Recent Advances in Biodegradable Conducting Polymers and Their Biomedical Applications

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Review
Recent Advances in Biodegradable Conducting
Polymers and Their Biomedical Applications
* Kenry, and Bin Liu
Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.8b00275 • Publication Date (Web): 09 May 2018
Downloaded from http://pubs.acs.org on May 9, 2018
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Page 1 of 48 Biomacromolecules
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4 1 Recent Advances in Biodegradable Conducting
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8 2 Polymers and Their Biomedical Applications
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11 3 Kenry, Bin Liu*
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15 5 Department of Chemical and Biomolecular Engineering, National University of Singapore,
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17 6 4 Engineering Drive 4, Singapore 117585, Singapore
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22 8 KEYWORDS: Conjugated polymers; Biodegradable polymers; Biomedical imaging; Tissue
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24 9 engineering and regenerative medicine; Biomedical implants.
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28 11 ABSTRACT
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30 12 The growing importance and interests in biodegradable conducting polymers (CPs) have fuelled rapid
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32 13 development of this unique class of polymeric materials in recent years. Possessing both the electrical
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34 14 conductivity of metallic conductors as well as the biodegradability of biocompatible polymers,
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36 15 biodegradable CPs are highly sought after. In fact, they have emerged as the ideal biomaterials with
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38 16 immense potentials to augment a wide range of practical biomedical applications. Herein, we provide
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40 17 a broad overview on the recent advances in the development of biodegradable CPs and their
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42 18 biomedical applications. We first introduce the fundamentals of conducting and biodegradable
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44 19 polymers, followed by discussions on the major strategies currently used to fabricate biodegradable
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46 20 CPs. We then highlight the potential biomedical applications of biodegradable CPs, specifically for
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48 21 tissue engineering and regenerative medicine, biomedical imaging, as well as biomedical implants,
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50 22 bioelectronics devices, and consumer electronics. We conclude this review article by offering our
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52 23 perspectives on the current challenges and future opportunities facing the development and practical
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54 24 applications of biodegradable CPs.
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3 1 1. INTRODUCTION
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5 2 For the past four decades since the first demonstration of conducting polymers (CPs) in the 1970s,1, 2
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7 3 the importance and interests in this special class of organic materials have grown exponentially. With
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9 4 an electrical conductivity approaching that of metals and inorganic semiconductor as well as the facile
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11 5 preparation and good processability of common polymers,3 CPs have tremendous potentials for a
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13 6 wide range of applications.4-6 The excellent in vitro and in vivo biocompatibility of CPs7-10 have
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15 7 rendered them to be increasingly explored for various biomedical applications, particularly for tissue
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17 8 engineering, drug delivery, bioimaging, and biosensing.11-20 More specifically, through electrical
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19 9 stimulation, CPs are able to regulate various cellular behaviours, including cellular adhesion,
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21 10 alignment, proliferation, differentiation, and regeneration of damaged tissues, such as skin, bone,
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23 11 nerve, and myocardium tissues.21-26
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25 12 While CPs have been recognized as promising biomaterials, their practical bioapplications
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27 13 and clinical translations are still hindered by numerous limitations, notably the poor solubility and
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29 14 non-biodegradability of conventional CPs.27, 28
For example, when brought into a physiological
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31 15 environment as an implant material for tissue engineering applications, the non-biodegradability of
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33 16 existing CPs may pose significant problems. Specifically, the inability of CPs to degrade may prolong
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35 17 their stay in vivo, which in turn, may trigger undesirable inflammatory response. Tremendous efforts
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37 18 have consequently been geared towards the synthesis of biodegradable electroactive polymers with
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39 19 excellent biodegradability.29 In fact, up to date, biodegradability remains one of the greatest holy
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41 20 grails in the development of CPs for biomedical applications.
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43 21 Encouragingly, CPs with biodegradable characteristic have been progressively realized
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45 22 through numerous design and fabrication strategies.12, 29
One of the earliest attempts to realize
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47 23 biodegradable CPs was through the blending of CPs with typical biodegradable polymers, such as
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49 24 polylactide (PLA), polycaprolactone (PCL), and polyurethane (PU).30-33 Despite the considerable
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51 25 breakthrough achieved via this blending technique, the biodegradability of the resultant composites
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53 26 for practical in vivo biomedical applications is still far from satisfactory. To address this, recent years
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27 have witnessed the emergence of other ingenious approaches in the preparation of biodegradable CPs.
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3 1 These include primarily the conducting oligomer-based preparation of linear, star-shaped,
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5 2 hyperbranched, and other complex biodegradable electroactive polymeric architectures, as well as the
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7 3 synthesis of biodegradable CPs based on modified monomers or polymers.12, 29, 34 The development of
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9 4 these strategies have, in fact, greatly expanded the toolbox of biodegradable CPs and opened up
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11 5 further opportunities for the practical implementation of their biomedical applications.
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13 6 This review article seeks to provide a broad overview on the recent advances in the
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15 7 development of biodegradable CPs and their biomedical applications. The fundamentals of
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17 8 conducting and biodegradable polymers are first introduced, followed by discussions on the major
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19 9 strategies currently being employed to generate biodegradable CPs. The potential biomedical
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21 10 applications of biodegradable CPs, specifically for tissue engineering and regenerative medicine,
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23 11 biomedical imaging, as well as biomedical implants, bioelectronics devices, and consumer electronics,
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25 12 are then highlighted. This review article eventually concludes with a summary and perspectives on the
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27 13 current challenges and future opportunities facing the development and practical applications of
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29 14 biodegradable CPs.
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33 16 2. FUNDAMENTALS OF CONDUCTING AND BIODEGRADABLE POLYMERS
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35 17 CPs are synthetic macromolecules possessing highly delocalized π-conjugated backbone structure and
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37 18 configurable side chains (Figure 1A).3, 4, 35, 36
Some of the most common examples of CPs are
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39 19 polyacetylene (PA), polypyrrole (PPy), polyaniline (PANi), polythiophene (PTh), poly(3,4-
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41 20 ethylenedioxythiophene) (PEDOT), polyfluorenes (PF), poly(p-phenylene vinylene) (PPV), poly(p-
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43 21 phenylene) (PPP), poly(p-phenylene ethynylene) (PPE), and their derivatives (Figure 1B).
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45 22 Structurally, the CP backbone is made of alternating single C-C, double C=C, or triple C≡C bonds,
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47 23 where highly delocalized electrons are weakly held together by π bonds, while the overall polymeric
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49 24 chain strength is regulated by the strong σ bonds.1, 3 In fact, the conjugated double or triple bonds
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51 25 along their backbone are primarily responsible for the exceptional electrical conductivity displayed by
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53 26 CPs. Furthermore, this conjugated backbone architecture endows CPs with other unique electronic
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27 and photophysical properties, such as tunable electron affinity, ionization energy, as well as high
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3 1 molar absorptivity, energy transfer efficiency, fluorescence quantum yield, and photostability. CPs
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5 2 also have intrinsically rigid and stiff hydrophobic backbone, which in turn, can facilitate π-π stacking
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7 3 of the polymers.
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9 4 The electrical conductivity of CPs has been recognized to originate from the nonlinear defects
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11 5 created during the polymerization of a monomer or during the doping process.37, 38 As a result, the
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13 6 conductivity of CPs can be manipulated via the same doping process, in which dopant molecules are
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15 7 deliberately introduced to remove or add electrons to the CP backbone. This doping process is
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17 8 typically dictated by numerous factors, notably conjugation length, polymeric chain length, and
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19 9 charge carrier length. In general, through doping, either p- or n-type dopants can be introduced to
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21 10 endow the CPs with positive or negative charges, respectively. When a p-type dopant is introduced,
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23 11 the polymer is oxidized and a hole charge carrier is generated. On the other hand, when an n-type
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25 12 dopant is added, the polymer is reduced and an electron is introduced in the conduction band to create
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27 13 an electron charge carrier. The charge carrier mobility is enhanced by the existence of the π–orbital
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29 14 system within the CP backbone. Interestingly, it is noteworthy that undoped polymers may have
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31 15 electrical conductivity as low as 1.0 × 10-10 – 1.0 × 10-6 S/cm similar to those of insulators and
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16 semiconductors.39 However, with slight doping, this conductivity can be significantly enhanced by 10
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17 or more orders of magnitude. For example, common doped CPs, such as doped PPy, PANi, PTh, and
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18 PEDOT, have high electrical conductivities of 1.0 × 102 – 7.5 ×103, 3.0 ×101 – 2.0 ×102, 1.0 ×101 –
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19 1.0 × 103, and 4 ×10-1 – 4 × 102 S/cm, respectively.12, 13
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20 While possessing outstanding electrical property, pristine CPs may not be effectively
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21 employed for biomedical applications due to their poor dispersibility in aqueous solutions.28, 40
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22 Nevertheless, with their flexible side chains, CPs can be easily conjugated with appropriate functional
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23 groups to impart them with desirable biophysical properties. For example, CPs can be endowed
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24 with water solubility by introducing hydrophilic polar side chains or charged (e.g., anionic or cationic)
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25 pendant groups along their conjugated backbone. CPs can also be prepared as water-soluble
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52 26 nanoparticles through a self-assembly process in aqueous solution, followed by the amphiphilic
