Star-shaped polymers of biodegradable aliphatic polyester, poly(ε-caprolactone), PCL, with different number of arms (three, four, and six) were synthesized by ring-opening polymerization initiated by multifunctional alcohols used as cores. As potential biomaterials, synthesized star-shaped poly(ε-caprolactone)s, sPCL, were thoroughly characterized in terms of their degradation under different pH conditions and in respect to their cytotoxicity. The in vitro degradation was performed in phosphate buffer (pH 7.4) and hydrochloric acid solution (pH 1.0) over 5 weeks. Degradation of sPCL films was followed by the weight loss measurements, GPC, FTIR, and AFM analysis. While the most of the samples were stable against the abiotic hydrolysis at pH 7.4 after 5 weeks of degradation, degradation was significantly accelerated in the acidic medium. Degradation rate of polymer films was affected by the polymer architecture and molecular weight. The molecular weight profiles during the degradation revealed random chain scission of the ester bonds indicating bulk degradation mechanism of hydrolysis at pH 7.4, while acidic hydrolysis proceeded through the bulk degradation associated with surface erosion, confirmed by AFM. The in vitro toxicity tests, cytotoxicity applying normal human fibroblasts (MRC5) and embryotoxicity assessment (using zebra fish model, Danio rerio), suggested those polymeric materials as suitable for biomedical application.
CameronDJAShaverMP. Aliphatic polyester polymer stars: synthesis, properties and applications in biomedicine and nanotechnology. Chem Soc Rev2011; 40(3): 1761–1776.
5.
KhannaKVarshneySKakkarA.Miktoarm star polymers: advances in synthesis, self-assembly, and applications. Polym Chem2010; 1(8): 1171–1185.
6.
BhagabatiPHazarikaDKatiyarV.Tailor-made ultra-crystalline, high molecular weight poly(ε-caprolactone) films with improved oxygen gas barrier and optical properties: a facile and scalable approach. Int J Biol Macromol2019; 124: 1040–1052.
7.
WoodruffMAHutmacherDW.The return of a forgotten polymer—polycaprolactone in the 21st century. Prog Polym Sci (Oxford)2010; 35(10): 1217–1256.
8.
GriffithMVenkatramanSS.Polycaprolactone-based biomaterials for tissue engineering and drug delivery: current scenario and challenges AU – Mondal, Debasish. Int J Polym Mater Pol Biomat2016; 65(5): 255–265.
9.
PonjavicMNikolicMSNikodinovic-RunicJ, et al. Degradation behavior of PCL/PEO/PCL and PCL/PEO block copolymers under controlled hydrolytic, enzymatic and composting conditions. Polym Test2017; 57: 67–77.
10.
PonjavicMNikolicMSJeremicS, et al. Influence of short central PEO segment on hydrolytic and enzymatic degradation of triblock PCL copolymers. J Polym Environ2018; 26: 2346–2359.
11.
WangJ-LWangLDongC-M.Synthesis, crystallization, and morphology of star-shaped poly(ε-caprolactone). J Polym Sci Pol Chem2005; 43(22): 5449–5457.
12.
CuiYMaXTangX, et al. Synthesis, characterization, and thermal stability of star-shaped poly(ε-caprolactone) with phosphazene core. Eur Polym J2004; 40(2): 299–305.
13.
NúñezEGeddeUW.Single crystal morphology of star-branched polyesters with crystallisable poly(ε-caprolactone) arms. Polymer2005; 46(16): 5992–6000.
14.
WangJ-LDongC-M.Physical properties, crystallization kinetics, and spherulitic growth of well-defined poly(ε-caprolactone)s with different arms. Polymer2006; 47(9): 3218–3228.
15.
DiniFBarsottiGPuppiD, et al. Tailored star poly (ε-caprolactone) wet-spun scaffolds for in vivo regeneration of long bone critical size defects. J Bioact Compat Polym2016; 31: 15–30.
16.
García-OlaizGDMontoya-VillegasKALicea-ClaverieA, et al. Synthesis and characterization of four- and six-arm star-shaped poly(ε-caprolactone)-b-poly(N-vinylcaprolactam): micellar and core degradation studies. React Funct Polym2015; 88: 16–23.
17.
