Preparation and Properties of Monodisperse Thermo-responsive Microgels
2.5 Monodisperse Thermo-responsive Hydrogel Microspheres and Microcapsules Fabricated
2.5.3 Fabrication of Monodisperse Microspheres with PNIPAM Core and Poly(2-Hydroxyethyl
Methacrylate) (PHEMA) Shell
Generally, the thermo-response rate of PNIPAM microspheres is fast, and the reversible volume-change ratio is large, which enable PNIPAM microspheres highly promising in numerous applications. However, the biocompatibility of PNIPAM has been disputed for a long period of time, which hinders the application of PNIPAM microspheres in the biomedical field to a large degree. Recently, some investigations have been carried out to try to improve the biocompatibility of PNIPAM-based microspheres by coating biocompatible materials onto the outer
2.5 Monodisperse Thermo-responsive Hydrogel Microspheres and Microcapsules. . . 51
Fig. 2.20 (a) Optical microscope image of the microgels in pure water at 22ıC. (b) Optical microscope image of the same microgels in pure water at 40ıC. The scale bar is 25m. (c) Temperature- dependent diameters of PNIPAM microgels with temperature changes (Reproduced with permission from Ref. [45], Copyright (2011), Wiley-VCH Verlag GmbH & Co. KGaA)
Fig. 2.21 Schematic illustration of the thermo-responsive behavior of the microsphere with PNIPAM core and PHEMA shell (Reproduced with permission from Ref. [46], Copyright (2010), Elsevier)
surface of PNIPAM microspheres. In this section, a microfluidic strategy for preparation of monodisperse microspheres with PNIPAM core and PHEMA shell is introduced [46].
The schematic illustrations of the structure and the thermo-responsive behavior of the microspheres with PNIPAM core and PHEMA shell are shown in Fig.2.21.
The monodisperse PNIPAM cores are fabricated via microfluidic emulsification and free-radical polymerization methods, and the PHEMA shells are grafted onto the shrunken PNIPAM cores with atom-transfer radical polymerization (ATRP) method.
At temperatures above the VPTT, the PNIPAM core shrinks and the PHEMA shell entirely covers the PNIPAM core (Fig.2.21a). When the environment temperature decreases below the LCST, the PNIPAM core swells dramatically and tries to fill to the point of bursting inside the PHEMA shell. Because the PHEMA shell is not deformable but the inside PNIPAM core swells to a large extent, a visible crack comes into being on the PHEMA shell very soon (Fig. 2.21b), then the crack gets larger and larger, and finally the PHEMA shell ruptures a large area along the crack (Fig.2.21c). Such thermo-responsive behavior of the microspheres with PNIPAM core and PHEMA shell is reversible and prompt when the temperature changes across the VPTT, which is adjustable by adding hydrophilic or hydrophobic comonomer for copolymerization of PNIPAM-based copolymeric cores.
Preparation of the core-shell microspheres includes two steps, namely, fabricat- ing PNIPAM core and PHEMA shell subsequently. In the first step, monodisperse water-in-oil (W/O) emulsion droplets are prepared by a microfluidic approach (Fig.2.22a), and the inner water phase contained NIPAM monomer and polyvinyl alcohol (PVA). The prepared W/O emulsion droplets act as templates for synthesiz- ing PNIPAM/PVA semi-interpenetrating polymer network (semi-IPN) microspheres in the subsequent free-radical polymerization (Fig. 2.22b). PVA on the surface of the semi-IPN microspheres provides active groups (i.e., hydroxyl groups) to graft PHEMA shell in the next step. In the second step, hydroxyl groups react with 2-bromoisobutyryl bromide (BIBB) in order to introduce atom-transfer radical polymerization (ATRP) initiator (Br) onto the microspheres firstly, and then PHEMA shell is fabricated by ATRP method (Fig.2.22c).
Figure 2.23 shows the optical micrographs of PNIPAM cores in soybean oil and microspheres with PNIPAM core and PHEMA shell at room temperature and the corresponding size distributions. The diameters of both the PNIPAM core and microspheres with PNIPAM core and PHEMA shell are uniform, and their size distributions are narrow. The mean diameters of the original PNIPAM core microspheres and the core-shell microspheres are 140 and 202m, respectively.
The calculated coefficient of variation (CV) values of them are 4.84 % and 3.18 %, respectively [46], which demonstrate that both the PNIPAM cores and the core-shell microspheres are of good monodispersity.
