()Tj /F5 1 Tf .72 0 TD [(79.90)-330.4(and)-332.8(5.43)]TJ /F11 1 Tf 6.2781 0 TD ()Tj /F5 1 Tf .72 0 TD [(1.42)-168(pg/mL.)]TJ -16.1214 -1.1116 TD (TGF-)Tj /F6 1 Tf 2.2175 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(3)-352.4(was)-362.2(not)-354.8(detectable)-362.8(in)-353.7(bDMEP,)-363.1(and)-355.8(BMP-9)-358.6(was)]TJ -3.7841 -1.1174 TD [(not)-297.2(detectable)-311(in)-301.8(either)-302.9(nDMEP)-302.1(or)-301.7(in)-301.8(bDMEP.)-299.7(The)-305.2(concen-)]TJ 0 -1.1116 TD [(trations)-453.6(of)-451.4(BMP-2,)-459.9(VEGF,)-454.1(and)-453.7(TGF-)]TJ /F6 1 Tf 15.8162 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(3)-450.3(were)-456.8(not)-452.7(signi-)]TJ -16.3691 -1.1116 TD [(cantly)-331.7(different)-340.7(between)-334.7(nDMEP)-336.6(and)-332.8(bDMEP.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(INDUCTION)-339.7(OF)-331.2(CARTILAGE)-343.2(REGENERATION)-332.9(BY)-335.8(MSN)-337.5(LOADED)-337.5(WITH)-329.6(DMEP)-16250.1(809)]TJ ET endstream endobj 55 0 obj <>stream /GS1 gs BT /F12 1 Tf 8.9663 0 0 8.9663 62.022 541.9274 Tm 0 0 0 rg 0 Tc 0 Tw [(Characteristics)-333.6(of)-336.7(MSNs)]TJ /F3 1 Tf 1.1128 -1.8336 TD [(Morphology)-374.5(and)-380(structure)-377.7(of)-374.7(MSNs.)]TJ /F5 1 Tf 9.843 0 0 9.843 226.148 525.4865 Tm [(TEM)-375.2(\(Fig.)-370.6(2A,)-375.1(B\))]TJ -16.6743 -1.1116 TD [(showed)-446.2(that)-437.8(the)-442.3(MSNs)-443.6(were)-445.3(spherical)-445.4(and)-442.2(had)-442.2(a)-440(radially)]TJ T* [(mesoporous)-329.8(structure.)-332.5(The)-328.2(particle)-329.4(sizes)-330.1(of)-324.7(the)-327.1(MSNs)-328.4(were)]TJ 0 -1.1174 TD (135.70)Tj /F11 1 Tf 2.9202 0 TD ()Tj /F5 1 Tf .7142 0 TD [(12.68)-169.1(nm.)-392.8(The)-397.3(N)]TJ 7.3823 0 0 6.5614 166.9039 490.9605 Tm (2)Tj 9.843 0 0 9.843 174.5007 492.6046 Tm [(adsorptiondesorption)-399.9(isotherm)]TJ -11.4273 -1.1116 TD [(of)-451.4(MSN)-454.2(\(Fig.)-451.3(2C\))-453.6(exhibits)-453.7(the)-453.8(type)-455(IV)-452.3(isotherm)-454.7(and)-453.7(H1)]TJ T* [(hysteresis)-358.6(loop,)-347.8(indicating)-359.4(a)-347.8(three-dimensional)-358.9(mesoporous)]TJ 0 -1.1174 TD [(channel)-339.6(structure)-334.8(with)-333.8(a)-336.3(main)-335.2(pore)-333.8(size)-335(of)-330.5(6)-168.1(n)0(m)-331.7(\(Fig.)-336.1(2D\).)]TJ /F3 1 Tf 8.9663 0 0 8.9663 72 434.3243 Tm [(Degradation)-390.5(of)-387.3(MSNs.)]TJ /F5 1 Tf 9.843 0 0 9.843 171.8362 434.3243 Tm [(We)-391.5(rst)-384.3(investigated)-385.7(the)-390.5(degra-)]TJ -11.1565 -1.1116 TD [(dability)-488.5(of)-486(MSNs)-489.6(by)-486(dispersing)-490.1(the)-482.6(particles)-491.6(in)-486.1(PBS)-487.8(for)]TJ T* [(4)-289.1(weeks.)-288.4(TEM)-288.8(images)-292.3(showed)-284.9(that)-288.1(after)-290.1(immersion)-290(in)-290.3(PBS,)]TJ 0 -1.1174 TD [(MSNs)-357.2(basically)-364.9(maintained)-361.7(their)-358.2(original)-361.7(morphology,)-355.6(and)]TJ 0 -1.1116 TD [(the)-494.2(mesoporous)-496.8(structures)-491.2(were)-497.1(still)-495.4(clear)-492.9(at)-493.1(12)-492.9(weeks,)]TJ T* [(indicating)-728.1(that)-725.8(MSNs)-731.6(were)-727.5(not)-723.4(signicantly)-729.9(degraded)]TJ 0 -1.1174 TD [(\(Fig.)-434(3AC\).)-431.3(After)-433.8(4)-427.3(weeks)-434.7(of)-428.4(incubation)-434.2(in)-434.3(PBS,)-427.9(MSNs)]TJ 0 -1.1116 TD [(showed)-446.2(blurred)-452.4(boundaries,)-448.7(and)-448(the)-442.3(mesoporous)-450.7(structure)]TJ 25.504 18.6614 TD [(partially)-323.7(disappeared)-327.7(\(Fig.)-318.8(3D\).)-318.6(In)-318.9(contrast,)-325.6(after)-324.7(1)-317.9(week)-318.6(of)]TJ 0 -1.1116 TD [(cocul)-8(ture)-276.4(with)-276.2(rBMMSCs,)-273.8(MSNs)-276.5(showed)-279.2(blurred)-279.6(edges)-278.3(and)]TJ T* [(collapsed)-531.8(mesoporous)-525.6(structures)-525.8(\(Fig.)-526.1(3E\).)-526.3(These)-527.2(results)]TJ 0 -1.1174 TD [(indicated)-457.3(that)-455.1(MSNs)-455.1(were)-456.8(able)-450.4(to)-457.3(be)-452.6(slowly)-451(degraded)-455.8(in)]TJ 0 -1.1116 TD [(PBS)-395.7(and)-390.4(that)-391.7(the)-390.5(existence)-394.8(of)-393.8(rBMMSCs)-391.3(could)-392.7(accelerate)]TJ T* [(the)-338.7(degradation)-338.4(process)-332.2(of)-336.2(MSNs.)]TJ /F3 1 Tf 8.9663 0 0 8.9663 323.0361 456.2645 Tm [(Cell)-684.1(viability)-675.9(of)-678.2(rBMMSCs)-680.1(cultured)-677.4(with)-684.3(MSNs.)]TJ /F5 1 Tf 9.843 0 0 9.843 536.8251 456.2645 Tm (The)Tj -22.7336 -1.1174 TD [(results)-256.4(of)-249.8(the)-252.3(CCK-8)-250.3(assay)-255.1(showed)-250.4(that)-253.5(0.1)-166.9(mg/mL)-251.2(of)-249.8(MSNs)]TJ 0 -1.1116 TD [(did)-268.4(not)-268.4(affect)-269.4(the)-263.8(cell)-271.9(viability)-265.1(over)-270.5(14)-267.1(days)-264.6(of)-267.1(incubation)-267.2(in)]TJ T* [(comparison)-302.5(with)-293.5(the)-298.3(control)-297.1(group)-299.2(\(0)-163.4(mg/mL\).)-301.8(MSNs)-293.8(at)-297.2(0.5)]TJ T* [(and)-321.2(1)-168.1(mg/mL)-320.3(decreased)-320.8(the)-321.4(cell)-318(number)-320(at)-320.3(1,)-321.3(4,)-315.6(and)-321.2(7)-317.9(days)]TJ 0 -1.1174 TD [(compared)-347.6(with)-345.4(the)-344.4(control)-348.9(group,)-343(but)-343.3(the)-344.4(inhibitory)-345.6(effects)]TJ 0 -1.1116 TD -.0158 Tc [(d)-15.8(i)10.7(sap)-15.8(p)10.8(ear)-15.8(e)9.7(d)-235.8(aft)-15.8(e)9.5(r)-235.7(1).4(4)-241.5(d).4(ays)-241.3(o).4(f)-235.7(i).3(n)-15.8(c)9.6(ubat)-15.8(i)10.5(on.)-238.1(In)-241.5(contr)-15.8(a)9.7(st)-15.8(,)-222.1(1)-15.8(0)-156.2(m)-.8(g/mL)]TJ T* 0 Tc [(of)-255.6(MSNs)-259.3(consistently)-257.6(inhibited)-259.3(cell)-254.7(viability)-259.4(over)-253.2(14)-255.6(days)-253(of)]TJ 0 -1.1174 TD [(incubation)-319(\(Fig.)-313(4\).)-316.6(Therefore,)-317.4(1)-168.1(mg/mL)-314.6(of)-313.2(MSNs)-316.9(was)-316.2(cho-)]TJ 0 -1.1116 TD [(sen)-338.3(for)-331.5(the)-332.9(subsequent)-341.4(experiments.)]TJ ET q 1 i 127.049 732.245 m 487.162 732.245 l 487.162 624.926 l 127.049 624.926 l W n q 360.113 0 0 107.32 127.049 624.926 cm /Im2 Do Q Q BT /F7 1 Tf 9.845 0 0 9.845 62.022 608.2014 Tm [(FIG.)-354(1.)]TJ /F5 1 Tf 4.1346 0 TD [(Concentrations)-358.5(of)-353.3(total)-352.2(protein)-354(and)-355.4(growth)-352.4(factors)-354.8(in)-353.4(nDMEP)-353.1(and)-355.4(bDMEP.)]TJ /F7 1 Tf 31.4532 0 TD (\(A\))Tj /F5 1 Tf 1.7391 0 TD [(Concentration)-351.9(of)-353.3(total)-357.9(protein.)]TJ /F7 1 Tf -37.3269 -1.0135 TD (\(B\))Tj /F5 1 Tf 1.5951 0 TD [(Concentration)-265.5(of)-261.1(TGF-)]TJ /F6 1 Tf 9.2597 0 TD (b)Tj /F5 1 Tf .5528 0 TD (1.)Tj /F7 1 Tf 1.0135 0 TD (\(C\))Tj /F5 1 Tf 1.6412 0 TD [(Concentration)-265.5(of)-261.1(bFGF.)]TJ /F7 1 Tf 9.8817 0 TD (\(D\))Tj /F5 1 Tf 1.6412 0 TD [(Concentration)-265.5(of)-261.1(IGF-1.)-262.3(Each)-266.6(bar)-263.3(represents)-260.9(the)-263.5(mean)]TJ /F11 1 Tf 21.9631 0 TD ()Tj /F5 1 Tf .7198 0 TD (SD.)Tj -48.2681 -1.0135 TD (*)Tj /F9 1 Tf .501 0 TD (p)Tj /F11 1 Tf .668 0 TD (<)Tj /F5 1 Tf .7141 0 TD [(0.05.)-332.2(bDMEP,)-333.4(basic)-335.5(solution-extracted)-334.2(DMEP;)-330.2(bFGF,)-336(basic)-329.8(broblast)-332.6(growth)-335.2(factor;)-332.1(DMEP,)-332.4(dentin)-329.9(matrix)-336.9(extracted)]TJ -1.883 -1.0135 TD [(proteins;)-448.1(IGF,)-444.6(insulin-like)-445.6(growth)-444.6(factor;)-447.3(nDMEP,)-442.8(neutral)-447.3(solution-extracted)-449.3(DMEP;)-445.4(SD,)-443.6(standard)-442.2(deviation;)-450.6(TGF-)]TJ /F6 1 Tf 48.4869 0 TD (b)Tj /F5 1 Tf .5528 0 TD (1,)Tj -49.0398 -1.0077 TD [(transforming)-336.9(growth)-335.2(factor-)]TJ /F6 1 Tf 11.3559 0 TD (b)Tj /F5 1 Tf .5528 0 TD [(1.)-332.6(Color)-334.4(images)-331.9(are)-339.3(available)-336.6(online.)]TJ ET q 1 i 215.66 336.983 m 552.189 336.983 l 552.189 64.687 l 215.66 64.687 l W n q 336.928 0 0 272.296 215.66 64.687 cm /Im3 Do Q Q BT /F7 1 Tf 9.845 0 0 9.845 62.022 233.7448 Tm [(FIG.)-336.7(2.)]TJ /F5 1 Tf 4.1174 0 TD [(Characterization)-335.5(of)]TJ -4.1174 -1.0135 TD (MSNs.)Tj /F7 1 Tf 3.1269 0 TD [(\(A,)-334.4(B\))]TJ /F5 1 Tf 2.9657 0 TD [(TEM)-334.4(images)-337.7(of)]TJ -6.0925 -1.0077 TD (MSNs.)Tj /F7 1 Tf 3.1269 0 TD (\(C\))Tj /F5 1 Tf 1.716 0 TD [(Nitrogen)-338.5(adsorption)]TJ -4.8429 -1.0135 TD [(desorption)-333.7(isotherms)-339.5(of)-330.2(MSNs.)]TJ /F7 1 Tf T* (\(D\))Tj /F5 1 Tf 1.6757 0 TD [(Pore)-292.9(size)-294.2(distribution)-289(curves)-296(of)]TJ -1.6757 -1.0135 TD [(MSNs.)-336.9(MSNs,)-331.1(mesoporous)-340.1(silica)]TJ 0 -1.0077 TD [(nanoparticles;)-341.5(TEM,)-332(transmission)]TJ 0 -1.0135 TD [(electron)-340(microscopy.)-333.5(Color)-334.4(images)]TJ T* [(are)-333.6(available)-342.4(online.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (810)Tj 48.7749 0 TD [(MAO)-329.9(ET)-338.7(AL.)]TJ ET endstream endobj 57 0 obj 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[(C)-411.1(for)-417.9(24)-169.2(h.)]TJ -19.7155 -1.1174 TD [(The)-339.7(maximum)-335.2(loading)-337.4(of)-336.2(total)-335.4(protein)-337.4(of)-336.2(MSNs)-334.1(was)-339.2(610)]TJ /F11 1 Tf 23.7242 0 TD ()Tj /F5 1 Tf -23.7242 -1.1116 TD (11)Tj /F6 1 Tf 1.1692 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(g/mg)-800.6(in)-797.2(nDMEP)-797.4(and)-799.3(673)]TJ /F11 1 Tf 12.4237 0 TD ()Tj /F5 1 Tf .72 0 TD (53)Tj /F6 1 Tf 1.1635 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(g/mg)-800.6(in)-797.2(bDMEP)]TJ -16.5822 -1.1116 TD [(\(F)26.8(i)16.1(g)16.2(.)-239.6(5)16.2(A\))25.8(.)