Biodegradable and electrically conducting polymers

Progress in Polymer Science 38 (2013) 1263–1286

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Biodegradable and electrically conducting polymers for biomedical applications Baolin Guo a,b , Lidija Glavas a , Ann-Christine Albertsson a,∗ a Department of Fibre and Polymer Technology, School of Chemical Science and Engineering, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden b Center for Biomedical Engineering and Regenerative Medicine, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China

a r t i c l e

i n f o

Article history: Received 10 January 2013 Received in revised form 21 March 2013 Accepted 28 March 2013 Available online 12 June 2013 Keywords: Macromolecular architecture Aliphatic polyesters Tissue regeneration Aniline oligomers Degradable conducting copolymers

a b s t r a c t Conducting polymers have been widely used in biomedical applications such as biosensors and tissue engineering but their non-degradability still poses a limitation. Therefore, great attention has been directed toward the recently developed degradable and electrically conductive polymers (DECPs). The different strategies for synthesis of degradable and conducting polymers containing conducting oligomers are summarized and discussed here as well as the influence of different macromolecular architectures such as linear, star-shaped, hyperbranched and cross-linked DECPs. Blends and composites of biodegradable and conductive polymers are also discussed. The developing trends and challenges with the design of DECPs are also presented. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1263 Blends and composites of degradable conductive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264 Erodible and electrically conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1268 Degradable conductive polymers containing conducting oligomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1269 4.1. Linear degradable conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1269 4.2. Grafted conducting degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1272 4.3. Star-shaped and hyperbranched degradable conducting polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1275 4.4. Degradable and conducting hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277 4.5. Self-assembly of degradable conductive polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1277 Concluding remarks and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1281 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1282

1. Introduction

∗ Corresponding author. Tel.: +46 8 790 8274. fax: +46 8 20 84 77. E-mail address: [email protected] (A.-C. Albertsson). 0079-6700/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.progpolymsci.2013.06.003

The past two decades have witnessed a significant advance in the biodegradable polymeric material field. Due to their excellent biocompatibility, biodegradable polymers have been widely used in biomedical applications,

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B. Guo et al. / Progress in Polymer Science 38 (2013) 1263–1286

including surgical sutures, bone fixation devices, vascular grafts, artificial skin, drug delivery systems, gene delivery systems, diagnostic applications and tissue engineering [1–3]. Tissue engineering, also called regenerative medicine, is an interdisciplinary field involving knowledge of medicine, biology, engineering and materials science. Tissue engineering aims to improve or replace failing or malfunctioning body tissue by combining scaffolds, cells and bioactive molecules [4–6]. The scaffolds are designed to be a temporary support for cells and to promote cell differentiation and proliferation toward the formation of the desired new tissue. Scaffolds have to combine several functions including biocompatibility with the host tissue, controlled biodegradability with non-toxic degradation products, adequate porosity for the transportation of small molecules, optimal mechanical strength and controllability during cell growth, implantation and sterilization [7–9]. The biomaterials used for scaffolding should also totally degrade when the support is no longer needed. Due to their degradability and mechanical properties, natural polymers such as chitosan, gelatin, heparin, and collagen have been widely used for the fabrication of scaffolds for tissue engineering [9–11]. However, natural polymers may suffer quality variation from batch to batch and have an undesirable immune response. The most widely used synthetic scaffolding materials are aliphatic polyesters such as polylactide, polycaprolactone, polyglycolide and their copolymers, owing to their excellent non-toxicity, biocompatibility, biodegradability, and good mechanical properties [12–14]. Nevertheless, the poor hydrophilicity of aliphatic polyesters does not promote cell attachment on their surfaces, and the surfaces of polyesters also lack natural sites for covalent bonding of cell-recognition signal molecules to induce cell attachment and regulate the cell behavior, and this limits the application of polyesters in tissue engineering [15,16]. Conducting polymers (CPs) as a novel generation of organic materials were first synthesized in the mid-1970s. CPs have electrical and optical properties similar to those of metals and inorganic semiconductors, but they also possess attractive properties similar to those of common polymers, such as ease of synthesis and good processability compared to metals [17,18]. CPs are widely used in the microelectronics industry, including battery technology, photovoltaic devices, light-emitting diodes, and electrochromic displays [19–21], and more recently also in biomedical applications [22–25]. Research on CPs for biomedical applications expanded greatly in the 1980s when it was found that these materials were compatible with many biological molecules. Cell and tissue compatibility of conductive polymers such as polypyrrole (PPy) [26,27], polyaniline (PANi) [28,29], polythiophene [30] and their derivatives [31–33] were demonstrated both in vitro and in vivo. CPs have been used in various biomedical applications including neural probes [34], neural prostheses [35] and controlled release systems [36–38]. By the mid-1990s, CPs were also shown to tune cellular activities through electrical stimulation (conductivities from 10−4 to 9 S/cm) such as cell growth [39–42] and cell migration [43] and this led to a considerable interest in conducting polymers and their derivatives for tissue engineering applications [33,44,45]. Many of these studies

are related to nerve, bone, muscle, keratinocytes, fibroblasts, cardiac cells, and mesenchymal stem cells [46–49], which are sensitive to electrical stimulation. This shows the importance of conducting polymers in tissue engineering, since the regulation of cellular behavior is crucial for the regeneration of damaged tissue [50–52]. However, there are practical problems when these conductive polymers are used in tissue engineering. The main drawbacks with the existing systems are poor polymer-cell interactions, the absence of cell interaction sites, hydrophobicity, poor solubility and processability, as well as uncontrollable mechanical properties [22,53–56]. Their inability to degrade is one of the greatest limitations for tissue engineering applications. Keeping conducting polymers in vivo for a long time may trigger an inflammatory response and the need for a second surgical procedure [57]. The synthesis of materials with both electroactive and degradable properties is highly desirable, and is still a challenge. This review focuses on the different fabrication and synthesis routes of degradable and electrically conducting polymers using both conducting polymers to form blends and composites as well as conducting oligomers to form degradable and conducting copolymers. The tissue engineering applications and the future trends of degradable and conducting polymers are also highlighted. 2. Blends and composites of degradable conductive polymers To overcome the drawbacks such as poor mechanical properties, poor processability, hydrophobicity and non-degradability of CPs, polymer blends and composites based on conducting polymers such as PPy and PANi and degradable polymers such as polylactide (PLA) [58–60], polycaprolactone (PCL) [59,61,62], poly(lactide-co-glycolide) (PLGA) [63], polycaprolactone fumarate [64,65], poly(lactide-co-polycaprolactone) (PLAco-PCL) [48], polyurethane [66], chitosan [58,67,68], gelatin [69,70], collagen [71,72], and heparin [31,73,74] have been explored and extensively investigated. These materials were found to be particularly suitable in applications such as tissue engineering. Polypyrrole substrates doped with chondroitin sulfate were electrochemically prepared and coupled with type I collagen [75]. The conjugated collagen formed a 3D fibrillar matrix in situ on the polypyrrole interface. Rat pheochromocytoma cells were cultured on the fibrillar collagen and showed increased differentiation and neurite outgrowth. This was further improved by electrical stimulation of the underlying conducting polymer substrate, which means that these materials have a potential to improve the neural-electrode interface of implant electrodes by encouraging neural cell attachment and differentiation. In another example, heparin was incorporated into polypyrrole during electrosynthesis [31]. The amount of heparin incorporated was controlled by varying the key conditions during polymer synthesis. Cell culture studies showed that the composites were excellent substrates for the growth of human endothelial cells. The composite possessed a high PPy content which is not degradable, and only a very thin PPy film can be produced by electrochemical polymerization.


Scheme 1. Chemical structure of chitosan.

PPy is most commonly prepared by chemical polymerization when used with other polymers in blends. PPy nanoparticles with a high electrical conductivity were synthesized using a micro-emulsion system based on the chemical oxidation of pyrrole [58]. A novel electrically conductive, biocompatible, easily processable and largely biodegradable composite material composed of PPy nanoparticles and poly(d,l-lactide) (PDLLA) was fabricated by emulsion polymerization of pyrrole in a PDLLA solution, followed by precipitation with ethyl alcohol and a wash with deionized water [58]. The membranes were prepared by casting the PPy/PDLLA composite onto a poly(tetra fluoro-ethylene) plate. The surface resistivity of the membrane with 3 wt% PPy was 1×103 /square as a result of the PPy nanoparticles aggregating together to form a conductive network within the PDLLA matrix. By changing the proportions of PPy in the blends from 5 wt% to 17 wt%, it was easy to modify the topography. This composite maintained an electrical conductivity in a typical cell culture environment for 1000 h. The growth of fibroblasts on these membranes was regulated by the direct electric current. The authors later assessed the composite membrane for the culture of human cutaneous fibroblasts with or without electrical stimulation (ES) [60]. In the presence of a direct electrical field strength of 100 mV/mm, cell viability on the PPy/PLLA membranes at 2 and 24 h was 2.2- and 4.0fold (p < 0.05) respectively of that on the same membranes without ES. Since PPy nanoparticles are not degradable, it is better to maintain the PPy content in the polymer blend as low as possible. A largely biodegradable conductor consisting of 5 wt% of conductive PPy and 95 wt% of biodegradable poly(l-lactide) (PPy/PLLA) was prepared in a manner similar to that used in the previous work [47]. The cell culture results showed that the PPy/PLLA conductors supported human cutaneous fibroblast adhesion, spreading, and proliferation in both the presence and absence of ES. The presence of ES greatly increased the expression of interleukin-6 and interleukin-8 mRNA and sharply enhanced the secretion of these two types of cytokines from human fibroblasts. The authors further decreased the PPy content using chitosan as a matrix. Chitosan (CS) (Scheme 1) was used because it has good biodegradability and biocompatibility as well as immunological, antibacterial, and wound-healing properties. It has been widely used for controlled drug delivery [76–79] and tissue engineering [80–83]. A biodegradable conductive membrane based on conductive PPy nanoparticles (PPy, 2.5 wt%) and biodegradable chitosan (97.5 wt%) was prepared by a co-solution casting method [67]. Schwann cells were cultured on the composite membrane because they act as a bioactive substrate for axonal migration and release

