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[(by)-449.5(fu)5.5(rth)5.5(e)-1.4(r)-449.4(d)-.2(ev)5.5(el)5.4(op)5.5(in)5.5(g)-455.2(b)-.2(i)5.4(o)-.2(compati)5.4(b)-.2(le)-450.6(an)5.5(d)-455.2(p)5.5(ati)5.4(e)-1.4(n)5.5(t)-.3(-)5.6(s)0(peci)5.4(c)]TJ
T*
.0129 Tc
[(ti)5.9(ssu)6(es)6.2(.)]TJ
7.3823 0 0 6.5614 91.5023 368.3338 Tm
.0145 Tc
(1315)Tj
9.843 0 0 9.843 116.0504 363.9684 Tm
.0072 Tc
[(Re)-6.6(ce)-6.6(nt)-564.2(ad)-5.4(v)-5.4(a)-.8(n)-5.4(c)-.8(e)-6.6(s)-558.1(i)-5.5(n)-564.1(st)-5.5(e)-6.6(m)-559.6(c)-6.6(e)-.8(l)-5.5(l)-564.2(bi)-5.5(ol)-5.5(og)-5.4(y)-564.1(a)-.8(n)-5.4(d)]TJ
-5.489 -1.1174 TD
.01 Tc
[(bioma)-3.8(t)3(e)-3.8(r)3.2(ials)-353.8(are)-349.4(n)-2.6(ow)-349.1(e)-3.8(x)3.1(pe)-3.8(cted)-354(to)-348.2(solve)-349.4(m)-3.8(any)-348.2(o)-2.6(f)-348.2(t)3(he)-3.8(se)-355.1(as-)]TJ
0 -1.1116 TD
.013 Tc
[(so)6.1(ci)6(at)6(ed)-402.8(ch)6.1(all)6(e)-.8(n)6.1(g).4(e)5(s)-408.4(b)6.1(y)-408.6(p)6.1(r).4(o)6.1(v).4(i)6(d).4(in)6.1(g)-408.6(p)6.1(at)6(ie)5(nt)6(-de)5(ri)6(ve)5(d)-408.6(p)6.1(lu)6.1(rip)6.1(o).4(-)]TJ
T*
.0073 Tc
[(t)-5.4(e)-.7(n)-5.3(t)-293.4(s)-5.1(t)-5.4(em)-294.5(c)-6.5(e)-6.5(l).3(l)-5.4(s)-293.1(a)-6.5(n).4(d)-299.1(t)-5.4(hr)-5.3(ou)-5.3(gh)-299.1(f)-5.3(u).4(r)-5.3(t).3(h)-5.3(e)-.7(r)-299(r)-5.3(e)-5.2(ne)-6.5(me)-6.5(nt)-299.2(of)-299(a)-6.5(d).4(v)-5.3(a)-.7(n)-5.3(c)-.7(e)-6.5(d)]TJ
T*
.0122 Tc
[(bi)5.2(omat)5.2(er)5.4(ials.)]TJ
7.3823 0 0 6.5614 114.6897 324.5102 Tm
.0145 Tc
(1619)Tj
9.843 0 0 9.843 72 309.1464 Tm
.0117 Tc
[(Mor)4.9(e)-428.3(recentl)4.7(y)-.9(,)-423.7(a)-2.1(s)-426.9(m)3.6(etho)4.8(do)4.8(lo)4.8(gies)-426.9(of)-421.3(tis)5(su)4.8(e)-428.3(e)-2.1(n)4.8(g)-.9(i)4.7(n)-.9(eeri)4.7(ng)]TJ
-1.0137 -1.1116 TD
.0119 Tc
[(have)-468.4(adv)5(a)-1.9(nced)-467.2(t)4.9(o)-467.2(recap)5(i)-.8(t)4.9(u)-.7(l)4.9(a)-1.9(te)-468.4(car)5.1(d)-.7(i)4.9(a)-1.9(c)-468.4(m)3.8(icrot)4.9(is)5.2(sue)-468.4(s)5.2(tru)5(c)-1.9(-)]TJ
T*
[(tu)5.1(res)-242.3(m)3.9(or)5.2(e)-237.9(e)-1.8(l)5(a)-1.8(b)5.1(orately)5.1(,)-239.1(t)-.7(h)5.1(e)-237.9(resto)5.1(r)-.6(ati)5(o)-.6(n)-236.8(o)-.6(f)-236.7(v)5.1(as)5.3(cul)5(a)-1.8(r)-236.7(n)5.1(et)5(wor)5.2(k)-.6(s)]TJ
