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[(polymers)-696.5(were)-693(most)-691(investigated.)-694.4(Synthetic)-697.9(or)-687.6(natural)]TJ 0 -1.1174 TD (polymers)Tj 7.3823 0 0 6.5614 96.4913 521.2912 Tm [(15,7)-7.8(,9,10,12,30)-7.9(,36,37,40)]TJ 9.843 0 0 9.843 176.6551 516.9258 Tm [(included)-264.8(polydimethylsiloxane)]TJ -11.8765 -1.1116 TD [(\(PDMS\),)-662.3(PLGA,)-667.2(Poly-l-lactic)-663.3(acid)-663.5(or)-658.8(poly\(l-lactide-co-)]TJ T* .0238 Tc [(cap)5.4(rol)5.3(acton)5.4(e)-1.5(\),)-480.7(po)5.4(lyacry)5.4(lamid)5.4(e)-485.3(hy)5.4(dro)5.4(gel)5.3(s)-.1(,)-480.7(c)-1.5(ol)5.3(lagen)5.4(,)-486.5(and)]TJ 0 -1.1174 TD 0 Tc [(bronectin.)-604.3(B)20.9(i)21.8(o)16.2(c)20.8(e)20.8(r)16.2(a)20.8(m)20.7(i)21.8(c)15(s)-576.9(i)21.8(n)21.9(c)20.8(l)16.1(u)21.9(d)21.9(e)15(d)-577.1(h)21.9(y)21.9(d)16.2(r)22(o)21.9(x)16.2(y)21.9(a)20.8(p)21.9(a)15(t)21.8(i)21.8(t)16.1(e)20.8(.)]TJ 7.3823 0 0 6.5614 261.0708 488.466 Tm -.0239 Tc (33)Tj 9.843 0 0 9.843 273.9401 484.0439 Tm -.0209 Tc [(Mea)-5.9(n)1(-)]TJ -21.7602 -1.1116 TD -.0217 Tc [(w)-6.4(h).2(il)-5.6(e,)-307.4(gra)-6.7(phe)-6.7(ne)]TJ 7.3823 0 0 6.5614 120.5858 477.4676 Tm -.025 Tc [(35,3)6.5(8)]TJ 9.843 0 0 9.843 139.2377 473.1022 Tm -.0196 Tc [(and)-302.9(m)1.1(e)-4.6(t)2.2(al)-303(m)-4.6(a)1.2(terials)]TJ 7.3823 0 0 6.5614 214.4692 477.4676 Tm -.0239 Tc (34)Tj 9.843 0 0 9.843 224.5039 473.1022 Tm -.0202 Tc [(were)-310.4(also)-303.5(included.)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 449.3479 Tm 0 Tc (Discussion)Tj /F4 1 Tf 9.843 0 0 9.843 69.7323 432.907 Tm [(The)-495.2(main)-496.5(purpose)-498.2(of)-491.7(this)-494(review)-499.5(is)-491.7(to)-497.7(summarize)-493.8(the)]TJ -1.0137 -1.1174 TD [(epigenetic)-367.4(effects)-368.2(of)-359.3(biomaterial)-368.7(cues)-363.6(on)-365.1(cell)-364.1(behaviors,)-361.2(to)]TJ 0 -1.1116 TD [(compare)-409.8(the)-407.8(differences)-408.3(and)-401.9(similaritie)-10.5(s)-404.1(between)-403.9(different)]TJ T* [(biomaterial)-443.5(cues,)-441.9(to)-434.3(reveal)-442.2(underlying)-438.6(relationship)-442.1(among)]TJ T* [(epigenetic)-396.2(alterations,)-388(mechanical)-392.7(transduction)-395.9(and)-384.6(chemi-)]TJ 0 -1.1174 TD [(cal)-293.7(signaling)-293.5(pathways,)-291.8(and)-286.7(to)-290.3(provide)-291.2(important)-289.1(insights)-291(to)]TJ 0 -1.1116 TD [(biomaterial)-339.9(designing)-333.7(for)-337.3(clinical)-335.4(applications.)]TJ /F9 1 Tf 8.9663 0 0 8.9663 59.7543 343.3889 Tm [(Denition)-340(and)-329.4(classication)-338.5(of)-330.4(biomaterial)-336.5(cues)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 326.9479 Tm [(There)-331.5(are)-328.1(various)-331.3(characteristics)-340.3(of)-324.7(biomateria)-10.3(ls)-324.7(that)-334.1(can)]TJ -1.0137 -1.1174 TD [(dictate)-397.5(cell)-398.6(behaviors)-392.3(in)-394(different)-398.3(manners.)-394.6(Hence,)-399.2(a)-393.9(clear)]TJ 0 -1.1116 TD [(denition)-287.8(and)-286.7(classication)-289.6(of)-284.4(biomaterial)-288(cues)-288.8(are)-282.1(urgently)]TJ T* [(needed)-551.5(to)-543.7(summarize)-551.4(and)-545.9(categorize)-546.9(previous)-551.3(investiga-)]TJ 0 -1.1174 TD [(tions.)-515.9(In)-514.8(this)-517.1(study,)-510(we)-516.8(dene)-514.5(biomaterial)-518.4(cues)-519.1(into)-511.5(the)]TJ 0 -1.1116 TD [(following)-535.3(categories:)-535.3(material)-538(nature/chemistry,)-534.1(stiffness/)]TJ T* [(elasticity/rigidi)-11.6(ty,)-339.8(mechanical)-346.6(forces/stimulus,)-345.9(and)-338.5(topogra-)]TJ 0 -1.1174 TD [(phy)-395(\(including)-392.7(shape,)-397(dimension,)-396(microstructure)-394.6(or)-393.8(nanos-)]TJ 0 -1.1116 TD [(tructure,)-279.7(and)-280.9(three-dimensionality\).)-286.4(Due)-276(to)-278.8(the)-275.3(diversity)-276.2(and)]TJ T* [(complexity)-389.3(of)-382.3(biomaterial)-385.9(cues,)-384.3(exploring)-379.9(the)-384.7(mechanisms)]TJ T* [(by)-388.1(which)-387.8(cells)-393.8(respond)-383(to)-388.2(inherent)-391.5(material)-388.3(characteris)-12.2(tics)]TJ 0 -1.1174 TD [(remains)-258.8(challenging.)-255.6(Therefore,)-254.1(setting)-251(a)-255.7(single)-249.7(variable)-254.4(and)]TJ 0 -1.1116 TD [(controlling)-370.9(the)-367.5(other)-363.9(characteristics)-374.9(of)-365(a)-365.1(material)-371(is)-365(im)19.5(p)16.2(o)0(r)20.9(-)]TJ T* [(ta)19.6(nt)-221.2(in)-221.2(th)26.5(e)-238.4(r)0(e)25.5(s)0(e)19.9(a)0(r)25.5(c)0(h)19.7(e)15(s)-237(t)0(o)-221.2(e)0(x)25.4(p)0(l)20.7(o)0(r)26.6(e)-238.4(c)15(o)0(m)19.6(p)16.2(le)19.6(x)-231.5(m)0(e)18.4(c)15(ha)19.7(n)16.2(i)0(s)20.9(m)0(s)25.6(.)-233.8(Ba)18.6(si)26.7(ng)]TJ 0 -1.1174 TD [(on)-451.5(a)-451.5(clear)-452.6(plot)-453.9(of)-445.7(regulating)-457.2(mechanisms)-454.5(from)-449.1(each)-457.1(bio-)]TJ 0 -1.1116 TD [(material)-296.1(cue,)-285.5(complex)-293.6(and)-286.7(personally)-295.6(designed)-287.5(biomaterials)]TJ T* [(can)-414.6(be)-412.3(engineered)-413.2(to)-411.3(meet)-417(the)-407.8(different)-415.6(needs)-416.6(for)-406.4(clinical)]TJ 0 -1.1174 TD (applications.)Tj /F9 1 Tf 8.9663 0 0 8.9663 59.7543 116.8441 Tm [(Biomaterial)-336.3(cues)-336.7(regulate)-334.5(epigenetic)-333.3(state)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 100.4031 Tm [(Biomaterial)-312.1(cues)-300.3(regulate)-312(epigenetic)-304(state)-307.4(in)-301.8(the)-304.1(manners)]TJ -1.0137 -1.1116 TD [(of)-514.8(chromatin)-509(remodeling,)-513.6(histone)-515.8(modication,)-514.7(and)-511.3(non-)]TJ 0 -1.1174 TD [(coding)-388(RNA,)-383.9(whereas)-386.2(the)-384.7(inuences)-381.8(on)-382.3(DNA)-386.1(methylation)]TJ 0 -1.1116 TD [(remain)-494.1(limited)-488.7(according)-485.8(to)-486.1(the)-488.4(existing)-488.2(researches.)-492.1(Me-)]TJ T* [(chanical)-261.4(transduction)-263.4(from)-253.2(membrane)-262.4(to)-255.8(nucleus)-263.4(is)-255.6(the)-258(basis)]TJ 25.5097 47.8862 TD [(of)-370.8(chromatin)-370.8(remodeling)-371.9(and)-373.1(histone)-371.8(modication)-373(induced)]TJ 0 -1.1174 TD [(by)-324.7(biomaterial)-328.4(cues,)-326.8(which)-324.5(is)-324.7(also)-328(supported)-322(by)-324.7(microarray)]TJ 0 -1.1116 TD [(analyses)-605.3(demonstrating)-605.5(large-scale)-611.2(changes)-604.3(in)-601.3(gene)-605.7(ex-)]TJ T* [(pression)-458.9(of)-451.4(nucle)-8(ar)-452.6(morphology,)-459.3(actomyosin)-458.1(contractility,)]TJ 0 -1.1174 TD [(and)-280.9(histone)-279.6(acetylation.)]TJ 7.3823 0 0 6.5614 405.0141 488.466 Tm (2,5)Tj 9.843 0 0 9.843 417.033 484.0439 Tm [(The)-276.4(moment)-281.1(a)-278.7(cell)-283.5(adheres)-281.7(to)-278.8(the)]TJ -10.7879 -1.1116 TD [(substrate,)-292(their)-294.9(interactions)-299.2(begin.)-292.5(The)-293.6(cell)-289.2(spreads)-297.6(and)-292.4(thus)]TJ T* [(cell)-283.5(shape)-278.3(changes)-281.7(under)-283.1(the)-281.1(guidance)-283.1(of)-278.6(material)-284.6(substrate.)]TJ 0 -1.1174 TD [(Material)-618.3(adhesiveness,)-619.9(micro-)-613.8(and)-615(nanotopography,)-620.3(and)]TJ 0 -1.1116 TD [(three-dimensionality)-448.9(will)-437.6(all)-442.5(lead)-444.6(to)-440.1(reorganization)-446.6(of)-439.9(the)]TJ T* [(cytoskeleton.)-342.9(Forces)-336.9(generated)-343(by)-342(the)-338.7(cytoskeleton)-339.5(compo-)]TJ T* [(nents,)-321.1(including)-328.3(actin)-324.9(and)-321.2(myosin)-324.6(can)-328.2(be)-320.1(transmitted)-327(to)-324.9(the)]TJ 0 -1.1174 TD [(nucleus)-263.4(and)-269.4(chromatin)-267.1(through)-261.2(physical)-270.4(links)-264.8(on)-261.4(the)-269.5(nuclear)]TJ 0 -1.1116 TD [(envelope)-340.7(and)-338.5(the)-338.7(lamin)-336.5(meshwork.)-343.6(The)-339.7(physical)-339.5(properties)]TJ T* [(of)-601.2(the)-609.4(nucleus)-603.2(govern)-606.8(the)-603.6(spatiotemporal)-607.9(packaging)-612.5(of)]TJ 0 -1.1174 TD [(chromatin.)-339.7(Therefore,)-346.2(when)-340.5(active)-344.4(forces)-342.7(modulate)-346.7(nuclear)]TJ 0 -1.1116 TD [(morphology,)-424.7(chromatin)-428.4(remodeling)-423.7(takes)-428.2(place)-429.6(in)-422.8(the)-425.1(nu-)]TJ T* [(cleus.)-397.1(Chromatin)-399.5(remodeling,)-404.1(including)-397.4(packaging)-399.4(and)-401.9(re-)]TJ 0 -1.1174 TD [(lease)-510(of)-509(histones)-510.9(and)-505.6(DNA,)-510.4(and)-511.3(histone)-510(modication)-511.2(as)]TJ 0 -1.1116 TD [(well,)-361.5(regulates)-364.8(transcription)-368.2(activation)-360.6(and)-361.6(repression,)-367.8(thus)]TJ T* [(inuencing)-474.2(cell)-473.5(behaviors)-478.7(and)-471(stem)-479(cell)-473.5(lineage)-478(commit-)]TJ T* [(ment.)-286.8(Histones,)-290.6(assembled)-290.8(with)-287.8(DNA)-288.1(to)-290.3(form)-287.8(nucleosomes,)]TJ 0 -1.1174 TD [(are)-368.5(the)-367.5(basic)-376.4(building)-366.3(blocks)-370.6(of)-370.8(chromatin.)-368.5(Therefore,)-375(his-)]TJ 0 -1.1116 TD [(tone)-397.4(modications)-402.7(and)-396.1(chromatin)-399.6(decondensation)-406(are)-397.3(cen-)]TJ T* [(tral)-639.4(to)-635.9(the)-638.2(remodeling)-636.9(process)-643.2(of)-635.7(chromatin,)-639.2(which)-635.5(is)]TJ 0 -1.1174 TD [(important)-467.7(for)-469.8(cell)-473.5(functions,)-469.6(such)-471.9(as)-469.7(proliferation,)-469.8(differ-)]TJ 0 -1.1116 TD [(entiation,)-333(and)-338.5(reprogramming.)]TJ 1.0137 -1.1116 TD [(A)-359.1(variety)-361.6(of)-359.3(topographies)-366.9(have)-363.8(been)-358.1(investigated)-368.4(in)-359.4(dif-)]TJ -1.0137 -1.1174 TD [(ferent)-348.8(studies.)-352(Collectively,)-355.9(micro-)-354.6(or)-347.7(nanogeometry)-352.1(or)-353.5(3D)]TJ 0 -1.1116 TD [(microenvironment)-358(can)-357(generally)-359.2(guide)-358.1(cells)-359.2(into)-356(two)-355.6(types)]TJ T* [(of)-319(shapes,)-323(cell)-318(shapes)-325.3(guided)-318.9(by)-319(anisotropic)-325.6(forces)-319.7(and)-321.2(cell)]TJ 0 -1.1174 TD [(shapes)-400.2(guided)-399.6(by)-393.9(isotropic)-402.9(forces.)-398(T)-25.3(h)-24.1(e)-422.7(f)-29.9(o)-24.1(r)-24.1(m)-25.4(e)-25.3(r)-421.5(i)-24.3(n)-29.9(c)-25.3(l)-24.3(u)-24.1(d)-24.1(e)-25.3(s)-421.4(a)]TJ 0 -1.1116 TD .0248 Tc [(varie)-6.3(t).5(y)-235.5(o).7(f)-235.5(cel)-5.2(l)-235.6(s).9(hapes)-4.9(,)-232.1(s)-4.9(u).7(ch)-235.5(as)-235.3(elo)-5.1(ngated)-235.5(s)-4.9(hapes)-235.3(g)-5.1(uided)-235.5(b).7(y)]TJ T* .0246 Tc [(paral)-5.4(l).3(el)-258.9(microgo)-5.3(oves,)]TJ 7.3823 0 0 6.5614 401.4424 181.5874 Tm .0359 Tc [(9,3)6(1)]TJ 9.843 0 0 9.843 417.8833 177.222 Tm .0245 Tc [(ali)-5.5(gned)-258.8(n).4(ano)-5.2(bers,)]TJ 7.3823 0 0 6.5614 497.1967 181.5874 Tm .0376 Tc (37)Tj 9.843 0 0 9.843 507.6282 177.222 Tm .0243 Tc [(and)-259(s).4(ingl)-5.7(e)]TJ -19.9919 -1.1116 TD .0247 Tc [(cell)-541(t).4(opog)-5.2(raphy)-540.8(such)-540.8(as)-540.7(rect)-5.3(angles)-540.6(wit)-5.3(h)-535.1(lar)-5.2(g).6(er)-540.8(aspect)]TJ 0 -1.1174 TD 0 Tc (ratios.)Tj 7.3823 0 0 6.5614 335.2251 159.6472 Tm (5,6,11)Tj 9.843 0 0 9.843 357.959 155.2818 Tm [(The)-431.9(latter)-435.5(one)-430.7(is)-428.4(generally)-434.1(a)-428.5(round)-431.7(shape.)]TJ 7.3823 0 0 6.5614 533.3101 159.6472 Tm (12,30)Tj 9.843 0 0 9.843 310.8472 144.3401 Tm [(For)-325.6(equal)-330.5(spreading,)-332.4(cell)-329.5(elongation)-330.5(leads)-330.3(to)-330.6(decreased)-332.3(cell)]TJ 0 -1.1116 TD (stiffness,)Tj 7.3823 0 0 6.5614 346.1101 137.7638 Tm (11)Tj 9.843 0 0 9.843 357.5054 133.3984 Tm [(elongated)-411.1(nuclear)-414.5(shape)-405.1(and)-413.4(decreased)-412.9(nuclear)]TJ -4.7402 -1.1174 TD [(matrix)-447(protein)-446.8(lamin)-445.9(A/C.)]TJ 7.3823 0 0 6.5614 419.244 126.7653 Tm (3)Tj 9.843 0 0 9.843 427.3511 122.3999 Tm [(Meanwhile,)-450.9(chromatin)-445.7(decon-)]TJ -11.8362 -1.1116 TD [(densed)-417.7(with)-420.2(a)-417(concomitant)-426.2(increase)-422.3(in)-417(histone)-417.9(acetylation)]TJ T* [(caused)-303.6(by)-301.7(decreased)-303.5(HDAC)-301.8(activity,)]TJ 7.3823 0 0 6.5614 458.3054 104.8819 Tm (37)Tj 9.843 0 0 9.843 468.6802 100.5165 Tm [(and)-298.2(thus)-303.8(an)-302.9(increase)]TJ -16.035 -1.1174 TD [(in)-497.7(gene)-496.3(expression.)-500.3(Cytoplasmic)-500.7(actomyosin)-498.5(and)-499.8(nuclear)]TJ 0 -1.1116 TD [(matrix)-366.3(protein)-372(lamin)-365.3(A/C)-368.2(are)-374.2(important)-369.8(transducers)-372.4(in)-365.2(this)]TJ T* [(process,)-393.2(since)-393.7(inhibition)-397.6(lamin)-394.1(A/C)-391.2(disrupts)-394.6(this)-396.1(process)]TJ 7.3823 0 0 6.5614 542.551 72 Tm (11)Tj 9.843 0 0 9.843 310.8472 56.6929 Tm [(and)-246.4(cytoplasmic-to-nuclear)-257.4(redistribution)-253.1(of)-244.1(HDAC)-255.7(depends)]TJ ET q 490.48 0 0 137.934 59.754 594.312 cm /Im3 Do Q BT /F5 1 Tf 9.845 0 0 9.845 59.7543 577.5306 Tm [(FIG.)-284.9(3.)]TJ /F4 1 Tf 4.0598 0 TD [(Number)-285.5(and)-280.6(distribution)-277.5(of)-284.2(investigated)-280.8(factors)-279.9(in)-284.3(the)-280.7(included)-281.3(articles.)]TJ /F5 1 Tf 29.1901 0 TD (\(a\))Tj /F4 1 Tf 1.4454 0 TD [(Number)-285.5(and)-274.8(distribution)-283.2(of)-278.4(factors)-285.7(in)]TJ -34.6952 -1.0135 TD [(the)-332.6(included)-333.1(articles)-334.3(classied)-334.7(according)-335.1(to)-330.4(cell)-329.1(behaviors.)]TJ /F5 1 Tf 24.3068 0 TD (\(b\))Tj /F4 1 Tf 1.549 0 TD [(Number)-337.3(and)-326.6(distribution)-335.1(of)-330.2(factors)-331.8(in)-330.4(the)-332.6(included)-333.1(articles)]TJ -25.8559 -1.0135 TD [(classied)-340.5(according)-335.1(to)-336.2(different)-334.1(biomaterial)-338.7(cues.)-332(Color)-334.4(images)-337.7(available)-336.6(online)-335.7(at)-337.3(www.liebertpub.com/teb)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(BIOMATERIAL)-342(CUES)-336.6(REGULATE)-334.8(EPIGENETIC)-335.5(STATE)-338.7(AND)-330.9(CELL)-340.8(FUNCTIONS)-15518.2(115)]TJ ET endstream endobj 85 0 obj <>stream Adobed          s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?N*̿b]A=`kXaH``sbG?iz&M-Yשּׁ>pGPX? 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[(Summary)-332(of)-337(Studies)-336(Which)-332.1(Investigated)-334.8(How)-333(Biomaterial)-335.2(Cues)-334.2(Regulate)-338(Epigenetic)-336.1(State)-332.8(Through)-333.7(Nuclear)-337(Deformation)]TJ /F10 1 Tf -9.1676 -1.8715 TD [(First)-334.4(author,)]TJ 0 -1.0135 TD [(year,)-332(journal)-4648.5(Materials)-4330.2(Groups)-334.7(and)-331.2(descriptions)-5853.4(Cells)-5103.6(Keywords)-334.4(and)-337(categories)-7822(Main)-333.4(results)]TJ /F4 1 Tf 0 -1.9061 TD [(Vergani,)-336.1(2004,)]TJ .9905 -1.0135 TD [(Int)-331.4(J)-334.8(Biochem)]TJ T* [(Cell)-334.7(Boil)]TJ 0 7.3837 -6.5625 -0 143.7732 103.2945 Tm (30)Tj 0 9.845 -9.845 -0 128.2393 132.0945 Tm (Poly-HEMA)Tj .0345 -1.0135 TD (Collagen)Tj 8.8394 1.0135 TD [(Round)-334.2(vs.)-333.4(spreading)]TJ .0288 -1.0135 TD (Groups:)Tj T* [(Poly-HEMA)-335(\(decreased)]TJ .9617 -1.0077 TD (adhesiveness\))Tj -.9617 -1.0135 TD -.0227 Tc [(Co)5.1(llagen)-328.9(\()-.7(in)5.1(creased)-334.7(a)3.9(dhesiv)5.1(e)-1.8(ness\))]TJ 13.6996 4.0483 TD 0 Tc (Fibroblasts:)Tj .0288 -1.0135 TD [(Chinese)-338.5(hamster)]TJ .9617 -1.0135 TD [(ovary)-334.4(broblasts)]TJ 0 -1.0077 TD [(\(CHO)-334.8(clone)-335.7(K1\))]TJ 9.0927 3.0348 TD [(Nuclear)-339.7(deformation)]TJ .0345 -1.0135 TD [(Material)-335.3(chemistry)]TJ T* [(Chromatin)-335.1(remodeling)]TJ 12.4845 2.027 TD [(Cell)-334.7(rounding)-330.6(led)-338.3(to)-330.4(more)-334.5(inactive)]TJ .9905 -1.0135 TD (nucleosomes.)Tj -.9617 -1.0135 TD [(Three)-336.7(oncogene)-333.9(\(c-)]TJ /F10 1 Tf 7.9698 0 TD (myc)Tj /F4 1 Tf 1.6124 0 TD .3316 Tc [(,c)331.6(-)]TJ /F10 1 Tf 1.3648 0 TD 0 Tc (fos)Tj /F4 1 Tf 1.169 0 TD [(,)-331.6(and)-332.4(c-)]TJ /F10 1 Tf 3.1442 0 TD (jun)Tj /F4 1 Tf 1.2784 0 TD (\))Tj -15.5769 -1.0077 TD [(expressions)-335.4(were)-335.4(higher)-335.5(in)-336.2(rounded)-330.6(cells)]TJ 0 -1.0135 TD [(than)-333.5(in)-336.2(spreading)-333.7(cells.)]TJ -53.8482 -1.0135 TD [(Le)-332.6(Beyec,)-335.3(2007,)]TJ .9905 -1.0077 TD [(Exp)-332.4(Cell)]TJ 0 -1.0135 TD (Res)Tj 0 7.3837 -6.5625 -0 193.6062 81.2409 Tm (12)Tj 0 9.845 -9.845 -0 178.0724 132.0945 Tm (Collagen)Tj .0345 -1.0077 TD (Poly-HEMA)Tj 0 -1.0135 TD [(3D)-331(lrECM)]TJ 8.8394 2.0212 TD [(Round)-334.2(vs.)-333.4(spreading)]TJ .0288 -1.0077 TD (Groups:)Tj 0 -1.0135 TD (25)Tj /F11 1 Tf 1.169 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(square)-336.3(collagen-coated)]TJ -.7601 -1.0135 TD [(islands)-250(surrounded)-247(by)-249.6(pluronic)]TJ T* [(F108)-332(on)-336(PDMS)-333.5(substrate)-333.7(vs.)]TJ 0 -1.0077 TD [(collagen)-334.3(substrate)]TJ -.9617 -1.0135 TD [(poly-HEMA)-335.2(vs.)-333.4(tissue)-335.4(culture)]TJ .9617 -1.0135 TD (plastic)Tj -.9617 -1.0135 TD [(3D)-336.8(lrECM)-330.6(vs.)