ZhangYZhaoQShaoH, et al. Synthesis and characterization of star-shaped block copolymer sPCL-b-PEG-GA. Adv Mater Sci Eng2014; 2014: 6.
18.
LangMWongRPChuC-C.Synthesis and structural analysis of functionalized poly (ϵ-caprolactone)-based three-arm star polymers. J Polym Sci Pol Chem2002; 40: 1127–1141.
19.
ChoiJKimI-KKwakS-Y.Synthesis and characterization of a series of star-branched poly(ε-caprolactone)s with the variation in arm numbers and lengths. Polymer2005; 46(23): 9725–9735.
20.
XieWGanZ.Thermal degradation of star-shaped poly(ɛ-caprolactone). Polym Degrad Stabil2009; 94(7): 1040–1046.
21.
NabidMRTabatabaei RezaeiSJSedghiR, et al. Self-assembled micelles of well-defined pentaerythritol-centered amphiphilic A4B8 star-block copolymers based on PCL and PEG for hydrophobic drug delivery. Polymer2011; 52(13): 2799–2809.
22.
Sailema-PalateGPVidaurreACampillo-FernándezAJ, et al. A comparative study on poly(ε-caprolactone) film degradation at extreme pH values. Polym Degrad Stabil2016; 130: 118–125.
23.
ChangH-MPrasannanATsaiH-C, et al. Ex vivo evaluation of biodegradable poly(ε-caprolactone) films in digestive fluids. Appl Surf Sci2014; 313: 828–833.
24.
LiSMChenXHGrossRA, et al. Hydrolytic degradation of PCL/PEO copolymers in alkaline media. J Mater Sci Mat Med2000; 11: 227–233.
25.
PetrovaSKolevIMiloshevS, et al. Synthesis of amphiphilic [PEO(PCL)2] triarm star-shaped block copolymers: a promising system for in cell delivery. J Mater Sci Mat Med2012; 23: 1225–1234.
26.
XieWJiangNGanZ.Effects of multi-arm structure on crystallization and biodegradation of star-shaped poly(ε-caprolactone). Macromol Biosci2008; 8(8): 775–784.
27.
ChengJDingJXWangYC, et al. Synthesis and characterization of star-shaped block copolymer of poly(ε-caprolactone) and poly(ethyl ethylene phosphate) as drug carrier. Polymer2008; 49(22): 4784–4790.
28.
PereiraCSMSilvaVMTMRodriguesAE.Ethyl lactate as a solvent: properties, applications and production processes – a review. Green Chem2011; 13: 2658–2671.
29.
PonjavicMNikolicMSJevticS, et al. Influence of a low content of PEO segment on the thermal, surface and morphological properties of triblock and diblock PCL copolymers. Macromol Res2016; 24(4): 323–335.
30.
HansenMBNielsenSEBergK.Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods1989; 119(2): 203–210.
31.
JaiswalMKoulV.Assessment of multicomponent hydrogel scaffolds of poly(acrylic acid-2-hydroxy ethyl methacrylate)/gelatin for tissue engineering applications. J Biomater Appl2013; 27(7): 848–861.
32.
TurunenMPKKorhonenHTuominenJ, et al. Synthesis, characterization and crosslinking of functional star-shaped poly(ε-caprolactone). Polym Int2002; 51(1): 92–100.
33.
WeiZLiuLYuF, et al. Synthesis and characterization of poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone) triblock copolymers with dibutylmagnesium as catalyst. J Appl Polym Sci2009; 111(1): 429–436.
34.
HuangM-HLiSCoudaneJ, et al. Synthesis and characterization of block copolymers of ε-caprolactone and DL-lactide initiated by ethylene glycol or poly(ethylene glycol). Macromol Chem Phys2003; 204(16): 1994–2001.
35.
MagnussonHMalmströmEHultA, et al. The effect of degree of branching on the rheological and thermal properties of hyperbranched aliphatic polyethers. Polymer2002; 43(7): 301–306.
36.
JiangYMaoKCaiX, et al. Poly(ethyl glycol) assisting water sorption enhancement of poly(ε-caprolactone) blend for drug delivery. J Appl Polym Sci2011; 122(4): 2309–2316.
37.
ChoiYKBaeYHKimSW.Star-shaped poly(ether−ester) block copolymers: synthesis, characterization, and their physical properties. Macromolecules1998; 31(25): 8766–8774.