-239.6(T)15(h)16.2(e)-238.4(a)15(m)15(o)0(u)26.6(n)16.2(t)-237.4(o)16.2(f)-243(T)15(G)15.3(F)16.3(-)]TJ /F6 1 Tf 12.2509 0 TD (b)Tj /F5 1 Tf .5414 0 TD -.0158 Tc [(1)-253(l).3(oa)-15.8(d)9.6(e)-.8(d)-253(i).3(n)-258.8(M)-.5(SNs)-252.8(w)-15.8(a)8.8(s)-252.8(5.23)]TJ /F11 1 Tf 10.9319 0 TD 0 Tc ()Tj /F5 1 Tf -23.7242 -1.1174 TD [(1.31)-168(ng/mg)-444.6(in)-440.1(nDMEP)-440.3(and)-442.2(16.81)]TJ /F11 1 Tf 14.1631 0 TD ()Tj /F5 1 Tf .72 0 TD [(3.87)-162.2(ng/mg)-444.6(in)-440.1(bDMEP)]TJ -14.8831 -1.1116 TD [(\(Fig.)-370.6(5B\).)-370.6(The)-374.3(maximum)-369.8(loading)-372(of)-365(Cyto-C)-371.6(in)-370.9(MSNs)-368.7(was)]TJ T* -.0153 Tc [(442)6.6(.5)]TJ /F11 1 Tf 2.3269 0 TD 0 Tc ()Tj /F5 1 Tf .7027 0 TD -.0151 Tc [(19)6.8(.0)]TJ /F6 1 Tf 1.8431 0 TD 0 Tc (m)Tj /F5 1 Tf .5357 0 TD -.0172 Tc [(g/mg.)-251(A)3.9(fter)-248.7(being)-248.7(i)-1.1(mmersed)-248.7(i)-1.1(n)-248.7(P)-.9(BS)-254.3(at)-254.6(1)-162.3(m)-2.2(g/)4.6(mL,)]TJ -5.4084 -1.1116 TD 0 Tc (45.64%)Tj /F11 1 Tf 3.2542 0 TD ()Tj /F5 1 Tf .72 0 TD [(3.49%)-561.8(of)-560.9(Cyto-C)-561.7(was)-569.6(gradually)-559.6(released)-572.1(from)]TJ -3.9742 -1.1174 TD [(MSNs)-339.9(in)-330.6(28)-330.5(days)-339.4(\(Fig.)-330.3(5C\).)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 411.6471 Tm [(Cell)-336.3(viability)-334.4(of)-336.7(rBMMSCs)-332.3(cultured)-336(with)-336.5(MSN-DMEP)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 395.2062 Tm [(After)-312.9(7)-306.4(days)-310.6(of)-307.4(culture,)-307.4(1)-168.1(mg/mL)-308.8(of)-307.4(MSNs)-311.1(decreased)-309.2(the)]TJ -1.0137 -1.1116 TD [(cell)-277.7(number)-273.9(of)-272.9(rBMMSCs.)-273.8(MSN-nDMEP)-273.5(decre)-9(ased)-271.5(the)-275.3(cell)]TJ 0 -1.1174 TD [(number)-343(at)-337.6(days)-345.2(1,)-338.6(3,)-338.6(and)-338.5(5,)-338.6(but)-337.5(had)-338.5(no)-342(inhibition)-340(at)-337.6(day)-344.3(7.)]TJ 0 -1.1116 TD [(However,)-343.5(MSN-bDMEP)-336.9(decreased)-338(the)-338.7(cell)-335.3(number)-337.3(at)-337.6(days)]TJ T* [(1,)-315.6(3,)-315.6(and)-315.5(5,)-315.6(but)-314.5(increased)-319.7(the)-315.6(cell)-318(number)-320(at)-314.5(day)-315.5(7)-312.1(\(Fig.)-318.8(6\).)]TJ /F12 1 Tf 8.9663 0 0 8.9663 59.7543 329.3857 Tm [(MSN-DMEP)-339.8(promoted)-332.9(chondrogenic)-337(differentiation)]TJ 0 -1.2266 TD [(of)-336.7(rBMMSCs)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 301.9464 Tm [(The)-581.6(expression)-583.3(of)-578.1(chondrogenic)-587(differentiation-related)]TJ -1.0137 -1.1116 TD [(genes)-335.9(\()]TJ /F9 1 Tf 2.949 0 TD (Acan)Tj /F5 1 Tf 2.062 0 TD (,)Tj /F9 1 Tf .5817 0 TD (Col2)Tj /F5 1 Tf 1.9468 0 TD (,)Tj /F9 1 Tf .5817 0 TD (Col10)Tj /F5 1 Tf 2.4536 0 TD [(,)-331.7(and)]TJ /F9 1 Tf 2.3615 0 TD (Sox9)Tj /F5 1 Tf 1.9468 0 TD [(\))-329.4(was)-333.4(detected)-342(by)-330.5(real-)]TJ -14.8831 -1.1116 TD [(time)-577.3(PCR)-575.4(after)-578.1(rBMMSCs)-575.7(were)-577.8(cocultured)-579.2(with)-575.7(MSN,)]TJ T* [(MSN-nDMEP,)-490.1(and)-482.5(MSN-bDMEP)-486.6(for)-487.1(14)-480.3(days.)-486.9(CIM)-483.3(was)]TJ 0 -1.1174 TD [(used)-276.1(as)-273.9(a)-273(negative)-271.7(control,)-277.5(and)-269.4(CIM)-275.9(with)-270.5(10)-169.2(ng/mL)-273(TGF-)]TJ /F6 1 Tf 23.2404 0 TD (b)Tj /F5 1 Tf .5529 0 TD (1)Tj 1.7164 28.3435 TD [(was)-252.8(used)-247.3(as)-250.8(a)-249.9(positive)-257.8(control.)-248.7(The)-253.3(MSN-bDMEP)-250.5(group)-253.1(had)]TJ 0 -1.1116 TD [(the)-494.2(highest)-498.5(expression)-496.9(of)]TJ /F9 1 Tf 11.2199 0 TD (Acan)Tj /F5 1 Tf 2.5573 0 TD [(compared)-497.3(with)-495.1(the)-494.2(other)]TJ -13.7772 -1.1116 TD [(groups.)-309.3(The)-310.9(expression)-312.6(of)]TJ /F9 1 Tf 10.8858 0 TD (Acan)Tj /F5 1 Tf 2.373 0 TD [(in)-307.6(the)-309.9(MSN-nDMEP)-313.8(group)]TJ -13.2588 -1.1116 TD [(was)-270.1(signicantly)-269.1(higher)-267.1(than)-270.6(that)-270.8(in)-267.3(the)-263.8(control,)-271.7(TGF-)]TJ /F6 1 Tf 21.7717 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(,)-268.4(and)]TJ -22.3246 -1.1174 TD [(MSN)-385.1(groups.)-378.4(There)-389.1(was)-379.5(no)-382.3(signicant)-387.8(difference)-390.1(between)]TJ 0 -1.1116 TD [(the)-338.7(control)-343.2(and)-338.5(MSN)-339(groups)-340.5(in)]TJ /F9 1 Tf 13.2128 0 TD (Acan)Tj /F5 1 Tf 2.396 0 TD [(expression)-347.1(\(Fig.)-336.1(7A\).)]TJ -15.6088 -1.1116 TD [(No)-371.7(statistically)-375.4(signicant)-376.2(difference)-378.6(was)-373.8(detected)-376.6(in)]TJ /F9 1 Tf 22.3419 0 TD (Col2)Tj /F5 1 Tf -22.3419 -1.1174 TD [(expression)-560.2(among)-555.1(the)-563.3(control,)-553.9(MSN,)-561.3(and)-557.4(MSN-nDMEP)]TJ 0 -1.1116 TD (groups.)Tj 1.0137 -1.1116 TD [(The)-322.4(MSN-bDMEP)-325.3(group)-322.3(had)-321.2(a)-324.8(signicantly)-326.7(higher)]TJ /F9 1 Tf 21.3282 0 TD (Col2)Tj /F5 1 Tf -22.3419 -1.1174 TD [(expression)-416.2(than)-408.9(the)-413.5(abovementioned)-419(groups,)-413(but)-412.4(a)-411.2(signi-)]TJ 0 -1.1116 TD [(cantly)-619.7(lower)]TJ /F9 1 Tf 5.9786 0 TD (Col2)Tj /F5 1 Tf 2.5688 0 TD [(expression)-623.6(than)-622(the)-620.9(positive)-620.7(control)]TJ -8.5474 -1.1116 TD (\(TGF-)Tj /F6 1 Tf 2.5515 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(\))-415.8(group)-414.4(\(Fig.)-416.7(7B\).)]TJ /F9 1 Tf 8.0002 0 TD (Col10)Tj /F5 1 Tf 2.8626 0 TD [(expression)-422(did)-412.4(not)-418.1(differ)]TJ -13.9673 -1.1116 TD [(statistically)-473.3(among)-474.4(the)-471.1(control,)-467.6(TGF-)]TJ /F6 1 Tf 15.7355 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(,)-470(MSN,)-469.1(and)-471(MSN-)]TJ -16.2884 -1.1174 TD 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[(of)-370.8(histological)-378.9(staining)-373(indicated)-382.4(that)-374.5(rBMMSCs)-374.1(in)-370.9(pellets)]TJ ET q 360.926 0 0 162.255 59.754 569.764 cm /Im4 Do Q BT /F7 1 Tf 9.845 0 0 9.845 433.1337 708.9447 Tm [(FIG.)-336.7(3.)]TJ /F5 1 Tf 4.1174 0 TD [(Degradation)-332.3(of)]TJ -4.1174 -1.0077 TD (MSNs)Tj /F9 1 Tf 2.8735 0 TD [(in)-336.2(vitro)]TJ /F5 1 Tf 3.0117 0 TD (.)Tj /F7 1 Tf .5816 0 TD (\(A\))Tj /F5 1 Tf 1.7218 0 TD (TEM)Tj -8.1887 -1.0135 TD [(image)-336.9(of)-330.2(MSNs)-339.2(before)]TJ T* (degradation.)Tj /F7 1 Tf 5.3209 0 TD (\(BD\))Tj /F5 1 Tf 2.885 0 TD (TEM)Tj -8.2059 -1.0135 TD [(images)-337.7(of)-330.2(MSNs)-339.2(in)-330.4(PBS)-337.6(at)]TJ 0 -1.0077 TD [(1)-265.9(week)]TJ /F7 1 Tf 3.1442 0 TD (\(B\))Tj /F5 1 Tf 1.3302 0 TD [(,)-268.3(2)-260.1(weeks)]TJ /F7 1 Tf 4.0425 0 TD (\(C\))Tj /F5 1 Tf 1.3878 0 TD [(,)-262.5(and)]TJ -9.9047 -1.0135 TD [(4)-265.9(weeks)]TJ /F7 1 Tf 3.53 0 TD (\(D\))Tj /F5 1 Tf 1.3821 0 TD (.)Tj /F7 1 Tf .5183 0 TD (\(E\))Tj /F5 1 Tf 1.5951 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[(at)-400.9(the)-396.3(concentration)-405.2(of)-399.6(100)-164.6(ng/mL)-399.7(promoted)-397.2(chondrogenic)]TJ T* [(dif)13.9(fer)12.9(ent)12.7(iat)12.6(ion)-233.8(of)-238.3(hu)15.1(man)-236.1(mul)12.6(tip)13.7(ote)18.4(nti)13.7(al)-239.6(mes)11.8(enc)11.7(hym)18.5(al)-239.6(cel)11.5(ls.)]TJ 7.3823 0 0 6.5614 544.8187 203.4141 Tm (35)Tj 9.843 0 0 9.843 313.0582 188.0503 Tm [(The)-293.6(min)12.6(im)13.7(um)-297.2(eff)12.9(ect)11.5(ive)-286.8(con)12.8(cen)11.7(tra)12.7(tio)13.7(n)-294.8(o)0(f)-295.9(gro)14(wth)-292.3(fac)17.4(tor)13.9(s)-300.4(was)]TJ T* [(app)12.8(rox)14(ima)11.5(tel)12.6(y)-306.4(abo)12.8(ve)-302.9(1)-162.4(ng/)13.8(mL)12.7(,)-308.7(whi)13(ch)-302.9(sug)14.2(ges)13(ts)-301.6(tha)12.7(t)-306.5(TGF)12.1(-)]TJ /F6 1 Tf 23.0043 0 TD (b)Tj /F5 1 Tf .5472 0 TD (1,)Tj -23.5514 -1.1116 TD [(IGF-1,)-510.7(and)-511.3(bFGF)-506(in)-509.2(DMEP)-508.3(might)-508.1(play)-506.8(a)-509.1(major)-509.1(role)-506.8(in)]TJ T* [(cartilage)-262.6(regeneration.)-257.7(Furthermore,)-260.9(different)-254.3(growth)-255.3(factors)]TJ 0 -1.1174 TD [(have)-513.6(synergistic)-509.7(effects)-512.2(on)-509.1(chondrogenesis.)-517.4(Studies)-509.9(have)]TJ 0 -1.1116 TD [(shown)-420.9(a)-422.7(signicant)-422.3(increase)-422.3(in)-422.8(cartilage)-423.9(matrix)-423.9(formation)]TJ T* [(when)-334.7(IGF-1)-334.5(is)-330.4(combined)-335(with)-333.8(the)-332.9(TGF-)]TJ /F6 1 Tf 16.4555 0 TD (b)Tj /F5 1 Tf .8812 0 TD [(superfamily)-338.2(such)]TJ -17.3367 -1.1174 TD [(as)-435.1(TGF-)]TJ /F6 1 Tf 3.4846 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1,)-430.7(BMP-2,)-431.1(and)-430.7(BMP-7.)]TJ 7.3823 0 0 6.5614 449.8582 115.7102 Tm (33,36)Tj 9.843 0 0 9.843 470.7211 111.3448 Tm [(The)-431.9(combination)-430.8(of)]TJ -16.0177 -1.1116 TD (TGF-)Tj /F6 1 Tf 2.2232 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1)-283.3(and)-280.9(bFGF)-287.2(was)-287.4(demonstrated)-288.7(to)-284.6(synergistically)-290.9(pro-)]TJ -2.7762 -1.1116 TD -.0159 Tc [(m)-15.9(o)9.5(te)-248.6(th)-15.9(e)-238.1(c)-.9(ho)-15.9(n)10.7(dro)-15.9(g)10.7(e)-.9(nic)-254.3(d).3(iff)-15.9(e)9.6(ren)-15.9(t)10.6(iati)-15.9(o)10.6(n)-247.4(of)-253.1(peri)-15.9(o)10.6(tic)-254.3(mesen)-15.9(c)9.5(hyme)]TJ /F9 1 Tf 0 -1.1174 TD 0 Tc [(in)-209.7(v)15(i)0(t)26.3(r)16.4(o)]TJ /F5 1 Tf 2.8107 0 TD (.)Tj 7.3823 0 0 6.5614 343.0487 82.885 Tm -.0162 Tc (15)Tj 9.843 0 0 9.843 352.5164 78.463 Tm 0 Tc [(D)15.3(M)15.3(E)15(P,)-211.7(a)15(s)-225.5(a)-221.1(c)15(o)16.2(m)15(pl)26.5(e)15(x)-225.7(o)16.2(f)-219.9(se)25.6(v)16.2(e)15(ra)25.5(l)-220.1(g)0(r)26.6(o)16.2(w)15.3(t)0(h)-209.7(f)16.2(ac)24.3(t)16(o)16.2(rs)26.8(,)-222.3(m)15(a)15(y)]TJ -4.0088 -1.1116 TD -.0159 Tc [(s)-15.9(h)10.9(ow)-340.4(a)-340.7(s).5(upe)-15.9(r)9.6(i).1(or)-339.5(eff)-15.9(e)9.6(ct)-339.7(than)-339.5(a)-340.7(s).5(in)-15.9(g)10.7(l).2(e)-340.7(grow)-15.9(t)9.7(h)-339.5(facto)-15.9(r)10.7(,)-336.1(p).3(r)-15.9(o)10.7(vid)-15.9(i)10.6(ng)]TJ T* [(n)-15.9(e)9.5(w)-334.6(hop)-15.9(e)-324.5(for)-333.7(pr)-15.9(o)10.7(m)-.9(oti)-15.9(n)10.6(g)-333.8(a)-.9(rt)-15.9(i)10.4(c)-.9(ul)-15.9(a)9.4(r)-333.7(cart)-15.9(i)10.4(lag)-15.9(e)-324.5(regen)-15.9(e)9.5(rat)-15.9(i)10.4(on.)