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substances that adjust the axonal outgrowth. It was found that the PPy/chitosan membranes could support Schwann cell adhesion, spreading, and proliferation with or without ES. The authors also studied the effect of current on the Schwann cell culturing. The cells exhibited a spindle shape and attached well to the conductive polymer with an electrical current of 100 mV/mm. ES at 600 or 1000 mV/mm for 24 h mostly gave cells that were round with broken membranes and many particulates. More importantly, ES applied through the PPy/chitosan membrane greatly enhanced the expression and secretion of nerve growth factor and brain-derived neurotrophic factor compared to that of control cells without ES (Fig. 1). These results lead to new possibilities of enhancing nerve regeneration in degradable conductive membranes through electrical stimulationincreased neurotrophin secretion. These phenomena may be explained by immediate electrical stimulation on conducting PPy increasing protein (fibronectin) adsorption, which changed the nerve cell interaction, and enhanced neurite extension [84]. Polyurethane (PU) with good mechanical properties, processability, biocompatibility, and degradability has been widely used in the biomedical field [85–88]. A series of electrically conducting PPy nanoparticle and PU composites with different ratios were prepared via an in situ chemical polymerization of Py in a PU emulsion mixture [66]. The composites obtained exhibited elastomeric properties as well as conductivity, and were shown to be cytocompatible with C2C12 myoblast cells. Nanomembranes with macroscopic size and molecular scale thickness could be used for drug delivery vehicles, biomimetic systems, and tissue engineering. Biodegradable free-standing nanomembranes with a thickness from 20 to 80 nm composed of conducting polymer (poly(3-thiophene methyl acetate) and polyester (poly(tetramethylene succinate)) were prepared by spin-coating. Adhesion and proliferation results from epithelial cell cultures show that these nanomembranes (blends of the two polymers) are superior to membranes of the two individual polymers as cellular matrix, indicating that these nanomembranes could be used as bioactive substrates for tissue regeneration [89,90]. The largely degradable conducting blends or composites discussed above were fabricated into membranes. In tissue engineering porous scaffolds are more desirable and have been developed. One example is the porous and conductive chitosan scaffolds that were prepared by incorporating conductive PPy particles into a chitosan matrix and employing a phase separation technique to create pores inside the scaffolds [68]. The pore structure of the scaffold could be efficiently controlled by adjusting the concentration of the aqueous NaOH solution, and the mechanical strength was tuned by controlling the pore parameters of the scaffolds. The conductivity of the scaffolds was close to 10−3 S/cm with a low PPy content of around 2 wt%. Electrospinning has several advantages, including relative ease of use, adaptability, and the ability to generate loosely connected 3D porous scaffolds with high porosity and a large surface area similar to the natural extracellular matrix. In addition, the electrospun fibers can be oriented

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Fig. 1. Images of DAPI staining of Schwann cells from the M−ES group a), M+ES group (100 mV/mm, b) 12 h after ES; cells from the M−ES group (c), M+ES group (100 mV/mm, d) 24 h after ES. M−ES: materials without electrical stimulation; M+ES: materials with electrical stimulation [67]. Copyright 2010. With the permission of John Wiley and Sons.

or aligned randomly, so that the mechanical properties and the biological response to the scaffold can be controlled [91–95]. Electrospinning has also been used to create degradable conducting scaffolds [96,97]. In situ chemical polymerization of Py in the presence of a biodegradable scaffold prepared by electrospinning has been explored to fabricate the largely degradable and conductive scaffolds. This method is simple and can maintain the porous structure of the scaffolds [63,96]. This fabrication technique also overcomes the poor mechanical properties and processing difficulties associated with the use of PPy in tissue engineering applications [59,63]. Degradable and conductive meshes were fabricated by coating PPy onto random and aligned electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers by solution polymerization of Py in the presence of the nanofibers (Fig. 2) [63]. The PPy-coated PLGA electrospun meshes showed a greater growth and differentiation of rat pheochromocytoma 12 (PC12) cells and hippocampal neurons than non-coated PLGA control meshes. PC12 cells with an electrical stimulation of 10 mV/cm on PPy–PLGA scaffolds showed 40–50% longer neurites and 40–90% more neurite formation than the unstimulated cells on the same scaffolds. In addition, the aligned PPy–PLGA fibers exhibited longer neurites and more neurite-bearing cells than random PPy–PLGA fibers (Fig. 2). All these data indicate that electrical stimulation and topographical guidance serve as combined effects for the differentiation of the PC-12 cells. Electrically conductive composites were prepared by polymerization of Py in cross-linked scaffolds of polycaprolactone fumarate (PCLF), which led to interpenetrating networks of polycaprolactone fumarate–polypyrrole

(PCLF–PPy). Five different kinds of anionic dopants were tested to determine the optimal electrical and biological properties of the materials [64]. In vitro cell culturing with PC12 cells and dorsal root ganglia (DRG) indicated that PCLF–PPy materials with naphthalene-2-sulfonic acid sodium salt or dodecylbenzenesulfonic acid sodium salt as dopants support cell attachment, proliferation and neurite extension. The same research group later prepared the largely degradable conducting PCLF–PPy tubular scaffolds by polymerizing pyrrole in the presence of polycaprolactone fumarate tubes with an external diameter of 3.0 mm and an internal diameter of 1.7 mm. The mechanical and electrical properties of these scaffolds were investigated under physiological conditions [65]. PCLF–PPy scaffolds showed good mechanical properties at 37 ◦ C which offers the possibility for suturing applications. The surface resistivity of the scaffolds was 2 k and the scaffolds were electrically stable during the electrical stimulation. The scaffolds have the ability to greatly enhance and direct neurite extension if an electrical current is applied through the PCLF–PPy scaffolds, which means that they are promising for future therapeutic treatments. Compared to PPy, little consideration has been given to PANi, although it is one of the most promising electrically conductive polymers owning to its ease of synthesis, environmental stability, controllable electrical conductivity, and simple doping/dedoping chemistry [98–100]. All these characteristics means that PANi materials are potential conductive substrates for tissue engineering applications [101–103]. For example, PANi has been blended with gelatin, and then co-electrospun into nanofibers [69]. SEM


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Fig. 2. Left column: PPy-coated PLGA meshes. (a) Photographs of uncoated PLGA meshes (white, left) and PPy–PLGA meshes (black, right). (b) SEM micrograph of single strands of PPy–PLGA fibers. (c) SEM image of section of the PPy–PLGA meshes. Right column: SEM images of PC12 cells cultured on (a) PPy-random fiber and (b) PPy-aligned fiber for 2 days, black arrows indicate the neurites [63]. Copyright 2009. With the permission of Elsevier.

indicated that uniform fibers with no phase segregation were formed when less than 3 wt% of PANi was used in the blended fibers. The average fiber length decreased from 803±121 nm to 61±13 nm and the tensile modulus increased from 499±207 MPa to 1384±105 MPa with increasing PANi content from 0 to ∼5% w/w in the blends. H9c2 rat cardiac myoblast cells were cultured on these nanofiber-coated glass cover slips, and it was found that all the blended fibers supported H9c2 cell attachment and proliferation to a similar degree to that of the control tissue culture-treated plastic (Fig. 3). By choosing different degradable polymers, the properties of the scaffold can be adjusted for different applications. Degradable conducting scaffolds with elastic properties permit more realistic mimicry of the mechanical and electrical characteristics of the natural extracellular matrix (ECM), so that they have a great potential application in soft tissue regeneration such as skin, skeletal muscle, and blood vessels. Electrically conductive nanofibers were prepared by electrospinning a composite of PANi, doped with camphorsulfonic acid (CPSA), with poly(l-lactide-co-␧-caprolactone) (PLCL) [48]. The CPSA-PANi/PLCL nanofibers exhibited a smooth fiber structure without coarse lumps or beds and consistent fiber diameters, 100–700 nm, with a polyaniline content ranging from 0 to 30 wt% (Fig. 4). The elastic properties of these fibers are indicated by their high elongation at break, ranging from 391.54±9.20 to 207.85±6.74%

depending on the PANi content. The electrical conductivity was significantly increased from 0.0015 to 0.0138 S/cm with increasing PANi content to 30 wt%. The cell adhesion tests using human dermal fibroblasts, NIH-3T3 fibroblasts, and C2C12 myoblasts showed a much stronger adhesion onto the CPSA-PANi/PLCL nanofibers than onto pure PLCL nanofibers. In addition, the growth of NIH-3T3 fibroblasts was enhanced by the stimulation of various direct current flows. The same authors optimized the electrospinning conditions to prepare fibers with a high pore volume, interconnectivity and a uniform mean fiber diameter, to rule out the contribution of geometric differences [104]. The authors then studied the effect of electrical stimulation on the proliferation and differentiation of C2C12 skeletal myoblasts. After 4 days of culture, the number of cells positive for sarcomeric myosin was 3.6-times greater on the electrically conductive fibers with 15 wt% PANi than on the PLCL fibers without PANi. The effect of these electroactive nanofibers on the response of neuronal cells was studied, and it was found that the expression levels of paxillin, cdc-42 and rac were positively affected, and proteins such as RhoA and ERK were found in a more activated state [105]. This indicated that these electroactive fibers have the potential to serve as a guidance scaffold for neuronal tissue engineering. Polyaniline or poly(aniline-co-ethyl-3-aminobenzoate) was blended with poly(lactic acid) and then electrospun into nanofibers. These nanofibrous scaffolds gave enhanced

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Fig. 3. Morphology of H9c2 myoblast cells after 20 h of post-seeding on: (a) gelatin fiber; (b) PANi-gelatin blend fiber with 0.66 wt% PANi; (c) PANi-gelatin blend fiber with 1.58 wt% PANi; (d) PANi-gelatin blend fiber with 2.98 wt% PANi; and (e) a glass matrix. Staining with nuclei-bisbenzimide and actin cytoskeleton-phalloidin, fiber-autofluorescence [69]. Copyright 2006. With the permission of Elsevier.

mammalian cell growth and antioxidant and antimicrobial capacity [106]. 3. Erodible and electrically conducting polymers Although, the amount of PANi or PPy in the degradable and conducting blends or composites discussed above was minimized, eliminating to some extent the need for degradability; the small amounts of PANi or PPy introduced into the body through these materials are expected to stay in vivo. Therefore, the synthesis of completely degradable and electrically conducting polymers is still highly anticipated. One strategy to synthesize degradable conducting polymers is to design erodible conducting polymers (Scheme 2).

These polymers do not degrade in the conventional way by breaking of chemical bond, but rather through gradual dissolution [107]. The ␤-substituted pyrrole monomers containing ionizable and/or hydrolyzable side groups underwent either oxidative electrochemical polymerization or chemical polymerization with ferric chloride as oxidant to generate conducting thin films and colloidal dispersion. Degradation experiments showed that the weight loss of hydrophilic carboxylic–acid-modified PPy (poly-1) pressed pellets, which are slightly soluble in water, was 27% while the weight loss of pellets of hydrophobic methyl ester modified PPy (poly-2) was 6% after 80 days of incubation at 37 ◦ C. The resistance of the thin films of poly-1 was 300 (±100) , and increased to 700 (±200) after incubation in water for 2 days. This indicates that the conductivity


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Fig. 4. Morphologies of CPSA-PANi/PLCL nanofiber scaffolds. (a–c) Macroscopics, (d–f) SEM micrographs, a: scaffolds not containing PANi, (b) scaffolds containing 15 wt% PANi, (c) scaffolds containing 30 wt% PANi. The scale bars in (d, e and f) represent 1 ␮m [48]. Copyright 2008. With the permission of John Wiley and Sons.

of the pellets is retained under aqueous conditions. The cytocompatibility of the poly-1 film using primary mesenchymal cells derived from human bone-marrow was studied, and the results showed that the poly-1 films supported the growth, proliferation, and differentiation of primary human cells. Another example of an erodible conducting polymer is based on a polythiophene composite [108]. An electroactive and fully erodible composite based on water-soluble poly(ammonium(3-thienyl)ethoxy-propansulfonate) (SPT) (negatively charged) and poly(ethyleneimine) (PEI) (positively charged) was prepared by the layer-by-layer technique as shown in Scheme 3. The multilayer films with up to 15 layers were created from polyelectrolyte solutions of 0.1 wt% SPT and 0.025 wt% PEI solution, either salt-free or containing 0.2 M sodium sulphate. The conductivity of these films was ranged from 7.815 × 10−3 S/cm to 2.762 × 10−2 S/cm depending on the thickness of the film. The erosion test of the multi-layer films in PBS (pH

= 7.4) at 37 ◦ C showed that these films were fully eroded between 83 days and 130 days depending on the number of layers and on the salt concentration in the solution by a dissolution mechanism. The multi-layer films can promote L929 and C2C12 cell adhesion and growth. 4. Degradable conductive polymers containing conducting oligomers 4.1. Linear degradable conducting polymers Oligomers of pyrrole, thiophene [109,110] and aniline [111–113] have well-defined structures, good solubility, high flexibility during synthesis and processing, and an electroactivity similar to that of their corresponding conducting polymers. In addition, the oligomers of pyrrole, thiophene and aniline would be consumed by macrophages, and subsequently cleared by the kidney [110,114,115], eliminating the need for surgical removal of

Scheme 2. Chemical structure of erodible conducting polymers by electrochemical polymerization [107].