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54 27 surfactant or block copolymer-mediated stabilization. Functionalization of CPs may also be employed
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56 28 to impart them with other biophysical properties, such as high cellular internalization and low
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3 1 cytotoxic profile. While these outstanding biophysical properties are highly desirable, they alone are
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5 2 not sufficient to warrant the practical biomedical applications of CPs. To fully realize the potential of
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7 3 CPs for biomedical applications, these polymeric materials need to be biodegradable too.
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9 4 Biodegradable polymers, which can be disintegrated into their smaller molecular components,
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11 5 are highly desirable for in vivo biomedical applications.41-44 These polymers typically comprise
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13 6 varying amount of biodegradable units, such as the hydrolyzable esters and hydrazones, which can be
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15 7 directly or sequentially cleaved upon encountering external stimulations, including acidic
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17 8 environment, high temperature, or certain enzymatic reactions.42, 45-47
In contrast to the non-
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19 9 biodegradable entities, the biodegradable polymers can be decomposed to generate non-toxic natural
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21 10 byproducts, notably water and carbon dioxide.44 Furthermore, the biodegraded polymeric components
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23 11 with lower molecular weights may have in principle shorter in vivo circulation time and may be
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25 12 excreted from the body much more easily via kidney.44, 48 As such, this body clearance will ensure that
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27 13 no undesirable inflammatory response will be elicited by the biodegradable polymers once they have
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29 14 achieved their intended objectives in the in vivo system.
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31 15 With the continuous explorations into the applications of CPs for a wide range of biomedical
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16 applications, particularly for controlled drug delivery, tissue engineering, and regenerative medicine,
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17 the importance of biodegradability of these biomaterials has been increasingly highlighted.29
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18 Unfortunately, CPs are inherently not biodegradable owing to their inert π-conjugated architecture.
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19 The absence of biodegradable feature in CPs has impeded their effective in vivo bioapplications and
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20 clinical translation. Continuous efforts have thus been aimed at developing CPs with biodegradable
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21 characteristic, although this endeavour of developing ideal polymeric systems with both electrical
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22 conductivity and biodegradability has remained a considerable challenge to date. One of the earliest
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23 attempts at synthesizing biodegradable CPs have made use of common biodegradable synthetic
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24 polyesters, such as polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), their
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25 copolymers poly(lactic-co-glycolic acid) (PLGA), and polyurethane (PU) (Figure 1C).30 In fact, these
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52 26 biodegradable aliphatic polyesters are highly suitable for biomedical applications and have long found
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54 27 practical utility, even before the discovery of CPs, due to their excellent biocompatibility and
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56 28 biodegradability. Through direct blending of CPs with these biodegradable polymers, the first CP
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3 1 composites with a certain degree of biodegradability have been successfully demonstrated. Since then,
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5 2 more design and fabrication strategies have emerged and achieved a wide range of CPs with various
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5 Figure 1. Backbone and chemical structures of conducting and biodegradable polymers. (A) Conducting
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42 6 polymer (CP) with its conjugated backbone structure which consists of alternating single and double bonds,
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44 7 where σ bond and π bond maintains the polymeric chain strength and facilitates electron delocalization,
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46 8 respectively. Reprinted with permission from ref.36 Copyright 2018 Wiley-VCH Verlag GmbH & Co. (B)
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48 9 Chemical structures of common CPs, such as polyacetylene (PA), polypyrrole (PPy), polyaniline (PANi),
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10 polythiophene (PTh), poly(3,4-ethylenedioxythiophene) (PEDOT), polyfluorenes (PF), poly(p-phenylene) (PPP),
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51 11 poly(p-phenylene vinylene) (PPV), and poly(p-phenylene ethynylene) (PPE). (C) Chemical structures of
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53 12 biodegradable polymers typically used for biomedical applications, such as polylactide (PLA), polyglycolide
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55 13 (PGA), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and polyurethane (PU).
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5 2 3. STRATEGIES TO FABRICATE BIODEGRADABLE CONDUCTING
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7 3 POLYMERS
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9 4 While CPs have been known to be inherently not biodegradable and are extremely stable under
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11 5 physiological conditions, an increasing number of studies has shown that through ingenious design
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13 6 and fabrication approaches, this group of attractive polymers can be modified and endowed with a
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15 7 certain degree of biodegradability.12, 29 In fact, these strategies have been utilized to generate three
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17 8 primary types of biodegradable CPs, i.e., (1) partially biodegradable CP composites based on the
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19 9 blends of conducting and biodegradable polymers, (2) biodegradable CPs based on conducting
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21 10 oligomers, and (3) biodegradable CPs based on modified monomers and/or integration of degradable
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23 11 monomer units and conjugated linkers.
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27 13 3.1. Partially Biodegradable CP Composites based on the Blends of Conducting and
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29 14 Biodegradable Polymers
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31 15 One of the earliest strategies to fabricate partially biodegradable CP composites relies on the direct
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33 16 blending of the conducting and biodegradable polymers to generate polymeric composites (Figure 2),
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35 17 in which CPs contribute to the electroactivity and conductivity of the composites while their
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37 18 controlled degradability is provided by the biodegradable polymers.31-33 For example, PPy has been
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39 19 successfully combined with various synthetic biodegradable matrices, such as PLGA, PLA, PCL, and
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41 20 PU, to prepare partially biodegradable functional polymeric composites in the forms of nanofibers
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43 21 (Figures 2A and 2B)30, 49 and nanoparticles (Figure 2D),50 using methods like electrospinning30, 49 and
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45 22 emulsification.50 The integration of PPy into these biodegradable polymer composites has been noted
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47 23 to enhance their electrical conductivity considerably. Specifically, the sheet resistance of electrospun
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49 24 PLGA nanofibers, which intrinsically behave like insulators, could be reduced to about 9.0 × 104 – 7.4
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51 25 × 103 Ω/square through PPy coating.30 Similarly, the incorporation of PPy nanoparticles into
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53 26 insulating PLA nanofibers could increase the surface conductivity of the composite PPy-PLA
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55 27 structures from less than 1.0 × 10-16 S/cm to as high as 1.0 × 10-4 S/cm.51 The increment in the content
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3 1 of PPy nanoparticles in the composite PPy-PLA nanofibers was also noted to gradually increase their
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5 2 lost weight from 14 to 24% in phosphate-buffered saline (PBS) at 37 oC over 12 weeks. In addition to
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7 3 synthetic biodegradable polymers, PPy has been prepared directly on a silk substrate to generate a
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9 4 biodegradable silk-PPy composite film, in which the disintegration behaviour of the composite film is
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11 5 significantly influenced by the degradation profile of the silk substrate.52, 53 Besides PPy, other CPs,
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13 6 such as PEDOT and PANi, have been blended or grafted with biodegradable polymers to assemble
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15 7 partially biodegradable functional polymeric structures with improved electrical conductivity.54, 55 For
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17 8 instance, PEDOT has been integrated with PLGA to realize biodegradable electroactive PEDOT-
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19 9 PLGA microfibers whose overall conductivity could be enhanced up to 7.0 × 10-2 – 2.8 × 10-1 S/cm by
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21 10 increasing the content of their polymerizable EDOT monomers (Figure 2C).54 PANi, on the other
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23 11 hand, has been grafted to gelatin and then crosslinked with genipin to form biodegradable
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25 12 electroactive hydrogels (GP hydrogels) with electrical conductivity ranging from 4.54 × 10-4 to 2.41 ×
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27 13 10-4 S/cm.55 These hydrogels had favourable degradability where significant weight loss of about 50%
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29 14 to 60% occurred after 7 to 14 d into the in vitro degradation test conducted in PBS with pH 7.4 at 37
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31 15 C.
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16 Direct blending of conducting and biodegradable polymers offers a simple and
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17 straightforward route to achieve partially biodegradable CP composites. In fact, one of the main
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18 advantages of this technique is that, by selecting appropriate types and ratios of the two polymers to
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19 be blended, the conductivity and degradation rate of the eventual copolymers can be regulated for a
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20 wide range of biomedical applications. For example, various partially biodegradable CP-based
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21 scaffolds have been realized recently due to the flexibility of the direct blending strategy in
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22 incorporating different conducting and biodegradable polymers. These polymeric composites have
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23 been collectively explored for various biomedical applications, notably for tissue engineering and
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24 regenerative medicine applications. However, it is important to highlight that, while this blending
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25 approach incorporates the strengths and desirable features of both polymers, the resultant polymer
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52 26 blends may not possess the original maximum conductivity and biodegradability of their individual
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54 27 constituents. For instance, due to the inherent non-biodegradability of PPy, the amount of PPy
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56 28 introduced into the polymer blends is typically kept to a minimum so that their overall biodegradation
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3 1 behavior will not be affected. As such, while the copolymers manage to maintain their
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5 2 biodegradability, they may not possess sufficient electrical conductivity for practical biomedical
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7 3 applications.
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9 4 More importantly, although the content of CPs in the polymeric blends can be minimized and
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11 5 this may eliminate the need for biodegradability to a certain degree, the small quantity of CPs is
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13 6 anticipated to be chemically inert and will stay in the physiological environment for an unknown