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 603.949 l 191.622 603.949 l W n q 360.926 0 0 128.069 191.622 603.949 cm /Im6 Do Q Q BT /F7 1 Tf 9.845 0 0 9.845 62.022 716.0313 Tm 0 Tc [(FIG.)-244.6(5.)]TJ /F5 1 Tf 4.0252 0 TD [(Protein)-244.4(loading)-244.5(and)]TJ -4.0252 -1.0135 TD [(release)-339.9(performance)-339.2(of)]TJ T* (MSNs.)Tj /F7 1 Tf 3.1269 0 TD (\(A\))Tj /F5 1 Tf 1.716 0 TD [(Amount)-336.3(of)-330.2(total)]TJ -4.8429 -1.0135 TD [(protein)-336.7(in)-330.4(nDMEP)-335.8(and)]TJ 0 -1.0077 TD [(bDMEP)-335.8(loaded)-336.7(on)-330.2(MSNs.)]TJ /F7 1 Tf 0 -1.0135 TD (\(B\))Tj /F5 1 Tf 1.6642 0 TD [(Amount)-336.3(of)-336(TGF-)]TJ /F6 1 Tf 7.0024 0 TD (b)Tj /F5 1 Tf .5528 0 TD .335 Tc [(1i)335(n)]TJ -9.2194 -1.0135 TD 0 Tc [(nDMEP)-335.8(and)-332.4(bDMEP)-335.8(loaded)]TJ T* [(on)-249.6(MSNs.)]TJ /F7 1 Tf 4.2901 0 TD (\(C\))Tj /F5 1 Tf 1.6354 0 TD [(Protein)-255.9(release)]TJ -5.9255 -1.0078 TD [(curve)-335.5(of)-336(MSNs.)-331.1(Each)-335.7(bar)]TJ 0 -1.0135 TD [(represents)-335.7(the)-338.3(mean)]TJ /F11 1 Tf 8.3038 0 TD ()Tj /F5 1 Tf .7198 0 TD (SD.)Tj -9.0236 -1.0135 TD (*)Tj /F9 1 Tf .501 0 TD (p)Tj /F11 1 Tf .668 0 TD (<)Tj /F5 1 Tf .7141 0 TD [(0.05.)-337.9(Color)-334.4(images)-331.9(are)]TJ -1.883 -1.0078 TD [(available)-336.6(online.)]TJ ET q 1 i 62.589 211.011 m 300.529 211.011 l 300.529 103.238 l 62.589 103.238 l W n q 238.023 0 0 107.773 62.589 103.238 cm /Im7 Do Q Q BT /F7 1 Tf 9.845 0 0 9.845 62.022 86.4567 Tm [(FIG.)-515.3(6.)]TJ /F5 1 Tf 4.2959 0 TD [(C)15.3(e)0(l)19.7(l)-427.3(vi)26.6(ab)19.9(il)26.5(it)20.7(y)-427.1(o)0(f)-416.6(r)16.3(BM)19.2(M)15.5(S)0(C)20.2(s)-427(cu)19.9(l)16.1(t)0(u)20.9(r)0(e)25.6(d)-427.1(wi)20.1(th)-416.8(M)15.5(S)0(N)20.4(-)]TJ -4.2959 -1.0135 TD [(DM)25.2(EP)-452.1(de)19.9(te)25.5(ct)19.7(ed)-452.3(by)-451.1(CC)24.8(K-)20.2(8)-461.7(a)0(s)20.1(s)0(a)25.8(y)0(.)-453.5(E)0(a)24.5(c)0(h)-452.3(b)0(a)19.9(r)-461.7(re)19.9(p)16.3(r)0(e)19.9(s)0(e)25.8(n)0(t)20.9(s)-461.5(th)20.9(e)]TJ 0 -1.0077 TD [(me)24.5(an)]TJ /F11 1 Tf 2.2977 0 TD ()Tj /F5 1 Tf .7025 0 TD [(SD)20.4(.)-279.8(*)16.3(In)21(di)26.6(ca)18.7(te)25.5(s)-283(a)-278.6(si)26.8(gn)21.1(i)26.8(ca)18.7(n)16.3(t)-283.3(d)16.3(i)0(f)20.9(f)0(e)25.6(r)0(e)19.9(n)0(c)25.6(e)-278.6(co)19.9(m)15.1(p)0(a)19.9(r)0(e)25.6(d)-283.2(w)15.5(i)0(t)20.7(h)]TJ -3.0002 -1.0135 TD [(th)20.9(e)-180.7(c)0(o)25.6(n)0(t)20.9(r)0(o)26.8(l)-185.4(g)16.3(r)0(o)21(u)0(p)-169(\()]TJ /F9 1 Tf 7.2961 0 TD (p)Tj /F11 1 Tf .6565 0 TD (<)Tj /F5 1 Tf .7025 0 TD [(0.)24.4(05)21.1(\).)-171.4(C)15.3(o)0(l)20.9(o)16.3(r)-185.3(i)0(m)25.5(a)0(g)19.9(e)15.1(s)-185.1(a)0(r)25.6(e)-186.4(a)15.1(v)0(a)19.9(i)0(l)26.5(a)0(b)19.9(l)16.1(e)-186.4(o)0(n)26.8(l)0(i)20.7(n)0(e)25.6(.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (812)Tj 48.7749 0 TD [(MAO)-329.9(ET)-338.7(AL.)]TJ ET endstream endobj 70 0 obj <>stream Adobed          s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?v7-iesc Ucs_Xڧsw*Ay*ߝo5.%o$OLC5?u ]|ڼZ):GOpv}I)pbԢǣ[2.L$R߾4J〄z^e?/?GI}rz6m\Ƅ4%ᓍwMp3bWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlU5<Ũv]>gPyp4F Yɻݼ8ǔ1OM:V;8m*#kVVh]: *C >jY/]kz&gJ?'ijulcb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ث&iF>\-g;=qA4-[]m"5oo1`ܓrS+tc[+ "82p٣?k!+:\wey 3,~4Γ0a48*#Xw"yWZEmPjeoª݈Rf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]̿<-MKbAju1~C g-Cl:@޹?g?mroLEI<1/d՘_R@Ipk"~]o3m2 t'D<}(I=7OsCV}6\m:9c=U`~Dg|yKf;<; xBW$94 ?]˦y#[,Q777^Jާ~IwFm'ӯc[鯤G$rO\%8'|ۯZdӛ}BegcQT}1JI'tG|_/~_yʭ]<ժBD=Q[uZ""xMA 6*lUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]OrkP~`YfhWVWџUje@66=Ufgy) g|i嘴@E,l}Jvcp[`3~`3+~gUF"hFzS /.4${ ^~Xhi6?1Ӯu=6NYDG!E;5$??M֯m&!Lxb=2"\ Try5:y~׳tOƁ`X$!$ Z~ E#rW~jӭ4o/!Kۘ ^ Tpyɲ+\^aEhz6$ebFtBP} 8]nɼwj^WJoҊ̄: 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" P!vȲٽvW/e2)4ތp;m{t-p#oE._+/_N:һ9Gu(vOb]qh_1tOŖuȏY}UnMqbK:ڜP5'3w} }-K&xd6ȶSJ8>8ڌV}BfeCӳz2!iٽvoF_8;7/VfeS)HYe˜~/C1nD]P|DqAߨOɘmS<146IW@|7&5;S#Hѐ6ݏ5gیC-7[ ϫH#ܻ =;Nc^ *Ozrߎ+MTW|D+24$T \=ObD\11kʎ`[M^8` qcHTw:9??Z:ӝ8+-~ž.?^Gէ>>stream /GS1 gs BT /F5 1 Tf 9.843 0 0 9.843 62.022 308.6361 Tm 0 0 0 rg 0 Tc 0 Tw [(structure)-507.6(with)-506.6(a)-503.4(high)-505.6(surface)-506.3(area)-509(and)-499.8(negat)-8(ive)-499.9(charges.)]TJ 0 -1.1116 TD [(These)-342.9(characteristics)-351.9(further)-343(enhanced)-347.5(the)-344.4(physical)-345.3(adsorp-)]TJ T* [(tion)-321.4(of)-324.7(growth)-318.6(factors)-326.7(by)-319(MSNs.)]TJ 7.3823 0 0 6.5614 193.4928 291.118 Tm (19,20)Tj 9.843 0 0 9.843 213.2787 286.7527 Tm [(The)-328.2(release)-323.3(of)-319(DMEP)]TJ -15.3669 -1.1174 TD [(in)-538(MSNs)-541.5(is)-537.8(strongly)-544.5(associated)-545.4(with)-535.4(the)-540.2(degradation)-545.7(of)]TJ 0 -1.1116 TD (MSNs.)Tj 7.3823 0 0 6.5614 89.5181 269.1779 Tm (50)Tj 9.843 0 0 9.843 100.8 264.8125 Tm [(MSNs)-403.3(with)-397.2(mesoporous)-404.7(structures)-399(have)-404.2(a)-399.7(higher)]TJ -3.9396 -1.1116 TD [(surface)-287.4(area)-290.1(in)-284.6(contact)-287.9(with)-287.8(water)-285.3(than)-287.9(solid)-282(silica)-291.3(particles,)]TJ 0 -1.1174 TD [(resulting)-305(in)-301.8(faster)-302.5(degradation)-309.6(and)-304(improved)-299.3(drug)-303.9(release.)]TJ 7.3823 0 0 6.5614 293.7259 247.2944 Tm (22)Tj 9.843 0 0 9.843 72 231.9306 Tm [(We)-339.7(also)-345.3(found)-339.5(that)-339.9(the)-338.7(degradation)-344.1(rate)-346.6(of)-336.2(MSNs)-345.7(cocul-)]TJ -1.0137 -1.1116 TD [(tured)-427.2(with)-420.2(rBMMSCs)-425.9(was)-425.6(faster)-423.5(than)-426.2(that)-420.5(in)-422.8(PBS,)-422.1(which)]TJ 0 -1.1174 TD [(may)-334(facilitate)-333.1(the)-332.9(release)-334.8(of)-324.7(loade)-8(d)-329.4(proteins)-332.6(and)-327(exert)-330.5(their)]TJ 0 -1.1116 TD [(biological)-491.9(effects.)-492.6(It)-486.1(may)-489.5(be)-492.9(possible)-487.9(to)-491.9(regulate)-490.6(protein)]TJ T* [(release)-392.4(from)-385.7(silica-based)-392.2(materials)-394.9(through)-387.9(controlled)-388.1(ero-)]TJ T* (sion.)Tj 7.3823 0 0 6.5614 80.9008 181.5307 Tm (51)Tj 9.843 0 0 9.843 90.8787 177.1653 Tm [(A)-261.1(model)-267.2(protein)-262.5(with)-264.7(a)-261.4(similar)-263.7(size)-265.8(to)-261.5(growth)-266.8(factors)]TJ -2.9317 -1.1174 TD [(has)-557.2(been)-559.7(successfully)-563.5(used)-558.3(to)-555.3(simulate)-565.5(the)-557.5(loading)-556.3(and)]TJ 0 -1.1116 TD [(release)-450(of)-445.7(the)-448.1(growth)-445.3(factors)-447.6(from)-449.1(MSNs.)]TJ 7.3823 0 0 6.5614 237.5432 159.5905 Tm (52)Tj 9.843 0 0 9.843 249.2787 155.2252 Tm [(Santos)-451(at)-447(el.)]TJ -19.0243 -1.1116 TD [(found)-495.1(that)-489.6(porous)-496(silica)-492.9(loaded)-498.6(with)-489.3(different)-496.2(concentra-)]TJ 0 -1.1174 TD [(tions)-489.4(of)-486(model)-486.1(protein)-492.9(shared)-486.8(similar)-488.3(release)-496.1(curves)-486.8(and)]TJ 0 -1.1116 TD [(the)-402(release)-403.9(amount)-400.8(was)-402.6(dose)-397(dependent.)]TJ 7.3823 0 0 6.5614 227.2818 126.7086 Tm (53)Tj 9.843 0 0 9.843 238.6204 122.3433 Tm [(Since)-399.5(MSNs)-403.2(in)]TJ -17.9415 -1.1116 TD [(the)-402(bDMEP)-400(group)-397.1(loade)-8(d)-398.5(more)-398.4(TGF-)]TJ /F6 1 Tf 15.7874 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1)-398.5(than)-403.1(those)-398.3(in)-399.7(the)]TJ -16.3403 -1.1174 TD [(nDMEP)-319.3(group,)-314.2(MSN-bDMEP)-313.8(should)-317.6(release)-317.5(more)-317.8(TGF-)]TJ /F6 1 Tf 23.2404 0 TD (b)Tj /F5 1 Tf .5529 0 TD (1)Tj -23.7933 -1.1116 TD [(than)-287.9(MSN-nDMEP,)-288.5(but)-285.7(with)-287.8(similar)-286.7(release)-288.7(curves)-285.2(with)-287.8(the)]TJ T* [(model)-336.3(protein)-331.6(Cyto-C.)]TJ 1.0137 -1.1116 TD [(It)-278.8(was)-287.4(reported)-281.9(that)-282.3(MSNs)-282.3(possessed)-282.2(low)-286.5(toxicity)]TJ /F9 1 Tf 20.3202 0 TD [(in)-278.8(vitro)]TJ /F5 1 Tf -21.334 -1.1174 TD [(against)-396(the)-396.3(various)-394.7(cell)-398.6(lines.)]TJ 7.3823 0 0 6.5614 182.1543 60.9449 Tm (54)Tj 9.843 0 0 9.843 193.4362 56.5795 Tm [(The)-391.6(major)-399.7(toxicity)-396.4(associ-)]TJ 12.153 25.6076 TD [(ated)-559.8(with)-558.5(silica)-556.3(is)-555.1(due)-557.4(to)-555.3(its)-556.3(surface)-558.1(chem)-8(istry)-552.7(\(silanol)]TJ 0 -1.1116 TD [(groups\),)-293.1(which)-295.7(can)-287.9(interact)-294.9(with)-293.5(the)-286.8(membrane)-297(components)]TJ T* [(leading)-390.4(to)-382.5(the)-384.7(lysis)-385.5(of)-382.3(cells)-382.3(and)-384.6(the)-384.7(consequent)-388.8(leaking)-384.7(of)]TJ 0 -1.1174 TD [(the)-586.3(cellular)-588.6(components.)]TJ 7.3823 0 0 6.5614 416.5794 280.1196 Tm (55)Tj 9.843 0 0 9.843 429.7322 275.7543 Tm [(Mesoporous)-588.6(silica)-585.1(exhibits)-586.1(a)]TJ -11.8535 -1.1116 TD [(lower)-278.3(toxicity)-269.7(compared)-272.7(with)-276.2(nonporous)-268.9(silica)-274.1(that)-270.8(could)-271.7(be)]TJ T* [(attributed)-330.6(to)-324.9(the)-321.4(lower)-330.2(density)-325.7(of)-324.7(silanol)-325.9(groups)-323.2(on)-324.7(the)-321.4(sur-)]TJ 0 -1.1174 TD [(face)-388(of)-388.1(these)-382.1(structures.)]TJ 7.3823 0 0 6.5614 410.2298 247.2944 Tm (56)Tj 9.843 0 0 9.843 421.3983 242.8724 Tm [(In)-388.1(our)-383.4(cell)-381.4(viability)-391.9(experiment,)]TJ -11.0068 -1.1116 TD [(MSNs)-368.7(at)-360.6(concentration)-370.7(of)-365(0.1,)-360.4(0.5,)-366.2(and)-361.6(1)-168.1(mg/mL)-366.4(exhibited)]TJ T* [(decre)-9(asing)-329.1(cytotoxic)-329.4(activity)-334.2(at)-326(day)-332.8(14.)