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Scheme 3. Chemical structure and fabrication of the erodible conducting polymers by the layer-by-layer method [108], (A) schematic diagram of the layer by layer (LBL) assembly, (B) chemical structures of poly[ammonium-(3-thienyl)ethoxypropanesulfonate] (SPT) and poly(ethyleneimine) (PEI), (C) 5, 10 and 15 bilayer films. Reproduced from reference [108] with the permission of the Royal Society of Chemistry, 2011.

the materials. New possibilities for the synthesis of degradable and conducting polymers are thus provided by the use of conducting oligomers. For example, a multi-block copolymer composed of conducting oligomers of pyrrole and thiophene and degradable ester linkages was synthesized by Schmidt and coworkers [110]. The authors first synthesized the oligomers of pyrrole and thiophene with two hydroxyl groups at each end, which were later coupled with adipoyl chloride to give the degradable conducting copolymer shown in Scheme 4. The copolymer can degrade in PBS with esterase, which indicated that these copolymers are biodegradable (by enzymes naturally found in the body). The data obtained by size exclusion chromatography indicated that the degradation took place at the polymer-solution interface and proceeded inwards with time following a surface erosion mechanism. Human neuroblastoma cells were seeded on these copolymer films, and it was shown that these films are non-toxic and support cell attachment and proliferation. The in vivo biocompatibility of these copolymers indicated that there is no detectable toxic effect of the materials or their degradation products. The conductivity

of the polymer films is of the order of 10−4 S/cm, but they can only be doped by iodine. To overcome this drawback and to increase the conductivity of the polymer, the same authors designed a copolymer composed of quarterthiophene oligomer and adipoyl chloride as shown in Scheme 5 [109]. This copolymer can be doped by ferric chloride (FeCl3 ) or ferric perchlorate (Fe(ClO4 )3 ). Cl− or ClO4 − are considered to be biocompatible counter-anions, and the residual iron has minimal toxicity. The erosion process started on the surface within 1–2 weeks after the copolymer was exposed to cholesterol esterase. The cytocompatibility of the copolymer was studied by subjection to Schwann cell culturing for 48 h, and it was found that the polymers exhibit no short-term cytotoxicity. Compared to the multi-step synthesis of pyrrole and thiophene oligomers, the synthesis of aniline oligomers such as aniline trimer, tetramer and pentamer is much easier. Aniline oligomers offer a new opportunity to design and synthesize well-defined and well-characterized species with defined functionality and properties [117–122]. Huang et al. [123] synthesized a triblock copolymer based on hydroxyl-capped PLA and carboxyl-capped aniline

Scheme 4. Degradable and conducting polymer based on conducting oligomers of pyrrole and thiophene and adipoyl chloride synthesized by a condensation polymerization [110].


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Scheme 5. Degradable conducting polymer based on a conducting quarterthiophene oligomer and adipoyl chloride synthesized by condensation polymerization [109].

pentamer by a coupling reaction. The triblock copolymer was soluble in dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), chloroform (CHCl3 ), tetrahydrofuran (THF) and toluene since the PLA segments, coupled onto both ends of the aniline pentamer segment, greatly increased the solubility of the copolymer, and thereby increased the processability of this conducting copolymer. The conductivity of the copolymer doped with camphorsulfonic acid was about 5 × 10−6 S/cm. The copolymer films were used to culture rat C6 glioma cells to test their cell compatibility, and it was found that the copolymer had a biocompatibility similar to that of TCPS, probably due to the well-known biocompatibility of PLA segments. However, these copolymers had poor mechanical strength due to their low molecular weight (2700–10000 g/mol). The authors later developed multiblock copolymers based on hydroxyl-capped polylactide and carboxyl-capped aniline pentamer with a molecular weight of 66.8 kDa (Scheme 6) [116]. The copolymer showed a tensile strength of 3.0 MPa, a breaking elongation of 95% and Young’s modulus of 33 MPa. The contact angle of

water on the copolymer films after doping with camphorsulfonic acid (CSA) decreased from around 90 degrees to 55 degrees, indicating that the polymer had become much more hydrophilic. The non-cytotoxicity of the copolymer was verified by a MTT assay with rat C6 cell line. The neurite length of rat neuronal pheochromocytoma PC-12 cells cultured on the CSA-doped copolymer films with electrical stimulation increased to 27.5 ␮m, while the neurite length was only 7.5 ␮m without electrically stimulation [116]. This indicated that, by applying ES, the differentiation of PC-12 cells could be accelerated. In the previously mentioned works, the degradable and conducting segments have been synthesized separately and combined by a condensation reaction. This strategy has several limitations, such as a multi-step reaction, tedious purification and in some cases also toxic reagents and low yields. Liu et al. [124] employed ring-opening polymerization to prepare ABA block polymers which are both degradable and electroactive (Scheme 7). This method is more simple than that employed in the previous work. They used double amino-capped aniline trimer to initiate

Scheme 6. Degradable conducting multi-block copolymers based on aniline pentamer and polylactide synthesized by condensation reaction [116].

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Scheme 7. Degradable and conducting triblock copolymers based on aniline trimer and polycaprolactone, synthesized by ring-opening polymerization [124].

␧-caprolactone with Sn(Oct)2 as a catalyst in anhydrous toluene. The triblock copolymer may work as a better sensor material than the aniline trimer due to its enhanced stability and sensitivity. In a further attempt to simplify the process of obtaining a degradable and conducting polymer, we developed a universal two-step synthesis approach to prepare degradable and conductive diblock or triblock copolymers by combining ring opening polymerization and oxidative coupling [125,126]. A series of degradable and conductive diblock copolymers and networks with different molecular weights of PCL and different aniline tetramer (AT) contents were synthesized by this approach (Scheme 8) [125]. We used aniline dimer (AD) to initiate ring-opening polymerization (ROP) of CL with Sn(Oct)2 as catalyst in bulk, since AD with its low molecular weight can dissolve in CL. This avoids the use of an organic solvent in the polymerization. The AD group in the AD-PCL was used for postpolymerization modification using an oxidative coupling reaction with AD, and a conductive AT segment was formed at the chain end of the macromolecules (Scheme 8). UV and CV results have demonstrated the excellent electroactivity of the polymers, and the conductivity of the polymers, 6.30 × 10−7 –1.03 × 10−5 S/cm, could be tuned by adjusting the AT content. If an appropriate amount of the crosslinker 2, 2-bis-(␧-caprolactone-4-yl) propane was added in the first step, a degradable and conductive network was obtained. The simple two-step synthesis was applied in order to produce a coil-rod-coil triblock copolymer composed of a middle aniline pentamer block and two polycaprolactone (PCL) bilateral blocks (Scheme 9) [126]. This synthesis approach is simple and accurate, and the triblock polymers obtained by this strategy have a well-defined structure and

controlled molecular weight and properties. These coilrod-coil triblock copolymers bearing an AP segment also exhibited a higher conductivity than the diblock copolymers based on aniline tetramer produced in our previous work [125]. 4.2. Grafted conducting degradable polymers In the previously mentioned works, the conductive segments were placed in the main chain, and the degradable segments were polyesters such as PLA, PGA and PCL. The degradable segment could also be an inorganic polymer such as a polyphosphazene. This is an intriguing group of polymers which can have a large number of different functional substituent groups attached to it [127,128]. Zhang et al. [129,130] functionalized polyphosphazenes with parent aniline pentamer and glycine ethyl ester by a nucleophilic substitution reaction (Scheme 10). One advantage of side-chain modification is that it is easy to control the aniline oligomer content in the copolymer, while maintaining the mechanical strength of the polymer. Aniline pentamer was used to introduce conductivity to the polymer while the glycine ethyl ester group ensured the degradability of the polymers. The conductivity of the polymer films was about 2 × 10−5 S/cm upon protonic doping. A weight loss of ca. 50% after 70 days degradation was obtained in PBS at 37 ◦ C. The in vitro culturing with RSC96 Schwann cells indicated the non-toxicity of the material, and it also showed that the material encourages cell adhesion and proliferation. Surface modification and functionalization can also be used to overcome the hydrophobicity and the lack of recognition sites for cells on the surfaces of the polyesters used for tissue engineering [131]. A two-step method for

Scheme 8. Synthesis of degradable electroactive diblock copolymers composed of aniline tetramer and polycaprolactone by combining a ring-opening polymerization and a post-functionalization [125]. Reproduced from reference [125] with the permission of the American Chemical Society, 2011.


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Scheme 9. Synthesis routes of the degradable conductive triblock copolymers based on aniline pentamer and polycaprolactone by ring-opening polymerization and oxidative coupling reaction [126]. Reproduced from reference [126] with the permission of the American Chemical Society, 2011.

Scheme 10. Degradable and conducting copolymers based on conducting aniline pentamer and polyphosphazenes synthesized by a nucleophilic substitution reaction on the side chain [130].

the functionalization and surface modification of PLA was developed in order to increase the hydrophilicity and to introduce conductive aniline oligomers onto the PLA surface to regulate the cell behavior in a later stage [131]. The carboxyl groups (-COOH) from acrylic acid (AA) and the anhydride groups from maleic anhydride (Ma) were first

grafted onto a PLA film by photografting. These carboxyl or anhydride groups were subsequently covalently coupled with the amino group (-NH2 ) of a conductive aniline tetramer segment (Scheme 11). The surface modification promotes hydrophilic and electroactive surface properties while maintaining the bulk properties of the polyester. This

Scheme 11. Surface grafting of polylactide (PLA) films with aniline tetramer (AT) by a UV surface grafting and a subsequent coupling reaction [131]. Reproduced from reference [131] with the permission of the American Chemical Society, 2012.

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Scheme 12. Synthesis of chitosan cross-linked with aniline pentamer [137].

combination may offer new possibilities in tissue engineering applications. Although many different degradable and conductive polymers with different conducting oligomers, different architectures and different properties have been synthesized, most of the polymers were soluble only in organic solvents, resulting in environmental problems and toxicity (especially in vivo). Degradable and electroactive polymers that can dissolve in a non toxic aqueous solvent would therefore be greatly desirable. Chitosan

contains a large number of amino groups along its main chain, and is easy to modify chemically [132–136]. Hu et al. [137] synthesized degradable and electroactive polymers using N-hydroxysuccinimide-capped aniline pentamer to crosslink chitosan in acetic/DMSO/DMF solution (Scheme 12). The copolymer can dissolve in acidic aqueous solution and it is electroactive and degradable. The authors also showed that the copolymer obviously improved PC-12 cell differentiation without electrical stimulation compared to chitosan.

Scheme 13. Biodegradable and electroactive polysaccharide crosslinker containing aniline tetramer [138].


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Scheme 14. Star-shaped degradable and conducting copolymers based on carboxyl-capped aniline trimer and polylactide synthesized by a condensation reaction [149].