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15 7 period of time if the partially biodegradable CP composites are introduced into the body. Clearly, the
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17 8 blending technique does not overcome the primary challenge of achieving a complete decomposition
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19 9 and clearance of CPs from the body after the polymeric composites have degraded. Therefore,
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21 10 increasing efforts in recent years have been devoted to developing alternative techniques which can
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23 11 enable the complete disintegration of biodegradable CP composites.
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48 13 Figure 2. Partially biodegradable CP-based functional nanostructures prepared using the blends of
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50 14 biodegradable and CPs. (A) Scanning electron microscopy (SEM) image of individual PPy-coated PLGA
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52 15 nanofibers. (B) SEM image of the PPy-coated PLGA nanofibrous mesh. All scale bars represent 1 µm.
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16 Reprinted from ref.30 , Copyright 2009, with permission from Elsevier. (C) Field emission SEM (FE-SEM)
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55 17 image of the aligned PEDOT-loaded PLGA microfibers. Scale bar represents 5 µm. Reprinted from ref.54
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3 1 Copyright 2012, with permission from Elsevier. (D) Transmission electron microscopy (TEM) image of the
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2 PPy-coated PLGA core-shell nanoparticles. Scale bar represents 200 nm. Reproduced from ref.50 with
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6 3 permission of The Royal Society of Chemistry. http://dx.doi.org/10.1039/c6ra18261e
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10 5 3.2. Biodegradable Conducting Polymers based on Conducting Oligomers
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12 6 To endow the conducting biodegradable polymers with better degradability and faster body clearance,
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14 7 small-sized short chains of conducting monomers, i.e., conducting oligomers, have been increasingly
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16 8 explored as viable alternatives to CPs as the conducting components of the electroactive
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18 9 biodegradable copolymers.56, 57 Conducting oligomers generally possess well-defined structures as
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20 10 well as an electroactivity and redox behaviour similar to their corresponding CPs.56-58 Nonetheless, in
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22 11 contrast to CPs, conducting oligomers have numerous advantages, including well-confined structure,
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24 12 higher flexibility in terms of synthesis and processing, better solubility, and capability to undergo
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26 13 gradual degradation and renal clearance. In fact, investigations into the oligomers of pyrrole, aniline,
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28 14 and thiophene have elucidated that, in addition to an electroactivity similar to that of their CP
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30 15 counterparts, these oligomers can be processed and copolymerized with biodegradable polymers more
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32 16 easily and they display a better biodegradable property. Various studies have also revealed that, in
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34 17 contrast to the oligomers of pyrrole and thiophene, aniline oligomers, primarily aniline trimer, aniline
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36 18 tetramer, and aniline pentamer, have a more facile and straightforward synthesis and processing
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38 19 steps.29, 56, 58 Most significantly, these oligomers can be taken up and internalized much more easily by
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40 20 the macrophages and subsequently excreted by kidney. Therefore, conducting oligomers have
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42 21 emerged as a viable option for the realization of totally biodegradable and conducting polymeric
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44 22 structures.
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46 23 Biodegradable CPs based on conducting oligomers are typically assembled by connecting the
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48 24 heteroaromatic oligomers with biodegradable polymeric segments via linkages, such as biodegradable
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50 25 ester bonds, in a linear macromolecular architecture. This approach has, in fact, been largely explored
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52 26 for the generation of biodegradable temporary scaffolds for tissue engineering applications. Similar
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54 27 design concept based on conducting oligomers has recently been applied for the synthesis of
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56 28 biodegradable electroactive PU film (Figure 3).59 Here, the biodegradable dopant mixture-free
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3 1 conducting PU elastomer (DCPU) was prepared through the chemical linking of conducting element
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5 2 (i.e., amine-capped aniline trimer), biodegradable element (i.e., PCL), and dopant molecules (i.e.,
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7 3 dimethylolpropionic acid (DMPA)) into a linear PU chain using 1,6-hexamethylene diisocyanate
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9 4 (Figure 3A). The electrical conductivity of DCPU elastomer could be tuned by varying the content of
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11 5 aniline trimer or DMPA in the PU backbone. The electrical conductivity of the dry state DCPU was
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13 6 noted to span from 5.5 × 10-8 to 1.2 × 10-5 S/cm. The control structures fabricated without aniline
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15 7 trimer and dopant showed low electrical conductivity of 5.5 × 10-12 and 2.7 × 10-10 S/cm, respectively.
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17 8 In a wet state in PBS, however, the DCPU films possessed higher electrical conductivity ranging from
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19 9 4.4 × 10-7 to 4.7 × 10-3 S/cm. These films also displayed high flexibility and elasticity, as evidenced
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21 10 from their ease of bending and knotting (Figures 3B and 3C), and could be degraded via hydrolysis
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23 11 and enzymatic reactions. More specifically, in vitro degradation tests on DCPU films in PBS at 37 oC
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25 12 revealed that the films experienced hydrolytic degradation with a low degradation rate, in which the
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27 13 remaining film mass reached about 96.6 to 98.2% after 8 weeks. Contrastingly, in a lipase/PBS
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29 14 solution, the degradation rate of the films was significantly higher. In fact, within 14 days, the
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31 15 remaining film mass could reach as low as 75.8%. Furthermore, using a salt leaching approach, the
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16 DCPU elastomer could be transformed into a porous scaffold with tunable pore size, which is suitable
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17 for numerous biomedical applications (Figures 3D and 3E).
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18 Interestingly, besides typical polyesters such as PLA, PCL, and PGA, hybrid inorganic-
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19 organic polymers, notably polyphosphazene and its derivatives, have been incorporated as the
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20 biodegradable segment of the biodegradable CPs.60-62 These polymers are unique because they possess
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21 versatile side chains which can be modified with a wide range of functional groups. This side chain
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22 modification enables the facile and precise tuning of the amount of oligomers in the biodegradable
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23 CPs such that their overall conductivity and biodegradability can be controlled. For instance, a
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24 biodegradable electroactive CP for potential application in nerve tissue engineering was synthesized
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25 by functionalizing aniline pentamer and glycine ethyl ester on polyphosphazene (PGAP copolymer).62
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52 26 PGAP showed an electrical conductivity of approximately 2 × 10-5 S/cm. In vitro study on the
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54 27 degradation profile of PGAP in PBS at 37 oC showed that they underwent a weight loss of about 50%
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56 28 over 70 days.
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3 1 While numerous biodegradable CPs have been demonstrated based on different conducting
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5 2 oligomers, it is noteworthy that a large number of these copolymers are only soluble in organic
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7 3 solvents, leading to unwanted environmental challenges.29 Copolymers with biodegradability in non-
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9 4 toxic aqueous solution are thus highly desirable. Driven by this, recent years have seen the rapid
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11 5 development of biodegradable electroactive copolymers based on the integration of conducting
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13 6 oligomers with biodegradable natural polymers. Some of the examples of these include chitosan-
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15 7 aniline pentamer-based copolymers63 and polysaccharide-aniline tetramer-based copolymers.64
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38 9 Figure 3. Biodegradable conducting elastomers prepared from conducting aniline trimer. (A) Synthetic route to
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40 10 the biodegradable dopant mixture-free conducting polyurethane elastomer (DCPU), in which the biodegradable
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11 element (i.e., PCL), conducting element (i.e., aniline trimer), and dopant molecules are chemically linked into a
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43 12 linear polyurethane chain. (B) Optical photograph of the fabricated DCPU film. (C) Optical photograph showing
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45 13 the high flexibility of DCPU film as demonstrated through its bending and knotting. (D) Optical photograph of
46
47 14 the porous DCPU scaffold obtained using the salt leaching approach. (E) SEM image of the corresponding
48
49 15 porous DCPU scaffold with an average pore size of approximately 116 µm. Scale bar represents 100 µm.
50
16 Reprinted from ref.59 under a Creative Commons Attribution 4 International License
51
52 17 https://creativecommons.org/licenses/by/4.0/ Copyright 2016 Xu et al.
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54 18
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1
2
3 1 In addition to those with linear macromolecular architecture, conducting oligomers have been
4
5 2 progressively processed into biodegradable conducting copolymers with other macromolecular
6
7 3 architectures, notably star-shaped, hyperbranched, and crosslinked network architectures (Figure 4).34
8
9 4 Macromolecular structures of polymers have been reported to play a key role in influencing their
10
11 5 morphological feature, electrical conductivity, mechanical and thermal properties, biodegradation rate,
12
13 6 and importantly, their overall performance.65, 66
In fact, two polymers with the same amount of
14
15 7 monomers and same molecular weights may exhibit different electrical conductivity and
16
17 8 biodegradability due to their different macromolecular architectures. By tuning the macromolecular
18
19 9 architectural diversity, the optimal electroactivity and biodegradability of the copolymers may be
20
21 10 achieved for specific biomedical applications. Consequently, a plethora of biodegradable CPs with
22
23 11 various macromolecular architectures have been synthesized and reported in the last few years. Some
24
25 12 examples of these are: (1) star-shaped branched biodegradable electroactive copolymers based on
26
27 13 aniline trimer and PLA,67 (2) hyperbranched biodegradable electroactive copolymers based on aniline
28
29 14 tetramer and PLA68 as well as based on aniline pentamer and PCL,66 and (3) crosslinked
30
31 15 biodegradable electroactive elastomers or hydrogels based on aniline trimer, PLLA, and PU-urea,69
32
33
16 based on aniline tetramer, chitosan, and glutaraldehyde,70 based on aniline tetramer, PLA, glycidyl
34
35
17 methacrylate, ethylene glycol dimethacrylate,71 as well as based on aniline pentamer, poly(glycerol
36
18 sebacate), and PU.72 These aniline oligomer-based biodegradable CPs typically display enhanced
37
38
19 electrical conductivity in the range of 10-6 to 10-4 S/cm.66, 69-71 For instance, with an increasing content
39
40
20 of aniline tetramer from 0 to 30%, the conductivity of the aniline tetramer-grafted chitosan-based
41
42
21 elastomers (DECPH films) could increase from 3.13 × 10-8 to 2.94 × 10-5 S/cm.70 At the same time,
43
44
22 this increment in aniline tetramer content from 0 to 25% led to an increasing weight loss from about 6
45
46
23 – 7% to 13 – 14% when these elastomers were immersed in buffer solutions with pH 2.1 and 7.4 for
47
48
24 48 h. Similarly, increasing the content of aniline tetramer from 10 to 40% in the hydrogels fabricated
49
50
25 from aniline tetramer, PLA, glycidyl methacrylate, and ethylene glycol dimethacrylate (DEC
51
52 26 hydrogels) could enhance their electrical conductivity from 4.69 × 10-7 to 1.05 × 10-4 S/cm.71
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1
2
3 1 Altogether, due to the versatility of the conducting oligomers coupled with the wide range of
4
5 2 available biodegradable polymers and macromolecular architectures, this strategy of preparing