-328.2(The)-328.2(reason)-331.3(may)-328.2(be)]TJ 0 -1.1174 TD [(that)-362.9(MSNs)-362.9(degraded)-363.6(gradually)-363.8(and)-361.6(the)-355.9(volume)-366.2(of)-359.3(the)-361.7(pore)]TJ 0 -1.1116 TD [(spaces)-470.5(increased,)-467.2(which)-462.7(may)-460.7(lead)-467.6(to)-463.1(the)-459.6(reduced)-466.2(surface)]TJ T* [(silano)-7.8(l)-329.5(density)-337.2(and)-332.8(overall)-338.6(cell-accessible)-341.5(surface.)]TJ 1.0137 -1.1116 TD [(The)-587.4(present)-585.9(study)-581.4(showed)-584.4(that)-587.6(MSN-bDMEP)-584.5(signi-)]TJ -1.0137 -1.1174 TD [(cantly)-302.9(promoted)-305(the)-304.1(proliferation)-305(of)-295.9(rBMMSCs,)-308.4(the)-298.3(expres-)]TJ 0 -1.1116 TD [(sion)-557.3(of)-555.1(chondrogenesis-related)-561(genes,)-558.2(and)-551.6(the)-557.5(formation)]TJ T* [(of)-330.5(cartilage-l)-11.5(ike)-327.1(matrix.)-335.2(These)-331.4(results)-331.2(suggested)-334.5(that)-334.1(MSN-)]TJ 0 -1.1174 TD [(DMEP)-341.3(could)-340.9(slowly)-341.6(release)-346.3(chondrogenesis-related)-347.9(growth)]TJ 0 -1.1116 TD [(factors)-246.1(that)-242(were)-238(maintained)-246.5(at)-239.6(effective)-245.1(concentrations)-244.9(for)-239.4(a)]TJ T* [(long)-396.2(time.)-402.1(MSN-bDMEP)-394.5(had)-401.9(a)-393.9(better)-400.8(chondrogenic)-397(effect)]TJ 0 -1.1174 TD [(than)-460.7(nDMEP.)-461(This)-454.8(may)-460.7(be)-458.4(associated)-459(with)-460.5(the)-459.6(increased)]TJ 0 -1.1116 TD [(concentrations)-630.8(of)-624.2(TGF-)]TJ /F6 1 Tf 10.1544 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1,)-620.8(bFGF,)-624.7(and)-620.8(IGF-1)-622.4(in)-624.4(MSN-)]TJ -10.7073 -1.1116 TD (bDMEP.)Tj 1.0137 -1.1116 TD [(In)-411.1(this)-413.4(study,)-412.1(the)-413.5(use)-413.2(of)-411.1(MSN-bDMEP)-411.7(effectively)-420.3(low-)]TJ -1.0137 -1.1174 TD [(ered)-432.9(the)-430.8(dose)-431.6(and)-430.7(frequency)-433.8(requirement)-431.7(of)-434.1(TGF-)]TJ /F6 1 Tf 21.1669 0 TD (b)Tj /F5 1 Tf .5529 0 TD [(1.)-430.7(We)]TJ ET q 420.92 0 0 354.784 96.775 377.461 cm /Im10 Do Q BT /F7 1 Tf 9.845 0 0 9.845 62.022 360.6802 Tm [(FIG.)-359.8(9.)]TJ /F9 1 Tf 4.1404 0 TD [(In)-359(vivo)]TJ /F5 1 Tf 3.2248 0 TD [(effects)-361.7(of)-359(MSN-bDMEP)-364.3(on)-359(cartilage)-359.6(regeneration)-362.4(in)-359.2(a)-359.2(rabbit)-358.7(osteochondral)-362.1(defect)-366.7(model)-358.7(at)-360.4(12)-353.3(weeks.)]TJ /F7 1 Tf -7.3652 -1.0077 TD (\(A1A8\))Tj /F5 1 Tf 3.8928 0 TD [(HE)-291.9(staining.)]TJ /F7 1 Tf 5.3382 0 TD (\(B1B8\))Tj /F5 1 Tf 3.7891 0 TD [(Alcian)-291.6(blue)-293.2(staining.)]TJ /F7 1 Tf 8.7012 0 TD (\(C1C8\))Tj /F5 1 Tf 3.8928 0 TD [(Safranin)-292.4(O-fast)-290.1(green)-289.5(staining.)-295(Areas)-290.1(indicated)-289.4(in)]TJ /F9 1 Tf 20.3737 0 TD (boxes)Tj /F5 1 Tf 2.5741 0 TD (are)Tj -48.5618 -1.0135 TD [(magnied)-310.9(below)-306.6(the)-309.5(respective)-308.4(images.)]TJ /F9 1 Tf 16.3888 0 TD [(Yellow)-307.7(arrows)]TJ /F5 1 Tf 6.1674 0 TD [(indicate)-305.6(the)-309.5(junction)-309.1(of)-307.2(defect)-309.1(area)-312.7(and)-303.6(normal)-313.7(cartilage.)-311.2(DZ,)-306.8(deep)]TJ -22.5562 -1.0135 TD [(zone;)-335.7(HE,)-335.6(hematoxylin)-337.4(and)-332.4(eosin;)-335.5(MZ,)-335.6(middle)-331.1(zone;)-335.7(SZ,)-334.6(supercial)-335.9(zone.)-337.9(Color)-334.4(images)-331.9(are)-339.3(available)-336.6(online.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (814)Tj 48.7749 0 TD [(MAO)-329.9(ET)-338.7(AL.)]TJ ET endstream endobj 82 0 obj <>stream Adobed       m  s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?N*S6*ثb͊6*ثb͊6*ثb͊6*ثco6m״ eAvYI\]APPͳG>P<2IJ`kĒ&D&Q̇>U b/ SO +MˮDYfdGFu6#H0~^>{~i;9,J_JXBe@pJ1Σ+]eKhAZgovKVR7/"{'CȥK7‹Qpw_'Y]G:ǡNVV{T,h9Mq[y<|hJ z{⻡`_%jZzW:^oleӣ3,"7,ޙb)Z$x1ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثbڞaoejY~⤢'Q;]/M{kxYIi}nu84 "+xB-]]]N>L4ljy0ٵmԑdӬnaxGHeN]}aojnYr8䦇 I5 :=;I^ #bl">eyNEАzRJUzdr˗][-춖\\%"Y_Z#ÔL9HSi:ƗX]Gyg/ؚ&䦝Gm"ִ=cCԥ5{9lo Ko:q]ߨ#pFblUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWg2xA}sdR=:E۝ڪ;d5zߘ5Q~K\6^,5{!ugkfif.$I$}*1+TK[[yLu4H˟f k{Y!#E ۰S_'?.,k62M`` ,%5bh, 58&LCzH쟼cQ@ omF'hm:*6X@-T҇z28I5K_y.#B 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[(growth)-243.7(factors)-240.3(is)-232.5(important)-243.1(for)-239.4(their)-237.3(biological)-238.5(effects.)-244.9(In)-232.6(the)]TJ /F9 1 Tf 0 -1.1116 TD [(in)-474.6(vivo)]TJ /F5 1 Tf 3.404 0 TD [(study,)-475.4(we)-470.8(used)-471.9(MSNs)-478.1(with)-472.1(fully)-472.3(loaded)-475.6(bDMEP)]TJ -3.404 -1.1116 TD [(\()-87.5(MSN-bDMEP\))-366.7(and)-367.3(the)-361.7(maximum)-369.8(concentration)-370.7(of)-365(MSNs)]TJ 0 -1.1174 TD [(that)-650.9(did)-648.5(not)-648.5(affect)-655.2(collagen)-651.9(gelation.)-648.5(Accordingly,)-652.6(the)]TJ 0 -1.1116 TD [(amount)-331.7(of)-324.7(TGF-)]TJ /F6 1 Tf 6.7158 0 TD (b)Tj /F5 1 Tf .8755 0 TD [(in)-324.9(60)]TJ /F6 1 Tf 2.2751 0 TD (m)Tj /F5 1 Tf .5529 0 TD [(L)-324.8(o)0(f)-324.7(collagen)-329.3(I)-323.6(with)-328.1(10)-163.5(mg/mL)-326.1(of)]TJ -10.4193 -1.1116 TD [(MSN-bDMEP)-429(is)]TJ /F6 1 Tf 7.2687 0 TD (*)Tj /F5 1 Tf 1.0022 0 TD [(10)-169.2(ng)-416.9(and)-424.9(the)-419.3(concentration)-428.3(of)-422.6(TGF-)]TJ /F6 1 Tf 15.4706 0 TD (b)Tj /F5 1 Tf -23.7415 -1.1174 TD [(in)-422.8(C)]TJ /F11 1 Tf 1.8661 0 TD (+)Tj /F5 1 Tf .5529 0 TD (S)Tj /F11 1 Tf .5529 0 TD (+)Tj /F5 1 Tf .5529 0 TD [(D)-416.7(was)-419.8(about)-421.5(160)-164.6(ng/mL,)-420.4(which)-422.4(was)-419.8(the)-419.3(effective)]TJ -3.5249 -1.1116 TD [(concentration)-485.9(to)-474.6(induce)-475.6(cartilage)-481.5(regeneration)]TJ /F9 1 Tf 19.8019 0 TD [(in)-474.6(vivo)]TJ /F5 1 Tf 2.9317 0 TD .4757 Tc [(.I)475.7(n)]TJ -22.7336 -1.1116 TD 0 Tc [(pr)15.1(ev)13.9(io)15(us)-146(st)15.1(ud)15.1(ie)13.8(s,)-142.6(TG)13(F-)]TJ /F6 1 Tf 8.8642 0 TD (b)Tj /F5 1 Tf .5414 0 TD [(1)-150.8(a)0(t)-147.5(a)-152(co)13.9(nc)13.9(en)13.9(tr)15(at)13.8(io)15(n)-150.8(o)0(f)-146.2(2)0(0)20.8()0(2)15.1(0)0(0)15.1(0)-162.4(ng)20.8(/m)13.7(L)]TJ -9.4056 -1.1116 TD [(was)-345(utilized)]TJ /F9 1 Tf 5.2644 0 TD [(in)-342.1(vivo)]TJ /F5 1 Tf 3.1448 0 TD [(and)-344.3(obtained)-345.5(favorable)-347.5(cartilage)-349(repair)]TJ -8.4092 -1.1174 TD (effects.)Tj 7.3823 0 0 6.5614 88.611 313.0582 Tm (6265)Tj 9.843 0 0 9.843 69.7323 297.7511 Tm [(The)-431.9(result)-439.8(showed)-434.7(that)-432(MSN-bDMEP)-434.8(could)-438.8(induce)-429.5(the)]TJ -1.0137 -1.1116 TD [(formation)-582.7(of)-583.9(cartilage-like)-586.3(structure)-582.4(in)-578.3(rabbit)-584(knee-joint)]TJ 0 -1.1174 TD [(articular)-324.7(cartilage)-325.9(defect,)-324.7(indicating)-319.1(that)-322.6(MSN-bDMEP)-319.6(was)]TJ 0 -1.1116 TD [(able)-421.6(to)-417(promote)-419.1(cartilage)-423.9(regeneration)]TJ /F9 1 Tf 16.3864 0 TD [(in)-417(situ)]TJ /F5 1 Tf 2.6437 0 TD [(.)-418.1(The)-420.4(results)]TJ -19.0301 -1.1116 TD [(of)-370.8(the)]TJ /F9 1 Tf 2.7992 0 TD [(in)-370.9(vivo)]TJ /F5 1 Tf 3.1966 0 TD [(study)-368.3(could)-363.9(be)-372(corroborated)-373.8(with)-368.4(the)-367.5(results)]TJ -5.9959 -1.1174 TD (of)Tj /F9 1 Tf 1.1692 0 TD [(in)-330.6(vitro)]TJ /F5 1 Tf 3.3406 0 TD [(cytology)-338.5(experiments.)]TJ -3.4961 -1.1116 TD [(In)-238.3(this)-240.6(study,)-239.3(we)-240.4(found)-241.6(that)-242(the)-240.7(hypertrophy)-243.7(marker)]TJ /F9 1 Tf 20.8329 0 TD (Col10)Tj /F5 1 Tf -21.8466 -1.1116 TD [(was)-419.8(highly)-421.6(expressed)-421.9(in)-417(the)-419.3(MSN-bDMEP)-423.3(group.)-417.9(Further)]TJ 0 -1.1174 TD [(research)-387.6(on)-382.3(the)-384.7(optimal)-384.9(concentration)-388(of)-382.3(DMEP)-387.4(is)-382.3(needed)]TJ 0 -1.1116 TD [(in)-342.1(subsequent)-341.4(studies.)-346.2(Simultaneously,)-345.1(modifying)-339.7(MSNs)-339.9(to)]TJ T* [(obtain)-313.3(relatively)-314.5(stable)-314.3(degradation)-309.6(and)-315.5(release)-311.8(rates)-313(is)-313.2(par-)]TJ T* [(ticularly)-375.6(important)-375.5(to)-376.7(enhance)-375.2(the)-373.2(production)-375.3(of)-370.8(the)-373.2(extra-)]TJ 0 -1.1174 TD [(cellular)-341(matrix)-331.8(of)-336.2(cartilage)-337.5(and)-332.8(inhibit)-336.5(hypertrophy.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 59.7543 138.7842 Tm (Conclusion)Tj /F5 1 Tf 9.843 0 0 9.843 69.7323 122.3433 Tm [(DMEP)-289.4(is)-290.1(a)-296(mixture)-286.8(of)-290.1(a)-290.2(variety)-292.5(of)-290.2(proteins.)-295.7(In)-290.1(this)-286.7(study,)]TJ -1.0137 -1.1174 TD [(we)-257.7(improved)-259(the)-258(extraction)-256.8(of)-255.6(DMEP)-254.9(by)-255.6(basic)-261.2(conditioning,)]TJ 0 -1.1116 TD [(which)-399.3(increased)-400.4(the)-396.3(content)-402(and)-396.1(activity)-397.6(of)-393.8(chondrogenic-)]TJ T* [(related)-305.2(growth)-301.3(factors)-303.6(compared)-301.5(with)-299.3(the)-298.3(traditional)-303(neutral)]TJ 0 -1.1174 TD [(solution)-377.6(extraction)-383.5(method.)