Wang et al. [138] synthesized a biodegradable and electroactive polysaccharide crosslinker with aniline tetramer segments (Scheme 13). This copolymer with a large amount of aldehyde and carboxyl groups could self-assemble in water into nanoparticles with functional groups on the periphery. The polymer can act as a crosslinker for other polymers with amino or amino-derivative groups to introduce electroactivity to materials such as gelatin, and to form hydrogels.

4.3. Star-shaped and hyperbranched degradable conducting polymers Architecture plays an important role in the performance of polymers [139–142]. Our group has synthesized linear [143,144], branched [145] and crosslinked networks [144,146,147] of degradable polymers, and the morphological and physical-mechanical properties depended greatly on the macromolecular architecture [148]. To achieve the

Scheme 15. Schematic structure of hyperbranched degradable conducting copolymers based on carboxyl-capped aniline pentamer and star-shaped polycaprolactone synthesized by condensation polymerization [150].

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Scheme 16. Molecular structure of the CCAP segment in the copolymer at various oxidation states [150]. Reproduced from reference [150] with the permission of the American Chemical Society, 2010.

optimal mechanical, degradation, thermal and biological properties for a particular biomedical application, it is desirable to promote architectural diversity. We, therefore, designed star-shaped degradable and electroactive polymers based on star-shaped PLA and carboxyl-capped aniline trimer (CCAT) by a coupling reaction between the hydroxyl group of PLA and carboxyl group of aniline trimer, as shown in Scheme 14 [149]. By introducing electroactive segments to the star-shaped degradable polymers, we obtained an additional parameter that can be utilized for optimizing cell-culture results. The copolymers exhibited an electroactivity similar to that of PANi as indicated by cyclic voltammetry. The hydrophilicity of the copolymer films after doping with HCl was much higher than that of PLA films, but the copolymers probably would have had a very low conductivity, due to their low CCAT content and the low conductivity of CCAT. We later employed the macromolecular structures to enhance and control the conductivity of the electroactive and degradable polymers, and this was exemplified by linear and hyperbranched copolymers based on PCLs and carboxyl-capped aniline pentamer (CCAP) [150]. The linear and hyperbranched copolymers were synthesized by the “A2 +Bn (n = 2, 3, 4)” approach (Scheme 15). The coupling condensation reaction took place between the hydroxyl groups in the PCLs and the carboxyl groups in CCAP with dicyclohexylcarbodiimide (DCC) as water

condensation agent and 4-dimethylaminopyridine (DMAP) as catalyst to form the different architectural copolymers. The cyclic voltammogram of the copolymers showed three well-defined reduction/oxidation peaks, which could be attributed to the transition from the leucoemeraldine state to the emeraldine I state, from the emeraldine I state to the emeraldine II state, and from the emeraldine II state to the pernigraniline state (Scheme 16). The conductivities of the copolymers were between 5.01 × 10−6 and 2.42 × 10−5 S/cm. More interesting, the conductivity of hyperbranched copolymers was 1.6–4.8 times higher than those of the linear counterparts. We thus concluded that the conductivity of the polymers could be enhanced by a suitable choice of macromolecular architecture. We prepared a series of degradable and electrically conducting films with good mechanical properties by blending the aforementioned hyperbranched degradable conducting polymer [150] and linear polycaprolactone in solution, and we further constructed electroactive tubular porous nerve conduits from these blends by a solutioncasting/particle-leaching method [151]. It is easy to control the aniline pentamer content from 6 wt% to 12 wt% in the blended films, and the conductivity of the films was between 3.1 × 10−7 and 3.4 × 10−6 S/cm. The scaffolds, as shown in Fig. 5, had a tubular shape and a porous surface as indicated by SEM and micro-CT. The total porosity of all the scaffolds was between 86.7% and 88.2%, which is

Fig. 5. Photographs of the tubular porous scaffolds: (a) polycaprolactone scaffold; (b) scaffold containing 9 wt% of emeraldine aniline pentamer in the blend of PCL and hyperbranched degradable conducting polymer [151]. Copyright 2012. With the permission of Elsevier.


suitable for tissue engineering applications [12]. All the scaffolds were non-toxic, as confirmed by a cytotoxicity assay on these scaffolds with HaCaT cells. These degradable, electroactive and non-toxic tubular porous scaffolds have a great potential in neural tissue engineering. 4.4. Degradable and conducting hydrogels Hydrogels, three-dimensional crosslinked hydrophilic polymer networks, represent an important class of biomaterials. Their characteristics include a rubbery nature, similar to soft tissue, easy control of migration of oxygen, nutrients and other bioactive molecules, and an excellent biocompatibility [152–155]. Because of these characteristics, hydrogels have been widely used in tissue engineering applications [156–159]. Electrically conducting hydrogels (ECHs) are polymeric blends or conetwork biomaterials which were developed recently by Guiseppi-Elie [160,161] and Wallace et al. [162]. ECHs combine the unique advantages of conductive polymers and hydrogels [161], but the non-degradability of ECH greatly limits their application in tissue engineering. We designed and synthesized the first example of degradable and conducting hydrogels [163]. These hydrogels were synthesized by joining together the photopolymerizable macromer acrylated poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (AC-PLA-PEG-PLA-AC), glycidyl methacrylate (GMA), and ethylene glycol dimethacrylate (EGDMA) to form a degradable network. Aniline tetramer (AT) modified GMA was also included in order to introduce the conductive part (Scheme 17). The swelling ratio, from 15% to 300% of these hydrogels was tuned by adjusting the AT content in the hydrogels, the crosslinking degree, and the pH of the medium. The conductivities of the hydrogels varied between 4.69 × 10−7 and 1.05 × 10−4 S/cm when the AT content was increased from 10 wt% to 40 wt%. The possibility of tuning both the conductivity and the hydration percentage offers new possibilities to meet the demands of specific biomedical applications. However, the degradation product of polylactide could lead to a local acidic environment in vivo. Due to the lower conductivity of the AT segment, 40 wt% of AT segments had to be used to obtain high conductivity in the hydrogels. The high aniline oligomer content in the polymer could lead to toxicity of the material [116]. To lower the aniline oligomer content while maintaining a high conductivity and to overcome the acidic degradation products from polylactide [163], we subsequently presented another approach taking advantage of the already existing hydrogels. By functionalizing less acidic PCLbased degradable hydrogels with carboxyl-capped aniline pentamer (CCAP), hydrogels with a higher conductivity and fewer acidic degradation products can be obtained [164]. The reaction was carried out between the hydroxyl groups of hydroxyethylmethacrylate (HEMA) in a photopolymerized glycidyl methacrylate (GMA) functionalized polycaprolactone-poly(ethylene glycol)-polycaprolactone (GMA-PCL-PEG-PCL) network and the carboxyl group of CCAP, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl) as water condensing agent and 4-dimethylaminopyridine (DMAP) as catalyst

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(Scheme 18). The conductivity of the hydrogels was 2.02 × 10−4 S/cm when the CCAP content was 17 wt%. This value is higher than that previously reported which was 1.05 × 10−4 S/cm with an AT content of 40 wt% [163]. Thus, a similar conductivity level can be obtained while significantly decreasing the aniline oligomer content in the hydrogels, and thereby probably reducing the possible toxicity of the hydrogel [116]. Degradable conducting hydrogels based on natural polymers such as gelatin and chitosan has also been synthesized. Liu et al. [165] synthesized biodegradable electroactive hydrogels composed of aniline oligomer and gelatin. They first grafted N-hydroxysuccinimide-capped aniline pentamer to the amino group of gelatin main chain (Scheme 19). They then froze the graft polymer together with gelatin to create scaffolds, which were later crosslinked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in ethanol. The hydrogel changed structure from a honeycomb to a bamboo raft structure when increasing the amount of aniline pentamer. The Rat Schwann cells 96 (RSC96) cultured on the hydrogels indicated that the hydrogels were non-toxic, and the good compatibility was ascribed to the excellent biocompatibility of gelatin. The results of the osteoblast culture showed that the hydrogels led to faster cell proliferation than pure gelatin and TCPS. Our group developed a facile strategy to synthesize degradable and conductive polysaccharide hydrogels [166]. The reactions between chitosan and aniline tetramer (AT) were based on the aldehyde groups of glutaraldehyde (GA) and amino groups of AT and chitosan (CS). GA was used simultaneously as a coupling agent for the AT segment and as a crosslinking agent for the CS. CS-GA-AT hydrogels were thus synthesized in a one-pot reaction with a mixture of CS, GA and AT at room temperature (Scheme 20). These hydrogels can form free-standing and flexible films, and they thereby overcome the disadvantage of PANi which is not easy to fabricate into a thin film. By varying the aniline tetramer content from 10 wt% to 30 wt%, the conductivity could be tuned between 2.97 × 10−7 S/cm and 2.94 × 10−5 S/cm. The hydrogels also exhibit a pH-sensitive behavior. 4.5. Self-assembly of degradable conductive polymers Well-defined and functional supramolecular architectures from the self-assembly of block copolymers have a great potential in materials science, nanotechnology, and biomimetic chemistry [167–169]. Recently, the selfassembly of rod-coil or coil-rod-coil block copolymers has attracted a lot of interest [170–174] due to the functionality of the rigid-rod block and the assembly behavior which differs from that of the classical coil-coil amphiphilic diblock or triblock copolymers. As mentioned before, aniline oligomers with well-defined structures, good solubility in some organic solvents, and excellent electroactivity, similar to that of PANi, have been widely used to prepare functional materials by our group [149,150,163,166] and by others [175]. Aniline oligomers with their rigid conformation are also good candidates for rod-coil and coil-rod-coil block copolymers that can assemble into functional nanomaterials [176–179]. Diblock or triblock copolymers based

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Scheme 17. Synthesis of the degradable and electroactive hydrogels based on aniline tetramer and polylactide-PEG-polylactide by photopolymerization and ring-opening polymerization [163]. Reproduced from reference [163] with the permission of the American Chemical Society, 2011.

on poly(ethylene glycol) (PEG) and aniline oligomers have been synthesized and the polymers assembled into nanoparticles [177,180]. For example, an aqueous electrically switchable vesicular system without the addition of any chemical redox agent and without altering the chemical composition, concentration, volume, or temperature was developed using a redox-responsive self-assembly of an amphiphilic diblock rod − coil polymer composed of a tetraaniline and a poly [(ethylene glycol) methyl ether] (Mn - 550) block [178]. This electrically switchable packing behavior has a great potential for the development of new vesicle systems for molecular delivery in biomedical or microfluidic devices. The disadvantage of micelles from copolymers with for example styrene [176] or ether bonds [177,178,180] in the main chain is that they are not degradable [181]. If conducting polymers with ester bonds are used in the main chain instead, degradable and electroactive nano-materials can be obtained by self-assembly. Wang et al. [182]

synthesized the degradable electroactive diblock oligomers tetraaniline-block-poly(l-lactide) by ringopening polymerization of LLA using tetraaniline as initiator, and studied their self-assembly behavior in a selective solvent (chloroform). The morphologies of diblock oligomers cast from chloroform changed from spherical micelles in the leucoemeraldine state to ring-like aggregates composed of much smaller spherical structures in the emeraldine state (Fig. 6). The change in morphology is attributed to the different chain conformation entropies of the aniline segments before and after oxidation and the drying effects of the solvent [182]. As mentioned before, our group has synthesized triblock copolymers composed of EMAP or LMAP with PCL (PCLLMAP-PCL and PCL-EMAP-PCL) [126]. These copolymers self-assembled into core-shell nanoparticles in a selective solvent (e.g. chloroform, selective for PCL) with the two PCL segments stretching out as the shell and the AP segments as core [126]. The self-assembly was verified by the


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Scheme 18. Schematic synthesis of electroactive degradable hydrogels composed of aniline pentamer and PCL-PEG-PCL by photopolymerization and condensation [164]. Reproduced from reference [164] with the permission of John Wiley and Sons, 2011. 1H

NMR spectra of PCL-LMAP-PCL and PCL-EMAP-PCL in CDCl3 . The diameter of the nanoparticles was in the range from 50 nm to 393 nm, and it increased with increasing molecular weight of the triblock copolymers. The nanoparticles of the PCL-LMAP-PCL copolymer were larger than those of the corresponding PCL-EMAP-PCL copolymer. The size of the aggregates from these triblock copolymers was thus controlled by the molecular weight of the triblock copolymers and by the oxidation state of AP. The sizetuning ability offers a great potential in applications such as controlled drug delivery, biosensors, and biodetection. The self-assembly behavior of dendritic polymers may differ from the self-assembly of block copolymers due to their unique properties. Dendritic triblock polymers composed of ester dendron and aniline trimer were synthesized and found to self-assemble in THF [183]. The self-assembly is greatly affected by the balance of the driving forces which originate from amphiphilic interactions of the building blocks, intermolecular interactions of ester dendrons and the intermolecular ␲–␲ stacking among oligoanilines.