0 -1.1174 TD
[(th)4.9(ro)4.9(ugh)4.9(ou)4.9(t)-352.3(e)3.8(ngi)4.8(neer)5(ed)-352.2(t)4.8(i)-.9(s)5.1(s)-.6(ues)-352(h)-.8(as)-352(emerg)4.9(e)-2(d)-352.2(a)3.8(s)-352(a)-353.3(maj)4.8(o)-.8(r)-352.1(i)4.8(n-)]TJ
0 -1.1116 TD
.0115 Tc
[(terest)-375.6(and)-369.7(c)-2.3(h)4.6(a)-2.3(l)4.5(l)-1.2(eng)4.6(e)-376.7(with)4.6(in)-369.7(th)4.6(e)-376.7()4.8(eld)4.6(.)]TJ
7.3823 0 0 6.5614 214.5259 269.6881 Tm
.0145 Tc
(2022)Tj
9.843 0 0 9.843 237.2031 265.3228 Tm
.0125 Tc
[(Th)5.6(is)-368.5(is)-374.3(b)5.6(e)-1.3(cau)5.6(s).1(e)]TJ
-17.7975 -1.1116 TD
[(th)5.5(e)-462.2(i)5.4(ncor)5.6(por)5.6(at)5.4(ed)-455.2(cell)5.4(s)-460.8(n)-.2(eed)-455.2(t)-.3(o)-455.2(b)-.2(e)-456.4(w)-1.1(i)5.4(t)-.3(h)5.5(i)-.3(n)-455.2(100)5.5(2)5.5(00)]TJ
/F8 1 Tf
21.6335 0 TD
0 Tc
(m)Tj
/F3 1 Tf
.5645 0 TD
.4689 Tc
[(mo)456.3(f)]TJ
-22.1979 -1.1174 TD
.0122 Tc
[(fu)5.3(ncti)5.2(onal)-363.4(v)-.4(as)5.5(cu)5.3(latu)5.3(re)-364.4(to)-363.3(se)]TJ
11.6116 0 TD
[(cu)5.3(re)-364.4(ox)5.3(ygen)-363.3(a)-1.6(n)5.3(d)-369(n)5.3(u)-.4(t)5.2(r)-.4(ient)-363.4(su)5.3(p-)]TJ
-11.6116 -1.1116 TD
.0126 Tc
[(pl)5.6(y)-276.5(a)4.6(nd)-276.5(d)5.7(i)-.1(f)5.8(fus)5.9(e)-277.6(o)5.7(ut)-276.6(was)5.9(t)-.1(e)-271.9(pro)5.7(du)5.7(ct)5.6(s,)-273.1(wh)5.7(ich)-276.5(a)-1.2(r)5.8(e)-277.6(p)5.7(r)0(er)5.8(eq)5.7(ui)5.6(sit)5.6(e)-1.2(s)]TJ
T*
.0073 Tc
[(t)-5.4(o)-385.5(ma)-6.5(in)-5.3(ta)-6.5(in)-391.2(ce)-6.5(ll)-5.4(ul)-5.4(ar)-391.2(vi)-5.4(ab)-5.3(il)-5.4(it)-5.4(y)-385.5(a)-6.5(nd)-385.5(o)-5.3(r).5(g)-5.3(a)-6.5(n-)-5.3(sp)-5.3(ec)-6.5(i)-5.4().6(c)-386.6(f)-5.3(un)-5.3(ct)-5.4(i)-5.4(o).4(n)-5.3(-)]TJ
T*
.013 Tc
[(al)6(it)6(y.)]TJ
7.3823 0 0 6.5614 82.7149 214.9228 Tm
.0138 Tc
(23,24)Tj
9.843 0 0 9.843 103.5212 210.5574 Tm
.0117 Tc
[(In)-369.5(parti)4.7(c)-2.1(u)4.8(l)-1(ar,)-371.9(c)-2.1(ard)4.8(i)-1(ac-)4.9(s)-.7(peci)4.7(c)-370.7(vascu)4.8(l)-1(atu)4.8(r)-.9(e)-370.7(for)4.9(ms)]TJ
-4.2161 -1.1174 TD
.012 Tc
[(sy)5.1(nchro)5.1(no)5.1(us)5.3(ly)-254(wi)5(th)-254(card)5.1(iac)-255.2(t)-.7(i)5(ssu)5.1(e)-255.2(a)-1.8(n)5.1(d)-259.8(ext)5(e)-1.8(n)5.1(s)-.4(i)5(v)-.6(el)5(y)-254(i)-.7(n)5.1(t)-.7(eracts)]TJ
