Progress in Polymer Science 37 (2012) 237280

Contents lists available at ScienceDirect

Progress in Polymer Science

journal homepage: www.elsevier.com/locate/ppolysci

Biodegradable synthetic polymers: Preparation, functionalization and

biomedical application
Huayu Tian, Zhaohui Tang, Xiuli Zhuang, Xuesi Chen , Xiabin Jing
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022,
China

a r t i c l e i n f o a b s t r a c t

Article history: Biodegradable polymers have been widely used and have greatly promoted the devel-
Received 8 November 2009 opment of biomedical elds because of their biocompatibility and biodegradability. The
Received in revised form 14 May 2011 development of biotechnology and medical technology has set higher requirements for
Accepted 30 June 2011
biomedical materials. Novel biodegradable polymers with specic properties are in great
Available online 18 July 2011
demand. Biodegradable polymers can be classied as natural or synthetic polymers accord-
ing to the source. Synthetic biodegradable polymers have found more versatile and diverse
Keywords:
Biodegradable
biomedical applications owing to their tailorable designs or modications. This review
Synthetic polymers presents a comprehensive introduction to various types of synthetic biodegradable poly-
Functionalization mers with reactive groups and bioactive groups, and further describes their structure,
Biomedical application preparation procedures and properties. The focus is on advances in the past decade in func-
tionalization and responsive strategies of biodegradable polymers and their biomedical
applications. The possible future developments of the materials are also discussed.
2011 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +86 431 85262112; fax: +86 431 85262112.
E-mail address: xschen@ciac.jl.cn (X. Chen).
Abbreviations: ADR, adriamycin; AP, 1,5-diamino pentane; APEG-DOX, polyacetal-doxorubicin; Apt, aptamers; AS-PNIPAM, amino-semitelechelic
PNIPAM; ASGPR, asialoglycoprotein receptor; ATQD, N-(4-aminophenyl)-N -(4 -(3-triethoxysilyl-propyl-ureido) phenyl-1,4-quinonenediimine); ATRP,
atom-transfer radical polymerization; BAA-NCA, -benzyl aspartic acid N-carboxy-anhydride; BMPCL, -(2-bromo-2-methyl propionyl)--caprolactone;
BECP, biodegradable electrically conducting polymer; BLA-NCA, benzyl-l-aspartate N-carboxyanhydride; BLG-NCA, -benzyl l-glutamate N-carboxy-
anhydride; BTMC, 5-benzyloxy-trimethylene carbonate; CaB, cathepsin B; CaD, cathepsin D; CMMPL, -chloromethyl--methyl--propionolactone; CPP,
cell penetrating peptide; c(RGDfK)-PEG-b-P(Lys-MP), c(RGDfK)-poly(ethylene glycol)-b-poly[-(3-mercaptopropino nyl)-lysine]; CT, computerized axial
tomography; DES, drug-eluting stents; DGBE, diethylene glycol bis(3-amino propyl) ether; DMSO, dimethyl sulfoxide; DOTA, designed macrocyclic 1,4,7,10-
tetraazacyclododecane-N,N ,N ,N  -tetraacetic acid; DOX, doxorubicin; DPT, dipropylene triamine; DTPA-Gd, diethylenetriaminepentaacetic acid Gd; Dtxl,
docetaxel; EGFR, endothelial growth factor receptor; EPR, enhanced permeability and retention; FOL, folic acid; gal-PEG-b-PBLG, galactose-conjugated
poly(ethylene glycol)-co-poly(-benzyl l-glutamate) block copolymer; Gd, gadolinium; GSH, glutathione; HEMA, 2-Hydroxyethylmethacrylate; HEMI,
N-hydroxylethylmaleimide; HO-R1-OH, di-hydroxyl compounds; ICG, indocyanine green; IgG, immunoglobulin G; l-DOPA, l-3,4-dihydroxyphenyl-l-
alanine; LCST, lower critical solution temperature; LP-NCA, l-phenylalanine NCA; M-PCL, maleimido-terminated PCL; M-PLLA, maleimido-terminated
PLLA; MAL-PEG-PCL, maleimide-terminated poly(ethylene glycol)-poly(-caprolactone); MBC, 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one; MBPEC,
mono-4-methoxybenzylidene-pentaerythritol carbonate; MMP-2, matrix metalloprotease-2; MMPs, matrix metalloproteinases; Mn-SPIO, manganese
doped superparamagnetic iron oxide; MP, 4-(3-aminopropyl) morpholine; MP-g-OEI, multi-armed poly(l-glutamic acid)-graft-oligoethylenimine;
mPEG, poly(ethylene glycol) methyl ether; MRI, magnetic resonance imaging; NCA, N-carboxy-anhydride; NGF, neurotrophic growth factors; NHS,
N-hydroxysuccinimide; NIPAM, N-isopropylacrylamide; NIR, near-infrared; NIRF, near-infrared uorescent; NSCLC, non-small cell lung cancer;
P(GA-co-BLG), poly[(l-glutamic acid)-co-(-benzyl l-glutamate)]; PAGA, poly(-(4-aminobutyl)-l-glycolic acid); PArg, polyarginine; PBALG, partially
allylated PBLG; PBCLG, partially chlorinated PBLG; PBLG, poly(-benzyl-l-glutamate); PBN3 LG, partially azidized PBLG; PBPLG, partially propargy-
lated PBLG; Ppy, polypyrrole; PCL, poly(-caprolactone); PCL-b-PBLG, poly(-caprolactone)-b-poly(-benzyl l-glutamate); PDI, polydispersity index;
PEI, polyethylenimine; PEG, polyethylene glycol; PEG-b-PEI, poly(ethylene glycol)-b-polyethyleneimine; PEG-b-P(Glu-DP), poly(ethylene glycol)-b-
poly(glutamic acid); PEG-b-P(LA-co-MCC/dtxel), poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate/docetaxel;
PEG-b-PLA-b-PLG, poly(ethyl glycol)-b-polylactide-b-poly(l-glutamic acid); PEG-P(Asp-Hyd), poly(ethylene glycol)-b-poly(aspartate-hydra zone); PEG-
P(Asp-Hyd-ADR), poly(ethylene glycol)-b-poly(aspartate-hydrazone-adriamycin); PEG-PBLA, poly(ethylene glycol)-poly(-benzyl-l-aspartate); PEGnLSer,
mono- and diethyleneglycol modied PLSer; PET, positron emission tomography; PGS, planar gamma scintigraphy; PHB, poly[(R)-3-hydroxybutyrate];

0079-6700/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.progpolymsci.2011.06.004
238 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2. Biopolymers with reactive groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.1. Aliphatic polyesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.1.1. Aliphatic polyesters with carboxyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.1.2. Aliphatic polyesters with amino groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.1.3. Aliphatic polyesters with chloride groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2.1.4. Aliphatic polyesters with keto or hydroxyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.1.5. Aliphatic polyesters with bromide groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.1.6. Aliphatic polyesters with C C groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.1.7. Aliphatic polyesters with reactive groups by copolymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.2. Polycarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
2.3. Poly(amino acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2.3.1. Poly(acidic amino acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
2.3.2. Poly(basic amino acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
2.3.3. Poly(neutral amino acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.4. Polyphosphoesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.5. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
3. Biopolymers with responsive activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
3.1. Stimuli-responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
3.1.1. Temperature responsive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
3.1.2. pH-responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
3.1.3. Photo responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
3.1.4. Redox responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
3.2. Electroactive biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
3.3. Specic bonding biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
3.4. Biopolymers for tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
3.4.1. Biopolymers for optical tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
3.4.2. Biopolymers for MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
3.4.3. Other biopolymer-based tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4. Biomedical application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4.1. Medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4.1.1. Drug-eluting stents (DES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
4.1.2. Orthopedic devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
4.1.3. Disposable medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
4.1.4. Other medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
4.2. Tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
4.3. Drug delivery and control release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
4.4. Gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
4.4.1. Poly(l-lysine)-based degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
4.4.2. Poly(-amino ester)s-based degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
4.4.3. Polyphosphoester-based degradable polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
4.4.4. Polyethylenimine modied with degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
4.4.5. Degradable polymers in siRNA delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
4.4.6. Other degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
4.5. Bioseparation and diagnostics applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

PHF-b-PEG, poly[(l-histidine)-co-(l-phenylalanine)]-block-poly(ethylene glycol); PLA, poly(lactic acid), polylactide; PLC-b-PLA, poly(l-cysteine)-

b-polylactide; PLCys, poly(l-cysteine); PLCys-b-PLLA, poly(l-cysteine)-b-poly(l-lactide); PLDOPA, poly(l-DOPA); PLDOPA-PLL, poly(l-DOPA)-co-
poly(l-lysine); PLGA, poly(lactide-co-glycolide); PLHis, poly(l-histidine); PLL, poly(l-lysine); PLL-b-PPA, poly(l-lysine)-block-poly(l-phenylalanine);
PLL-co-PArg-b-PLLeu, poly(l-lysine)-co-polyarginine-b-poly(l-leucine); PLL-g-PCL, poly(l-lysine)-g-poly(-caprolactone); PLL-g-PEG, poly(l-lysine)-g-
poly(ethylene glycol); PLL-g-PLLA, poly(l-lysine)-g-poly(l-lactide); PLLA, poly(l-lactide); PLSer, poly(l-serine); PMDETA, pentamethyldiethylene-triamine;
PNIPAM, poly(N-isopropylacrylamide); PNIPAM-b-(HEMA-PCL), poly(N-isopropylacrylamide)-b-[2-hydroxyethyl methacrylate-poly(-caprolactone)];
PNIPAM-b-PGA, poly(N-isopropylacrylamide)-block-poly(glutamic acid); PNIPAM-b-P(GA-co-BLG), PNIPAM-b-poly[(l-glutamic acid)-co-(-benzyl-l-
glutamate)]; PPA, polyphosphoramidate; PPE, polyphosphoester; PPE-EA, poly(2-aminoethyl propylene phosphate); PPZ, polyphosphazene; PS
2, performance status; PSI, polysuccinimide; PTMC-b-PBLG, poly(trimethylene carbonate)-b-poly(-benzyl l-glutamate); p-TSA, p-toluenesulfonic
acid; PZLL-PDGBE-PZLL, poly(-benzyloxycarbonyl l-lysine)-block-poly[diethylene glycol bis(3-amino propyl) ether]-block-poly(-benzyloxycarbonyl
l-lysine); QDs, quantum dots; QD-strep, quantum dot-streptavidin; RGD, arginine-glycine-aspartic acid; ROP, ring-opening polymerization; SCL, shell cross-
linked; siRNA, small interfering RNA; Sn(OTf)2 , triuoromethane sulfonate; SPDP, N-succinimidyl 3-(2-pyridyldithio)-propionate; SPIO, superparamagnetic
iron oxide; SPECT, single photon emission computed tomography; Sr-PO, amino isopropoxyl strontium; TMBPEC, 6-trimethoxybenzy-lidene-
pentaerythritol carbonate; TSP50, testis-specic protease 50; VEGF, vascular endothelial growth factor; Z2 Arg-NCA, di-N-benzyloxycarbonyl-l-arginine
N-carboxyanhydride; ZLCys-NCA, -benzyloxycarbonyl-l-cysteine N-carboxyanhydride1 .
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
1. Introduction
A biomaterial can be dened as a material intended to
interface with biological systems to evaluate, treat, aug-
ment or replace any tissue, organ or function of the body
[1]. Biomaterials play an important role in human health.
Biopolymers are the main type of biomaterials. According
to their degradation properties, biopolymers can be fur-
ther classied into biodegradable and non-biodegradable
biopolymers. Many implants, such as bone substitution
materials, some bone xing materials, and dental mate-
rials, should possess long term stable performance in the
body. In recent years, developments in tissue engineer-
ing, regenerative medicine, gene therapy, and controlled
drug delivery have promoted the need of new properties
of biomaterials with biodegradability. Biologically derived
and synthetic biodegradable biopolymers have attracted
considerable attention [1]. Polysaccharides and protein are
typical biologically derived biopolymers, while aliphatic
polyesters and polyphosphoester (PPE) are typical syn-
thetic biopolymers.
Biopolymers with diverse specic properties are needed
for in vivo applications because of the diversity and
complexity of in vivo environments. Nowadays, syn-
thetic biopolymers have become attractive alternatives
for biomedical applications for the following reasons: (1)
although most biologically derived biodegradable poly-
mers possess good biocompatibility, some may trigger an
immune response in the human body, possibly one that
could be avoided by the use of an appropriate synthetic
biopolymer; (2) chemical modications to biologically
derived biodegradable polymers are difcult; (3) chem-
ical modications likely cause the alteration of the bulk
properties of biologically derived biodegradable polymers.
A variety of properties can be obtained and further mod-
ications are possible with properly designed synthetic
biopolymers wihout altering the bulk properties.
Specic properties are sometimes required for biomate-
rials. For example, tissue engineering scaffolds should have
both good biocompatibility and cell adhesive properties, in
addition to needed biodegradable properties. Drug delivery
systems should be endowed with stimuli-responsive prop-
erties for intelligent-control release. Functionalization is
inevitable to improve the properties of traditional synthetic
biopolymers. There are two commonly used functionaliza-
tion strategies: (1) functional groups are introduced to the
monomers of polymers, sometimes in a protected form
before polymerization, to be deprotected after polymer-
ization; (2) functional groups are introduced to polymer
chains by further chemical modication of the as-prepared
polymers.
This review is focused on recent progress of different
strategies of functionalization of synthetic biodegradable
polymers and the applications of these.
2. Biopolymers with reactive groups
2.1. Aliphatic polyesters
Aliphatic polyesters, such as poly(lactic acid) (PLA),
poly(glycolic acid), poly(-caprolactone) (PCL) and their
239
copolymers, have been widely investigated for biomedical
application because of their biodegradability, bioresorba-
bility, and biocompatibility. Aliphatic polyesters with
reactive groups have attracted attention because of the
demand of synthetic biopolymers with tunable properties,
including features such as hydrophilicity, biodegradation
rates, bioadhesion, drug/targeting moiety attachment, etc.
[2]. In particular, polymeric biomaterials with properties
that can be tailored by introducing functional groups,
such as carboxyl, hydroxyl, amino, ketal, bromo, chloro,
carboncarbon double bonds or triple bonds, etc., are
needed.
Aliphatic polyesters with reactive groups can be pre-
pared by the homopolymerization or copolymerization
of cyclic monomers bearing protected functional groups
(Fig. 1). Representative examples of the monomers and the
polymers are shown in Table 1.
2.1.1. Aliphatic polyesters with carboxyl groups
Aliphatic polyesters with pendant carboxyl groups can
be prepared by the ring-opening polymerization (ROP)
of cyclic esters bearing benzyl-protected carboxyl groups.
Ouchi and Fujino prepared poly(-malic acid) as a car-
boxyl functional analogy of PLA by the ROP of malide
dibenzyl ester followed by acid deprotection [3]. Kimura
et al. rst reported the synthesis of poly[(-malic acid)-alt-
(glycolic acid)], a glycolide-based poly(ester) with pendant
carboxylic acid, by the ROP of 3(S)-[(benzyloxycarbonyl)-
methyl]-1,4-dioxane-2,5-dione followed by debenzyla-
tion. These aliphatic copolyesters are hydrolyzed more
rapidly than PLA [4]. Weck and coworkers prepared side-
chain-functionalized lactide analogues from commercially
available amino acids. The resulting functionalized cyclic
monomers can be homopolymerized and copolymerized
with lactides and then quantitatively deprotected, form-
ing functional PLA-based materials with amino, hydroxyl
or carboxyl side chains [5]. Guerin et al. reported the syn-
thesis and polymerization of benzyl malolactonate [14].
The benzyl protecting groups could be readily removed
by catalytic hydrogenolysis to give poly(-malic acid).
He et al. reported the synthesis of poly(l-lactide-co-
-malic acid) with a high molecular weight by the
copolymerization of l-lactide and benzyl malolactonate
[15]. PCLs with pendant carboxylic acid groups were
prepared by Hedrick and coworkers via the ROP of
benzyl -(-caprolactone)carboxylate or tert-butyl--(-
caprolactone)carboxylate followed by acid deprotection
[6] (Fig. 2).
2.1.2. Aliphatic polyesters with amino groups
Hedrick and coworkers synthesized
amino-functionalized PCL by the ROP of 4-triuoroacetyl-
7-oxo-1,4-oxazaperhydroepine followed by the
deprotection with NaBH4 [6]. Fitier et al. reported
the preparation of an aliphatic polyester bearing lateral
amino groups by the ROP of N-tritylated serine -lactones
[16].
2.1.3. Aliphatic polyesters with chloride groups
Liu and coworkers synthesized a chloro-substituted
four-membered lactone, -chloromethyl--methyl--
240 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

O
O Homopolymerization O
O R
R n

(CH2)x O
O Copolymerization (CH2)x
O + O O
R R m O n
O O

R: reactive groups, including protected carboxyl, amino, chloro, ketal,

hydroxyl, bromo, carbon-carbon double bonds, etc

Fig. 1. Preparation of aliphatic polyesters with reactive groups.