The self-assembly morphology of the triblock copolymer was easily changed from vesicles to fibrils by de-protecting oligoanilines (Scheme 21). The mechanism behind this transition is ascribed to the re-balancing of the driving forces. The authors later synthesized oligoaniline-containing dendron-rod-dendron dumb bell shape block oligomer based on ester dendron and aniline heptamer [184]. They found that the surface morphology can be changed from fibrils to flat single-layer films and to porous networks simply by oxidizing the conductive oligomer block in solution. This change is induced by a conformational transition of the oliganilines during oxidation. Some of the grafted degradable and conducting polymers mentioned previously can also undergo assembly. Aniline pentamer grafted chitosan was synthesized and the copolymer underwent self-assembly into 200–300 nm micelles [137]. The freeze-dried micelles exhibited a bowl-like morphology. The authors considered that the self-assembly was triggered by the change in pH and

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Scheme 19. Synthetic route to aniline pentamer grafted gelatin copolymer [165].

Scheme 20. Synthesis of CS-GA-AT hydrogels in a one-pot reaction [166]. Reproduced from reference [166] with the permission of the American Chemical Society, 2011.

Scheme 21. Chemical structure of dendron-b-oligoaniline-b-dendron triblock copolymer [183].


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Fig. 6. Surface morphologies of different aniline tetramer-b-PLLA oxidation states cast from 0.1% chloroform: (a) spherical aggregates in the leucoemeraldine state, (b) ring-like structures in the emeraldine state, (c) schematic illustration of the surface morphology changes induced by oxidation of the aniline segment and drying [182]. Copyright 2006. With the permission of John Wiley and Sons.

the presence of salt. Due to its amphiphilic nature, multialdehyde sodium alginate-graft-tetraaniline (MASA-TA) self-assembled into nanospheres with hydrophilic MASA as shell and hydrophobic TA as core [138]. The large carboxylic ions in MASA provide a lot of negative charges on the micelle surface and this prevents the micelle aggregation. The thin shell, about 30 nm, as determined by TEM, contained a large amount of reactive aldehyde and carboxyl groups, and this offers new possibilities to couple drugs or bioactive molecules for specific applications. 5. Concluding remarks and outlook Polymers exhibiting both conductivity and degradability represent a new class of biomaterials and dozens of different degradable and electrically conductive polymers (DECPs) have been synthesized during the past decade. Nevertheless, this library still needs to be expanded to meet the demands of specific applications. One of the challenges of degradable and conducting polymers is the optimization of their conductivity. New DECPs that have a low content of the conducting species and still possess sufficient conductivity are still very desirable. We employed macromolecular architecture (star-shaped and branched) to enhance the conductivity of the polymers, and more attention should be paid to this during the design of new DECPs. One of drawbacks associated with conducting polymers is their poor processability, which is overcome by combining them with degradable polymers. Nevertheless,

most of the developed DECPs are only soluble in organic solvents, which most probably are toxic and cause environmental problems. One solution to this predicament is to design hydrophilic and water soluble DECPs and is therefore another developing direction for the future. The research on DECPs based on conducting oligomers has mainly been centered around aniline oligomers due to their ease of synthesis and good processability. It would be interesting to find new pathways to synthesize pyrrole and thiophene oligomers and compare and combine these with aniline oligomers in order to obtain DECPs with different properties and functions. In would also be of interest to find another coupling chemistry for the coupling of aniline oligomers to the degradable segments, which is currently performed using DCC/DMAP chemistry. This coupling chemistry has drawbacks, such as low efficiency, and would be another direction in the future to develop new, more efficient and versatile synthetic pathways toward the degradable and conducting polymers. The degradable and electrically conductive polymers have been shown to improve cell adhesion as well as proliferation and they could be used as scaffold materials for neural, cardiovascular, and bone tissue regeneration for which electroactivity is important. So, further cell culturing to study of the interaction between cells and DECPs, especially star-shaped and branched DECPs, will be a necessity in the future in order to fully use these materials in biomedical applications.

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So far, research has focused on the synthesis of these degradable and conducting polymers. The next step is to look closely into their degradation behavior, including the rate of degradation, the degradation products and the effect of degradation on the mechanical and electroactive properties since the degradation of the materials plays a key role in their in vivo applications. The focus of DECPs has been on the use in tissue engineering as scaffold material due to the improved cell activities that the materials induce. The possibility of using DECPs in drug delivery systems has not been as explored. By taking advantage of the electrically switchable nature of DECPs, nanocarriers can be designed with specific properties such as morphology and drug release rate. An interesting field for DECPs would be as nanocarriers for neural drugs. Although many questions in the field of degradable and conducting polymers remain to be answered, the authors foresee a continued acceleration and growth of this area. Degradable and conducting polymers have been proven to be a very important group of biomaterials and they will make further contributions to biomedical science in the decades to come. Acknowledgments The authors gratefully acknowledge the China Scholarship Council (CSC), the ERC Advanced Grant, PARADIGM (Grant agreement no: 246776) and The Royal Institute of Technology (KTH) for financial support of this work. References [1] Tian HY, Tang ZH, Zhuang XL, Chen XS, Jing XB. Biodegradable synthetic polymers: preparation, functionalization and biomedical application. Progress in Polymer Science 2012;37:237–80. [2] Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Progress in Polymer Science 2007;32:762–98. [3] Ulery BD, Nair LS, Laurencin CT. Biomedical applications of biodegradable polymers. Journal of Polymer Science Part B: Polymer Physics 2011;49:832–64. [4] Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920–6. [5] Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials 2000;21:2529–43. [6] Ravichandran R, Sundarrajan S, Venugopal JR, Mukherjee S, Ramakrishna S. Advances in polymeric systems for tissue engineering and biomedical applications. Macromolecular Bioscience 2012;12:286–311. [7] Yang SF, Leong KF, Du ZH, Chua CK. The design of scaffolds for use in tissue engineering. Part 1. Traditional factors. Tissue Engineering 2001;7:679–89. [8] Chen GP, Ushida T, Tateishi T. Scaffold design for tissue engineering. Macromolecular Bioscience 2002;2:67–77. [9] Van Vlierberghe S, Dubruel P, Schacht E. Biopolymer-based hydrogels as scaffolds for tissue engineering applications: a review. Biomacromolecules 2011;12:1387–408. [10] Malafaya PB, Silva GA, Reis RL. Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Macromolecular Bioscience 2007;59: 207–33. [11] Kluge JA, Mauck RL. Synthetic/biopolymer nanofibrous composites as dynamic tissue engineering scaffolds. Advances in Polymer Science 2012;256:101–30. [12] Freed LE, Vunjaknovakovic G, Biron RJ, Eagles DB, Lesnoy DC, Barlow SK, Langer R. Biodegradable polymer scaffolds for tissue engineering. Biotechnology 1994;12:689–93. [13] Albertsson AC, Varma IK. Recent developments in ring opening polymerization of lactones for biomedical applications. Biomacromolecules 2003;4:1466–86.

[14] Place ES, George JH, Williams CK, Stevens MM. Synthetic polymer scaffolds for tissue engineering. Chemical Society Reviews 2009;38:1139–51. [15] Jiao YP, Cui FZ. Surface modification of polyester biomaterials for tissue engineering. Biomedial Materials 2007;2:R24–37. [16] Rasal RM, Janorkar AV, Hirt DE. Poly(lactic acid) modifications. Progress in Polymer Science 2010;35:338–56. [17] Heeger A. Semiconducting and metallic polymers: the fourth generation of polymeric materials. Synthetic Metals 2002;125: 23–42. [18] Shirakawa H. The discovery of polyacetylene film: the dawning of an era of conducting polymers (Nobel lecture). Angewandte Chemie International Edition 2001;40:2575–80. [19] Stenger-Smith JD. Intrinsically electrically conducting polymers, synthesis, characterization, and their applications. Progress in Polymer Science 1998;23:57–79. [20] Gurunathan K, Murugan AV, Marimuthu R, Mulik UP, Amalnerkar DP. Electrochemically synthesized conducting polymeric materials for applications towards technology in electronics, optoelectronics and energy storage devices. Materials Chemistry and Physics 1999;61:173–91. [21] Long YZ, Li MM, Gu CZ, Wan MX, Duvail JL, Liu ZW, Fan ZY. Recent advances in synthesis, physical properties and applications of conducting polymer nanotubes and nanofibers. Progress in Polymer Science 2011;36:1415–42. [22] Guimard NK, Gomez N, Schmidt CE. Conducting polymers in biomedical engineering. Progress in Polymer Science 2007;32:876–921. [23] Bendrea AD, Cianga L, Cianga I. Review paper: progress in the field of conducting polymers for tissue engineering applications. Journal of Biomaterials Applications 2011;26:3–84. [24] Chikar JA, Hendricks JL, Richardson-Burns SM, Raphael Y, Pfingst BE, Martin DC. The use of a dual PEDOT and RGDfunctionalized alginate hydrogel coating to provide sustained drug delivery and improved cochlear implant function. Biomaterials 2012;33:1982–90. [25] Green RA, Lovell NH, Poole-Warren LA. Impact of co-incorporating laminin peptide dopants and neurotrophic growth factors on conducting polymer properties. Acta Biomaterials 2010;6: 63–71. [26] Wang XD, Gu XS, Yuan CW, Chen SJ, Zhang PY, Zhang TY, Yao J, Chen F, Chen G. Evaluation of biocompatibility of polypyrrole in vitro and in vivo. Journal of Biomedial Materials Research Part A 2004;68:411–22. [27] Ramanaviciene A, Kausaite A, Tautkus S, Ramanavicius A. Biocompatibility of polypyrrole particles: an in-vivo study in mice. Journal of Pharmacy and Pharmacology 2007;59:311–5. [28] Humpolicek P, Kasparkova V, Saha P, Stejskal J. Biocompatibility of polyaniline. Synthetic Metals 2012;162:722–7. [29] Wang CH, Dong YQ, Sengothi K, Tan KL, Kang ET. In-vivo tissue response to polyaniline. Synthetic Metals 1999;102:1313–4. [30] Zhao HC, Zhu B, Sekine J, Luo SC, Yu HH. Oligoethylene-glycolfunctionalized polyoxythiophenes for cell engineering: syntheses characterizations, and cell compatibilities. ACS Applied Materials & Interfaces 2012;4:680–6. [31] Garner B, Georgevich A, Hodgson AJ, Liu L, Wallace GG. Polypyrrole-heparin composites as stimulus-responsive substrates for endothelial cell growth. Journal of Biomedical Materials Research 1999;44:121–9. [32] Kim DH, Wiler JA, Anderson DJ, Kipke DR, Martin DC. Conducting polymers on hydrogel-coated neural electrode provide sensitive neural recordings in auditory cortex. Acta Biomaterials 2010;6:57–62. [33] Persson KM, Karlsson R, Svennersten K, Loffler S, Jager EWH, Richter-Dahlfors A, Konradsson P, Berggren M. Electronic control of cell detachment using a self-doped conducting polymer. Advanced Materials 2011;23:4403–8. [34] Cui XY, Wiler J, Dzaman M, Altschuler RA, Martin DC. In vivo studies of polypyrrole/peptide coated neural probes. Biomaterials 2003;24:777–87. [35] George PM, Lyckman AW, LaVan DA, Hegde A, Leung Y, Avasare R, Testa C, Alexander PM, Langer R, Sur M. Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics. Biomaterials 2005;26:3511–9. [36] Svirskis D, Travas-Sejdic J, Rodgers A, Garg S. Electrochemically controlled drug delivery based on intrinsically conducting polymers. Journal of Controlled Release 2010;146:6–15. [37] Li YH, Ewen RJ, Campbell SA, Smith JR. Electrochemically controlled release of antischistosomiasis agents from polypyrrole. Journal of Materials Chemistry 2012;22:2687–94.