0 -1.1116 TD
[(wi)4.9(th)-392.4(it)-392.5(th)5(rou)5(gh)-392.4(a)-393.5(v)-.7(ariety)-392.4(of)-392.3(paracri)4.9(n)-.7(e,)-394.7(au)5(to)5(cri)4.9(n)-.7(e,)-394.7(an)5(d)-398.1(e)3.9(n-)]TJ
T*
.0125 Tc
[(do)5.6(cr)5.7(in)5.6(e)-444.8(f)5.7(act)5.5(or)5.7(s)-443.4(f)5.7(or)-437.8(org)5.6(an)-437.9(develo)5.6(pmen)5.6(t)-443.7(a)4.5(nd)-437.9(matu)5.6(re)-439(fun)5.6(c-)]TJ
0 -1.1174 TD
.0129 Tc
[(ti)5.9(on)6(al)5.9(ity)6(.)]TJ
7.3823 0 0 6.5614 98.4756 171.0425 Tm
.0145 Tc
(2530)Tj
9.843 0 0 9.843 125.2346 166.6771 Tm
.0092 Tc
[(It)-792.6(is)-786.5(be)-4.6(coming)-786.7(inc)-4.6(r)-3.4(ea)-4.6(singly)-786.7(clea)-4.6(r)-786.7(t)-3.5(ha)-4.6(t)]TJ
-6.4221 -1.1116 TD
.013 Tc
[(va)5(sc)5(ul)6(atu)6.1(r).4(e)-265.7(i).3(n)-264.6(c)-.8(a)5(rdi)6(ac)-265.7(ti)6(ssu)6.1(e)-271.5(i)6(s)-270.1(o)6.1(f)-270.3(g).4(r)6.2(a)-.8(n)6.1(d)-270.3(i)6(m)-.8(p)6.1(o).4(r)6.2(t).3(an)6.1(ce)-265.7(at)-264.7(bo)6.1(th)]TJ
T*
.0118 Tc
[(a)-733.5(t)-.9(rans)5.1(cr)5(ipt)4.8(i)-.9(o)4.9(n)-.8(al)-738.2(l)4.8(e)-2(v)4.9(e)-2(l)-732.4(a)-2(n)4.9(d)-738.1(i)4.8(n)-738.1(car)5(d)-.8(iac)-733.5(fun)4.9(ct)4.8(io)4.9(n)-738.1(a)3.8(s)-737.9(a)]TJ
0 -1.1174 TD
.0133 Tc
[(wh)6.4(ol)6.3(e.)]TJ
7.3823 0 0 6.5614 89.1779 138.2173 Tm
.0145 Tc
(3135)Tj
9.843 0 0 9.843 112.9322 133.7953 Tm
.0117 Tc
[(In)-484.7(th)4.8(is)-484.5(revi)4.7(ew,)-487.1(w)-1.8(e)-485.9(d)4.8(is)5(cus)5(s)-484.5(techn)4.8(i)-1(q)4.8(u)-.9(es)-490.3(b)4.8(e)-2.1(i)4.7(n)-.9(g)]TJ
-5.1722 -1.1116 TD
.012 Tc
[(us)5.3(ed)-495.9(to)-495.9(int)5(e)-1.8(g)5.1(r)-.6(ate)-497.1(fun)5.1(ct)5(io)5.1(nal)-501.8(c)4(ard)5.1(i)-.7(ac)-502.9(t)5(i)-.7(ss)5.3(ues)-501.5(i)5(nto)]TJ
/F9 1 Tf
21.2821 0 TD
.0134 Tc
[(in)-494.5(vi)6.4(vo)]TJ
/F3 1 Tf
-21.2821 -1.1116 TD
.0116 Tc
[(models)4.9(.)-492.9(I)-1(n)-490.6(a)-2.2(d)4.7(d)-1(i)4.6(tio)4.7(n,)-492.9(we)-497.5(add)4.7(r)-1(ess)-490.4(r)-1(ecen)4.7(t)-496.5(a)3.6(dv)4.7(an)4.7(ces)-496.2(i)4.6(n)-496.3(e)3.6(n-)]TJ
0 -1.1174 TD
.0118 Tc
[(gi)4.8(neer)5(ed)-807.2(vas)5.1(c)-2(u)4.9(l)-.9(arized)-807.2(card)4.9(iac)-814.1(t)4.8(iss)5.1(u)-.8(es)-812.7(ut)4.8(il)4.8(izin)4.9(g)-812.9(t)-.9(h)4.9(r)-.8(ee-)]TJ