propionolactone (CMMPL). CMMPL was polymerized and
copolymerized with various amounts of -caprolactone.
The pendant chloromethyl groups of the copolymers
were converted into quaternary ammonium salts by the
reaction with pyridine, which increased the hydrophilicity
of the copolymer [7,17].
2.1.4. Aliphatic polyesters with keto or hydroxyl groups
Aliphatic polyesters bearing keto groups were syn-
thesized by the ROP of 5-ethylene ketal -caprolactone
followed by deprotection [8,9,18,19]. The keto groups of the
copolymers were efciently reduced into hydroxyl groups
by using NaBH4 in a mixture of CH2 Cl2 /EtOH at room
temperature without any apparent chain degradation,
resulting in aliphatic polyesters with pendant hydroxyl
groups [9]. PCL containing pendant hydroxyl groups were
prepared by the ROP of -caprolactone monomer bearing
triethylsilyloxy pendant groups that can be selectively
deprotected into hydroxyl groups under mild conditions
[20]. Hedrick and coworkers reported the synthesis and
polymerization of -benzyloxy--caprolactone and -2,2-
bis(phenyldioxymethyl)propionate--caprolactone; the
catalytic hydrogenolysis of the benzyl protection group
of the products afforded PCL with pendant hydroxyl or
bishydroxyl groups, respectively [6].
2.1.5. Aliphatic polyesters with bromide groups
Hedrick and coworkers reported the preparation of
aliphatic polyesters with pendant bromide groups by the
ROP of a bromo-substituted cyclic ester, -(2-bromo-2-
methyl propionyl)--caprolactone (BMPCL) containing a
pendent-activated alkyl bromide functional group [10].
The pendent-activated alkyl bromide group could initi-
ate controlled atom-transfer radical polymerization (ATRP)
of methyl methacrylate; therefore, PCL-graft-poly(methyl
methacrylate) copolymers were obtained in a simple one-
step approach by the concurrent polymerization of an
-caprolactone, BMPCL, and methyl methacrylate with an
appropriate initiator for the ROP and a catalyst for the ATRP.
2.1.6. Aliphatic polyesters with C C groups
Unsaturated aliphatic polyesters can be prepared by
the ROP of cyclic esters bearing double bonds. Hedrick
and coworkers reported the preparation of unsaturated
aliphatic homopolyesters or random copolyesters bearing
pendant double bonds by the ROP of 4-(acryloyloxy)--
caprolactone, or 6-hydroxynon-8-enoic acid lactone with
-caprolactone and l-lactide [11,12]. Bizzarri and cowork-
ers reported the preparation of aliphatic polyesters bearing
double bonds by the ROP of four-membered lactones in
the presence of a quaternary ammonium salt as the ini-
tiator [13,21]. Unsaturated aliphatic polyesters with inner
double bonds were prepared by the ROP of unsaturated
-caprolactones with inner double bonds. Jrme and
coworkers prepared unsaturated aliphatic polyesters by
the ROP of 6,7-dihydro-2(5H)-oxepinone and 6,7-dihydro-
2(3H)-oxepinone using aluminum isopropoxide as the
initiator [2224].
2.1.7. Aliphatic polyesters with reactive groups by
copolymerization
The copolymerization of morpholine-2,5-dione deriva-
tives with lactide or lactones is a convenient way to prepare
aliphatic biopolymers bearing reactive groups. Feijen and
coworkers demonstrated the ROP of either -caprolactone
or dl-lactide with morpholine-2,5-dione derivatives could
protect functional substituents such as benzyl-protected
carboxylic acid, benzyloxycarbonyl-protected amine and
p-methoxy-protected thiol groups. Polyesteramides with
pendant carboxylic acid groups, pendant amine groups, or
pendant thiol groups were obtained after deprotection of
the copolymers [25].

Fig. 2. Preparation of PCL with pendant carboxylic acid groups [6].

Copyright 2000, American Chemical Society. Reprinted with permission.
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 241

2.2. Polycarbonate
Aliphatic polyesters and copolyesters are among the
most commonly used degradable materials for the
preparation of clinical devices. In this eld, aliphatic
polycarbonates are good materials because they possess
functionalizable side chains (OH, NH2 , COOH, etc.) that
Table 1
Aliphatic polyesters and functional cyclic monomers.
can easily meet the need for functionalization of bio-
materials. Moreover, aliphatic polycarbonates have good
biocompatibility, low toxicity, and good biodegradability
[26,27]. High molecular weight aliphatic polycarbonates
can be prepared by the ROP of cyclic carbonates [28]. The
most commonly used cyclic carbonates for ROP are the
ve- and six-membered cyclic monomers. Polymerization

Monomer Polyester Reference

[3]

[4]

[5]

[5]

[5]

[6]

[6]
242 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

Table 1 (Continued)

Monomer Polyester Reference

[6]

[6]

[6]

[7]

[8]

[9]
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Table 1 (Continued)
Monomer Polyester
of ve-membered cyclic aliphatic carbonates can pro-
duce poly(ester-carbonate)s with a content of units lower
than 50 mol% through a partial decarboxylation regardless
of the initiator and reaction conditions [27]. In con-
trast to ve-membered cyclic carbonates, six-membered
cyclic carbonates are easily polymerized and copoly-
merized with various heterocyclic monomers to form
polycarbonates without any decarboxylation under proper
conditions.
In the 1930s, cyclic carbonates, rst reported by
Carothers and coworker [29], were obtained by depoly-
merization of respective linear polycarbonates at a high
temperature and in the presence of different catalysts. In
recent years, researchers synthesized several functional-
ized cyclic carbonate monomers. For the rst time, Bisht
and coworker [30] designed and synthesized a novel
carbonate monomer, 5-methyl-5-benzyloxycarbonyl-1,3-
dioxan-2-one (MBC); Zhuo and coworkers [31] prepared
5-methyl-5-methoxycarbonyl-1,3-dioxan-2-one and 5-
methyl-5-ethoxy carbonyl-1,3-dioxan-2-one in a similar
way to that for MBC. Cyclic carbonates with pen-
dant amino groups [32,33], double-bonds [28,3436]
and triple-bond [37] have seldom been reported. Lee
et al. [38] rst reported water soluble polycarbonate
with pendant amino and carboxylic groups on the main-
243
Reference
[10]
[11]
[12]
[13]
chain carbon. Zhuo and coworkers [39] successfully
prepared the poly(carbonate-ester)s with amido-amine
pendent groups by the reaction of poly(MSTC-co-CL) with
ethylenediamine. Jing and coworkers [37] synthesized 5-
methyl-5-propargyloxycarbonyl-1,3-dioxan-2-one. More
cyclic carbonate monomers containing hydroxyl groups
have been prepared. For example, Cross and cowork-
ers [40] synthesized a six-membered cyclic carbonate
monomer with ketal protected saccharide containing
two hydroxyl groups. Zhuo and coworkers [41] rst
reported 5-benzyloxy-trimethylene carbonate (BTMC)
that was synthesized from 2-benzyloxy-1,3-propanediol.
Moreover, Cao and coworkers [42] prepared 5-ethyl-5-
benzyloxymethyl trimethylene carbonate in a similar way
to that for BTMC.
A great variety of functional cyclic carbonate monomers
have been successfully used for homopolymerization and
copolymerization with various heterocyclic monomers
through ROP. Bisht and coworker [30] rst synthesized
the MBCs homopolymer by lipase-catalyzed ROP, of which
the protecting benzyl groups were removed by catalytic
hydrogenation to give polycarbonate containing pendant
carboxylic groups. Jing and coworkers [43] prepared block
copolymer PCL-b-PMBC of -caprolactone and MBC by
the ROP of the -CL and MBC monomers with amino
244 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

Table 2
Polymers and functional cyclic carbonate monomers.

Monomer Polymer Referen-ce

O O

R1 R2
* O O O *

R1 R2
n
R1 = CH3 ; R2 = COOCH2 Ph [30,41]
H2 C O

H2 C O [43]
R1 = H; R2 = OCH2 CH CH2 [36]
H2 C

H2 C [28]
R1 = CH3 ; R2 = COOCH3 [31]
R1 = CH3 ; R2 = COOCH2 CH3 [31]
O

O
O O
*
O O O n
R1 R2
O
R1 R2
or
O

* *
O O O
m R1 R2 n
O

R1 = CH3 ; R2 = CH2 OOCCH CHPh [44]

R1 = CH3 ; R2 = COOCH2 CH = CH2 [35]
R1 = CH3 ; R2 = COOCH2 C CH [35]
R1 = H; R2 = NHCOOCH2 Ph [33]
H2 C

H2 C [34]
H2 C O
Ph
H2 C O [45]
Q

Q Q Q

RGI ,
Q Q Q n
T3 T4
Q
T3 T4 or
Q

RGI ,
Q m Q Q n
T3 T4
Q

R1 = CH3 ; R2 = COOCH2 Ph [46]

 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 245

Table 2 (Continued)

Monomer Polymer Referen-ce

H2C O
Ph
H2C O [47]
R1 = CH3 ; R2 = COOCH2 CH CH2 [48]
O

O O

R1 R2 H
PEG O O n
R1 R2

R1 = CH3 ; R2 = CO2 CH2 Ph-o-NO2 [49]

R1 = CH3 ; R2 = CO2 CH2 Ph [50]
O

O O
O

O C
O O H

COOCH2Ph CO2H [38]

HO C N
H
O
n

O O

O O

O * O
O O m O n*

O O
[51]

O O

O
O OH OH
O O
O O O
O O O O
O * [39]
O
*
O n
O O O

isopropoxyl strontium (Sr-PO) as an initiator. Zhuo and
coworkers [44] prepared poly[(5-benzyloxy-trimethylene
carbonate)-co-(5,5-dimethyl-trimethylene carbonate)] by
using immobilized porcine pancreas lipase on silica par-
ticles with different sizes to catalyze ROP. Representative
examples of the monomers and the polymers are shown in
Table 2 [30,43,4553,3336,28,31,38,40].
Free functional pendant groups on poly(ester-
carbonate)s are expected to facilitate further modications
such as attaching drug molecules and short pep-
tides onto the functional groups of the polymers.
Grinstaff and coworker [54] attached a nonsteroidal
anti-inammatory drug, 4-isobutylmethylphenylacetic
acid, to the copolymer by esterication of free hydroxyl
groups of 4-isobutylmethylphenylacetic acid. Jing and
coworkers successfully attached antitumor drugs pacli-
taxel [55] and docetaxel (Dtxl) [56], biotin [57] and
oligopeptide Gly-Arg-Gly-Asp-Ser-Tyr (RGD) [33] to
the pendants on the backbone of the copolymers.
The results indicate further possible application of
poly(ester-carbonate)s in specic drug delivery and tissue
engineering.
246 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 3. Synthesis of functional PBLGs through the ester exchange reaction (A) the click reaction, and the thiol-ene reaction of functional PBLGs (B) [60].
Copyright 2009, Elsevier Ltd. Reprinted with permission.
2.3. Poly(amino acids)
Poly(amino acids) are an important kind of biocom-
patible and biodegradable synthetic polymers and have
been studied for biomedical application in many elds [58].
However, their application is limited because of their insol-
ubility or pH-dependent solubility and lack of functional
groups [59]. This section summarizes recent develop-
ments in the functional modications of poly(amino acids)
focusing on the preparation of materials with potential
applications in medicine. Representative examples of the
poly(amino acids) before and after functionalization are
shown in Table 3.
2.3.1. Poly(acidic amino acids)
2.3.1.1. Poly(l-glutamic acid). Poly(l-glutamic acid) (PLG)
is composed of naturally occurring l-glutamic acid residues
linked together through amide bonds with active carboxyl
groups on the side. Methods can be used in function-
alizing PLG include: (1) polymerizing or copolymerizing
monomers with functional groups, (2) modifying the
monomer with functional molecules, (3) functional modi-
cation of the side groups, such as condensation, aminolysis
and ester exchange, and (4) introduction of a second com-
ponent to achieve a block, branch, hyper-branched or
dendron-like architecture.
Functionalizing poly(-benzyl-l-glutamate) (PBLG)
through ester exchange with functional alcohols such
as 2-chloroethanol, 2-azidoethanol and poly(ethylene
glycol) methyl ether (mPEG) is a convenient method to
obtain polymers that have controlled amounts of func-
tional groups on the side chains without protection and
de-protection processes. Huang and coworkers used the
ROP of N-carboxy-anhydride (NCA) and ester exchange
to prepare functional PBLG with functional alcohols [60].
PBLG was synthesized in anhydrous chloroform by the ROP
of -benzyl l-glutamate N-carboxy-anhydride (BLG-NCA)
at room temperature using n-hexylamine as an initiator
[73]. Functional PBLGs were then synthesized by the ester
exchange reactions between PBLG and functional alcohols
in 1,2-dichloroethane using p-toluenesulfonic acid (p-TSA)
as a catalyst [60]. Four kinds of functional PBLGs including
partially chlorinated PBLG (PBCLG), partially azidized
PBLG (PBN3 LG), partially allylated PBLG (PBALG) and par-
tially propargylated PBLG (PBPLG) were synthesized. The
activity of the functional groups on PBLG was examined
through click chemistry between PBN3 LG or PBPLG and
propargyl mPEG2000 or 2-azidoethanol, or the thiol-ene
reaction between PBALG and thioglycol yielding PBPN3 LG,
PBN3 LG-g-mPEG and PBALG-s-OH, respectively (Fig. 3). In
a similar manner, Lin and coworkers synthesized the graft
copolymer, PBLG-g-mPEG, through the ROP and the ester
change reaction [74].
Condensation reactions are a common method to func-
tionalize PLG and its copolymers. Jing and coworkers
reported the synthesis of RGD-grafted triblock copoly-
mer poly(ethyl glycol)-b-polylactide-b-poly(l-glutamic
acid)/RGD (PEG-b-PLA-b-PLG/RGD) by the combination
of a condensation reaction and ROP. The PEG-PLA-NH2
macroinitiator was prepared by the ROP of l-lactide in
the presence of methoxy-poly(ethylene glycol) (Mn = 750)
with stannous octanoate as the catalyst followed by the
replacement of the hydroxy end group by an amino group
via a two-step reaction [75]. The resulting PEG-PLA-NH2
was used as a macroinitiator for the living polymer-
ization of -benzyl-l-glutamate to eventually obtain
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 247

Table 3
Poly(amino acids) before and after functionalization.

Monomer or Poly(amino acid) before functionalization Poly(amino acid) after functionalization Method for functionalization Reference

O
H
N
n
O
H
O N
n
O
R
O
O
R1

Cl Ester Exchange [58]

Cl

N3

N3

R=H R1 = RGD Condensation Reaction [59]

HO OH
HO
H H
HO N [60]
H OH NH
H H O

SH
HN [61]

O
O
O
O N O
H O O Ring Opening Polymerization [62]

O
O
O O
O N O
H O
O
O
O
H
N
n
O
O H
O N
n
R
O
R1
248 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

Table 3 (Continued)

Monomer or Poly(amino acid) before functionalization Poly(amino acid) after functionalization Method for functionalization Reference

O
NH
O OH N
OH
OH
R=H Condensation Reaction [63,64]

O O OH O
O
NH2
OH

H
N Aminolysis Reaction [65]
HN NH2

NH2
O
[66]
N

HN NH2 [67]