-375.4(Then,)-378.8(our)-377.7(designed)-379.7(MSN)-379.3(with)]TJ 0 -1.1116 TD [(suitable)-391.5(physicochemical)-392.4(characteristics)-392.2(can)-385.8(load)-385.8(and)-390.4(con-)]TJ T* [(trol)-453.9(the)-453.8(release)-455.8(of)-457.2(chondrogenic-related)-455.5(growth)-456.8(factors)-453.4(in)]TJ 25.5097 67.9242 TD -.0159 Tc [(DMEP)-15.9(,)-296.7(t)-15.9(h)10.6(ereb)-15.9(y)-300.3(pro)-15.9(m)9.5(o).3(tin)-15.9(g)-300.3(t).2(he)-317.7(chond)-15.9(r)10.7(oge)-15.9(n)9.5(e)-.9(si)-15.9(s)-300.3(o).3(f)-310.7(r)-15.9(B)9.7(MMSC)-15.9(s)9.9(.)]TJ 0 -1.1174 TD 0 Tc [(MSNs)-242(loaded)-239.5(with)-241.7(DMEP)-243.4(have)-242.9(the)-240.7(potential)-243.2(to)-244.2(be)-239.5(applied)-246.4(to)]TJ 0 -1.1116 TD [(cartilage)-469.9(regeneration)-473.1(as)-463.9(an)-464.1(alternative)-472.3(to)-468.9(expensive)-468.4(syn-)]TJ T* [(thetic)-331.9(growth)-335.9(factors.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 310.8472 668.636 Tm (Acknowledgments)Tj /F5 1 Tf 9.843 0 0 9.843 320.8251 652.1951 Tm [(The)-339.7(authors)-342.8(thank)-340.9(the)-338.7(National)-346.5(Natural)-345.2(Science)-340.6(Founda-)]TJ -1.0137 -1.1174 TD [(tion)-350.2(of)-353.5(China)-353.4(\(81700953,)-353.1(81870753,)-352.1(and)-355.8(81901054\),)-353.2(Open)]TJ 0 -1.1116 TD [(Funding)-727.6(of)-727.9(Guangdong)-731.9(Provincial)-733.5(Key)-731.1(Laboratory)-734.6(of)]TJ T* [(Stomatology)-527.4(\(KF2021120104\),)-526.4(and)-522.8(the)-528.7(China)-526.2(Postdocto-)]TJ 0 -1.1174 TD [(ral)-546(Science)-542.2(Foundation)-547.9(\(2019M660010\))-545.1(for)-544.6(funding)-543.5(this)]TJ 0 -1.1116 TD (research.)Tj /F8 1 Tf 8.9663 0 0 8.9663 310.8472 573.7321 Tm [(Authors)-334(Contributions)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 557.2912 Tm [(S.M.:)-834.7(Conceptualizati)-12.5(on,)-835(methodology,)-841.9(investigation,)]TJ -1.0137 -1.1116 TD [(visualization,)-419.1(writingoriginal)-418.9(draft,)-419.1(and)-419.2(writingreview)]TJ 0 -1.1174 TD [(and)-257.9(editing.)-266.1(S.W.:)-260.1(Conceptualization,)-265.8(methodology,)-260.1(funding)]TJ 0 -1.1116 TD [(acquisition,)-404.1(and)-401.9(writingreview)-407(and)-401.9(editing.)-398.6(Y.N.:)-403.7(Meth-)]TJ T* [(odology)-364.9(and)-367.3(resources.)-367.7(J.W.:)-369.5(Investigation.)-371.7(P.J.:)-367(Investiga-)]TJ 0 -1.1174 TD [(tion.)-267.3(J.Z.:)-264.7(Funding)-266.9(acquisition.)-265.9(Y.D.:)-271.2(Project)-263.5(administration,)]TJ 0 -1.1116 TD [(supervision,)-431.3(funding)-422.5(acquisition,)-432.9(and)-424.9(writingreview)-435.8(and)]TJ T* (editing.)Tj /F8 1 Tf 8.9663 0 0 8.9663 310.8472 456.9448 Tm [(Disclosure)-336.7(Statement)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 440.5038 Tm [(No)-331.4(competing)-336.3(nancial)-334.9(interests)-340.5(exist.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 310.8472 416.8062 Tm [(Funding)-334.6(Information)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 400.3652 Tm [(This)-264.7(work)-264.4(was)-270.1(supported)-264.4(by)-267.1(the)-263.8(National)-271.6(Natural)-270.3(Science)]TJ -1.0137 -1.1116 TD [(Foundation)-271.5(of)-272.9(China)-272.8(\(81700953,)-278.3(81870753,)-271.5(and)-269.4(81901054\),)]TJ T* [(Open)-317.5(Funding)-313(of)-318.9(Guangdong)-317.2(Provincial)-318.8(Key)-316.4(Laboratory)-319.9(of)]TJ T* [(Stomatology)-377.6(\(KF20211201)-7(04\),)-375.3(and)-378.8(the)-379(China)-382.2(Postdoctoral)]TJ 0 -1.1174 TD [(Science)-334.9(Foundation)-334.8(\(2019M660010\).)]TJ /F8 1 Tf 8.9663 0 0 8.9663 310.8472 332.9007 Tm [(Supplementary)-335.6(Material)]TJ /F5 1 Tf 9.843 0 0 9.843 320.8251 316.4597 Tm [(Supplementary)-335.9(Data)]TJ 0 -1.1116 TD [(Supplementary)-335.9(Table)-337.5(S1)]TJ /F8 1 Tf 8.9663 0 0 8.9663 310.8472 281.8204 Tm (References)Tj /F5 1 Tf 9.2951 0 0 9.2951 315.496 265.7763 Tm [(1.)-500.4(Correa,)-464(D.,)-459.3(and)-468.2(Lietman,)-461.2(S.A.)-462.4(Articular)-465.6(cartilage)-470.1(repair:)]TJ 1.2503 -1.1223 TD [(current)-281.9(needs,)-282.8(methods)-283.9(and)-279.1(research)-284(directions.)-284.1(Semin)-281.3(Cell)]TJ 0 -1.1284 TD [(Dev)-335.6(Biol)]TJ /F7 1 Tf 4.0621 0 TD (62,)Tj /F5 1 Tf 1.5797 0 TD [(67,)-335.8(2017.)]TJ -6.8921 -1.1223 TD [(2.)-500.4(Ge,)-408.7(Z.,)-404.7(Li,)-410.3(C.,)-407.6(Heng,)-409(B.C.,)-412.6(Cao,)-405.9(G.,)-410.5(and)-407.2(Yang,)-409(Z.)-410.8(Func-)]TJ 1.2503 -1.1284 TD [(tional)-540.1(biomaterials)-543.7(for)-541.8(cartilage)-549.4(regeneration.)-546.7(J)-536(Biomed)]TJ 0 -1.1223 TD [(Mater)-333.4(Res)-337.9(A)]TJ /F7 1 Tf 5.6113 0 TD (100,)Tj /F5 1 Tf 2.0859 0 TD [(2526,)-330(2012.)]TJ -8.9476 -1.1284 TD [(3.)-500.4(Fortier,)-408.1(L.A.,)-406.5(Barker,)-409.1(J.U.,)-409.8(Strauss,)-410.7(E.J.,)-404.1(McCarrel,)-412.3(T.M.,)]TJ 1.2503 -1.1223 TD [(and)-242.5(Cole,)-253(B.J.)-248.3(The)-244.4(role)-250.5(of)-246.6(growth)-248.2(factors)-244.4(in)-249.8(cartilage)-250.5(repair.)]TJ 0 -1.1284 TD [(Clin)-333.6(Orthop)-333.5(Relat)-336(Res)]TJ /F7 1 Tf 9.5209 0 TD (469,)Tj /F5 1 Tf 2.0798 0 TD [(2706,)-336.1(2011.)]TJ -12.8511 -1.1284 TD [(4.)-500.4(Shi,)-332.2(S.,)-332.5(Mercer,)-334.6(S.,)-332.5(Eckert,)-330.2(G.J.,)-336.7(and)-327.9(Trippel,)-337.7(S.B.)-331.4(Growth)]TJ 1.2503 -1.1223 TD [(factor)-489.1(regulation)-492.3(of)-484.4(growth)-486(factors)-494.4(in)-487.6(articular)-492.6(chondro-)]TJ 0 -1.1284 TD [(cytes.)-331(J)-334.7(Biol)-333.6(Chem)]TJ /F7 1 Tf 8.1547 0 TD (284,)Tj /F5 1 Tf 2.0798 0 TD [(6697,)-336.1(2009.)]TJ -11.4849 -1.1223 TD [(5.)-500.4(Muramatsu,)-540.1(T.,)-532.8(Hamano,)-541.1(H.,)-532.5(Fukumashi,)-537.2(K.,)]TJ /F9 1 Tf 21.1704 0 TD [(et)-540.6(al.)]TJ /F5 1 Tf 2.83 0 TD (An)Tj -22.7501 -1.1284 TD [(experimental)-598.2(study)-597(of)-600.3(chondrogenesis)-600.2(and)-596.3(osteogenesis)]TJ 0 -1.1223 TD [(in)-780.4(rat)-781(submandibular)-784.8(gland)-779(induced)-783.5(by)-781(implantation)]TJ 0 -1.1284 TD [(of)-521(demineralized)-523.2(dentin.)-522.4(Bull)-522.6(Tokyo)-521.1(Dent)-518.1(Coll)]TJ /F7 1 Tf 20.9509 0 TD (34,)Tj /F5 1 Tf 1.7688 0 TD (15,)Tj -22.7197 -1.1223 TD (1993.)Tj -1.2503 -1.1284 TD [(6.)-500.4(Yagihashi,)-521.7(K.,)-520.3(Miyazawa,)-524.6(K.,)-514.2(Togari,)-521.1(K.,)-520.3(and)-523.1(Goto,)-520.1(S.)]TJ 1.2503 -1.1223 TD [(Demineralized)-421.1(dentin)-418.7(matrix)-420.6(acts)-422.3(as)-418.4(a)-413(scaffold)-421.4(for)-419.8(repair)]TJ 0 -1.1284 TD [(of)-502.7(articular)-510.9(cartilage)-506.7(defects.)-508.6(Calcif)-509.3(Tissue)-504.8(Int)]TJ /F7 1 Tf 20.469 0 TD (84,)Tj /F5 1 Tf 1.7505 0 TD (210,)Tj -22.2195 -1.1223 TD (2009.)Tj /F8 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(INDUCTION)-339.7(OF)-331.2(CARTILAGE)-343.2(REGENERATION)-332.9(BY)-335.8(MSN)-337.5(LOADED)-337.5(WITH)-329.6(DMEP)-16250.1(815)]TJ ET endstream endobj 89 0 obj <>stream /GS1 gs BT /F5 1 Tf 9.2951 0 0 9.2951 66.6708 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(7.)-500.4(Somerman,)-392.2(M.,)-389.9(Nathanson,)-388.1(M.,)-389.9(Sauk,)-392(J.,)-389.8(and)-388.9(Manson,)-387.8(B.)]TJ 1.2503 -1.1223 TD [(Human)-390.3(dentin)-394.3(matrix)-390.1(induces)-392.2(cartilage)-390.8(formation)-392.8(in)-390.1(vitro)]TJ 0 -1.1284 TD [(by)-543.1(mesenchymal)-552.8(cells)-543.8(derived)-547.9(from)-547.6(embryonic)-541.7(muscle.)]TJ 0 -1.1223 TD [(J)-334.7(Dent)-335.1(Res)]TJ /F7 1 Tf 4.8306 0 TD (66,)Tj /F5 1 Tf 1.5858 0 TD [(1551,)-336.1(1987.)]TJ -7.6667 -1.1283 TD [(8.)-500.4(Chun,)-420.2(S.Y.,)-425.8(Lee,)-419.5(H.J.,)-422(Choi,)-425.7(Y.A.,)]TJ /F9 1 Tf 16.2179 0 TD [(et)-418.7(al.)]TJ /F5 1 Tf 2.5983 0 TD [(Analysis)-424.9(of)-423.5(the)]TJ -17.5658 -1.1223 TD [(soluble)-509.4(human)-510.7(tooth)-505.8(proteome)-511(and)-510.9(its)-510.7(ability)-509.2(to)-512(induce)]TJ 0 -1.1284 TD [(dentin/tooth)-259.2(regeneration.)-253.9(Tissue)-260.8(Eng)-252.4(Part)-259.5(A)]TJ /F7 1 Tf 18.2123 0 TD (17,)Tj /F5 1 Tf 1.5065 0 TD [(181,)-256.7(2011.)]TJ -20.9692 -1.1223 TD [(9.)-500.4(Park,)-498(E.-S.,)-501.8(Cho,)-499.3(H.-S.,)-501.5(Kwon,)-504(T.-G.,)]TJ /F9 1 Tf 17.9561 0 TD [(et)-498(al.)]TJ /F5 1 Tf 2.7569 0 TD (Proteomics)Tj -19.4627 -1.1284 TD [(analysis)-250.6(of)-252.7(human)-248.5(dentin)-254(reveals)-252.4(distinct)-252.3(protein)-250.4(expression)]TJ 0 -1.1223 TD [(proles.)-332.3(J)-334.7(Proteome)-337(Res)]TJ /F7 1 Tf 10.3138 0 TD (8,)Tj /F5 1 Tf 1.0796 0 TD [(1338,)-336.1(2009.)]TJ -13.1439 -1.1284 TD [(10.)-500.5(Finkelman,)-358.8(R.D.,)-360.6(Mohan,)-358(S.,)-350.8(Jennings,)-363(J.C.,)-358.2(Taylor,)-356.4(A.K.,)]TJ 1.7505 -1.1223 TD [(and)-510.9(Baylink,)-509.1(D.J.)-507.4(Quantitation)-515.1(of)-508.8(growth)-510.4(factors)-506.6(IGF-I,)]TJ 0 -1.1284 TD [(SGF/IGF-II,)-449(and)-449.9(TGF-)]TJ /F6 1 Tf 9.5209 0 TD (b)Tj /F5 1 Tf 1.0003 0 TD [(in)-445(human)-449.7(dentin.)-449.2(J)-444.5(Bone)-448.7(Miner)]TJ -10.5212 -1.1284 TD (Res)Tj /F7 1 Tf 1.8359 0 TD (5,)Tj /F5 1 Tf 1.0796 0 TD [(717,)-336(2009.)]TJ -4.6659 -1.1223 TD [(11.)-500.5(Ja)]TJ 2.2018 .0427 TD ()Tj .3843 -.0427 TD [(gr,)-374.7(M.,)-371.6(Eckhardt,)-379.2(A.,)-373.9(Pataridis,)-378.4(S.,)-375.2(and)-376.7(Miks)]TJ 18.1391 .0427 TD ()Tj .3538 -.0427 TD ()Tj -.0183 .0427 TD ()Tj .2989 -.0427 TD [(k,)-378.4(I.)