0 -1.1116 TD
[(di)4.9(mens)5.2(io)5(nal)-432.8(\()-.7(3)5(D)-1.6(\))-438.4(p)5(rin)5(t)-.8(i)4.9(n)-.7(g)-438.4(s)5.2(tr)5.1(ategi)4.9(e)-1.9(s)5.2(.)-440.8(F)5.2(i)-.8(n)5(a)-1.9(l)4.9(l)-.8(y,)-435(we)-439.6(di)4.9(scuss)]TJ
T*
.0123 Tc
[(cu)5.4(rr)5.5(en)5.4(t)-478.5(l)5.3(imitati)5.3(on)5.4(s,)-474.9(chal)5.3(leng)5.4(es,)-469.2(a)-1.5(nd)-472.6(t)5.3(h)-.3(e)-473.8(fut)5.3(ur)5.5(e)-479.5(d)5.4(ir)5.5(ectio)5.4(ns)]TJ
T*
.0101 Tc
[(a)-3.7(n)3.2(d)-336.6(p)-2.5(erspec)-3.7(tives)-336.4(i)-2.6(n)-330.8(w)-3.4(hic)-3.7(h)-330.8(the)-332()]TJ
13.3568 0 TD
.0094 Tc
[(eld)-337.3(o)2.5(f)-337.2(e)-4.4(nginee)-4.4(ring)-337.3(ca)-4.4(rdia)-4.4(c)]TJ
-13.3568 -1.1174 TD
.0121 Tc
[(ti)5.1(ssu)5.2(es)-328.6(pr)5.3(og)5.2(res)5.4(s)-.3(es)-334.4(t)5.1(o)-.5(ward)5.2(.)]TJ
/F6 1 Tf
8.9663 0 0 8.9663 313.0582 610.5258 Tm
0 Tc
[(Engineered)-341.5(Biomaterials)-330.6(to)-336.6(Recapitulate)-338.4(the)-334.6(Native)]TJ
0 -1.2203 TD
[(Extracellular)-336.9(Matrix)]TJ
/F3 1 Tf
9.843 0 0 9.843 323.0361 583.1432 Tm
[(One)-299.1(critical)-295(challenge)-297.1(in)-296.1(the)-292.6(eld)-299.3(of)-290.1(tissue)-295.6(engineering)-298.1(is)]TJ
-1.0137 -1.1116 TD
[(to)-417(engineer)-415.6(biomaterials)-415.6(that)-414.8(provide)-417.9(physiologically)-416.7(rele-)]TJ
0 -1.1174 TD
[(vant)-391.6(microenvironments)-393.4(to)-388.2(incorporated)-397(cells.)]TJ
7.3823 0 0 6.5614 500.4282 565.5684 Tm
(36)Tj
9.843 0 0 9.843 511.6534 561.203 Tm
[(Cells)-393.7(sen-)]TJ
-20.1762 -1.1116 TD
[(sitive)-8(ly)-762.6(respond)-768.9(to)-762.6(their)-767.2(immediate)-770.8(surroundings,)-770.9(the)]TJ
T*
[(microenvironmen)-11.2(t,)-419.4(such)-420.1(as)-423.6(spatial)-419.2(arrangement,)-430.5(mechano-)]TJ
0 -1.1174 TD
[(chem)-8(ical)-335.3(cues,)-338.3(nutrient)-338.6(availability,)-337.7(and)-338.5(gas)-338.3(exchange.)]TJ
7.3823 0 0 6.5614 533.7069 532.7432 Tm
(3746)Tj
9.843 0 0 9.843 313.0582 517.3794 Tm
[(To)-400.8(achieve)-398.4(organ-level)-401.7(functionali)-9.2(ty,)-397.4(the)-396.3(biomaterial)-403.2(must)]TJ
0 -1.1116 TD