O
H
N
n

O
H
N
n
NH
R

NH
R1

O
R=H Condensation Reaction [68]
SH
O
O Michael Addition [69]
n

O
O
n
O
H
N
n O
H
N
O n
R
O
R1

O
O
O
O N O
H O Ring Opening Polymerization [70]
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Table 3 (Continued)
Monomer or Poly(amino acid) before functionalization Poly(amino acid) after functionalization
O
O
O O
O N O
H
O
O
a well-dened polymer-polypeptide triblock copolymer
(Mw/Mn < 1.2). PEG-b-PLA-b-PLG was obtained by remov-
ing the protective benzyl groups in PEG-b-PLA-b-PBLG
through catalytic hydrogenation; RGD was grafted onto
PEG-b-PLA-b-PLG by rst activating the side chain carboxyl
groups of PEG-b-PLA-b-PLG with N-hydroxysuccinimide
(NHS) and then coupling them with RGD [61,76].
Kiick and coworkers synthesized a family of galactose-
functionalized PLA-based glycopolymers of various molec-
ular weights using a condensation reaction between
PLG and N-(-aminocaproyl)--d-galactosylamine [62].
Similarly, Kataoka and coworkers synthesized thiolated
poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-P(Glu-
DP)) via ROP and a condensation reaction subsequently
[63].
Polymerizing or copolymerizing monomers with func-
tional groups is widely used in the preparation of polymers
with well controlled molecular weight and architecture.
Wu and coworkers used the ROP of NCA to synthesize
mono- and diethyleneglycol functionalized PLGs directly
[64]. EGn-l-glutamates were rst prepared through the
reaction of l-glutamic acid and monoethylene glycol
monomethyl ether or di(ethylene glycol) monomethyl
ether; then the reaction of EGn-l-glutamates with triphos-
gene yielded EGn-l-glutamate-NCAs. The formation of NCA
allowed facile polymerization into high molecular weight
polymers with a narrow polydispersity index (PDI) via ROP.
PLG may be functionalized by the incorporation of
components into the system to form copolymers with
different architectures, such as block, graft, dendron-like
and so on. Chen and coworkers synthesized a series
of poly(N-isopropylacrylamide) (PNIPAM) and poly[(l-
glutamic acid)-co-(-benzyl l-glutamate)] (P(GA-co-BLG))
diblock copolymers using radical polymerization and ROP
[77]. PNIPAM is a widely used polymer, with temper-
ature sensitivity exhibiting a reversible coil-to-globule
transition at about 32 C (the lower critical solution tem-
perature, LCST). It is soluble in water below the LCST.
However, when the temperature increases above the
LCST, the polymer becomes insoluble and precipitates
from its aqueous solution. Amino-semitelechelic PNIPAM
(AS-PNIPAM) was synthesized by monomer telomeriza-
tion of N-isopropylacrylamide (NIPAM) with AIBN as the
initiator and AETHCl as the chain transfer reagent. Temper-
ature sensitive PNIPAM-b-PBLG diblock copolymers were
prepared by the ROP of BLG-NCA using AS-PNIPAM as
the macroinitiator. PNIPAM-b-poly[(l-glutamic acid)-co-
(-benzyl-l-glutamate)] (PNIPAM-b-P(GA-co-BLG)) were
synthesized through partial debenzylation of PNIPAM-
b-PBLG using HBr/CH3 COOH. An alternative synthetic
approach was investigated by synthesizing graft copoly-
mers instead of block copolymers, using the same materials
249
Method for functionalization Reference
as those used in the preparation of the PLG-g-PNIPAM graft
copolymer [78].
Block copolymers prepared with biocompatible and
biodegradable components are targets for applications in
the medical eld. Guillaume and coworkers reported an
approach to synthesize poly(trimethylene carbonate)-b-
poly(-benzyl l-glutamate) (PTMC-b-PBLG) and poly(-
caprolactone)-b-poly(-benzyl l-glutamate) (PCL-b-PBLG)
via the ROP of TMC or CL and BLG-NCA [79]. A PTMC-
NH2 or a PCL-NH2 macroinitiator was synthesized by ROP
in THF for TMC or in toluene for CL using diethyl zinc
as the catalyst and t-Boc-NH(CH2 )3 OH as the initiator
followed by removing t-Boc groups with triuoroacetic
acid at 0 C for 45 min upon stirring. The well-dened
PTMC-b-PBLG and PCL-b-PBLG diblock copolymers were
obtained using PTMC-NH2 or PCL-NH2 as a macroinitiator
via ROP. A Dextran-b-PBLG block copolymer was syn-
thesized via ROP and click chemistry in Schatzs group
[80]. First, the reducing end of dextran (Mn = 6600 g mol1 ,
PDI = 1.35) was modied with an alkyne group by reduc-
tive amination with propargylamine in acetate buffer (pH
5.0) in the presence of sodium cyanoborohydride, which
reduced double bonds in Schiff bases selectively; sec-
ondly, PBLG that was end-functionalized with an azide
group and had a degree of polymerization (DP) of 59 was
obtained through the ROP of BLG-NCA with 1-azido-3-
aminopropane as the initiator; thirdly, the nal dextron
Dextran-b-PBLG block copolymer was obtained via cou-
pling of dextran and PBLG blocks in dimethyl sulfoxide
(DMSO) at room temperature using a copper(I) cata-
lyst (CuBr) and ligand pentamethyldiethylene-triamine
(PMDETA). An extension in this chemistry was proposed
by Jing and coworkers, reporting a well-dened Y-shaped
copolymer (poly(l-lactide))2 -b-PBLG (PLLA-PBLG) via the
consecutive ROP of l-lactide and living NCA polymerization
[81].
Multi-armed PBLGs were prepared via the ROP of BLG-
NCA by Chen and coworkers [82,83]. The macroinitiator
poly(ethylene glycol)-b-Polyethyleneimine (PEG-b-PEI)
diblock copolymer was prepared via a two-step reaction:
(1) mPEG was allowed to react with HMDI in large excess
to obtain PEG-NCO; (2) PEG-NCO in CHCl3 was drop-
wise added into a CHCl3 solution of hyper branched PEI.
Then multi-armed PBLGs were synthesized via ROP with
PEG-b-PEI diblock copolymer or PEI as the macroinitia-
tor by dissolving the mixture in dried chloroform and
stirring for 72 h at room temperature. Dong and cowork-
ers synthesized dendron-like PBLG/linear poly(ethylene
oxide) block copolymers with both asymmetrical and sym-
metrical topologies (i.e., ABn type Dm-PBLG-b-PEG and
BnABn type Dm-PBLG-b-PEG-b-Dm-PBLG; n = 2m , m = 0, 1,
2, and 3; Dm is the propargyl focal point of poly(amido
250 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 4. Synthesis of dendron-like PBLG/linear poly(ethylene oxide) block copolymers with both asymmetrical and symmetrical topologies via the combi-
nation of ROP and click chemistry [84].
Copyright 2009, American Chemical Society. Reprinted with permission.
amine) type dendrons having 2m terminal primary amine
groups) via the combination of ROP and click chemistry
[84]. Two synthesis methods, arm-rst and core-rst
approaches, were used to prepare Dm-PBLG-b-PEG and
Dm-PBLG-b-PEG-b-Dm-PBLG. In the arm-rst approach,
the propargyl modied dendrons Dm with 2m terminal pri-
mary amine groups were synthesized and then used as
an initiator in the ROP of BLG-NCA, followed by coupling
of the product with azide-terminated PEG (i.e., mPEG-N3
or N3 -PEG-N3 ) through click chemistry to produce the
dendron-like/linear PBLG-b-PEG hybrid copolymers. In the
core-rst strategy, the dendrons Dm were click con-
jugated with azide-terminated PEG to generate primary
amine-terminated PEG-dendrons (i.e., PEG-Dm), which
were then used to initiate BLG-NCA to produce the targeted
hybrid copolymers, with both asymmetrical and symmet-
rical topologies (Fig. 4).
2.3.1.2. Poly(aspartic acid). Poly(aspartic acid) can be syn-
thesized from aspartic acid by the ROP of -benzyl aspartic
acid N-carboxy-anhydride (BAA-NCA) followed by removal
of the protective benzyl groups. The two main approaches
to modify poly(aspartic acid) are: (1) functional mod-
ication of the side groups, such as condensation and
aminolysis, and (2) introduction of a second component
to achieve different architectures.
Condensation is a simple and common method
to modify poly(aspartic acid) and its copolymers.
Kataoka and coworkers reported the synthesis of
poly(ethylene glycol)-b-poly(aspartate-hydrazone-
adriamycin) (PEG-P(Asp-Hyd-ADR)) using poly(ethylene
glycol)-poly(-benzyl-l-aspartate) (PEG-PBLA) as a tem-
plate [65,66]. PEG-b-PBLA was synthesized via the ROP of
benzyl-l-aspartate N-carboxyanhydride (BLA-NCA) with
mPEG-NH2 as the macroinitiator. Hydrazide groups were
attached to the end of the aspartate side carboxyl groups
of the block copolymer through an acid anhydride reaction
after removing the benzyl groups of PEG-b-PBLA. ADR
was then conjugated to the polymer backbone through an
acid-labile hydrazone bond between C13 of ADR and the
hydrazide groups of the PEG-b-P(LA-Hyd) block copolymer
(Fig. 5).
Aminolysis is extensively used in functionalizing PBAA
with functional amines, such as dipropylene triamine
(DPT), 1,5-diamino pentane (AP), 4-(3-aminopropyl) mor-
pholine (MP), etc.; it is a convenient and simple method
to obtain polymers with a controlled fraction of functional
groups. PEG-b-poly-(3-[(3-aminopropyl)amino] propyl
aspartamide) was prepared through ROP and an aminoly-
sis reaction by Kataoka and coworkers. PEG-b-PBLA was
synthesized by ROP and PEG-b-DPT was obtained by a
side-chain aminolysis reaction of PEG-b-PBLA. In a similar
way, poly([5-aminopentyl]-,-aspartamide) and PEG-b-
poly[(3-morpholinopropyl) aspartamide]-b-poly-l-lysine
were synthesized by the same research group via the ROP
of BLA-NCA and an aminolysis reaction using AP and MP,
respectively [6769].
2.3.2. Poly(basic amino acid)
2.3.2.1. Polylysine. Poly(l-lysine) (PLL) with reactive
amido groups on the side chain can be prepared through
the ROP of -carbobenzoxy-l-lysine N-carboxyanhydride
(ZLL-NCA) and deprotection. PLL is a polyelectrolyte (poly-
cation) which displays pH-dependent solubility, limited
circulation lifetime due to aggregation with oppositely
charged biopolymers, and high toxicity [59,85]. Similar to
those for PLG and poly(aspartic acid), several approaches
are effective in functionalizing PLL: (1) functional modi-
cation of the side groups, such as condensation, Michael
addition and so on, and (2) introduction of a second compo-
nent to achieve block, branch, dendron-like architectures,
etc.
A condensation reaction is a simple and convenient
way to functionalize poly(l-lysine) directly. Cyclic RGD
functional block copolymer c(RGDfK)-poly(ethylene
glycol)-b-poly[-(3-mercaptopropionyl)-lysine]
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 5. Synthesis of PEGp(AspHydADR) block copolymers. The Schiff base formed between the C13 ketone of ADR and the hydrazide groups of the
PEGp(AspHyd) block polymer is most effectively cleavable under acidic conditions at about pH 5.0, which corresponds to the pH value of lysosome in
cells. Boc = tert-butoxycarbonyl, TFA = triuoroacetic acid [65].
Copyright 2003, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission.
(c(RGDfK)-PEG-b-P(Lys-MP)) was prepared by ROP
and a condensation reaction in Kataokas group [70].
Acetal-PEG-b-PLys was synthesized through the ROP
of ZLL-NCA with acetal-PEG-NH2 as the macroini-
tiator and deprotection; subsequent reaction with
N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP)
yielded acetal-poly(ethylene glycol)-b-poly[-3-(2-
pyridyldithio)propionyl lysine] (acetal-PEG-P(Lys-PDP)).
c(RGDfK)-PEG-P(Lys-MP) was achieved through terminal
group modication and cleavage of the disulde bonds of
PDP with dithiothreitol.
Michael addition is an effective and fascinating method
to modify PLL with active amino groups. Li and cowork-
ers synthesize poly(l-lysine)-g-poly(-caprolactone) (PLL-
g-PCL) and poly(l-lysine)-g-poly(l-lactide) (PLL-g-PLLA)
graft copolymers via the ROP of l-Lys-NCA, CL, LLA and
Michael addition [71]. PLL was synthesized by the ROP of
ZLL-NCA with n-butylamine as the initiator and was kept
at 40 C for 72 h, followed by deprotection with HBr/HOAc.
Maleimido-terminated PLLA (M-PLLA) and maleimido-
terminated PCL (M-PCL) were synthesized by the ROP
of LLA and CL monomer with N-hydroxylethylmaleimide
(HEMI) as the initiator and Tin (II) triuoromethane
sulfonate (Sn(OTf)2 ) as the catalyst. The graft copoly-
mers PLL-g-PCL and PLL-g-PLLA were synthesized via the
Michael addition of M-PLLA and M-PCL with amino groups
on the side chains of PLL.
Chens group investigated an synthetic approach in
which BLG-NCA was replaced by ZLL-NCA; after the
removal of the benzyl protecting group to prepare a
series of PNIPAM-b-PLL diblock copolymers using radi-
cal polymerization and ROP as described in the above
paragraph for PLG [86]. Jing and coworkers prepared
a series of poly(-benzyloxycarbonyl l-lysine)-block-
poly[diethylene glycol bis(3-amino propyl) ether]-block-
poly(-benzyloxycarbonyl l-lysine) (PZLL-PDGBE-PZLL)
via the ROP of ZLL-NCA with diethylene glycol bis(3-
251
amino propyl) ether (DGBE) as the initiator [87]. In
the same group, Jing and coworkers synthesized poly(l-
lysine)-block-poly(l-phenylalanine) (PLL-b-PLPA) diblock
copolypeptides via the ROP of NCA [88]. The PZLL-b-
PLPAs were synthesized in two steps: (1) synthesizing of
PZLL by the ROP of ZLL-NCA in DMF with proportional
n-hexylamine as the initiator, and (2) synthesizing of PZLL-
b-PPA through the ROP of l-phenylalanine NCA (LP-NCA)
in DMF in the presence of PZLL-NH2 as the macroinitiator.
Harada et al. prepared a PLL-b-PAMAM dendron copoly-
mer through ROP and the Michael addition [89]. The
block copolymer was synthesized in two steps: (1) a
PAMAM dendron with generation 3.5 was synthesized
via four Michael additions with methyl acrylate and
three amidations with ethylenediamine using tert-butyl N-
(2-aminoethyl)-carbamate, of which one primary amino
group was protected by t-Boc groups, as the starting
reagent followed by deprotection of t-Boc with triu-
oroacetic; (2) a PLL-b-PAMAM dendron copolymer was
prepared by the ROP of ZLL-NCA with a PAMAM dendron
as the macroinitiator; subsequently the benzyloxycarbonyl
group was removed by HBr and the methyl ester at the
periphery was converted to carboxylate groups.
Rendle and coworkers used a condensation reaction and
the ROP of ZLL-NCA to synthesize mannose-capped lysine-
based dendrimers [90]. Six generations of lysine-based
dendrimers, G0 to G5, containing two to sixty-four valence
amines, respectively, protected by t-Boc, were synthesized
by a condensation reaction with benzhydrylamine as the
core. The nal mannose-capped lysine-based dendrimers
were obtained through a condensation reaction between
deprotected dendrimers and mannosyl derivatives.
2.3.2.2. Polyarginine (PArg). PArg is composed of argi-
nine residues with guanidino groups which can help
cell uptake of nanoparticles. The functionalization of
PArg with the ROP of NCA is difcult. In a report by
252 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Demings group [91] the block copolymer poly(l-lysine)-
co-polyarginine-b-poly(l-leucine) (PLL-co-PArg-b-PLLeu)
was synthesized via the ROP of NCA in three step
preparation: (1) di-N-benzyloxycarbonyl-l-arginine N-
carboxyanhydride (Z2 Arg-NCA) was synthesized through
the reaction between tri-N-benzyloxycarbonyl-l-arginine
and , -dichloromethylmethyl ether in dry methy-
lene chloride, with a similar preparation for ZLL-NCA;
(2) poly(di-N-benzyloxycarbonyl-l-arginine-random-
N-benzyloxy-carbonyl-l-lysine)-b-Poly(l-leucine),
PZLL-co-PZ2 Arg-b-PLLeu, was synthesized by the ROP
of ZLL-NCA and Z2 Arg-NCA with Co(PMeB3 B)B4 as the
catalyst, followed by addition of BLG-NCA in the dry box;
(3) PLL-co-PArg-b-PLLeu was obtaind after deprotection
with HBr.
2.3.2.3. Poly l-histidine. The electron lone pair on the
unsaturated nitrogen of the imidazole ring endows
poly(l-histidine) (PLHis) with an amphoteric nature.
Protonationdeprotonation on the side chain can facilitate
synthesize of LHis-NCA by a ROP, but the method is difcult
and has limited application.
Bae and coworkers prepared PLHis and block copoly-
mers with PEG, PLLA-b-PEG. PLHis was synthesized by the
ROP of protected l-Histidine NCA (i.e., Nim -DNP-l-histidine
NCA) (NDLhis-NCA); the coupling of PLHis with PEG yielded
PLHis-b-PEG block copolymer after deprotection [92,93].
The block copolymer was prepared in three steps as fol-
lows: (1) NDLhis-NCA was obtained by a reaction between
Nim -DNP-l-histidine and thionyl chloride in THF at room
temperature; (2) PLHis was synthesized by the ROP of
NDLhis-NCA with hexylamine or isopropylamine as the ini-
tiator, followed by polymerization at room temperature
for 72 h, with evolution of carbon dioxide; (3) PLHis-b-
PEG was prepared via a coupling reaction with NHS and
EDC under deprotection of 2-mercaptoethanol., A triblock
copolymer PLLA-b-PEG-b-PLHis was prepared by a simi-
lar method with the ROP of NDLhis-NCA, via coupling and
deprotecting reactions [94].
In the same group, poly(l-histidine-co-phenylalanine)-
b-poly(ethylene glycol) (i.e., PLHis-co-PPhe-b-PEG) was
prepared by the ROP of NDLhis-NCA and Phe-NCA, via a
condensation reaction and deprotection as described above
[95,96].
2.3.3. Poly(neutral amino acid)
In the neutral amino acid family, there exist amino
acids with active groups, such as l-serine with a hydroxy
group, l-3,4-dihydroxyphenyl-l-alanine (l-DOPA) with a
dihydroxybenzyl group, and l-cysteine with a mercapto
group.
Demings group prepared functionalized poly(l-
serine) (PLSer), poly(l-cysteine) (PLCys) and poly(l-DOPA)
(PLDOPA) through the ROP of modied monomers
in combination with other components [72]. Mono-
and diethyleneglycol modied PLSer (PEGnLSer) poly-
mers were synthesized by the ROP of functionalized
LSer-NCA directly in three steps: (1) EGn-l-Serines
were obtained by coupling N -tertbutyloxy-carbonyl-
l-serine and 1-bromo-2-(2-methoxyethoxy) ethane or
2-bromoethyl methyl ether with sodium hydride fol-
O
P O R1 O
n
R2
Fig. 6. General structure of PPE.
lowed by deprotection with HCl; (2) EGn-l-Serine-NCAs
were prepared with the reaction between EGn-l-Serines
and 1,1-diclorodimethylether; (3) PEGnLSers were pre-
pared by the ROP of EGn-l-Serine-NCAs directly and the
degree of polymerization of the polymer was controlled
with a narrow PDI. In a similar way, well-controlled
diethyleneglycol-modied poly(l-cysteine) was pre-
pared by using (2-(2-methoxyethoxy)ethyl)chloroformate
instead of 1-bromo-2-(2-methoxyethoxy) ethane.
A series of water soluble poly(l-DOPA)-co-poly(l-
lysine) (PLDOPA-PLL) copolymers were prepared by the
ROP of -amino acid NCA monomers [97]. PLDOPA-co-PLL
copolymers were synthesized via the ROP of N-
carbobenzyloxy-l-lysine NCA and O,O -dicarbobenzyloxy-
l-DOPA NCA with sodium tert-butoxide as the initiator
followed by the removal of carbobenzyloxy groups with
HBr in acetic acid at room temperature.
In addition, synthesis of copolymers including PLCys
and other components is an efcient approach to modify
PLCys. Jing and coworkers synthesized poly(l-cysteine)-
b-poly(l-lactide) (PLCys-b-PLLA) diblock copolymer by
the ROP of NCA [98]. PLCys-b-PLLA was prepared in
two steps: (1) PLLA-NH2 was obtained through the ROP
of l-lactide with stannous octoate as the catalyst and
NH2 -protected aminoethanol as the initiator followed by
deprotection; (2) the nial copolymer PLCys-b-PLLA was
prepared by the ROP of -benzyloxycarbonyl-l-cysteine
N-carboxyanhydride (ZLCys-NCA) with PLLA-NH2 as a
macroinitiator and then removal of the t-Boc group.
2.4. Polyphosphoesters
PPEs with repeating phosphoester units in the backbone
(Fig. 6) are attractive biocompatibile and biodegrad-
able biomaterials because of their structural similarity
to the naturally occurring nucleic acid and easy func-
tionality as compared to conventional polyesters [99].
The synthesis of PPE as the analogue of nucleic and
teichoic acid was pioneered by Penczek and coworkers
at the end of 1970s [100,101]. Since then, a num-
ber of synthesis methodologies and mechanisms have
been extensively investigated, including ROP, polyaddition,
polycondensation, polytransesterication and enzyme-
catalyzed polymerization [102108]. PPEs with different
properties, such as stimuli-responsiveness, photo-cross-
linkability, and reactiveness, can be easily achieved by
varying the R1 or R2 group (Fig. 6). In the 1990s, Zhuos
group and Leongs group further developed the synthesis
strategies of functional PPEs for various biomedical appli-
cations such as tissue engineering scaffolds and drug/gene
delivery vehicles [109,110]. Several functional groups such
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 253