B. Guo et al. / Progress in Polymer Science 38 (2013) 1263–1286 [38] Wadhwa R, Lagenaur CF, Cui XT. Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode. Journal of Controlled Release 2006;110:531–41. [39] Wong JY, Langer R, Ingber DE. Electrically conducting polymers can noninvasively control the shape and growth of mammalian-cells. Proceedings of the National Academy of Sciences of the United States of America 1994;91:3201–4. [40] Jakubiec B, Marois Y, Zhang Z, Roy R, Sigot-Luizard MF, Dugre FJ, King MW, Dao L, Laroche G, Guidoin R. In vitro cellular response to polypyrrole-coated woven polyester fabrics: potential benefits of electrical conductivity. Journal of Biomedical Materials Research 1998;41:519–26. [41] Collazos-Castro JE, Polo JL, Hernandez-Labrado GR, Padial-Canete V, Garcia-Rama C. Bioelectrochemical control of neural cell development on conducting polymers. Biomaterials 2010;31:9244–55. [42] Quigley AF, Razal JM, Thompson BC, Moulton SE, Kita M, Kennedy EL, Clark GM, Wallace GG, Kapsa RMI. A conducting-polymer platform with biodegradable fibers for stimulation and guidance of axonal growth. Advanced Materials 2009;21:4393–7. [43] Gumus A, Califano JP, Wan AMD, Huynh J, Reinhart-King CA, Malliaras GG. Control of cell migration using a conducting polymer device. Soft Matter 2010;6:5138–42. [44] Schmidt CE, Shastri VR, Vacanti JP, Langer R. Stimulation of neurite outgrowth using an electrically conducting polymer. Proceedings of the National Academy of Sciences of the United States of America 1997;94:8948–53. [45] Ateh DD, Vadgama P, Navsaria HA. Culture of human keratinocytes on polypyrrole-based conducting polymers. Tissue Engineering 2006;12:645–55. [46] Ateh DD, Navsaria HA, Vadgama P. Polypyrrole-based conducting polymers and interactions with biological tissues. Journal of the Royal Society Interface 2006;3:741–52. [47] Shi GX, Zhang Z, Rouabhia M. The regulation of cell functions electrically using biodegradable polypyrrole-polylactide conductors. Biomaterials 2008;29:3792–8. [48] Jeong SI, Jun ID, Choi MJ, Nho YC, Lee YM, Shin H. Development of electroactive and elastic nanofibers that contain polyaniline and poly(l-lactide-co-epsilon-caprolactone) for the control of cell adhesion. Macromolecular Bioscience 2008;8:627–37. [49] Ghasemi-Mobarakeh L, Prabhakaran MP, Morshed M, NasrEsfahani MH, Baharvand H, Kiani S, Al-Deyab SS, Ramakrishna S. Application of conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering. Journal of Tissue Engineering and Regenerative Medicine 2011;5:E17–35. [50] Ravichandran R, Sundarrajan S, Venugopal JR, Mukherjee S, Ramakrishna S. Applications of conducting polymers and their issues in biomedical engineering. Journal of the Royal Society Interface 2010;7:S559–79. [51] Green RA, Lovell NH, Wallace GG, Poole-Warren LA. Conducting polymers for neural interfaces: challenges in developing an effective long-term implant. Biomaterials 2008;29:3393–9. [52] Abidian MR, Corey JM, Kipke DR, Martin DC. Conducting-polymer nanotubes improve electrical properties, mechanical adhesion, neural attachment, and neurite outgrowth of neural electrodes. Small 2010;6:421–9. [53] Thomas CA, Zong K, Schottland P, Reynolds JR. Poly(3,4alkylenedioxypyrrole)s as highly stable aqueous-compatible conducting polymers,vith biomedical implications. Advanced Materials 2000;12:222–5. [54] Green RA, Hassarati RT, Goding JA, Baek S, Lovell NH, Martens PJ, Poole-Warren LA. Conductive hydrogels: mechanically robust hybrids for use as biomaterials. Macromolecular Bioscience 2012;12:494–501. [55] Kishi R, Hiroki K, Tominaga T, Sano KI, Okuzaki H, Martinez JG, Otero TF, Osada Y. Preparation of electro-conductive double-network hydrogels. Journal of Polymer Science Part B: Polymer Physics 2012;50:790–6. [56] Hu WL, Chen SY, Yang ZH, Liu LT, Wang HP. Flexible electrically conductive nanocomposite membrane based on bacterial cellulose and polyaniline. Journal of Physical Chemistry B 2011;115:8453–7. [57] Zelikin A, Shastri V, Lynn D, Farhadi J, Martin I, Langer R, Moss SC. Bioerodible polypyrrole. Materials Research Society Symposium Proceedings 2002;711:193–7. [58] Shi GX, Rouabhia M, Wang ZX, Dao LH, Zhang Z. A novel electrically conductive and biodegradable composite made of polypyrrole nanoparticles and polylactide. Biomaterials 2004;25: 2477–88. [59] Xie JW, MacEwan MR, Willerth SM, Li XR, Moran DW, SakiyamaElbert SE, Xia Y. Conductive core-sheath nanofibers and their

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80] [81]

1283

potential application in neural tissue engineering. Advanced Functional Materials 2009;19:2312–8. Shi GX, Rouabhia M, Meng SY, Zhang Z. Electrical stimulation enhances viability of human cutaneous fibroblasts on conductive biodegradable substrates. Journal of Biomedical Materials Research Part A 2008;84:1026–37. Kim YD, Kim JH. Synthesis of polypyrrole-polycaprolactone composites by emulsion polymerization and the electrorheological behavior of their suspensions. Colloid and Polymer Science 2008;286:631–7. Basavaraja C, Kim WJ, Kim DG, Huh DS. Synthesis and characterization of soluble polypyrrole-poly(epsilon-caprolactone) polymer blends with improved electrical conductivities. Materials Chemistry and Physics 2011;129:787–93. Lee JY, Bashur CA, Goldstein AS, Schmidt CE. Polypyrrole-coated electrospun PLGA nanofibers for neural tissue applications. Biomaterials 2009;30:4325–35. Runge MB, Dadsetan M, Baltrusaitis J, Knight AM, Ruesink T, Lazcano EA, Lu L, Windebank AJ, Yaszemski MJ. The development of electrically conductive polycaprolactone fumaratepolypyrrole composite materials for nerve regeneration. Biomaterials 2010;31:5916–26. Moroder P, Runge MB, Wang HA, Ruesink T, Lu LC, Spinner RJ, Windebank AJ, Yaszemski MJ. Material properties and electrical stimulation regimens of polycaprolactone fumarate-polypyrrole scaffolds as potential conductive nerve conduits. Acta Biomaterials 2011;7:944–53. Broda CR, Lee JY, Sirivisoot S, Schmidt CE, Harrison BS. A chemically polymerized electrically conducting composite of polypyrrole nanoparticles and polyurethane for tissue engineering. Journal of Biomedical Materials Research Part A 2011;98:509–16. Huang JH, Hu XY, Lu L, Ye Z, Zhang QY, Luo ZJ. Electrical regulation of Schwann cells using conductive polypyrrole/chitosan polymers. Journal of Biomedical Materials Research Part A 2010;93: 164–74. Wan Y, Wu H, Wen DJ. Porous-conductive chitosan scaffolds for tissue engineering. 1. Preparation and characterization. Macromolecular Bioscience 2004;4:882–90. Li MY, Guo Y, Wei Y, MacDiarmid AG, Lelkes PI. Electrospinning polyaniline-contained gelatin nanofibers for tissue engineering applications. Biomaterials 2006;27:2705–15. Ghasemi-Mobarakeh L, Prabhakaran MP, Morshed M, NasrEsfahani MH, Ramakrishna S. Electrical stimulation of nerve cells using conductive nanofibrous scaffolds for nerve tissue engineering. Tissue Engineering Part A 2009;15:3605–19. Kang ET, Neoh KG, Huang SW, Lim SL, Tan KL. Surfacefunctionalized polyaniline films. Journal of Physical Chemistry B 1997;101:10744–50. Kim HS, Hobbs HL, Wang L, Rutten MJ, Wamser CC. Biocompatible composites of polyaniline nanofibers and collagen. Synthetic Metals 2009;159:1313–8. Li YL, Neoh KG, Cen L, Kang ET. Physicochemical and blood compatibility characterization of polypyrrole surface functionalized with heparin. Biotechnology and Bioengineering 2003;84: 305–13. Stewart EM, Liu X, Clark GM, Kapsa RMI, Wallace GG. Inhibition of smooth muscle cell adhesion and proliferation on heparin-doped polypyrrole. Acta Biomaterials 2012;8:194–200. Liu X, Yue ZL, Higgins MJ, Wallace GG. Conducting polymers with immobilised fibrillar collagen for enhanced neural interfacing. Biomaterials 2011;32:7309–17. Kumar M, Muzzarelli RAA, Muzzarelli C, Sashiwa H, Domb AJ. Chitosan chemistry and pharmaceutical perspectives. Chemical Reviews 2004;104:6017–84. Agnihotri SA, Mallikarjuna NN, Aminabhavi TM. Recent advances on chitosan-based micro- and nano-particles in drug delivery. Journal of Controlled Release 2004;100:5–28. Guo BL, Yuan JF, Gao QY. pH and ionic sensitive chitosan/carboxymethyl chitosan IPN complex films for the controlled release of coenzyme A. Colloid and Polymer Science 2008;286:175–81. Gulbake A, Jain SK, Chitosan:. a potential polymer for colonspecific drug delivery system. Expert Opinion on Drug Delivery 2012;9:713–29. Rinaudo M. Chitin and chitosan: properties and applications. Progress in Polymer Science 2006;31:603–32. Suh JKF, Matthew HWT. Application of chitosan-based polysaccharide biomaterials in cartilage tissue engineering: a review. Biomaterials 2000;21:2589–98.