-339.2(tissue)-335.4(culture)]TJ .9617 -1.0077 TD (plastic)Tj 12.7379 9.1043 TD [(Epithelial)-336.8(cells:)]TJ .0288 -1.0077 TD (HMT-3522-S1)Tj .9617 -1.0135 TD [(and)-332.4(-T4-2)-340.1(human)]TJ T* [(mammary)-335.2(epithelial)]TJ T* (cells)Tj 9.0927 4.0483 TD [(Nuclear)-339.7(deformation)]TJ .0345 -1.0077 TD (Topography)Tj 0 -1.0135 TD [(Chromatin)-335.1(remodeling)]TJ .9617 -1.0135 TD [(\(histone)-331.7(acetylation\))]TJ 11.5229 3.0348 TD [(Cell)-334.7(rounding)-330.6(induced)-337.7(global)-335.7(histone)]TJ .9905 -1.0077 TD [(deacetylation)-336.1(\(deacetylation)-342.9(of)-330.2(histones)]TJ 0 -1.0135 TD [(H3)-331(and)-338.1(H4\),)-335.4(chromatin)-335.2(condensation,)-335.6(a)]TJ T* [(decrease)-255.5(in)-249.8(nuclear)-252.5(size,)-251.5(and)-246(a)-249.8(reduction)-253.5(in)]TJ T* [(gene)-248.2(expression)-248.2(\(according)-249.7(to)-244(microarray\).)]TJ -.9617 -1.0077 TD [(Disruption)-333.5(of)-336(the)-332.6(actin)-335.9(cytoskeleton)-338.2(with)]TJ .9617 -1.0135 TD [(cytochalasin)-339.4(D)-330.1(phenocopied)-337(the)-332.6(3D)]TJ T* [(lrECM-induced)-335.3(cell)-334.9(rounding)]TJ T* [(and)-332.4(histone)-336.5(deacetylation.)]TJ -53.8482 -2.0212 TD (Roca-Cusachs,)Tj .9905 -1.0135 TD (2008,)Tj 0 -1.0077 TD [(Biophys)-330.4(J)]TJ 0 7.3837 -6.5625 -0 293.2157 106.3559 Tm (11)Tj 0 9.845 -9.845 -0 277.6818 132.0945 Tm [(Fibronectin)-4251.9(Groups:)-336(round)-333.2(vs.)-333.4(elongated)]TJ 8.9027 -1.0135 TD [(Small)-335.7(vs.)-333.4(large)-335.7(spreading)-333.7(area)]TJ 0 -1.0077 TD [(Shape:)-336.5(circle,)-335.7(square,)-334(rectangle)]TJ 0 -1.0135 TD [(Spreading)-333.7(area:)-336.9(300,)-334.6(900,)]TJ .9617 -1.0135 TD [(and)-332.4(2500)]TJ /F11 1 Tf 3.9504 0 TD (m)Tj /F4 1 Tf .5471 0 TD (m)Tj 0 7.3837 -6.5625 -0 313.1715 281.1967 Tm (2)Tj 0 9.845 -9.845 -0 327.5149 219.7417 Tm [(Fibronectin-coated)-340.9(islands)]TJ .9617 -1.0077 TD [(surrounded)-333.4(by)-336(nonadhesive)]TJ 0 -1.0135 TD [(pluronic)-337.7(F108)]TJ 12.7379 7.083 TD [(Endothelial)-337.6(cells:)]TJ .0288 -1.0135 TD [(Lung)-333.4(human)]TJ .9617 -1.0077 TD (microvascular)Tj 0 -1.0135 TD [(endothelial)-337.6(cells)]TJ T* (\(HMVEC-L\))Tj 9.0927 4.0483 TD [(Nuclear)-339.7(deformation)-337.2(&)]TJ .9962 -1.0135 TD (Proliferation)Tj -.9617 -1.0077 TD (Topography)Tj 12.4845 2.0212 TD [(Larger)-303.1(spreading)-304.9(area)-306.9(with)-304.6(the)-303.8(same)-306.7(circular)]TJ .9905 -1.0135 TD [(shape)-335.4(induced)-331.9(increased)-341.8(cell)-334.9(stiffening,)]TJ 0 -1.0077 TD [(larger)-336.7(nuclear)-333.1(volume,)-334.3(increased)-341.8(DNA)]TJ 0 -1.0135 TD [(synthesis,)-335.8(increased)-336.1(cell)-334.9(proliferation,)]TJ T* [(and)-332.4(higher)-335.5(F-actin)-337.7(content.)]TJ -.9617 -1.0135 TD [(For)-319.5(equal)-324.2(spreading,)-319.8(cell)-323.4(elongation)-323.7(induced)]TJ .9617 -1.0077 TD [(a)-336.2(dramatic)-335.4(decrease)-336.1(in)-336.2(cell)-334.9(stiffness)-338.2(and)]TJ 0 -1.0135 TD [(contractility)-339.9(and)-332.4(an)-331.4(alignment)-335.4(of)]TJ T* [(actin)-335.9(laments.)]TJ -53.8482 -1.0135 TD [(Khatau,)-335.1(2009,)]TJ .9905 -1.0077 TD (PNAS)Tj 0 7.3837 -6.5625 -0 372.9259 91.5023 Tm (10)Tj 0 9.845 -9.845 -0 367.37 132.0945 Tm [(Fibronectin)-4251.9(Micro-stripes:)-339.9(10,)-327.8(30,)-333.6(50)]TJ /F11 1 Tf 19.2163 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj -9.9047 -1.0077 TD [(wide)-334.4(adhesive)-339.7(bronectin-)]TJ 0 -1.0135 TD [(coated)-337.9(micropatterned)]TJ T* [(stripes)-336.3(alternated)-337.6(with)-333.4(stripes)]TJ T* [(covered)-338.7(with)-333.4(nonadhesive)]TJ 0 -1.0077 TD [(polyethylene)-338.4(glycol)-335.7(\(PEG\))]TJ 12.7379 5.056 TD (Fibroblasts:)Tj .0288 -1.0077 TD [(Mouse)-335(embryonic)]TJ .9617 -1.0135 TD (broblasts)Tj 9.0927 2.0212 TD [(Nuclear)-339.7(deformation)]TJ .0345 -1.0077 TD (Topography)Tj 12.4845 1.0077 TD [(Topography)-305.9(regulated)-312.2(nuclear)-310.1(shape)-306.6(through)]TJ .9905 -1.0077 TD [(a)-336.2(dome-like)-335.2(actin)-335.9(cap)-333.5(composed)-333.7(of)]TJ 0 -1.0135 TD [(contractile)-338.8(actin)-335.9(lament)-333.1(bundles)]TJ T* [(containing)-335.2(phosphorylated)-338.8(myosin.)]TJ -.9617 -1.0135 TD [(The)-333.5(perinuclear)-338.4(actin)-335.9(cap)-333.5(was)-338.8(specically)]TJ .9617 -1.0077 TD [(disorganized)-257.4(or)-255.4(eliminated)-262.9(by)-249.6(inhibition)-258.4(of)]TJ 0 -1.0135 TD [(actomyosin)-267(contractility)-270.8(and)-269(rupture)-267.4(of)-261.1(the)]TJ T* [(LINC)-335.2(complexes,)-333.7(which)-335.4(connected)-342(the)]TJ 0 -1.0077 TD [(nucleus)-337.5(to)-330.4(the)-332.6(actin)-335.9(cap.)]TJ -53.8482 -1.0135 TD [(Thakar,)-335.3(2009,)]TJ .9905 -1.0135 TD [(Biophys)-330.4(J)]TJ 0 7.3837 -6.5625 -0 462.614 106.3559 Tm (31)Tj 0 9.845 -9.845 -0 457.0015 132.0945 Tm (PDMS)Tj .0345 -1.0135 TD (Fibronectin)Tj 8.8394 1.0135 TD (10)Tj /F11 1 Tf 1.1632 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-336.2(wide)-334.4(microgrooves)]TJ -1.6872 -1.0135 TD [(Fibronectin)-336.1(islands)-336.3(surrounded)]TJ .9617 -1.0135 TD [(by)-336(PEG)]TJ -.9617 -1.0077 TD [(Spreading)-333.7(area:)-336.9(1000,)-335.6(1500)]TJ /F11 1 Tf 11.4365 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj 0 7.3837 -6.5625 -0 482.5132 345.4865 Tm (2)Tj 0 9.845 -9.845 -0 496.8566 219.7417 Tm [(CSI:)-333.2(1\(circle\),)-338.6(0.45)-334.6(and)-332.4(0.3)]TJ .9617 -1.0135 TD (\(ellipse\))Tj 12.7379 5.0618 TD [(Vascular)-334.7(smooth)]TJ .9905 -1.0135 TD [(muscle)-337.7(cells)]TJ T* (\(SMCs\))Tj 9.0927 2.027 TD [(Nuclear)-339.7(deformation)-337.2(&)]TJ .9962 -1.0135 TD (Proliferation)Tj -.9617 -1.0135 TD (Topography)Tj 12.4845 2.027 TD [(Elongated)-335.2(SMCs)-333.7(demonstrated)-339.2(lower)-335.4(cell)]TJ .9905 -1.0135 TD [(and)-332.4(nucleus)-337.5(shape)-335.4(indices,)-335.3(less)-333.2(spreading.)]TJ -.9617 -1.0135 TD [(Neuron-derived)-335.1(orphan)-335.3(receptor-1)-336.1(\(NOR-1\))]TJ .9617 -1.0077 TD [(decreased)-337.1(according)-335.1(to)-336.2(DNA)-333.7(microarray)]TJ 0 -1.0135 TD [(proling)-284.5(in)-284.3(elongated)-289.2(SMCs)-281.8(and)-286.3(knocking)]TJ T* [(down)-333(NOR-1)-335.8(suppressed)-334.2(DNA)-339.4(synthesis)]TJ T* [(in)-330.4(SMCs.)]TJ 12.5997 -1.0077 TD (\()Tj /F10 1 Tf .334 0 TD (continued)Tj /F4 1 Tf 3.9561 0 TD (\))Tj /F6 1 Tf 8.9663 0 0 8.9663 299.6786 34.2425 Tm (116)Tj ET endstream endobj 96 0 obj <>stream 0 0 0 rg /GS1 gs 50.967 56.126 .28348 699.76 re f 79.994 56.126 .28346 699.76 re f BT /F7 1 Tf 0 9.845 -9.845 -0 45.5244 357.7322 Tm 0 Tc 0 Tw (Table)Tj /F4 1 Tf 3.0002 0 TD (1.)Tj /F7 1 Tf 1.2496 0 TD (\(Continued\))Tj /F10 1 Tf -34.8853 -1.8715 TD [(First)-340.1(author,)]TJ 0 -1.0135 TD [(year,)-337.7(journal)-4648.5(Materials)-4330.2(Groups)-334.6(and)-331.2(descriptions)-5853.4(Cells)-5103.6(Keywords)-334.4(and)-331.2(categories)-7827.8(Main)-333.4(results)]TJ /F4 1 Tf 0 -1.9061 TD [(Li,)-334.9(2011,)]TJ .9962 -1.0135 TD [(Biophys)-330.4(J)]TJ 0 7.3837 -6.5625 -0 98.3055 105.789 Tm (9)Tj 0 9.845 -9.845 -0 92.6929 131.5275 Tm [(PDMS)-6166.9(Microgrooves:)-332.9(10)]TJ /F11 1 Tf 16.2679 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(i)0(n)-336.2(width)]TJ -6.9563 -1.0135 TD [(and)-332.4(3)]TJ /F11 1 Tf 2.4474 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(i)0(n)-336.2(height,)-333.3(with)]TJ -3.0002 -1.0135 TD (10)Tj /F11 1 Tf 1.169 0 TD (m)Tj /F4 1 Tf .5471 0 TD [(m)-336.2(distance)-334.1(between)-339.7(each)]TJ -1.716 -1.0135 TD [(groove)-335.3(vs.)-333.4(no-pattern)-335.1(PDMS)]TJ -.9617 -1.0077 TD [(Mechanical)-339.4(stimulus:)]TJ .9617 -1.0135 TD [(compression)-336.7(or)-336(stretch)]TJ T* [(perpendicular)-340.4(to)-330.4(the)]TJ T* (microgrooves)Tj 12.7379 7.0888 TD [(hMSCs)-7095.2(Nuclear)-339.7(deformation)]TJ 10.1178 -1.0135 TD [(Topography&)-331.1(Mechanical)]TJ .9617 -1.0135 TD (stimulus)Tj -.9617 -1.0135 TD [(Chromatin)-335.1(remodeling)]TJ .9617 -1.0077 TD [(\(histone)-331.8(acetylation\))]TJ 11.5228 4.0483 TD [(MSCs)-333.7(on)-330.2(microgrooves)-337.9(\(10)]TJ /F11 1 Tf 11.4998 0 TD (m)Tj /F4 1 Tf .5471 0 TD [(m)-336.2(wide\))-335.4(had)]TJ -11.0564 -1.0135 TD [(elongated)-335.3(nuclear)-338.9(shape,)-333(a)-336.2(decrease)-336.1(in)]TJ T* [(HDAC)-335.7(activity,)-336.8(and)-332.4(an)-331.4(increase)-340.9(of)]TJ T* [(histone)-336.5(acetylation.)]TJ -.9617 -1.0077 TD [(Compression)-336.5(or)-330.2(stretch)-337.7(perpendicular)-340.4(to)-330.4(the)]TJ .9617 -1.0135 TD [(microgrooves)-297.5(caused)-297.2(a)-295.9(decrease)-301.5(in)-295.8(HDAC)]TJ T* [(activity,)-336.8(accompanied)-334.8(by)-336(the)-332.6(increase)-340.9(in)]TJ T* [(histone)-336.5(acetylation,)-336.4(and)-332.4(slight)-334.5(changes)-338.5(of)]TJ 0 -1.0077 TD [(nuclear)-333.1(shape.)]TJ -.9617 -1.0135 TD [(Knocking)-263.5(down)-258.1(nuclear)-264(matrix)-262(protein)-261.8(lamin)]TJ .9617 -1.0135 TD [(A/C)-333.2(abolished)-333.9(mechanical)-339.8(strain-induced)]TJ 0 -1.0077 TD [(changes)-332.7(in)-336.2(HDAC)-335.7(activity.)]TJ -53.8539 -1.0135 TD [(Versaevel,)-340.3(2012,)]TJ .9962 -1.0135 TD [(Nat)-333.4(Commun)]TJ 0 7.3837 -6.5625 -0 217.8708 120.1889 Tm (6)Tj 0 9.845 -9.845 -0 212.2582 131.5275 Tm [(Fibronectin)-4251.9(Shapes:)-331.6(circles,)-342.2(squares,)]TJ 9.8644 -1.0135 TD (rectangles)Tj -.9617 -1.0135 TD [(Aspect)-337.3(ratios)-335.5(1:2,)-334.8(1:4,)-329(and)-338.1(1:10)]TJ -.0403 -1.0077 TD [(Areas:)-337.3(600,)-334.6(800,)-334.6(1200,)-329.8(1600,)]TJ 1.002 -1.0135 TD (2000)Tj /F11 1 Tf 2.1652 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj 0 7.3837 -6.5625 -0 247.748 263.1117 Tm (2)Tj 0 9.845 -9.845 -0 212.2582 354.0471 Tm [(Endothelial)-337.6(cells:)]TJ .0288 -1.0135 TD [(Primary)-337.5(human)]TJ .9617 -1.0135 TD [(umbilical)-335.6(vein)]TJ 0 -1.0077 TD [(endothelial)-337.6(cells)]TJ 0 -1.0135 TD (\(ECs\))Tj 9.0927 4.0483 TD [(Nuclear)-339.7(deformation)-337.2(&)]TJ .9962 -1.0135 TD (Proliferation)Tj -.9617 -1.0135 TD (Topography)Tj 0 -1.0077 TD [(Chromatin)-335.1(remodeling)]TJ 12.4845 3.0348 TD [(Central)-333.1(actin)-335.9(bers)-334(generated)-336.3(lateral)]TJ .9905 -1.0135 TD [(compressive)-337.9(forces,)-334(and)-332.4(orientation)-336.4(and)]TJ T* [(deformation)-337.2(of)-330.2(the)-338.3(nucleus)-331.7(are)-339.3(regulated)]TJ 0 -1.0077 TD [(by)-330.2(lateral)-339.2(compressive)-337.9(forces)-336.3(driven)-335.5(by)]TJ 0 -1.0135 TD [(tension)-336.5(in)-330.4(central)-339(actomyosin)-336.1(bers.)]TJ -53.8539 -1.0135 TD [(Pan,)-335.6(2012,)]TJ .9962 -1.0135 TD (Biomaterials)Tj 0 7.3837 -6.5625 -0 267.6472 116.4472 Tm (7)Tj 0 9.845 -9.845 -0 262.0912 131.5275 Tm [(PLGA)-6271.9(Micropillars)-338.1(or)-330.2(micropits)]TJ 9.9047 -1.0135 TD [(with)-333.4(0.2,)-331.2(1,)-332.6(5)]TJ /F11 1 Tf 5.6952 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(height)]TJ 6.4496 1.0135 TD [(Bone)-334.4(marrow)-337.3(stromal)]TJ .9905 -1.0135 TD [(cells)-335.7(\(BMSCs\))]TJ 9.0927 1.0135 TD [(Nuclear)-339.7(deformation)]TJ .0345 -1.0135 TD (Topography)Tj 12.4845 1.0135 TD [(The)-333.6(nuclei)-336.9(of)-330.2(BMSCs)-335.7(were)-335.4(severely)]TJ .9905 -1.0135 TD [(deformed)-333.9(on)-336(PLGA)-334.8(micropillars)-338.4(of)-330.2(5)]TJ /F11 1 Tf 15.4674 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj -16.0203 -1.0077 TD [(height,)-333.3(3)]TJ /F11 1 Tf 3.7603 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(width,)-337.7(and)-332.4(6)]TJ /F11 1 Tf 6.4265 0 TD (m)Tj /F4 1 Tf .5528 0 TD [(m)-330.4(spacing.)]TJ -11.2925 -1.0135 TD [(Besides)-240.4(circular)-247.9(and)-240.2(elliptoid)-241.3(shapes,)-247.4(some)]TJ T* [(unusual)-336.3(nucleus)-331.7(shapes,)-339.5(such)-333.2(as)-331.2(square,)]TJ 0 -1.0077 TD [(cross,)-331.6(dumbbell,)-336.4(and)-332.4(asymmetric)-338.4(sphere)]TJ 0 -1.0135 TD [(protrusion)-332.6(have)-334.5(been)-334.5(achieved.)]TJ -.9617 -1.0135 TD [(Despite)-338.5(severe)-331.8(deformation)-337.2(of)-336(cell)-334.9(nuclei,)]TJ .9617 -1.0135 TD [(BMSCs)-335.6(were)-335.4(able)-334.7(to)-336.2(proliferate)-337.4(and)]TJ 0 -1.0077 TD (differentiate.)Tj -53.8539 -1.0135 TD [(Badique,)-336.3(2013,)]TJ .9962 -1.0135 TD (Biomaterials)Tj 0 7.3837 -6.5625 -0 367.3133 116.4472 Tm (4)Tj 0 9.845 -9.845 -0 361.7007 131.5275 Tm (PLLA)Tj .0288 -1.0135 TD (PDMS)Tj 8.8451 1.0135 TD [(Chemistry:)-336.1(PLLA)-335.2(vs.PDMS)]TJ .0288 -1.0135 TD [(Stiffness:)-339.3(PLLA)-329.4(485)-170(MPa,)]TJ T* [(PDMS)-333.5(2.5,)-337(6,)-332.6(12)-163.2(MPa)]TJ 0 -1.0077 TD [(Topography:)-335.9(micropillars)-338.4(with)]TJ .9617 -1.0135 TD [(length)-335.7(of)-330.2(pillars)-336.7(and)-332.4(distances)]TJ T* [(between)-333.9(pillars)-336.7(in)-336.2(the)-332.6(range)]TJ T* [(from)-333.4(2)-335(t)0(o)-330.4(2)0(0)]TJ /F11 1 Tf 5.3958 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj 6.7893 6.0753 TD [(osteosarcoma)-340(cells:)]TJ .0288 -1.0135 TD (SaOs-2)Tj T* (MG-63)Tj 0 -1.0077 TD [(OHS-4)-334.7(cells)]TJ 10.0544 3.0348 TD [(Nuclear)-339.7(deformation)]TJ .0345 -1.0135 TD [(Chemistry)-334.9(&)-330.4(Stiffness)-338.2(&)]TJ .9617 -1.0135 TD (Topography)Tj 11.5228 2.027 TD [(Nucleus)-332.6(deformation)-337.2(could)-334.5(be)-337.2(strongly)]TJ .9905 -1.0135 TD [(modulated)-335.2(by)-330.2(geometric)-336.4(constraints,)-339.3(for)]TJ T* [(example,)-337.6(topographies)-331.1(with)-339.1(varying)-330.7(pillar)]TJ 0 -1.0077 TD [(size)-334.5(and)-332.4(spacing.)-335.1(Chemistry)-340.7(and)-332.4(stiffness)]TJ 0 -1.0135 TD [(had)-332.4(no)-336(dominant)-333.1(effect)-337.9(on)-330.2(deformation.)]TJ -.9617 -1.0135 TD [(The)-241.4(dominant)-240.9(parameters)-240.3(inuencing)-242.8(nuclear)]TJ .9617 -1.0135 TD [(deformation)-239.3(on)-238.1(micropillar)-245.4(substrates)-236.7(were)]TJ 0 -1.0077 TD [(the)-332.6(substrate)-339.5(geometry)-334.1(together)-333.1(with)-339.1(cell)]TJ 0 -1.0135 TD [(phenotype)-333.9(and)-332.4(cytoskeleton)-338.2(organization.)]TJ -53.8539 -1.0135 TD [(Jain,)-336.7(2013,)]TJ .9962 -1.0077 TD (PNAS)Tj 0 7.3837 -6.5625 -0 456.9448 90.9354 Tm (5)Tj 0 9.845 -9.845 -0 451.3889 131.5275 Tm [(Fibronectin)-4251.9(Areas)]TJ 8.9027 -1.0077 TD [(Aspect)-337.3(ratio:)-335.9(square)-336.3(\(AR)-333(1:1\),)]TJ .9617 -1.0135 TD [(rectangle)-336.4(\(AR)-338.8(1:5\))-332.4(of)-330.2(equal)]TJ T* [(area)-335.7(\(1800)]TJ /F11 1 Tf 4.5089 0 TD (m)Tj /F4 1 Tf .5528 0 TD (m)Tj 0 7.3837 -6.5625 -0 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7g_dx[.1EO֧}?3~ygN9Oܭ?__kq߯ ==_#?jq[*~Qn-sS7GX?w[A:w'i+?ڂ2%v2?э"O,|5(?hƚ> >?TSccf_?1tTHu}CjW=vW_lp\WʍrҐ.T06!*UlUثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb endstream endobj 138 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(applications)-570(in)-561(regenerative)-566.4(medicine,)-564.4(disease)-569.6(modeling,)]TJ 0 -1.1174 TD [(and)-615(drug)-620.7(screening.)-615.8(Patient-specic)-627.1(somatic)-616.1(cell)-623.3(repro-)]TJ 0 -1.1116 TD [(gramming)-369.6(is)-365(likely)-365.3(to)-365.2(have)-363.8(a)-365.1(large)-370.8(impact)-361.8(on)-365.1(medicine)-370.9(by)]TJ T* [(providing)-470.9(a)-474.6(source)-475.2(of)-468.7(cells)-474.4(for)-469.8(disease)-477.5(modeling)-472.2(and)-471(re-)]TJ T* [(generative)-712.8(medicine.)-708.4(In)-704.8(2006,)-704.8(terminally)-712(differentiated)]TJ 0 -1.1174 TD [(mammalian)-322.6(cells)-324.7(were)-324.4(reprogrammed)-324.3(for)-320(the)-315.6(rst)-320.9(time)-323.8(to)-319.1(a)]TJ 0 -1.1116 TD [(pluripotent)-491.8(state)-485.9(by)-486(transfer)-494.8(of)-486(a)-486.1(combination)-494.1(of)-486(dened)]TJ T* [(genetic)-460.7(factors.)]TJ 7.3823 0 0 6.5614 124.4976 652.8187 Tm (42)Tj 9.843 0 0 9.843 136.4031 648.4534 Tm [(Now)-454.3(it)-463.2(is)-457.1(well)-461.7(recognized)-459.3(that)-460.8(induced)]TJ -7.5567 -1.1174 TD [(pluripotent)-238.4(stem)-242.9(cells)-238.3(\(iPSCs\))-238.7(can)-236(be)-239.5(produced)-241.5(from)-236(somatic)]TJ 0 -1.1116 TD [(cells)-301.6(by)-295.9(the)-304.1(forced)-296.9(expression)-306.8(of)-295.9(four)-298.1(or)-301.7(fewer)-302.4(transcription)]TJ T* [(fa)19.7(c)15(t)0(o)20.7(r)0(s)-243.9(\()0(f)20.9(o)16.2(r)-260.2(e)15(xa)19.7(m)15(p)0(l)20.7(e)0(,)]TJ /F10 1 Tf 8.461 0 TD [(Oc)18.8(t4)]TJ /F4 1 Tf 2.1714 0 TD [(\(O)25.8(\),)]TJ /F10 1 Tf 1.8546 0 TD [(So)26.6(x2)]TJ /F4 1 Tf 2.1656 0 TD [(\(S)21(\),)]TJ /F10 1 Tf 1.6934 0 TD -.0152 Tc [(Kl)-15.2(f)5.4(4)]TJ /F4 1 Tf 1.9468 0 TD 0 Tc [(\(K)20(\))16.2(,)-256.9(an)19.7(d)]TJ /F10 1 Tf 3.5365 0 TD [(c-)19.7(M)15.1(y)0(c)]TJ /F4 1 Tf -21.8293 -1.1174 TD [(\()-81.7(M\),)-334.8(or)]TJ /F10 1 Tf 3.3867 0 TD (Oct4)Tj /F4 1 Tf 1.9468 0 TD (,)Tj /F10 1 Tf .5817 0 TD (Sox2)Tj /F4 1 Tf 1.9525 0 TD (,)Tj /F10 1 Tf .5817 0 TD (Nanog)Tj /F4 1 Tf 2.6667 0 TD [(,)-331.7(and)]TJ /F10 1 Tf 2.3615 0 TD (Lin28)Tj /F4 1 Tf 2.3327 0 TD (\).)Tj 7.3823 0 0 6.5614 223.4267 608.9951 Tm (4345)Tj 9.843 0 0 9.843 72 593.6313 Tm [(However,)-343.5(low)-338.4(reprogramming)-347.5(efciency)-342.8(and)-338.5(safety)-342.9(con-)]TJ -1.0137 -1.1116 TD [(sideration)-370.6(has)-361.4(hindered)-368.3(its)-366.2(clinical)-369.9(transformation.)