-374.6(Com-)]TJ -19.609 -1.1284 TD [(prehensive)-301.6(proteomic)-303.2(analysis)-299.4(of)-301.5(human)-297.3(dentin.)-302.9(Eur)-297.4(J)-304.2(Oral)]TJ 0 -1.1223 TD (Sci)Tj /F7 1 Tf 1.6163 0 TD (120,)Tj /F5 1 Tf 2.0798 0 TD [(259,)-336(2012.)]TJ -5.4466 -1.1284 TD [(12.)-500.5(Roberts-Clark,)-500.6(D.J.,)-501.3(and)-498.7(Smith,)-496.2(A.J.)-501.3(Angiogenic)-498.2(growth)]TJ 1.7505 -1.1223 TD [(factors)-323.7(in)-323(human)-321.7(dentine)-325.4(matrix.)-323.1(Arch)-319.7(Oral)-325.3(Biol)]TJ /F7 1 Tf 20.1519 0 TD (45,)Tj /F5 1 Tf 1.5736 0 TD (1013,)Tj -21.7255 -1.1284 TD (2000.)Tj -1.7505 -1.1223 TD [(13.)-500.5(Bessho,)-441.2(K.,)-441(Tanaka,)-436.3(N.,)-441(Matsumoto,)-441.5(J.,)-438.5(Tagawa,)-444(T.,)-435.2(and)]TJ 1.7505 -1.1284 TD [(Murata,)-510.5(M.)-505.7(Human)-512.3(dentin-matrix-derived)-513.8(bone)-504.9(morpho-)]TJ 0 -1.1223 TD [(genetic)-335.7(protein.)-335.8(J)-334.7(Dent)-335.1(Res)]TJ /F7 1 Tf 11.4971 0 TD (70,)Tj /F5 1 Tf 1.5858 0 TD [(171,)-336(1990.)]TJ -14.8333 -1.1284 TD [(14.)-500.5(Bessho,)-483.9(K.,)-477.6(Tagawa,)-486.7(T.,)-477.9(and)-480.4(Murata,)-486.1(M.)-475.2(Purication)-486(of)]TJ 1.7505 -1.1223 TD [(rabbit)-610.1(bone)-614.7(morphogenetic)-613(protein)-610.2(derived)-615(from)-608.6(bone,)]TJ 0 -1.1284 TD [(dentin,)-552.9(and)-553.6(wound)-557.3(tissue)-551.1(after)-556(tooth)-554.6(extraction.)-557.6(J)-554.3(Oral)]TJ 0 -1.1223 TD [(Maxillofac)-337.2(Surg)]TJ /F7 1 Tf 6.9592 0 TD (48,)Tj /F5 1 Tf 1.5797 0 TD [(162,)-336(1990.)]TJ -10.2894 -1.1284 TD [(15.)-500.5(Frenz,)-441.4(D.A.,)-436.7(Liu,)-434.9(W.,)-437.7(Williams,)-445.3(J.D.,)]TJ /F9 1 Tf 17.9744 0 TD [(et)-437(al.)]TJ /F5 1 Tf 2.6349 0 TD [(Induction)-439.7(of)]TJ -18.8588 -1.1223 TD [(chondrogenesis:)-398.5(requirement)-395.4(for)-395.4(synergistic)-393.1(interaction)-398.5(of)]TJ 0 -1.1284 TD [(basic)-587.1(broblast)-582(growth)-583.6(factor)-586.7(and)-584.1(transforming)-583.8(growth)]TJ 0 -1.1223 TD [(factor-beta.)-335.4(Development)]TJ /F7 1 Tf 10.6737 0 TD (120,)Tj /F5 1 Tf 2.0859 0 TD [(415,)-336(1994.)]TJ -14.5101 -1.1284 TD [(16.)-500.5(Toh,)-307.4(W.S.,)-306.6(Liu,)-300.7(H.,)-306.8(Heng,)-305.3(B.C.,)]TJ /F9 1 Tf 15.059 0 TD [(et)-302.8(al.)]TJ /F5 1 Tf 2.3665 0 TD [(Combined)-308(effects)-309.6(of)]TJ -15.675 -1.1223 TD (TGF)Tj /F6 1 Tf 1.8847 0 TD (b)Tj /F5 1 Tf .555 0 TD [(1)-384.4(and)-388.9(BMP2)-391.8(in)-390.1(serum-free)-388(chondrogenic)-394.3(differenti-)]TJ -2.4397 -1.1284 TD [(ation)-650.3(of)-649.1(mesenchymal)-650.4(stem)-649.4(cells)-653.6(induced)-649.3(hyaline-like)]TJ 0 -1.1223 TD [(cartilage)-335.9(formation.)-338(Growth)-335.1(Factors)]TJ /F7 1 Tf 15.0102 0 TD (23,)Tj /F5 1 Tf 1.5797 0 TD [(313,)-336(2005.)]TJ -18.3404 -1.1284 TD [(17.)-500.5(Yaeger,)-273.6(P.C.,)-270.5(Masi,)-271(T.L.,)-272.7(de)-272.9(Ortiz,)-270(J.L.B.,)]TJ /F9 1 Tf 18.9137 0 TD [(et)-272.3(al.)]TJ /F5 1 Tf 2.2994 0 TD (Synergistic)Tj -19.4627 -1.1223 TD [(action)-575.4(of)-569.8(transforming)-571.6(growth)-571.4(factor-)]TJ /F6 1 Tf 16.2606 0 TD (b)Tj /F5 1 Tf 1.1223 0 TD [(and)-571.9(insulin-like)]TJ -17.3828 -1.1284 TD [(growth)-339.7(factor-I)-341.5(induces)-337.3(expression)-345.3(of)-338.1(type)-339.7(II)-334.3(collagen)-342(and)]TJ 0 -1.1223 TD [(aggrecan)-288.7(genes)-282.7(in)-286.4(adult)-284.3(human)-285.1(articular)-285.2(chondrocytes.)-289.8(Exp)]TJ 0 -1.1284 TD [(Cell)-337.8(Res)]TJ /F7 1 Tf 3.8425 0 TD (237,)Tj /F5 1 Tf 2.0859 0 TD [(318,)-329.9(1997.)]TJ -7.6789 -1.1223 TD [(18.)-500.5(Gao,)-268.6(S.,)-271.6(Wang,)-271.5(Y.,)-270.2(Diao,)-274.2(X.,)-270.2(Luo,)-270.8(G.,)-270.2(and)-266.9(Dai,)-274.1(Y.)-270.2(Effect)-271.4(of)]TJ 1.7505 -1.1284 TD [(pore)-391.4(diameter)-392.7(and)-395(cross-linking)-391.5(method)-394.4(on)-390.6(the)-388.3(immobili-)]TJ 0 -1.1223 TD [(zation)-551(efciency)-559.5(of)]TJ /F9 1 Tf 8.9049 0 TD [(Candida)-554.2(rugosa)]TJ /F5 1 Tf 7.3191 0 TD [(lipase)-556.2(in)-548.6(SBA-15.)]TJ -16.224 -1.1284 TD [(Bioresour)-336.7(Technol)]TJ /F7 1 Tf 7.9046 0 TD (101,)Tj /F5 1 Tf 2.0859 0 TD [(3830,)-330(2010.)]TJ -11.741 -1.1223 TD [(19.)-500.5(Young,)-282.9(S.,)-277.6(Wong,)-279.5(M.,)-280.1(Tabata,)-283.2(Y.,)-282.4(and)-279.1(Mikos,)-279.2(A.G.)-284.2(Gelatin)]TJ 1.7505 -1.1284 TD [(as)-302.5(a)-303.2(delivery)-303.5(vehicle)-305.2(for)-303.9(the)-302.9(controlled)-303.2(release)-305.4(of)-301.5(bioactive)]TJ T* [(molecules.)-334.8(J)-334.7(Control)-336.3(Release)]TJ /F7 1 Tf 12.229 0 TD (109,)Tj /F5 1 Tf 2.0798 0 TD [(256,)-336(2005.)]TJ -16.0593 -1.1223 TD [(20.)-500.5(Rabinow,)-310(B.E.)-312.1(Nanosuspensions)-319.1(in)-310.8(drug)-307.9(delivery.)-315.8(Nat)-310.6(Rev)]TJ 1.7505 -1.1284 TD [(Drug)-333.8(Discov)]TJ /F7 1 Tf 5.5503 0 TD (3,)Tj /F5 1 Tf 1.0857 0 TD [(785,)-329.9(2004.)]TJ -8.3864 -1.1223 TD [(21.)-500.5(Li,)-270(Z.,)-276.6(Barnes,)-271.7(J.C.,)-272.8(Bosoy,)-273.1(A.,)-270.2(Stoddart,)-271.8(J.F.,)-277(and)-273(Zink,)-270.3(J.I.)]TJ 9.2951 0 0 9.2951 78.2929 202.1102 Tm [(Mesoporous)-243.3(silica)-244.5(nanoparticles)-244.1(in)-243.7(biomedical)-243.7(applications.)]TJ T* [(Chem)-332.4(Soc)-336.9(Rev)]TJ /F7 1 Tf 6.5079 0 TD (41,)Tj /F5 1 Tf 1.5858 0 TD [(2590,)-330(2012.)]TJ -9.8442 -1.1284 TD [(22.)-500.5(Yamada,)-386.8(H.,)-380(Urata,)-384.6(C.,)-383.2(Aoyama,)-382.6(Y.,)]TJ /F9 1 Tf 17.3584 0 TD [(et)-388.2(al.)]TJ /F5 1 Tf 2.5251 0 TD [(Preparation)-386.6(of)]TJ -18.133 -1.1223 TD [(colloidal)-580.8(mesoporous)-585.2(silica)-580(nanoparticles)-585.7(with)-586.5(different)]TJ 0 -1.1284 TD [(diameters)-416.3(and)-413.3(their)-414.7(unique)-413.2(degradation)-417.9(behavior)-413.9(in)-414.5(static)]TJ 0 -1.1223 TD [(aqueous)-337.9(systems.)-331(Chem)-338.5(Mater)]TJ /F7 1 Tf 12.8206 0 TD (24,)Tj /F5 1 Tf 1.5858 0 TD [(1462,)-330(2012.)]TJ -16.1569 -1.1284 TD [(23.)-500.5(Miao,)-412.2(G.,)-404.4(Li,)-410.3(Z.,)-410.8(Meng,)-406.7(Y.,)]TJ /F9 1 Tf 13.8453 0 TD [(et)-406.5(al.)]TJ /F5 1 Tf 2.5739 0 TD [(Preparation,)-411(character-)]TJ -14.6687 -1.1223 TD [(ization,)-605.5(in)-609.6(vitro)-605.7(bioactivity)-604.9(and)-608.5(protein)-604.1(loading/release)]TJ 0 -1.1284 TD [(property)-351(of)-350.3(mesoporous)-353.4(bioactive)-353.8(glass)-350.2(microspheres)-357.8(with)]TJ 0 -1.1223 TD [(different)-564.5(compositions.)-563.2(Adv)-557(Powder)-560.8(Technol)]TJ /F7 1 Tf 19.914 0 TD (30,)Tj /F5 1 Tf 1.8115 0 TD (1848,)Tj -21.7255 -1.1284 TD (2019.)Tj -1.7505 -1.1223 TD [(24.)-500.5(Wu,)-559.7(Q.,)-556.9(Liu,)-563(C.,)-560.1(Fan,)-556.5(L.,)]TJ /F9 1 Tf 13.6928 0 TD [(et)-558.9(al.)]TJ /F5 1 Tf 2.8788 0 TD [(Heparinized)-564(magnetic)]TJ -14.8211 -1.1284 TD [(mesoporous)-359.5(silica)-366.5(nanoparticles)-360(as)-363.5(multifunctional)-362.8(growth)]TJ 0 -1.1223 TD [(factor)-287.8(delivery)-285.2(carriers.)-287.7(Nanotechnology)]TJ /F7 1 Tf 16.657 0 TD (23,)Tj /F5 1 Tf 1.5309 0 TD [(485703,)-287.6(2012.)]TJ 7.069 70.8975 TD [(25.)-500.5(Croissant,)-1016.1(J.G.,)-1013.7(Fatieiev,)-1021.4(Y.,)-1014.3(and)-1011(Khashab,)-1016.6(N.M.)]TJ 1.7505 -1.1223 TD [(Degradability)-369.9(and)-364.5(clearance)-363.8(of)-362.5(silicon,)-368.6(organosilica,)-361.8(silse-)]TJ 0 -1.1284 TD [(squioxane,)-697.6(silica)-689.8(mixed)-693.1(oxide,)-687.5(and)-693.9(mesoporous)-695(silica)]TJ 0 -1.1223 TD [(nanoparticles.)-366.2(Adv)-361.9(Mater)]TJ /F7 1 Tf 10.7956 0 TD (29,)Tj /F5 1 Tf 1.6102 0 TD [(2017)-360.4([Epub)-358.7(ahead)-361(of)-356.4(print];)]TJ -12.4058 -1.1283 TD (10.1002/adma.201604634.)Tj -1.7505 -1.1223 TD [(26.)-500.5(Lin,)-386.1(C.-Y.,)-387.5(Yang,)-384.6(C.-M.,)-385.2(and)-382.8(Linde)]TJ 16.2423 .0366 TD ()Tj .3843 -.0366 TD [(n,)-384.5(M.)-383.7(Dissolution)-389.5(and)]TJ -14.876 -1.1284 TD [(morphology)-429.7(evolution)-430.7(of)-429.6(mesoporous)-432.7(silica)-427.5(nanoparticles)]TJ 0 -1.1223 TD [(under)-379.3(biologically)-379.3(relevant)-380.9(conditions.)-375.2(J)-377.4(Colloid)-376.1(Interface)]TJ 0 -1.1284 TD (Sci)Tj /F7 1 Tf 1.6163 0 TD (608,)Tj /F5 1 Tf 2.0859 0 TD [(995,)-329.9(2022.)]TJ -5.4527 -1.1223 TD [(27.)-500.5(Lin,)-245.8(B.,)-242.9(Hu,)-239.8(H.,)-245.8(Deng,)-244.3(Z.,)]TJ /F9 1 Tf 12.2351 0 TD [(et)-241.8(al.)]TJ /F5 1 Tf 2.2445 0 TD [(Novel)-243.8(bioactive)-244(glass)-246.6(cross-)]TJ -12.7291 -1.1284 TD [(linked)-827.3(PVA)-823.8(hydrogel)-824.4(with)-818.3(enhanced)-829.2(chondrogenesis)]TJ 0 -1.1223 TD [(properties)-384.5(and)-382.8(application)-390.1(in)-377.9(mice)-386.1(chondrocytes)-387.3(for)-383.2(carti-)]TJ 0 -1.1284 TD [(lage)-337.8(repair.)-336.7(J)-334.7(Non-Cryst)-334.1(Solids)]TJ /F7 1 Tf 13.0463 0 TD (529,)Tj /F5 1 Tf 2.0798 0 TD [(119594,)-336.4(2020.)]TJ -16.8766 -1.1284 TD [(28.)-500.5(Ren,)-442.5(L.,)-441.3(Cong,)-438.5(N.,)-441(Han,)-439.3(H.,)]TJ /F9 1 Tf 14.138 0 TD [(et)-437(al.)]TJ /F5 1 Tf 2.6349 0 TD [(The)-439.6(effect)-444.5(of)-441.7(sodium)]TJ -15.0224 -1.1223 TD [(metasilicate)-530.9(on)-524.8(the)-528.6(three-dimensional)-526.6(chondrogenesis)-527(of)]TJ 0 -1.1284 TD [(mesenchymal)-339.4(stem)-338.3(cells.)