O
Deprotection
A P O R1 O
TE
Cl 4, n
O C (H)
NH (H)N R'2
R' 2
P O R1 O
n O O
H Cl
2, CH R2OH, TEA
Cl P O R1 O P O R1 O
3
n Deprotection n
Cl O R2

H
NH N N+
R2'N(H): H2N EA NH MEA NH TMEA

H2N NH PA

NH N DMEA N
H2N BA NH NH DEEA

H2N N N H2N N NH2

NH2 H2N NH2

SP DEA DPA
O O O O
R2O: H2N H2N N HO
3
H
EA HA MEA EH

Fig. 7. Postpolymerization modication of polyphosphite.

as hydroxyl, amino and unsaturated bonds were intro- PPEs more favorable for side chain (R2) functionalization.
duced as the R1 or R2 group for PPEs. Recently, controlled Two general methods, postpolymerization modication
ROP initiated by stannous octoate or aluminum isopropox- and polymerization of functionalized monomers, have
ide was employed by Wang and colleagues to synthesize been widely used in the preparation of PPEs with side chain
PPEs with well-dened architectures and versatile func- (R2) functionalities.
tionalities [111113]. These living polymerization methods In the case of postpolymerization modication, poly(H-
may facilitate the synthesis of PPEs with tunable properties phosphate), also called polyphosphite, are usually synthe-
for biomedical applications [114]. sized as precursor polymers. Several methods reported
PPEs with R1 functionalities were rst prepared by to prepare side chain functionalized polymers are shown
Penczek and coworkers as teichoic acids mimics [100,101]. in Fig. 7. A direct approach to convert the PH bond to
Interactions between bio-related polymers and cations the PN bond resulting in polyphosphoramidates (PPAs)
were studied, important for the use of these polymers with diverse amino groups (R2 in Fig. 7) in the poly-
for active transportation of cations (Mg2+ , Ca2+ ) through mer pendants was achieved through the Atherton-Todd
biomembranes and mimicks of the biomineralization pro- reaction in the presence of CCl4 as an oxidant. All of the
cesses [115]. Polycondensation of di-hydroxyl compounds
(HO-R1-OH) with ethyl dichlorophosphate is an effective
route to the R1 functional PPEs. Low-molecular-weight
O TEA O
PLAs can serve as HO-R1-OH compounds to prepare PPEs O O
P + HO R P
with a wide range of physical properties based on the OR
Cl O
variation of phosphoester mass fraction. Wen at al. [116] O
synthesized a novel HO-R1-OH compound to prepare a PPE O
carrying a positive charge in its backbone, and a lipophilic OR: O O O O n
cholesterol structure in a side chain. The biodegradable 1 2 3 4
polymer obtained self-assembled into micelles in aqueous H
buffer, and could efciently condense and deliver plasmid O N O
O O
DNA into different cell lines. An unsaturated HO-R1-OH
compound was also synthesized and used to prepare PPEs. O O
5 6
The unsaturated groups in the polymer backbone allowed
O
thermally-induced free radical cross-linking between poly- O
O
mer chains to form a biodegradable gel in situ, which may O OH
be promising as an injectable tissue engineering scaffolds O
[117]. 7 8
Different from the tetravalency of carbon atoms in
polyesters, the pentavalency of phosphorous atoms makes Fig. 8. Cyclic phosphoester monomers.
254 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
synthesized PPAs are biodegradable cationic polymers and
have been extensively studied as the non-viral gene car-
riers [118120]. Functional PPEs with PO connected side
chains also could be obtained using polyphosphite as the
starting material. A chlorination process was adopted to
convert the PH bond into the PCl bond followed by a
reaction with hydroxyl-compounds to generate PPEs with
functional side chains (Fig. 7, R2). This method was First
reported by Wang et al. to synthesize poly(2-aminoethyl
propylene phosphate) (PPE-EA) with a biodegradable phos-
phoester backbone and a -aminoethoxy side chain that
was shown to be an effective, nontoxic and biodegradable
gene carrier [121]. Subsequently, PPEs with HA and MEA
were synthesized to study the effect of side chain struc-
tures on the gene transfer efciency [122]. Using the same
method, Huang et al. also prepared a biodegradable PPE
with hydroxyl pendant groups as a nonionic noncondens-
ing agent to enhance gene expressing in muscles [123].
More recently, Koseva et al. [124] reported a new method
to prepare functional PPEs with reactive 1,3-dioxolan-2-
one pendants through homolytic addition of PH groups to
the C C double bond of 4-ethenyl-1,3-dioxolan-2-one. The
ring-opening aminolysis of the cyclic carbonate in the side
chains led to the ability of the polymers to conjugate with
peptides/proteins or drug molecules conveniently, render-
ing new functional PPEs as candidates for drug delivery
application.
ROP of cyclic phosphoester monomers provides another
strategy to prepare side chain-functionalized PPEs. Recent
efforts on the controlled ROP of cyclic phosphoester
monomers have developed synthetic PPEs with vari-
ous architectures and dened compositions [125129].
Functionalized PPEs can be achieved by the ROP of func-
tionalized monomers. A monomer bearing vinyl group
(monomer 5, Fig. 8) was employed in the synthesis of
vinyl group-functional PPEs that were used to prepare
hydrogels with different physical properties through cross-
linking of the vinyl group in the pendants [130,131]. Unlike
monomers with a vinyl group, monomers with amino and
hydroxyl groups need to be protected (monomer 6 and 7,
Fig. 8) for them to be compatible with the polymerization
conditions. For example, an amphiphilic triblock copoly-
mer PEG-b-PCL-b-PPEEA was synthesized by sequential
polymerization of -caprolactone and monomer 6, fol-
lowed by deprotection to release amino groups. An
amphiphilic and cationic block copolymer self-assembled
into micelles as a promising delivery vehicle for small inter-
fering RNA (siRNA) [132]. Similarly, Song et al. reported
a series of diblock PPEs bearing reactive hydroxyl groups
that could self-assemble into either micelles or vesicles
in aqueous solution [133]. A novel unprotected hydroxyl
functionalized cyclic monomer 8 in Fig. 8) was recently
designed and synthesized by Liu et al. [134], and a
hyperbranched PPE was successfully synthesized by self-
condensing ROP of this monomer in the absence of a
catalyst.
2.5. Others
Polyanhydrides [135] and polyurethane [136] have been
utilized for a variety of biomedical applications because
Fig. 9. Functional end group-bearing PNIPAMs synthesized by chain
transfer radical polymerization.
of their biocompatibility and degradability. The function-
alization of these biopolymers can further improve their
properties, such as biological activity, hydrophilicity, cyto-
compatibility, etc.
Uhrich and coworkers reported the chemical incorpo-
ration of mono-functional antiseptics based upon phenols
into polyanhydrides via pendant ester linkages. Because
a wide range of bioactive materials may be used to form
pendant ester linkages, this method can be potentially
expanded for the incorporation of many other bioactive
materials, including mono-functional therapeutic agents
into a polymer. These materials may be useful in antisep-
tic coatings for surfaces such as tables, oors, and medical
instruments in healthcare settings or applied to prevent
and control infection [137].
Gao and coworkers reported the modication of
polyurethane by grafting polymerization of methacrylic
acid, acrylamide, hydroxyethyl methacrylate, or N,N-
dimethylaminoethyl methacrylate. In vitro human
endothelial cell cultures of the modied polyurethane
scaffolds showed improved hydrophilicity and endothelial
cell adhesion in comparison with the unmodied control
matrix [138,139].
3. Biopolymers with responsive activities
3.1. Stimuli-responsive biopolymers
Due to the ability to mimick the basic response
process of living systems, stimuli-responsive polymers
have attracted increased attention. These polymers can
respond to small changes in environmental stimuli with
distinct transitions in physical-chemical properties, includ-
ing conformation, polarity, phase structure and chemical
composition [140]. According to the stimulus differ-
ences, stimuli-responsive polymers may be classied as
temperature-, pH-, photo-, electro- and multi-responsive
polymers. Nowadays various materials based on these
intelligent polymers have been designed and applied in
biomedical elds including drug delivery, tissue engineer-
ing, bioseparation and biosensor designing [141]. Among
them, synthetic biodegradable polymer based materi-
als attracted attention due to their promising in vivo
applications. Therefore, designing convenient and effec-
tive synthetic strategies to modify biopolymers to provide
intelligent functions is important for further progress of
biomedical materials.
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
3.1.1. Temperature responsive
Temperature is the most commonly studied among var-
ious environmental stimuli because of its physiological
signicance. Most temperature-responsive polymers con-
tain both hydrophilic and hydrophobic moieties. When the
temperature changes to an appropriate range, the balance
between these moieties is broken and reversible phase
separation or precipitation can occur. PNIPAM is one of
the most popular thermosensitive polymers, undergoing
a rapid coil-to-globule (hydration-to-dehydration) transi-
tion in an aqueous solution at its LCST of 3132 C [142]. The
LCST can be appropriately elevated or reduced by copoly-
merizing NIPAM with more hydrophilic monomer or more
hydrophobic monomers, respectively. Although there are
many other temperature-responsive polymers synthesized
by the radical polymerization, PNIPAM is discussed here
as a typical example. There are mainly two strategies to
conjugate PNIPAM with synthetic biopolymers. One is to
prepare end-functionalized PNIPAM rst for use as an ini-
tiator for the ROP of cyclic monomers or for coupling with
a synthetic biopolymers. Another pathway is to synthesize
functionalized biopolymer macroinitiators rst for use in
the polymerization of NIPAM. The end functionalization of
PNIPAM is conveniently achieved through the chain trans-
fer radical polymerization of NIPAM (structures are shown
in Fig. 9).
Amine-terminated PNIPAM can also be obtained by
RAFT polymerization using an amine-bearing initiator
[143]. It is well known that most biodegradable synthetic
polymers are prepared by the polymerization of cyclic
monomers initiated by hydroxyl or amine groups. There-
fore, various temperature-sensitive block copolymers
have been obtained by this strategy. PNIPAM-b-PLA was
prepared through the ROP of lactide initiated by PNIPAM-
OH; PNIPAM-b-PLA self-assembled into micelles with
temperature-sensitive shells [144]. A similar approach
was used in our group to prepare temperature- and
pH-responsive polypeptide-based block polymers such
as poly(N-isopropylacrylamide)-block-poly(glutamic acid)
(PNIPAM-b-PGA) and PNIPAM-b-PLL [77,86]. As demon-
strated in the preceding paragraphs, many functional
groups can be incorporated into synthetic biopolymers.
Conjugation is a popular method to introduce functional
end group-bearing PNIPAM to synthetic biopolymers. For
example, PGA-g-PNIPAM and PLL-g-PNIPAM were synthe-
sized through the condensation of amine and carboxyl
groups in the presence of carbodiimide [78,145]. However,
a limitation of the conjugation reaction is that the puri-
cation of the nal product is complicated by unwanted
polymers.
Recent progress in controlled living radical polymer-
ization provided more alternative routes to synthesis of
PNIPAM-based biodegradable polymers. These techniques
made it possible to prepare well-dened and controlled
molecular weight polymers not easily obtained by tradi-
tional radical polymerization. PLA-b-PNIPAAM-b-PLA was
synthesized by the ROP of lactide initiated from two
hydroxyl groups of a RAFT agent and then used as an
initiator for the RAFT polymerization of NIPAM [146].
Amphiphilic triblock copolymers with two hydrophilic
PNIPAM blocks anking a central hydrophobic poly[(R)-
255
3-hydroxybutyrate] (PHB) were prepared, in which the
PNIPAM was initiated by the PHB macroinitiator through
ATRP [147]. Polypeptide copolymers containing PNIPAM
were also synthesized using similar approaches. For exam-
ple, PNIPAM-b-PGA was synthesized by a combination of
the ROP of BLG-NCA and the RAFT polymerization of NIPAM
[143]. It should be pointed out that the order of ROP and
RAFT polymerization in this system could be interchanged,
with a narrower PDI when PNIPAM is used as the initiator.
2-Hydroxyethylmethacrylate (HEMA) is a commonly
used monomer to promote favorable biocompatibility
of its polymers. Because of the pendent hydroxyl group,
HEMA is also used as an initiator for the preparation
of polyesters bearing double bonds at the end. The
resulting macromonomer can be copolymerized with
NIPAM or initiated by the PNIPAM macroinitiator. For
example, poly(N-isopropylacrylamide)-b-[2-hydroxyethyl
methacrylate-poly(-caprolactone)] (PNIPAM-b-(HEMA-
PCL)) was synthesized by combining a macromonomer
method with RAFT polymerization [148]. The molecular
weights of the macromonomers were generally low, which
favors further polymerization.
Copolymers of polyester and PEG exhibiting reversible
solgel phase-transition in response to temperature have
also attracted considerable interest [149]. Their molecular
architectures can be designed as ABA, BAB, AB and (AB)n
types, and they are also expanded into other structures,
such a star-shape polymers [150]. Its thermo-responsive
properties mainly depend on molecular parameters such
as the copolymer composition, hydrophilic/hydrophobic
block length and molecular weight. Recently, Lee and
coworkers prepared a series of this kind of in situ gelling
copolymers with pH sensitive segments. The gelling of
these materials could be tuned by the combination of pH
and temperature stimuli, which could expand the applica-
tion of this kind of materials [149].
3.1.2. pH-responsive biopolymers
pH is a well-studied stimulus because of pH vari-
ation within the body. For example, the pH in the
stomach is acidic while in the intestine is more basic
(pH 58). Generally, the pH in normal tissue and blood
is about 7.4, but in some tumors the pH is 0.51.0
lower than the normal. When the polymers are taken
up by cells there is also pH variation at different states.
For example, in endosomes the pH is about 5.06.5,
whereas lysosomes have an even lower pH (4.55.0)
[151]. Thus, synthetic biodegradable polymers respon-
sive to pH have promising application in drug delivery. A
number of polypeptides bearing pendant ionizable groups
exhibit pH-responsive properties, such as poly(glutamic
acid), poly(aspartic acid), poly(histidine), poly(lysine) and
poly(arginine). Among these, poly(glutamic acid) and
poly(aspartic acid) are acidic polypeptides while the oth-
ers are basic., Poly(glutamic acid) and poly(histidine) are
the most practical pH-responsive polypeptides for in vivo
application because their appropriate pH sensitivity ranges
and the physiological pH ranges overlap each other [58].
Moreover, poly(glutamic acid) undergoes a sharp helix-
to-coil conformational induced by pH changes, which can
mimic the naturally occurring peptides to some extent.
256 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 10. Structure of amino-pendent polyacetals.
Poly(histidine) contains imidazole groups that can be eas-
ily protonated at pH 6.55.0 to give a positively charged
polyion, so this material can be used as a carrier for genetic
materials. The pKa of polypeptides can be tuned by intro-
ducing hydrophobic groups to expand their application. For
example, Kim et al. synthesized poly[(l-histidine)-co-(l-
phenylalanine)]-block-poly(ethylene glycol) (PHF-b-PEG)
diblock copolymers to prepare pH-sensitive polymeric
micelles [152]. It was found that the pKa value of the
copolymer can be controlled by adjusting the ratio of
histidine to phenylalanine in the copolypeptide and by
adjusting its molecular weight. In our previous work, the
inuence of hydrophobic benzyl groups on the phase tran-
sition of PNIPAM-b-P(GA-co-BLG) copolymers was studied.
The diblock copolymer responded sharply to a narrow pH
change in the region of pH 7.45.5 when the BLG content
in the P(GA-co-BLG) block was more than 30 mol% [77].
The introduction of pH-responsive properties can also
be achieved by the conjugation of ionizable groups with
the polymer chain. For example, citraconic anhydride
reacted with an amine modied PEG-b-PAsp was neg-
atively charged owing to the carboxylate groups. The
citraconic amide is stable at both neutral and basic pH, but it
becomes unstable at acidic pH and promptly degrades back
to the cationic primary amine [153]. This approach can be
used to prepare a charge-conversion polymer in response
to endosomal pH for gene delivery.
However, the disadvantage of biodegradable polyions is
that the excess charges can induce undesired interactions
with serum proteins leading to rapid elimination of the
polyions before reaching specic sites. One strategy to
overcome this difculty is to develop polymers bearing
acid-labile groups, including mainly acetal/ketal and
hydrazide. These groups are uncharged and cleavable in
acidic media. Bae et al. designed acid-sensitive amphiphilic
block copolymers in which ADR was conjugated to the
polymer backbone through an acid-labile hydrazone
bond between C13 of ADR and the hydrazide groups of
the poly(ethylene glycol)-b-poly(aspartate-hydra zone)
(PEG-P(Asp-Hyd)) block [65]. Tomlinson et al. [154] pre-
pared water soluble and hydrolytically labile polyacetals,
bearing pendant amine groups suitable for drug con-
jugation (Fig. 10). Then doxorubicin was conjugated to
polyacetal to get a polyacetal-doxorubicin (APEG-DOX).
This polyacetals-drug conjugate displayed pH-dependent
polymer main-chain degradation. In mild degradation
conditions, this conjugate can generate serinol-succ-
DOX, which displayed antitumor activity in vitro. In vivo
biodistribution studies in B16F10 tumor beared animals
showed that APEG-DOX had prolonged plasma circula-
tion. Moreover, administration of APEG-DOX conjugates
led to signicantly less deposition of DOX in liver and
the spleen. Polycarbonate and PEG diblock copolymers
comprising acid-labile groups were prepared by the ROP
of mono-2,4,6-trimethoxybenzylidene-pentaerythritol
carbonate (TMBPEC) and mono-4-methoxybenzylidene-
pentaerythritol carbonate (MBPEC). The resultant micelles
showed a high drug loading capacity and a signicantly
faster drug release rate at endosomal pH values than that
at the physiological pH [155]. However, a limitation of
these micelles is that they are not stable at physiological
pH level for a long time.
3.1.3. Photo responsive biopolymers
Light is indispensable in human lives and also is a useful
stimulus for clinical operation. Therefore, synthesis of pho-
tosensitive polymers has attracted great interest in recent
years. The most studied photo-chromic groups are azide
groups, cinnamoyl groups, spiropyran, coumarin and 2-
nitrobenzyl groups (Fig. 11) [156158].
Photosensitive properties can be applied as a trigger of
conformational change of polypeptides. For example, the
conformation of PLL modied with azobenzene was inves-
tigated in connection with their photochromic behavior
caused by the trans  cis photoisomerization of the azo
groups present in the side chains. These photosensitive
polypeptides exhibited photoinduced  helix changes,
explained on the basis of the differences in geometry and
hydrophobic character of the trans and the cis azoben-
zene units [159]. Fissi et al. prepared spiropyran modied
high molecular weight poly(glutamic acid). It was demon-
strated that the photoisomerization of the photochromic
side chains is able to trigger the coil/-helix transition
of the macromolecular main chains only in a narrow
window of solvent composition [160]. Besides polypep-
tides, aliphatic polyesters with chromophoric units have
also been extensively investigated. For example, photo-
cross-linkable polycarbonate was prepared by the ROP
of a functionalized cyclic carbonate monomer containing
a cinnamate moiety [46]. Li and coworkers reported a
well-dened photosensitive polymer, with chromophores
connected by pH-labile cyclic acetal linkages [161]. It was
demonstrated that the stability of pH-labile cyclic acetal
linkages could be tuned by the photoisomerization of cin-
namyl chromophores, which makes these polycarbonates
interesting in potential applications for photosensor devel-
opment and light-triggered drug delivery.
Coumarin has widespread occurrence in plants and
is used in biology, medicine, cosmetic and polymer sci-
ence [162]. It is used as a photoinduced cross linker in
biomedical applications. Yamamoto et al. prepared co-
poly(l-lysine) containing -7-coumaryloxyacetyl-l-lysine
residues. When irradiated by light, the photo-cross-linking
reaction proceeded slowly between coumarin moieties in
the side chains to give a cis head-to-head cyclo coumarin
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 257