-368.1(Barriers)]TJ T* [(for)-417.9(reprogramming)-422.3(are)-414.5(known)-421.1(to)-417(be)-418.1(attributable)-420.5(in)-417(epige-)]TJ 0 -1.1174 TD [(netic)-359.4(state,)-356.9(reecting)-353.3(the)-355.9(remarkable)-362.5(stability)-357.1(of)-353.5(the)-355.9(differ-)]TJ 0 -1.1116 TD [(entiated)-611.7(state)-606.9(of)-606.9(somatic)-610.3(cells.)-610.3(The)-610.4(success)-609.6(of)-606.9(nuclear)]TJ T* [(reprogramming)-491.4(is)-491.7(limited)-488.7(by)-486(epigenetic)-494.1(mechanisms)-489(that)]TJ 0 -1.1174 TD [(stabilize)-411.1(the)-407.8(state)-411.1(of)-405.3(gene)-404.2(expression)-410.5(in)-405.5(somatic)-414.5(cells)-405.3(and)]TJ 0 -1.1116 TD [(thereby)-488.2(resist)-485.7(efcient)-484.7(reprogramming.)-489.1(Transcription)-484.5(fac-)]TJ T* [(tors,)-531.9(chromatin)-537.8(modications,)-538.6(and)-534.4(noncoding)-529.6(RNAs)-536.9(can)]TJ 0 -1.1174 TD [(regulate)-582.7(the)-574.8(efciency)-579(of)-578.1(reprogramming.)]TJ 7.3823 0 0 6.5614 239.7543 499.4077 Tm (46)Tj 9.843 0 0 9.843 252.7936 494.9857 Tm [(Histone)-580(H3)]TJ -19.3814 -1.1116 TD [(acetylation)-443.5(\(AcH3\))-447.2(is)-439.9(known)-438.4(to)-440.1(be)-441.1(a)-440(permissive)-446.4(environ-)]TJ T* [(ment)-398.6(for)-400.7(reprogramming)-405(by)-399.6(stemness)-397.8(factors,)-405(thus)-396(HDAC)]TJ 0 -1.1174 TD [(acts)-559.6(as)-556.1(an)-556.3(inhibitor)-551.8(of)-555.1(reprogramming.)-564(HDAC)-555.2(inhibitor)]TJ 0 -1.1116 TD [(chemical)-481.5(compounds,)-482.1(such)-483.4(as)-481.2(valproic)-477.9(acid)-484.9(\(VPA\),)-477(have)]TJ T* [(shown)-438.2(great)-434.1(promise)-436.2(in)-434.3(enhancing)-434(the)-436.6(efciency)-435(of)-434.1(iPSC)]TJ T* [(formation)-340.8(and)-338.5(even)-340.8(eliminate)-343.5(the)-338.7(need)-340.8(for)-337.3(some)-340.7(oncogenic)]TJ 0 -1.1174 TD [(transcription)-448.9(factors)-453.4(such)-448.9(as)]TJ /F10 1 Tf 12.2567 0 TD (c-Myc)Tj /F4 1 Tf 2.9547 0 TD (and)Tj /F10 1 Tf 1.8949 0 TD (Klf4)Tj /F4 1 Tf 1.7279 0 TD [(.)-446.9(Meanwhile,)]TJ -18.8342 -1.1116 TD [(one)-442.2(of)-434.1(the)-442.3(rst)-441.9(noticeable)-442.3(changes)-443(during)-438.7(the)-436.6(reprogram-)]TJ T* [(ming)-587.5(of)-589.7(somatic)-593.1(broblasts)-593.6(is)-589.6(their)-588.6(transformat)-9.9(ion)-585.2(into)]TJ 0 -1.1174 TD [(tightly)-451.7(packed)-453.6(clusters)-454.5(of)-451.4(rounded)-458.1(cells)-451.4(in)-451.6(a)-451.5(process)-453.1(that)]TJ 0 -1.1116 TD [(resembles)-889.8(mesenchymal-to-epithelial)-897(transition)-887.9(\()-81.7(MET\),)]TJ T* [(which)-445.4(plays)-444.3(an)-446.9(essential)-445.4(role)-443.4(in)-445.8(initiating)-444.9(reprogramming)]TJ 0 -1.1174 TD [(into)-373.3(iPSCs.)]TJ 7.3823 0 0 6.5614 107.5464 356.9385 Tm (47)Tj 9.843 0 0 9.843 118.6582 352.5164 Tm [(Higher)-371.6(H3K4)-380.5(methylation)-379.1(level)-376.7(is)-370.8(correlated)]TJ -5.7539 -1.1116 TD [(with)-235.9(MET)-237(process,)-231.9(thus)-234.7(histone)-239.3(demethylase)-236.9(inhibitors,)-233.6(such)]TJ T* [(as)-573.4(tranylcypromine)-574.5(hydrochloride,)-573.2(can)-570.1(also)-570(increase)-572.1(the)]TJ T* [(efciency)-337(of)-336.2(cell)-335.3(reprogramming)-335.9(\(Fig.)-336.1(5\).)]TJ 1.0137 -1.1174 TD [(Interestingly,)-250.7(biomaterial)-253.5(topography)-248.4(has)-246.2(been)-248.6(discovered)]TJ -1.0137 -1.1116 TD [(to)-250(replace)-254.4(the)-252.3(effects)-253(of)-249.8(small-molecule)-259(epigenetic)-252.2(modiers)]TJ T* [(and)-488.3(signicantly)-488(improve)-488.3(reprogramming)-485.7(efciency,)-490.2(pro-)]TJ 0 -1.1174 TD [(viding)-427.3(a)-422.7(safer)-428(and)-419.2(more)-427.2(convenient)-429.5(alternative)-426.2(to)-422.8(cell)-427.4(re-)]TJ 0 -1.1116 TD [(programming.)-249.6(Specically,)-256.4(topographies)-246(of)-249.8(microgrooves)-252.8(or)]TJ T* [(aligned)-263.7(nanobers)-259.5(provoke)-262.3(an)-256.8(increase)-266.8(in)-255.8(AcH3,)-264.2(H3K4me2,)]TJ 0 -1.1174 TD [(and)-390.4(H3K4me3,)-395.4(through)-387.9(downregulation)-399.1(of)-388.1(HDAC)-394(activity)]TJ 0 -1.1116 TD [(and)-332.8(upregulation)-326.9(of)-330.5(the)-332.9(expression)-329.8(of)-330.5(WD)-327.9(repeat)-332.7(domain)-331.7(5)]TJ T* [(\(WDR5\),)-463.4(a)-457.3(subunit)-457(of)-462.9(H3)-458.1(methyltransferase,)-466.9(thus)-459.4(signi-)]TJ 0 -1.1174 TD [(cantly)-464.2(enhancing)-468.6(reprogramming)-462.6(efciency)-469.5(in)-463.1(broblasts.)]TJ 0 -1.1116 TD [(Blebbistatin,)-458.2(inhibitor)-453.9(of)-451.4(myosin-II)-454.5(disrupting)-448.9(actomyosin)]TJ T* [(contractility,)-448.2(can)-449.1(eliminate)-447.1(these)-445.5(effects.)-452.2(Meanwhile,)-445.1(par-)]TJ T* [(allel)-325(microgrooves)-321.9(have)-323.5(also)-322.3(drawn)-324.3(attention)-323.8(in)-319.1(the)-321.4(eld)-322.3(of)]TJ 0 -1.1174 TD [(cardiac)-582.7(tissue)-577.8(engineering.)-578(No)-579(single)-572.3(cockt)-8(ail)-574.9(or)-578.1(repro-)]TJ 0 -1.1116 TD [(gramming)-565.5(strategy)-569.9(has)-563(yet)-563.3(become)-570(a)-560.9(gold)-569(standard)-564(for)]TJ T* [(conversion)-341.6(of)-342(somatic)-339.6(cells)-342(to)-342.1(cardiomyocyte-like)-344.1(cells)-342(be-)]TJ 0 -1.1174 TD [(cause)-383.2(of)-382.3(the)-379(low)-384.4(reprogramming)-382(efciency.)-386.6(Under)-381.9(the)-379(ex-)]TJ 0 -1.1116 TD [(istence)-662.1(of)-653(myocardin,)-662.1(Tbx5,)-654.1(and)-655.3(Mef2c,)-663(microgrooves)]TJ T* [(mimic)-516.2(the)-517.2(effects)-517.9(of)-514.8(VPA)-511.7(and)-517.1(markedly)-519.3(augmented)-515.9(the)]TJ 0 -1.1174 TD [(expression)-393.2(of)-393.8(cardiomyocyte-specic)-401.1(proteins.)-393.6(In)-393.8(addition,)]TJ 0 -1.1116 TD [(the)-574.8(anisotropy)-576.7(resulting)-581.4(from)-570(parallel)-582.9(microgrooves)-575.3(can)]TJ T* [(induce)-325.8(cellular)-323.7(alignment,)-322.6(mimicking)-325(the)-321.4(native)-326(ventricular)]TJ 0 -1.1174 TD [(myocardium)-724.3(and)-718.7(augmenting)-729(sarcomere)-724(organization.)]TJ 7.3823 0 0 6.5614 293.7259 72 Tm (39)Tj 9.843 0 0 9.843 62.022 56.6362 Tm [(Moreover,)-424.4(graphene)-427(can)-420.3(also)-426(improve)-424.9(cellular)-421.6(reprogram-)]TJ 25.504 67.9184 TD [(ming)-322.5(efciency)-325.5(by)-319(inducing)-321.3(MET)-323.4(process,)-324.1(which)-324.5(is)-318.9(known)]TJ 0 -1.1174 TD [(to)-261.5(affect)-263.6(H3K4me3)-259.5(levels.)]TJ 7.3823 0 0 6.5614 417.4865 718.5825 Tm (38)Tj 9.843 0 0 9.843 427.4644 714.1605 Tm [(Compared)-261(with)-259(small-molecule)]TJ -11.6231 -1.1116 TD [(drug,)-555(using)-546.8(biomaterials)-559.6(to)-549.5(enhance)-553.8(cell)-554.2(reprogramming)]TJ T* [(efciency)-579(is)-566.6(safer)-572(and,)-572.3(therefore,)-569.8(more)-571.2(potential)-571.5(in)-572.5(the)]TJ T* [(clinical)-341.1(use)-332.6(of)-336.2(human)-330.4(cells)-336.2(\(Table)-338.5(3)-335.2(and)-332.8(Fig.)-335(5\).)]TJ /F2 1 Tf 8.9663 0 0 8.9663 323.0361 659.3384 Tm [(Stem)-494.3(cell)-491.1(differentiation.)]TJ /F4 1 Tf 9.843 0 0 9.843 432.2267 659.3384 Tm [(Stem)-473.3(cells)-480.2(demonstrate)-483.4(pref-)]TJ -12.1069 -1.1174 TD [(erential)-358.2(lineage)-351.3(biases)-354.3(during)-352.3(differentiation)-354.6(by)-353.5(responding)]TJ 0 -1.1116 TD [(to)-428.5(material)-434.3(cues)-427(including)-426.2(topography,)-430.4(material)-434.4(chemistry)]TJ T* [(and)-240.6(substrate)-236.7(elasticity.)-243(Therefore,)-242.6(tailored)-236.1(biomaterials)-242.9(play)]TJ 0 -1.1174 TD [(impor)-6.8(tant)-535.7(roles)-542.2(in)-538(osteogenic,)-547.9(chondrogenic,)-538.6(neurogenic,)]TJ 0 -1.1116 TD [(and)-292.4(cardiogenic)-293.5(differentiation.)-294.7(Biomaterials)-295.7(inuence)-294.5(stem)]TJ T* [(cell)-554.2(lineage)-547.1(commitment)-553.1(and)-545.9(facilitate)-551.9(differentiation)-550.5(of)]TJ 0 -1.1174 TD [(stem)-467.5(cells)-462.9(especially)-470.9(under)-461.7(the)-465.4(existence)-463.9(of)-462.9(chemical)-464.2(in-)]TJ 0 -1.1116 TD [(duction)-516(medium.)-514.9(The)-512.5(structural)-514.6(composition)-515.8(of)-509(both)-517.1(the)]TJ T* [(nucle)-8(us)-457(and)-459.5(the)-459.6(cytoskeleton)-460.4(alters)-464(in)-457.3(differentiated)-464(stem)]TJ T* [(cells,)-506.7(bu)20.8(t)-490.8(w)0(h)20(e)0(t)19.5(h)0(e)19.7(r)-490.6(nu)20.8(cl)19.5(ea)18.5(r)-490.6(s)0(t)20.9(i)0(f)20.7(f)0(n)20.9(e)0(s)14.1(s)-484.7(in)15(cr)19.7(ea)18.5(se)19.9(s)-490.5(o)0(r)-480.2(d)0(e)19.7(c)0(r)19.7(e)0(a)18.5(s)0(e)19.9(s)]TJ 0 -1.1174 TD [(wi)14.1(th)-359.4(on)20.8(se)19.9(t)-369.8(o)0(f)-359.3(d)0(i)20.7(f)0(f)15.1(e)0(r)19.7(e)0(n)19.7(t)0(i)20.6(a)0(t)19.6(i)0(o)20.7(n)-369.7(re)19.7(ma)18.4(in)-359.4(co)19.7(nt)14.9(ro)20.9(ve)19.7(rs)21.1(ia)19.6(l.)-361.8(So)21(me)-361.7(re)19.7(-)]TJ 0 -1.1116 TD [(se)14.1(ar)19.7(ch)19.7(es)-394.8(pr)20.9(op)20.8(os)21(e)-405.4(t)0(h)20.7(a)0(t)-395.2(w)0(i)19.8(t)0(h)-394(t)0(h)20.7(e)-399.7(be)13.9(gi)20.7(nn)20.8(in)20.7(g)-404.3(o)0(f)-388.1(d)0(i)14.9(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(t)0(i)20.6(a)0(t)19.5(i)0(o)15(n)0(,)]TJ T* [(nu)15.1(cl)19.5(ea)18.5(r)-248.7(s)0(t)15.1(i)0(f)20.7(f)0(n)20.9(e)0(s)19.9(s)-254.3(in)20.7(cr)19.7(ea)18.5(se)19.9(s,)-246.2(wh)20(ic)19.6(h)-254.5(m)0(e)18.4(a)0(n)19.7(s)-248.6(in)20.7(cr)14(ea)18.5(se)19.9(d)-248.8(l)0(a)13.8(m)15(in)-244.2(A/)19.8(C)]TJ 0 -1.1174 TD [(le)13.8(ve)19.7(l.)]TJ 7.3823 0 0 6.5614 334.2046 510.2361 Tm [(2,)20.4(4)16.2(8)0(,)20.4(4)16.2(9)]TJ 9.843 0 0 9.843 359.1495 505.8707 Tm [(Wh)18.6(il)20.6(e)-342.1(t)0(h)20.7(e)-336.3(ot)20.7(he)19.7(rs)-330.3(ho)20.8(ld)-330.6(th)20.7(e)-336.3(i)0(d)15(e)0(a)-327.1(t)0(h)20.7(a)0(t)-331.8(n)0(u)20.8(c)0(l)19.6(e)0(a)18.5(r)-340.9(st)20.9(if)20.7(f-)]TJ -4.6826 -1.1116 TD [(ne)13.9(ss)-255.2(de)19.7(cr)19.7(ea)18.5(se)14.1(s)-265.9(w)0(i)19.8(t)0(h)-255.8(l)0(o)15(w)0(e)18.8(r)-266(la)19.5(mi)19.5(n)-266(A)0(/)19.8(C)-272.8(le)19.5(ve)19.7(l.)]TJ 7.3823 0 0 6.5614 481.3794 499.2944 Tm (3)Tj 9.843 0 0 9.843 487.6723 494.929 Tm [(Un)20(li)14.8(ke)-256.8(ab)19.7(un)20.8(da)19.7(nt)]TJ -17.7399 -1.1116 TD [(st)15.1(ud)20.8(ie)19.5(s)-306.2(o)0(n)-301.7(c)0(e)18.5(l)0(l)-296.2(s)0(h)21(a)0(p)19.7(e)-313.3(an)19.7(d)-306.4(n)0(u)20.8(c)0(l)19.5(e)0(a)18.5(r)-312.1(de)19.7(fo)20.9(rm)19.6(at)19.5(io)20.7(n,)-298.3(re)19.7(se)19.9(ar)13.9(ch)19.7(es)-296.9(on)]TJ 0 -1.1174 TD [(ho)15.1(w)-399.4(e)0(p)19.7(i)0(g)20.7(e)0(n)19.7(e)0(t)19.5(i)0(c)-389.4(r)0(e)19.7(g)0(u)20.8(l)0(a)19.6(t)0(i)20.6(o)0(n)15.1(s)-398.3(mo)19.6(du)20.8(la)19.5(te)-389.4(st)20.9(em)-390.5(ce)18.5(ll)-388.4(li)20.6(na)19.7(ge)-389.3(co)19.7(m-)]TJ 0 -1.1116 TD [(mi)19.5(tm)19.5(en)13.9(t)-485(r)0(e)19.7(m)0(a)18.4(i)0(n)-474.6(l)0(i)20.6(m)0(i)19.5(t)0(e)19.6(d)0(.)-476.8(T)0(h)19.6(e)-486.1(st)15.1(em)-476.9(ce)18.5(ll)-474.8(tr)20.7(an)19.7(sc)19.9(ri)15(pt)20.7(om)19.6(e)-486.1(a)0(l)19.5(s)0(o)]TJ T* [(ex)13.9(hi)20.7(bi)20.7(ts)-318.9(va)19.7(ri)20.7(ab)19.7(le)-320.3(ex)19.7(pr)20.9(es)19.9(si)15.1(on)-319(of)-313.2(ke)13.9(y)-323.6(r)0(e)19.7(g)0(u)15.1(l)0(a)19.5(t)0(o)20.7(r)0(y)-318.9(g)0(e)19.7(n)0(e)-320.1(p)0(r)20.9(o)0(d)20.8(u)0(c)19.7(t)0(s)]TJ 0 -1.1174 TD [(th)15(at)-366.4(is)-365(ut)20.7(il)20.6(iz)19.6(ed)-366.2(fo)20.9(r)-381.2(d)0(i)20.7(s)0(t)20.9(i)0(n)20.7(c)0(t)-366.4(d)0(i)20.7(f)0(f)15.1(e)0(r)19.7(e)0(n)19.7(t)0(i)20.6(a)0(t)19.6(i)0(o)20.7(n)-375.5(po)20.8(te)19.5(nt)15(ia)19.5(l)-375.6(a)0(n)19.7(d)-375.5(po)20.8(s-)]TJ 0 -1.1116 TD [(si)15.1(bl)20.7(y)-381.2(p)0(r)20.9(o)0(v)20.8(i)0(d)20.7(e)0(s)-371.8(h)0(e)19.7(t)0(e)13.8(r)0(o)20.9(g)0(e)19.7(n)0(e)19.7(o)0(u)20.8(s)-381(me)18.4(ch)19.7(an)19.7(ic)19.6(al)-372.1(pr)15.1(op)20.8(er)19.7(ti)20.6(es)-371.8(to)-370.9(st)20.9(em)]TJ T* [(ce)12.8(ll)20.6(s.)-373(In)-376.5(ad)19.7(di)20.7(ti)20.6(on)20.8(,)-383.6(a)0(c)18.5(t)0(i)20.6(v)0(a)13.9(t)0(i)20.6(o)0(n)-370.8(o)0(f)-376.5(m)0(y)19.6(o)0(c)19.7(a)0(r)19.7(d)0(i)20.7(n)0(-)20.9(r)0(e)14(l)0(a)19.5(t)0(e)19.5(d)-381.2(tr)15(an)19.7(sc)19.9(ri)20.7(p-)]TJ T* [(ti)14.8(on)-445.7(fa)19.7(ct)19.5(or)20.9(,)-458.4(a)0(n)-441.1(a)0(c)18.5(t)0(i)14.8(n)0(-)20.9(d)0(e)19.7(p)0(e)19.7(n)0(d)20.8(e)0(n)19.7(t)-456.2(tr)20.7(an)19.7(sc)14.1(ri)20.7(pt)20.7(io)20.7(n)-456.1(c)0(o)19.7(f)0(a)19.7(c)0(t)19.5(o)0(r)15.1(,)-452.7(ha)19.7(ve)]TJ 0 -1.1174 TD [(be)13.9(en)-366.2(sh)21(ow)20(n)-381.2(t)0(o)-365.2(u)0(p)20.8(r)0(e)14(g)0(u)20.8(l)0(a)19.6(t)0(e)-366.3(i)0(t)20.6(s)-381(ta)19.6(rg)20.9(et)-372.1(ge)19.7(ne)19.7(s)-381(i)0(n)20.7(v)0(o)20.8(l)0(v)20.7(e)0(d)-366.2(i)0(n)-370.9(a)0(c)18.5(t)0(i)20.6(n)]TJ 0 -1.1116 TD [(cy)13.9(to)20.7(sk)21(el)19.5(et)19.6(on)-272.9(pa)19.7(th)20.7(wa)18.8(y)-277.6(t)0(o)-273(s)0(t)20.9(a)0(b)19.7(i)0(l)20.6(i)0(z)13.8(e)-278.7(nu)20.8(cl)19.6(ea)18.5(r)-283.3(m)0(o)19.6(r)0(p)20.9(h)0(o)20.8(l)0(o)20.7(g)0(y)-272.9(d)0(u)20.8(r)0(i)20.7(n)0(g)]TJ T* [(ce)12.8(ll)20.6(ul)20.7(ar)-314.4(di)20.7(ff)20.9(er)19.7(en)19.7(ti)14.8(at)19.5(io)20.7(n.)]TJ 1.0137 -1.1174 TD [(Histone)-557(modication)-557.3(is)-555.1(an)-550.5(important)-559.8(epigenetic)-557.5(regu-)]TJ -1.0137 -1.1116 TD [(lation)-492(method)-481.4(which)-491.5(inuences)-485.5(gene)-490.5(expression)-485.3(and)-488.3(cell)]TJ T* [(differentiation.)-484.8(Our)-476.4(research)-479.7(group)-472(has)-476.6(revealed)-480.1(how)-476.5(na-)]TJ 0 -1.1174 TD [(notubes)-435(promote)-436.4(osteogenic)-440.8(differentiation)-435.3(through)-434(epige-)]TJ 0 -1.1116 TD [(netic)-474.6(regulation.)-472.2(Titanium)-467.8(dioxide)-469.9(\(TiO)]TJ 7.3823 0 0 6.5614 478.488 317.9338 Tm (2)Tj 9.843 0 0 9.843 482.1731 319.5779 Tm [(\))-467.6(nanotubes)-473(with)]TJ -17.1812 -1.1116 TD [(the)-465.4(dimension)-461.6(of)-457.2(70)-169.2(nm)-458.4(diameter)-463(promote)-465.2(the)-459.6(osteogenic)]TJ T* [(differentiation)-354.6(especially)-355.7(under)-352.2(the)-350.2(condition)-351.3(of)-347.7(osteogenic)]TJ 0 -1.1174 TD [(medium,)-440(and)-442.2(this)-436.4(promotion)-437.6(is)-439.9(based)-439.6(on)-434.2(enhanced)-445.4(H3K4)]TJ 0 -1.1116 TD [(methylatio)-9.3(n)-496.4(level)-497.7(at)-498.8(the)-499.9(promoter)-500.8(regions)-504.1(of)-497.5(osteogenic-)]TJ T* [(related)-633.5(genes)-629.7(by)-630(inhibiting)-628(histone)-631(demethylase)-634.4(retino-)]TJ 0 -1.1174 TD [(blasto)-7.8(ma)-505.7(protein)-504.4(2)-507.9(\(RBP2\).)]TJ 7.3823 0 0 6.5614 429.1086 258.1795 Tm (34)Tj 9.843 0 0 9.843 441.4676 253.8141 Tm [(Later,)-513.7(we)-505.3(discover)-506.4(similar)]TJ -13.0457 -1.1116 TD [(phenomenon)-273.8(in)-267.3(single-layered)-273.6(graphene.)]TJ 7.3823 0 0 6.5614 474.2928 247.2377 Tm (35)Tj 9.843 0 0 9.843 484.3274 242.8724 Tm [(Another)-269(research)]TJ -17.4001 -1.1116 TD [(also)-552.7(demonstrates)-547.7(that)-553(retinoblastoma)-550.3(protein)-550.5(are)-547(down-)]TJ 0 -1.1174 TD [(regulated)-416.8(in)-405.5(MSCs)-414.9(cultured)-408.8(on)-411.1(PDMS)-409(substrates)-410.4(with)-408.7(na-)]TJ 0 -1.1116 TD [(nogratings)-380.8(of)-376.5(350)-170.3(nm)-372(linewidth,)-378.8(700)-170.3(nm)-377.8(pitch,)-373.2(and)-378.8(280)-164.6(nm)]TJ T* [(depth)-254.5(compared)-261.2(with)-253.2(planar)-256.7(substrates.)]TJ 7.3823 0 0 6.5614 467.5463 203.4141 Tm (3)Tj 9.843 0 0 9.843 473.7258 199.0488 Tm [(Therefore,)-254.1(common)]TJ -16.323 -1.1174 TD [(mech)-8(anisms)-342.8(underlie)-345.4(how)-344(biomaterials)-352.3(promote)-344.3(osteogenic)]TJ 0 -1.1116 TD [(differentiation)-343.1(of)-330.5(cells)-336.2(\(Table)-338.5(2\).)]TJ 1.0137 -1.1116 TD [(Meanwhile,)-617.9(with)-610.3(the)-609.4(recen)-9(t)-606(progress)-614.3(of)-612.7(micro-RNAs)]TJ -1.0137 -1.1116 TD [(\(miRNAs\))-502.3(containing)-503.3(highly)-496.4(conserved)-502.8(noncoding)-500.8(RNAs)]TJ 0 -1.1174 TD [(with)-247.4(lengths)-239.3(ranging)-245.1(from)-241.7(18)-244.1(to)-238.5(23)-244.1(nucleotides,)]TJ 7.3823 0 0 6.5614 499.918 148.5921 Tm (50)Tj 9.843 0 0 9.843 509.7258 144.2267 Tm [(it)-238.6(becomes)]TJ -19.9804 -1.1116 TD [(clear)-314.4(that)-311.1(the)-304.1(signaling)-310.8(networks)-310.3(are)-310.9(even)-312(more)-306.3(precise)-316.4(and)]TJ T* [(complex)-247.5(with)-247.4(miRNAs)-246.7(participating)-248.8(in)-244.2(almost)-245.2(every)-243.9(cellular)]TJ 0 -1.1174 TD [(process.)