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[(BMP)12.2(-9,)-230.2(and)-223.3(vas)13(cul)12.7(ar)-233.7(end)12.8(oth)13.8(eli)12.6(al)-228.1(gro)14(wth)-228.9(fac)11.7(tor)-228(\(VE)11.9(GF)14.4(\))-237.2(wer)12(e)]TJ
0 -1.1116 TD
[(assayed)-321.8(with)-310.8(ELISA)-319.6(kits)-315.5(\(R&D)-312.8(Systems\))-316(strictly)-321.3(according)]TJ
T*
[(to)-336.4(the)-332.9(manufacturers)-343.7(instructions.)]TJ
/F12 1 Tf
8.9663 0 0 8.9663 313.0582 462.1038 Tm
[(Physicochemical)-338.9(and)-335.7(biological)-332(characteristics)]TJ
0 -1.2203 TD
[(of)-336.7(selected)-333.4(MSNs)]TJ
/F3 1 Tf
1.1128 -1.8336 TD
[(Morphology)-501(and)-500.1(structure)-497.8(of)-501.1(MSNs.)]TJ
/F5 1 Tf
9.843 0 0 9.843 481.5495 434.7211 Tm
[(MSNs)-483.9(were)-491.4(syn-)]TJ
-17.1178 -1.1174 TD
[(thesized)-265.8(as)-256.6(described)-266.7(previously.)]TJ
7.3823 0 0 6.5614 443.2251 428.1448 Tm
(29)Tj
9.843 0 0 9.843 453.203 423.7227 Tm
[(Detailed)-261.2(information)-262.5(can)]TJ
-14.238 -1.1116 TD
[(be)-441.1(found)-437.5(in)-434.3(Supplementary)-439.6(Data.)-437.4(The)-437.6(morphology)-438.6(of)-439.9(the)]TJ
T*
[(MSNs)-305.3(was)-304.6(investigated)-305(using)-304.9(transmission)-303.4(electron)-306.3(micros-)]TJ
0 -1.1174 TD
[(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
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[(All)-505.5(animal)-511.5(experiments)-512.2(were)-508.7(approved)-506.4(by)-509.1(the)-505.7(Institu-)]TJ
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T*
[(versity)-481.2(Health)-488.1(Science)-484.6(Center.)-485.8(Articular)-485.7(cartilage)-487.2(defec)-9(ts)]TJ
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[(\(weight:)-472(2.02.5)-167.9(kg;)]TJ
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(n)Tj
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[(3)-473.4(per)-471(group\).)-470.8(Rabbits)-470.7(were)-474.1(anes-)]TJ
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T*
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[(MSN)-287.1(\(C)]TJ
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3.4443 0 TD
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[(S\))-290(group,)-285.4(60)]TJ
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[(L)-290.3(o)0(f)-290.1(collagen)-289(I)-289.1(with)-287.8(10)-169.2(mg/mL)]TJ
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[(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
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21.2476 0 TD
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[(bDMEP)-238.7(\(C)]TJ
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[(D\))-239.2(group,)-239.3(60)]TJ
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5.2759 0 TD
(m)Tj
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[(L)-244.2(o)0(f)-238.3(collagen)-243(I)-237.2(with)-241.7(10)-169.2(mg/mL)]TJ
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[(of)-837.3(MSN-bDMEP)-843.7(\()-87.5(MSNs)-841(with)-840.7(maximum)-842.1(loading)-844.3(of)]TJ
T*
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[(joints)-335.1(were)-335.9(closed)-337.2(with)-333.8(suture.)]TJ
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[(formaldehyde)-478.8(solution)-481.3(for)-475.5(24)-169.2(h.)-476.8(Subsequently,)-479.7(the)-476.9(tissues)]TJ
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[(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
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18.719 0 TD
(m)Tj
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[(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
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[(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
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[(analysis)-264.4(of)-261.4(variance)-267(and)-263.7(Students)-264.4(unpaired)]TJ
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17.7802 0 TD
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[(-test.)-263.6(A)]TJ
/F9 1 Tf
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(p)Tj
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-21.7774 -1.1116 TD
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(Results)Tj
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0 -1.8336 TD
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0 -1.2266 TD
[(factor)-333.7(content)]TJ
/F5 1 Tf
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[(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
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T*
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()Tj
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16.4497 0 TD
()Tj
/F5 1 Tf
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[(0.56,)-482.5(4.58)]TJ
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()Tj
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[(and)-482.5(9.18)]TJ
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(3)Tj
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[(150.05,)-663.2(6.63)]TJ
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[(2.81,)-661(and)-666.8(3.23)]TJ
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()Tj
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[(5.60)-168(pg/mL,)]TJ
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[(and)-332.8(VEGF)-335.5(were)-335.9(50.27)]TJ
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[(79.90)-330.4(and)-332.8(5.43)]TJ
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[(1.42)-168(pg/mL.)]TJ
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(TGF-)Tj
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[(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
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[(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
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[(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
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[(3)-450.3(were)-456.8(not)-452.7(signi-)]TJ
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[(cantly)-331.7(different)-340.7(between)-334.7(nDMEP)-336.6(and)-332.8(bDMEP.)]TJ
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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
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8.9663 0 0 8.9663 62.022 541.9274 Tm
0 0 0 rg
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[(Characteristics)-333.6(of)-336.7(MSNs)]TJ
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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
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[(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
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2.9202 0 TD
()Tj
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[(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
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[(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
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[(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
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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
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[(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
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[(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
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[(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
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9.843 0 0 9.843 536.8251 456.2645 Tm
(The)Tj
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[(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
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[(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
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[(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
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