N N

(A) R N
N R ' or T
R R

O
R
O O

(B) R
O
' O
O R
R
O
O

(C) R2 R2
O O
N ' N

R1 R1

RO OR RO OR

(D)

O O O O

O O O O

(E) RO
CHO

NO2 NO

Fig. 11. Chemical structures and photo-induced transitions of chromophores. (A) Reversible trans (left) and cis (right) geometric isomers of azobenzene. (B)
Reversible photodimerization of cinnamoyl groups. (C) Reversible photoisomerization of spirobenzopyran derivatives [156]. Copyright 2009, Royal Society
of Chemistry. Reprinted with permission. (D) Photo-cross-linking of the coumarin-modied polymers [157]. Copyright 2001, Wiley-VCH Verlag GmbH &
Co. KGaA. Reprinted with permission. (E) Dissociation of 2-nitrobenzyl derivatives [158]. Copyright 2007, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted
with permission.

[163]. Matsuda and coworker prepared a series of liquid
polymers of coumarin-endcapped poly(-caprolactone-co-
trimethylene carbonate) with different arms. These liquid
photocurable precursors were used to obtain desired
geometries of cross-linked biodegradable materials for the
microfabrication of medical devices and drug encapsula-
tion [164].
3.1.4. Redox responsive biopolymers
The distinct redox potential difference between the
intracellular space (reducing) and the extracellular space
(oxidizing) provides an opportunity for promising delivery
of drug based on disulde-containing polymers [165].
Disulde bonds are widespread covalent bonds in nat-
ural peptides and proteins and play an important role
in the folding and stability of proteins. They are readily
cleaved in reducing conditions and reoxidized in oxi-
dizing conditions. Due to these unique properties some
micelles sensitive to redox were prepared. In our previous
work, poly(l-cysteine)-b-polylactide (PLC-b-PLA) was
prepared. Because of the ease of disulde exchange with
thiols, the obtained micelles are reversible shell cross-
linked (SCL) micelles [98]. Lu et al. designed macrocyclic
1,4,7,10-tetraazacyclododecane-N,N ,N ,N -tetraacetic
acid (DOTA) Gd(III) chelate and PGA conjugate containing
a degradable disulde spacer as a magnetic resonance
imaging (MRI) contrast agent. The degradable disulde
spacer between Gd(III)-DOTA and PGA is crucial for the
release and excretion of Gd(III) chelates, which shows
great promise to solve the safety problems suffered by
macromolecular Gd(III) complexes [166]. The cleavage of
disulde bonds can also be designed as a trigger for drug
258 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
delivery. Tang et al. prepared a disulde-linked biodegrad-
able diblock copolymer of PCL and poly(ethyl ethylene
phosphate) to develop a micellar nanoparticle system for
intracellular drug release triggered by glutathione (GSH)
in tumor cells. As expected the intracellular DOX release
was accelerated at a higher GSH concentration, which led
to more signicant growth inhibition to A549 cells [167].
Kataoka and coworkers prepared PEG-SS-P[Asp(DET)
containing biocleavable disulde linkage between PEG
and polycation segments to trigger PEG detachment.
They explained that the detachment of PEG at the cell
surface can increase the cellular uptake of the micelles.
On the other hand, the detachment of PEG inside endo-
somes would cause the interaction between the exposed
cation segments and the endosomal membrane and/or
would increase endosomal pressure, enabling effective
endosomal escape [168].
Many other stimuli-responsive polymers are used in
the biomedical elds including polymers that are respon-
sive to glucose, electric or magnetic elds, ionic strength
responsive polymers. However, little work has been done
to incorporate these stimuli-responsive polymers into
synthetic biodegradable polymers. Therefore, they not
included here.
3.2. Electroactive biomaterials
After the discovery that electrical signals can reg-
ulate cell attachment, proliferation and differentiation
[169], many researchers sought to incorporate conduct-
ing polymers into biomaterials to take advantage of
electrical stimuli. In conducting polymers, polypyrrole
(Ppy) has been widely studied in biomedical applications.
Schmidt and coworkers made signicant contributions to
the application of PPy in the biomedical eld [170,171].
They rst employed PPy for tissue engineering purposes,
demonstrating that an electrical stimulus in neurotrophic
growth factors (NGF) induced PC-12 cells cultured on
PPy signicantly enhanced PC-12 neurite outgrowth and
spreading. Moreover, they further studied the cause of this
enhancement and concluded that the electrical stimula-
tion increased the adsorption of serum proteins, which
helped improve the growth and proliferation of cells. Sub-
sequently, Lakard et al. [172], George et al. [173] and several
other groups investigated cell adhesion and proliferation
by culturing different cell lines on PPy [174176].
Another conducting polymer, PANi, was studied by
Mattioli-Belmonte et al., demonstrating that PANi was
biocompatible in vitro and in long-term animal studies
in vivo [177]. Wei and coworkers [178] reported that PANi
lms functionalized with the bioactive laminin-derived
adhesion peptide YIGSR (Tyr-Ile-Gly Ser-Arg) exhibited
signicant enhanced PC-12 cell attachment and differen-
tiation.
Despite the advantage of these conducting polymers,
some issues related to their application still exist: poor
solubility in most common solvents, poor polymer-cell
interaction and the lack of biodegradability. Therefore, it
is a very important and challenging task to overcome these
limitations if conductive polymers are to be applied as tis-
sue engineering scaffolds.
As models of conducting polymers, oligomers showed
many advantages over polymers, such as good solubility
and easier synthesis. Because of the same redox behavior,
oligomers were used instead of conductive polymers
to obtain electroactive biomaterials. In 2002, Rivers et
al. rst incorporated pyrrole and thiophene oligomers
with aliphatic chains using degradable ester linkages to
fabricate a biodegradable electrically conducting poly-
mer (BECP). The polymer showed good biocompatibility
in vitro and in vivo as shown in Fig. 12 [169]. Guo et al.
[179] demonstrated that the electroactive silsesquioxane
precursor, N-(4-aminophenyl)-N -(4 -(3-triethoxysilyl-
propyl-ureido) phenyl-1,4-quinonenediimine) (ATQD),
containing aniline trimer covalently modied by oligopep-
tide could be a kind of promising biomaterial for tissue
engineering. Bioactive material ATQD-RGD could support
PC-12 cell adhesion and proliferation and could stimulate
spontaneous neuritogenesis in PC-12 cells in the absence
of NGF as shown in Fig. 13.
Based on the above work, Chen and coworkers., chose
aniline oligomers (especially aniline pentamer with dicar-
boxyl end groups) as an electroactivity resource, which
was incorporated with degradable polymers such as PLA,
PCL and natural biopolymer chitosan, to prepare new
biodegradable electroactive biomaterials. First, triblock
and multiblock copolymers of PLLA and aniline pentamer
were prepared by a condensation polymerization reaction
[180,181]. These copolymers possessed good electroactiv-
ity, solubility and biodegradability similar to pure PLA.
In vitro cell evaluation showed that the electroactive
copolymers were innocuous and could indeed promote
the attachment and growth of rat C6 glioma cells. More-
over, in comparison experiments with and without applied
electrical potentials, the doped electroactive copolymers
improved the differentiation of PC-12 cells, as shown in
Fig. 14.
Most electroactive polymers containing oligomers can-
not dissolve in water, hindering their application in vivo.
A new kind of water-soluble electroactive polymer, aniline
pentamer cross-linking chitosan, was prepared by Chens
group [182,183]. This new polymer showed good elec-
troactivity even in aqueous solution. The MTT assay, cell
adhesion test, and degradation assessment in the presence
of enzyme conrmed that these polymers had good bio-
compatibility and biodegradability. Electroactive polymers
can improve the neuronal differentiation of PC-12 cells,
even without the extra electrical stimulation, as shown in
Fig. 15.
For conducting polymers, high conductivity is consid-
ered to affect the growth and differentiation of cells;
however, oligomers without high conductivity and poly-
mers containing oligomers also showed improvement in
cell differentiation even without extra electrical stim-
ulation. In order to nd the reason, aniline pentamer
cross-linking chitosan with a low molecular weight was
prepared [183]. Adding this electroactive polymer in
culture medium can promote the differentiation and pro-
liferation of the cells because the cells readily exhibited
neural-like phenotype (Fig. 16(a and b)). While the cells
showed only proliferation without electroactive polymer
in culture medium (Fig. 16(c and d)). In the culture medium,
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 259

Fig. 12. In 2002, Rivers et al. rstly incorporated pyrrole and thiophene oligomers with aliphatic chains using degradable ester linkages to fabricate a
BECP. Biocompatibility assessment of BECP showed good biocompatibility in vitro and in vivo for this polymer. (A) Human neuroblastoma cells cultured in
vitro on BECP lms demonstrated attachment and neurite extension after 1 day(left) and signicant proliferation after 8 days (right), indicating good cell
compatibility. (B) BECP and FDA-approved poly(lactic-co-glycolic) (PLGA) (control) were implanted subcutaneously in rats to assess in vivo compatibility.
Histological tissue sections (stained with hematoxylin and eosin) of implanted BECP (left) and PLGA (right) demonstrated comparably low inammatory
responses on the 29th day [169].
Copyright 2002, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission.

the only difference due to the electroactive polymers may
be the exchange of the ions between the medium and
polymer, and between the polymer and cells, so that the
electroactivity changed the ion exchange between the cells
and the medium.
Although conducting polymers have good biocompati-
bility and can stimulate cell differentiation under electrical
stimulation, the non-degradability of the polymer and dif-
culty in processing have inhibited the medical applications.
Polymers containing electroactive oligomers not only have
good solubility and biocompatibility, but also can stimulate
the differentiation of cells even without extra stimula-
tion. If the mechanism between the electroactivity and
cell differentiation could be elucidated, the electroactive
biomaterials could have more applications in elds such
as neuronal tissue engineering, cardiovascular tissue engi-
neering, etc.
3.3. Specic bonding biopolymers
Alternative biodegradable platforms have been
described in studies of nanoconjugate drug deliv-
ery polymers such as poly(l-glutamic acid)s, PLHis,
polysaccharides, and PLLA, PLGA [184186]. As drug or
DNA carriers, they can self-assemble into small sized
(10200 nm) particles when conjugate to hydrophilic,
hydrophobic or pH and thermo sensitive polymers. This
enhances the permeability and retention effect in tumor
vasculature and makes them suitable for injection and
enhances their deposition in tumors, a strategy called
passive targeting [187]. Passive targeting can make
nanoparticles approach tumor cells and deposit to a
degree, but not interact with cancer cells directly. This
results in decreased efciency for tumor therapy.
Specic targeted delivery is an active targeting method
directed to a particular function group-target conjugate
to help overcome the deciency in the passive targeting
protocol. Targeted delivery can deposit anticancer drugs
or DNA at desired sites, reducing systemic toxicity and
enhancing therapeutic efcacy [188190]. Active targeting
is achieved by linking targeting ligands such as antibodies,
peptides, nucleic acid aptamers (Apt), carbohydrates, and
small molecules to the surface of long-circulating nanopar-
ticles, to deliver the drug encapsulated nanoparticles to
specially identied sites to minimize undesired effects
[191]. Specic targeting can be induced by conjugation of
targeting ligands to the shell of the micelles, which are
prone to uptake into tumor cells. Recent studies showed
that targeted nanoparticles have better antitumor activity
compared with nontargeted nanoparticles [192195].
Antibodies that retain the specicity for their targets
are now more commonly used for active targeting ther-
apeutics. Several antibodies have been used in clinic to
target receptors expressed specically on tumor cells.
For example, Herceptin is an antibody against Her-2
and Avastin (bevacizumab) is a monoclonal antibody
targeting the vascular endothelial growth factor (VEGF)
[196]. McCarron et al. constructed nanoparticles com-
prising a layer of peripheral antibodies (Ab), directed
towards the Fas receptor (CD95/Apo-1) covalently attached
to PLGA nanoparticles loaded with camptothecin. Cytotox-
icity studies of the camptothecin contained nanoparticles
comprising a layer of peripheral antibodies on HCT116 cells
showed that they were very effective, with almost 100%
efciency at 72 h [197].
Peptides with short sequences of 510 amine acids can
be used in binding assays to target tumors. One example is
a cRGD peptide with a sequence of cyclic (Arg-Gly-Asp-d-
 260
H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 13. Wei et al. demonstrated that the electroactive silsesquioxane precursor, ATQD, containing aniline trimer covalently modied by oligopeptide could be a kind of promising biomaterial for tissue engineering.
Bioactive material ATQD-RGD could support PC-12 cell adhesion and proliferation and could stimulate spontaneous neuritogenesis in PC-12 cells in the absence of NGF as shown in this gure. (A) Phase contrast
images of PC-12 cell morphology of (a) TCP, (b) TCP with NGF, (c) ATQD-RGD, and (d) ATQD-RGD with NGF on day 10; (B) Neurite length distribution chart for ATQD-RGD substrates with and without NGF [179].
Copyright 2007, American Chemical Society. Reprinted with permission.
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280 261

Fig. 14. Triblock and multiblock copolymers of PLA and aniline pentamer possessed good electroactivity, solubility and biodegradability similar to pure
PLA. In vitro cell evaluation showed that the electroactive copolymers were innocuous and could indeed promote the attachment and growth of rat C6
glioma cells. Moreover, in the comparison experiments with and without applying electrical potentials, the doped electroactive copolymers had the ability
of improving the differentiation of PC-12 cells. (A) Representative uorescence micrographs of PC-12 cells for the substrates (a) TCPS () without electrical
stimulation, (b) TCPS (+) exposed to electrical stimulation, (c) EM PLAAP () doped with CSA without electrical stimulation, (d) EM PLAAP (+) doped with
CSA exposed to electrical stimulation on day 4; (B) the mean neurite length of PC-12 cells cultured on the substrates of EM PLAAP (), TCPS (+), and EM
PLAAP (+) on day 4 [181].
Copyright 2008, American Chemical Society. Reprinted with permission.