-468.1(Given)-468.4(the)-465.4(pivotal)-470(role)-466.4(of)-462.9(miRNAs)-465.6(in)-468.9(regulatory)]TJ 0 -1.1116 TD [(circuitries)-315.4(th)20.7(at)-285.7(co)19.7(nt)20.7(ro)15.1(l)-295(s)0(e)19.9(l)0(f)20.7(-)0(r)20.9(e)0(n)19.7(e)0(w)13(a)0(l)-285.7(a)0(n)19.7(d)-294.8(pl)20.7(ur)20.9(ip)20.7(ot)15(en)19.7(cy)-285.6(of)-284.4(st)20.9(em)]TJ T* [(ce)12.8(ll)20.6(s,)-326.9(th)20.7(e)-336.3(i)0(m)19.5(p)0(o)20.8(r)0(t)20.7(a)0(n)19.7(t)-341(ro)20.9(le)19.6(s)-335(o)0(f)-330.5(m)0(i)19.5(R)0(N)18.9(A)0(s)-325.4(i)0(n)-324.9(c)0(e)18.5(l)0(l)14.8()0(s)21(u)0(b)20.8(s)0(t)20.9(r)0(a)19.7(t)0(e)-331.8(i)0(n)20.7(t)0(e)19.6(r)0(-)]TJ 0 -1.1174 TD [(ac)12.8(ti)20.6(on)20.8(s)-248.6(n)0(e)19.7(e)0(d)-239.5(t)0(o)-238.5(b)0(e)-239.5(s)0(y)15.3(s)0(t)20.9(e)0(m)18.5(a)0(t)19.5(i)0(c)19.5(a)0(l)19.5(l)0(y)-238.5(i)0(n)14.9(v)0(e)19.7(s)0(t)20.9(i)0(g)20.7(a)0(t)19.5(e)0(d)19.7(.)-251.1(No)20(w,)-241.6(th)20.7(er)19.7(e)-249.9(a)0(r)19.7(e)]TJ 0 -1.1116 TD [(on)15.1(ly)-255.7(a)-267.2(f)0(e)19.7(w)-266.9(re)14(se)19.9(ar)19.7(ch)19.7(es)19.9(.)-268.4(P)0(H)20.1(B)0(H)18.9(H)0(x)-256.5(p)0(r)15.1(o)0(m)19.6(o)0(t)20.7(e)-267.2(th)20.7(e)-267.2(c)0(h)19.7(o)0(n)20.8(d)0(r)15.1(o)0(g)20.8(e)0(n)19.7(e)0(s)19.9(i)0(s)]TJ T* [(of)-261.4(mo)19.6(us)15.3(e)-267.2(M)0(S)20.1(C)0(s)-262.2(w)0(i)19.8(t)0(h)-261.5(t)0(h)20.7(e)-273(ex)19.7(is)20.9(te)19.5(nc)13.9(e)-267.2(o)0(f)-261.4(c)0(h)19.7(o)0(n)20.8(d)0(r)15.1(o)0(g)20.8(e)0(n)19.7(i)0(c)-262.7(m)15(ed)13.9(iu)20.7(m.)]TJ /F6 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (126)Tj 49.8245 0 TD [(LV)-332.3(ET)-338.7(AL.)]TJ ET endstream endobj 142 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(Ac)18.8(co)13.9(rd)20.9(in)20.7(g)-646.2(t)0(o)-630.1(h)0(i)14.9(g)0(h)20.8(-)0(t)20.7(h)0(r)20.9(o)0(u)20.8(g)0(h)20.8(p)0(u)15.1(t)-640.6(an)19.7(al)19.5(ys)15.3(is)20.9(,)-642.8(d)0(i)20.7(f)0(f)15.1(e)0(r)19.7(e)0(n)19.7(t)0(i)20.6(a)0(l)19.5(l)0(y)-635.9(e)0(x)19.7(-)]TJ 0 -1.1174 TD [(pr)15.1(es)19.9(se)19.9(d)-312.1(g)0(e)19.7(n)0(e)19.7(s)-311.9(in)20.7(cl)19.5(ud)15.1(e)-307.5(m)0(i)19.5(R)0(-)14.1(2)0(9)20.8(a)-313.3(an)19.7(d)-312.1(m)15(iR)13.9(-2)20.9(9b)20.8(,)-308.7(w)0(h)14.2(i)0(c)19.6(h)-312.1(di)20.7(re)19.7(ct)19.5(ly)]TJ 0 -1.1116 TD [(ta)19.6(rg)15.1(et)-308.8(3)]TJ /F8 1 Tf 3.0526 0 TD ()Tj /F4 1 Tf .2361 0 TD [(UT)18.8(R)-318.9(o)0(f)]TJ /F10 1 Tf 3.4385 0 TD [(Co)19.8(l2)20.7(a1)]TJ /F4 1 Tf 3.2139 0 TD [(en)19.7(co)19.7(di)20.7(ng)-307.5(ty)20.7(pe)-308.6(II)-307.4(co)19.7(ll)20.6(ag)19.7(en)13.9(,)-314.5(a)0(n)19.7(d)-317.9(th)20.7(ei)19.5(r)]TJ -9.9413 -1.1116 TD [(ac)18.5(ti)14.8(vi)20.7(ti)20.6(es)-636.7(ar)14(e)-647.3(r)0(e)19.7(g)0(u)20.8(l)0(a)19.5(t)0(e)19.6(d)-651.9(by)]TJ /F10 1 Tf 11.9975 0 TD [(So)20.8(x9)]TJ /F4 1 Tf 1.9065 0 TD [(,)-648.5(t)0(h)20.7(e)-653.1(SR)20(Y-)20(re)19.7(la)19.6(te)19.6(d)-651.9(h)0(i)20.7(g)0(h)20.8(-)]TJ -13.9039 -1.1116 TD [(mo)19.6(bi)15(li)20.6(ty)-273(gr)20.9(ou)20.8(p)-283.3(b)0(o)20.8(x)-283.3(ge)19.7(ne)-274.1(9.)]TJ 7.3823 0 0 6.5614 166.4503 685.7006 Tm -.0162 Tc (14)Tj 9.843 0 0 9.843 176.5417 681.3352 Tm 0 Tc [(On)-273.8(th)20.7(e)-284.5(o)0(t)20.7(h)0(e)19.7(r)-283.3(ha)19.7(nd)20.8(,)-285.7(1)0(0)]TJ /F11 1 Tf 8.8757 0 TD (m)Tj /F4 1 Tf .5414 0 TD [(m-)19.6(wi)19.8(de)]TJ -21.2821 -1.1174 TD [(mi)19.5(cr)14(og)20.8(ro)20.9(ov)20.8(ed)-452.6(PH)14.4(BH)18.9(Hx)-452.3(pr)20.9(om)19.6(ot)14.9(e)-463(o)0(s)21(t)0(e)19.6(o)0(g)20.8(e)0(n)19.7(i)0(c)-458.5(d)0(i)20.7(f)0(f)20.9(e)0(r)14(e)0(n)19.7(t)0(i)20.6(a)0(t)19.6(i)0(o)20.7(n)]TJ 0 -1.1116 TD -.0203 Tc [(o)-20.3(f)-517.8(M)-20.3(S)-.2(C)-20.3(s)-518.7(with)-516.7(inc)-5.3(r)1.7(eased)-516.7(expressi)]TJ 13.7599 0 TD [(on)-516.7(of)-516.7(osteogene)-5.3(s)1.8(is-related)]TJ -13.7599 -1.1116 TD -.0273 Tc [(marker)-362.4(g).4(enes,)-364.8(i).3(ncluding)]TJ /F10 1 Tf 9.6763 0 TD -.0275 Tc [(Cbfa1,)-359.2(Col1a1,)]TJ /F4 1 Tf 6.2608 0 TD -.0271 Tc (and)Tj /F10 1 Tf 1.7279 0 TD (Bmp2)Tj /F4 1 Tf 2.2232 0 TD .3317 Tc [(.T)358.2(h)359.4(e)-4.6(m)358.2(i)359.3(R)358.4(-)]TJ -19.8883 -1.1174 TD -.0252 Tc [(N)-4.1(A)-240.3(mic)-4.4(r)2.5(oarra)-4.4(y)2.5(s)-239.2(r)-3.2(evea)-4.4(l)-233.8(t)-3.4(ha)-4.4(t)-239.5(1)2.5(8)-239.4(d)2.5(if)]TJ 12.8038 0 TD -.023 Tc [(ferent)4.6(iall)4.6(y)-237.2(e)3.5(xp)]TJ 5.4717 0 TD -.024 Tc [(ressed)-238.2(m)2.5(iRNAs)]TJ -18.2755 -1.1116 TD -.0273 Tc [(o)-5.4(n)-247.3(mi)-5.5(cr)-5.3(og)-5.4(ro)-5.4(ov)-5.4(ed)-247.3(p)-5.4(a)-.8(t)-5.5(t).3(er)-5.3(n)-247.3(h)-5.4(ad)-247.3(mu)-5.4(lt)-5.5(ip)-5.4(le)-248.4(t)-5.5(a)-.8(r)-5.3(g).4(e)-6.5(t)-247.4(ge)-6.5(ne)-6.5(s,)-249.6(co)-5.4(nt)-5.5(ri)-5.5(bu)-5.4(ti)-5.5(ng)]TJ T* 0 Tc [(compr)-7.9(ehensi)-8.9(vely)-368.6(to)-370.9(the)-367.5(cellul)-9.3(ar)-366.2(regula)-9(tion)-367.5(proces)-8.7(s,)-367.2(includ)-8(-)]TJ 0 -1.1174 TD [(ing)-337.5(MAPK)-341(and)-338.5(Smad)-334.9(signal)-7.8(ing)-337.5(pathwa)-9.9(ys)]TJ 7.3823 0 0 6.5614 227.5086 608.9951 Tm (8)Tj 9.843 0 0 9.843 234.4818 604.5731 Tm [(\(Tabl)-8(e)-336.3(2\).)]TJ -16.7377 -1.1116 TD [(DNA)-743.2(methylation)-747.7(leads)-745(to)-745.3(gene)-744(suppression.)-742(DNA)]TJ -1.0137 -1.1116 TD [(methylation)-350.3(refers)-348.5(to)-342.1(addition)-344.4(of)-342(a)-347.8(methyl)-343.3(group)-345.3(to)-342.1(a)-347.8(cyto-)]TJ T* [(sine)-385.6(base)-386.7(residue)-384.3(in)-382.5(DNA,)-383.7(which)-382(often)-386.9(localizes)-389.1(next)-380.1(to)-382.5(a)]TJ 0 -1.1174 TD [(guanine)-309.7(base.)-309.5(Methylated)-309.5(cytosines)-311.6(can)-310.9(be)-302.9(further)-308.4(modied)]TJ 0 -1.1116 TD [(by)-365.1(hydroxylation.)-370.6(Methylated)-367.1(cytosines)-369.2(can)-362.7(lead)-369.7(to)-365.2(the)-361.7(re-)]TJ T* [(cruitment)-382.4(of)-382.3(specic)-379.6(methyl)-377.9(DNA-binding)-383.6(proteins,)-382.1(which)]TJ 0 -1.1174 TD [(may)-552.9(lead)-554(to)-555.3(transcriptional)-556.1(repression.)-557.9(The)-552.8(inuence)-553.7(of)]TJ 0 -1.1116 TD [(biomaterials)-634.5(on)-624.2(DNA)-628(methylation)-626.7(remains)-627.5(limited.)-624.6(Al-)]TJ T* [(though)-346.6(it)-348(is)-342(well)-346.5(recognized)-349.8(that)-345.6(substrate)-351.9(elasticity)-349(directs)]TJ 0 -1.1174 TD [(stem)-461.7(cell)-456.2(lineage)-460.7(commitment,)-458.6(DNA)-460.9(methylation)-459.7(proles)]TJ 0 -1.1116 TD [(remain)-361.6(unaltered)-365(as)-360.3(the)-361.7(elasticity)-366.3(of)-359.3(the)-355.9(hydrogel)-361.4(substrate)]TJ T* (varies.)Tj 7.3823 0 0 6.5614 85.833 477.4676 Tm (32)Tj 9.843 0 0 9.843 96.7181 473.1022 Tm [(Nano-HAp)-358.1(is)-353.5(usually)-354.5(considered)-360(to)-353.7(promote)-355.8(oste-)]TJ -3.7553 -1.1174 TD [(ogenic)-291.3(differentiation)-297(of)-290.2(MSCs,)-291.7(but)-285.7(a)-290.2(signicant)-295.6(increase)-289.8(in)]TJ /F10 1 Tf 0 -1.1116 TD (ALP)Tj /F4 1 Tf 2.1714 0 TD [(promoter)-391.4(methylation)-390.6(leading)-390.4(to)-394(unexpected)-390.2(suppres-)]TJ -2.1714 -1.1116 TD [(sion)-534.2(of)-532.1(ALP,)-532.8(BSP,)-537.3(and)-528.6(OSC)-534.9(RNA)-536(levels)-533.1(is)-532(reported.)]TJ 7.3823 0 0 6.5614 291.4582 444.5857 Tm (33)Tj 9.843 0 0 9.843 59.7543 429.2786 Tm [(Therefore,)-323.2(further)-314.2(researches)-321.6(on)-319(biomaterial)-316.8(cues)-317.6(and)-315.5(DNA)]TJ 0 -1.1174 TD [(methylation)-338.7(are)-333.9(expected.)]TJ /F9 1 Tf 8.9663 0 0 8.9663 59.7543 390.8408 Tm [(Similarities)-339.9(and)-335.7(differences)-330.8(of)-336.7(cell)-333(functions)]TJ 0 -1.2266 TD [(guided)-335.2(by)-332.7(various)-333.8(biomaterial)-336.5(cues)]TJ /F2 1 Tf 1.1128 -1.8336 TD (Topography.)Tj /F4 1 Tf 9.843 0 0 9.843 129.8267 363.4015 Tm [(Topography,)-431.5(including)-426.2(shape,)-425.8(dimension,)]TJ -7.119 -1.1116 TD [(microstructure)-250.6(or)-244.1(nanostructure,)-245.9(and)-246.4(three-dimensionality,)-250.7(is)]TJ T* -.0207 Tc [(o)-20.7(n)-20.7(e)-411.1(o)-20.7(f)-408.8(the)-385.8(m)-5.7(ost)-390.5(i)1.1(nvestigated)-390.4(fa)-5.7(ctors)-390.2(i)1.1(n)-390.4(m)0(ate)-5.7(r)1.3(ia)-5.7(lc)-5.7(e).1(ll)-390.5(intera)-5.7(c-)]TJ 0 -1.1174 TD -.0217 Tc [(t)-5.6(i).1(on)-5.5(s,)-480.1(and)-477.8(c)-.9(a)-6.7(n)-477.8(dic)-6.7(t).1(at)-5.6(e)-473.2(v)-5.5(ari)-5.6(ous)-477.6(c)-6.7(e)-.9(ll)-477.9(b)-5.5(e)-.9(hav)-5.5(i).1(or)-5.5(s,)-480.1(inc)-6.7(l).1(ud)-5.5(ing)-477.8(c)-.9(e)-6.7(l).1(l)]TJ 0 -1.1116 TD [(p)-5.4(r).4(ol)-5.5(ife)-6.6(r).4(at)-5.5(ion)-5.4(,)]TJ 7.3823 0 0 6.5614 108.8504 323.9432 Tm -.0249 Tc (6,11,31)Tj 9.843 0 0 9.843 132.0378 319.5779 Tm -.0218 Tc [(di)-5.7(ffe)-6.8(rent)-5.7(iat)-5.7(i)0(on)-5.6(,)]TJ 7.3823 0 0 6.5614 187.937 323.9432 Tm -.0294 Tc [(51)-5.5(,5)-5.5(2)]TJ 9.843 0 0 9.843 205.9086 319.5779 Tm -.0203 Tc [(and)-240.3(r)1.7(eprogramm)-5.3(i)1.5(ng.)]TJ 7.3823 0 0 6.5614 283.011 323.9432 Tm -.0246 Tc (37,39)Tj 9.843 0 0 9.843 59.7543 308.6361 Tm .0131 Tc [(Topograph)6.2(y)-483.3(r).5(eg)6.2(ulates)-477.4(cell)-477.7(b).5(ehavio)6.2(rs)-483.1(by)-477.6(inuen)6.2(cing)-477.6(cell)]TJ T* .0123 Tc [(adhesion,)-423.1(spreading,)-423.1(and)-426.5(s)-.1(ubsequent)-432.4(cytoskeletal)-432.4(reorga-)]TJ 0 -1.1174 TD .0131 Tc [(nization)-402.7(l).4(e)5.1(a)-.7(ding)-402.7(to)-402.7(chan)6.2(ges)-402.5(i).4(n)-402.7(cellular)-402.7(m)5(echanic)5.1(al)-402.8(trans-)]TJ 0 -1.1116 TD .0126 Tc [(duction,)-376.7(nuclear)-380.1(alterations,)-376.7(a)-1.2(nd)-380.2(consequently)-380.2(changes)-380(i)-.1(n)]TJ T* 0 Tc [(ge)19.7(ne)-389.3(ex)19.7(pr)20.9(es)14.1(si)20.9(on)20.8(s.)-384.5(Th)19.6(es)14.1(e)-393.9(r)0(e)19.7(g)0(u)15.1(l)0(a)19.6(t)0(i)20.6(o)0(n)20.8(s)-398.3(de)19.7(pe)19.7(nd)-388.1(on)-382.3(cy)19.7(to)15(sk)21(el)19.5(et)19.6(al)]TJ 0 -1.1174 TD [(me)18.4(ch)19.7(an)13.9(ic)19.5(al)-458.5(tr)20.7(an)19.7(sd)21(uc)19.7(ti)20.6(on)-463(sy)21(st)20.9(em)18.5(,)-470(a)0(n)19.7(d)-467.6(in)20.7(te)19.6(rr)20.9(up)20.8(ti)20.6(on)15.1(s)-467.4(t)0(o)-457.3(a)0(c)18.5(t)0(o)20.7(-)]TJ 0 -1.1116 TD [(my)19.6(os)15.3(in)-307.6(or)-313.2(la)19.6(mi)19.5(n)-323.6(A)0(/)19.8(C)-324.7(bl)20.7(oc)19.7(k)-323.6(t)0(h)20.7(e)0(s)19.9(e)-324.8(su)21(bs)21(tr)15(at)19.5(e)19.7(ce)18.5(ll)-313.5(in)20.7(te)19.6(ra)19.7(ct)19.6(io)20.7(ns)15.3(.)]TJ T* [(Wi)18.4(th)-267.3(th)20.7(e)-278.7(s)0(a)19.9(m)0(e)-269.5(c)0(e)18.5(l)0(l)-267.4(s)0(h)21(a)0(p)19.7(e)0(,)-264.9(l)0(a)19.6(r)0(g)15.1(e)0(r)-262.5(s)0(p)15.3(r)0(e)19.7(a)0(d)19.7(i)0(n)20.7(g)-277.6(ar)19.7(ea)-269.5(in)20.7(du)20.8(ce)-269.5(la)19.6(rg)20.9(er)]TJ 0 -1.1174 TD [(nu)15.1(cl)19.5(ea)18.5(r)-467.6(a)0(n)19.7(d)-467.6(tr)20.7(an)19.7(sc)19.9(ri)15(pt)20.7(io)20.7(n)-467.6(a)0(c)18.5(t)0(i)20.6(v)0(a)19.7(t)0(i)20.6(o)0(n)15.1(,)-464.2(an)19.7(d)-467.6(s)0(m)19.8(a)0(l)13.8(l)0(e)19.5(r)-467.6(ar)19.7(ea)-459.5(le)19.6(ad)]TJ 0 -1.1116 TD [(to)-451.6(ch)19.7(ro)20.9(ma)18.4(ti)20.6(n)-456.1(c)0(o)13.9(n)0(d)20.8(e)0(n)19.7(s)0(a)19.9(t)0(i)20.6(o)0(n)-445.7(a)0(n)13.9(d)-456.1(a)-457.3(g)0(l)20.7(o)0(b)20.8(a)0(l)-452.7(r)0(e)19.7(d)0(u)20.8(c)0(t)19.5(i)0(o)20.7(n)-461.9(in)-445.8(ge)19.7(ne)]TJ T* [(ex)19.7(pr)15.1(es)19.9(si)20.9(on)]TJ 7.3823 0 0 6.5614 100.9133 203.4141 Tm (12)Tj 9.843 0 0 9.843 110.8346 199.0488 Tm [(\(F)21(ig)15(.)-262.6(4)0(\))20.9(.)-268.4(Wi)18.4(th)-255.8(th)20.7(e)-267.2(s)0(a)19.9(m)0(e)-258(s)0(p)21(r)0(e)19.7(a)0(d)13.9(i)0(n)20.7(g)-266(ar)19.7(ea)18.5(,)-262.6(d)0(i)15(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(t)]TJ -5.1895 -1.1174 TD [(sh)15.3(ap)19.7(es)19.9(,)-539.1(s)0(u)21(c)0(h)-533.3(a)0(s)-527.3(c)0(i)13.8(r)0(c)19.7(l)0(e)-527.6(v)0(e)19.7(r)0(s)15.3(u)0(s)-526.1(s)0(q)15.3(u)0(a)19.7(r)0(e)-527.5(o)0(r)-532.1(r)0(e)19.7(c)0(t)19.5(a)0(n)19.7(g)0(l)20.7(e)0(s)14.1(,)-539.1(ci)19.5(rc)19.7(le)]TJ 0 -1.1116 TD [(ve)19.7(rs)15.3(us)-468.5(tr)20.7(ia)13.8(ng)20.8(le)19.6(,)-481.5(a)0(n)19.7(d)-479.2(o)21(we)18.8(rs)-474.3(ve)19.7(rs)21.1(us)-474.3(st)20.9(ar)19.7(s,)-470.9(le)13.8(ad)-469.9(to)-468.9(is)15.1(ot)20.7(ro)20.9(pi)20.7(c)]TJ T* [(fo)15.1(rc)19.7(es)-371.8(or)-370.8(an)19.7(is)20.9(ot)14.9(ro)20.9(pi)20.7(c)-382.4(f)0(o)20.9(r)0(c)19.7(e)0(s)-371.8(a)0(n)13.9(d)-381.2(co)19.7(ns)21(eq)19.7(ue)19.7(nt)20.7(ly)-370.9(in)15(u)21(en)19.7(ce)-373.1(ce)18.5(ll)]TJ T* [(pr)15.1(ol)20.7(if)20.7(er)19.7(at)19.5(io)20.7(n)-427.3(a)0(n)19.7(d)-421.6(di)20.7(ff)15.1(er)19.7(en)19.7(ti)20.6(at)19.5(io)20.7(n.)-413.5(To)19.6(po)20.8(gr)15.1(ap)19.7(hi)20.7(es)-412.1(wh)20(ic)19.6(h)-427.3(g)0(u)20.8(i)0(d)20.7(e)]TJ 0 -1.1174 TD [(ce)18.5(ll)14.8(s)-237(i)0(n)20.7(t)0(o)-232.7(e)0(l)19.5(o)0(n)20.8(g)0(a)19.7(t)0(e)19.5(d)-243(sh)21(ap)19.7(es)19.9(,)-245.3(s)0(u)21(c)0(h)-228(a)0(s)-233.6(m)0(i)19.5(c)0(r)19.7(o)0(g)20.8(r)0(o)20.9(o)0(v)15.1(e)0(s)-227.8(a)0(n)19.7(d)-243(al)19.6(ig)20.7(ne)19.7(d)]TJ 0 -1.1116 TD [(na)19.7(no)15.1(b)21(er)19.7(s,)-263.5(le)19.6(ad)-262.5(to)-261.5(gl)14.9(ob)20.8(al)-262.7(en)19.7(ha)19.7(nc)19.7(em)18.5(en)19.7(t)-277.7(o)0(f)-261.4(h)0(i)20.7(s)0(t)20.9(o)0(n)20.8(e)-278.7(ac)18.5(et)19.6(yl)20.7(at)19.6(io)20.7(n)]TJ T* -.02 Tc [(a)-20(n)-.3(d)-464.6(H)-20(3)-5.8(K)-20(4)-455(m)-20(et)-20(hy)-20(la)-20(ti)-20(on)-20(,)-456.5(t)-20(hu)-20(s)-454(f)-20(ac)-20(il)-20(i)-5.2(t)-20(at)-20(in)-20(g)-454.2(t)-20(he)-465.8(p)-20(r).9(o)-20(c)-.3(e)-20(s)-5.9(s)-464.4(o)-20(f)-454.1(r)-20(e-)]TJ 0 -1.1174 TD 0 Tc [(pr)15.1(og)20.8(ra)19.7(mm)18.4(in)20.7(g)-277.6(a)0(n)19.7(d)-277.6(ne)19.7(ur)20.9(al)-268.4(di)20.7(ff)15.1(er)19.7(en)19.7(ti)20.6(at)19.5(io)20.7(n.)-269.5(To)19.6(po)20.8(gr)20.9(ap)13.9(hi)20.7(es)-268.1(wh)20(ic)19.5(h)]TJ 0 -1.1116 TD [(gu)15.1(id)20.7(e)-359.4(c)0(e)18.5(l)0(l)14.8(s)-358(in)15(to)-353.7(m)15(o)0(r)15.1(e)-359.4(sp)15.3(re)19.7(ad)19.7(in)20.7(g)-364(a)0(n)19.7(d)-364(po)20.8(ly)20.7(go)20.8(na)19.7(l)-364.1(s)0(h)21(a)0(p)19.7(e)0(s)19.9(,)-366.3(su)21(ch)]TJ T* [(as)-377.5(na)19.7(no)15.1(tu)20.7(be)19.7(s)]TJ 7.3823 0 0 6.5614 110.7779 93.8268 Tm -.0162 Tc (34)Tj 9.843 0 0 9.843 121.8897 89.4614 Tm -.0206 Tc [(a)-20.6(n)-.9(d)-401.8(r)-20.6(a)-6.6(n)-20.6(do)-20.6(m)-392.6(n)-20.6(a)-6.7(n)-20.6(o)-20.6(be)-20.6(rs)-20.6(,)]TJ 7.3823 0 0 6.5614 215.6598 93.8268 Tm -.0162 Tc (22)Tj 9.843 0 0 9.843 226.7149 89.4614 Tm 0 Tc [(ge)13.9(ne)19.7(ra)19.7(ll)20.6(y)-387(p)0(r)20.9(o)0(m)19.6(o)0(t)20.7(e)]TJ -16.9623 -1.1174 TD [(th)15(e)-393.9(p)0(r)20.9(o)0(c)19.7(e)0(s)19.9(s)-392.6(of)-388.1(os)21(te)19.6(og)20.8(en)19.7(ic)-389.4(di)20.7(ff)20.9(er)19.7(en)19.7(ti)20.6(at)19.5(io)15(n)-392.8(a)0(n)19.7(d)-392.8(le)19.6(ad)-383.5(to)-388.2(hi)20.7(gh)20.8(er)]TJ 0 -1.1116 TD [(pr)15.1(ol)20.7(if)20.7(er)19.7(at)19.5(io)20.7(n)-364(r)0(a)19.7(t)0(e)19.6(.)-360.5(Me)18.8(an)19.7(wh)20(il)14.8(e,)-351.3(mi)19.5(cr)19.7(ot)20.7(op)20.8(og)20.8(ra)19.7(ph)15.1(y)-358.2(a)0(n)19.7(d)-364(na)19.7(no)20.8(to)20.7(-)]TJ T* [(po)15.1(gr)20.9(ap)19.7(hy)-532.1(re)14(gu)20.8(la)19.5(te)-533.4(ce)12.8(ll)-532.4(be)19.7(ha)19.7(vi)14.9(or)20.9(s)-542.3(f)0(r)15.2(o)0(m)-533.3(d)0(i)20.7(f)0(f)15.1(e)0(r)19.7(e)0(n)19.7(t)-542.6(si)15.1(gn)20.8(al)19.6(in)20.7(g)]TJ 25.5097 67.9242 TD [(pa)19.7(th)20.7(wa)18.8(ys)21(.)-418.1(I)0(n)-411.1(3)0(D)-412(e)0(n)19.7(v)0(i)20.7(r)0(o)20.9(n)0(m)19.6(e)0(n)19.7(t)0(,)-407.8(r)0(o)15.1(u)0(n)20.8(d)-415.8(ce)18.5(ll)14.8(s)-415.6(d)0(e)19.7(m)0(o)19.6(n)0(s)21(t)0(r)15(a)0(t)19.5(e)-417(de)19.7(-)]TJ 0 -1.1174 TD [(cr)19.7(ea)18.5(se)19.9(d)-237.2(h)0(i)20.7(s)0(t)20.9(o)0(n)20.8(e)-238.4(ac)18.5(et)19.5(yl)14.9(at)19.5(io)20.7(n)-237.2(l)0(e)19.5(v)0(e)19.7(l)0(.)-223.5(M)0(i)19.8(c)0(r)19.7(o)0(t)14.9(o)0(p)20.8(o)0(g)20.8(r)0(a)19.7(p)0(h)20.8(y)-237.2(in)20.7(u)21(en)19.7(ce)18.5(s)]TJ 0 -1.1116 TD [(Rh)19.8(o/)20.7(Rh)19.8(oA)-463.8(si)20.9(gn)20.8(al)19.5(in)20.7(g)-473.4(p)0(a)19.7(t)0(h)20.7(w)0(a)18.8(y)0(.)]TJ 7.3823 0 0 6.5614 432.5668 707.5841 Tm [(21)24.7(,5)28.1(3)]TJ 9.843 0 0 9.843 453.4298 703.2188 Tm -.0204 Tc [(A)-20.4(s)-484.1(f)-20.4(o).5(r)-493.8(n)-20.4(an)-20.4(ot)-20.4(op)-20.4(og)-20.4(r)-5.3(a)-20.4(ph)-20.4(y,)]TJ -14.4857 -1.1116 TD 0 Tc [(su)21(ch)-314.4(as)-314.2(na)19.7(no)20.8(tu)15(be)19.7(s)-323.4(a)0(n)19.7(d)-323.6(na)19.7(no)20.8(gr)20.9(oo)20.8(ve)19.7(s,)-315.4(le)19.6(ad)19.7(s)-323.4(t)0(o)-313.4(d)0(i)14.9(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(t)0(i)20.6(a)0(l)-314.5(e)0(x)19.7(-)]TJ T* [(pr)20.9(es)19.9(si)20.9(on)-238.3(of)-238.3(ge)19.7(ne)19.7(s)-248.6(m)0(a)18.5(i)0(n)20.7(l)0(y)-238.5(i)0(n)20.7(v)0(o)15.1(l)0(v)20.7(e)0(d)-239.5(i)0(n)-232.7(W)0(n)18.6(t)0(/)]TJ /F11 1 Tf 16.7319 0 TD (b)Tj /F4 1 Tf .5472 0 TD [(-c)19.7(at)19.5(en)19.7(in)-238.5(si)20.9(gn)20.8(al)19.5(in)20.7(g)]TJ -17.2791 -1.1174 TD [(pa)19.7(th)20.7(wa)18.8(y,)]TJ 7.3823 0 0 6.5614 345.9401 674.7021 Tm [(2)16.2(3)0(,)20.4(5)16.2(3,)28.1(54)]TJ 9.843 0 0 9.843 377.0645 670.3369 Tm [(wh)14.2(er)19.7(ea)18.5(s)-605.7(n)0(a)19.7(n)0(o)20.8(g)0(r)20.9(a)0(t)19.6(i)0(n)15(g)0(s)-595.3(c)0(a)18.5(n)-605.9(in)20.7(u)21(en)19.7(ce)-597.8(ge)19.7(ne)]TJ -6.7273 -1.1116 TD [(ex)19.7(pr)20.9(es)19.9(si)15.1(on)-255.6(in)-261.5(bo)15.1(th)-261.5(Rh)19.8(o/)20.7(Rh)19.8(oA)-262.3(an)19.7(d)-271.8(W)0(n)18.6(t)-271.9(si)20.9(gn)20.8(al)19.6(in)20.7(g)-271.8(p)0(a)19.7(t)0(h)15(w)0(a)18.8(y)0(s)21(.)]TJ 7.3823 0 0 6.5614 542.6644 663.7605 Tm -.0162 Tc (55)Tj /F2 1 Tf 8.9663 0 0 8.9663 320.8251 637.455 Tm 0 Tc [(Stiffness)-462.3(or)-461.8(elasticity.)]TJ /F4 1 Tf 9.843 0 0 9.843 418.1668 637.455 Tm [(Stiffness)-454.2(or)-451.4(elasticity)-458.5(inuences)]TJ -10.9031 -1.1116 TD [(cell)-277.7(differentiation,)-283.2(nuclear)-282(deformation,)-278.5(and)-280.9(cell)-277.7(spreading.)]TJ 0 -1.1174 TD [(Stiffer)-527.2(substrates)-531.4(lead)-531(to)-532.2(decreased)-533.9(nuclear)-529.7(height)]TJ 7.3823 0 0 6.5614 523.1053 619.8801 Tm (56)Tj 9.843 0 0 9.843 535.6912 615.5148 Tm (and)Tj -22.843 -1.1116 TD [(larger)-400.7(cell)-404.4(spreading)-403.8(area.)]TJ 7.3823 0 0 6.5614 417.4298 608.9384 Tm (16,56)Tj 9.843 0 0 9.843 438.0093 604.5731 Tm [(As)-400.3(for)-406.4(differentiation,)-404.1(stem)]TJ -12.919 -1.1116 TD [(cells)-393.8(commit)-396.4(to)-394(specic)-402.6(lineage)-397.4(whose)-393.3(original)-396.2(niches)-400.5(are)]TJ 0 -1.1174 TD [(similar)-321.3(with)-322.3(the)-321.4(existing)-321.2(matrix)-326(stiffness.)