6
7 3 biodegradable CPs has become one of the most widely adopted approaches in recent years.
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9 4
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11 5
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20 6
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22 7 Figure 4. Different macromolecular architectures of the biodegradable CPs based on conducting oligomers: (A)
23
8 linear copolymer, (B) star-shaped, (C) hyperbranched copolymer, and (D) crosslinked network architectures.
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25 9 Reprinted by permission from ref.34 Copyright 2014 Science China Press and Springer-Verlag Berlin Heidelberg.
26
27 10 https://link.springer.com/journal/11426
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29 11
30
31 12 3.3. Biodegradable Conducting Polymers based on Modified Monomers and/or Integration of
32
33 13 Degradable Monomer Units and Conjugated Linkers
34
35 14 In addition to biodegradable-conducting polymer blending and conducting oligomer-based approaches,
36
37 15 some of the more increasingly explored strategies in the development of biodegradable CPs include
38
39 16 the modification of conducting monomers and/or the integration of degradable monomer units or
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41 17 conjugated linkers to generate bioerodible CPs.73-76 Instead of achieving partial degradation based on
42
43 18 conventional chemical bond scission, these modified CPs can be eroded gradually to realize enhanced
44
45 19 and full biodegradation. One of the earliest studies demonstrating this concept showed that pyrrole
46
47 20 monomers could be modified and then polymerized to achieve erodible PPy.73 Here, ionisable (e.g.,
48
49 21 acid) and/or hydrolysable (e.g., ester) functional groups were first introduced to the backbone of
50
51 22 pyrrole monomers to obtain β-substituted pyrrole monomers. This was followed by the oxidative
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53 23 electrochemical and ferric chloride-mediated chemical polymerization of modified pyrrole monomers
54
55 24 to achieve erodible PPy. Conductive thin films fabricated from the acid-functionalized PPy displayed
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1
2
3 1 a low average resistance of about 300 Ω. Importantly, the modified PPy was noted to be able to
4
5 2 degrade gradually under physiological conditions and mediate the proliferation and differentiation of
6
7 3 primary human cells. More clearly, at 37 oC, thin films fabricated from acid-modified PPy could
8
9 4 dissolve within 24 h in a solution with pH 8.2, although they displayed a noticeably slower dissolution
10
11 5 rate at pH 5. Similarly, pellets formed from the acid-modified PPy showed twice the erosion rate at
12
13 6 pH 7.2 than at pH 5. In fact, incubated in a solution with pH 7.2 at 37 oC, these pellets showed a mass
14
15 7 loss of 27% over 80 days. As a comparison, under the same incubation condition, the mass loss
16
17 8 exhibited by the methyl ester-functionalized PPy was only 6%. This suggests that the degradation
18
19 9 rates of these erodible CPs could be modified by introducing and tuning the amount of different
20
21 10 functional side groups.
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23 11 Besides pyrrole-based erodible CPs, a separate study has reported the development of a
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25 12 thiophene-based erodible CP composite for biomedical applications.74 In the study, employing a layer-
26
27 13 by-layer technique, fully erodible and electroactive polymeric films were assembled from the
28
29 14 positively charged poly(ethyleneimine) and the negatively charged poly(ammonium(3-
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31 15 thienyl)ethoxypropanesulfonate) (SPT-PEI polymeric film). The synthesized multi-layered films were
32
33
16 observed to exhibit high electrical conductivity, ranging from 7.82 × 10-3 to 2.76 × 10-2 S/cm, and
34
35
17 could support muscle cell adhesion and proliferation. Significantly, these polymeric films were able to
36
18 undergo full degradation in an aqueous environment with physiologically relevant pH at 37 oC over
37
38
19 83 to 130 days.74 Similarly, based on thiophene monomer, a recent work has demonstrated the
39
40
20 synthesis of biodegradable fluorescent CP nanoparticles (CPNs) for biomedical imaging through the
41
42
21 integration of biodegradable imidazole units in the conjugated backbone (Figure 5).75 Here, the
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22 thiophene monomer unit was first copolymerized with imidazole monomer to generate fully
45
46
23 conjugated biodegradable CPNs (Figure 5A). The thiophene monomer was then modified with either
47
48
24 methoxy (OMe) or oligoethyleneoxy (OEG) side groups in order to provide both improved stability to
49
50
25 the resultant nanoparticles in aqueous solutions as well as enhanced solubility of the degraded
51
52 26 products. The assembled CPNs were noted to undergo decomposition through an imidazole
53
54 27 degradative oxidation mechanism when exposed to reactive oxygen species (ROS), such as hydrogen
55
56 28 peroxide produced by lipopolysaccharide-activated macrophages (Figure 5B). Intriguingly, the
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1
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3 1 degradation of both OMe- and OEG-functionalized CPNs could be observed as early as 11.5 h after
4
5 2 incubation with activated macrophages. In short, the degradative oxidation of imidazole could be
6
7 3 initiated by ROS, through which the CP backbone at the imidazole unit was cleaved, resulting in a
8
9 4 complete decomposition of the CPNs into soluble fragments with much lower molecular weights.
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26 5
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28 6 Figure 5. Synthetic and degradation processes of the imidazole-based CPNs. (A) Synthetic route to the
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30 7 biodegradable CPNs through the Sonogashira dispersion polymerization of the monomers of thiophene with
31
8 imidazole. The thiophene monomer was functionalized with either methoxy (i.e., OMe for CPN P1) or
32
33 9 oligoethyleneoxy (i.e., OEG for CPN P2) side groups. (B) Degradation mechanism of the biodegradable CPNs
34
35 10 in the presence of reactive oxygen species (ROS). Reprinted from ref.75 under a Creative Commons Attribution
36
37 11 4 International License https://creativecommons.org/licenses/by/4.0/ Copyright 2017 Repenko et al.
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39 12
40
41 13 Further to monomer modification and biodegradable unit integration, one of the more recent
42
43 14 examples has showed that fully erodible CPs can be prepared through the incorporation of degradable
44
45 15 conjugated linkers. In this work, based on imine chemistry, a fully decomposable polymer PDPP-PD
46
47 16 was synthesized as the building block of totally disintegrable transient electronics (Figure 6).76
48
49 17 Diketopyrrolopyrrole (DPP) dye, which was prepared from natural resources, was included into the
50
51 18 CP composite due to its high charge carrier mobility, ease of chemical functionalization, and excellent
52
53 19 biodegradability.76, 77 Imine bond (-C=N-), in contrast, was implemented as the conjugated linker due
54
55 20 to its high stability in an environment with neutral pH as well as its facile hydrolysis in a mildly acidic
56
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1
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3 1 environment.76, 78
DPP was first prepared via the reaction between 2-thiophenecarbonitrile and
4
5 2 succinic ester in tert-amyl acohol, followed by the attachment of branched alkyl chains (Figure 6A).
6
7 3 The addition of two aldehyde groups into the DPP monomer subsequently yielded DPP-CHO. Finally,
8
9 4 a condensation reaction between p-phenylenediamine and DPP-CHO catalyzed by p-toluenesulfonic
10
11 5 acid (PTSA) produced the biodegradable conducting PDPP-PD polymer, with an average hole
12
13 6 mobility of about 4.2 × 10-2 – 3.4 × 10-1 cm2/V.s. The CP was noted to be able to retain its stability
14
15 7 under neutral and basic conditions, but undergo decomposition both in solutions and in solid-state
16
17 8 under acidic conditions. More clearly, based on its absorption spectrum and physical color, PDPP-PD
18
19 9 solution decomposed into its monomer DPP-CHO after 10 d and it totally disintegrated after 40 days
20
21 10 under acidic condition. At the same time, the spin-coated PDPP-PD thin film experienced gradual
22
23 11 degradation after being immersed in an aqueous buffer solution with pH 4.6. The total decomposition
24
25 12 of the polymer was proposed to be driven by the acid-catalyzed imine bond hydrolyzation, followed
26
27 13 by the water-induced decomposition of DPP monomers via lactam ring hydrolyzation (Figure 6B).
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52 14
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54 15 Figure 6. Synthetic and degradation processes of the imine-based CP. (A) Synthetic route to the decomposable
55
16 conducting CP, i.e., PDPP-PD with the imine biodegradable linkers. (B) Proposed mechanism of PDPP-PD
56
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1
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3 1 decomposition through a two-step process, where this process of decomposition is initiated by imine bond
4
2 hydrolysis in the presence of acid, followed by the decomposition of DPP monomers via lactam ring hydrolysis.
5
6 3 Reprinted with permission from ref.76 Copyright 2017 National Academy of Sciences of the United States of
7
8 4 America.
9
10 5 It is important to highlight that, while only a limited number of studies have focused on this
11
12 6 strategy of assembling biodegradable CPs, it is possibly one of the best approaches to realize
13
14 7 polymers with both excellent electrical conductivity and full biodegradability. Therefore, it is
15
16 8 anticipated that active efforts will be progressively geared towards optimizing and enhancing this
17
18 9 polymer preparation approach in the near future.
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20 10
21
22 11 4. BIOMEDICAL APPLICATIONS OF BIODEGRADABLE CONDUCTING
23
24 12 POLYMERS
25
26 13 As a special class of polymeric materials with excellent morphological, electrical, and biological
27
28 14 properties, biodegradable CPs have demonstrated great potential for a wide range of biomedical
29
30 15 applications.29, 61, 73, 74 The unique combination of strong electroactivity and tunable biodegradability
31
32 16 has propelled active explorations into their potential biomedical applications in tissue engineering and
33
34 17 regenerative medicine, biomedical imaging, biomedical implants, bioelectronics devices, and
35
36 18 consumer electronics (Table 1).
37
38 19
39
40 20 4.1. Tissue Engineering and Regenerative Medicine
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42 21 One of the earliest investigations into the biomedical applications of biodegradable CPs has focused
43
44 22 on their potential utility in the field of tissue engineering and regenerative medicine.33, 34, 79, 80 With
45
46 23 attractive features such as high electrical conductivity, controlled biodegradability, redox stability,
47
48 24 and three-dimensional architecture, biodegradable CPs are highly sought after for tissue engineering
49
50 25 applications. In recent years, tissue engineering and regenerative medicine have been progressively
51
52 26 seen as viable therapeutic approaches to treat physiological disorders with long-lasting and
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54 27 devastating effects.80-82 These include bone defects, peripheral nerve injuries, and spinal cord damages.
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56 28 To achieve its therapeutic outcomes, tissue engineering relies on the precise reconstruction of the
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1
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3 1 complex native cellular and tissue microenvironments using a wide range of strategies, including
4
5 2 biomaterials.83-88 In general, biomaterials used as scaffolds for tissue engineering and regenerative
6
7 3 medicine are expected to be highly biocompatible and have architectural and physical properties
8
9 4 similar to those of the host tissues such that these biomaterials are able to stimulate certain cellular
10
11 5 and tissue behaviours, notably cellular adhesion, proliferation, differentiation, and tissue formation.49,
12 83-86, 88
13 6 At the same time, they should be biodegradable. This is because these temporary scaffolds need
14
15 7 to decompose over time to be replaced by the newly generated cells and tissues. As a result, the
16
17 8 selection and design of biomaterials are extremely important to create the ideal artificial
18
19 9 microenvironments capable of mediating the cell-biomaterial interactions in order to achieve the
20
21 10 desired clinical outcome.
22
23 11 Over the last few decades, both natural and synthetic polymers have been widely used to
24
25 12 fabricate tissue engineering scaffolds.89-91 However, a large number of these biomaterials do not have
26
27 13 sufficient bioactivity to induce a full recovery of the tissue function. Synthetic organic CPs, such as
28
29 14 PPy, PANi, PTh, and PEDOT, have been widely evaluated more recently as biomaterial scaffolds for
30
31 15 tissue engineering application due to their outstanding electrical conductivity and biocompatibility.5, 6,
32 11, 27, 89
33
16 In fact, a wide range of cells, such as bone, muscle, and neuronal cells, has been reported to be
34
35
17 extremely responsive towards electrical stimulation.63, 68, 79, 81, 89, 92 As such, the electrical conductivity
36
18 of CPs serves as a potentially effective cue that enables local electrical stimulation of cells and tissues
37
38
19 for their enhanced growth and differentiation. For example, PPy has been widely reported to improve
39
40
20 neural activities, neurite extension, and axonal outgrowth.79, 92 Nevertheless, the effective applications
41
42
21 of CPs in tissue engineering and regenerative medicine are still hampered by numerous drawbacks,
43
44
22 such as their poor solubility in aqueous solutions, restricted processability, brittleness, and non-
45
46
23 biodegradability. Encouragingly, earlier attempts of using synthetic non-conducting biodegradable
47
48
24 polymers, such as PLA, PCL, and PLGA, for tissue engineering applications, coupled with the rapid
49
50
25 advances in polymer fabrication techniques, have prompted the development of integrated polymeric
51
52 26 systems comprising both electrical conductivity and biodegradability features. In one of the published
53
54 27 studies, an electrically conducting biodegradable polymeric composite was developed based on the