-336.5(Dent)-335.1(Mater)-333.4(J)]TJ /F7 1 Tf 16.2423 0 TD (40,)Tj /F5 1 Tf 1.5797 0 TD [(853,)-336(2021.)]TJ -19.5724 -1.1223 TD [(29.)-500.5(Shen,)-538.4(D.,)-538.6(Yang,)-537.1(J.,)-536.1(Li,)-538.4(X.,)]TJ /F9 1 Tf 14.1075 0 TD [(et)-534.6(al.)]TJ /F5 1 Tf 2.8301 0 TD [(Biphase)-543.4(stratication)]TJ -15.1871 -1.1284 TD [(approach)-754.1(to)-756(three-dimensional)-758.3(dendritic)-754.4(biodegradable)]TJ 0 -1.1223 TD [(mesoporous)-335.1(silica)-336(nanospheres.)-338.1(Nano)-335.7(Lett)]TJ /F7 1 Tf 17.6146 0 TD (14,)Tj /F5 1 Tf 1.5858 0 TD [(923,)-329.9(2014.)]TJ -20.9509 -1.1284 TD [(30.)-500.5(Hulth,)-592.9(A.,)-581.3(Johnell,)-588.8(O.,)-587.4(Miyazono,)-587.8(K.,)]TJ /F9 1 Tf 18.9137 0 TD [(et)-589.4(al.)]TJ /F5 1 Tf 2.9337 0 TD [(Effect)-588.6(of)]TJ -20.097 -1.1223 TD [(transforming)-431.3(growth)-431.1(factor-)]TJ /F6 1 Tf 11.5458 0 TD (b)Tj /F5 1 Tf .982 0 TD [(and)-425.5(platelet-derived)-433.8(growth)]TJ -12.5278 -1.1284 TD [(factor-BB)-416(on)-408.9(articular)-419.4(cartilage)-415.2(in)-408.4(rats.)-414.4(J)-407.9(Orthop)-412.8(Res)]TJ /F7 1 Tf 22.7257 0 TD (14,)Tj /F5 1 Tf -22.7257 -1.1223 TD [(547,)-336(1996.)]TJ -1.7505 -1.1284 TD [(31.)-500.5(Schmidt,)-500.7(M.,)-493.6(Chen,)-497.6(E.,)-490.1(and)-498.7(Lynch,)-494.8(S.)-491.1(A)-495.8(review)-500.5(of)-490.6(the)]TJ 1.7505 -1.1223 TD [(effects)-474.3(of)-472.2(insulin-like)-474.2(growth)-467.7(factor)-470.8(and)-474.3(platelet)-468.9(derived)]TJ 0 -1.1284 TD [(growth)-601.9(factor)-598.9(on)-591.9(in)-597.4(vivo)-597.7(cartilage)-598.2(healing)-599.9(and)-596.3(repair.)]TJ 0 -1.1223 TD [(Osteoarthr)-337.3(Cartilage)]TJ /F7 1 Tf 8.5877 0 TD (14,)Tj /F5 1 Tf 1.5797 0 TD [(403,)-336(2006.)]TJ -11.9179 -1.1284 TD [(32.)-500.5(Johnstone,)-289.9(B.,)-285.6(Hering,)-289(T.M.,)-282.2(Caplan,)-288(A.I.,)-285(Goldberg,)-289.3(V.M.,)]TJ 1.7505 -1.1223 TD [(and)-474.3(Yoo,)-471.7(J.U.)-470.8(In)-472.2(vitro)-471.5(chondrogenesis)-472.1(of)-472.2(bone)-474.4(marrow-)]TJ 0 -1.1284 TD [(derived)-383.2(mesenchymal)-376(progenitor)-381.2(cells.)-379.2(Exp)-374.4(Cell)-380.5(Res)]TJ /F7 1 Tf 22.2256 0 TD (238,)Tj /F5 1 Tf -22.2256 -1.1223 TD [(265,)-336(1998.)]TJ -1.7505 -1.1284 TD [(33.)-500.5(Longobardi,)-491.2(L.,)-484(ORear,)-490(L.,)-484(Aakula,)-492.2(S.,)]TJ /F9 1 Tf 19.2187 0 TD [(et)-485.8(al.)]TJ /F5 1 Tf 2.7325 0 TD [(Effect)-484.9(of)]TJ -20.2007 -1.1223 TD [(IGF-I)-298.8(in)-292.5(the)-290.7(chondrogenesis)-295.2(of)-295.4(bone)-291.5(marrow)-297.5(mesenchymal)]TJ 0 -1.1284 TD [(stem)-356.6(cells)-354.8(in)-353.5(the)-351.7(presence)-361(or)-350.3(absence)-358.5(of)-350.3(TGF-)]TJ /F6 1 Tf 19.1455 0 TD (b)Tj /F5 1 Tf .9027 0 TD (signaling.)Tj -20.0482 -1.1223 TD [(J)-334.7(Bone)-338.9(Miner)-335.3(Res)]TJ /F7 1 Tf 7.7826 0 TD (21,)Tj /F5 1 Tf 1.5858 0 TD [(626,)-329.9(2006.)]TJ -11.1189 -1.1284 TD [(34.)-500.5(Solchaga,)-607.8(L.A.,)-595.6(Penick,)-603.3(K.,)-599.6(Porter,)-603.7(J.D.,)]TJ /F9 1 Tf 20.1092 0 TD [(et)-601.6(al.)]TJ /F5 1 Tf 2.9642 0 TD (FGF-2)Tj -21.3229 -1.1223 TD [(enhances)-267.2(the)-266.3(mitotic)-264.8(and)-260.8(chondrogenic)-266.2(potentials)-268.9(of)-264.9(human)]TJ 0 -1.1284 TD [(adult)-284.3(bone)-285.4(marrow-derived)-292.9(mesenchymal)-284.5(stem)-289.6(cells.)-281.6(J)-285.9(Cell)]TJ 0 -1.1223 TD (Physiol)Tj /F7 1 Tf 3.3363 0 TD (203,)Tj /F5 1 Tf 9.2951 0 0 9.2951 379.6723 327.6849 Tm [(398,)-336(2005.)]TJ -7.1666 -1.1284 TD [(35.)-500.5(Majumdar,)-614.1(M.K.,)-605.2(Wang,)-606.9(E.,)-606(and)-608.5(Morris,)-607.2(E.A.)-607.7(BMP-2)]TJ 1.7505 -1.1223 TD [(and)-767(BMP-9)-766.3(promotes)-762.1(chondrogenic)-766.3(differentiation)-769.1(of)]TJ 0 -1.1284 TD [(human)-492.4(multipotential)-493.9(mesenchymal)-491.9(cells)-488.9(and)-492.6(overcomes)]TJ 0 -1.1223 TD [(the)-284.6(inhibitory)-282(effect)-285.9(of)-283.2(IL-1.)-281.6(J)-285.9(Cell)-282.9(Physiol)]TJ /F7 1 Tf 17.6634 0 TD (189,)Tj /F5 1 Tf 2.031 0 TD [(275,)-281.1(2001.)]TJ -21.4449 -1.1284 TD [(36.)-500.5(An,)-325.2(C.,)-328.3(Cheng,)-327(Y.,)-325.1(Yuan,)-323.6(Q.,)-325.1(and)-327.9(Li,)-324.9(J.)-322.6(IGF-1)-327(and)-321.8(BMP-2)]TJ 1.7505 -1.1223 TD [(induces)-605.7(differentiation)-604.4(of)-600.3(adipose-derived)-607.1(mesenchymal)]TJ 0 -1.1284 TD [(stem)-417.6(cells)-409.7(into)-414.2(chondrocytes-like)-417.8(cells.)-415.8(Ann)-410.7(Biomed)-411.4(Eng)]TJ /F7 1 Tf T* (38,)Tj /F5 1 Tf 1.5858 0 TD [(1647,)-336.1(2010.)]TJ -3.3363 -1.1223 TD [(37.)-500.5(Tabatabaei,)-1322.4(F.S.,)-1311.5(Tatari,)-1311.6(S.,)-1314.5(Samadi,)-1310.4(R.,)-1316.4(and)]TJ 1.7505 -1.1284 TD [(Moharamzadeh,)-310.7(K.)-306.8(Different)-303.8(methods)-308.3(of)-301.5(dentin)-302.8(processing)]TJ 0 -1.1223 TD [(for)-517.4(application)-524.3(in)-518.1(bone)-517.1(tissue)-520.6(engineering:)-521.2(a)-516.7(systematic)]TJ 0 -1.1284 TD [(review.)-335.9(J)-334.7(Biomed)-338.2(Mater)-333.4(Res)-337.9(A)]TJ /F7 1 Tf 13.156 0 TD (104,)Tj /F5 1 Tf 2.0859 0 TD [(2616,)-330(2016.)]TJ -16.9925 -1.1223 TD [(38.)-500.5(Smith,)-386.4(A.J.,)-391.6(Matthews,)-386.6(J.B.,)-388.7(and)-388.9(Hall,)-389.5(R.C.)-388.2(Transforming)]TJ 1.7505 -1.1284 TD [(growth)-297(factor-beta1)-298.8(\(TGF-beta1\))-303.3(in)-292.5(dentine)-295(matrix.)-298.6(Ligand)]TJ 0 -1.1223 TD [(activation)-841.3(and)-834.1(receptor)-835.1(expression.)-839.4(Eur)-834.1(J)-834.8(Oral)-837.6(Sci)]TJ /F7 1 Tf 0 -1.1284 TD [(106\(Suppl)-337.9(1\),)]TJ /F5 1 Tf 6.0748 0 TD [(179,)-336(1998.)]TJ -7.8253 -1.1223 TD -.0184 Tc [(3)-18.4(9)-18.4(.)-518.9(Sloan,)-408.8(A.J.)5.9(,)-414.9(M).5(o)5.9(s)-5.5(eley,)-408.8(R)1.1(.,)-408.8(Dobie,)-408.8(K.,)-408.8(W)1.5(addington,)-408.8(R.J.,)-408.8(a)1.7(nd)]TJ 1.7505 -1.1284 TD .2867 Tc [(S)302(m)305.3(i)305.4(t)305.4(h)304.9(,A)303.3(.)304.9(J)305.7(.T)303(G)303.3(F)308.1(-)]TJ /F6 1 Tf 6.825 0 TD 0 Tc (b)Tj /F5 1 Tf .8417 0 TD -.0189 Tc [(latency-associated)-311.8(p)5.4(e)-4.9(ptides)-310.9(\(LAPs\))-308(in)-311.8(h)5.4(u)-.7(-)]TJ -7.6667 -1.1223 TD -.018 Tc [(man)-182.8(d).2(entin)-188.9(matrix)-182.8(an)6.3(d)-188.9(pulp.)-182.7(Connect)-182.2(Tissue)-187(R)1.5(es)]TJ /F7 1 Tf 18.56 0 TD -.0182 Tc (43,)Tj /F5 1 Tf 1.3784 0 TD [(381,)-189(2)6.1(002.)]TJ -21.6889 -1.1284 TD 0 Tc [(40.)-500.5(Shi,)-387.1(M.,)-383.8(Zhu,)-380.6(J.,)-383.7(Wang,)-387.4(R.,)]TJ /F9 1 Tf 13.583 0 TD [(et)-382.1(al.)]TJ /F5 1 Tf 2.5251 0 TD [(Latent)-382.1(TGF-)]TJ /F6 1 Tf 5.1721 0 TD (b)Tj /F5 1 Tf .9332 0 TD (structure)Tj -20.4629 -1.1223 TD [(and)-334(activation.)-341.2(Nature)]TJ /F7 1 Tf 9.3989 0 TD (474,)Tj /F5 1 Tf 2.0798 0 TD [(343,)-336(2011.)]TJ -13.2292 -1.1284 TD [(41.)-500.5(Wang,)-491.1(S.,)-485(Niu,)-489.5(Y.,)-489.8(Jia,)-485.1(P.,)]TJ /F9 1 Tf 13.7599 0 TD [(et)-485.8(al.)]TJ /F5 1 Tf 2.7325 0 TD [(Alkaline)-491.3(activation)-487.5(of)]TJ -14.7419 -1.1223 TD [(endogenous)-277.4(latent)-275.9(TGF)]TJ /F6 1 Tf 9.4538 0 TD (b)Tj /F5 1 Tf .555 0 TD [(1)-268.5(b)0(y)-274.7(a)0(n)-272.9(injectable)-278.2(hydrogel)-275.5(directs)]TJ -10.0088 -1.1284 TD [(cell)-306.7(homing)-304.8(for)-303.9(in)-304.7(situ)-303.5(complex)-301.2(tissue)-307.1(regeneration.)-308.8(Bioact)]TJ 0 -1.1223 TD (Mater)Tj /F7 1 Tf 2.7325 0 TD (15,)Tj /F5 1 Tf 1.5797 0 TD [(316,)-336(2021.)]TJ /F8 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (816)Tj 48.7749 0 TD [(MAO)-329.9(ET)-338.7(AL.)]TJ ET endstream endobj 93 0 obj <>stream /GS1 gs BT /F5 1 Tf 9.2951 0 0 9.2951 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(42.)-500.5(Graham,)-317.8(L.,)-313.2(Cooper,)-317.2(P.R.,)-313.1(Cassidy,)-312.7(N.,)]TJ /F9 1 Tf 18.0232 0 TD [(et)-315(al.)]TJ /F5 1 Tf 2.3909 0 TD [(The)-311.5(effect)-316.4(of)]TJ -18.6637 -1.1223 TD [(calcium)-420.7(hydroxide)-422(on)-415(solubilisation)-421.9(of)-417.4(bio-active)-423.3(dentine)]TJ 0 -1.1284 TD [(matrix)-335.2(components.)-337.4(Biomaterials)]TJ /F7 1 Tf 13.8575 0 TD (27,)Tj /F5 1 Tf 1.5797 0 TD [(2865,)-336.1(2006.)]TJ -17.1876 -1.1223 TD [(43.)-500.5(Tomson,)-294.3(P.,)-283.7(Lumley,)-292.7(P.,)-289.9(Smith,)-288.8(A.,)-288.5(and)-291.3(Cooper,)-292.8(P.)-289.8(Growth)]TJ 1.7505 -1.1283 TD [(factor)-354.9(release)-354.2(from)-352.4(dentine)-349.8(matrix)-353.5(by)-354(pulp-capping)-352.9(agents)]TJ 0 -1.1223 TD [(promotes)-353.5(pulp)-353.8(tissue)-349.8(repair-associated)-360.5(events.)-349.5(Int)-355.9(Endod)-350.3(J)]TJ /F7 1 Tf 0 -1.1284 TD (50,)Tj /F5 1 Tf 1.5858 0 TD [(281,)-329.9(2017.)]TJ -3.3363 -1.1223 TD [(44.)-500.5(Mantripragada,)-466.8(V.P.,)-462.4(and)-456(Jayasuriya,)-465.5(A.C.)-458.1(IGF-1)-461.2(release)]TJ 1.7505 -1.1284 TD [(kinetics)-726.7(from)-724.5(chitosan)-727.2(microparticles)-733.5(fabricated)-729.3(using)]TJ 0 -1.1223 TD [(environmentally)-441.3(benign)-431.4(conditions.)-436.2(Mater)-431(Sci)-433.9(Eng)-435.4(C)]TJ /F7 1 Tf 22.7257 0 TD (42,)Tj /F5 1 Tf -22.7257 -1.1284 TD [(506,)-336(2014.)]TJ -1.7505 -1.1223 TD [(45.)-500.5(Quaas,)-382(B.,)-371(Burmeister,)-382.9(L.,)-374.2(Li,)-373.7(Z.,)]TJ /F9 1 Tf 15.9983 0 TD [(et)-376(al.)]TJ /F5 1 Tf 2.5129 0 TD [(Stability)-371.5(and)-376.7(bio-)]TJ -16.7607 -1.1284 TD [(logical)-367.6(activity)-367.1(of)]TJ /F9 1 Tf 7.685 0 TD [(E.)-362(coli)]TJ /F5 1 Tf 3.0984 0 TD [(derived)-364.9(soluble)-363(and)-364.5(precipitated)]TJ -10.7834 -1.1284 TD [(bone)-334.1(morphogenetic)-338.5(protein-2.)