1284


[82] Jana S, Florczyk SJ, Leung M, Zhang MQ. High-strength pristine porous chitosan scaffolds for tissue engineering. Journal of Materials Chemistry 2012;22:6291–9. [83] Zakhem E, Raghavan S, Gilmont RR, Bitar KN. Chitosan-based scaffolds for the support of smooth muscle constructs in intestinal tissue engineering. Biomaterials 2012;33:4810–7. [84] Kotwal A, Schmidt CE. Electrical stimulation alters protein adsorption and nerve cell interactions with electrically conducting biomaterials. Biomaterials 2001;22:1055–64. [85] Krol P. Synthesis methods, chemical structures and phase structures of linear polyurethanes. Properties and applications of linear polyurethanes in polyurethane elastomers, copolymers and ionomers. Progress in Materials Science 2007;52:915–1015. [86] Campos E, Cordeiro R, Santos AC, Matos C, Gil MH. Design and characterization of bi-soft segmented polyurethane microparticles for biomedical application. Colloids and Surfaces B 2011;88:477–82. [87] Pereira IHL, Ayres E, Patricio PS, Goes AM, Gomide VS, Junior EP, Orefice RL. Photopolymerizable and injectable polyurethanes for biomedical applications: synthesis and biocompatibility. Acta Biomaterials 2010;6:3056–66. [88] Son JS, Lee SH, Lee B, Kim HJ, Ko JH, Park YH, Chun HJ, Kim CH, Kim JH, Kim MS. Polyurethanes for biomedical application. Journal of Tissue Engineering and Regenerative Medicine 2009;6:427–31. [89] Armelin E, Gomes AL, Perez-Madrigal MM, Puiggali J, Franco L, del Valle LJ, Rodriguez-Galan A, Campos JSC, Ferrer-Anglada N, Aleman C. Biodegradable free-standing nanomembranes of conducting polymer:polyester blends as bioactive platforms for tissue engineering. Journal of Materials Chemistry 2012;22:585–94. [90] Perez-Madrigal MM, Armelin E, del Valle LJ, Estrany F, Aleman C. Bioactive and electroactive response of flexible polythiophene: polyester nanomembranes for tissue engineering. Polymer Chemistry 2012;3:979–91. [91] Agarwal S, Wendorff JH, Greiner A. Use of electrospinning technique for biomedical applications. Polymer 2008;49:5603–21. [92] Sill TJ, von Recum HA. Electro spinning: applications in drug delivery and tissue engineering. Biomaterials 2008;29:1989–2006. [93] Prabhakaran MP, Ghasemi-Mobarakeh L, Jin GR, Ramakrishna S. Electrospun conducting polymer nanofibers and electrical stimulation of nerve stem cells. Journal of Bioscience and Bioengineering 2011;112:501–7. [94] Zhang YX, Rutledge GC. Electrical conductivity of electrospun polyaniline and polyaniline-blend fibers and mats. Macromolecules 2012;45:4238–46. [95] Chronakis IS, Grapenson S, Jakob A. Conductive polypyrrole nanofibers via electrospinning: electrical and morphological properties. Polymer 2006;47:1597–603. [96] Aznar-Cervantes S, Roca MI, Martinez JG, Meseguer-Olmo L, Cenis JL, Moraleda JM, Jose M, Otero TF. Fabrication of conductive electrospun silk fibroin scaffolds by coating with polypyrrole for biomedical applications. Bioelectrochemistry 2012;85:36–43. [97] Kai D, Prabhakaran MP, Jin GR, Ramakrishna S. Polypyrrolecontained electrospun conductive nanofibrous membranes for cardiac tissue engineering. Journal of Biomedical Materials Research Part A 2011;99:376–85. [98] Gospodinova N, Terlemezyan L. Conducting polymers prepared by oxidative polymerization: polyaniline. Progress in Polymer Science 1998;23:1443–84. [99] Bhadra S, Khastgir D, Singha NK, Lee JH. Progress in preparation, processing and applications of polyaniline. Progress in Polymer Science 2009;34:783–810. [100] Bagherzadeh MR, Ghasemi M, Mahdavi F, Shariatpanahi H. Investigation on anticorrosion performance of nano and micro polyaniline in new water-based epoxy coating. Progress in Organic Coatings 2011;72:348–52. [101] Gizdavic-Nikolaidis M, Ray S, Bennett JR, Easteal AJ, Cooney RP. Electrospun functionalized polyaniline copolymer-based nanofibers with potential application in tissue engineering. Macromolecular Bioscience 2010;10:1424–31. [102] Di L, Wang LP, Lu YN, He L, Lin ZX, Wu KJ, Ren QS, Wang JY. Protein adsorption and peroxidation of rat retinas under stimulation of a neural probe coated with polyaniline. Acta Biomaterials 2011;7:3738–45. [103] Moura RM, de Queiroz AAA. Dendronized polyaniline nanotubes for cardiac tissue engineering. Artificial Organs 2011;35:471–7. [104] Jun I, Jeong S, Shin H. The stimulation of myoblast differentiation by electrically conductive sub-micron fibers. Biomaterials 2009;30:2038–47. [105] Bhang SH, Jeong SI, Lee TJ, Jun I, Lee YB, Kim BS, Shin H. Electroactive electrospun polyaniline/poly[(l-lactide)-co-(e-caprolactone)]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

[126]

fibers for control of neural cell function. Macromolecular Bioscience 2012;12:402–11. Gizdavic-Nikolaidis M, Ray S, Bennett J, Swift S, Bowmaker G, Easteal A. Electrospun Poly(aniline-co-ethyl 3-aminobenzoate)/Poly(lactic Acid) Nanofibers and Their Potential in Biomedical Applications. Journal of Polymer Science Part A: Polymer Chemistry 2011;49:4902–10. Zelikin AN, Lynn DM, Farhadi J, Martin I, Shastri V, Langer R. Erodible conducting polymers for potential biomedical applications. Angewandte Chemie International Edition 2002;41:141–4. Mawad D, Gilmore K, Molino P, Wagner K, Wagner P, Officer DL, Wallace GG. An erodible polythiophene-based composite for biomedical applications. Journal of Materials Chemistry 2011;21:5555–60. Guimard NKE, Sessler JL, Schmidt CE. Toward a biocompatible and biodegradable copolymer incorporating electroactive oligothiophene units. Macromolecules 2009;42:502–11. Rivers TJ, Hudson TW, Schmidt CE. Synthesis of a novel, biodegradable electrically conducting polymer for biomedical applications. Advanced Functional Materials 2002;12:33–7. Sadighi JP, Singer RA, Buchwald SL. Palladium-catalyzed synthesis of monodisperse, controlled-length, and functionalized oligoanilines. Journal of the American Chemical Society 1998;120: 4960–76. Wei ZX, Faul CFJ. Aniline oligomers - Architecture, function and new opportunities for nanostructured materials. Macromolecular Rapid Communications 2008;29:280–92. Ding CF, Wang Y, Zhang SS. Synthesis and characterization of degradable electrically conducting copolymer of aniline pentamer and polyglycolide. European Polymer Journal 2007;43:4244–52. Green TR, Fisher J, Matthews JB, Stone MH, Ingham E. Effect of size and dose on bone resorption activity of macrophages by in vitro clinically relevant ultra high molecular weight polyethylene particles. Journal of Biomedical Materials Research 2000;53:490–7. Nasongkla N, Chen B, Macaraeg N, Fox ME, Frechet JMJ, Szoka FC. Dependence of pharmacokinetics and biodistribution on polymer architecture: effect of cyclic versus linear polymers. Journal of the American Chemical Society 2009;131:3842–3. Huang LH, Zhuang XL, Hu J, Lang L, Zhang PB, Wang YS, Chen XS, Wei Y, Jing X. Synthesis of biodegradable and electroactive multiblock polylactide and aniline pentamer copolymer for tissue engineering applications. Biomacromolecules 2008;9:850–8. Chen R, Benicewicz BC. Preparation and properties of poly(methacrylamide)s containing oligoaniline side chains. Macromolecules 2003;36:6333–9. Hu J, Huang LH, Lang L, Liu YD, Zhuang XL, Chen XS, Wei Y, Jing X. The Study of Electroactive Block Copolymer Containing Aniline Pentamer Isolated from Different Solvents. Journal of Polymer Science Part A: Polymer Chemistry 2009;47:1298–307. Udeh CU, Fey N, Faul CFJ. Functional block-like structures from electroactive tetra(aniline) oligomers. Journal of Materials Chemistry 2011;21:18137–53. Liu YD, Hu J, Zhuang XL, Zhang PBA, Chen XS, Wei Y, Wang X. Preparation and characterization of biodegradable and electroactive polymer blend materials based on mPEG/tetraaniline and PLLA. Macromolecular Bioscience 2011;11:806–13. Jia XT, Chao DM, Berda EB, Pei SH, Liu HT, Zheng T, Wang C. Fabrication of electrochemically responsive surface relief diffraction gratings based on a multifunctional polyamide containing oligoaniline and azo groups. Journal of Materials Chemistry 2011;21:18317–24. Hardy CG, Islam MS, Gonzalez-Delozier D, Ploehn HJ, Tang CB. Oligoaniline-Containing Supramolecular Block Copolymer Nanodielectric Materials. Macromolecular Rapid Communications 2012;33:791–7. Huang LH, Hu J, Lang L, Wang X, Zhang PB, Jing XB, Wang XH, Chen XS, Lelkes PI, MacDiarmid AG, Yen W. Synthesis and characterization of electroactive and biodegradable ABA block copolymer of polylactide and aniline pentamer. Biomaterials 2007;28:1741–51. Liu SW, Wu YP, Zhang Y, Chi ZG, Wei Y, Xu JR. Synthesis and characterization of functional ABA block polymer containing aniline trimer. Chemistry Letters 2009;38:840–1. Guo BL, Finne-Wistrand A, Albertsson AC. Universal two-step approach to degradable and electroactive block copolymers and networks from combined ring-opening polymerization and postfunctionalization via oxidative coupling reactions. Macromolecules 2011;44:5227–36. Guo BL, Finne-Wistrand A, Albertsson AC. Simple route to sizetunable degradable and electroactive nanoparticles from the


[127]

[128]

[129]

[130]

[131]

[132] [133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

[147]