55
56 28 combination of PPy and poly(D, L-lactide-co-epsilon-caprolactone) (PDLLA/CL).92 This
57
58
19
59
1
2
3 1 PPy/PDLLA/CL scaffold was shown to promote both the proliferation and neuronal differentiation of
4
5 2 PC12 cells as well as the regeneration of nerves in rats. In another study, a hybrid polymeric system
6
7 3 comprising biodegradable PLA/PLGA copolymer and conducting PPy doped with p-toluenesulfonate
8
9 4 was demonstrated to accelerate directed axonal growth and enhance the migration of Schwann cells
10
11 5 for an effective peripheral nerve repair.79
12
13 6 While the blends of electrically conducting and biodegradable polymers have been utilized
14
15 7 for regenerative medicine applications with considerable success, the biodegradability of the hybrid
16
17 8 composites is still largely not satisfactory. Consequently, more and more efforts have been directed
18
19 9 towards developing biodegradable CP-based tissue engineering scaffolds using oligomers.93 While
20
21 10 they typically have a good electroactivity similar to that of their polymer counterparts, oligomers have
22
23 11 tunable solubility, better processability, and biodegradability. They are more versatile as a result and
24
25 12 can be integrated or copolymerized with degradable polymers with ease, thus providing a greater
26
27 13 flexibility in terms of biodegradable conducting scaffold design. For example, a recent work has
28
29 14 highlighted the development of a biodegradable electroactive polymeric network based on the star-
30
31 15 shaped six-armed PLA and aniline trimer (PHAT polymer) for bone tissue engineering.67 PHAT was
32
33
16 noted to undergo gradual degradation with a weight loss of about 50% over 120 h. Furthermore, it
34
35
17 markedly improved the proliferation and osteogenic differentiation of C2C12 myoblasts. The use of
36
18 biodegradable CPs for bone tissue engineering has also been reported in one of the latest studies, in
37
38
19 which a block copolymer comprising PCL and aniline tetramer (AT-PCL polymer) was first
39
40
20 electrospun and then processed into a fibrous scaffold.94 The increasing addition of aniline tetramer
41
42
21 considerably reduced the sheet resistance of the AT-PCL composite from 2.47 × 107 to 3.0 × 106
43
44
22 Ω/square, revealing an enhanced electrical conductivity. Importantly, this polymeric composite
45
46
23 demonstrated an excellent biocompatibility and promoted the proliferation and osteogenic
47
48
24 differentiation of MC3T3-E1 precursor cells.
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50
25 Similarly, using the electroactive aniline tetramer, a biodegradable conducting shape memory
51
52 26 polymer structure has been assembled for accelerating the myogenic differentiation of myoblasts for
53
54 27 skeletal muscle tissue regeneration (Figure 7).68 Here, the four-armed PLA was first processed to
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56 28 acquire the ductile hyperbranched PLA (HPLA), and then copolymerized with the amino-capped
57
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20
59
1
2
3 1 aniline tetramer to generate a range of electroactive biodegradable copolymers HPLAAT (Figure 7A).
4
5 2 The amount of aniline tetramer in the HPLAAT copolymers was fixed at 3%, 6%, 9%, and 12% and
6
7 3 the resultant copolymers were termed as HPLAAT3, HPLAAT6, HPLAAT9, and HPLAAT12,
8
9 4 respectively. The thermal stability of the different HPLAAT copolymers was then examined (Figure
10
11 5 7B). While the four-armed PLA degraded thermally at a temperature range between 210 and 290 oC,
12
13 6 the thermal degradation of HPLA occurred between 200 and 280 oC. However, the inclusion of
14
15 7 aniline tetramer into HPLA altered the thermal degradation profiles of the resultant HPLAAT
16
17 8 copolymers. In fact, all HPLAAT copolymers displayed an improved thermal stability, in which their
18
19 9 thermal degradation occurred in two phases, i.e., from 250 to 320 oC and then from 320 to 330 oC.
20
21 10 Subsequent to their thermal degradation profiles, the enzymatic degradation behaviours of all
22
23 11 polymeric structures in proteinase K solution at 37 oC were evaluated (Figure 7C). Interestingly, the
24
25 12 HPLAAT copolymers displayed a slower degradation rate than HPLA, suggesting that the inclusion
26
27 13 of aniline tetramer reduced the enzymatic degradation rate of the copolymers. More clearly, while
28
29 14 HPLA had weights of about 52 and 35% at 24 and 72 h, respectively, higher weights of 78 and 55%
30
31 15 were still retained by HPLAAT3 at the same time points. Further addition of aniline tetramer,
32
33
16 nevertheless, only led to slight decrease in the degradation rate, with similar degradation profiles
34
35
17 showed by HPLAAT6, HPLAAT9, and HPLAAT12. Eventually, the influence of the biodegradable
36
18 electroactive HPLAAT on the cellular behaviours of C2C12 myoblasts was assessed (Figure 7D).
37
38
19 The myoblasts were cultured on the HPLA and HPLAAT substrates for 7 days in the presence of
39
40
20 differentiation medium. It was observed that HPLAAT improved the proliferation and myogenic
41
42
21 differentiation of the myoblasts considerably as compared to HPLA. This was evident from the higher
43
44
22 amount of myotubes (in green) formed on HPLAAT than on HPLA. Quantitative evaluation of the
45
46
23 myotube maturation index, i.e., ratio of the amount of myotubes with nuclei greater than five to the
47
48
24 total amount of myotubes, further confirmed the enhanced myogenic differentiation on HPLAAT.
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28 2 Figure 7. Biodegradable CP for enhanced skeletal muscle regeneration. (A) Synthetic route to biodegradable CP,
29
30 3 i.e., hyperbranched polylactide copolymerized with aniline tetramer (HPLAAT). (B) Thermogravimetric
31
32 4 analysis (TGA) curves of different polymers, i.e., biodegradable PLA and HPLA, and biodegradable
33
34 5 electroactive HPLAAT with varying contents of aniline tetramer. (C) Decomposition profiles of HPLA and
35
6 HPLAAT with varying contents of aniline tetramer over time. (D) C2C12 myoblasts cultured on different
36
37 7 HPLA and HPLAAT polymeric substrates: (a) HPLA, (b) HPLAAT3, (c) HPLAAT6, (d) HPLAAT9, and (e)
38
39 8 HPLAAT12, in the presence of differentiation medium for 7 days. Tubulin and nuclei of the cells are stained in
40
41 9 green and blue, respectively. Scale bars represent 200 µm. Reprinted from ref.68 Copyright 2015, with
42
43 10 permission from Elsevier.
44
45 11
46
47 12 More recently, a study has reported the significant improvement of the myelin gene
48
49 13 expression and neurotrophin secretion of Schwann cells, via the use of conducting biodegradable
50
51
14 copolymer films, which was then utilized to enhance the peripheral nerve growth and regeneration of
52
15 neuronal cells (Figure 8).72 Here, the polycondensation of glycerol, sebacic acid, and aniline
53
54
16 pentamer was first employed to prepare the prepolymer poly(glycerol sebacate)-co-aniline pentamer
55
56
17 (PGSAP) (Figure 8A). The crosslinking of PGSAP with hexamethylene diisocyanate was then used
57
58
22
59
1
2
3 1 to generate the conducting PGSAP-H polyurethane films, with electrical conductivity ranging from
4
5 2 1.4 × 10-6 to 8.5 × 10-5 S/cm. Subsequent to the preparation of PGSAP-H polyurethane, the enzymatic
6
7 3 biodegradation profiles of the copolymer films were assessed in PBS in the presence of lipase enzyme
8
9 4 at 37 oC. All PGSAP-H polyurethane films displayed lower degradation rates and had lower weight
10
11 5 loss as compared to the control PGS-H film. Furthermore, with an increasing aniline pentamer content
12
13 6 from 5 to 15%, the average degradation rate of PGSAP-H polyurethane films reduced considerably
14
15 7 from 1.39 to 0.06% per hour. While PGS-H film had an average weight loss of 85% over 48 h,
16
17 8 PGSAP-H with 15% aniline pentamer still retained about 83% of its original weight after the
18
19 9 degradation process for 336 h. This suggests that the degradation rates of the PGSAP-H copolymer
20
21 10 films could be tuned by varying their amount of aniline pentamer. After establishing the degradation
22
23 11 profiles of the copolymer films, their effect on the neurite growth and elongation of PC12 cells was
24
25 12 studied. The RSC96 Schwann cells were first seeded for several days on different substrates, i.e.,
26
27 13 tissue culture polystyrene (TCP), PGS-H, and PGSAP-H, and the neurotrophin-filled media were then
28
29 14 transferred to replace the original media in which PC12 cells were cultured. The normal medium in
30
31 15 the absence of nerve growth factor (NGF) (NM) was used as negative control, whereas the normal
32
33
16 medium in the presence of NGF (NM+NGF) as well as the NGF-included medium on TCP
34
35
17 (TCP+NGF) served as positive controls. The neuronal cells were cultured for several more days in the
36
18 neurotrophin-filled media and their neurite outgrowth and elongation profiles were subsequently
37
38
19 analyzed (Figures 8B to 8D). Intriguingly, the neuronal cells cultured on PGSAP-H film exhibited a
39
40
20 large number of neurites with an average length of about 50 µm, which was similar to those observed
41
42
21 from the NM+NGF and TCP+NGF groups, but much longer than those found on TCP and PGS-H
43
44
22 film (Figures 8B and 8C). More clearly, the neurite lengths of the neuronal cells cultured on PGSAP-
45
46
23 H film and the positive control groups ranged from 40 to 60 µm or even beyond 60 µm, while those
47
48
24 found on TCP and PGS-H film were mostly between 0 and 40 µm (Figure 8D). Together, these
49
50
25 results show that the biodegradable conducting PGSAP-H polyurethane films could promote the
51
52 26 neurotrophin secretion of Schwann cells, which in turn, could be used to enhance the neurite growth
53
54 27 and elongation of neuronal cells.
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41 1
42 2 Figure 8. Biodegradable CP for enhanced peripheral nerve regeneration. (A) Synthetic routes to the conducting
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44 3 poly(glycerol sebacate)-co-aniline pentamer (PGSAP) prepolymer and the biodegradable electroactive PGSAP-
45
46 4 H polyurethane films. PGSAP prepolymer was first prepared through the polycondensation of aniline pentamer,
47
48 5 glycerol, and sebacic acid. The crosslinking of the prepolymer with HDI would generate the PGSAP-H
49
6 polyurethane film. (B) Optical microscopy images of PC12 cells cultured on different substrates under different
50
51 7 culture conditions. The yellow arrows indicate the neurites. Scale bars represent 50 µm. (C) The corresponding
52
53 8 neurite length of PC12 cells cultured on different substrates under different culture conditions. (D) Neurite
54
55
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24
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1
2
3 1 length distribution of PC12 cells in each culture condition. * represents statistically significant difference for P
4
2 < 0.05. Reprinted from ref.72 Copyright 2016, with permission from Elsevier.
5
6
3
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4 4.2. Biomedical Imaging
9
10
5 In recent years, explorations into the potential biomedical applications of biodegradable CPs have
11
12 6 extended beyond the field of tissue engineering and regenerative medicine into biomedical imaging.75,
13
14 7 95, 96
As one of the emerging bioapplications of biodegradable CPs, biomaging plays a central role in
15
16 8 the development of biology and medicine.97-99 This is because biomedical imaging enables the real-
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18 9 time monitoring and elucidation of various physiological processes and pathological mechanisms.100-
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20 10
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At the same time, more precise and effective disease diagnosis and prognosis are increasingly
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22 11 made possible because of the development of advanced biological imaging techniques.103, 104
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24 12 Although a plethora of exogenous contrast agents has been developed for biomedical imaging,
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26 13 most of these structures are largely non-biodegradable.105-108 The non-biodegradable characteristic of
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28 14 these contrast agents may pose significant health and safety concerns as they will tend to accumulate
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30 15 in major organs and experience an extended in vivo stay, triggering inflammatory response and other
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32 16 adverse biological effects.109-113 This will considerably limit the in vivo imaging applications of non-
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34 17 biodegradable exogenous contrast agents. As a result, recent efforts have been geared towards
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36 18 developing exogenous imaging probes with high brightness and contrast, excellent biocompatibility,
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38 19 and importantly, controlled biodegradability.
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40 20 With their rigid hydrophobic backbone, flexible side chains, and strong intrinsic fluorescence,
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42 21 CPs have recently been exploited as effective imaging probes capable of providing high signal-to-
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44 22 noise ratio and excellent imaging contrast.40, 114-116 This is because the rigid hydrophobic backbone of
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46 23 CPs can regulate their interactions with target biological entities and facilitate their cellular uptakes.
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48 24 Also, the side chains of CPs can be easily functionalized to enhance their water dispersibility and
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50 25 specific molecular targeting capability. Additionally, the extremely photostable intrinsic fluorescence
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52 26 feature of CPs can be used for the long-term tracking of various cellular and physiological
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54 27 processes.117-119 The development of biodegradable CPs lately has also fueled further the interests in
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56 28 their biomedical imaging applications. In fact, intracellularly degradable CPs with smaller fragments
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3 1 have been shown to possess enhanced selective targeting and imaging capabilities.95 Moreover, the
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5 2 degree of biodegradability of CPs can be controlled by incorporating and varying the amount of