Phe-Lys), which targets the v 3 integrin. Nasongkla et al.
conjugated cRGD to maleimide-terminated poly(ethylene
glycol)-PCL (MAL-PEG-PCL) copolymer with a uorescent
marker in the micelle core [198]. The result by ow cytom-
etry showed that the percentage of cell uptake increased
with increasing cRGD density on the micelle surface and
there was a 30-fold increase with 76% cRGD attachment.
Nucleic acid ligands such as Apt and spiegelmers
are DNA or RNA oligonucleotides that represent novel
classes of target agents. In vivo studies were car-
ried out by Farokhzad and coworkers [194] by intra-
tumoral injection of xenografted nude mice with LNCaP
tumor cells using Dtxl-encapsulated nanoparticles of
poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene gly-
col) copolymer with the A10 2 -uoropyrimidine RNA
Apt. The result showed that ve of seven xenografted
nude mice demonstrated complete tumor reduction
with Dtxl-Nanoparticles-Apt bioconjugates injection while
only two of seven xenografted nude mice demon-
strated complete tumor reduction with Dtxl-Nanparticles
injection. This result demonstrates the potential util-
ity of nanoparticle-Apt bioconjugates for cancer ther-
apy.
Carbohydrates such as galactose and mannose are found
to be specic ligands to the asialoglycoprotein receptor
(ASGPR), which is overexpressed in hepatocellular carci-

Fig. 15. Aniline pentamer cross-linking chitosan can obviously improve the neuronal differentiation of PC-12 cells even without the extra electrical
stimulation. The visualization of PC-12 neurite outgrowth by micrographs are given here for the substrates (A) without electroactivity (chitosan), and (B)
with electroactivity (aniline pentamer cross-linking chitosan) on the fth day [183].
Copyright 2008, American Chemical Society. Reprinted with permission.
262 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

Fig. 16. After adding the aniline pentamer cross-linking chitosan polymer in the culture medium directly, the cells showed obvious differentiation with
electroactivity, but the cells showed obvious proliferation without electroactivity. Here is the visualization of C-6 outgrowth by micrographs in the culture
medium with electroactivity ((a) and (b)), and without electroactivity ((c) and (d)).

noma [199], making it a useful target for liver-specic
chemotherapy. Cho and coworkers loaded paclitaxel inside
the galactose-conjugated poly(ethylene glycol)-co-poly(-
benzyl l-glutamate) block copolymer (gal-PEG-b-PBLG)
micelles [200]. A comparison study showed that the
in vitro cytotoxicity of micelles loaded with galactose
demonstrated a 30% increase compared to an analogous
non-ASGPR expressing cell line SK-Hep01.
As a form of vitamin B, folic acid (FOL) is a small
organic molecule for cancer targeting. The expression of
folate receptors is higher in many epithelial tumors than
in normal tissue. It is over expressed in more than 90% of
ovarian carcinoma. For example, the FOL receptor is over-
expressed (100300 times) in a variety of tumors [201].
Park and coworkers functionalized DOX-containing PEG-
PLGA micelles with FOL to show signicantly increased
uptake and cytotoxicity in KB cells [200].
3.4. Biopolymers for tracing and bioimaging
Bioimaging and tracing, such as optical imaging, MRI,
nuclear imaging, and ultrasound have been important tools
for disease diagnosis and treatment, and are used in clinical
applications to provide predominantly either anatomical
information or functional information at a macroscopic
level [202]. However, current imaging probes are poor in
sensitivity and specicity, hampering their application. In
recent years, biopolymer-based bioimaging probes have
emerged from the combination of imaging components
and biodegradable synthetic polymers such as block, graft,
branched, multivalent copolymers and dendron-like poly-
mers with enhanced stability, low toxicity, long half-life
and improved target specicity [203]. This section reviews
the current development in biopolymer-based imaging and
tracing probes and their potentials in biomedical applica-
tions.
3.4.1. Biopolymers for optical tracing and bioimaging
Optical tracing and bioimaging are among the most
important technologies in the biomedical eld and suit
clinical application in that uorescent probes have low
toxicity, high sensitivity, and can recognize molecules, pro-
teins, etc. Optical tracing and bioimaging include many
different acquisition techniques using light with vari-
ous wavelengths. Near-infrared uorescent (NIRF) imaging
probes are particularly useful because near-infrared (NIR)
light can penetrate tissue due to relative weak absorption
of NIR by the components in the surface tissue, such as
hemoglobin, water and lipids. Ideal NIRF probes for opti-
cal imaging in vivo should have the characteristics of peak
uorescence in a range from 700 to 900 nm, high quan-
tum yields, narrow excitation/emission spectra, functional
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
groups for chemical conjugations, high chemical and photo
stability, excellent biocompatibility, biodegradability, exc-
retability, etc. [204]. Biopolymer based NIRF probes are
more available in clinic because of their long half-life in vivo
circulation, stability, low toxicity, high targeting ability and
a low background signal. In this part, the development of
biopolymer based NIRF probes is summarized.
3.4.1.1. Biopolymer-based organic probes. Most NIRF
biopolymer-based organic probes are similar to indocya-
nine green (ICG) in structure. ICG is a tricarbocyanine
dye, approved for clinical ophthalmic retinal angiography,
cardiac function, and liver function testing by FDA. Many
NIRF cyanine dyes have been synthesized, and several of
them including Cy5.5 and Alexa 680 are commercially
available [205].
The most widely-applied biopolymer-based organic
probes, for which some barriers such as rapid clearance
in vivo were avoided, were developed by Weissleder and
colleagues. This group explored the use of biocompati-
ble and optically quenched NIRF imaging probes with an
enzymatically cleavable polymer backbone that can gen-
erate a strong NIRF signal after enzyme activation [206].
A graft copolymer consisting of PLL sterically grafted by
multiple MPEG chains was used as a vehicle of quenched
probes to tumors. Each PLL backbone includes an average
of 92 MPEG molecules and 11 Cy5.5 molecules, yielding
(Cy5.5)11 -PLL-g-MPEG92 . The graft copolymer contains 44
unmodied lysines on the backbone as sites for cleavage
by enzymes, such as trypsin and cathepsines with lysine-
lysine specicity. In in vivo experiments, the NIRF probe
carrier accumulated in solid tumors due to its long circu-
lation time and the enhanced permeability and retention
(EPR) effect. EPR effects exit in solid tumors. They have
rich blood vessels which have irregular and imcomplete
architectures. Large gaps exit between endothelial cells.
At same time, impaired lymphatic clearance also exit in
solid tumors. All these factors lead to high selective per-
meability and retention of macromolecules and lipids in
solid tumors, which was dened as EPR effect [187]. In vivo
imaging showed a 12-fold increase in NIRF signal after the
copolymer was cleaved by lysosomal proteases in tumor
cells, allowing the detection of tumors with submillimeter-
sized diameters.
The family of matrix metalloproteinases (MMPs) that is
overexpressed in tumor comprising over 20 enzyme sub-
types is an important target site for NIRF probes. Matrix
metalloprotease-2 (MMP-2) (i.e., gelatinase) can cause the
degradation of the extracellular matrix, and is involved
in tumor inltration and tumor-induced neovasculariza-
tion. The MMP-2-activatable NIRF probes with the MMP-2
substrate peptide Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys(FITC)-
Cys-NH2 can be used to distinguish an MMP-2-positive cell
line, the human brosarcoma cell line (HT1080), from an
MMP-2-negative cell line, the human breast cancer cell line
(adenocarcinoma, BT20), and to determine the expression
level of tumoral MMP-2 in vivo [207].
As MMPs, cathepsins including cathepsin D (CaD)
and cathepsin B (CaB) are overexpressed in tumor and
have potential use as tumor imaging targeting sites. A
biopolymer PLL-g-MPEG based NIRF probe with CaD-
263
specic peptide Gly-Pro-Ile-Cys(Et)-Phe-Phe-Arg-Leu-Gly-
Lys(FITC)-Cys-NH2 was prepared by Weissleder and
coworkers, and used to demonstrate for the rst time that
CaD enzyme has activity directly in vivo [208].
3.4.1.2. Biopolymer-based inorganic probes. Compared
with organic probes, inorganic probes such as quantum
dots (QDs) and gold nanoparticles (AuNPs) have several
advantages, including tunable excitation and emission
wavelengths, high quantum yields, specic targeting
ability, high quality photos and chemical stability [209].
Biopolymer conjugated inorganic probes have long cir-
culation time, low immunogenicity, low toxicity and the
ability to penetrate leaky endothelial barriers to overcome
the limitation of nude inorganic probes [204].
QDs are among the most promising and fascinating
uorescent labels for biotracing and bioimaging. Wu and
coworkers used amphiphilic PEG-b-PLL diblock copoly-
mer coated QDs that could highly specically link to
immunoglobulin G (IgG) and streptavidin to label the
breast cancer marker Her2 on the surface of xed and live
cancer cells. Compared with organic dyes such as Alexa 488,
functional QDs are more specic, bright and photostable.
This group simultaneously detected two cellular targets
with one excitation wavelength through functional QDs
with different emission spectra [210].
Chen and coworkers reported a biopolymer based probe
labeled with arginine-glycine-aspartic acid (RGD) peptide
using PEG as the linker (Fig. 17) [211]. The probe was
demonstrated to target integrin v 3 overexpressed by the
majority of tumor vasculature in vitro, ex vivo, and in living
mice. After six hours of the injection of the QD705-PEG-
RGD probe, the maximum uorescence signal intensity was
shown in tumor tissue, with good contrast to nude QD705
and Cy5.5-RGD.
Park and colleagues prepared polyethylene glycol
(PEG) modied-12 nm quantum dot-streptavidin (QD-
strep) nanoparticles with a biotin-cell penetrating peptide
(CPP) bound to the surface via biotin-streptavidin interac-
tions, which could be specically dePEGylated in response
to the presence of the matrix MMP-2 enzyme (Fig. 18)
[212]. More than nine PEG chains per single QD were
needed to effectively inhibit the cellular uptake of modi-
ed QD particles. The cellular uptake of modied QD was
down to around 20% compared with that of a nude QD. After
the cleavage of the MMP-2-specic substrate in the immo-
bilized PEG chains, the cells took up the QDs by exposing
cell-penetrating peptides to the cell membrane.
AuNPs are also potential uorescent agents for bio-
tracing and imaging. Mason and coworkers prepared a
biopolymer based uorescent probe using 15 nm AuNPs
stabilized by heterobifunctional PEG and covalently com-
bined with F19 monoclonal antibodies [213]. Darkeld
microscopy was used to image the tissue samples near
the nanoparticle resonance scattering maximum (560 nm).
Tumor tissue samples treated with gold nanoparticles
with nonspecic control antibodies and healthy pancreatic
tissue treated with mAb-F19-conjugated gold nanoparti-
cles both exhibited correctly negative results and showed
no tissue imaging. Similarly, gold nanoparticles and gold
nanorods immobilized by a PLGA-g-MPEG graft copolymer
264 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280

Fig. 17. A biopolymer based probe was labeled with RGD peptide using PEG as the linker. PEG denotes poly(ethylene glycol) (Mw = 2000) [211].
Copyright 2006, American Chemical Society. Reprinted with permission.