[148]

self-assembly of conducting coil-rod-coil triblock copolymers. Chemistry of Materials 2011;23:4045–55. Potin P, Dejaeger R. Polyphosphazenes - Synthesis, Structures, Properties, Applications. European Polymer Journal 1991;27:341–8. Lakshmi S, Katti DS, Laurencin CT. Biodegradable polyphosphazenes for drug delivery applications. Macromolecular Bioscience 2003;55:467–82. Zhang QS, Yan YH, Li SP, Feng T. Synthesis of a novel biodegradable and electroactive polyphosphazene for biomedical application. Biomedial Materials 2009;4:035008/1-9. Zhang QS, Yan YH, Li SP, Feng T. The synthesis and characterization of a novel biodegradable and electroactive polyphosphazene for nerve regeneration. Materials Science and Engineering C 2010;30:160–6. Guo BL, Finne-Wistrand A, Albertsson AC. Electroactive hydrophilic polylactide surface by covalent modification with tetraaniline. Macromolecules 2012;45:652–9. Sashiwa H, Aiba SI. Chemically modified chitin and chitosan as biomaterials. Progress in Polymer Science 2004;29:887–908. Guo BL, Yuan JF, Gao QY. Preparation and release behavior of temperature- and pH-responsive chitosan material. Polymer International 2008;57:463–8. Dunnhaupt S, Barthelmes J, Iqbal J, Perera G, Thurner CC, Friedl H, Bernkop-Schnuerch A. In vivo evaluation of an oral drug delivery system for peptides based on S-protected thiolated chitosan. Journal of Controlled Release 2012;160:477–85. Cui LM, Tang C, Yin CH. Effects of quaternization and PEGylation on the biocompatibility, enzymatic degradability and antioxidant activity of chitosan derivatives. Carbohydrate Polymers 2012;87:2505–11. Shi BY, Shen ZY, Zhang H, Bi JX, Dai S. Exploring N-ImidazolylO-Carboxymethyl Chitosan for High Performance Gene Delivery. Biomacromolecules 2012;13:146–53. Hu J, Huang LH, Zhuang XL, Zhang PB, Lang L, Chen XS, Wei Y, Jing X. Electroactive aniline pentamer cross-linking chitosan for stimulation growth of electrically sensitive cells. Biomacromolecules 2008;9:2637–44. Wang QA, He W, Huang JQ, Liu SW, Wu GF, Teng W, Wang Q, Dong Y. Synthesis of water soluble, biodegradable, and electroactive polysaccharide crosslinker with aldehyde and carboxylic groups for biomedical applications. Macromolecular Bioscience 2011;11:362–72. Hadjichristidis N, Iatrou H, Pitsikalis M, Mays J. Macromolecular architectures by living and controlled/living polymerizations. Progress in Polymer Science 2006;31:1068–132. Zhu XY, Zhou YF, Yan DY. Influence of Branching Architecture on Polymer Properties. Journal of Polymer Science Part B: Polymer Physics 2011;49:1277–86. Stridsberg KM, Ryner M, Albertsson AC. Controlled ring-opening polymerization: Polymers with designed macromolecular architecture. Advances in Polymer Science 2002;157:41–65. Fox ME, Szoka FC, Frechet JMJ. Soluble Polymer Carriers for the Treatment of Cancer: The Importance of Molecular Architecture. Accounts of Chemical Research 2009;42:1141–51. Srivastava RK, Albertsson AC. Enzyme-catalyzed ring-opening polymerization of seven-membered ring lactones leading to terminal-functionalized and triblock polyesters. Macromolecules 2006;39:46–54. Hakkarainen M, Hoglund A, Odelius K, Albertsson AC. Tuning the release rate of acidic degradation products through macromolecular design of caprolactone-based copolymers. Journal of the American Chemical Society 2007;129:6308–12. Numata K, Srivastava RK, Finne-Wistrand A, Albertsson AC, Doi Y, Abe H. Branched poly(lactide) synthesized by enzymatic polymerization: Effects of molecular branches and stereochernistry on enzymatic degradation and alkaline hydrolysis. Biomacromolecules 2007;8:3115–25. Finne A, Albertsson AC. Polyester hydrogels with swelling properties controlled by the polymer architecture, molecular weight, and crosslinking agent. Journal of Polymer Science Part A: Polymer Chemistry 2003;41:1296–305. Hoglund A, Odelius K, Hakkarainen M, Albertsson AC. Controllable degradation product migration from cross-linked biomedical polyester-ethers through predetermined alterations in copolymer composition. Biomacromolecules 2007;8: 2025–32. Alward DB, Kinning DJ, Thomas EL, Fetters LJ. Effect of Arm Number and Arm Molecular-Weight on the Solid-State Morphology

[149]

[150]

[151]

[152] [153]

[154] [155] [156]

[157]

[158]

[159]

[160]

[161]

[162] [163]

[164]

[165]

[166]

[167] [168] [169]

[170]

[171]

[172]

[173]

1285

of Poly(Styrene-Isoprene) Star Block Copolymers. Macromolecules 1986;19:215–24. Guo BL, Finne-Wistrand A, Albertsson AC. Molecular architecture of electroactive and biodegradable copolymers composed of polylactide and carboxyl-capped aniline trimer. Biomacromolecules 2010;11:855–63. Guo BL, Finne-Wistrand A, Albertsson AC. Enhanced electrical conductivity by macromolecular architecture: Hyperbranched electroactive and degradable block copolymers based on Poly(epsilon-caprolactone) and aniline pentamer. Macromolecules 2010;43:4472–80. Guo BL, Sun Y, Finne-Wistrand A, Mustafa K, Albertsson AC. Electroactive tubular porous scaffolds with degradability and non-cytotoxicity for neural tissue regeneration. Acta Biomaterials 2012;8:144–53. Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chemical Reviews 2001;101:1869–79. Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Advanced Materials 2006;18:1345–60. Vermonden T, Censi R, Hennink WE. Hydrogels for Protein Delivery. Chemical Reviews 2012;112:2853–88. Seliktar D. Designing cell-compatible hydrogels for biomedical applications. Science 2012;336:1124–8. Kai D, Prabhakaran MP, Stahl B, Eblenkamp M, Wintermantel E, Ramakrishna S. Mechanical properties and in vitro behavior of nanofiber-hydrogel composites for tissue engineering applications. Nanotechnology 2012;23, 095705/1-10. Kim IL, Mauck RL, Burdick JA. Hydrogel design for cartilage tissue engineering: A case study with hyaluronic acid. Biomaterials 2011;32:8771–82. Li YL, Rodrigues J, Tomas H. Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications. Chemical Society Reviews 2012;41:2193–221. Censi R, Di Martino P, Vermonden T, Hennink WE. Hydrogels for protein delivery in tissue engineering. Journal of Controlled Release 2012;161:680–92. Guiseppi-Elie A, Wilson A, Ann M, Brown KE. Electroconductive hydrogels: novel materials for the controlled electrorelease of bioactive peptides. Polymeric Preprints American Chemical Society 1997;38(2):608. Guiseppi-Elie A. Electroconductive hydrogels: Synthesis, characterization and biomedical applications. Biomaterials 2010;31:2701–16. Small CJ, Too CO, Wallace GG. Responsive conducting polymerhydrogel composites. Polymer Gels and Networks 1997;5:251–65. Guo BL, Finne-Wistrand A, Albertsson AC. Degradable and electroactive hydrogels with tunable electrical conductivity and swelling behavior. Chemistry of Materials 2011;23:1254–62. Guo BL, Finne-Wistrand A, Albertsson AC. Versatile functionalization of polyester hydrogels with electroactive aniline oligomers. Journal of Polymer Science Part A: Polymer Chemistry 2011;49:2097–105. Liu YD, Hu J, Zhuang XL, Zhang PBA, Wei Y, Wang XH, Chen XS. Synthesis and Characterization of Novel Biodegradable and Electroactive Hydrogel Based on Aniline Oligomer and Gelatin. Macromolecular Bioscience 2012;12:241–50. Guo BL, Finne-Wistrand A, Albertsson AC. Facile synthesis of degradable and electrically conductive polysaccharide hydrogels. Biomacromolecules 2011;12:2601–9. Lee M, Cho BK, Zin WC. Supramolecular structures from rod-coil block copolymers. Chemical Reviews 2001;101:3869–92. Mao ZW, Xu HL, Wang DY. Molecular Mimetic Self-Assembly of Colloidal Particles. Advanced Functional Materials 2010;20:1053–74. Cayre OJ, Chagneux N, Biggs S. Stimulus responsive core-shell nanoparticles: synthesis and applications of polymer based aqueous systems. Soft Matter 2011;7:2211–34. Stupp SI, LeBonheur V, Walker K, Li LS, Huggins KE, Keser M, Amstutz A. Supramolecular materials: Self-organized nanostructures. Science 1997;276:384–9. He PT, Li XJ, Deng MG, Chen T, Liang HJ. Complex micelles from the self-assembly of coil-rod-coil amphiphilic triblock copolymers in selective solvents. Soft Matter 2010;6:1539–46. Wang HB, Wang HH, Urban VS, Littrell KC, Thiyagarajan P, Yu LP. Syntheses of amphiphilic diblock copolymers containing a conjugated block and their self-assembling properties. Journal of the American Chemical Society 2000;122:6855–61. Tian LR, Zhong KL, Liu YJ, Huang ZG, Jin LY, Hirst LS. Synthesis and self-assembly of coil-rod-coil molecules with lateral methyl

1286

[174]

[175]

[176]

[177]

[178]

B. Guo et al. / Progress in Polymer Science 38 (2013) 1263–1286 and ethyl groups in the center of the rod segment. Soft Matter 2010;6:5993–8. Jin LY, Bae J, Ryu JH, Lee M. Ordered nanostructures from the selfassembly of reactive coil-rod-coil molecules. Angewandte Chemie International Edition 2006;45:650–3. Buga K, Majkowska A, Pokrop R, Zagorska M, Djurado D, Pron A, Oddou JL, Lefrant S. Postpolymerization grafting of aniline tetramer on polythiophene chain: Structural organization of the product and its electrochemical and spectroelectrochemical properties. Chemistry of Materials 2005;17:5754–62. Wang HF, Han YC. Vesicles formed by oligostyrene-blockoligoaniline-block-oligostyrene triblock oligomer. Macromolecular Rapid Communications 2009;30:521–7. Hu J, Zhuang XL, Huang LH, Lang L, Chen XS, Wei Y, Jing X. pH/Potential-Responsive Large Aggregates from the Spontaneous Self-Assembly of a Triblock Copolymer in Water. Langmuir 2008;24:13376–82. Kim H, Jeong SM, Park JW. Electrical Switching between Vesicles and Micelles via Redox-Responsive Self-Assembly of Amphiphilic Rod-Coils. Journal of the American Chemical Society 2011;133:5206–9.

[179] Dane TG, Cresswell PT, Bikondoa O, Newby GE, Arnold T, Faul CFJ, Briscoe WH. Structured oligo(aniline) nanofilms via ionic selfassembly. Soft Matter 2012;8:2824–32. [180] Yang ZF, Wang XT, Yang YK, Liao YG, Wei Y, Xie XL. Synthesis of electroactive tetraaniline-PEO-tetraaniline triblock copolymer and its self-assembled vesicle with acidity response. Langmuir 2010;26:9386–92. [181] Knop K, Hoogenboom R, Fischer D, Schubert US. Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives. Angewandte Chemie International Edition 2010;49:6288–308. [182] Wang HF, Guo P, Han YC. Synthesis and surface morphology of tetraaniline-block-poly(L-lactate) diblock oligorners. Macromolecular Rapid Communications 2006;27:63–8. [183] Xiong W, Wang HF, Han YC. Fibrils Formed by dendron-boligoaniline-b-dendron block Co-oligomer. Macromolecular Rapid Communications 2010;31:1886–91. [184] Xiong W, Wang HF, Han YC. Oxidation induced self-assembly transformation of dendron-b-oligoaniline-b-dendron dumbbell shape triblock oligomer. Soft Matter 2011;7:8516–24.