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7 3 flexible degradable linkers within CPs. This has been illustrated in a recent work where a series of
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9 4 biodegradable PPEs with controlled backbone flexibility was prepared by varying the quantity of
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11 5 biodegradable disulfide-containing monomeric linkers integrated into the aromatic PPE backbone.120
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13 6 Similarly, based on the disulfide-containing CPs, a recent work has demonstrated the
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15 7 preparation, selective targeting, and enhanced localization of biodegradable CPNs into the
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17 8 mitochondria of HeLa cancer cells (Figure 9).95 Here, biodegradable nanoparticles (i.e., CPN-1) were
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19 9 generated based on a self-assembly process of CPs, whose backbone was modified with flexible
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21 10 disulfide monomeric linkers (i.e., PPE-1) (Figure 9A). This backbone modification was anticipated to
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23 11 change the self-assembly and cellular entry pathway of the CPNs. As control, CPs without degradable
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25 12 linkers (i.e., PPE-2) and the resultant non-degradable CPNs (i.e., CPN-2) were also prepared. Both
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27 13 CPNs were able to be internalized by HeLa cancer cells. However, in contrast to the non-degradable
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29 14 CPN-2, CPN-1 was noted to disassemble and degrade intracellularly into conjugated oligomers with
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31 15 low molecular weight. These fluorescent conjugated oligomers were then effectively used to label
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16 mitochondria. In fact, CPN-1 displayed a high specific mitochondrial co-localization based on its high
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17 Pearson’s correlation coefficient (PCC) value of 0.89, which is a quantitative metric signifying co-
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18 localization. CPN-2, in contrast, displayed a low PCC value of 0.26 and a low mitochondrial co-
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19 localization. Both CPNs were subsequently functionalized with hyaluronic acid (HA) to improve their
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20 hydrophilicity. Similar to the unfunctionalized nanoparticles, the biodegradable CPN-1/HA and non-
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21 biodegradable CPN-2/HA complexes exhibited high and low mitochondrial co-localizations,
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22 respectively, based on their PCC values (i.e., 0.78 and 0.37, respectively) (Figure 9B). Fluorescence
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23 spectroscopic evaluation of the mitochondria of live HeLa cancer cells was further utilized to confirm
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24 the selective mitochondrial co-localization of CPN-1 (Figure 9C).
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2 Figure 9. Biodegradable CP for intracellular targeting and labeling application. (A) Schematic showing the
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26 3 chemical structures of CPs PPE-1 and PPE-2 with and without biodegradable linkers, respectively, and the
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28 4 cellular entry of their respective nanoparticles CPN-1 and CPN-2. (B) Fluorescence microscopy images
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30 5 illustrating HeLa cancer cells incubated with CPN/HA (in green). The mitochondria of HeLa cells were stained
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32 6 in red while their nuclei were stained in blue. Scale bars represent 20 µm. (C) Fluorescence intensity of the
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7 mitochondria and cytosol of the CPN-treated HeLa cells. Reproduced from ref.95 with permission of The Royal
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35 8 Society of Chemistry.
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37 9 http://dx.doi.org/10.1039/c6cc00810k
38 10
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40 11 In another work highlighting the biomedical imaging application of biodegradable CPs,
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42 12 biodegradable and highly fluorescent CPNs were prepared via the integration of degradable imidazole
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44 13 units into the backbone of fully conjugated thiophene (Figure 10).75 Specifically, the uniformly
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46 14 distributed biodegradable CPNs were synthesized using the Sonogashira dispersion polymerization of
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48 15 thiophene with imidazole monomers (Figure 10A). The thiophene monomer unit was complexed with
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50 16 different side groups, either methoxy (i.e., OMe for P1) or oligoethyleneoxy (i.e., OEG for P3) side
51
52 17 groups. The nanoparticles were noted to have rough surface and uniform size of about 200 nm. As
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54 18 controls, the thiophene monomer was also co-polymerized with benzene monomer to generate non-
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56 19 biodegradable nanoparticles P2 and P4, with hydrodynamic diameters of 492 nm and 574 nm,
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1
2
3 1 respectively. Subsequent to the nanoparticle preparation, the biodegradability of these nanoparticles,
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5 2 particularly P1, were examined by exposing them to ROS (i.e., H2O2 in water). In accordance to
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7 3 imidazole oxidation, the nanoparticles were anticipated to decompose after exposure to ROS (Figure
8
9 4 10B). It was observed that after exposure to 20 µM H2O2 for 48 h, the turbid nanoparticle solution
10
11 5 turned transparent. The dynamic of the biodegradation process of P1 nanoparticles was then
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13 6 monitored using a confocal fluorescence microscopy (Figure 10C). Interestingly, the fluorescent
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15 7 nanoparticles decomposed and disappeared completely after only 12 min. Finally, the biodegradability
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17 8 profile of all prepared nanoparticles were evaluated in the presence of ROS-producing macrophages
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19 9 stimulated by lipopolysaccharides in the cell culture (Figure 10D). Impressively, even at the low ROS
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21 10 concentration produced by the activated macrophages, both P1 and P3 nanoparticles degraded with
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23 11 the complete disappearance of their fluorescence after 11.5 h. However, the OEG-functionalized P3
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25 12 nanoparticles were noted to have a faster degradation rate than the OMe-functionalized P1
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27 13 nanoparticles probably due to the OEG-enhanced solubility of P3 nanoparticle fragments in solutions.
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29 14 The non-degradable P2 and P4 nanoparticles, on the other hand, did not disintegrate over the course
30
31 15 of observation. In short, this work has illustrated that fully biodegradable CPNs at biologically
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16 relevant ROS concentrations can be achieved through the incorporation of imidazole units and the
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17 resultant fluorescent CPNs can be potentially used for highly sensitive biomedical imaging.
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2 Figure 10. Biodegradable CP for biomedical imaging application. (A) Synthetic route to degradable and non-
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50 3 degradable CP nanoparticles (CPNs). Biodegradable CPNs P1 and P3 were obtained through the Sonogashira
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52 4 dispersion polymerization of the monomers of thiophene with imidazole, while polymerization of the monomers
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54 5 of thiophene with benzene resulted in non-degradable CPNs P2 and P4. The thiophene monomer was
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56 6 functionalized with either methoxy (i.e., OMe) or oligoethyleneoxy (i.e., OEG) side groups. (B) Schematic
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3 1 illustrating the reactive oxygen species (ROS)-mediated decomposition process of the imidazole-based
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2 biodegradable CPNs. (C) Time-dependent decomposition process of the imidazole-based biodegradable CPNs
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6 3 P1 exposed to H2O2 solution, as evidenced through: (a) confocal fluorescence microscopy and (b) brightfield
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8 4 images. Scale bars represent 20 µm. (D) Evaluation of the time-dependent degradation process of the four
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10 5 fluorescent CPNs: (a) OMe-functionalized degradable P1, (b) OMe-functionalized non-degradable P2, (c) OEG-
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12 6 functionalized degradable P3, and (d) OEG-functionalized non-degradable P4 CPNs, in the presence of H2O2-
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7 producing macrophages using confocal fluorescence microscopy. Macrophages (in blue) were treated with the
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15 8 degradable and non-degradable OMe- and OEG-functionalized CPNs (indicated by white arrows). Scale bars
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17 9 represent 35 µm. Reprinted from ref.75 under a Creative Commons Attribution 4 International License
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19 10 https://creativecommons.org/licenses/by/4.0/ Copyright 2017 Repenko et al.
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21 11
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23 12 4.3. Biomedical Implants, Bioelectronic Devices, and Consumer Electronics
24
25 13 The synergistic combination of outstanding electrical conductivity and tunable biodegradability of
26
27 14 biodegradable CPs has also been progressively exploited for their potential applications in biomedical
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29 15 implants, bioelectronics devices, sensors, and consumer electronics.53, 76, 121, 122 With their attractive
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31 16 morphological and biophysicochemical properties, biodegradable CPs are poised to play a crucial role
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33 17 in solving some of major challenges in these fields. One of these challenges revolves around the
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35 18 health and environmental impacts of electronic devices.123, 124 With the escalating concerns on the
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37 19 safety and toxicity of electronic devices towards human health, whether when they are used as
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39 20 biomedical implants or after they are discarded at the end of their lifetimes, there have been growing
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41 21 attentions on the development of transient and temporary devices which will undergo full degradation
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43 22 over a specific period of time.125-127
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45 23 The rise of temporary biomedical implants and their associated components in recent years is
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47 24 a great testament to the major shift in focus in the development of electronic devices.128, 129 In general,
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49 25 implantable biomedical devices and their associated components, such as implantable biosensors,
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51 26 power sources, and resonators, are highly beneficial for health monitoring as well as disease diagnosis
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53 27 and therapy.130-137 Consequently, they have found increasing healthcare and biomedical applications.
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28 To realize temporary biomedical implants which will further augment the strengths of the existing
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3 1 permanent implants while at the same time, addressing their long-term safety issues, active efforts
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5 2 have been channeled towards designing a class of biomedical implants which can be degraded
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7 3 gradually and excreted from the human body in a programmed manner at the end of their intended use.
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9 4 This is highly desirable as a complete biodegradability will effectively minimize the need for surgical
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11 5 removal of the implants, reduce the risks of infections, and at the same time, improve the life quality
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13 6 of patients. Therefore, there have been intensive quests into suitable basic building blocks of the
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15 7 various components of biodegradable implants. Interestingly, biodegradable CPs and their associated
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17 8 composites have emerged as promising candidates for constructing biodegradable medical implants
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19 9 and bioelectronic devices.138-140
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21 10 For example, biodegradable CPs have been exploited for the fabrication of an all-polymer and
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23 11 biodegradable electrical RLC resonator circuit (i.e., electrical circuit consists of resistor (R), inductor
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25 12 (L), and capacitor (C)) driven by radio frequency.121 This RLC resonator could be potentially used for