Fig. 18. Schematic presentation of MMP-2-enzyme-specic dePEGylation and intracellular QD delivery [212].
Copyright 2009, American Chemical Society. Reprinted with permission.
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
showed excellent stability in aqueous solution at different
pH values and elevated temperatures as well as in serum.
These characteristics make these very powerful materials
for in vivo applications including drug delivery or imaging
[214].
3.4.2. Biopolymers for MRI
MRI can provide superb anatomical information and
produce high quality imaging in vivo with high spatial
and temporal resolutions. Compared with other imaging
modalities, MRI yields several advantages such as being
non-invasive, non-ionizing radiation, excellent soft tissue
contrast, high sensitivity to blood ow and discrimination
in any imaging plane. Biopolymer-based MRI bioimag-
ing probes have some advantages such as low toxicity,
increasing contrast, long half-life of in vivo circulation and
easy functionalization. They have promising potentials in
biomedical applicaition [202,203]. Several paramagnetic
(Gadolinium (Gd) based) and superparamagnetic (iron
oxide) MRI probes are discussed in detail below.
3.4.2.1. Biopolymer-based paramagnetic probes. Paramag-
netic or positive contrast MRI probes are metal ions with
unpaired electrons, such as Gd3+ , Mn2+ , etc. Biopolymer-
based paramagnetic MRI probes are available in clinics
because of their advantages, such as low toxicity and sta-
bility.
Gd is an excellent MRI probe because of its short T1
and ferromagnetic properties. Gd-chelate probes modied
with biocompatible synthetic polymers such as polypep-
tides and PEG have unique pharmacological properties and
can be used in vivo. Gupta et al. reported a biopolymer-
based MRI probe that was Gd-labeled and functionalized
with a PLL-g-MPEG-DTPA (diethylenetriaminepentaacetic
acid) graft copolymer to modulate functional properties
[215]. In their experiments, twelve rats were treated with
1.5-T MRI after intravenous injection of Gd labeled MPEG-
PLL-DTPA with a dose of 35 mol kg1 . The vasculatures of
the infected and contralateral normal legs were depicted
well immediately after intravenous injection of the probe.
The biopolymer-based probe was accumulated at the site of
infection 12 h after injection and was more pronounced at
24 h; the signal intensity at inammation sites went down
to the baseline after 72 h.
Lu and colleagues synthesized biodegradable
biopolymer-based Gd-DTPA l-cystine bisamide copoly-
mers (GCAC) as safe and effective probes for MRI and
evaluated their biodegradability and efcacy in MR blood
pool imaging in an animal model [216]. The polymeric
Gd(III) chelates readily degraded into smaller molecules
in incubation with 15 mM cysteine via disulde-thiol
exchange reactions in vitro and in vivo and showed strong
contrast enhancement in the blood pool, major organs
and tissues of rats at a dose of 0.1 mmol Gd kg1 . The
GCAC MRI probe, which can degrade into low molec-
ular weight Gd(III) chelates and can be rapidly cleared
from the body, has potential for use in cardiovascular
and tumor MRI. In a similar manner and by the same
group, PLGA-cystamine-(Gd-DO3A) was synthesized in
high yield with 55% Gd-DO3A conjugation efciency and
the contrast-enhanced MRI was investigated in mice
265
bearing MDA-MB-231 breast carcinoma xenografts [217].
The PLGA-cystamine-(Gd-DO3A) MRI probe resulted in
signicant contrast enhancement in the blood pool, major
organs and tumor tissue, but minimal long-term tissue
retention.
Biodegradable polysuccinimide (PSI) derivatives conju-
gated with diethylenetriaminepentaacetic acid Gd (DTPA-
Gd) [PSI-g-mPEG-C16-(DTPA-Gd)] were synthesized as
biopolymer-based MRI probes by Cho and colleagues [218].
In vitro MRI tests with a concentration of Gd below
9.4 104 M showed an image contrast better than that of
Omniscan , a commercial product; the signal intensity of
PSI-mPEG-C16-(DTPA-Gd) at 1.2 104 M (Gd) was similar
to the signal intensity of Omniscan at 4.7 104 M (Gd).
3.4.2.2. Biopolymer-based superparamagnetic probes.
Superparamagnetic or negative contrast MRI probes based
on iron oxides can provide higher contrast and good bio-
compatibility, and are easily produced. Biopolymer-based
superparamagnetic MRI probes are fascinating for their
stability, low toxicity and good contrast [219].
Rife and coworkers immobilized 8.8 nm superpara-
magnetic iron oxide (SPIO) particles with hydrophilic
triblock copolymers containing controlled concentrations
of carboxylic acid groups in the central segments and
poly(ethylene oxide) tails (PEO-b-COOH-b-PEO). This MRI
probe was stable at the physiological pH (7.4) and lower pH
values than 7.4, suggesting that it will be stable in blood.
The saturation magnetization of this probe was approxi-
mately 6570 emu g1 , which was better than others [220].
Superparamagnetic polymeric micelles with SPIOs sta-
bilized by amphiphilic MPEG-b-PCL were prepared by Gao
and colleagues as a new MRI probe with high sensitivity
[221]. The hydrophilic PEG corona made the MRI probes
stable in aqueous solution with an ultrasensitive MRI
detection limit of 5.2 g mL1 (5 nM). Similarly, an alterna-
tive synthetic approach was investigated with manganese
doped superparamagnetic iron oxide (Mn-SPIO) nanopar-
ticles in place of SPIO to form ultrasensitive MRI contrast
agents for liver imaging by Ais group [222]. The MPEG-b-
PCL based MRI probes had a T2 relaxivity of 270 (Mn+Fe)
mM1 s1 . With these probes, the liver contrast signal
intensity changed 80% at 5 min after intravenous injection
and the time window for enhanced-MRI could reach at least
36 h.
Gao and coworkers prepared multifunctional poly-
meric micelles from cRGD-PEG-b-PLA, composed of DOX
that can be released through a pH-dependent mech-
anism. In this process cRGD ligands rst target v 3
integrins on tumor endothelial cells. and subsequently
induce receptor-mediated endocytosis for cell uptake, and
then SPIO nanoparticles are loaded inside the hydrophobic
core for MRI detection [223]. With the biopolymer-based
mulitifunctional MRI probes, efcient v 3 -mediated
endocytosis led to a more signicant darkening contrast
of MRI from cRGD-encoded micelles compared with that
without cRGD. Specically, at a level of 6.25 Fe g mL1 , the
MRI signal intensity decreased from 73.8 7.0 for micelles
without cRGD to 30.2 3.5 for cRGD-encoded micelles.
266 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
3.4.3. Other biopolymer-based tracing and bioimaging
In addition to optical bioimaging and tracing, nuclear
bioimaging including planar gamma scintigraphy (PGS),
single photon emission computed tomography (SPECT),
positron emission tomography (PET), ultrasound imaging,
and X-ray computerized axial tomography (CT) are also
important imaging technologies used in clinic.
Nuclear imaging techniques have the advantages of
excellent sensitivity, so that a minute quantity of tracer
molecules is needed and rich biochemical information on
pathological conditions. Therefore, these techniques are
widely used in clinics. PGS can compress the complex
anatomical structure of organs into a two dimensional
representation, with quantication of tissue distribution
as a percentage of the injected dose. Biopolymer-based
PGS probes have been developed with high stability and
specicity. To increase targeting, Torchilin prepared a
polychelating agent-biotin conjugate through the interac-
tion of biotin-maleimide with PLL modied with multiple
residues of diethylenetriaminepentaacetic acid, which con-
tained amino-terminal pyridylthio-propionate groups. It
can be easily loaded with multiple metal atoms such,
as 111 In, and can interact specically with avidin (as
agarose) [224]. 111 In-loaded DTPA-PLL-Biotin could be
delivered to an avidin-containing matrix with almost 15
times more radioactivity than DTPA-biotin under the same
conditions. Similarly, Li and colleagues prepared a PGS
radiotracer 111 In-DTPA-PEG-C225 using PEG as a linker
between the monoclonal antibody and metal chelator
DTPA. The probes can be selectively localized to A431
tumor xenografts, in which the endothelial growth fac-
tor receptor (EGFR) is overexpressed 3-fold higher than
in MDA-MB-468 xenografts. They probes also can reduce
liver uptake level, resulting in improved visualization of
EGFR-positive tumors [225,226].
Single photon emission computed tomography (SPECT)
can be used to obtain three-dimensional information
with the same probes as those for PGS, and PET, offer-
ing more accurate imaging data with the limitation of
short half-life of PET probes. 99m Technetium-labeled DTPA-
PEG-folate targeting the lymphatic system of metastatic
tumors was prepared and tested by Lu and coworkers
[227]. The biopolymer based SPECT radionuclide entered
KB cells through the folate receptor endocytosis pathway
in vitro. DTPA-PEG-folate was in excess of 98% in radiola-
beled yield while specic activity of 7.4 kBq (0.2 Ci g1 )
was achieved. After subcutaneous injection, the probes
exhibited an initial increase and subsequent decline of
accumulation in popliteal nodes in normal Wistar rats.
A fast accumulation and clearance was observed with a
radioactivity amount of 5.91 1.55% ID g1 in the lymph
nodes at 15 min post-injection; it increased to the maxi-
mum (13.43 2.21% ID g1 ) at 1 h and then decreased to
2.31 0.28% ID g1 at 4 h. Except for the kidney, uptake
of [99m Tc]DTPA-PEG-folate by other tissues was rather lit-
tle. The lymphatic vessels were readily visualized by SPECT
with this probe in a normal rabbit imagine study.
Ultrasound bioimaging has many advantages, such as
versatility, being noninvasive, low risk and being cost-
effective, so it is widely used in clinics. The most used
approach of ultrasound bioimaging is the intravenous
injection of microbubbles, based on the principle of using
sound waves to detect a difference in density between
the probe (microbubbles) and the surrounding medium
(blood or soft tissue) at different time points during the
examination. Many biocompatible, biodegradable and non-
toxic polymers such as PLA, PCL, poly(d,l-lactic-co-glycolic
acid) and even polypeptides can be used to encapsu-
late microbubbles used as ultrasound bioimaging probes
[228,229].
Like MRI, CT has high spatial and temporal resolutions
and can provide superb anatomical information. Therefore,
it is one of the most useful diagnostic tools. Current con-
trast agents for CT are based on iodinated small molecules
because of their high X-ray absorption coefcient, with
the limitation of short imaging times. Biopolymer-based
CT probes are more available in clinics for their long cir-
culation time in plasma and good efcacy/safety prole
in vivo. AuNPs coated with PEG imparted with antibiofoul-
ing properties were prepared as a CT probe by Jon and
coworkers [230]. The X-ray absorption coefcient of this CT
probe was 5.7 times higher than that of Ultravist , a current
iodine-based CT contrast probe. This new probe showed a
much longer blood circulation time (>4 h) than Ultravist
(<10 min) after intravenous injection, and accumulated in
the organs containing phagocytic cells, such as the spleen
and the liver. In addition, a high contrast (2-fold) between
hepatoma and the normal liver tissue on CT imaging was
achieved after intravenous injection of this new CT probe.
4. Biomedical application
4.1. Medical devices
Synthetic biodegradable polymers have attracted con-
siderable attention for applications in medical devices, and
will play an important role in the design and function of
medical devices. The general criteria of polymer materi-
als used for medical devices include mechanical properties
and adegradation time appropriate to the medical pur-
pose. In addition, the materials should not evoke toxic or
immune responses, and they should be metabolized in the
body after fullling their tasks. According to these require-
ments, various synthesized biodegradable polymers have
been designed and used. Some synthesized biodegradable
polymers that have been used or show potential in selected
elds are summarized below.
4.1.1. Drug-eluting stents (DES)
DES have been widely used as a default treatment
for patients with coronary artery disease. Biodegradable
polymers are always used as a biodegradable and biore-
sorbable coatings on stents to control the release of drugs
[231]. Studies of some stainless steel stents coated with
sirolimus and PLA, such as Excel (JW Medical System,
China), Cura (Orbus Neich, Fort Lauderdale, Florida) and
Supralimus (Sahajanand Medical Technologies, India),
showed some interesting preliminary results [231,232]. In
addition, stents coated with polyurethane as drug control
layers were also reported [233].
Beside being used as biodegradable coatings, biodegrad-
able polymers are also candidate materials for fully
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
biodegradable stents [234] because of their suitable prop-
erties for controlled drug release and good mechanical
performance to prevent stents from deforming or fractur-
ing. PLLA was used to prepare a fully degradable stent [235]
and an everolimus-PLLA stent (BVS , Abbott Laboratories,
IL, USA), which were under clinical evaluations [236].
4.1.2. Orthopedic devices
In the 1960s, poly(glycolide) was used to prepare com-
pletely biodegradable and bioresorbable sutures [237].
Since then, poly(glycolide), poly(lactide) and other materi-
als such as poly(dioxanone), poly(trimethylene carbonate),
PCL and poly [d,l-(lactide-co-glycolide)] have been widely
used for medical devices [238].
Orthopedic devices made from biodegradable materials
have advantages over metal or nondegradable materials.
They can transfer stress over time to the damaged area as
it heals, allowing of the tissues, and there is no need of
a second surgery to remove the implanted devices. Many
commercial orthopedic xation devices such as pins and
rods for bone fracture xation, and screws and plates for
maxillofacial repair are made of PLLA, poly(glycolide) and
other biodegradable polymers [238,239]. As summarized in
the review by Middleton and Tipton [238], many orthope-
dic xation devices are commercially available. However,
the research on devices for load-bearing bone repair and
implantable medical devices still has a long way to go.
4.1.3. Disposable medical devices
In the 21st century, environment factors concern
all manufacturing industries. Many disposable medical
devices, such as syringes, injection pipes, surgical gloves,
pads, etc., are usually made of non-degradable plastics,
resulting in serious environmental and economic issues.
PLA, poly(glycolide), poly[d,l-(lactide-co-glycolide)] and
PCL are all biodegradable. Therefore, they are promising
materials for use in disposable medical devices meeting
environmental friendly requirements. These biodegrad-
able polymers have been used to prepare some disposable
medical devices and will likely have a widening commer-
cial application.
4.1.4. Other medical devices
Biodegradable polymers have also been used to pre-
pare anastomosis rings used for intestinal resection [240],
drug delivery devices [241243], in situ forming implants
[244,245] and stents used in urology [246].
4.2. Tissue engineering
Tissue engineering is an interdisciplinary eld that
applies the principles of engineering and life sciences
towards the development of biological substitutes used to
restore, maintain or improve tissue functions [247,248].
The main purpose of tissue engineering is to overcome the
lack of tissue donors and the immune repulsion between
receptors and donors. In the process of tissue engineering,
cells are cultured on a scaffold to form a natural tissue, and
then the formed tissue is implanted in the defect part in the
patients. In some cases, a scaffold or a scaffold with cells is
implanted in vivo directly, and the hosts body works as
267
Table 4
Some applications and potential applications of synthetic biopolymers.
Polymer Tissue engineering
Polyanhydrides Bone tissue engineering [262]
Polyurethane Vascular tissue engineering [263]
Bone tissue engineering [264]
Polyelectroactive materials Nerve tissue engineering [177]
Polyphosphoester Bone tissue engineering [266]
Poly(propylene fumarate) Bone tissue engineering [273]
Polyesterurathane Genitourinary tissue engineering [272]
a bioreactor to construct new tissues (Fig. 19). A success-
ful tissue engineering implant largely depends on the role
played by three-dimensional porous scaffolds. The ideal
scaffolds should be biodegradable and bioabsorbable to
support the replacement of new tissues. In addition, the
scaffolds must be biocompatible without inammation or
immune reactions and possess proper mechanical proper-
ties to support the growth of new tissues.
Synthetic biopolymers such as PLLA, PCL, PGA,
poly(glycolide) and poly[d,l-(lactide-co-glycolide)] have
excellent biocompatibility and good mechanical properties
and have been licensed by FDA for in vivo applications, so
they have been the most widely used materials for tissue
engineering scaffolds [249]. Considerable research has
been carried out about PLLA, PCL, PGA, poly(glycolide) and
poly[d,l-(lactide-co-glycolide)] used in bone tissue engi-
neering [249252], cartilage tissue engineering [253,254],
cardiovascular tissue engineering [255], arterial replace-
ment [256], heart valve tissue engineering [257], small
intestine tissue engineering [258], nerve regeneration
tissue engineering [259261], engineering of dermal sub-
stitutes for skin regeneration [262], ligament replacement
[263], genitourinary tissue engineering [264,265] and
other elds. Other synthetic polymers such as polyan-
hydride [266], polyurethane [267,268], polyelectroactive
materials [181], PPE [269,270] polycarbonate [33,56],
poly(ester amide) [271], poly(amino acid) [272,273]
biodegradable hydrogels [274,275] polyesterurathane
[276], poly(propylene fumarate) [277] are also biodegrad-
able and have shown many potential applications in tissue
engineering. Table 4 lists the application or potential
applications of these biodegradable polymers in tissue
engineering.
A limitation of these synthetic polymers is that the
materials lack biological cues that can promote cell adhe-
sion, proliferation and tissue recovery. In order to improve
the bioproperties of synthesized polymers and to enhance
their interactions with cells, composites of synthetic
biodegradable polymers and natural polymers or natural
polymer modied synthetic biodegradable polymers, and
biodegradable polymers blends have been used to pre-
pare tissue engineering scaffolds [278282]. In addition,
biopolymers with functional groups or synthesized poly-
mers modied with different methods are showing many
potential applications. For example, Deng et al. [76] pre-
pared a new type of triblock copolymer poly(glutamic
acid)-b-poly(l-lactide)-b-poly(glutamic acid), with PLLA
chains as the hydrophobic part and poly(glutamic acid) as
the hydrophilic part. RGD was connected to the polymer
268 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 19. In the process of tissue engineering, cells are cultured on a scaffold to form a natural tissue, and then the formed tissue is implanted in the defect
part in the patients. In some cases, a scaffold or a scaffold with cells is implanted in vivo directly, and the hosts body works as a bioreactor to construct
new tissues [248].
Copyright 2009, Royal Society of Chemistry. Reprinted with permission.
chains, to prepare a polymer with improved biocompatibil-
ity and enhancied cells adhesion and spreading, showing
potential applications in tissue engineering. Huang et al.
[180] prepared a kind of bioelectroactive triblock copoly-
mer (PLLA-PA-PLLA) possessed good electroactivity and
biodegradability, demonstrating potential applications as
a scaffold in neuronal or cardiovascular tissue engineer-
ing. Wang et al. [283] reviewed various methods modifying
bulk or surface properties of PLA for use as scaffolds in
tissue engineering.
Synthesized biodegradable polymers have been used
to prepare nanocomposites in tissue engineering to
combine advantages of different materials together. Poly-
mer/bioceramic composites such as PLLA/hydroxyapatite
and PLLA/bioactive glass nanocomposites have been widely
studied in bone tissue engineering [284,285]. Other inor-
ganic based biodegradable polymer composites such as
carbon nano-tube based composites are also used in tissue
engineering [286].
However, most of the present research concerning
the above-discussed materials is still under development;
practical applications remain for the future.
4.3. Drug delivery and control release
Biodegradable polymers with reactive groups or
responsive characteristics have been widely investigated
for applications drug delivery and control release.
Biodegradable polymers, such as poly(-malic acid),
with reactive pendant carboxyl groups, can conju-