As mentioned above, the microfluidic emulsification is an intriguing emulsifica- tion method for preparing highly monodisperse emulsions. The monodispersity of W/O emulsions generated by microfluidic emulsification method is good. With the monodisperse W/O emulsion droplets as templates, monodisperse microspheres are subsequently synthesized. The reaction rate of free-radical polymerization is fast, which is beneficial to remain the monodispersity of the templates. The activator TEMED which can be dissolved in water better than in oil is fully dissolved in the outer oil phase in the experiments. After the single W/O emulsions form at the orifice, TEMED molecules uniformly and quickly diffuse into the inner monomer water phase and initiate the free-radical polymerization as soon as they encounter
2.5 Monodisperse Thermo-responsive Hydrogel Microspheres and Microcapsules. . . 53
Fig. 2.22 Schematic illustration of the preparation procedure of the microsphere with PNIPAM core and PHEMA shell. (a) Microfluidic preparation of monodisperse emulsion droplets containing NIPAM monomer and PVA polymer, (b) polymerization of PNIPAM core with the emulsion droplet as synthesis template, and (c) fabrication of PHEMA shell on the PNIPAM core via ATRP method (Reproduced with permission from Ref. [46], Copyright (2010), Elsevier)
Fig. 2.23 (a, b) Optical micrographs of PNIPAM cores in soybean oil (a) and microspheres with PNIPAM core and PHEMA shell (b) at room temperature and (c) the corresponding size
distributions (Reproduced with permission from Ref.
[46], Copyright (2010), Elsevier)
2.5 Monodisperse Thermo-responsive Hydrogel Microspheres and Microcapsules. . . 55
Fig. 2.24 Dynamic thermo-responsive characteristics of prepared microspheres with PNIPAM core and PHEMA shell during cooling-down process (a) and heating-up process (b). The scale bars are 100m (Reproduced with permission from Ref. [46], Copyright (2010), Elsevier)
with initiator APS. With high concentration of initiator APS (4 % molar ratio to monomer), the free-radical polymerization process is prompt and accomplished within several minutes. During the ATRP, PNIPAM core microspheres are uniformly distributed in the well-mixed HEMA monomer solution by gently magnetic stirring.
Therefore, PHEMA polymers are uniformly grafted onto the PNIPAM cores to form the monodisperse core-shell microspheres with homogeneous thickness.
The dynamic thermo-responsive characteristics of core-shell microspheres pre- pared with PVA concentration of 2 % and grafting time of 2 h are shown in Fig.2.24.
During the cooling-down process (60 ıC!25 ıC), the core-shell microsphere swells gradually, and at 50 s, there appears an obvious crack on the PHEMA shell of the microsphere (see the white dotted line in Fig.2.24a). With the PNIPAM core microsphere swells further, the crack becomes larger and larger, and eventually the PHEMA shell of the core-shell microsphere ruptures a large area about 30 % of the whole surface area at 240 s. The microsphere with PNIPAM core and PHEMA shell rapidly reaches to the swelling equilibrium state at 240 s when the temperature is cooling down from 60ıC to 25ıC. The thermo-responsive PNIPAM core begins to swell at the temperature below the LCST, which acts as an expansive force on the outer PHEMA shell. The PHEMA shell is stretched to some degree until it cannot afford the larger and larger expansive force from the expanding PNIPAM core. Then, the thinnest area of the PHEMA shell breaks at first and loses the restraint for the further swelling of PNIPAM core. Therefore, the ruptured area becomes larger and larger along the crack on the surface of PHEMA shell till the PNIPAM core reaches to the swelling equilibrium.
Inversely, during the heating-up process (25ıC!60ıC), the core-shell micro- sphere rapidly shrinks, and the ruptured PHEMA shell recovers to the state before the cooling-down process within 120 s (Fig.2.24b). With the temperature heating
up, the inner PNIPAM core shrinks, and the PHEMA shell promptly recovers to the original covering state on the PNIPAM core surface in absence of the expansive force. The as-prepared microspheres with PNIPAM core and PHEMA shell exhibit the thermo-responsive swelling/shrinking and more importantly the “open/close”
switching characteristics during the cooling-down/heating-up processes, and the thermo-responsive function of the proposed microspheres is highly reversible by changing the temperature across the LCST (Fig.2.24).
The thermo-responsive swelling/shrinking behavior of the PNIPAM core and the corresponding opening/closing behavior of the PHEMA shell crack of the microspheres enable such microspheres to be competent to deliver water-soluble drugs in a controllable way. Before delivering, the encapsulated drugs in PNIPAM core are protected by the biocompatible PHEMA shell at temperatures above the LCST, in which case the crack of the PHEMA shell is closed. On request to deliver the encapsulated drugs at specific site or programmed time, the local temperature is decreased below the LCST, so that the PNIPAM core swells and the crack of the PHEMA shell opens to provide unblocked channels for the encapsulated drugs to release.