Review Functionalized Synthetic Biodegradable Polymer Scaffolds for Tissue Engineering Xiaohua Liu, Jeremy M. Holzwarth, Peter X. Ma* Scaffolds (artificial ECMs) play a pivotal role in the process of regenerating tissues in 3D. Biodegradable synthetic polymers are the most widely used scaffolding materials. However, synthetic polymers usually lack the biological cues found in the natural extracellular matrix. Significant efforts have been made to synthesize biode- gradable polymers with functional groups that are used to couple bioactive agents. Presenting bioactive agents on scaffolding surfaces is the most efficient way to elicit desired cell/material interactions. This paper reviews recent advancements in the development of functionalized biodegradable polymer scaffolds for tissue engineering, emphasizing the syntheses of functional biodegradable polymers, and surface modification of polymeric scaffolds. 1. Introduction scaffold serves as a template for tissue regeneration and plays a pivotal role in cell adhesion, proliferation, As a multi-disciplinary field, tissue engineering integrates differentiation, and new tissue formation in three dimen- materials science with regenerative medicine by applying sions (3D). Ideally, a scaffold should be designed to possess the principles of engineering and biology to clinical the following characteristics: (i) a biocompatible and issues.[1] A typical tissue engineering strategy can be biodegradable substrate with controllable degradation separated into three components: a scaffold [an artificial rates; (ii) a 3D and highly porous architecture to accom- extracellular matrix (ECM)], cells, and biological factors. The modate cell attachment, penetration, proliferation, and ECM deposition; (iii) an interconnected pore network to X. Liu, Dr. P. X. Ma facilitate nutrient and waste exchange; (iv) a suitable Department of Biologic and Materials Sciences, University of mechanical strength to support regeneration; and (v) a Michigan, Ann Arbor, MI 48109, USA proper surface chemistry and surface topography to E-mail: [email protected] promote cellular interactions and tissue development.[2,3] X. Liu With the advancement of developmental biology and Department of Biomedical Sciences, Baylor College of Dentistry, nanotechnology, recent research on scaffolding has more Texas A&M HSC, Dallas, TX 75246, USA focused on the design and synthesis of functionalized Dr. P. X. Ma, J. M. Holzwarth scaffolds that can elicit desirable cell/material interactions to Department of Biomedical Engineering, University of Michigan, guide cell behavior and enhance new tissue formation.[4–8] Ann Arbor, MI 48109, USA Dr. P. X. Ma Scaffolds can be produced from a variety of materials, Macromolecular Science and Engineering Center, and including metals, ceramics, and polymers. Metallic alloys [9] Department of Materials Science and Engineering, University of are popular for both dental and bone implants while Michigan, Ann Arbor, MI 48109, USA ceramics with good osteoconductivity have been used for Macromol. Biosci. 2012, 12, 911–919 ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com DOI: 10.1002/mabi.201100466 911 X. Liu, J. M. Holzwarth, P. X. Ma www.mbs-journal.de bone tissue engineering.[10] However, both metals and Xiaohua Liu is an Assistant Professor in the ceramics have significant drawbacks. Metals are not Biomedical Sciences Department, Baylor College of Dentistry, Texas A&M Health Science Center. biodegradable and do not provide a biomimetic matrix Prior to this, he received a PhD in Polymer Chem- for cell growth and tissue formation. Ceramics also have istry from Tsinghua University in China (2002). limited biodegradability and are difficult to process into He then worked with Dr. Peter Ma as a post- highly porous structures due to their brittleness. In contrast, doctoral fellow at the University of Michigan polymers have great processing flexibility and their before he joined Baylor College of Dentistry. biodegradability can be imparted through molecular His current research interests are biomaterials design. Therefore, polymers are dominant scaffolding design and synthesis and controlled drug deliv- materials in tissue engineering. In general, naturally ery for biomedical applications. derived polymers have the potential advantage of biolo- Jeremy M. Holzwarth received his BS in Chemical gical recognition that may positively support cell adhesion Engineering from Cornell University in 2009 and and function. However, complexities associated with his MS in Biomedical Engineering from the natural polymeric materials, including complex structural University of Michigan in 2011. He is currently composition, purification, immunogenicity, and pathogen a Biomedical Engineering PhD candidate under