[(recap)-9(itulate)-356.1(physiological)-356.8(properties)-364.7(of)-353.5(the)-355.9(native)-360.5(extracel-)]TJ
0 -1.1174 TD
[(lular)-461.9(matrix)-458.5(\(ECM\))-457.8(so)-457(that)-460.8(the)-459.6(incorporated)-460.4(cells)-457.1(exhibit)]TJ
0 -1.1116 TD
[(their)-375.5(original)-379(phenotypes)-376.2(and)-373.1(the)-373.2(resultant)-381(tissues)-371.4(function)]TJ
T*
[(as)-417.9(observ)-7.5(ed)]TJ
/F9 1 Tf
5.2816 0 TD
[(in)-417(vivo)]TJ
/F3 1 Tf
2.8799 0 TD
[(.)-412.4(I)0(n)-416.9(addition,)-417(the)-419.3(scaffold)-419.9(biomaterials)]TJ
-8.1615 -1.1116 TD
[(also)-258.9(need)-254.4(to)-250(exhibit)-256.9(mechanical)-260.2(stability)-253.4(to)-255.8(support)-255.3(cells)-255.6(in)-250(a)]TJ
0 -1.1174 TD
[(relevant)-865(3D)-855.5(spatial)-862.7(arrangement.)-862.4(Compared)-860.1(to)-860.5(two-)]TJ
0 -1.1116 TD
[(dimensiona)-8.9(l)-542.6(\(2D\))-546.6(tissue)-549.1(culture)-551.7(on)-543.6(plastic)-551.6(dishes,)-546.6(many)]TJ
T*
[(engineered)-251.9(organ)-248.5(systems)-245.8(have)-242.9(successfully)-252.5(provided)-246.2(tissue-)]TJ
0 -1.1174 TD
[(specic)-489(3D)-481.1(microenvironments)-491.4(for)-481.3(the)-482.6(incorporated)-489.2(cells)]TJ
0 -1.1116 TD
[(and)-338.5(obtained)-333.9(targeted)-335.1(functionali)-9.2(ties.)]TJ
7.3823 0 0 6.5614 462.1605 412.1573 Tm
[(22,4)-8.6(752)]TJ
9.843 0 0 9.843 323.0361 396.8503 Tm
[(Hydrogels)-610.9(have)-611.5(been)-611.5(most)-604.6(widely)-613.7(used)-610.1(as)-607.9(an)-608.1(ECM)]TJ
-1.0137 -1.1174 TD
[(scaffold)-345.1(for)-337.3(engineered)-344.1(cardiac)-346.5(tissues.)-340.3(Hydrogels)-345.9(are)-339.7(clas-)]TJ
0 -1.1116 TD
[(sied)-426.9(into)-425.1(three)-428.4(categories:)-425.9(natural,)-428.4(synthetic,)-430.6(and)-424.9(hybrid.)]TJ
T*
[(Naturally)-698.9(derived)-695.5(hydrogels)-690.6(generally)-693.3(comprised)-698.8(ECM)]TJ
0 -1.1174 TD
[(derived-compone)-11(nts)-273.9(\(such)-277.1(as)-273.9(decellularized)-282.1(ECM)-277.1([dECM]\),)]TJ
0 -1.1116 TD
[(polysa)-7.7(ccharides)-285.2(\(such)-282.9(as)-285.4(alginate\),)-287.9(and)-280.9(peptide)-286.8(chains)-285.3(\(such)]TJ
T*
[(as)-510(collagen)-513.7(or)-503.3(spider)-508.8(silk\).)]TJ
