Amphiphilic multiblock copolymers of PLLA, PEO and PPO blocks: Synthesis, properties and cell affinity
Graphical abstract
Introduction
The development of biomaterials with features that support the healing of damaged tissues is currently attracting great research interest in materials science and medicine. Bioabsorbable polyesters, such as poly(l-lactide) (PLLA), are being used in biomedical devices, such as surgical sutures [1], drug delivery systems [2] and porous scaffolds for tissue engineering [3], due to their feasible degradation through the hydrolysis of ester bonds with non-toxic products in vivo [4]. Bioabsorbable devices negate the necessity for additional surgery for implant removal and can promote cell growth and regeneration [5]. However, the bioabsorption capacity of neat PLLA devices can be impaired because of PLLA’s hydrophobic surface and high crystallinity, which also can represent drawbacks to cell adhesion and mechanical resistance, respectively [6].
Modifications of the PLLA structure using methods such as copolymerization with more hydrophilic and amorphous polymers have been accomplished to modify the required biomaterial properties for a specific application [7], [8], [9]. Copolymerization may modulate these properties by varying hydrophilic/hydrophobic and amorphous/crystalline ratios [10]. Poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) polyethers are biocompatible and hydrophilic polymers that can be used as macroinitiators of ring-opening polymerization (ROP) of LLA in the presence of specific catalysts. PEO and PPO generate a flexible middle block, whereas PLLA engenders semicrystallinity and hard blocks. PEO, PPO and PLLA blocks’ features can enhance PLLA bulk and surface properties, improving the amphiphilic multiblock copolymers’ potential as biomaterials for tissue engineering.
The synthesis of diblock PLLA-b-PEO and triblock PLLA-b-PEO-b-PLLA copolymers for biomedical applications has been continuously reported in prior decades, particularly in drug delivery systems, biocompatible coatings and electrospun scaffolds [7], [11], [12]. Block copolymers comprising PLLA and PPO blocks were studied as biodegradable copolymers by Kimura et al. [13]. PLLA-b-PPO-b-PLLA copolymers were synthesized by the copolymerization of LLA using monodispersed PPO (2 and 4 kg mol−1) as macroinitiators and Me3-Al-H2O as a catalyst at 150 °C under 100 mmHg of pressure with stirring for 6 h. These copolymers were melt-spun, and the modulus of the fibers decreased with increasing PPO content in the copolymers. During both in vitro and in vivo degradation tests, fibers presented a time-dependent decrease in tensile strength and an increase in surface erosion with a much higher degradation rate compared with PLLA [13].
PEO-b-PPO copolymers are commonly referred to as modifiers of thermal and mechanical PLLA properties, as a plasticizer [14], or as modifiers of the PLLA surface character, as a hydrophilic additive [15]. Lee et al. synthesized PLLA-b-PEO-b-PPO-b-PEO-b-PLLA copolymers from four grades of PEO-b-PPO-b-PEO (Pluronic®) copolymers – L-62 (Mn = 2500 g mol−1, EO/PO = 20/80), L-122 (Mn = 4900 g mol−1, EO/PO = 20/80), F-68 (Mn = 8400 g mol−1, EO/PO = 80/20) and F-127 (Mn = 11,500 g mol−1, EO/PO = 70/30) – by ring-opening polymerization of LLA in the presence of tin(II)-2-ethylhexanoate [Sn(Oct)2] at 160 °C to manufacture drawn filaments for sutures. All PLLA-b-PEO-b-PPO-b-PEO-b-PLLA copolymers presented a PLLA/Pluronic® wt% ratio of 90/10, and the molar masses ranged from 4 to 109 kg mol−1. PLLA-b-PEO-b-PPO-b-PEO-b-PLLA filaments present higher flexibilities and hydrolytic degradation rates compared with PLLA due to soft Pluronic® block insertion [16].