gate drugs (via ester or amide bonds) to form a
biodegradable macromolecular prodrug to reduce the
side-effects of free drugs. Drugs can be released via the
degradation of biodegradable polymers. Ohya et al. pre-
pared poly(-malic acid)/DOX conjugates by attaching
DOX to poly(-malic acid) via ester or amide bonds
[287]. The poly(-malic acid)/amide/DOX conjugate
showed much lower cytotoxic activity than free DOX
and poly(-malic acid)/amide/DOX conjugate [287].
Jing and coworkers reported a poly(ethylene glycol)-
block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene
carbonate)/Dtxl (PEG-b-P(LA-co-MCC/Dtxl)) conjugate
[56]. The poly(ethylene glycol)-block-poly(l-lactide-
co-2-methyl-2-carboxyl-propylene carbonate/docetaxel
(PEG-b-P(LA-co-MCC)/Dtxl) conjugate showed high cyto-
toxic activity against HeLa cancer cells. Poly(amino acids)
such as poly(glutamic acid) and poly(l-lysine) have a
high density of side reactive groups (carboxyl or amine)
for coupling reactions. Poly(glutamic acid)-paclitaxel
conjugate (CT-2103 , Cell Therapeutics) has reached
phase III clinical stage [288], showing promise for the
treatment of patients with advanced non-small cell lung
cancer (NSCLC) and impaired performance status (PS
2). Patients on CT-2103 required fewer red blood cell
transfusions, a smaller dose of hematopoietic growth
factors, less opioid analgesics, and fewer clinic visits than
patients receiving gemcitabine or vinorelbine [288]. Yoo
et al. reported a folate-targeted biodegradable polymeric
micellar system with DOX [289]. FOL and DOX were
separately conjugated to poly[d,l-(lactide-co-glycolide)]-
mPEG to form DOX-poly[d,l-(lactide-co-glycolide)]-mPEG
and poly[d,l-(lactide-co-glycolide)]-PEG-FOL. The two
di-block copolymers were mixed with free base DOX in
an aqueous solution to form mixed micelles, entrapping
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
DOX aggregates within the core while exposing FOL on the
micellar surface. The folate-targeted micelles exhibited
enhanced and more selective targeting ability than folate
unconjugated micelles in vitro tests. The results of in vivo
animal experiments with the folate-targeted micellar
system also showed signicant regression in tumor vol-
ume and an increased accumulation of DOX in the tumor
tissue. These results indicate that cellular-specic drug
delivery systems can be obtained by attaching specic-
site-targeting groups to biodegradable polymers with
active groups.
Stimuli-responsive biodegradable polymers, have been
widely explored as potential drug-delivery systems
[290293]. Kim and coworkers prepared a MPEG-PCL
diblock copolymer aqueous solution that was a sol at room
temperature, undergoing a sol-to-gel phase transition as
the temperature was increased above room tempera-
ture [294]. A drug-loaded MPEG-PCL solution at room
temperature immediately transformed into a gel on subcu-
taneously injection into rats. Sustained release of drug was
observed over 30 days in the system. Huang and cowork-
ers reported the application of pH-responsive micelles of
poly(acrylic acid-b-dl-lactide) in drug delivery and con-
trolled release [295]. The release of prednisone acetate
from the polymeric micelles in vitro showed a burst
release at pH 7.4, while only a small part of loaded drug
was released at pH 1.4. This pH-responsive delivery system
has potential application for gastrointestinal tract deliv-
ery systems, where the pH environment is strongly acidic
in the stomach, but basic in the intestine. Wang et al.
developed reactive micelles based on diblock copolymer of
poly(ethyl ethylene phosphate) and PCL [127]. The micelles
were surface-conjugated with galactosamine to target the
ASGPR of HepG2 cells. Paclitaxel-loaded micelles bearing
galactose ligands targeted HepG2 cells via ASGP-R medi-
ation, which made the micelles with galactose ligands
showing comparable activity to free paclitaxel for inhibit-
ing proliferation of HepG2 cells. And population of HepG2
cells arrested in G2/M phase was in positive response
to paclitaxel released from the paclitaxel-loaded galac-
tosamine conjugated micelles. This result indicates that
surface functionalized micelles have potential for us as
drug delivery systems for enhanced chemotherapy.
4.4. Gene delivery
Gene delivery has great potential for treating various
human diseases [296]. Recently, nonviral vectors have been
proposed as safer alternatives to viral vectors for gene
delivery [297]. However, many carriers are non-degradable
and the risk arises of accumulation in the body, espe-
cially after repeated administration. Furthermore, most
of cationic polymers show high cytotoxicity because of
adverse interactions between the cationic polymers and
the membranes when the gene carriers cross certain bar-
riers to enter the cells (Fig. 20) [298], causing loss of
cytoplasmic proteins, permeabilization of cellular mem-
branes and collapse of the membrane potential [299]. A
good gene carrier should be able to deliver the target
gene to specic cells with high efcacy; it should also be
degradable and be excreted from the body after a given
269
time period. Consequently, there is a need for biodegrad-
able gene delivery polymers. Recently, some research has
evaluated non-degradable polymers with biodegradable
polycations via hydrolyzable linkers as gene carriers.
4.4.1. Poly(l-lysine)-based degradable polymers
Poly(l-lysine) was initially used for DNA delivery
[300,301]. However, the efcacy and utility of PLL is ham-
pered by its low transfection efciency and a rather high
toxicity [85]. This problem is especially serious in high
molecular weight PLL (Mw 25 kDa), while lower molecular
weight PLL (Mw 3 kDa) can hardly form stable nanosized
complexes with DNA [302]. To reduce the cytotoxicity
of PLL, biodegradable and hydrophobic PLGA grafts were
attached to the PLL backbone [303]. Furthermore, PLL was
modied with PEG and other various targeting moieties
to improve its transfection efciency. Wolfert et al. [304]
demonstrated that PEG-b-PLL exhibited higher transfec-
tion efciency and lower cytotoxicity than PLL in human
primary embryonic kidney cells. Park et al. also attached
PEG to the termini of PLL grafts [305,306]. In order to pro-
vide endosomal escape properties, histidine groups were
conjugated to lysine units, which resulted in 6-fold higher
transfection activity than that of PLL without signicant
cytotoxicity. After tail vein injection, these polymer sys-
tems remained in the circulation for 3 days [307,308]. In
recent years, PLL has been modied with many cell ligands
such as sugar residues [309], antibodies [310,311], folate
[312], cell adhesion peptides [313], and endogenous lipids
[314].
4.4.2. Poly(-amino ester)s-based degradable polymers
Poly(-amino ester)s can be synthesized by Michael
addition of primary amines to diacrylate esters [315].
Poly(-amino ester)s are suitable for gene delivery because
they contain degradable linkages. The ease in synthesis
and lack of byproducts make them even more favorable
candidates for the purpose discussed above [316,317].
Poly(4-hydroxy-l-proline ester) was the rst biodegrad-
able cationic polymer used as a gene carrier [318],
to protect DNA from enzyme degradation. Poly(-(4-
aminobutyl)-l-glycolic acid) (PAGA) was synthesized by
Kim and coworkers [319,320]. A complex of PAGA and
DNA showed slower degradation than the polymer alone
and a 3-fold higher transfection activity in vitro compared
with PLL, without cytotoxicity [320]. In vivo animal stud-
ies with PAGA showed that serum IL-10 level peaked 5
days after tail vein injection and the detection window for
serum IL-10 lased for more than 9 weeks [319]. Langer and
coworkers synthesized thiol-reactive 2-(pyridyldithio)-
ethylamine (PDA) with poly(amino ester) [321]. When the
polymers/DNA complexes were subjected intracellularly,
the existence of GSH accelerated DNA separation from the
complexes and its release into the cells. Especially when a
thiolated ligand was attached to the polyplexes, the poly-
mers showed nearly 20-fold higher transfection efciency
than PEI-25k in vitro [322]. Anderson et al. used poly(-
amino ester) for in vivo evaluation and nearly 4 times higher
than PEI-25k and 26 times higher transfection than naked
270 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 20. Barriers to gene delivery. Design requirements for gene delivery systems include the ability to (I) package therapeutic genes, (II) gain entry into
cells, (III) escape from the endo-lysosomal pathway, (IV) affect DNA/vector release, (V) travel through the cytoplasm and into the nucleus, and (VI) enable
gene expression [298].
Copyright 2007, Elsevier Ltd. Reprinted with permission.
DNA was observed when poly(-amino ester) was intratu-
morally administrated [323].
4.4.3. Polyphosphoester-based degradable polymers
PPE-based degradable polymers such as PPA, PPE and
polyphosphazene (PPZ) are known to be biodegradable
and biocompatible in gene delivery. The polymers can
be obtained by the ROP and subsequent derivatization
of 4-methyl-2-oxo-2-hydro-1,3,2,-dioxaphospholane with
spermidine and aminohexyl or(methyl-)aminoethyl side
chains [121,324]. PPE-EA consists of a phosphoester back-
bone and aminoethoxy side chains [30]. PPE-EA could
condense plasmid DNA efciently and provide pDNA resis-
tance against attacks from nucleases. After 49 days,
complete DNA was observed to be released from the
AE-PPE polyplexes at a suitable polymer/DNA ratio. The
transfection efciencies of PPE-AE polyplexes were about
two-fold higher than that of pLL-mediated transfection.
PPE-EA based polyplexes also showed enhanced gene
expression in vivo [31]. PPA consists of a phosphoester
backbone and different pendant chains via phosphorami-
date bonds, and its molecular weight is about 4050 K
[118]. PPZs were prepared with dimethylaminoethyl side
chains connected to the backbones either by oxygen
(DMAE-PPZ) or nitrogen (DMAEA-PPZ) [325]. DMAEA-
PPZ was carried out successfully in vivo and a high
expression level of the reporter gene in tumor was
observed, while very low levels were seen in organs
[326].
4.4.4. Polyethylenimine modied with degradable
polymers
PEI has been used for gene delivery under both
in vitro [327,328] and in vivo [329] conditions. How-
ever, many studies demonstrated that the cytotoxicity
of PEI may be due to a large excess of free polymer
complexation with pDNA [330,331] owing to a lack of
biodegradability [332,333]. Therefore, it is important to
modify PEI with degradable polymers that can retain the
high transfection efciency of PEI. Many studies have
established that hydrophobic moieties affect transfec-
tion activity of cationic polymers [334,335]. Kwon and
coworkers reported the synthesis of a peptide-based
(NHCHCO) PEI-25k analogue with higher transfec-
tion efciency and greater biocompatibility as compared
with PEI-25k in vivo [336]. Tian et al. investigated the
hydrophobic amino acid poly(-benzyl l-glutamate) seg-
ments at the hyperbranched chain ends. The polymer
could effectively condense pDNA and improve transfec-
tion efciency signicantly relative to that for PEI-25k
in HeLa cells [337]. Transferrin, an 80 kDa glycopro-
tein, is a suitable ligand for tumor targeting because
its receptors are over-expressed in cancers. Thereby,
transferrin-PEI was used as a gene carrier in vivo, resulting
in 100500 times higher luciferase reporter gene expres-
sion in tumors compared with that in other organs [338].
Chen et al. reported a series of multi-armed poly(l-glutamic
acid)-graft-oligoethylenimine (MP-g-OEI) copolymers that
possessed different charge densities. All the MP-g-OEI
copolymers exhibited lower cytotoxicity and higher gene
 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
Fig. 21. TSP50 was immobilized onto biodegradable polymer bers. Then TSP50-immobilized polymer bers could selectively adsorb the anti-TSP 50 [363].
Copyright 2008, Elsevier Ltd. Reprinted with permission.
transfection efciency than PEI-25k in the absence and
presence of serum with different cell lines [339].
4.4.5. Degradable polymers in siRNA delivery
RNAi has been widely used to silence the expres-
sion of a specic target gene by a post-transcriptional
silencing mechanism. For efcient siRNA delivery, siRNA
should be stably and efciently delivered into the target
tissue and cells. In recent years, many cationic degrad-
able polymers have been used as the delivery agents for
RNAi [340,341]. PLL was early tested for siRNA delivery,
and then polyplexes were investigated using glycosylated
PLL [342] and PEG-PLL [343]. Recently, researchers pro-
posed to obtain polymer micelles using PEG conjugated
to siRNA instead of PEG-polycation complexes [344]. In
this case, biodegradable linkages, such as disulde link-
ages that can be degraded by GSH [345,346], ester linkages
that can be cleaved by esterases [347], and amide linkages
degraded by amidases [348], must be used between siRNA
and polymers. Recently, Desigaux et al. demonstrated that
lipidic aminoglycoside derivatives displayed a remarkably
high efciency for siRNA-based gene knockdown in GFP-
expressing human lung cancer d2GFP cells and HEK293
cells [349].
4.4.6. Other degradable polymers
Biodegradable microparticle-based polymers such as
poly[d,l-(lactide-co-glycolide)] are commonly used for
gene delivery systems. Poly[d,l-(lactide-co-glycolide)] is
able to interact with DNA to form DNA-coated par-
ticles, which protects DNA from nuclease attacks and
promotese delivery into cells [350]. Poly[d,l-(lactide-
co-glycolide)]-pDNA microparticles provided high levels
of sustained expression for 100 days [351]. In order
to increase the transfection efciency of encapsulated
pDNA, poly(-amino ester)s were coformulated with
poly[d,l-(lactide-co-glycolide)]-pDNA microparticles. Sur-
prisingly, enhanced immunogenicity of the particles
was shown in mice [352]. The triblock copolymer of
poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol)-
b-poly(d,l-lactic-co-glycolic acid) also increased cellular
271
uptake and transfection efciency about 10-fold in various
cells [353].
So far, various biodegradable polymers have been
proved to be efcient in gene delivery. Some examples
of those biodegradable polymers are dendrimers modied
with degradable polymers [354], poly(amido ethylen-
imine)s [322], poly(2-(dimethylamino)ethyl methacrylate)
[355], and other synthetic biodegradable polycations [356].
4.5. Bioseparation and diagnostics applications
The development of biomedical polymers conjugated
with peptide or protein domains has mostly focused on
their use as bioactive materials in controlled drug deliv-
ery or tissue engineering. A new challenge arises in the
development of materials for bioseparation and diagnos-
tics applications. For these applications, materials that
are biocompatible with reduced non-specic absorption
and denaturation, that are able to amplify and transmit
signals, and that are benecial for high-throughput screen-
ing with enhanced sensitivity and reduced size are in
great demand. To meet these demands, polymeric mate-
rials in various shapes, such as membranes, thin lms,
micro/nano-particles, hydrogels, and micro/nano-bers
have been widely investigated.
Surface modication with polymers and polymer coated
surfaces are useful for preparing biochips with wide variety
applications in food industry, diagnostics, environmental
monitoring, etc. The development of the oligonucleotide
and protein microarrays is receiving intense interest
due to their high-throughput analysis ability, which
offers the potential for powerful tools in diagnostics,
drug discovery, and genomic analysis. One of the two
main tasks for this application is the fabrication of
suitable substrates for protein or DNA immobilization.
Thus, polymer surface modication or surfaces coated
with functional polymers are needed for the purpose to
improve biocompatibility and introduce functional groups
for immobilization of the targeted analyte [357]. For
example, Kuennemann and co-worker have examined a
platform biosensor surface for immobilization of proteins
with poly(l-lysine)-g-poly(ethylene glycol) (PLL-g-PEG)
272 H. Tian et al. / Progress in Polymer Science 37 (2012) 237280
[358,359]. The PLL-g-PEG coated sensor surface showed
very low non-specic absorption and its structure could
be ne-tuned by varying the polymer compositions. As a
result, the density of the proteins on the surface was almost
quantitatively controlled, which is signicant for improv-
ing sensitivity of the sensors. Moreover, the reversibility
of the surface immobilization enables the regeneration of
the biosensors. Therefore, such ne-tunable platforms are
promising for use as biosensors.
Bioresponsive hydrogels that change properties in
response to selective biological recognition events have
recently gained increasing interest for application in drug
delivery, diagnostics, and tissue engineering [360]. For
diagnostics applications, the biological events are repre-
sented by the macroscopic volume changes that generate
signals for detection. For example, Miyata et al. have
reported tumor marker (-fetoprotein, AFP) responsive
gels fabricated by a biomolecular imprinting technology
[361]. Lectin Con A and polyclonal anti-AFP antibodies were
conjugated into the gels to introduce the recognition sites
for specic biomarker binding. The shrinking behavior of
the gels in response to AFP molecules enables the visible
and accurate detection of biomarker molecules, indicating
that the biomolecule imprinted gels have potential appli-
cation in sensing application for diagnostics.
Polymeric micro/nano-spheres and micro/nano-bers
have attracted increasing attention because they can be
used as substrates to immobilize biomolecules for biomed-
ical applications, such as controlled drug delivery, tissue
engineering, diagnostics and bioseparation. Due to their
large specic surface areas and relatively small size,
these materials are suited to the immobilization of more
compact biomolecules with a reduced device size, but
enhanced sensitivity. Jiang and coworkers have reported
that using electrospinning polymer nanobrous mem-
branes as the solid substrates for microudic immunoassay
can dramatically improve the sensitivity and signal-to-
noise ratio as compared to the commercially available
polymer membranes [362]. Jing and co-workers inves-
tigated the immobilization of testis-specic protease 50
(TSP50) on biodegradable polymer bers [363]. The results
showed that the TSP50-immobilized polymer bers could
selectively adsorb the anti-TSP 50 (Fig. 21), even in the pres-
ence of high concentration of BSA (104 times). The anti-TSP
50 can then be eluted simply by changing the pH, and the
polymer bers are reusable.
5. Conclusions
Compared to biologically derived biodegradable poly-
mers, synthetic biodegradable polymers do not have
immunogenicity, but it is easier for them to be chemically
modied and functionalized. Functionalization of synthetic
biodegradable polymers has extended the application
scope for these biomaterials and has greatly promoted
the development in the biomedical eld. The developing
trends in the functionalization of synthetic biodegradable
polymers can be predicted as followings: (1) Functional-
ization processes will become easier and highly efcient
as functionalization processes with mild reaction con-
ditions and without harmful effects on bulk properties
of polymers are pursued; (2) Functionalization will be
increasingly related to biomimetics, such that synthetic
biodegradable polymers will not simply combine differ-
ent functions into one polymer, but instead, the different
functions should have synergistic actions; (3) The applica-
tion of synthetic biodegradable polymers will be further
expanded, including promising potential for in vivo appli-
cations. Since development in synthetic biodegradable
polymers are closely related to chemistry, materials science
and biomedical science, any new technology in these elds
will promote the development of synthetic biodegradable
polymers. Synthetic biodegradable polymers have been
very important and will make more contribution to the
development of biomedical science in the future.
Acknowledgments
The authors thank Jun Hu, Changwen Zhao, Junchao
Wei, Chunsheng Xiao, Jianxun Ding, Yadong Liu, Jie Chen,
Zhaopei Guo for their help in this review. The authors
are thankful to the National Natural Science Founda-
tion of China (20604028, 20774092, 50873102, 20974109,
21074129 and Key Program No: 50733003), and the
National Natural Science Foundation of China-A3 Foresight
Program (20921140264), the International Cooperation
fund of Science and Technology (Key project 20071314)
and Support Project (2007BAE42B02) from the Ministry
of Science and Technology of China, the Knowledge
Innovation Project of Chinese Academy of Sciences (KGCX-
YW-208) for nancial support to this work.
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