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27 13 constructing biodegradable biomedical implants and bioelectronic devices. Here, two different
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29 14 blended biodegradable CP composites comprising PPy nanoparticles embedded in biodegradable
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31 15 PLLA and PCL polymer matrices, i.e., PLLA-PPy and PCL-PPy composites, were synthesized and
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16 recognized as suitable building blocks of all-polymer RLC resonators. The lowest electrical resistivity
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17 of 4.3 × 10-1 and 1.6 × 10-1 Ω-cm could be achieved for PLLA-PPy and PCL-PPy, respectively, when
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18 both composites were incorporated with 39% PPy. Separately, based on a silk fibroin-polypyrrole
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19 (SF-PPy) composite, a recent work has demonstrated the development of a partially biodegradable
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20 magnesium-air bioelectric battery.53 Architecturally, this bioelectric battery consists of a bioresorable
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21 Mg alloy-based anode and a cathode made of the biodegradable SF-PPy film. It was noted that the
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22 biocompatible SF-PPy film incorporated with 3.9% PPy possessed a sheet resistance in the order of 1
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23 × 103 Ω/square, an electrical conductivity of about 1.1. S/cm, and a moderate oxygen reduction
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24 catalytic activity. Also, after a 15-day incubation in a buffered protease solution, the SF-PPy
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25 composite disintegrated with an 82% weight loss. This has further realized the vision of a
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52 26 biodegradable implantable bioelectric battery, which can serve as an external energy source to power
53
54 27 the effective operation of implantable biodegradable electronics.
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3 1 Similarly, using the biocompatible and fully biodegradable silk fibroin as the flexible
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5 2 supporting substrate, a micropatterned silk-CP biosensor has been fabricated via a photolithography
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7 3 process (Figure 11).122 Here, a water-based photoreactive conductive ink was first prepared by
8
9 4 blending poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (i.e., PEDOT:PSS) with sericin
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11 5 protein photoresist (i.e., SPP) (Figure 11A). The SPP-PEDOT:PSS ink was then coated on a fibroin
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13 6 protein photoresist- (FPP)-coated film to initiate the fabrication process of a flexible and
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15 7 biodegradable biosensor. This conductive ink was subsequently crosslinked to form the desired
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17 8 micropatterns through a photomask-mediated UV light exposure and the un-crosslinked ink was
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19 9 removed in water. In fact, the large-area PEDOT:PSS microstructures with the smallest feature size of
20
21 10 about 5 µm could be fabricated on a flexible silk fibroin sheet or glass (Figure 11B). Along with an
22
23 11 increasing content of PEDOT:PSS from 11 to 50%, the SPP-PEDOT:PSS ink displayed a reduced
24
25 12 average resistivity from 39 to 1 Ω-cm. To evaluate its biodegradability profile, the SPP-PEDOT:PSS
26
27 13 on FPP biosensor was incubated in an enzymatically active protease solution at 37 oC for a few weeks.
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29 14 Both the SPP matrix and FPP film fully degraded in the protease solution after 4 weeks. While the
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31 15 biocompatible PEDOT:PSS is not biodegradable, by blending it with SPP, the PEDOT:PSS
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16 component of the eventual microstructures experiencing proteolytic degradation could be lost as fine
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17 fibrous strands. Subsequent to confirming the biodegradability of the SPP-PEDOT:PSS on FPP film,
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18 its performance as a highly selective glucose biosensor was demonstrated (Figure 11C). Glucose
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19 oxidase (GOx) enzyme was first functionalized on the surface of the micropatterned silk-CP biosensor
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20 to realize the glucose biosensor. The GOx-immobilized biosensor exhibited a linear response against
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21 all the tested glucose concentrations as well as an excellent selectivity by detecting only glucose, but
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22 not other tested sugars, including fructose, galactose, and sucrose. The sensor also had a high
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23 structural stability, conformability, and could be potentially used as a wearable biosensor.
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2 Figure 11. Biodegradable CP for biosensing application. (A) Schematic illustrating the fabrication process of a
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25 3 large-area conducting PEDOT:PSS microstructure on a flexible substrate. (B) Large-area PEDOT:PSS
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27 4 microstructures fabricated on different substrates: (a) flexible silk fibroin sheets, as evidenced through optical
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29 5 photographs, and (b-c) glass, as evidenced through: (b) optical micrograph and (c) SEM image. Scale bar
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31 6 represents 100 µm. (C) Current variation of the microfabricated SPP-PEDOT:PSS glucose biosensor as a
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7 function of glucose concentration. Inset demonstrates the high selectivity of the biosensor towards glucose, but
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34 8 not other forms of sugars, such as fructose, galactose, and sucrose. Reprinted from ref.122 Copyright 2016, with
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36 9 permission from Elsevier.
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38 10
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40 11 Beyond biomedical implants and bioelectronics device, the emerging concept of transient
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42 12 electronics has greatly influenced consumer electronics. In fact, the development of transient
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44 13 consumer electronics with controlled degradability has been actively emphasized in recent years due
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46 14 to the sharp escalation in the already colossal demands in consumer electronics in the last decade.126
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48 15 These growing demands have been partly fueled by an evolving trend in the utilization of consumer
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50 16 electronics, particularly smartphones, tablets, and smart watches, as portable and wearable devices for
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52 17 real-time health monitoring and other daily activities.141-143 Unfortunately, all these factors have
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54 18 inevitably contributed to the shorter consumer electronic use lifetimes as well as the exponential
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56 19 growth of electronic waste. As conventional consumer electronics are largely not biocompatible and
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3 1 biodegradable, the resultant electronic waste will certainly pose severe ecological and health issues.123,
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5 2 To mitigate these ecological challenges, green electronics with zero footprint have been widely
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7 3 promoted and explored in the last few years.125-127
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9 4 One of the key directions in the quest to realize green electronics is to identify the most
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11 5 suitable fundamental building blocks of these electronics. This has greatly motivated the design and
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13 6 development of novel electroactive, biocompatible, and environmentally benign biodegradable CPs,
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15 7 which can be prepared from natural resources and decomposed back to the environment. In one of the
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17 8 most recent examples demonstrating this effort, biocompatible and fully disintegrable CPs (i.e.,
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19 9 PDPP-PD) were fabricated using imine chemistry and used as a component to develop totally
20
21 10 decomposable transient thin-film transistors and organic electronics (Figure 12).76 Here, imine bond
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23 11 was employed as a reversible conjugated linker, which is generally stable under conditions with
24
25 12 neutral pH, but can be hydrolyzed under mild acidic conditions(Figure 12A).76, 78 The biodegradable
26
27 13 conducting PDPP-PD polymer possessed an average hole mobility of about 4.2 × 10-2 – 3.4 × 10-1
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29 14 cm2/V.s. The biodegradability profile of the imine-based PDPP-PD in the presence of acetic acid was
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31 15 examined through changes in its absorption spectrum and solution color (Figure 12B). It was noted
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16 that the peak absorbance at 680 nm reduced considerably after 3 h and disappeared after 10 days.
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17 Furthermore, during this period, the originally blue PDPP-PD solution turned purple. In fact, after a
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18 10-day decomposition, both PDPP-PD and its monomer DPP-CHO had similar absorption spectrum
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19 and solution color. The purple PDPP-PD solution eventually turned completely transparent after 40
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20 days, suggesting the full disintegration of PDPP-PD in acidic condition. In addition to the solution
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21 form, the CPs were also biodegradable in a solid-state form. While a large number of the currently
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22 demonstrated disintegrable organic electronics have made use of gold as their electrode material, gold
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23 is generally not decomposable. In this work, instead of gold, iron was utilized as both the source-drain
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24 and gate electrode material to fabricate an ultralight, fully disintegrable, and transient electronic
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25 circuit (Figure 12C). Impressively, upon exposure to a mildly acidic environment, the iron electrodes
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52 26 degraded fast within an hour (Figure 12D). Beyond 30 days, other components of the electronic
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54 27 circuit, particularly CPs, alumina, and cellulose substrate, were noted to be fully degraded, illustrating
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56 28 the further realization of totally biodegradable and transient electronics.
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24 2 Figure 12. Biodegradable CP for bioelectronics application. (A) Schematic of a flexible device where
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26 3 degradable polymer PDPP-PD serves as the active component of the device. (B) Absorbance of the polymer
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28 4 PDPP-PD undergoing degradation over time. Inset shows the optical photographs of the polymer solution before
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30 5 and after degradation for 10 and 40 days. (C) Schematic of the structure of a totally disintegrable electronic
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6 device with its individual components. (D) Optical photographs showing the degradation process of the
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33 7 electronic device over time. Scale bars represent 5 mm. Reprinted with permission from ref.76 Copyright 2017
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35 8 National Academy of Sciences of the United States of America.
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5 1 Table 1. Electrical properties, biodegradability, and potential biomedical applications of some of the biodegradable CP-based structures highlighted in this article.
6 Biodegradable Distinct Features of the Electrical Electrical sheet Degradability Weight Loss Potential Biomedical References
7 CP-based Synthesis of conductivity resistance Test Duration * Over Test Applications
8 Structures Copolymers (S/cm) (Ω/square) Duration *
30
9 PPy-PLGA Polymer blending/coating N.A. 7.4 × 103 – 2 weeks N.A. Neural tissue engineering
10 nanofibers 9.0 × 104
11 PPy-PLA Polymer blending/coating 1 × 10-6 – N.A. 12 weeks 14 – 24% Tissue engineering 51
-4
12 nanofibers 1 × 10
54
13 PEDOT-PLGA Polymer blending/coating 7.0 × 10-2 – N.A. N.A. N.A. Neural tissue engineering
14 microfibers 2.8 × 10-1
15 GP hydrogels Polymer grafting 4.54 × 10-4 – N.A. 21 days 50 – 60% Tissue engineering 55
16 2.41 × 10-4
17 5.5 × 10-8 – 1.2 × 59
DCPU films Aniline trimer N.A. 8 weeks 12 – 14% Tissue engineering and
18 incorporation 10-5 (dry state); (hydrolytic (hydrolytic soft/stretchable/wearable
19 4.4 × 10-7 – 4.7 × degradation); 14 degradation); electronics
20 10-3 (wet state) days (enzymatic 25% (enzymatic
degradation) degradation)
21
PGAP films Aniline pentamer 2 × 10-5 N.A. 70 days 50% Nerve tissue engineering 62
22 incorporation
23 DECPH films Aniline tetramer 3.13 × 10-8 – N.A. 48 h 13 – 14% Cardiovascular tissue 70
24 incorporation 2.94 × 10-4 engineering and controlled
25 drug delivery
26 DEC hydrogels Aniline tetramer 4.69 × 10-7 – N.A. N.A. N.A. Tissue engineering and 71
27 incorporation 1.05 × 10-4 drug delivery