-319.4(For)-319.9(example,)-327(soft)]TJ 0 -1.1116 TD [(matrices)-261.2(\(0.11)-170.2(kPa\))-258.8(that)-265(mimic)-262.8(brain)-260.2(are)-264.8(neurogenic,)-260(stiffer)]TJ T* [(matrices)-393.7(\(817)-166.7(kPa\))-391.3(that)-397.5(mimic)-389.5(muscle)-396(are)-391.5(myogenic,)-396.1(and)]TJ 0 -1.1174 TD [(comparatively)-343.1(rigid)-339.8(matrices)-341.9(\()]TJ /F8 1 Tf 12.4006 0 TD (>)Tj /F4 1 Tf .5529 0 TD [(34)-163.5(kPa\))-339.4(that)-339.9(mimic)-343.5(collage-)]TJ -12.9536 -1.1116 TD [(nous)-603.2(bone)-610.3(prove)-605.6(osteogenic.)]TJ 7.3823 0 0 6.5614 433.644 543.1747 Tm (17)Tj 9.843 0 0 9.843 447.0235 538.8093 Tm [(Stiffness)-609.7(or)-606.9(elasticity)-614(is)]TJ -13.8348 -1.1116 TD [(usually)-556.1(controlled)-555.1(under)-559.6(the)-557.5(same)-554.9(material)-561.1(substrate)-559.2(by)]TJ T* [(changing)-362.6(the)-367.5(thickness)-363.5(or)-365(component)-365(ratio)-364(of)-365(the)-361.7(material.)]TJ 0 -1.1174 TD [(Elastomeric)-386.8(polymer)-390.4(networks)-385.1(have)-386.9(been)-386.9(commonly)-392.7(used,)]TJ 0 -1.1116 TD [(as)-348.8(their)-352.5(elasticity)-354.8(can)-351.2(be)-348.9(controlled)-353.5(by)-347.8(simply)-353.5(adapting)-351.2(the)]TJ T* [(density)-354.5(of)-347.8(crosslinks)-357.4(in)-353.7(the)-350.2(network.)-353.1(Cells)-359.1(on)-347.8(the)-355.9(substrate)]TJ 0 -1.1174 TD [(with)-259(low)-257.7(elastic)-259.1(modulus)-262.3(cannot)-256.7(form)-259(stable)-262.4(focal)-261.4(adhesions)]TJ 0 -1.1116 TD [(and)-396.1(differentiate)-405.3(as)-400.6(a)-399.7(result)-405.2(of)-399.6(decreased)-401.4(activation)-406.7(of)-399.6(the)]TJ T* [(extracellular)-343.1(signal-related)-348.6(kinase)-342.9(\(ERK\)/mitogen-activated)]TJ 0 -1.1174 TD [(protein)-372(kinase)-377.5(\()-81.7(MAPK\))-376.6(signaling)-374.1(pathway.)]TJ 7.3823 0 0 6.5614 486.4818 444.5857 Tm (16)Tj 9.843 0 0 9.843 497.5369 440.1636 Tm (Interestingly,)Tj -18.9667 -1.1116 TD [(stiffness-induced)-263.8(mechanical)-266(dosing)-260(can)-259.1(be)-256.8(memorized)-263.6(with)]TJ T* [(YAP/TAZ)-369.8(acting)-372.1(as)-366(an)-372(intracellular)-370.9(mechanical)-375.4(rheostat)]TJ 0 -1.1174 TD [(that)-270.8(stores)-272.4(information)-274(from)-270.5(past)-276.2(physical)-270.4(environments)-276(and)]TJ 0 -1.1116 TD [(in)20.7(u)21(en)19.7(ce)18.5(s)-294.6(t)0(h)20.7(e)-296(ce)18.5(ll)20.6(s)-284.2(fa)19.7(te)19.6(.)]TJ 7.3823 0 0 6.5614 408.3589 400.7054 Tm (57)Tj 9.843 0 0 9.843 418.5637 396.3401 Tm 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[(picture.)-497.5(Several)-500.7(studies)-498.3(have)-496.3(investigated)-500.8(the)-494.2(changes)-500.6(in)]TJ 0 -1.1116 TD [(genomic)-403.1(proling)-400.5(under)-404.1(the)-402(guidance)-398.3(of)-405.3(biomaterial)-403.2(cues,)]TJ T* [(and)-355.8(most)-356.9(of)-353.5(differentially)-365(expressed)-358.6(genes)-359(are)-356.9(members)-357.9(of)]TJ 0 -1.1174 TD [(Rho/ROCK,)-397.4(MAPK,)-390.5(ERK,)-390(Wnt,)-389.3(YAP/TAZ,)-396.3(and)-390.4(JNK)-390.7(sig-)]TJ 0 -1.1116 TD [(naling)-451.5(pathways)-455.4(according)-451.2(to)-445.8(KEGG)-451.7(and)-453.7(Gene)-451.1(Ontology)]TJ T* (analysis.)Tj 7.3823 0 0 6.5614 96.2645 60.9449 Tm [(5,19)-8.6(,54,55)]TJ 9.843 0 0 9.843 131.074 56.5795 Tm [(Howev)-8.4(er,)-340.8(an)-348.9(epigenomic)-344.3(proling)-348.7(of)-342(how)]TJ 18.4887 67.9242 TD [(biomateria)-10.3(l)-387.1(cues)-398.2(inuence)-392.4(the)-396.3(epigenetic)-396.2(state)-393.8(of)-388.1(cells)-399.6(are)]TJ 0 -1.1174 TD [(expected)-341.9(to)-330.6(be)-337.4(revealed.)]TJ /F2 1 Tf 8.9663 0 0 8.9663 323.0361 689.499 Tm [(Epigenetic)-472.3(alterations)-467.4(as)-471.8(an)-464.1(important)-474.4(safety)-463.9(evaluation)]TJ -1.1128 -1.2203 TD [(tool)-300.2(for)-294.6(biomaterials.)]TJ /F4 1 Tf 9.843 0 0 9.843 403.8235 678.5573 Tm [(Epigenetic)-304.1(regulation)-301.7(of)-295.9(biomaterials)]TJ -9.2213 -1.1174 TD [(not)-412.4(only)-407.7(plays)-409.8(an)-406.5(important)-410.1(role)-408.8(in)-405.5(regenerative)-416.7(medicine)]TJ 0 -1.1116 TD [(but)-498.8(also)-495.1(can)-495.2(be)-492.9(a)-491.8(potential)-496.6(tool)-494.2(for)-498.6(safety)-492.6(evaluation)-498.7(of)]TJ T* [(biomateria)-10.3(ls.)-472.1(Epigenetic)-476.9(alteration)-475.8(is)-468.7(a)-474.6(mechanism)-476.6(which)]TJ 0 -1.1174 TD [(can)-357(explain)-355.9(the)-355.9(long-lasting)-354.5(and)-350(memorable)-361.5(effects)-356.7(of)-353.5(bio-)]TJ 0 -1.1116 TD [(material)-434.3(cues.)-424.7(Meanwhile,)-433.6(epigenetic)-430.8(regulation)-428.4(is)-422.6(an)-429.6(im-)]TJ T* [(portant)-395(step)-385.6(that)-391.7(breaks)-388.9(through)-388(the)-390.5(barrier)-390.2(of)-388.1(cell)-387.1(lineage)]TJ 0 -1.1174 TD [(commitme)-9.3(nt.)-524.1(Recent)-529.6(technological)-537.9(advances)-531.6(have)-525.1(led)-528.7(to)]TJ 0 -1.1116 TD [(rapid)-358.1(progress)-360.9(in)-353.7(the)-355.9(characterization)-366.1(of)-353.5(epigenetic)-361.6(modi-)]TJ T* [(cations)-309.6(that)-305.3(control)-302.9(gene)-306.2(expression)-306.8(in)-301.8(a)-307.5(generally)-307.4(heritable)]TJ 0 -1.1174 TD [(way,)-256.4(and)-246.4(are)-253.3(likely)-250.1(involved)-252.1(in)-250(dening)-250.8(cellular)-254.6(phenotypes,)]TJ 0 -1.1116 TD [(devel)-8(opmental)-375.5(stages,)-380.7(and)-378.8(disease)-385.3(status)-376.3(from)-379.9(one)-378.8(genera-)]TJ T* [(tion)-402.1(to)-394(the)-396.3(next.)-400.8(Epigenomic)-401.9(proling)-394.8(has)-401.7(the)-396.3(potential)-398.7(to)]TJ T* [(provid)-6.7(e)-572.5(mechanistic)-582.6(information)-579.3(in)-578.3(toxicological)-582.9(assess-)]TJ 0 -1.1174 TD (ment.)Tj 7.3823 0 0 6.5614 335.3385 529.455 Tm (8587)Tj 9.843 0 0 9.843 356.5416 525.0897 Tm [(The)-276.4(assessment)-280(of)-278.6(epigenetic)-281(effects)-276(may)-276.4(also)-276.2(be)]TJ -4.4177 -1.1116 TD [(approached)-539.8(with)-535.4(new)-535.2(model)-532.2(systems)-533.8(that)-535.7(could)-530.9(directly)]TJ T* [(assess)-290.4(transgenerational)-295.5(effects)-293.3(or)-284.4(potentially)-291.6(sensitive)-288.7(stem)]TJ 0 -1.1174 TD [(cell)-381.4(populations.)-385.5(These)-377.5(would)-380.9(enhance)-386.7(the)-379(range)-382.2(of)-376.6(safety)]TJ 0 -1.1116 TD [(assessment)-343.4(tools)-333.9(for)-331.5(evaluating)-337.4(newly)-336(designed)-333.6(materials.)]TJ 1.0137 -1.1116 TD [(Meanwhile,)-376(inammation)-374.2(is)-370.8(an)-372(important)-375.5(and)-373.1(inevitable)]TJ -1.0137 -1.1174 TD [(process)-418.6(of)-416.9(materialhost)-422.5(interaction,)-417(which)-416.6(may)-420.4(alter)-417(epi-)]TJ 0 -1.1116 TD [(genet)-8(ic)-349.1(state.)-351.2(Proinammatory)-354.2(activities)-354.8(of)-353.5(cytokines,)-355.6(such)]TJ T* [(as)-348.7(interleukin)-343.2(\(IL\)-1,)-345.2(IL-6,)-343(and)-344.3(tumor)-340.9(necrosis)-344.9(factor-alpha)]TJ T* [(\(T)13.9(NF)20.1(-)]TJ /F11 1 Tf 2.5055 0 TD (a)Tj /F4 1 Tf .5414 0 TD [(\),)-240.6(ar)19.7(e)-255.7(l)0(o)20.7(w)0(e)18.8(r)-254.5(on)-238.3(Ti)19.5(O)]TJ 7.3823 0 0 6.5614 417.9401 424.8566 Tm (2)Tj 9.843 0 0 9.843 421.5117 426.5007 Tm [(-c)19.7(oa)19.7(te)19.6(d)-254.5(t)0(i)20.6(t)0(a)19.5(n)0(i)20.7(u)0(m)-245.3(a)0(l)19.5(l)0(o)20.7(y)-254.5(\(T)19.7(i6)20.7(Al)19.8(4)-156.6(V)0(\))]TJ -11.0183 -1.1174 TD [(im)19.5(pl)14.9(an)19.7(ts)-543.5(co)19.7(mp)19.6(ar)19.7(ed)-544.8(wi)19.8(th)-543.7(si)20.9(li)20.6(ca)-545.9(\(S)21(iO)]TJ 7.3823 0 0 6.5614 462.2739 413.8582 Tm (2)Tj 9.843 0 0 9.843 465.9022 415.5022 Tm [(\)-)20.9(co)19.7(at)19.5(ed)-544.8(im)19.5(pl)20.7(an)19.7(t)-554.2(a)0(n)19.7(d)]TJ -15.5282 -1.1116 TD [(st)15.1(ai)19.5(nl)20.7(es)19.9(s)-381(s)0(t)15.1(e)0(e)18.5(l)0(.)]TJ 7.3823 0 0 6.5614 369.5243 408.9259 Tm -.0162 Tc (88)Tj 9.843 0 0 9.843 380.5794 404.5605 Tm 0 Tc [(Me)18.8(an)19.7(wh)20(il)20.6(e)-382.4(T)0(i)19.5(O)]TJ 7.3823 0 0 6.5614 443.5085 402.9164 Tm (2)Tj 9.843 0 0 9.843 450.992 404.5605 Tm [(na)19.7(no)20.8(tu)20.7(be)19.7(s)-386.8(a)0(t)19.6(t)0(e)19.5(n)0(u)20.8(a)0(t)19.5(e)-382.4(ma)18.4(c-)]TJ -14.0134 -1.1116 TD [(ro)15.1(ph)20.8(ag)19.7(e)-388.2(i)0(n)20.7()0(a)19.8(m)0(m)18.4(a)0(t)19.5(o)0(r)20.9(y)-392.7(ac)18.5(ti)20.6(vi)20.7(ty)-376.7(th)20.7(ro)15.1(ug)20.8(h)-387(i)0(n)20.7(h)0(i)20.7(b)0(i)20.7(t)0(i)20.6(o)0(n)-382.3(o)0(f)-376.5(M)0(A)19.1(P)0(K)]TJ 0 -1.1174 TD [(an)13.9(d)-554(N)0(F)20.1(-)]TJ /F11 1 Tf 3.5653 0 TD (k)Tj /F4 1 Tf .5414 0 TD .5551 Tc [(Bp)555.1(a)574.8(t)555.1(h)570.1(w)555.1(a)573.9(y)555.1(s)576.1(.)]TJ 7.3823 0 0 6.5614 404.277 386.9857 Tm 0 Tc (89)Tj 9.843 0 0 9.843 417.0897 382.6204 Tm [(It)-549.5(is)-549.3(al)19.5(so)-549.2(re)19.7(po)20.8(rt)20.7(ed)-550.5(th)20.7(at)-550.7(co)19.7(ll)20.6(ag)19.7(en)]TJ -10.5691 -1.1116 TD [(me)18.4(mb)19.6(ra)14(ne)19.7(s)-427.1(c)0(o)19.7(a)0(t)19.5(e)0(d)-423.8(w)0(i)19.8(t)0(h)-417(g)0(r)15.1(a)0(p)19.7(h)0(e)19.7(n)0(e)-418.1(o)0(x)20.8(i)0(d)15(e)-428.5(de)19.7(mo)19.6(ns)21(tr)20.7(at)13.8(e)-428.5(l)0(o)20.7(w)0(e)18.8(r)]TJ T* [(PG)14.4(E2)-262.6(le)19.5(ve)19.7(ls)20.9(,)-274.1(a)0(n)19.7(d)-271.8(le)19.6(ss)-261(TN)18.8(F)]TJ /F11 1 Tf 10.7303 0 TD (a)Tj /F4 1 Tf .8236 0 TD [(an)19.7(d)-271.8(C)0(O)18.9(X)0(2)-262.3(e)0(x)19.7(p)0(r)15.1(e)0(s)19.9(s)0(i)20.9(o)0(n)-261.4(i)0(n)-261.5(h)0(u)20.8(m)0(a)18.5(n)]TJ -11.554 -1.1174 TD [(de)13.9(nt)20.7(al)-567.9(pu)15.1(lp)-566.8(st)15.1(em)-569(ce)18.5(ll)20.6(s.)]TJ 7.3823 0 0 6.5614 409.5495 354.1605 Tm (90)Tj 9.843 0 0 9.843 422.5889 349.7385 Tm [(Bu)19.8(t)-583(w)0(h)20(e)0(t)19.5(h)0(e)19.7(r)-582.8(th)20.7(es)19.9(e)-584(b)0(i)20.7(o)0(m)19.6(a)0(t)19.6(e)0(r)19.7(i)0(a)19.5(l)0(-)]TJ -11.1278 -1.1116 TD [(re)14(la)19.6(te)19.5(d)-329.4(i)0(n)20.7()0(a)19.8(m)0(m)18.4(a)0(t)19.6(i)0(o)20.7(n)-335.2(pr)20.9(oc)19.7(es)19.9(s)-335(l)0(e)19.5(a)0(d)19.7(s)-329.2(to)-324.9(ep)19.7(ig)20.7(en)19.7(et)19.5(ic)-320.3(ch)19.7(an)19.7(ge)13.9(s)-329.2(r)0(e)19.7(-)]TJ T* [(ma)18.4(in)-227(un)20.8(di)20.7(sc)19.9(ov)20.8(er)14(ed)19.7(.)-233.8(T)0(h)19.6(e)0(r)19.7(e)0(f)19.7(o)0(r)20.9(e)0(,)-224.6(e)0(p)19.7(i)0(g)20.7(e)0(n)19.7(e)0(t)19.6(i)0(c)-228.1(c)0(h)19.7(a)0(n)19.7(g)0(e)19.7(s)-231.3(in)15(du)20.8(ce)18.5(d)-231.5(b)0(y)]TJ 0 -1.1174 TD [(in)15(a)19.8(mm)18.4(at)19.5(io)20.7(n)-392.8(p)0(r)20.9(o)0(c)19.7(e)0(s)14.1(s)-392.6(af)19.7(te)19.6(r)-398.5(b)0(i)20.7(o)0(m)19.6(a)0(t)19.6(e)0(r)19.7(i)0(a)19.5(l)-398.6(im)19.5(pl)20.7(an)19.7(ta)19.5(ti)20.6(on)-388.1(ar)19.7(e)-393.9(e)0(x)19.7(-)]TJ 0 -1.1116 TD -.0208 Tc [(p)-20.8(e)-6.9(c)-20.8(t)-1.3(e)-20.8(d)-254.5(to)-252.3(be)-253.4(uncovere)-5.8(d,)-254.6(and)-252.3(t)-4.8(his)-252.1(w)-5.5(ill)-252.4(a)-5.8(l)1(so)-258(become)-253.4(a)-253.4(p)1.1(aramount)]TJ T* -.0215 Tc [(p)-5.3(a)-.7(ra)-6.5(mete)-6.5(r)-333.6(f).5(o)-5.3(r)-333.6(the)-334.8(e)-6.5(val)-5.4(u).4(at)-5.5(ion)-333.6(o)-5.3(f)-333.6(b).4(io)-5.3(mate)-6.5(ria)-6.5(l)-333.8(com)-6.6(p).4(ati)-5.4(b).4(il)-5.5(ity)-5.3(.)]TJ /F9 1 Tf 8.9663 0 0 8.9663 313.0582 270.2551 Tm 0 Tc (Outlook)Tj /F4 1 Tf 9.843 0 0 9.843 323.0361 253.8141 Tm [(Noncoding)-651.4(RNAs)-657.8(play)-650.8(important)-652(regulating)-653(roles)-651.7(in)]TJ -1.0137 -1.1116 TD [(various)-417.7(biochemical)-421.6(processes.)]TJ 7.3823 0 0 6.5614 438.8597 247.2377 Tm (26)Tj 9.843 0 0 9.843 450.3117 242.8724 Tm [(It)-411.2(has)-413.2(been)-415.7(reported)-420.1(that)]TJ -13.9443 -1.1116 TD [(various)-377.4(microRNAs)-383.6(regulate)-375.4(cell)-381.4(functions)-374(under)-375.3(the)-379(exis-)]TJ 0 -1.1174 TD [(tence)-469.9(of)-457.2(biomaterial)-466.6(cues.)-465(For)-463.9(example,)-465.3(it)-463.2(has)-459.3(been)-467.5(well)]TJ 0 -1.1116 TD [(recognized)-551.4(that)-541.5(microRNAs)-550.7(regulate)-548.2(important)-542.6(signaling)]TJ T* [(pathways,)-349.4(such)-339.4(as)-343(Wnt,)-343.2(MAPK,)-344.4(Smad,)-338.4(and)-344.3(BMP)-339.1(signaling)]TJ 0 -1.1174 TD [(pathways.)-677.7(Meanwhile,)-681.2(microRNAs)-677.4(act)-673.9(as)-677.1(switches)-674.2(for)]TJ 0 -1.1116 TD [(MSCs)-391.9(to)-388.2(differentiate)-393.8(into)-390.6(either)-389.3(osteogenic)-394.7(or)-388.1(adipogenic)]TJ T* (lineage.)Tj 7.3823 0 0 6.5614 344.1826 170.5323 Tm (8)Tj 9.843 0 0 9.843 350.2487 166.1669 Tm [(Different)-243.7(miRNAs)-240.9(have)-242.9(been)-242.9(reported)-247.3(to)-238.5(regulate)-242.9(a)]TJ -3.7784 -1.1116 TD [(master)-309.6(transcription)-310.7(factor)-308.5(for)-302.7(osteogenesis,)-313.6(such)-304.9(as)-308.4(Runx2,)]TJ 0 -1.1174 TD [(as)-285.4(well)-283.2(as)-285.4(molecules)-285.4(in)-284.5(the)-281.1(Wnt)-282.2(or)-284.4(BMP)-281.5(signal)-7.8(ing)-279.9(pathway,)]TJ 0 -1.1116 TD [(and)-430.7(control)-429.6(the)-425.1(balance)-433(between)-432.7(osteoblast)-428(and)-430.7(adipocyte)]TJ T* (differentiation.)Tj 7.3823 0 0 6.5614 372.1322 126.7086 Tm (91)Tj 9.843 0 0 9.843 385.3983 122.3433 Tm [(With)-594.4(the)-592.1(discovery)-599.6(of)-589.7(long)-597.8(noncoding)]TJ -7.3494 -1.1174 TD [(RNA)-276.8(and)-275.2(circular)-277.4(RNA,)-274.5(the)-275.3(researches)-281.3(on)-272.9(noncoding)-276.2(RNAs)]TJ 0 -1.1116 TD [(will)-368.5(go)-370.8(deeper)-367.2(and)-367.3(more)-369.6(regulating)-370.8(mechanisms)-373.8(remain)-367.4(to)]TJ T* [(be)-337.4(investigated.)]TJ 1.0137 -1.1174 TD [(High-throughput)-513.1(biomaterial)-512.7(selection)]TJ 7.3823 0 0 6.5614 479.5652 82.885 Tm (92,93)Tj 9.843 0 0 9.843 501.2219 78.463 Tm [(offers)-508.6(us)-503.1(an)]TJ -19.1165 -1.1116 TD [(opport)-6.7(unity)-334.1(for)-337.3(mass)-334.7(screening)-341.6(when)-340.5(the)-332.9(underlying)-340.7(mech-)]TJ T* [(anism)-7.8(s)-502(are)-506.7(vague.)-506.6(This)-506.6(was)-506.2(a)-509.1(breakthrough)-505.2(for)-510.1(material)]TJ /F6 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (128)Tj 49.8245 0 TD [(LV)-332.3(ET)-338.7(AL.)]TJ ET endstream endobj 150 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(discovery,)-320.8(but)-320.2(we)-321(are)-316.6(eager)-320(to)-319.1(embrace)-324.6(the)-315.6(era)-322.4(for)-320(material)]TJ 0 -1.1174 TD [(design)-433.9(and)-436.4(customization.)-437.5(Further)-435(studies)-435(are)-437.6(expected)-434.1(to)]TJ 0 -1.1116 TD [(investigate)-436.4(how)-436.1(epigenetic)-436.5(regulations)-435.1(correlate)-435.2(with)-437.5(che-)]TJ T* [(mical)-447.1(signaling)-443.2(pathways.)-447.4(A)-439.7(clear)-441.1(picture)-448(of)-439.9(the)-442.3(network)]TJ T* [(among)-537.8(epigenetic)-534.4(alterations,)-537.7(signaling)-535.4(milieus,)-537.9(and)-534.4(cell)]TJ 0 -1.1174 TD [(functions)-477.6(will)-478(provide)-475.5(paramount)-474.4(information)-475.6(for)-475.5(disease)]TJ 0 -1.1116 TD [(treatment)-314.5(and)-309.7(regenerative)-318.7(medicine.)-311(Only)-310.7(by)-307.5(revealing)-313.1(the)]TJ T* [(mechanism)-522.7(of)-509(how)-516.8(different)-513.5(biomaterial)-518.4(cues)-519.1(direct)-516(cell)]TJ 0 -1.1174 TD [(functions,)-360.1(can)-362.7(we)-361.3(design)-359(more)-358.1(intelligent)-360.8(and)-361.6(highly)-358.2(func-)]TJ 0 -1.1116 TD [(tionalized)-395.2(biomaterials)-392.6(from)-391.5(material)-394(chemistry)-387.9(chosen,)-392.3(to)]TJ T* [(topography)-340.6(design,)-339.4(and)-344.3(then)-339.8(3D)-337.1(construction)-344(to)-336.4(meet)-342.2(com-)]TJ 0 -1.1174 TD [(plex)-334(clinical)-341.1(needs.)