transmission, have driven the development of synthetic Peter X. Ma at the University of Michigan. His polymers for use as scaffolding materials. Synthetic research interests include the design of scaffolds polymers have a higher degree of processing flexibility for tissue engineering and the effect of and no immunological concerns compared to natural ECM nanofibrous architecture on embryonic stem cell differentiation. proteins. By incorporating bioactive agents into synthetic polymers, functionalized scaffolds that combine the Peter X. Ma received his BS degree in Polymer advantage of both synthetic and natural polymeric Chemistry and Chemical Engineering from materials can be fabricated. Tsinghua University (Beijing, China), and PhD This paper covers the design and fabrication of functio- in Polymer Science and Engineering from Rutgers University. He then did his postdoctoral research nalized biodegradable polymer scaffolds, focusing on the at MIT and Harvard Medical School on Biomater- synthesis of functional biodegradable polymers and the ials and Tissue Engineering. He is currently the surface modification of polymeric scaffolds. Selected Richard H. Kingery Endowed Collegiate Professor examples from both our and other groups are presented at the University of Michigan with quadruple for the purpose of illustration. Additionally, the cellular appointments in the Department of Biologic response on functionalized scaffolds will be briefly and Materials Sciences in the School of Dentistry, discussed. Since the methods of scaffolding fabrication the Departments of Biomedical Engineering, and incorporation of growth factors into scaffolds have Materials Science and Engineering, and the been extensively reviewed in detail elsewhere,[2,3,11–18] Macromolecular Science and Engineering Center they will not be the focus of this paper. in the College of Engineering. He is a Fellow of the American Institute of Medical and Biological Engineering (AIMBE) and a Fellow of Biomater- 2. Synthesis of Functional Biodegradable ials Science and Engineering (FBSE). Polymers moieties onto the scaffolding surface. Considerable efforts Poly(a-hydroxyacids), including poly(glycolic acid) (PGA), have been made to improve the functionality of these poly(lactic acid) (PLA), and their copolymer poly[(lactic polymers to further expand their applications.[2–5,23] One acid)-co-(glycolic acid)] (PLGA), are the most widely used strategy is to copolymerize the a-hydroxyacids with other synthetic polymeric materials in tissue engineering.[19] monomers containing functional pendant groups such as These polymers are well characterized and have gained FDA amino and carboxyl groups. In one study, L-lactide and (RS)- approval for certain human use (e.g., sutures). Poly(a- b-benzyl malate were copolymerized by ring-opening hydroxyacids) have been fabricated into 3D scaffolds via a polymerization, and poly{(L-lactide)-co-[(RS)-b-malic acid]} number of techniques. For example, poly(L-lactic acid) with pendant carboxyl groups was obtained by removing (PLLA) has been fabricated into nano-fibrous scaffolds to the benzyl groups.[24] Leemhuis et al. synthesized two mimic the physical architecture of natural collagen (a main functionalized dilactones (benzyloxymethylmethyl glyco- component of ECM).[20] The nano-fibrous PLLA scaffolds lide and benzyloxymethyl glycolide) with protected hydro- have been demonstrated to enhance cell adhesion and xyl groups, which were then copolymerized with L- differentiation.[21,22] However, there are no functional lactide.[25] Deprotection of the benzyloxymethyl groups groups available on the poly(a-hydroxyacids) chains, which gave the corresponding hydroxylated PLLA copolymers. limits the capacity to incorporate biologically active Noga et al. further modified the pendant hydroxyl groups of 912 Macromol. Biosci. 2012, 12, 911–919 ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.MaterialsViews.com Functionalized Synthetic Biodegradable Polymer Scaffolds ... www.mbs-journal.de PLLA copolymers with succinic anhydride to obtain the hydroxyl groups in the PCL copolymers were also obtained corresponding carboxylic acid functionalized copolymers to by copolymerization of e-caprolactone with another attach amine-containing biological molecules.[26] Chen et monomer, 5-ethyleneketal-e-caprolactone, followed by a al. synthesized two cyclic carbonate monomers (acryloyl deacetylization step to reduce the ketone groups into carbonate and methacryloyl carbonate), which were hydroxyl groups.[57] The syntheses of these functional co- copolymerized with D,L-lactide to incorporate acryloyl monomers, as well as the de-protection process, however, groups in the copolymers.[27] The acryloyl groups were are often complex and tedious. amenable to