28 Modified PPy β-substituted pyrrole N.A. N.A. 24 h ~ 100% Tissue engineering 73
29 thin films + monomer incorporation

30 Modified PPy β-substituted pyrrole N.A. N.A. 80 days 6 – 27% Tissue engineering 73
31 pellets monomer incorporation

32 SPT-PEI films Modified thiophene 7.82 × 10-3 – N.A. 83 – 130 days ~ 100% Tissue engineering 74
33 monomer incorporation 2.76 × 10-2

75
34 Thiophene-based Degradable imidazole N.A. N.A. 11.5 h ~ 100% Biomedical imaging
35 CP nanoparticles unit incorporation
36 PDPP-PD films # Incorporation of imine N.A. N.A. 40 days (in ~ 100% (in Green electronic devices 76
bond as degradable solution form) solution form)

37
conjugated linker
38 PHAT hydrogels Aniline trimer N.A. N.A. 120 h 50% Bone tissue engineering 67
39 incorporation
40
41 36
42
43
44
46
47
1
2
3
4
5 AT-PCL fibers Aniline tetramer N.A. 3.0 × 106 – N.A. N.A. Bone tissue engineering 94
6 incorporation 2.47 × 107

68
7 HPLAAT films Aniline tetramer N.A. N.A. 72 h 40 – 45% Muscle tissue engineering
8 incorporation
9 PGSAP-H Aniline pentamer 1.4 × 10-6 – N.A. 96 – 336 h 17 – 80% Peripheral nerve tissue 72
polyurethane incorporation 8.5 × 10-5 engineering

10
films
11 SF-PPy films Polymer blending/coating 1.1 1 × 103 15 days 82% Biodegradable bioelectric 53
12 battery
13 SPP- Polymer blending/coating N.A. N.A. 4 weeks N.A. Biosensing 122
14 PEDOT:PSS on
15 FPP films ^
16 1 Notes:
17 2 N.A. indicates data not available.
18 3 * Degradability tests here evaluated the in vitro hydrolytic and/or enzymatic degradation of biodegradable CPs at 37 oC.
19 4 + Modified PPy thin films had an average resistance of about 300 Ω.
5 # PDPP-PD films had a hole mobility of 4.2 × 10-2 – 3.4 × 10-1 cm2/V.s.
20
6 ^ SPP-PEDOT:PSS films had average resistivity of about 1 – 39 Ω-cm.
21 7
22
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41 37
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1
2
3 1 5. CONCLUSIONS AND FUTURE PERSPECTIVES
4
5 2 With their highly π-conjugated molecular backbone and versatile side chains, CPs exhibit numerous
6
7 3 outstanding physicochemical properties, primarily excellent electrical conductivity, water
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9 4 dispersibility, and biocompatibility. As emphasized in this article, while these unique organic
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11 5 materials are increasingly sought after and have tremendous game-changing potential to augment
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13 6 numerous applications, their translation into practical biomedical and clinical applications is still
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15 7 restricted by many factors, with biodegradability being one of the main Achilles’ heel.
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17 8 Biodegradability, in fact, plays a crucial role in enabling the effective in vivo biomedical applications
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19 9 of CPs. This is because after being introduced into a physiological environment and accomplishing
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21 10 their intended objectives, such as to serve as temporary tissue scaffolds or transient biomedical
22
23 11 implants, CPs need to be gradually degraded. Unfortunately, failure to undergo degradation will
24
25 12 undeniably lead to the accumulation and prolonged in vivo stay of CPs, potentially prompting
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27 13 undesirable inflammatory response and consequent adverse effects. To overcome this major drawback,
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29 14 ongoing efforts have been focused on the development of biocompatible CPs with inherent
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31 15 biodegradable feature. While a plethora of CPs with varying degree of biodegradability has been
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33 16 demonstrated in the last decade, there still exist major challenges, in terms of synthesis and
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35 17 applications, which prevent these biodegradable CPs from reaching their fullest potential.
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37 18 The first major challenge involves the synthesis of biodegradable CPs, specifically in the
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39 19 optimization of their electrical conductivity and biodegradability. To date, it is still challenging to
40
41 20 retain the conductivity of biodegradable CPs and at the same time, ensure their biodegradability for
42
43 21 practical applications. One of the main reasons behind this obstacle is that, in contrast to those of non-
44
45 22 conjugated degradable polymers, the molecular building blocks of biodegradable fully conjugated
46
47 23 CPs are highly limited. To overcome this, one could possibly look more into diversifying the
48
49 24 macromolecular architectures and biodegradable linkers used to assemble decomposable CPs in order
50
51 25 to optimize their conductivity and biodegradability. Alternatively, one might possibly take a leaf from
52
53 26 nature in rationally identifying other more potent fundamental building blocks or biodegradable
54
27 linkers, similar to those previously illustrated work in identifying and employing the biodegradable
55
56
57
58
38
59
1
2
3 1 imidazole unit75 or imine bond,76 in developing the next-generation biodegradable CPs. It is therefore
4
5 2 clear that the current library of the biodegradable CPs still needs a significant expansion in order to
6
7 3 cater to the demands of specific biomedical applications.
8
9 4 Another major challenge is associated with the biomedical applications of biodegradable CPs,
10
11 5 particularly for tissue engineering applications. Although literature has been filled with reports on the
12
13 6 applications of biodegradable CPs for enhancing the adhesion, proliferation, and differentiation of
14
15 7 electroresponsive cells and tissues, both the in vitro and in vivo biodegradation profiles of these
16
17 8 polymeric structures, are still pretty much unknown. In fact, how well the temporary CP-based
18
19 9 scaffolds degrade, either when the cells or tissues are still being supported or when they have repaired
20
21 10 themselves and regenerated, as well as how well the cells and tissues integrate with their surrounding
22
23 11 microenvironment before and after the decomposition of the temporary scaffolds, still largely remain
24
25 12 a mystery. Intriguingly, all these aspects have not been really elucidated and understood and they are
26
27 13 definitely worth the explorations.
28
29 14 Separately, an exciting emerging area of applications of biodegradable organic CPs is
30
31 15 bioelectronics and consumer electronics. The escalating demands for electronic devices with
32
33
16 enhanced performance, coupled with the shorter lifetime of electronic devices and the exponential
34
35
17 growths of non-biodegradable solid electronic waste, bring with them many ecological and
36
18 environmental problems. Biodegradable CPs are in a unique position and well-suited to disrupt the
37
38
19 current trend. Encouragingly, they possess tremendous potential and an enviable role to realize
39
40
20 sustainable and green electronics in order to address the emerging ecological challenges. As such, the
41
42
21 exciting opportunity available to biodegradable CPs for advancing low-cost transient electronics has
43
44
22 never been greater.
45
46
23 Overall, we foresee a bright future for the synthesis, processing, and biomedical applications
47
48
24 of biodegradable CPs. Although current challenges in realizing the full potential of biodegradable CPs
49
50
25 are aplenty, we believe that these will be overcome swiftly and steadily in the near future along with
51
52 26 the progressive advancements in the material design, synthesis, and characterization techniques. The
53
54 27 future prospect of biodegradable CPs is definitely exciting. We anticipate that, with further progress
55
56 28 in the development of this class of outstanding organic materials, biodegradable CPs are poised to
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59
1
2
3 1 emerge as the game-changing biomaterials capable of augmenting and revolutionizing many practical
4
5 2 applications and ultimately, making a positive impact in the future.
6
7 3
8
9 4 AUTHOR INFORMATION
10
11 5 Corresponding Author
12
13 6 *Email: cheliub@nus.edu.sg. Fax: +65 6779 1936.
14
15 7
16
17
8 Author Contributions
18
19
20 9 The manuscript was written through contributions of all authors. All authors have given
21
22 10 approval to the final version of the manuscript.
23
24 11
25
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Recent Advances in Biodegradable Conducting Polymers and Their Biomedical Applications

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is published by the American Chemical Society. 1155 Sixteenth Street N.W.,

27 incorporation 1.05 × 10-4 drug delivery

29 thin films + monomer incorporation

31 pellets monomer incorporation

33 monomer incorporation 2.76 × 10-2

bond as degradable solution form) solution form)

6 incorporation 2.47 × 107

polyurethane incorporation 8.5 × 10-5 engineering

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