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 579.4014 Tm (Conclusion)Tj /F4 1 Tf 9.843 0 0 9.843 69.7323 562.9604 Tm [(Biomaterial)-605.9(cues,)-603.2(including)-604.7(material)-601.4(nature/chemistry,)]TJ -1.0137 -1.1116 TD [(stiffness/elasticit)-14.3(y/rigidity,)-377.9(mechanical)-386.9(forces/stimulus,)-386.2(and)]TJ 0 -1.1174 TD [(topography)-398.2(\(including)-392.7(shape,)-391.2(dimension,)-396(microstructure)-394.6(or)]TJ 0 -1.1116 TD [(nanostructure,)-395.6(and)-396.1(three-dimensionality\))-398.1(can)-391.5(inuence)-398.2(cell)]TJ T* [(behaviors)-461.4(by)-457.2(epigenetic)-459.6(regulation.)-460.6(Elongated)-457.2(cell)-462(shapes)]TJ 0 -1.1174 TD [(lead)-502.2(to)-497.7(cell)-502.3(softening,)-504.1(decreased)-499.3(nuclear)-506.6(lamin)-497.7(A/C,)-498.4(de-)]TJ 0 -1.1116 TD [(creased)-444.1(HDAC)-445.8(activity,)-441.3(and)-436.4(increased)-446.4(histone)-440.9(acetylation)]TJ T* [(and)-430.7(H3K4)-432.4(methylation.)-428.6(Meanwhile,)-433.6(spreading)-432.6(cell)-433.2(shapes)]TJ 0 -1.1174 TD [(causes)-384.1(higher)-376.5(actin)-382.5(level,)-380.1(cell)-381.4(stiffening,)-378.6(increased)-383.1(nuclear)]TJ 0 -1.1116 TD [(volume,)-565.5(chromatin)-560.9(decondensation,)-565(increased)-567.4(DNA)-558.8(syn-)]TJ T* [(thesis,)-420(and)-419.2(higher)-416.8(proliferation)-420.2(rate.)-419.2(Biomaterials,)-425.9(such)-414.3(as)]TJ T* [(microgrooves,)-342.6(aligned)-344.4(nanobers,)-343.6(and)-338.5(graphene,)-344(can)-339.7(act)-339.8(as)]TJ 0 -1.1174 TD [(promising)-425.9(facilitators)-426(for)-417.9(somatic)-420.3(cell)-427.4(reprogramming.)-420(By)]TJ 0 -1.1116 TD [(increasing)-740.3(histone)-734.7(acetylation,)-740.7(H3K4)-731.9(methylation,)-733.8(and)]TJ T* [(MET,)-269.2(biomaterials)-271.7(can)-270.6(replace)-265.9(the)-269.5(role)-270.6(of)-261.4(chemical)-274.1(drugs)-264.5(in)]TJ 0 -1.1174 TD [(the)-361.7(process)-366.7(of)-359.3(reprogramming.)-362.4(Biomaterial)-363.9(cues)-363.6(can)-362.7(direct)]TJ 0 -1.1116 TD [(stem)-277.4(cell)-271.9(lineage)-270.6(commitment)-276.6(through)-272.8(epigenetic)-275.2(regulating)]TJ T* [(methods,)-289.9(including)-287.9(histone)-285.4(modication,)-290.1(DNA)-288.1(methylation,)]TJ 0 -1.1174 TD [(and)-338.5(noncoding)-333.8(RNAs.)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 342.255 Tm (Acknowledgments)Tj /F4 1 Tf 9.843 0 0 9.843 69.7323 325.8141 Tm [(This)-408.7(work)-408.4(is)-411.1(supported)-408.4(by)-405.4(grant)-409.9(\(31600787,)-405(81371118\))]TJ -1.0137 -1.1116 TD [(from)-282(the)-286.8(National)-283.1(Natural)-281.8(Science)-288.8(Foundation)-283(of)-278.6(China,)-282(the)]TJ T* [(grant)-565.5(of)-560.9(Young)-559.3(Elite)-566.9(Scientist)-559.6(Sponsorship)-564.6(Program)-562.8(by)]TJ T* [(CAST)-364.4(\(2015QNRC0)-9.1(01\),)-358(the)-367.5(Project)-361.4(for)-366.1(Culturing)-362.6(Leading)]TJ 0 -1.1174 TD [(Talents)-276.2(in)-244.2(Sc)14.1(ie)19.6(nt)20.7(i)20.9(c)-261.4(a)0(n)19.7(d)-254.5(Te)18.5(ch)19.7(no)15.1(lo)20.7(gi)20.7(ca)18.5(l)-260.4(I)0(n)20.9(n)0(o)20.8(v)0(a)19.7(t)0(i)20.6(o)0(n)-249.9(o)0(f)-249.8(B)0(e)18.6(i)0(j)20.6(i)0(n)20.7(g)]TJ 0 -1.1116 TD [(\(Z)19.7(17)15.1(11)20.8(00)20.8(00)20.8(11)20.8(17)20.8(16)20.8(9\))15.1(,)-510.3(a)0(n)13.9(d)-513.7(th)20.7(e)-514.9(g)0(r)20.9(a)0(n)19.7(t)-513.8(of)-509(Pe)19.8(ki)20.7(ng)-503.3(Un)20(iv)15(er)19.7(si)20.9(ty)]TJ T* [(Sc)14.1(ho)20.8(ol)-313.4(an)19.7(d)-323.6(H)0(o)20(s)0(p)21(i)0(t)20.6(a)0(l)-314.5(o)0(f)-313.2(S)0(t)20.9(o)0(m)19.6(a)0(t)19.5(o)0(l)14.9(o)0(g)20.8(y)-323.6(\(P)21(KU)19.1(SS)21.2(20)20.8(15)20.8(01)15.1(07)20.8(\).)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 237.1464 Tm [(Disclosure)-336.7(Statement)]TJ /F4 1 Tf 9.843 0 0 9.843 69.7323 220.7054 Tm [(No)-337.1(competing)-336.3(nancial)-334.9(interests)-334.7(exist.)]TJ /F6 1 Tf 8.9663 0 0 8.9663 59.7543 197.348 Tm (References)Tj /F4 1 Tf 9.2951 0 0 9.2951 64.4031 181.2472 Tm [(1.)-500.4(Makhija,)-276(E.,)-270.5(Jokhun,)-274.5(D.S.,)-273.4(and)-273(Shivashankar,)-274.4(G.V.)-272(Nuclear)]TJ 1.2503 -1.1223 TD [(deformability)-329.4(and)-321.8(telomere)-331.7(dynamics)-324.8(are)-328.3(regulated)-326.2(by)-323.5(cell)]TJ 0 -1.1284 TD [(geometric)-283(constraints.)-283.4(Proc)-284.5(Natl)-279.7(Acad)-285(Sci)-281.4(U)-276.2(S)-283.6(A)]TJ /F5 1 Tf 20.0787 0 TD (113,)Tj /F4 1 Tf 2.031 0 TD (E32,)Tj -22.1097 -1.1223 TD (2016.)Tj -1.2503 -1.1284 TD [(2.)-500.4(Talwar,)-264.6(S.,)-259.4(Jain,)-265.7(N.,)-258(and)-260.8(Shivashankar,)-262.2(G.V.)-259.8(The)-262.7(regulation)]TJ 1.2503 -1.1223 TD [(of)-417.4(gene)-417.6(expression)-418.5(during)-411.3(onset)-418.2(of)-417.4(differentiation)-415.3(by)-415(nu-)]TJ 0 -1.1284 TD [(clear)-618.9(mechanical)-624.7(heterogeneity.)-617.1(Biomaterials)]TJ /F5 1 Tf 19.8591 0 TD (35,)Tj /F4 1 Tf 1.8664 0 TD (2411,)Tj -21.7255 -1.1223 TD (2014.)Tj -1.2503 -1.1284 TD [(3.)-500.4(Kulangara,)-474.8(K.,)-465.4(Yang,)-470(J.,)-462.9(Chellappan,)-475.2(M.,)-463.1(Yang,)-470(Y.,)-471.5(and)]TJ 1.2503 -1.1223 TD [(Leong,)-507(K.W.)-500.4(Nanotopography)-501.7(alters)-503.6(nuclear)-503.3(protein)-506.5(ex-)]TJ 0 -1.1284 TD [(pression,)-450.7(proliferation)-441.9(and)-449.9(differentiation)-445.8(of)-441.7(human)-449.8(mes-)]TJ T* [(enchymal)-317.7(stem/stromal)-318.6(cells.)-318.2(PLoS)-319.3(One)]TJ /F5 1 Tf 16.6509 0 TD (9,)Tj /F4 1 Tf 1.0613 0 TD [(e114698,)-316.4(2014.)]TJ 8.051 70.8975 TD [(4.)-500.4(Badique,)-391.9(F.,)-387.4(Stamov,)-397.4(D.R.,)-391.1(Davidson,)-389.8(P.M.,)-393(Veuillet,)-393.2(M.,)]TJ 1.2503 -1.1223 TD [(Reiter,)-509.3(G.,)-502(Freund,)-510.5(J.N.,)-507.4(Franz,)-508.5(C.M.,)-504.7(and)-504.8(Anselme,)-509.3(K.)]TJ 0 -1.1284 TD [(Directing)-274.2(nuclear)-271.5(deformation)-275.3(on)-268.6(micropillared)-272.6(surfaces)-272.8(by)]TJ 0 -1.1223 TD [(substrate)-362.9(geometry)-370.7(and)-364.5(cytoskeleton)-365.5(organization.)-368.8(Bioma-)]TJ 0 -1.1283 TD (terials)Tj /F5 1 Tf 2.7873 0 TD (34,)Tj /F4 1 Tf 1.5858 0 TD [(2991,)-330(2013.)]TJ -5.6235 -1.1223 TD [(5.)-500.4(Jain,)-442.5(N.,)-447.1(Iyer,)-448.6(K.V.,)-442.8(Kumar,)-447.6(A.,)-447.1(and)-443.8(Shivashankar,)-451.2(G.V.)]TJ 1.2503 -1.1284 TD [(Cell)-282.9(geometric)-283(constraints)-283.3(induce)-283.2(modular)-281(gene-expression)]TJ 0 -1.1223 TD [(patterns)-467.3(via)-467.6(redistribution)-464.6(of)-466.1(HDAC3)-467.7(regulated)-466.4(by)-469.9(acto-)]TJ 0 -1.1284 TD [(myosin)-243(contractility.)-251.3(Proc)-247.9(Natl)-249.2(Acad)-248.4(Sci)-250.9(U)-245.7(S)-247(A)]TJ /F5 1 Tf 19.2248 0 TD (110,)Tj /F4 1 Tf 1.9944 0 TD (11349,)Tj -21.2192 -1.1223 TD (2013.)Tj -1.2503 -1.1284 TD [(6.)-500.4(Versaevel,)-411(M.,)-408.2(Grevesse,)-412.4(T.,)-410.8(and)-407.2(Gabriele,)-413.1(S.)-411.8(Spatial)-407.1(co-)]TJ 1.2503 -1.1223 TD [(ordination)-445.4(between)-447.7(cell)-453.1(and)-443.8(nuclear)-448.4(shape)-447.4(within)-446(micro-)]TJ 0 -1.1284 TD [(patterned)-332.3(endothelial)-341.3(cells.)-336.5(Nat)-335(Commun)]TJ /F5 1 Tf 17.1449 0 TD (3,)Tj /F4 1 Tf 1.0796 0 TD [(671,)-336(2012.)]TJ -19.4749 -1.1284 TD [(7.)-500.4(Pan,)-343.1(Z.,)-343.7(Yan,)-341.8(C.,)-340.5(Peng,)-343.2(R.,)-346.6(Zhao,)-342.2(Y.,)-343.4(He,)-347.7(Y.,)-343.4(and)-340.1(Ding,)-343.2(J.)]TJ 1.2503 -1.1223 TD [(Control)-537.6(of)-539.3(cell)-538.5(nucleus)-538.6(shapes)-544.2(via)-540.8(micropillar)-536.5(patterns.)]TJ 0 -1.1284 TD (Biomaterials)Tj /F5 1 Tf 5.4649 0 TD (33,)Tj /F4 1 Tf 1.5858 0 TD [(1730,)-330(2012.)]TJ -8.3011 -1.1223 TD [(8.)-500.4(Wang,)-247.1(Y.,)-245.8(Jiang,)-241.4(X.L.,)-247.9(Yang,)-244.3(S.C.,)-246.1(Lin,)-245.8(X.,)-245.8(He,)-250.1(Y.,)-245.8(Yan,)-244.2(C.,)]TJ 1.2503 -1.1284 TD [(Wu,)-315.8(L.,)-313.2(Chen,)-314.6(G.Q.,)-314.7(Wang,)-320.3(Z.Y.,)-315(and)-315.7(Wu,)-309.7(Q.)-319(MicroRNAs)]TJ 0 -1.1223 TD [(in)-304.7(the)-309(regulation)-315.4(of)-307.6(interfacial)-313.5(behaviors)-309.4(of)-307.6(MSCs)-311.6(cultured)]TJ 0 -1.1284 TD [(on)-463.8(microgrooved)-465.1(surface)-462.6(pattern.)-468.1(Biomaterials)]TJ /F5 1 Tf 20.0116 0 TD (32,)Tj /F4 1 Tf 1.7078 0 TD (9207,)Tj -21.7194 -1.1223 TD (2011.)Tj -1.2503 -1.1284 TD [(9.)-500.4(Li,)-471.3(Y.,)-477.6(Chu,)-474.9(J.S.,)-478.3(Kurpinski,)-479(K.,)-471.5(Li,)-477.4(X.,)-477.6(Bautista,)-475.4(D.M.,)]TJ 1.2503 -1.1223 TD [(Yang,)-329.7(L.,)-331.5(Sung,)-326.8(K.L.,)-333.3(and)-327.9(Li,)-331(S.)-326.4(Biophysical)-335.5(regulation)-333.7(of)]TJ 0 -1.1284 TD [(histone)-381.3(acetylation)-382.1(in)-377.9(mesenchymal)-382.1(stem)-381(cells.)-379.2(Biophys)-382.5(J)]TJ /F5 1 Tf 0 -1.1223 TD (100,)Tj /F4 1 Tf 2.0798 0 TD [(1902,)-336.1(2011.)]TJ -3.8303 -1.1284 TD [(10.)-500.5(Khatau,)-370.2(S.B.,)-368(Hale,)-369.9(C.M.,)-364.4(Stewart-Hutchinson,)-376.6(P.J.,)-368.5(Patel,)]TJ 1.7505 -1.1223 TD [(M.S.,)-338.1(Stewart,)-338.4(C.L.,)-342.6(Searson,)-337.1(P.C.,)-337.5(Hodzic,)-345.8(D.,)-337.3(and)-340.1(Wirtz,)]TJ 0 -1.1284 TD [(D.)-428.7(A)-434.8(perinuclear)-442.8(actin)-434.9(cap)-429.7(regulates)-441.2(nuclear)-436.2(shape.)-435.3(Proc)]TJ 0 -1.1223 TD [(Natl)-334.6(Acad)-333.8(Sci)-336.3(U)-331.1(S)-332.4(A)]TJ /F5 1 Tf 9.1123 0 TD (106,)Tj /F4 1 Tf 2.0859 0 TD [(19017,)-330.2(2009.)]TJ -12.9487 -1.1284 TD [(11.)-500.5(Roca-Cusachs,)-559.4(P.,)-558.2(Alcaraz,)-558(J.,)-554.4(Sunyer,)-559.3(R.,)-560.1(Samitier,)-555.5(J.,)]TJ 1.7505 -1.1223 TD [(F)15.3(a)0(r)17.6(r)0(e)17.6(,)-366(R.)19.4(,)-366(a)0(n)19.9(d)-372.2(Na)18.3(va)19.9(j)12.6(a)0(s)20.8(,)-372.1(D.)-355.5(Mi)19.3(cr)17.6(op)24.1(at)20.5(t)12.6(e)0(r)17.6(n)0(i)18.6(n)0(g)-354(o)0(f)-362.5(s)12.9(i)12.6(n)0(g)18(l)12.6(e)-370.3(e)0(n)19.9(d)0(o)18(-)]TJ 0 -1.1284 TD [(t)12.6(h)0(e)19.9(l)12.6(ia)20.5(l)-402.1(c)0(e)15.7(l)12.6(l)-402.1(s)0(h)18.9(a)14(pe)-394.8(re)17.6(ve)26(al)20.5(s)-407.9(a)-400.8(t)12.6(i)0(g)18.6(h)0(t)-390.1(c)0(o)19.9(u)0(p)24.1(l)0(i)19.2(n)0(g)-390.6(b)0(e)19.9(t)12.6(we)18.3(en)-394.8(nu)24.1(cl)20.5(ea)15.7(r)]TJ 0 -1.1223 TD [(vo)24.1(l)12.6(u)0(m)18.4(e)-321.5(in)-316.9(G1)-312.9(a)14(n)0(d)-311.4(p)0(r)21.8(o)0(l)18.6(i)12.6(fe)17.6(ra)23.7(ti)19.2(on)18(.)-317.2(B)0(i)19.9(o)0(p)18(h)0(y)24.1(s)-322.5(J)]TJ /F5 1 Tf 17.4011 0 TD [(94)18(,)]TJ /F4 1 Tf 1.5553 0 TD [(49)24.1(84)18(,)-317.2(2)0(0)18(0)0(8)24.1(.)]TJ -20.7069 -1.1284 TD [(12.)-500.5(Le)-378.4(Beyec,)-390.3(J.,)-377.6(Xu,)-386.2(R.,)-383.2(Lee,)-382.9(S.Y.,)-383.1(Nelson,)-383.4(C.M.,)-382.7(Rizki,)-380.7(A.,)]TJ 1.7505 -1.1223 TD [(Alcaraz,)-429.9(J.,)-426.3(and)-431.6(Bissell,)-433.5(M.J.)-425.8(Cell)-429.3(shape)-429.1(regulates)-435.1(global)]TJ 0 -1.1284 TD [(histone)-539.9(acetylation)-540.7(in)-542.5(human)-541.2(mammary)-541.1(epithelial)-541.8(cells.)]TJ 0 -1.1223 TD [(Exp)-331.7(Cell)-337.8(Res)]TJ /F5 1 Tf 5.7882 0 TD (313,)Tj /F4 1 Tf 2.0859 0 TD [(3066,)-330(2007.)]TJ -9.6246 -1.1284 TD [(13.)-500.5(Cui,)-236.5(Y.,)-239.7(Xiao,)-237.6(Z.,)-240.1(Chen,)-235.3(T.,)-240.1(Wei,)-240.3(J.,)-237.3(Chen,)-241.4(L.,)-233.9(Liu,)-239.7(L.,)-240.1(Chen,)]TJ 1.7505 -1.1223 TD [(B.,)-267.3(Wang,)-265.4(X.,)-270.2(Li,)-263.9(X.,)-270.2(and)-266.9(Dai,)-268(J.)-267.7(The)-268.8(miR-7)-269.1(identied)-267.1(from)]TJ 0 -1.1284 TD [(collagen)-250.5(biomaterial-based)-250.2(three-dimensional)-252.1(cultured)-248.6(cells)]TJ 0 -1.1223 TD [(regulates)-386.3(neural)-389.2(stem)-387.1(cell)-386(differentiation.)-391(Stem)-384.8(Cells)-385.8(Dev)]TJ /F5 1 Tf 0 -1.1284 TD (23,)Tj /F4 1 Tf 1.5797 0 TD [(393,)-336(2014.)]TJ -3.3302 -1.1223 TD [(14.)-500.5(Yan,)-354(C.,)-358.8(Wang,)-356.9(Y.,)-355.6(Shen,)-355.4(X.Y.,)-357.4(Yang,)-360.2(G.,)-355.6(Jian,)-357.2(J.,)-353.2(Wang,)]TJ 1.7505 -1.1284 TD [(H.S.,)-438(Chen,)-436.6(G.Q.,)-436.7(and)-437.7(Wu,)-437.8(Q.)-440.9(MicroRNA)-441.2(regulation)-437.4(as-)]TJ 0 -1.1223 TD [(sociated)-408.2(chondrogenesis)-411.1(of)-405.2(mouse)-412.3(MSCs)-409.2(grown)-407.2(on)-408.9(poly-)]TJ 0 -1.1284 TD [(hydroxyalkanoates.)-336.8(Biomaterials)]TJ /F5 1 Tf 13.6196 0 TD (32,)Tj /F4 1 Tf 1.5858 0 TD [(6435,)-336.1(2011.)]TJ -16.9559 -1.1284 TD [(15.)-500.5(Kim,)-543.9(D.H.,)-546.5(and)-547.5(Wirtz,)-547.3(D.)-544.6(Cytoskeletal)-552.7(tension)-546(induces)]TJ 1.7505 -1.1223 TD [(the)-357.8(polarized)-356.7(architecture)-361.1(of)-356.4(the)-357.8(nucleus.)-361.8(Biomaterials)]TJ /F5 1 Tf 22.7197 0 TD (48,)Tj /F4 1 Tf -22.7197 -1.1284 TD [(161,)-329.9(2015.)]TJ -1.7505 -1.1223 TD [(16.)-500.5(Trappmann,)-245.3(B.,)-242.9(Gautrot,)-239.8(J.E.,)-245.5(Connelly,)-240.9(J.T.,)-245.5(Strange,)-245.9(D.G.,)]TJ 1.7505 -1.1284 TD [(Li,)-251.7(Y.,)-251.9(Oyen,)-250.4(M.L.,)-251.7(Cohen,)-253.8(S.M.,)-252.7(Boehm,)-253.3(H.,)-251.9(Li,)-251.7(B.,)-255.1(Vogel,)]TJ 0 -1.1223 TD [(V.,)-343.4(Spatz,)-340.9(J.P.,)-344.1(Watt,)-343.5(F.M.,)-344.2(and)-340.1(Huck,)-341.9(W.T.)-342.1(Extracellular-)]TJ 0 -1.1284 TD [(matrix)-518.2(tethering)-516.6(regulates)-520.4(stem-cell)-519.4(fate.)-517(Nat)-518(Mater)]TJ /F5 1 Tf 22.7197 0 TD (11,)Tj /F4 1 Tf -22.7197 -1.1223 TD [(642,)-329.9(2012.)]TJ -1.7505 -1.1284 TD [(17.)-500.5(Engler,)-472.3(A.J.,)-476.9(Sen,)-477.3(S.,)-472.8(Sweeney,)-481.7(H.L.,)-473.6(and)-474.3(Discher,)-481.6(D.E.)]TJ 1.7505 -1.1223 TD [(Matrix)-237.3(elasticity)-242.1(directs)-247.6(stem)-240.8(cell)-239.6(lineage)-238.2(specication.)-244.6(Cell)]TJ /F5 1 Tf 0 -1.1284 TD (126,)Tj /F4 1 Tf 2.0798 0 TD [(677,)-336(2006.)]TJ -3.8303 -1.1223 TD .3599 Tc [(1)359.9(8)359.9(.)-140.6(J)385(e)380(a)380(n)378.1(,R)379.4(.)384.2(P)381.3(.)378.1(,)0(G)382.6(r)381.8(a)379.9(y)378.1(,D)382.6(.)378.1(S)381.3(.)384.2(,)0(S)381.3(p)378.1(e)380(c)386.1(t)378.6(o)378.1(r)381.8(,)0(A)382.6(.)378.1(A)382.6(.)384.2(,)-6.1(a)386.1(n)378.1(d)-.1(C)379.4(h)384.2(e)379.9(n)378.1(,C)379.4(.)384.2(S)381.3(.C)379.4(h)378.1(a)386(r)375.7(-)]TJ 1.7505 -1.1284 TD -.0211 Tc [(acterization)-338.4(o)-2.9(f)-334.6(t)-2.4(he)-336.5(nuclear)-334.6(defo)]TJ 12.2473 0 TD -.0209 Tc [(rmation)-332.1(caused)-338.2(b)-2.7(y)-332.1(c)-.8(hanges)-337.3(in)]TJ -12.2473 -1.1223 TD -.0211 Tc [(endothelial)-331.7(cell)-331.7(s)-2.1(hape.)-338.3(J)-331.4(Biomech)-332.3(Eng)]TJ /F5 1 Tf 9.2951 0 0 9.2951 470.2109 107.9999 Tm -.0243 Tc [(12)-6.1(6)]TJ /F4 1 Tf 1.4333 0 TD .3111 Tc [(,5)329.3(5)335.4(2)329.3(,2)335.4(0)329.3(0)335.4(4)329.3(.)]TJ -18.5783 -1.1284 TD 0 Tc [(19.)-500.5(Kilian,)-456.4(K.A.,)-455(Bugarija,)-460.8(B.,)-456.4(Lahn,)-452(B.T.,)-458.5(and)-456(Mrksich,)-456.8(M.)]TJ 1.7505 -1.1223 TD [(Geometric)-357.8(cues)-361.9(for)-358.8(directing)-364.1(the)-357.8(differentiation)-360.4(of)-362.5(mesen-)]TJ 0 -1.1284 TD [(chymal)-368.1(stem)-374.9(cells.)-373.1(Proc)-375.9(Natl)-371.2(Acad)-370.4(Sci)-372.9(U)-373.8(S)-369(A)]TJ /F5 1 Tf 19.6029 0 TD (107,)Tj /F4 1 Tf 2.1164 0 TD (4872,)Tj -21.7194 -1.1223 TD (2010.)Tj /F6 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(BIOMATERIAL)-342(CUES)-336.6(REGULATE)-334.8(EPIGENETIC)-335.5(STATE)-338.7(AND)-330.9(CELL)-340.8(FUNCTIONS)-15518.2(129)]TJ ET endstream endobj 154 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(20.)-500.5(McBeath,)-364.8(R.,)-358.8(Pirone,)-363.5(D.M.,)-355.1(Nelson,)-365.1(C.M.,)-358.3(Bhadriraju,)-365.9(K.,)]TJ 1.7505 -1.1223 TD [(and)-309.6(Chen,)-308.5(C.S.)-307(Cell)-307.3(shape,)-307.2(cytoskeletal)-314.3(tension,)-308.2(and)-309.6(RhoA)]TJ 0 -1.1284 TD [(regulate)-417.5(stem)-411.5(cell)-416.5(lineage)-415(commitment.)-415.6(Dev)-414.9(Cell)]TJ /F5 1 Tf 21.0607 0 TD (6,)Tj /F4 1 Tf 1.165 0 TD (483,)Tj -22.2256 -1.1223 TD (2004.)Tj -1.7505 -1.1283 TD [(21.)-500.5(Seo,)-343.1(C.H.,)-348.4(Jeong,)-339.6(H.,)-343.4(Feng,)-349.3(Y.,)-343.4(Montagne,)-343.8(K.,)-343.4(Ushida,)-346.8(T.,)]TJ 1.7505 -1.1223 TD [(Suzuki,)-275.8(Y.,)-270.2(and)-273(Furukawa,)-272.6(K.S.)-273.3(Micropit)-273.6(surfaces)-278.9(designed)]TJ 0 -1.1284 TD [(for)-377.1(accelerating)-387.4(osteogenic)-384.1(differentiation)-384.8(of)-380.8(murine)-378.4(mes-)]TJ 0 -1.1223 TD [(enchymal)-250.7(stem)-253(cells)-251.1(via)-254.1(enhancing)-251.2(focal)-248.8(adhesion)-252.1(and)-254.7(actin)]TJ 0 -1.1284 TD [(polymerization.)-337.6(Biomaterials)]TJ /F5 1 Tf 12.1375 0 TD (35,)Tj /F4 1 Tf 1.5797 0 TD [(2245,)-336.1(2014.)]TJ -15.4677 -1.1223 TD [(22.)-500.5(Liu,)-306.8(W.,)-303.5(Wei,)-307.4(Y.,)-306.8(Zhang,)-305.8(X.,)-300.7(Xu,)-306.9(M.,)-304.5(Yang,)-305.3(X.,)-306.8(and)-303.5(Deng,)]TJ 1.7505 -1.1284 TD [(X.)-294.6(Lower)-291.3(extent)-294.8(but)-286.5(similar)-297.3(rhythm)-288.8(of)-295.4(osteogenic)-292.6(behavior)]TJ 0 -1.1223 TD [(in)-463.3(hBMSCs)-469.2(cultured)-462.1(on)-463.8(nanobrous)-467.4(scaffolds)-463.4(versus)-469.2(in-)]TJ 0 -1.1284 TD [(duced)-503.2(with)-507.2(osteogenic)-506.1(supplement.)