Xiong et al. inserted PLLA blocks at both ends of Pluronic® F-127 and F-87 (Mn = 7700 g mol−1, EO/PO = 70/30) copolymers [17], [18]. LLA and Pluronic® were stirred and heated together to a molten phase before the addition of a Sn(Oct)2 catalyst (0.1 wt% of LLA). Polymerization proceeded in an argon environment at 180 °C for 15 h. In aqueous solutions, PLLA/Pluronic® F-127 copolymers (Mn = 23, 29 and 48 kg mol−1) are able to arrange themselves in onion-like vesicles with two or three layers, presenting diameters of approximately 80–100 nm [19]. The release of hydrophobic and hydrophilic model drugs by these vesicles [20], and also their hydrolytic [21] and enzymatic [22] degradation in vitro, were evaluated in several studies. PLLA/Pluronic® F-87 copolymers (Mn = 9.0, 9.4 and 10.4 kg mol−1) can self-assemble in several structures, such as micelles with diameters of approximately 20 nm or network-like aggregates with diameters of approximately 300–700 nm.
None of the above mentioned studies reported the physical and chemical properties and morphologies of these copolymers in their solid state. Therefore, in the present study, special effort was made to characterize the physical and chemical properties and morphologies of this class of materials. With this purpose in mind, amphiphilic multiblock PLLA-b-P(EO-PO)-b-PLLA copolymers were synthesized via ring-opening polymerization of LLA using PEO-b-PPO-b-PEO and PPO-b-PEO-b-PPO block copolymers and random PEO-ran-PPO copolymers with different molar masses and PEO block mass ratios (i.e., from 0 to 30 wt%) as macroinitiators. The chemical structures of PLLA-b-P(EO-PO)-b-PLLA copolymers were characterized by hydrogen nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). Thermal properties were investigated by differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). In addition, atomic force microscopy (AFM) and water contact angle tests revealed the morphologies and hydrophilicity of the copolymers’ surfaces. Copolymers cell affinity and proliferation were evaluated by PicoGreen® assays.
Section snippets
Materials
l-lactide (LLA, 144 g mol−1, Sigma–Aldrich), poly(ethylene oxide) – PEO8 (Fluka, Mn = 8 kg mol−1, Mw/Mn = 1.1) and PEO29 (Sigma–Aldrich, Mn = 29 kg mol−1, Mw/Mn = 1.2) – and block and random P(EO-PO) copolymers (Sigma–Aldrich) – PPO1-b-PEO1-b-PPO1 (Mn = 3 kg mol−1, Mw/Mn = 1.0), PEO1-b-PPO4-b-PEO1 (Mn = 6 kg mol−1, Mw/Mn = 1.2), PEO3-b-PPO2-b-PEO3 (Mn = 8 kg mol−1, Mw/Mn = 1.1), PEO2-ran-PPO1 (Mn = 3 kg mol−1, Mw/Mn = 1.1) and PEO7-ran-PPO3 (Mn = 10 kg mol−1, Mw/Mn = 1.2) - where indices indicate the molar mass of each block in kilograms
Results and discussion
PLLA-b-P(EO-PO)-b-PLLA amphiphilic copolymers were synthesized by a coordination-insertion mechanism of ring-opening polymerization of the cyclic dimer LLA (144 g mol−1) onto dihydroxyl polyether macroinitiators in the presence of Sn(Oct)2 as a catalyst. The pre-activation step allowed the catalyst/polyether macroinitiator coordination, resulting in Sn–OR metallic alkoxide, where R represents the polyether chain. The LLA dimer therein is able to coordinate to the metallic alkoxide and
Conclusions
PLLA bulk and surface properties could be modified by ring-opening polymerization of LLA using PEO-b-PPO-b-PEO, PPO-b-PEO-b-PPO and random PEO-ran-PPO blocks as macroinitiators. The polyethers composition, architecture and molar mass, as well as polyether/PLLA mass ratio in the copolymers, can be widely varied to design the morphology, hydrophobicity, degree of crystallinity, flexibility, cell attachment capacity, and, consequently, biocompatibility of the studied copolymers. This series of
Acknowledgments
The authors would like to thank the financial support of the São Paulo Research Foundation – FAPESP (processes number 2010/17804-7 and 2012/24821-0) and the technical support of the Laboratory for Surface Science (LCS) (project AFM-NSIIIa – 15635 and 16435) at the Brazilian Nanotechnology National Laboratory (LNNano) in the Brazilian Center for Research in Energy and Materials (CNPEM). The authors would also like to thank Prof. Edvaldo Sabadini for support in the water contact angles study and
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