-338.4(Pharm)-333(Res)]TJ /F7 1 Tf 17.6756 0 TD (36,)Tj /F5 1 Tf 1.5858 0 TD [(1,)-335.7(2019.)]TJ -21.0119 -1.1223 TD [(46.)-500.5(Vemuri,)-422.8(S.,)-424(Beylin,)-423.5(I.,)-417.4(Sluzky,)-422.2(V.,)]TJ /F9 1 Tf 16.6509 0 TD [(et)-418.7(al.)]TJ /F5 1 Tf 2.5983 0 TD [(The)-421.3(stability)-422.6(of)]TJ -17.4987 -1.1284 TD [(bFGF)-276.3(against)-275.8(thermal)-278.5(denaturation.)-277.3(J)-279.8(Pharm)-272(Pharmacol)]TJ /F7 1 Tf 22.7257 0 TD (46,)Tj /F5 1 Tf -22.7257 -1.1223 TD [(481,)-336(1994.)]TJ -1.7505 -1.1284 TD [(47.)-500.5(Siwanowicz,)-421.6(I.,)-411.3(Popowicz,)-422.2(G.M.,)-416.1(Wisniewska,)-415.5(M.,)]TJ /F9 1 Tf 23.2991 0 TD [(et)-418.7(al.)]TJ /F5 1 Tf 2.1774 0 TD (,)Tj -23.726 -1.1223 TD [(Structural)-479.2(basis)-472.2(for)-474.7(the)-473.7(regulation)-474(of)-472.2(insulin-like)-474.2(growth)]TJ 0 -1.1284 TD [(factors)-335.9(by)-335.7(IGF)-336.6(binding)-329.2(proteins.)-335.1(Structure)]TJ /F7 1 Tf 17.5536 0 TD (13,)Tj /F5 1 Tf 1.5797 0 TD [(155,)-336(2005.)]TJ -20.8838 -1.1223 TD [(48.)-500.5(Hinck,)-353.7(A.P.,)-352.6(Archer,)-357.1(S.J.,)-356.3(Qian,)-353.5(S.W.,)]TJ /F9 1 Tf 17.7488 0 TD [(et)-357.7(al.)]TJ /F5 1 Tf 2.4641 0 TD (Transforming)Tj -18.4624 -1.1284 TD [(growth)-449.4(factor)]TJ /F6 1 Tf 6.0748 0 TD (b)Tj /F5 1 Tf .555 0 TD [(1:)-445(three-dimensional)-459.5(structure)-451.5(in)-445(solution)]TJ -6.6299 -1.1223 TD [(and)-431.6(comparison)-425(with)-427.9(the)-431(X-ray)-425.9(structure)-433.2(of)-423.5(transforming)]TJ 0 -1.1284 TD [(growth)-333.6(factor)]TJ /F6 1 Tf 5.8431 0 TD (b)Tj /F5 1 Tf .555 0 TD [(2.)-329.6(Biochemistry)]TJ /F7 1 Tf 6.8189 0 TD (35,)Tj /F5 1 Tf 1.5858 0 TD [(8517,)-336.1(1996.)]TJ -16.5533 -1.1223 TD [(49.)-500.5(Zhu,)-295.2(X.,)-288.5(Komiya,)-292.4(H.,)-288.5(Chirino,)-293.7(A.,)]TJ /F9 1 Tf 15.8031 0 TD [(et)-290.6(al.)]TJ /F5 1 Tf 2.3421 0 TD (Three-dimensional)Tj -16.3947 -1.1284 TD [(structures)-536.1(of)-539.3(acidic)-536.9(and)-529.2(basic)-538.3(broblast)-533.2(growth)-534.8(factors.)]TJ 0 -1.1223 TD (Science)Tj /F7 1 Tf 3.4583 0 TD (251,)Tj /F5 1 Tf 2.0859 0 TD [(90,)-329.7(1991.)]TJ -7.2947 -1.1284 TD [(50.)-500.5(He,)-298.9(Q.,)-288.5(Shi,)-295.6(J.,)-292.2(Zhu,)-295.2(M.,)-292.3(Chen,)-296.3(Y.,)-294.6(and)-291.3(Chen,)-296.3(F.)-289.8(The)-299.3(three-)]TJ 1.7505 -1.1223 TD [(stage)-306.5(in)-298.6(vitro)-306.9(degradation)-302.1(behavior)-304.1(of)-301.5(mesoporous)-304.6(silica)-305.5(in)]TJ 0 -1.1284 TD [(simulated)-293.3(body)-287.2(uid.)-289.6(Microporous)-294.9(Mesoporous)-292.1(Mater)]TJ /F7 1 Tf 22.2256 0 TD (131,)Tj /F5 1 Tf -22.2256 -1.1223 TD [(314,)-336(2010.)]TJ -1.7505 -1.1284 TD [(51.)-500.5(Yang,)-360.2(S.-A.,)-355.1(Choi,)-358.6(S.,)-356.9(Jeon,)-351.6(S.M.,)-356.4(and)-358.4(Yu,)-355.7(J.)-359.2(Silica)-358.1(nano-)]TJ 1.7505 -1.1223 TD [(particle)-264.4(stability)-264(in)-262(biological)-263.7(media)-264.3(revisited.)-265.7(Sci)-263.1(Rep)]TJ /F7 1 Tf 22.2134 0 TD (8,)Tj /F5 1 Tf 1.0125 0 TD (1,)Tj -23.2259 -1.1284 TD (2018.)Tj -1.7505 -1.1223 TD [(52.)-500.5(Bhattacharyya,)-394.9(S.,)-387.4(Wang,)-387.4(H.,)-392.2(and)-388.9(Ducheyne,)-387.5(P.)-393.5(Polymer-)]TJ 1.7505 -1.1284 TD [(coated)-433.8(mesoporous)-426.6(silica)-433.6(nanoparticles)-433.2(for)-425.9(the)-431(controlled)]TJ 0 -1.1223 TD [(release)-342(of)-332(macromolecules.)-339.7(Acta)-333.3(Biomater)]TJ /F7 1 Tf 17.761 0 TD (8,)Tj /F5 1 Tf 1.0857 0 TD [(3429,)-330(2012.)]TJ -20.5971 -1.1284 TD [(53.)-500.5(Santos,)-311.6(E.M.,)-312.7(Radin,)-308.1(S.,)-308.1(and)-315.7(Ducheyne,)-308.2(P.)-314.2(Solgel)-305.8(derived)]TJ 1.7505 -1.1223 TD [(carrier)-386(for)-377.1(the)-376.1(controlled)-382.5(release)-378.5(of)-380.8(proteins.)-377.8(Biomaterials)]TJ /F7 1 Tf 0 -1.1284 TD (20,)Tj /F5 1 Tf 1.5858 0 TD [(1695,)-330(1999.)]TJ -3.3363 -1.1223 TD [(54.)-500.5(Napierska,)-358(D.,)-355.6(Thomassen,)-351(L.C.,)-354.8(Lison,)-355(D.,)-349.5(Martens,)-357.3(J.A.,)]TJ 1.7505 -1.1284 TD [(and)-535.3(Hoet,)-530.4(P.H.)-529.4(The)-531.1(nanosilica)-536(hazard:)-533.8(another)-535.7(variable)]TJ 0 -1.1223 TD [(entity.)-338.9(Part)-332.7(Fibre)-332.8(Toxicol)]TJ /F7 1 Tf 10.7286 0 TD (7,)Tj /F5 1 Tf 1.0857 0 TD [(1,)-335.7(2010.)]TJ -13.5647 -1.1284 TD [(55.)-500.5(Jafari,)-256.5(S.,)-247.2(Derakhshankhah,)-259.8(H.,)-251.9(Alaei,)-253.6(L.,)]TJ /F9 1 Tf 18.5295 0 TD [(et)-247.9(al.)]TJ /F5 1 Tf 2.2567 0 TD (Mesoporous)Tj -19.0357 -1.1223 TD [(silica)-342.1(nanoparticles)-341.7(for)-340.5(therapeutic/diagnostic)-343(applications.)]TJ 0 -1.1284 TD [(Biomed)-338.2(Pharmacother)]TJ /F7 1 Tf 9.4172 0 TD (109,)Tj /F5 1 Tf 2.0859 0 TD [(1100,)-330(2019.)]TJ -13.2536 -1.1284 TD [(56.)-500.5(Tao,)-360.4(Z.,)-362(Toms,)-361.1(B.B.,)-357.7(Goodisman,)-365.1(J.,)-359.3(and)-358.4(Asefa,)-366(T.)-355.9(Meso-)]TJ 1.7505 -1.1223 TD [(porosity)-428.4(and)-419.4(functional)-425.2(group)-423.9(dependent)-428.1(endocytosis)-427.9(and)]TJ 0 -1.1284 TD [(cytotoxicity)-300(of)-295.4(silica)-293.3(nanomaterials.)-298.6(Chem)-295.8(Res)-295.2(Toxicol)]TJ /F7 1 Tf 22.7257 0 TD (22,)Tj /F5 1 Tf -22.7257 -1.1223 TD [(1869,)-336.1(2009.)]TJ -1.7505 -1.1284 TD [(57.)-500.5(Solorio,)-804.2(L.D.,)-803(Fu,)-808.4(A.S.,)-804(Herna)]TJ 15.6323 .0427 TD ()Tj .3843 -.0427 TD [(ndez-Irizarry,)-810.5(R.,)-798(and)]TJ -14.2661 -1.1223 TD [(Alsberg,)-465.2(E.)-459.5(Chondrogenic)-461.9(differentiation)-464.1(of)-460(human)-461.9(mes-)]TJ 0 -1.1284 TD [(enchymal)-506.8(stem)-496.9(cell)-501.9(aggregates)-507.1(via)-498.1(controlled)-504.5(release)-500.5(of)]TJ 0 -1.1223 TD [(TGF)11.5(-)]TJ /F6 1 Tf 2.2018 0 TD (b)Tj /F5 1 Tf 9.2951 0 0 9.2951 101.537 170.759 Tm [(1)-231.9(fro)13.2(m)-231.5(inco)14.1(rpo)15.5(ra)11.5(ted)-223.6(pol)12.3(ym)12.3(er)-232.5(mi)12.9(cro)11.3(sp)12.8(her)11.3(es.)-223.3(J)-231(Bio)13.7(med)]TJ -2.7447 -1.1284 TD [(Mate)16.7(r)-331.8(Res)-319.6(A)]TJ /F7 1 Tf 5.5686 0 TD (92,)Tj /F5 1 Tf 1.5736 0 TD [(113)17.9(9,)-323.5(2010)17.7(.)]TJ 18.1208 60.7728 TD [(58.)-500.5(DeLise,)-395.6(A.M.,)-397.8(Fischer,)-403.6(L.,)-392.5(and)-401.1(Tuan,)-397.1(R.)-395.3(Cellular)-399.2(interac-)]TJ 1.7505 -1.1223 TD [(tions)-498.8(and)-498.7(signaling)-496.9(in)-499.8(cartilage)-500.6(development.)-500.7(Osteoarthr)]TJ 0 -1.1284 TD (Cartilage)Tj /F7 1 Tf 4.0194 0 TD (8,)Tj /F5 1 Tf 1.0796 0 TD [(309,)-336(2000.)]TJ -6.8494 -1.1223 TD [(59.)-500.5(Mercier,)-883.1(N.R.,)-885.2(Costantino,)-880.1(H.R.,)-885.2(Tracy,)-879.5(M.A.,)-885.7(and)]TJ 1.7505 -1.1283 TD [(Bonassar,)-368.7(L.J.)-367.4(Poly)-368.9(\(lactide-co-glycolide\))-375.8(microspheres)-376.1(as)]TJ 0 -1.1223 TD [(a)-406.9(moldable)-416.6(scaffold)-409.2(for)-413.7(cartilage)-415.2(tissue)-410.8(engineering.)-411.9(Bio-)]TJ 0 -1.1284 TD (materials)Tj /F7 1 Tf 4.0194 0 TD (26,)Tj /F5 1 Tf 1.5797 0 TD [(1945,)-336.1(2005.)]TJ -7.3496 -1.1223 TD [(60.)-500.5(Malda,)-276.3(J.,)-280(Van)-280.7(Blitterswijk,)-278.7(C.,)-279.5(Van)-280.7(Geffen,)-277.8(M.,)]TJ /F9 1 Tf 21.573 0 TD [(et)-278.4(al.)]TJ /F5 1 Tf 2.3177 0 TD (Low)Tj -22.1402 -1.1284 TD [(oxygen)-615(tension)-613.1(stimulates)-615.3(the)-620.1(redifferentiation)-617.3(of)-612.5(ded-)]TJ 0 -1.1223 TD [(ifferentiated)-493(adult)-485.6(human)-486.3(nasal)-489.5(chondrocytes.)-491(Osteoarthr)]TJ 0 -1.1284 TD (Cartilage)Tj /F7 1 Tf 4.0194 0 TD (12,)Tj /F5 1 Tf 1.5797 0 TD [(306,)-336(2004.)]TJ -7.3496 -1.1223 TD [(61.)-500.5(F)15.3(u)18.2(t)12.6(r)15.8(e)14(g)0(a)26(,)-378.2(K)16.6(.)0(,)-366.1(R)13.4(ob)30.2(e)14(y)0(,)-366.2(P)15.3(.G)28.7(.,)-366.1(K)16.6(l)12.6(e)14(i)12.6(n)18.2(,)-384.3(T)16.3(.)0(J)31.2(.)0(,)-366.1(C)13.4(r)15.8(a)14(wf)26.3(o)18.2(r)0(d)27.9(,)-384.3(R)19.5(.)0(W)25.9(.)18.2(,)-384.3(a)13.9(n)18.2(d)]TJ 1.7505 -1.1284 TD -.0173 Tc [(Do)-17.3(r)10.6(a)-3.3(n,)-505.3(M)-4.5(.)-17.3(R)14.3(.)-511.4(A)-507(s)1.7(i)-4.7(n).9(g)-17.3(l)7.4(e)-503.5(d)-17.3(a)8.7(y)-505.4(of)-507.7(TG)-17.3(F)8.4(-)]TJ /F6 1 Tf 15.0468 0 TD 0 Tc (b)Tj /F5 1 Tf .5367 0 TD [(1)-488.1(e)14(xp)30.2(os)31.1(ur)27.9(e)-492.3(a)13.9(c)14(t)18.7(i)12.6(v)18.2(a)14(t)12.6(e)13.9(s)]TJ -15.5835 -1.1284 TD -.0138 Tc 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TD [(treatment)-361.8(of)-368.6(articular)-364.5(cartilage)-366.4(defects)-368.2(in)-359.6(the)-363.9(rabbit.)-366.2(Arth-)]TJ 0 -1.1223 TD (roscopy)Tj /F7 1 Tf 3.4949 0 TD (18,)Tj /F5 1 Tf 1.5858 0 TD [(892,)-336(2002.)]TJ -6.8311 -1.1284 TD [(63.)-500.5(Singh,)-332.5(N.,)-337.3(Shiwani,)-338(S.,)-338.6(Singh,)-338.6(G.,)]TJ /F9 1 Tf 15.9556 0 TD [(et)-333.3(al.)]TJ /F5 1 Tf 2.4336 0 TD (TGF-)Tj /F6 1 Tf 2.214 0 TD (b)Tj /F5 1 Tf .555 0 TD [(1)-335.6(improves)]TJ -19.4078 -1.1223 TD [(articular)-242.5(cartilage)-250.5(damage)-244.8(in)-243.7(rabbit)-244.1(knee.)-240.8(Pak)-245.4(Vet)-243.5(J)]TJ /F7 1 Tf 20.7313 0 TD (32,)Tj /F5 1 Tf 1.4882 0 TD (412,)Tj -22.2195 -1.1284 TD (2012.)Tj -1.7505 -1.1223 TD [(64.)-500.5(Wang,)-369.1(W.,)-376.7(Li,)-373.7(B.,)-371(Yang,)-372.4(J.,)]TJ /F9 1 Tf 13.6867 0 TD [(et)-376(al.)]TJ /F5 1 Tf 2.5068 0 TD [(The)-372.5(restoration)-371.9(of)-374.7(full-)]TJ -14.443 -1.1284 TD 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