-507.6(ACS)-503.7(Nano)]TJ /F5 1 Tf 20.469 0 TD (7,)Tj /F4 1 Tf 1.2564 0 TD (6928,)Tj -21.7255 -1.1284 TD (2013.)Tj -1.7505 -1.1223 TD [(23.)-500.5(Wang,)-442.3(W.,)-437.7(Zhao,)-445.9(L.,)-441.3(Ma,)-436.9(Q.,)-441(Wang,)-442.3(Q.,)-441(Chu,)-444.4(P.K.,)-438(and)]TJ 1.7505 -1.1284 TD [(Zhang,)-299.7(Y.)-294.6(The)-299.3(role)-299.3(of)-295.4(the)-302.9(Wnt/beta-catenin)-301.6(pathway)-297.1(in)-298.6(the)]TJ 0 -1.1223 TD [(effect)-603.1(of)-606.4(implant)-600.8(topography)-605.1(on)-598(MG63)-605.2(differentiation.)]TJ 0 -1.1284 TD (Biomaterials)Tj /F5 1 Tf 5.471 0 TD (33,)Tj /F4 1 Tf 1.5797 0 TD [(7993,)-336.1(2012.)]TJ -8.8012 -1.1223 TD [(24.)-500.5(Aragona,)-452.6(M.,)-450.9(Panciera,)-455.7(T.,)-453.5(Manfrin,)-453.9(A.,)-453.2(Giulitti,)-450.7(S.,)-454.5(Mi-)]TJ 1.7505 -1.1284 TD [(chielin,)-453(F.,)-448.4(Elvassore,)-450.8(N.,)-447.1(Dupont,)-453.3(S.,)-448.4(and)-449.9(Piccolo,)-450.4(S.)-448.4(A)]TJ 0 -1.1223 TD [(mechanical)-948(checkpoint)-946.1(controls)-951(multicellular)-946.1(growth)]TJ 0 -1.1284 TD [(through)-405.3(YAP/TAZ)-408.3(regulation)-400.8(by)-402.8(actin-processing)-410.7(factors.)]TJ 0 -1.1223 TD (Cell)Tj /F5 1 Tf 2.0127 0 TD (154,)Tj /F4 1 Tf 2.0798 0 TD [(1047,)-336.1(2013.)]TJ -5.8431 -1.1284 TD [(25.)-500.5(Bintu,)-504.6(L.,)-508.4(Ishibashi,)-505.1(T.,)-508.4(Dangkulwanich,)-510.6(M.,)-505.8(Wu,)-504.9(Y.Y.,)]TJ 1.7505 -1.1223 TD [(Lubkowska,)-349.7(L.,)-349.8(Kashlev,)-351.2(M.,)-353.3(and)-346.2(Bustamante,)-358(C.)-346.6(Nucleo-)]TJ 0 -1.1284 TD [(somal)-259.2(elements)-267.5(that)-259.8(control)-262.6(the)-260.2(topography)-263.6(of)-258.8(the)-260.2(barrier)-265.9(to)]TJ 0 -1.1223 TD [(transcription.)-335.1(Cell)]TJ /F5 1 Tf 7.6667 0 TD (151,)Tj /F4 1 Tf 2.0798 0 TD [(738,)-336(2012.)]TJ -11.4971 -1.1284 TD [(26.)-500.5(Frye,)-254(M.,)-255.7(Jaffrey,)-253.4(S.R.,)-258.3(Pan,)-251.6(T.,)-258.3(Rechavi,)-255.8(G.,)-251.9(and)-254.7(Suzuki,)-257.5(T.)]TJ 1.7505 -1.1223 TD [(RNA)-380.4(modications:)-381.6(what)-383.9(have)-381(we)-384.2(learned)-381.3(and)-382.8(where)-379(are)]TJ 0 -1.1284 TD [(we)-335.4(headed?)-335(Nat)-335(Rev)-338.8(Genet)]TJ /F5 1 Tf 11.5824 0 TD (17,)Tj /F4 1 Tf 1.5858 0 TD [(365,)-329.9(2016.)]TJ -14.9187 -1.1223 TD [(27.)-500.5(Dalby,)-384.2(M.J.,)-389.2(Gadegaard,)-388.1(N.,)-386.1(and)-382.8(Oreffo,)-391.8(R.O.)-385(Harnessing)]TJ 1.7505 -1.1284 TD [(nanotopography)-463.6(and)-456(integrin-matrix)-465.6(interactions)-464.8(to)-457.2(inu-)]TJ 0 -1.1223 TD [(ence)-336.5(stem)-332.2(cell)-337.2(fate.)-334.1(Nat)-335(Mater)]TJ /F5 1 Tf 12.8023 0 TD (13,)Tj /F4 1 Tf 1.5797 0 TD [(558,)-336(2014.)]TJ -16.1325 -1.1284 TD [(28.)-500.5(Murphy,)-331.9(W.L.,)-323.9(McDevitt,)-332(T.C.,)-330.4(and)-327.9(Engler,)-332(A.J.)-330.5(Materials)]TJ 1.7505 -1.1223 TD [(as)-333(stem)-338.3(cell)-331.1(regulators.)-341.9(Nat)-335(Mater)]TJ /F5 1 Tf 14.2905 0 TD (13,)Tj /F4 1 Tf 1.5858 0 TD [(547,)-329.9(2014.)]TJ -17.6268 -1.1284 TD [(29.)-500.5(Lee,)-376.8(J.,)-371.5(Abdeen,)-370.8(A.A.,)-375.7(Wycislo,)-373.6(K.L.,)-369.9(Fan,)-373.6(T.M.,)-373.7(and)-370.6(Ki)23.1(-)]TJ 1.7505 -1.1223 TD -.0136 Tc [(lia)-13.6(n)6.3(,)-404(K.)-13.6(A)9(.)-404(I)-13.6(n)8.2(ter)-13.6(f)5.9(ac)-13.6(i)6.9(a).4(l)-403.5(g)-13.6(e)6.3(o)-13.6(m)10.9(e).4(tr)-13.6(y)-394.4(d)-13.6(i)11.1(c).4(t)-13.6(a)6.9(te)-13.6(s)-395.4(c).4(a)-13.6(n)6.3(cer)-406.4(ce)-13.6(l)6.9(l)-403.5(tu)-13.6(m)10.9(o)-13.6(r)8.2(i)-1(-)]TJ 0 -1.1284 TD 0 Tc [(ge)26(ni)18.6(c)14(i)12.6(t)12.6(y)0(.)-311.3(N)0(a)24.4(t)-322.8(M)12.8(a)0(t)20.5(e)14(r)]TJ /F5 1 Tf 8.1303 0 TD [(15)24.1(,)]TJ /F4 1 Tf 1.5431 0 TD [(85)18(6,)-305.2(20)24.1(16)24.1(.)]TJ -11.4239 -1.1223 TD [(30.)-500.5(Vergani,)-317.8(L.,)-313.2(Grattarola,)-323.6(M.,)-310.6(and)-321.8(Nicolini,)-315.8(C.)-316.1(Modications)]TJ 1.7505 -1.1284 TD [(of)-417.4(chromatin)-419.1(structure)-421(and)-419.4(gene)-417.6(expression)-424.6(following)-418.2(in-)]TJ 0 -1.1223 TD [(duced)-277.5(alterations)-275.6(of)-277.1(cellular)-282.7(shape.)-276.7(Int)-270.5(J)-279.8(Biochem)-275.5(Cell)-276.8(Biol)]TJ /F5 1 Tf 0 -1.1284 TD (36,)Tj /F4 1 Tf 1.5858 0 TD [(1447,)-330(2004.)]TJ -3.3363 -1.1223 TD [(31.)-500.5(Thakar,)-532(R.G.,)-525.3(Cheng,)-528.2(Q.,)-532.5(Patel,)-529.4(S.,)-527.7(Chu,)-523.7(J.,)-530(Nasir,)-525.9(M.,)]TJ 1.7505 -1.1284 TD [(Liepmann,)-516.8(D.,)-520.3(Komvopoulos,)-513.7(K.,)-520.3(and)-517(Li,)-514(S.)-515.4(Cell-shape)]TJ 0 -1.1223 TD [(regulation)-406.9(of)-405.2(smooth)-401.5(muscle)-409.9(cell)-404.3(proliferation.)-411.5(Biophys)-400.8(J)]TJ /F5 1 Tf 0 -1.1284 TD (96,)Tj /F4 1 Tf 1.5858 0 TD [(3423,)-330(2009.)]TJ -3.3363 -1.1284 TD [(32.)-500.5(Schellenberg,)-644.8(A.,)-636.2(Joussen,)-643.1(S.,)-637.5(Moser,)-646.1(K.,)-636.2(Hampe,)-644.7(N.,)]TJ 1.7505 -1.1223 TD [(Hersch,)-414.9(N.,)-416.6(Hemeda,)-417.3(H.,)-410.5(Schnitker,)-416.4(J.,)-414.2(Denecke,)-422(B.,)-413.7(Lin,)]TJ 0 -1.1284 TD [(Q.,)-373.9(Pallua,)-371(N.,)-373.9(Zenke,)-371(M.,)-371.6(Merkel,)-376.3(R.,)-371(Hoffmann,)-371.1(B.,)-371(and)]TJ 0 -1.1223 TD [(Wagner,)-430.8(W.)-431.5(Matrix)-432.4(elasticity,)-437.3(replicative)-433.2(senescence)-433.6(and)]TJ 0 -1.1284 TD [(DNA)-584.6(methylation)-586.7(patterns)-583.2(of)-582(mesenchymal)-589.4(stem)-582.3(cells.)]TJ 0 -1.1223 TD (Biomaterials)Tj /F5 1 Tf 5.471 0 TD (35,)Tj /F4 1 Tf 1.5797 0 TD [(6351,)-336.1(2014.)]TJ -8.8012 -1.1284 TD [(33.)-500.5(Ha,)-445.3(S.W.,)-446.9(Jang,)-443.1(H.L.,)-443.1(Nam,)-451.1(K.T.,)-443.1(and)-443.8(Beck,)-446.9(G.J.)-446.4(Nano-)]TJ 1.7505 -1.1223 TD [(hydroxyapatite)-460.5(modulates)-458.6(osteoblast)-463.8(lineage)-457.7(commitment)]TJ 0 -1.1284 TD [(by)-299.1(stimulation)-306.6(of)-301.5(DNA)-304(methylation)-306.1(and)-303.5(regulation)-303.2(of)-301.5(gene)]TJ 0 -1.1223 TD [(expression.)-339.3(Biomaterials)]TJ /F5 1 Tf 10.3321 0 TD (65,)Tj /F4 1 Tf 1.5858 0 TD [(32,)-329.7(2015.)]TJ -13.6684 -1.1284 TD [(34.)-500.5(Lv,)-282.8(L.,)-288.8(Liu,)-288.5(Y.,)-282.4(Zhang,)-287.5(P.,)-283.7(Zhang,)-287.5(X.,)-288.5(Liu,)-282.4(J.,)-286.1(Chen,)-290.2(T.,)-282.7(Su,)]TJ 1.7505 -1.1223 TD [(P.,)-363(Li,)-367.6(H.,)-361.7(and)-364.5(Zhou,)-368.5(Y.)-361.6(The)-366.4(nanoscale)-370.4(geometry)-364.6(of)-362.5(TiO)]TJ 6.9712 0 0 6.196 297.6377 127.3889 Tm (2)Tj 9.2951 0 0 9.2951 78.2929 118.4315 Tm [(nanotubes)-404.7(inuences)-405.7(the)-400.5(osteogenic)-408.5(differentiation)-403.1(of)-405.2(hu-)]TJ T* [(man)-406.8(adipose-derived)-418.1(stem)-411.5(cells)-409.6(by)-408.9(modulating)-406.1(H3K4)-412.4(tri-)]TJ 0 -1.1284 TD [(methylation.)-336.7(Biomaterials)]TJ /F5 1 Tf 10.8505 0 TD (39,)Tj /F4 1 Tf 1.5858 0 TD [(193,)-336(2015.)]TJ -14.1868 -1.1223 TD [(35.)-500.5(Liu,)-398.3(Y.,)-398.3(Chen,)-393.9(T.,)-398.6(Du,)-398.4(F.,)-393.5(Gu,)-398.4(M.,)-396(Zhang,)-397.2(P.,)-399.6(Zhang,)-397.2(X.,)]TJ 1.7505 -1.1284 TD [(Liu,)-373.9(J.,)-377.6(Lv,)-374.3(L.,)-374.2(Xiong,)-373.9(C.,)-377.1(and)-376.7(Zhou,)-374.6(Y.)-373.8(Single-layer)-380(gra-)]TJ 0 -1.1223 TD [(phene)-515.4(enhances)-511.1(the)-516.4(osteogenic)-512.2(differentiation)-519(of)-508.8(human)]TJ 27.0074 70.8975 TD [(mesenchymal)-473.6(stem)-472.5(cells)-470.6(in)-469.4(vitro)-465.4(and)-474.3(in)-463.3(vivo.)-469.7(J)-468.9(Biomed)]TJ 0 -1.1223 TD (Nanotechnol)Tj /F5 1 Tf 5.4588 0 TD (12,)Tj /F4 1 Tf 1.5858 0 TD [(1270,)-330(2016.)]TJ -8.7951 -1.1284 TD [(36.)-500.5(Horna,)-698.1(D.,)-697.2(Ramirez,)-702.9(J.C.,)-693.6(Cifuentes,)-698(A.,)-697.2(Bernad,)-699.6(A.,)]TJ 1.7505 -1.1223 TD [(Borros,)-424.2(S.,)-417.9(and)-419.4(Gonzalez,)-421.6(M.A.)-422.1(Efcient)-424.2(cell)-416.5(reprogram-)]TJ 0 -1.1283 TD [(ming)-365.5(using)-365.2(bioengineered)-361.5(surfaces.)-370.5(Adv)-361.9(Healthc)-367.8(Mater)]TJ /F5 1 Tf 23.2259 0 TD (1,)Tj /F4 1 Tf -23.2259 -1.1223 TD [(177,)-336(2012.)]TJ -1.7505 -1.1284 TD [(37.)-500.5(Downing,)-339.1(T.L.,)-339.7(Soto,)-338.4(J.,)-334.9(Morez,)-340.1(C.,)-334.4(Houssin,)-335.8(T.,)-337.6(Fritz,)-338.4(A.,)]TJ 1.7505 -1.1223 TD [(Yuan,)-518.8(F.,)-515.5(Chu,)-517.6(J.,)-517.8(Patel,)-517.2(S.,)-515.5(Schaffer,)-523.8(D.V.,)-516(and)-517(Li,)-514(S.)]TJ 0 -1.1284 TD [(Biophysical)-426.9(regulation)-425.2(of)-417.4(epigenetic)-425.2(state)-421.8(and)-425.5(cell)-422.6(repro-)]TJ 0 -1.1223 TD [(gramming.)-335.7(Nat)-335(Mater)]TJ /F5 1 Tf 9.222 0 TD (12,)Tj /F4 1 Tf 1.5797 0 TD [(1154,)-336.1(2013.)]TJ -12.5522 -1.1284 TD [(38.)-500.5(Yoo,)-246.1(J.,)-243.4(Kim,)-245.1(J.,)-243.4(Baek,)-245.6(S.,)-241.1(Park,)-248(Y.,)-245.8(Im,)-240.1(H.,)-245.8(and)-242.5(Kim,)-245(J.)-243.3(Cell)]TJ 1.7505 -1.1223 TD [(reprogramming)-479.4(into)-475.2(the)-479.8(pluripotent)-475.5(state)-476.7(using)-475(graphene)]TJ 0 -1.1284 TD [(based)-337.6(substrates.)-337.8(Biomaterials)]TJ /F5 1 Tf 12.6132 0 TD (35,)Tj /F4 1 Tf 1.5858 0 TD [(8321,)-336.1(2014.)]TJ -15.9495 -1.1284 TD [(39.)-500.5(Morez,)-285.3(C.,)-273.4(Noseda,)-284.5(M.,)-280.1(Paiva,)-279.9(M.A.,)-275.8(Belian,)-281.4(E.,)-282.7(Schneider,)]TJ 1.7505 -1.1223 TD [(M.D.,)-416.1(and)-413.3(Stevens,)-413.5(M.M.)-413.7(Enhanced)-412.1(efciency)-413.1(of)-417.4(genetic)]TJ 0 -1.1284 TD [(programming)-466.5(toward)-459.7(cardiomyocyte)-464.7(creation)-460.2(through)-460.2(to-)]TJ 0 -1.1223 TD [(pographical)-338.7(cues.)-337.5(Biomaterials)]TJ /F5 1 Tf 12.906 0 TD (70,)Tj /F4 1 Tf 1.5858 0 TD [(94,)-329.7(2015.)]TJ -16.2423 -1.1284 TD [(40.)-500.5(Gilchrist,)-244.2(C.L.,)-239(Ruch,)-235.3(D.S.,)-236.8(Little,)-242.6(D.,)-233.6(and)-236.4(Guilak,)-243.5(F.)-234.9(Micro-)]TJ 1.7505 -1.1223 TD [(scale)-652.3(and)-651.2(meso-scale)-652.1(architectural)-653.5(cues)-654.6(cooperate)-654.2(and)]TJ 0 -1.1284 TD [(compete)-244.4(to)-237.6(direct)-236.1(aligned)-240(tissue)-240(formation.)-240.4(Biomaterials)]TJ /F5 1 Tf 22.7257 0 TD (35,)Tj /F4 1 Tf -22.7257 -1.1223 TD [(10015,)-336.3(2014.)]TJ -1.7505 -1.1284 TD [(41.)-500.5(Morgan,)-372.7(J.T.,)-373.6(Wood,)-371(J.A.,)-373.3(Shah,)-373.7(N.M.,)-373.4(Hughbanks,)-372.2(M.L.,)]TJ 1.7505 -1.1223 TD [(Russell,)-360.9(P.,)-356.9(Barakat,)-355.7(A.I.,)-358.2(and)-352.3(Murphy,)-356.3(C.J.)-358.1(Integration)-354.5(of)]TJ 0 -1.1284 TD [(basal)-385.8(topographic)-377.1(cues)-380.2(and)-382.8(apical)-378.3(shear)-382.6(stress)-382.3(in)-377.9(vascular)]TJ 0 -1.1223 TD [(endothelial)-341.3(cells.)-336.5(Biomaterials)]TJ /F5 1 Tf 12.6986 0 TD (33,)Tj /F4 1 Tf 1.5858 0 TD [(4126,)-330(2012.)]TJ -16.0349 -1.1284 TD [(42.)-500.5(Takahashi,)-362.1(K.,)-361.7(and)-358.4(Yamanaka,)-360.8(S.)-356.9(Induction)-360.4(of)-362.4(pluripotent)]TJ 1.7505 -1.1223 TD [(stem)-594.5(cells)-592.6(from)-596.4(mouse)-589.1(embryonic)-596.6(and)-590.2(adult)-595.4(broblast)]TJ 0 -1.1284 TD [(cultures)-339.2(by)-335.7(dened)-329.3(factors.)-342(Cell)]TJ /F5 1 Tf 13.4488 0 TD (126,)Tj /F4 1 Tf 2.0859 0 TD [(663,)-329.9(2006.)]TJ -17.2852 -1.1223 TD [(43.)-500.5(Park,)-437(I.H.,)-431.4(Zhao,)-433.7(R.,)-432(West,)-434.7(J.A.,)-434.2(Yabuuchi,)-437.6(A.,)-434.9(Huo,)-429(H.,)]TJ 1.7505 -1.1284 TD [(Ince,)-438.3(T.A.,)-437(Lerou,)-436.2(P.H.,)-438(Lensch,)-437.3(M.W.,)-437.2(and)-437.7(Daley,)-437.2(G.Q.)]TJ 0 -1.1223 TD [(Reprogramming)-506.2(of)-502.7(human)-504.6(somatic)-507.1(cells)-507.2(to)-499.8(pluripotency)]TJ 0 -1.1284 TD [(with)-336.5(dened)-335.4(factors.)-335.9(Nature)]TJ /F5 1 Tf 11.7715 0 TD (451,)Tj /F4 1 Tf 2.0859 0 TD [(141,)-329.9(2008.)]TJ -15.6079 -1.1223 TD [(44.)-500.5(Yu,)-563.1(J.,)-560.5(Vodyanik,)-561.5(M.A.,)-562.5(Smuga-Otto,)-559.9(K.,)-563(Antosiewicz-)]TJ 1.7505 -1.1284 TD [(Bourget,)-359.5(J.,)-359.3(Frane,)-362.1(J.L.,)-355.3(Tian,)-359.9(S.,)-356.9(Nie,)-359.5(J.,)-359.3(Jonsdottir,)-354.1(G.A.,)]TJ 0 -1.1223 TD [(Ruotti,)-461.4(V.,)-453.2(Stewart,)-460.4(R.,)-456.4(Slukvin,)-460.3(I.I.,)-456.5(and)-456(Thomson,)-459.1(J.A.)]TJ 0 -1.1284 TD [(Induced)-487.5(pluripotent)-493.8(stem)-484.7(cell)-489.7(lines)-484.7(derived)-493(from)-486.6(human)]TJ 0 -1.1223 TD [(somatic)-336.3(cells.)-336.5(Science)]TJ /F5 1 Tf 9.344 0 TD (318,)Tj /F4 1 Tf 2.0859 0 TD [(1917,)-330(2007.)]TJ -13.1804 -1.1284 TD [(45.)-500.5(Wernig,)-261.3(M.,)-255.7(Meissner,)-252.9(A.,)-258(Foreman,)-258.3(R.,)-255.1(Brambrink,)-258(T.,)-252.3(Ku,)]TJ 1.7505 -1.1223 TD [(M.,)-505.8(Hochedlinger,)-511.2(K.,)-502(Bernstein,)-508.9(B.E.,)-501.2(and)-504.8(Jaenisch,)-511.7(R.)]TJ 0 -1.1284 TD [(In)-514.9(vitro)-514.2(reprogramming)-516(of)-514.9(broblasts)-514.2(into)-511.8(a)-516.7(pluripotent)]TJ 0 -1.1223 TD [(ES-cell-like)-338.6(state.)-336.5(Nature)]TJ /F5 1 Tf 10.6249 0 TD (448,)Tj /F4 1 Tf 2.0859 0 TD [(318,)-329.9(2007.)]TJ -14.4613 -1.1284 TD [(46.)-500.5(Pasque,)-444.4(V.,)-441(Jullien,)-447.9(J.,)-438.5(Miyamoto,)-442.3(K.,)-447.1(Halley-Stott,)-441.1(R.P.,)]TJ 1.7505 -1.1223 TD [(and)-364.5(Gurdon,)-364.7(J.B.)-364.2(Epigenetic)-361.9(factors)-366.4(inuencing)-365.4(resistance)]TJ 0 -1.1284 TD [(to)-335.2(nuclear)-338.6(reprogramming.)-333.1(Trends)-337.8(Genet)]TJ /F5 1 Tf 17.0718 0 TD (27,)Tj /F4 1 Tf 1.5858 0 TD [(516,)-336(2011.)]TJ -20.408 -1.1223 TD [(47.)-500.5(Li,)-288.3(R.,)-285.6(Liang,)-286.9(J.,)-286.1(Ni,)-281.9(S.,)-289.8(Zhou,)-283.1(T.,)-282.7(Qing,)-288.3(X.,)-288.5(Li,)-282.2(H.,)-288.5(He,)-286.7(W.,)]TJ 1.7505 -1.1284 TD [(Chen,)-314.6(J.,)-310.5(Li,)-306.6(F.,)-314.2(Zhuang,)-305.9(Q.,)-312.9(Qin,)-312.6(B.,)-310(Xu,)-306.9(J.,)-310.5(Li,)-312.7(W.,)-309.6(Yang,)]TJ T* [(J.,)-341(Gan,)-335.7(Y.,)-343.4(Qin,)-337(D.,)-337.3(Feng,)-337.1(S.,)-338.6(Song,)-339(H.,)-337.3(Yang,)-341.9(D.,)-337.3(Zhang,)]TJ 0 -1.1223 TD [(B.,)-627.2(Zeng,)-622.8(L.,)-624.3(Lai,)-622.1(L.,)-624.3(Esteban,)-626(M.A.,)-623.5(and)-620.7(Pei,)-623.1(D.)-623.9(A)]TJ 0 -1.1284 TD [(mesenchymal-to-epithelial)-623.6(transition)-608.6(initiates)-615.9(and)-608.5(is)-608.8(re-)]TJ 0 -1.1223 TD [(quired)-281.3(for)-279.5(the)-284.6(nuclear)-277.6(reprogramming)-284.2(of)-283.2(mouse)-278.1(broblasts.)]TJ 0 -1.1284 TD [(Cell)-337.8(Stem)-336(Cell)]TJ /F5 1 Tf 6.4164 0 TD (7,)Tj /F4 1 Tf 1.0857 0 TD [(51,)-335.8(2010.)]TJ -9.2525 -1.1223 TD [(48.)-500.5(Pajerowski,)-405(J.D.,)-403.7(Dahl,)-402.3(K.N.,)-406.2(Zhong,)-399.1(F.L.,)-401.7(Sammak,)-401.7(P.J.,)]TJ 1.7505 -1.1284 TD [(and)-273(Discher,)-274.2(D.E.)-272.3(Physical)-278.8(plasticity)-274.5(of)-271(the)-272.4(nucleus)-276.3(in)-268.1(stem)]TJ 0 -1.1223 TD [(cell)-312.8(differentiation.)-311.7(Proc)-308.9(Natl)-304.1(Acad)-309.4(Sci)-311.9(U)-306.7(S)-308(A)]TJ /F5 1 Tf 19.1699 0 TD (104,)Tj /F4 1 Tf 2.0554 0 TD (15619,)Tj -21.2253 -1.1284 TD (2007.)Tj -1.7505 -1.1223 TD [(49.)-500.5(Constantinescu,)-491.8(D.,)-477.6(Gray,)-484.5(H.L.,)-485.8(Sammak,)-481(P.J.,)-484.4(Schatten,)]TJ 1.7505 -1.1284 TD [(G.P.,)-255.1(and)-248.6(Csoka,)-252.9(A.B.)-250.8(Lamin)-255.9(A/C)-250.2(expression)-253.8(is)-255(a)-248.3(marker)-251.4(of)]TJ 0 -1.1223 TD [(mouse)-595.2(and)-590.2(human)-590(embryonic)-590.5(stem)-594.5(cell)-587.3(differentiation.)]TJ 0 -1.1284 TD [(Stem)-336(Cells)]TJ /F5 1 Tf 4.794 0 TD (24,)Tj /F4 1 Tf 1.5858 0 TD [(177,)-329.9(2006.)]TJ -8.1303 -1.1223 TD [(50.)-500.5(Hobert,)-508.6(O.)-508(Gene)-504.6(regulation)-510.6(by)-506.5(transcription)-505.8(factors)-512.7(and)]TJ 1.7505 -1.1284 TD [(microRNAs.)-337.2(Science)]TJ /F5 1 Tf 8.8744 0 TD (319,)Tj /F4 1 Tf 2.0859 0 TD [(1785,)-330(2008.)]TJ -12.7108 -1.1223 TD [(51.)-500.5(Yim,)-397.5(E.K.,)-400.4(Darling,)-398.4(E.M.,)-398.1(Kulangara,)-401.6(K.,)-398.3(Guilak,)-395.9(F.,)-399.6(and)]TJ 1.7505 -1.1284 TD [(Leong,)-549.7(K.W.)-549.2(Nanotopography-induced)-555.7(changes)-549.5(in)-542.5(focal)]TJ 0 -1.1223 TD [(adhesions,)-922.3(cytoskeletal)-924.2(organization,)-923.8(and)-919.5(mechanical)]TJ /F6 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (130)Tj 49.8245 0 TD [(LV)-332.3(ET)-338.7(AL.)]TJ ET endstream endobj 158 0 obj <>stream /GS1 gs BT /F4 1 Tf 9.2951 0 0 9.2951 76.0252 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(properties)-299.1(of)-289.3(human)-297.3(mesenchymal)-296.7(stem)-295.6(cells.)-293.8(Biomaterials)]TJ /F5 1 Tf 0 -1.1223 TD (31,)Tj /F4 1 Tf 1.5858 0 TD [(1299,)-330(2010.)]TJ -3.3363 -1.1284 TD [(52.)-500.5(Abagnale,)-264.9(G.,)-258(Steger,)-264.1(M.,)-261.8(Nguyen,)-262.9(V.H.,)-259.8(Hersch,)-262.4(N.,)-258(Sechi,)]TJ 1.7505 -1.1223 TD [(A.,)-447.1(Joussen,)-454(S.,)-448.4(Denecke,)-446.4(B.,)-450.3(Merkel,)-449.5(R.,)-450.3(Hoffmann,)-450.4(B.,)]TJ 0 -1.1283 TD [(Dreser,)-295.2(A.,)-288.5(Schnakenberg,)-292.2(U.,)-288.5(Gillner,)-294.1(A.,)-288.5(and)-285.2(Wagner,)-296.6(W.)]TJ 0 -1.1223 TD [(Surface)-356.6(topography)-349(enhances)-352.6(differentiation)-354.3(of)-350.3(mesenchy-)]TJ 0 -1.1284 TD [(mal)-272(stem)-265.2(cells)-269.4(towards)-269.9(osteogenic)-274.3(and)-266.9(adipogenic)-269.1(lineages.)]TJ 0 -1.1223 TD (Biomaterials)Tj /F5 1 Tf 5.471 0 TD (61,)Tj /F4 1 Tf 1.5797 0 TD [(316,)-336(2015.)]TJ -8.8012 -1.1284 TD [(53.)