7.3823 0 0 6.5614 427.0676 335.4519 Tm
[(50,53)-7.8(58)]TJ
9.843 0 0 9.843 459.7794 331.0865 Tm
[(These)-509.9(are)-512.4(optimal)-505.8(for)]TJ
-14.9061 -1.1116 TD
[(recap)-9(itulating)-270.9(ECM-mediated)-280.5(biochemical)-277.6(signaling)-276.2(as)-273.9(seen)]TJ
/F9 1 Tf
0 -1.1174 TD
[(in)-365.2(vivo)]TJ
/F3 1 Tf
3.1851 0 TD
[(and)-367.3(are)-362.7(susceptible)-367(to)-365.2(biodegradability,)-370.8(which)-364.8(may)]TJ
-3.1851 -1.1116 TD
[(be)-274.1(desirable)-272.6(when)-271.4(engineering)-275(cardiac)-271.6(tissue)-272.6(implants)-270.6(to)-273(aid)]TJ
T*
[(in)-595.6(integration)-590.9(into)-592.2(the)]TJ
/F9 1 Tf
10.2926 0 TD
[(in)-589.8(vivo)]TJ
/F3 1 Tf
3.6344 0 TD
(tissue.)Tj
7.3823 0 0 6.5614 475.0865 291.6282 Tm
(59,60)Tj
9.843 0 0 9.843 497.5369 287.2629 Tm
(Alternatively,)Tj
-18.7421 -1.1174 TD
[(synthe)-7.7(tic)-430.9(hydrogels)-431.4(are)-431.8(often)-433(biologicall)-9.3(y)-427.3(inert,)-436.5(but)-429.6(allow)]TJ
0 -1.1116 TD
[(for)-452.5(ne-tuning)-455.7(to)-445.8(recap)-9(itulate)-448.3(key)-453.7(aspects)-454.4(of)-451.4(the)-448.1(targeted)]TJ
T*
[(native)-337.5(microenvironment.)]TJ
1.0137 -1.1174 TD
[(The)-362.8(core)-363.8(components)-365.9(of)-365(the)-361.7(synthetic)-363.8(hydrogels)-362.3(used)-362.5(in)]TJ
-1.0137 -1.1116 TD
[(many)-634.6(recent)-638(reports)-636.6(commonly)-634.6(comprised)-635.4(polyethylene)]TJ
T*
[(glycol)-347.9(\(PEG\))-341.4(or)-342(its)-343.2(modied)-344.1(derivatives.)]TJ
7.3823 0 0 6.5614 478.2046 225.8645 Tm
(61)Tj
9.843 0 0 9.843 488.9196 221.4991 Tm
[(Tunable)-345.4(chemi-)]TJ
-17.8666 -1.1116 TD
[(cal/photo-c)-10.2(rosslinkable)-378.4(moieties)-381.2(can)-374.2(be)-377.7(integrated)-383.5(into)-373.3(hy-)]TJ
0 -1.1174 TD
[(drogel)-405.3(polymeric)-405.4(networks)-402.4(for)-400.7(the)-396.3(ne-tu)-7.7(ning)-396.2(of)-399.6(substrate)]TJ
0 -1.1116 TD
[(physio)-6.5(chemical)-504.5(properties.)]TJ
7.3823 0 0 6.5614 422.0219 192.9826 Tm
(57,62)Tj
9.843 0 0 9.843 443.5652 188.6173 Tm
[(Biochemical)-509(cues)-501.9(such)-500.7(as)]TJ
-13.2588 -1.1116 TD
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