38.
AoyagiYYamashitaKDoiY.Thermal degradation of poly[(R)-3-hydroxybutyrate], poly[ε-caprolactone], and poly[(S)-lactide]. Polym Degrad Stabil2002; 76: 53–59.
39.
PersenaireOAlexandreMDegéeP, et al. Mechanisms and kinetics of thermal degradation of poly(ε-caprolactone). Biomacromolecules2001; 2(1): 288–294.
40.
SivalingamGKarthikRMadrasG.Kinetics of thermal degradation of poly(ε-caprolactone). J Analyt Appl Pyrol2003; 70(2): 631–647.
41.
BittigerHMarchessaultRHNiegischWD.Crystal structure of poly-ε-caprolactone. Acta Crystal B1970; 26(12): 1923–1927.
42.
GöpferichA.Mechanisms of polymer degradation and erosion. Biomaterials1996; 17(2): 103–114.
43.
FukushimaKFeijooJLYangM-C.Abiotic degradation of poly(dl-lactide), poly(ε-caprolactone) and their blends. Polym Degrad Stabil2012; 97: 2347–2355.
44.
Castilla-CortázarIMás-EstellésJMeseguer-DueñasJM, et al. Hydrolytic and enzymatic degradation of a poly(ε-caprolactone) network. Polym Degrad Stabil2012; 97(8): 1241–1248.
45.
FukushimaKFeijooJLYangM-C.Comparison of abiotic and biotic degradation of PDLLA, PCL and partially miscible PDLLA/PCL blend. Eur Polym J2013; 49(3): 706–717.
46.
ChristopherXFLMonicaMSSwee-HinT, et al. Dynamics of in vitro polymer degradation of polycaprolactone-based scaffolds: accelerated versus simulated physiological conditions. Biomed Mater2008; 3(3): 034108.
47.
HeYInoueY.Novel FTIR method for determining the crystallinity of poly(ε-caprolactone). Polym Int2000; 49(6): 623–626.
48.
WohlfarthC. Viscosity of ethyl lactate. In: LechnerMD (ed.) Viscosity of pure organic liquids and binary liquid mixtures. Berlin, Heidelberg: Springer, 2017, pp. 176–176.
49.
CausaAFilipponeGAciernoD, et al. Surface morphology, crystallinity, and hydrophilicity of poly(ε-caprolactone) films prepared via casting of ethyl lactate and ethyl acetate solutions. Macromol Chem Phys2015; 216: 49–58.
50.
PoulardCDammanP.Control of spreading and drying of a polymer solution from Marangoni flows. EPL-Europhys Let2007; 80(6): 64001.
51.
TanziMCVerderioPLampugnaniMG, et al. Cytotoxicity of some catalysts commonly used in the synthesis of copolymers for biomedical use. J Mater Sci Mat Med1994; 5: 393–396.
52.
SchappacherMLe HellayeMBareilleR, et al. Comparative in vitro cytotoxicity toward human osteoprogenitor cells of polycaprolactones synthesized from various metallic initiators. Macromol Biosci2010; 10(1): 60–67.
53.
SchwachGCoudaneJEngelR, et al. Influence of polymerization conditions on the hydrolytic degradation of poly(dl-lactide) polymerized in the presence of stannous octoate or zinc-metal. Biomaterials2002; 23(4): 993–1002.
54.
StafiejPKüngFThiemeD, et al. Adhesion and metabolic activity of human corneal cells on PCL based nanofiber matrices. Mater Sci Eng C2017; 71: 764–770.
55.
BarbarisiMMarinoGArmeniaE, et al. Use of polycaprolactone (PCL) as scaffolds for the regeneration of nerve tissue. J Biomed Mater Res A2015; 103(5): 1755–1760.
56.
LieschkeGJCurriePD.Animal models of human disease: zebrafish swim into view. Nat Rev Genet2007; 8(5): 353–367.
57.
MacRaeCAPetersonRT.Zebrafish as tools for drug discovery. Nat Rev Drug Discov2015; 14(10): 721–731.
58.
BarrosTPAldertonWKReynoldsHM, et al. Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Brit J Pharmacol2008; 154(7): 1400–1413.
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