-500.5(Ogino,)-562.9(Y.,)-563(Liang,)-567.5(R.,)-560.1(Mendonca,)-562.1(D.B.,)-568(Mendonca,)-562.1(G.,)]TJ 1.7505 -1.1223 TD [(Nagasawa,)-660.8(M.,)-646.1(Koyano,)-653.3(K.,)-654.5(and)-651.2(Cooper,)-652.7(L.F.)-651.7(RhoA-)]TJ 0 -1.1284 TD [(mediated)-622.1(functions)-621.8(in)-615.7(C3H10T1/2)-618.9(osteoprogenitors)-621.8(are)]TJ 0 -1.1223 TD [(substrate)-423.9(topography)-416.1(dependent.)-416(J)-420.1(Cell)-417.1(Physiol)]TJ /F5 1 Tf 20.0604 0 TD (231,)Tj /F4 1 Tf 2.1652 0 TD (568,)Tj -22.2256 -1.1284 TD (2016.)Tj -1.7505 -1.1284 TD [(54.)-500.5(Yu,)-245.9(W.,)-248.6(Zhang,)-244.8(Y.,)-245.8(Xu,)-245.9(L.,)-246.1(Sun,)-247.4(S.,)-247.2(Jiang,)-241.4(X.,)-245.8(and)-248.6(Zhang,)-244.8(F.)]TJ 1.7505 -1.1223 TD [(Microarray-based)-317.1(bioinformatics)-310.3(analysis)-311.6(of)-307.6(osteoblasts)-310.6(on)]TJ 0 -1.1284 TD (TiO)Tj 6.9712 0 0 6.196 91.0488 566.7022 Tm (2)Tj 9.2951 0 0 9.2951 98.8724 568.2329 Tm [(nanotube)-472.5(layers.)-467.7(Colloids)-473(Surf)-465.6(B)-468.5(Biointerfaces)]TJ /F5 1 Tf 20.2678 0 TD (93,)Tj /F4 1 Tf -22.7257 -1.1223 TD [(135,)-336(2012.)]TJ -1.7505 -1.1284 TD [(55.)-500.5(McMurray,)-287.3(R.J.,)-285(Gadegaard,)-284.4(N.,)-282.4(Tsimbouri,)-283.7(P.M.,)-283.2(Burgess,)]TJ 1.7505 -1.1223 TD [(K.V.,)-326.9(McNamara,)-338(L.E.,)-327.5(Tare,)-324.3(R.,)-328.3(Murawski,)-330.4(K.,)-331.2(Kingham,)]TJ 0 -1.1284 TD [(E.,)-410.8(Oreffo,)-410.1(R.O.,)-409.4(and)-407.2(Dalby,)-414.7(M.J.)-407.5(Nanoscale)-414.7(surfaces)-413.1(for)]TJ 0 -1.1223 TD [(the)-668.9(long-term)-667.3(maintenance)-673.7(of)-667.4(mesenchymal)-668.7(stem)-667.7(cell)]TJ 0 -1.1284 TD [(phenotype)-338.5(and)-334(multipotency.)-336.9(Nat)-335(Mater)]TJ /F5 1 Tf 16.6875 0 TD (10,)Tj /F4 1 Tf 1.5858 0 TD [(637,)-329.9(2011.)]TJ -20.0238 -1.1223 TD [(56.)-500.5(Lovett,)-286.5(D.B.,)-287.4(Shekhar,)-289.2(N.,)-282.4(Nickerson,)-286.7(J.A.,)-287.9(Roux,)-286(K.J.,)-287.9(and)]TJ 1.7505 -1.1284 TD [(Lele,)-394.6(T.P.)-389.5(Modulation)-393.6(of)-386.9(Nuclear)-395.1(Shape)-396.3(by)-384.5(Substrate)-397.1(Ri-)]TJ 0 -1.1223 TD [(gidity.)-334.7(Cell)-337.8(Mol)-334.6(Bioeng)]TJ /F5 1 Tf 10.1674 0 TD (6,)Tj /F4 1 Tf 1.0857 0 TD [(230,)-329.9(2013.)]TJ -13.0036 -1.1284 TD [(57.)-500.5(Yang,)-366.3(C.,)-358.8(Tibbitt,)-366.6(M.W.,)-364(Basta,)-360.2(L.,)-362(and)-364.5(Anseth,)-365.1(K.S.)-364.8(Me-)]TJ 1.7505 -1.1223 TD [(chanical)-370.6(memory)-366.4(and)-364.5(dosing)-371.5(inuence)-363.8(stem)-368.8(cell)-367.7(fate.)-370.7(Nat)]TJ 0 -1.1284 TD (Mater)Tj /F5 1 Tf 2.7325 0 TD (13,)Tj /F4 1 Tf 1.5797 0 TD [(645,)-336(2014.)]TJ -6.0626 -1.1223 TD [(58.)-500.5(Zhou,)-484.4(J.,)-475.1(Li,)-483.5(B.,)-480.8(Han,)-482(Y.,)-477.6(and)-480.4(Zhao,)-482.5(L.)-477.8(The)-482.3(osteogenic)]TJ 1.7505 -1.1284 TD [(capacity)-614.6(of)-606.4(biomimetic)-610.5(hierarchical)-617.3(micropore/nanorod-)]TJ 0 -1.1223 TD [(patterned)-356.7(Sr-HA)-359.1(coatings)-355.2(with)-354.8(different)-357.1(interrod)-356.5(spacings.)]TJ 0 -1.1284 TD (Nanomedicine)Tj /F5 1 Tf 6.1907 0 TD (12,)Tj /F4 1 Tf 1.5797 0 TD [(1161,)-336.1(2016.)]TJ -9.5209 -1.1223 TD [(59.)-500.5(Dumas,)-243.1(V.,)-239.7(Guignandon,)-238.5(A.,)-239.7(Vico,)-243.7(L.,)-240(Mauclair,)-240(C.,)-242.9(Zapata,)]TJ 1.7505 -1.1284 TD [(X.,)-331.2(Linossier,)-336.2(M.T.,)-331(Bouleftour,)-331.2(W.,)-327.9(Granier,)-332.3(J.,)-334.9(Peyroche,)]TJ 0 -1.1223 TD [(S.,)-430.1(Dumas,)-432.2(J.C.,)-425.3(Zahouani,)-431.8(H.,)-428.8(and)-425.5(Rattner,)-436.3(A.)-422.6(Femtose-)]TJ 0 -1.1284 TD [(cond)-541.5(laser)-540.6(nano/micro)-541.2(patterning)-547.2(of)-539.3(titanium)-539.4(inuences)]TJ 0 -1.1223 TD [(mesenchymal)-272.3(stem)-265.2(cell)-264(adhesion)-264.3(and)-266.9(commitment.)-263.1(Biomed)]TJ 0 -1.1284 TD (Mater)Tj /F5 1 Tf 2.7325 0 TD (10,)Tj /F4 1 Tf 1.5797 0 TD [(55002,)-336.3(2015.)]TJ -6.0626 -1.1223 TD [(60.)-500.5(Cunha,)-424.5(A.,)-416.6(Zouani,)-421.2(O.F.,)-419.7(Plawinski,)-422.2(L.,)-416.9(Botelho,)-423.7(D.R.A.,)]TJ 1.7505 -1.1284 TD [(Almeida,)-363.3(A.,)-355.6(Vilar,)-361.5(R.,)-358.8(and)-358.4(Durrieu,)-358.6(M.C.)-358.2(Human)-359.8(mesen-)]TJ 0 -1.1223 TD [(chymal)-423(stem)-417.6(cell)-422.6(behavior)-420(on)-415(femtosecond)-423.3(laser-textured)]TJ 0 -1.1284 TD [(Ti-6Al-4)-172.8(V)-331.1(surfaces.)-340(Nanomedicine)-335.7(\(Lond\))]TJ /F5 1 Tf 17.95 0 TD (10,)Tj /F4 1 Tf 1.5797 0 TD [(725,)-336(2015.)]TJ -21.2802 -1.1223 TD [(61.)-500.5(Thormann,)-363(U.,)-361.7(Alt,)-354.7(V.,)-361.7(Heimann,)-363.8(L.,)-355.9(Gasquere,)-364.5(C.,)-358.8(Heiss,)]TJ 1.7505 -1.1284 TD [(C.,)-249(Szalay,)-247.7(G.,)-239.7(Franke,)-246.3(J.,)-249.5(Schnettler,)-243.3(R.,)-249(and)-242.5(Lips,)-245.1(K.S.)-248.9(The)]TJ 0 -1.1223 TD [(biocompatibility)-671.1(of)-667.4(degradable)-666.5(magnesium)-672.2(interference)]TJ 0 -1.1284 TD [(screws:)-315.9(an)-315.6(experimental)-317.6(study)-316.4(with)-312.1(sheep.)-319.4(Biomed)-313.8(Res)-313.5(Int)]TJ /F5 1 Tf T* (2015,)Tj /F4 1 Tf 2.5861 0 TD [(943603,)-330.3(2015.)]TJ -4.3366 -1.1223 TD [(62.)-500.5(Lee,)-474.4(J.W.,)-467.5(Han,)-469.8(H.S.,)-468.5(Han,)-469.8(K.J.,)-470.8(Park,)-467.5(J.,)-469(Jeon,)-467.5(H.,)-471.5(Ok,)]TJ 1.7505 -1.1284 TD [(M.R.,)-376.6(Seok,)-373.7(H.K.,)-375.7(Ahn,)-380.2(J.P.,)-374.6(Lee,)-376.8(K.E.,)-376(Lee,)-376.8(D.H.,)-375.7(Yang,)]TJ 0 -1.1223 TD [(S.J.,)-258.7(Cho,)-255.4(S.Y.,)-255.1(Cha,)-259.6(P.R.,)-258.3(Kwon,)-253.9(H.,)-258(Nam,)-255.9(T.H.,)-260.1(Han,)-256.4(J.H.,)]TJ 0 -1.1284 TD [(Rho,)-310.3(H.J.,)-312.3(Lee,)-315.8(K.S.,)-309.9(Kim,)-312.1(Y.C.,)-311.8(and)-315.7(Mantovani,)-312.9(D.)-312.9(Long-)]TJ 0 -1.1223 TD [(term)-353.7(clinical)-359.1(study)-353(and)-352.3(multiscale)-358.1(analysis)-354.3(of)-350.3(in)-353.5(vivo)-353.8(bio-)]TJ 0 -1.1284 TD [(degradation)-405.7(mechanism)-408.1(of)-405.2(Mg)-402.1(alloy.)-406.4(Proc)-400.3(Natl)-407.8(Acad)-407(Sci)]TJ 0 -1.1223 TD .3348 Tc (USA)Tj /F5 1 Tf 2.9886 0 TD 0 Tc (113,)Tj /F4 1 Tf 2.0859 0 TD [(716,)-336(2016.)]TJ -6.825 -1.1284 TD [(63.)-500.5(Li,)-300.5(Z.,)-301(Gu,)-300.8(X.,)-300.7(Lou,)-301.3(S.,)-302(and)-297.4(Zheng,)-299.7(Y.)-300.7(The)-305.4(development)-299.3(of)]TJ 1.7505 -1.1223 TD [(binary)-500.9(Mg-Ca)-499.2(alloys)-497.1(for)-499.1(use)-491.7(as)-497.6(biodegradable)-501.7(materials)]TJ 0 -1.1284 TD [(within)-336.2(bone.)-334.2(Biomaterials)]TJ /F5 1 Tf 10.8993 0 TD (29,)Tj /F4 1 Tf 1.5797 0 TD [(1329,)-336.1(2008.)]TJ -14.2295 -1.1223 TD [(64.)-500.5(Zhao,)-409.3(D.,)-404.4(Witte,)-410.2(F.,)-399.6(Lu,)-410.9(F.,)-399.6(Wang,)-411.8(J.,)-402(Li,)-404.2(J.,)-408.1(and)-407.2(Qin,)-404.1(L.)]TJ 1.7505 -1.1284 TD [(Current)-294.6(status)-288.8(on)-293(clinical)-292(applications)-291.7(of)-289.3(magnesium-based)]TJ 0 -1.1223 TD [(orthopaedic)-411.8(implants:)-404.5(a)-406.9(review)-409(from)-407.3(clinical)-407.9(translational)]TJ 0 -1.1284 TD [(perspective.)-342(Biomaterials)]TJ /F5 1 Tf 10.6249 0 TD (112,)Tj /F4 1 Tf 2.0859 0 TD [(287,)-329.9(2017.)]TJ -14.4613 -1.1223 TD [(65.)-500.5(Thorfve,)-566.9(A.,)-569.1(Bergstrand,)-566.8(A.,)-563(Ekstrom,)-570.6(K.,)-563(Lindahl,)-567.2(A.,)]TJ 1.7505 -1.1284 TD [(Th)22.2(om)24.5(s)12.9(e)0(n)19.9(,)-292.8(P)15.3(.)0(,)-280.7(L)0(a)24.1(r)0(s)22.7(s)12.9(on)24.1(,)-292.8(A)0(.)22.6(,)-292.8(a)14(n)0(d)-280.8(T)0(e)24.1(n)0(g)24.1(v)0(a)19.9(l)12.6(l)12.6(,)-292.8(P)15.3(.)-292.8(Ge)24.4(ne)-285.1(e)14(x)0(p)24.1(r)0(e)23.7(s)0(s)19.8(i)12.6(on)]TJ 0 -1.1223 TD [(pr)21.8(o)21.2(l)12.6(i)12.6(n)0(g)-579.7(o)0(f)-588.1(p)0(e)26(r)0(i)22.4(-)0(i)22.4(m)12.5(pl)24.7(a)14(n)0(t)-585.2(h)0(e)19.9(a)14(l)12.6(i)12.6(n)0(g)-585.8(o)0(f)-582(P)15.3(LG)20.7(A-)20.2(L)16.3(i)]TJ /F8 1 Tf 19.4566 0 TD (+)Tj /F4 1 Tf 1.1467 0 TD [(i)12.6(m)12.5(pl)24.7(an)19.9(t)12.6(s)]TJ 6.4103 70.8975 TD [(suggests)-270.5(an)-272.9(activated)-278.7(Wnt)-272.6(signaling)-271.3(pathway)-272.7(in)-274.2(vivo.)-274.5(PLoS)]TJ 0 -1.1223 TD (One)Tj /F5 1 Tf 2.0005 0 TD (9,)Tj /F4 1 Tf 1.0796 0 TD [(e102597,)-334.7(2014.)]TJ -4.8306 -1.1284 TD [(66.)-500.5(Wang,)-369.1(H.Y.,)-375.7(and)-370.6(Malbon,)-375.9(C.C.)-369.9(Wnt)-376.3(signaling,)-375(Ca2)]TJ /F8 1 Tf 23.0978 0 TD (+)Tj /F4 1 Tf .555 0 TD [(,)-372.1(and)]TJ -21.9024 -1.1223 TD [(cyclic)-433.2(GMP:)-430.7(visualizing)-433.8(Frizzled)-432.6(functions.)-432.8(Science)]TJ /F5 1 Tf 22.2195 0 TD (300,)Tj /F4 1 Tf -22.2195 -1.1283 TD [(1529,)-330(2003.)]TJ -1.7505 -1.1223 TD [(67.)-500.5(Sollazzo,)-418.2(V.,)-410.5(Pezzetti,)-421.8(F.,)-417.9(Massari,)-417.4(L.,)-410.8(Palmieri,)-421.4(A.,)-416.6(Bru-)]TJ 1.7505 -1.1284 TD [(nelli,)-271.6(G.,)-276.3(Zollino,)-269.6(I.,)-277.1(Lucchese,)-275.2(A.,)-270.2(Caruso,)-279.7(G.,)-270.2(and)-273(Carinci,)]TJ 0 -1.1223 TD [(F.)-405.7(Evaluation)-406.5(of)-405.2(gene)-411.5(expression)-406.3(in)-408.4(MG63)-404(human)-407.1(osteo-)]TJ 0 -1.1284 TD [(blastlike)-390.8(cells)-397.5(exposed)-392.8(to)-390.1(tantalum)-391.7(powder)-393.2(by)-390.6(microarray)]TJ 0 -1.1223 TD [(technology.)-472.3(Int)-465.7(J)-468.9(Periodontics)-476.3(Restorative)-476.2(Dent)]TJ /F5 1 Tf 20.5544 0 TD (31,)Tj /F4 1 Tf 1.72 0 TD (e17,)Tj -22.2744 -1.1284 TD (2011.)Tj -1.7505 -1.1223 TD [(68.)-500.5(Lu,)-282.8(T.,)-282.7(Wen,)-283.5(J.,)-280(Qian,)-280.3(S.,)-283.7(Cao,)-284(H.,)-282.4(Ning,)-282.2(C.,)-285.6(Pan,)-282.1(X.,)-282.4(Jiang,)]TJ 1.7505 -1.1284 TD [(X.,)-416.6(Liu,)-416.6(X.,)-416.6(and)-413.3(Chu,)-420(P.K.)-413.6(Enhanced)-424.3(osteointegration)-416.1(on)]TJ T* [(tantalum-implanted)-987.2(polyetheretherketone)-988.1(surface)-981.1(with)]TJ 0 -1.1223 TD [(bone-like)-334.2(elastic)-334.3(modulus.)-334.7(Biomaterials)]TJ /F5 1 Tf 16.5289 0 TD (51,)Tj /F4 1 Tf 1.5797 0 TD [(173,)-336(2015.)]TJ -19.8591 -1.1284 TD [(69.)-500.5(Le)24.1(vi)18.6(ne)19.9(,)-329.4(B)0(.)19.4(R)13.4(.,)-323.4(Sp)21.2(or)21.8(er)23.7(,)-335.5(S)15.3(.,)-323.4(Po)21.2(gg)24.1(ie)20.5(,)-335.5(R)13.4(.A)22.6(.,)-323.4(De)18.3(l)12.6(l)12.6(a)0(,)-321.6(V)0(.)22.6(C)0(.)19.4(,)-329.4(an)19.9(d)-335.6(J)12.9(a-)]TJ 1.7505 -1.1223 TD [(c)14(o)0(b)18(s)12.9(,)-378.2(J)12.9(.J)19(.)-372.1(E)0(x)22.2(p)0(e)19.9(r)0(i)16.3(m)12.5(en)19.9(t)12.6(a)0(l)-363.8(a)0(n)19.9(d)-378.3(c)14(l)0(i)19.2(n)0(i)18.6(c)14(al)-363.8(pe)19.9(rf)19.5(or)21.8(ma)20.3(nc)19.9(e)-376.4(o)0(f)-362.5(p)0(o)18(r)0(o)21.8(u)0(s)]TJ 0 -1.1284 TD [(t)12.6(a)0(n)19.9(t)12.6(al)20.5(um)-237.7(i)12.6(n)-250.2(or)21.8(t)12.6(h)0(o)18(p)0(e)19.9(d)0(i)24.7(c)-248.3(su)18.9(rg)21.8(er)23.7(y.)-238.1(Bi)19.9(om)18.4(a)14(t)0(e)20.5(r)0(i)16.3(a)14(ls)]TJ /F5 1 Tf 17.8342 0 TD [(27)18(,)]TJ /F4 1 Tf 1.476 0 TD [(46)18(71)24.1(,)-244(2)0(0)18(0)0(6)24.1(.)]TJ -21.0607 -1.1223 TD [(70.)-500.5(Autefage,)-572.2(H.,)-569.1(Gentleman,)-569(E.,)-569.4(Littmann,)-572.4(E.,)-569.4(Hedegaard,)]TJ 1.7505 -1.1284 TD [(M.A.,)-690.6(Von)-691.2(Erlach,)-690(T.,)-691.4(ODonnell,)-693(M.,)-688.8(Burden,)-695.4(F.R.,)]TJ 0 -1.1223 TD [(Winkler,)-303.6(D.A.,)-308.6(and)-303.5(Stevens,)-309.8(M.M.)-303.9(Sparse)-306.4(feature)-310.5(selection)]TJ 9.2951 0 0 9.2951 327.118 505.4739 Tm [(methods)-509.6(identify)-512.2(unexpected)-517.8(global)-510.2(cellular)-520.6(response)-510.3(to)]TJ T* [(strontium-containing)-334.5(materials.)-342.6(Proc)-333.3(Natl)-334.6(Acad)-339.9(Sci)-336.3(U)-331.1(S)-332.4(A)]TJ /F5 1 Tf 0 -1.1284 TD (112,)Tj /F4 1 Tf 2.0798 0 TD [(4280,)-336.1(2015.)]TJ -3.8303 -1.1223 TD [(71.)-500.5(Zhao,)-256.8(L.,)-252.2(Wang,)-259.3(H.,)-258(Huo,)-258.3(K.,)-251.9(Zhang,)-257(X.,)-258(Wang,)-259.3(W.,)-254.7(Zhang,)]TJ 1.7505 -1.1284 TD [(Y.,)-563(Wu,)-571.9(Z.,)-563.3(and)-571.9(Chu,)-566.4(P.K.)-566(The)-567.7(osteogenic)-567.1(activity)-574.5(of)]TJ 0 -1.1223 TD [(strontium)-390.9(loaded)-393(titania)-391.4(nanotube)-393.3(arrays)-397.3(on)-390.6(titanium)-393(sub-)]TJ 0 -1.1284 TD [(strates.)-332.2(Biomaterials)]TJ /F5 1 Tf 8.6121 0 TD (34,)Tj /F4 1 Tf 1.5858 0 TD [(19,)-329.7(2013.)]TJ -11.9484 -1.1223 TD [(72.)-500.5(Ray,)-540.1(S.,)-533.8(Thormann,)-539.9(U.,)-538.6(Sommer,)-540.1(U.,)-538.6(Khassawna,)-546(T.E.,)]TJ 1.7505 -1.1284 TD [(Hundgeburth,)-234.9(M.,)-237.4(Henss,)-236.6(A.,)-233.6(Rohnke,)-235.6(M.,)-237.4(Lips,)-239(K.S.,)-236.7(Heiss,)]TJ 0 -1.1223 TD [(C.,)-303.9(Heinemann,)-307.3(S.,)-302(Hanke,)-309.7(T.,)-301(Durselen,)-311(L.,)-301(Schnettler,)-310.4(R.,)]TJ 0 -1.1284 TD [(and)-620.7(Alt,)-623.1(V.)-623.9(Effects)-624.4(of)-618.6(macroporous,)-623.3(strontium)-622.7(loaded)]TJ 0 -1.1223 TD [(xerogel-scaffolds)-495.3(on)-494.3(new)-500.2(bone)-492.7(formation)-496.5(in)-493.7(critical-size)]TJ 0 -1.1284 TD [(metaphyseal)-314.8(fracture)-312.9(defects)-313.4(in)-310.8(ovariectomized)-316(rats.)-310.7(Injury)]TJ /F5 1 Tf 0 -1.1223 TD [(47)-329.6(Suppl)-335(1,)]TJ /F4 1 Tf 5.2392 0 TD [(S52,)-332.8(2016.)]TJ -6.9897 -1.1284 TD [(73.)-500.5(Boda,)-302.4(S.K.,)-303.8(Thrivikraman,)-308(G.,)-300.7(Panigrahy,)-307.2(B.,)-303.9(Sarma,)-306.8(D.D.,)]TJ 1.7505 -1.1223 TD [(and)-480.4(Basu,)-478.4(B.)-480.7(Competing)-478.4(roles)-481.5(of)-478.3(substrate)-478.8(composition,)]TJ 0 -1.1284 TD [(microstructure,)-445.6(and)-443.8(sustained)-445.9(strontium)-439.7(release)-445.6(in)-445(direct-)]TJ 0 -1.1223 TD [(ing)-317(osteogenic)-329.2(differentiation)-323.8(of)-319.8(hMSCs.)-324(ACS)-320.7(Appl)-324.8(Mater)]TJ 0 -1.1284 TD (Interfaces)Tj /F5 1 Tf 4.2878 0 TD (9,)Tj /F4 1 Tf 1.0857 0 TD [(19389,)-330.2(2016.)]TJ -7.1239 -1.1223 TD [(74.)-500.5(Xia,)-316.8(L.,)-313.2(Lin,)-312.9(K.,)-312.9(Jiang,)-314.6(X.,)-319(Fang,)-312.7(B.,)-316.1(Xu,)-313(Y.,)-312.9(Liu,)-319(J.,)-310.5(Zeng,)]TJ 1.7505 -1.1284 TD [(D.,)-319(Zhang,)-318(M.,)-322.8(Zhang,)-318(X.,)-319(Chang,)-320.9(J.,)-322.7(and)-321.8(Zhang,)-318(Z.)-319.3(Effect)]TJ 0 -1.1223 TD [(of)-453.9(nano-structured)-465(bioceramic)-464.3(surface)-456.5(on)-457.7(osteogenic)-463.4(dif-)]TJ 0 -1.1284 TD [(ferentiation)-297.3(of)-295.4(adipose)-294.6(derived)-297.8(stem)-295.7(cells.)-293.8(Biomaterials)]TJ /F5 1 Tf 22.7197 0 TD (35,)Tj /F4 1 Tf -22.7197 -1.1223 TD [(8514,)-330(2014.)]TJ -1.7505 -1.1284 TD [(75.)-500.5(Eyckmans,)-516.5(J.,)-511.7(Roberts,)-517.2(S.J.,)-514.9(Bolander,)-516.3(J.,)-517.8(Schrooten,)-514.6(J.,)]TJ 1.7505 -1.1284 TD -.0279 Tc [(Chen)-3.6(,)-339(C)-2.3(.)-3.6(S)-.4(.,)-339(an)-3.6(d)-339.1(L)-5.5(uy)-3.6(t)-3.1(e)-1.7(n,)-339(F)-6.5(.)2.5(P.)-339(M)-2.9(a)-1.7(p)-3.6(p)2.5(i)-3.1(n)-3.6(g)-339.1(cal)-3.1(ci)-3.1(um)-338.7(p)-3.6(h)-3.6(o)2.5(s)-2.8(p)-3.6(hat)-3.1(e)-343.3(ac-)]TJ 0 -1.1223 TD -.0283 Tc [(ti)-3.5(v)-4(a)-2.2(ted)-296.8(g)-4(ene)-301(n)2.1(et)-3.5(wo)-4(rk)-4(s)-295.9(a)-2.2(s)-295.9(a)-294.9(s)-3.2(t)2.6(r)-6.4(a)-2.2(teg)-4(y)-296.8(fo)-4(r)-293(t)-3.5(arg)-4(e)-2.2(ted)-296.8(o)-4(st)-3.5(eo)-4(i)-3.5(n)2.1(d)-4(u)2.1(ct)-3.5(i)-3.5(o)2.1(n)]TJ 0 -1.1284 TD -.0267 Tc [(of)-334.1(human)-331.8(p)-2.4(rogenitors.)-331.7(B)-1.1(iomaterials)]TJ /F5 1 Tf 14.0099 0 TD -.0243 Tc [(34)6.1(,)]TJ /F4 1 Tf 1.5004 0 TD [(461)6.1(2,)-329.3(20)6.1(13)6.1(.)]TJ -17.2608 -1.1223 TD 0 Tc [(76.)-500.5(Oh,)-374(J.Y.,)-379.4(Kim,)-379.2(Y.S.,)-377(Jung,)-377.9(Y.,)-380(Yang,)-378.5(S.J.,)-380.7(and)-376.7(Park,)-382.1(C.R.)]TJ 1.7505 -1.1284 TD [(Preparation)-264.6(and)-254.7(exceptional)-266.8(mechanical)-264.9(properties)-262.5(of)-258.8(bone-)]TJ 0 -1.1223 TD [(mimicking)-564.1(size-tuned)-575.5(graphene)-565(oxide@carbon)-569.9(nanotube)]TJ 0 -1.1284 TD [(hybrid)-332(paper.)-334.8(ACS)-332.9(Nano)]TJ /F5 1 Tf 10.5273 0 TD (10,)Tj /F4 1 Tf 1.5858 0 TD [(2184,)-330(2016.)]TJ -13.8636 -1.1223 TD [(77.)-500.5(Lu,)-270.6(J.,)-273.9(Cheng,)-272.1(C.,)-267.3(He,)-274.5(Y.S.,)-273.3(Lyu,)-270.8(C.,)-273.4(Wang,)-271.5(Y.,)-270.2(Yu,)-276.4(J.,)-267.8(Qiu,)]TJ 1.7505 -1.1284 TD [(L.,)-416.9(Zou,)-417.1(D.,)-422.7(and)-419.4(Li,)-416.4(D.)-422.6(Multilayered)-422.3(Graphene)-420.2(Hydrogel)]TJ 0 -1.1223 TD [(Membranes)-294.8(for)-291.7(Guided)-292.7(Bone)-296.2(Regeneration.)-299.1(Adv)-294.8(Mater)]TJ /F5 1 Tf 22.7197 0 TD (28,)Tj /F4 1 Tf -22.7197 -1.1284 TD [(4025,)-330(2016.)]TJ -1.7505 -1.1223 TD [(78.)-500.5(Shin,)-295.7(S.R.,)-294.9(Li,)-294.4(Y.C.,)-293.5(Jang,)-296.7(H.L.,)-296.7(Khoshakhlagh,)-297(P.,)-296(Akbari,)]TJ 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