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![]() J. Biomedical Science and Engineering, 2009, 2, 36-40 Published Online February 2009 in SciRes. http://www.scirp.org/journal/jbise JBiSE Biodegradable and bioactive porous polyurethanes scaffolds for bone tissue engineering Mei-Na Huang1, Yuan-Liang Wang1*, Yan-Feng Luo1 National 985 Research Center of Bioinspired Material Science and Engineering, Bioengineering College,Chongqing University, Chongqing 400030, People’s Republic of China, Correspondence to Yuan-Liang Wang (wyl@cqu.edu.cn). Tel. /fax: +86-23-65102509. Received September 22nd, 2008; revised November 12th, 2008; accepted November 19th, 2008 ABSTRACT Biodegradable porous polyurethanes scaffold have themselves opportunities in service, in- cluding controlled degradation rate, no-toxic degradation products. However, polyurethanes are lack of bioactive groups, which limits their application. This review gives the common modification methods, surface functionalization and blending modification. In finally, the review puts forward to the bulk modification as a new method to enhance the bioactivity of polyure- thanes. Keywords: Polyurethanes, Bioactivity, Biodeg- radation, Bone Repair 1. INTRODUCTION Currently, tissue engineering involving synthetic materi- als offers a practical approach for bone repair and regen- eration. In this approach, a 3-D porous biodegradable scaffold is beneficial to guide cell attachment, prolifera- tion and tissue regeneration [1,2]. Therefore, a number of researchers are interested in developing biodegradable polymeric scaffolds for bone engineering repair [3,4,5,6]. Polyurethane, which concludes the polyurethane urea elastomer, is regarded as a kind of bone repair materials for its nice mechanical property and their special shape memory function. Biodegradable polyurethanes, made from degradable polyester/polyether with hydrophilic group of ether bond, aliphatic diisocyanate, having the hydrophobic group of alkly and chain extenders [7,8]. Due to these special group, polyurethanes have controlled degradation rate, in general, the degradation time can reach to some months with changing of the ratio polyester/polyether to diiso- cyanate [7,9], which fits to the growth rate of osteoblast. Moreover, the degradation give rise to non-toxic prod- ucts, which will not produce side effect for body. Besides polyester/polyether and diisocyanate, chain extender is also a key factor. In order to regulate the pH of degrada- tion products, and avoid the acid auto-catalytic effect in the degradation process, and then further controlling the easily control of degradation rate, some researches choose diamines [10]. Guan et al [4] synthesized (poly (etherurethane urea), PEUU) with PCL and 1, 4-diiso- cyanatobutane (BDI) and putrescine. And then, PEUU was made into highly porous, biodegradable polyure- thane scaffold for tissue engineering. In this study, BDI was used, since it could release putrescine, a polyamine that is essential for cell growth and proliferation. Zhang et al [11] synthesized polyurethane by reacting of highly pure lysine diisocyanate with glucose, which resulted in major degradation products lysine and glucose (LDI- glucose), and then completely degradate and enter into human circulation system. The degradation mechanisms of polymers are impor- tant and need to be investigated further. Non-toxic deg- radation products are necessary and, moreover, me- chanical properties are also influenced by degradation mechanisms. LDI-glucose [11] polymer, for example, is degraded by hydrolysis of urethane bonds to liberate lysine, glucose, ethanol, and CO2. Ethanol could inhibit cell-cell adhesion, but a study reported that concentra- tions less than 30mM are harmless to the cell. Moreover, in contrast to PLA and PLGA degradation mechanisms, the study showed that the degradation of polyurethane with diamine no significant increase in pH of the solu- tion. PEUU degradation products were also shown to be non-toxic to endothelial cells. The polymer showed a linear degradation with no signs of autocatalytic effects when compared to PLA or PLGA degradation behaviour. In addition, regulating ratio of polyester/polyether to diisocyanate can change the molecular weight of poly- urethane, and then control their degradation rate. The two regulation methods make it be balance with growth of cell/tissue and realize the real tissue engineering re- pair. However, polyurethanes as a potential, biodegradable materials are lack of bioactive groups, which limits their applications. Therefore, how to ensure biodegradation and bioactive of polyurethane are two key factors for it’s application in bone repair [12,13]. A further requirement for scaffold, particularly used for bone engineering, is controllable interconnected porosity for cells to grow into the desired physical form and to compete vasculari- zation of the ingrown tissue [12]. Other highly desirable SciRes Copyright © 2009 ![]() M. N. Huang et al. / J. Biomedical Science and Engineering 2 (2009) 36-40 37 SciRes Copyright © 2009 JBiSE features concerning the scaffold processing are near-net -sHAe fabrication and scalability for cost-effective in- dustrial production [12,14]. In the paper, we only discuss how to enhance the bio- activity of porous polyurethane scaffold. In general, bio- active functionalization methods of polyurethanes can be concluded to three major design strategies [15,16,17, 18,19]. One approach is blending the polyurethanes with tricalcium phosphate/ hydroxyapatite or other inorganic ceramic [16,17,18,19]. Various bioactive factors further enhance the cellular compatibility. The inorganic ce- ramic have another advantage, the function of bone in- duction and the conduction [16,17,18,19]. The other ap- proach involves endowing the biomaterials with bioac- tivity by incorporating soluble bioactive molecules, such as growth factors and plasmid DNA, into biomaterial carriers so that the bioactive molecules can be released from the materials and trigger or modulate new tissue formation [20,21,22]. The last one is incorporation of cell-binding peptides into biomaterials via chemical or physical modification. The cell-binding peptides include a native long chain of extracellular matrix (ECM) pro- teins as well as short peptide sequences derived from intact ECM proteins that can incur specific interactions with cell receptors [15,23,24,25] This paper reviews above methods and focuses on their opportunities as a kind of bone repair materials, and puts forward a new method to improve the bioactivity of biodegradable polyurethanes. 2. BIOACILITY OF POLYURETHANE Tissue engineering applies methods from materials en- gineering and life sciences to artificial construction new tissue. Two common approaches are transplanting the biomaterials with cell [26] or the biomaterials with some bioactive factor/bioactive substance for the cell homing to realize restoration. Facing the complex biological and sensitive human body, requirements of biomaterials are extremely challenging. The First and most, compared to other bioactive materials, polyurethanes are lack of bio- active factors and cytocompatibility [27], which can be well solved by introduction of bioactive substances, in- cluding the inorganic phosphate, growth factors and ex- tracellular matrix. 2.1. Introduction of Inorganic Phosphate Into Polyurethanes Hydroxyapatite, glasses, glass-ceramics or calcium phosphates having similar components with natural bone [14,20], are important categories of bioactive materials. Coating and blending are the most common methods to modify polymer with inorganic phosphate. Biomimetic method is a chemical modification with inorganic phos- phate [28,29,30]. Hydroxyapatite (HA), the most important inorganic phosphate, has been extensively investigated over the past few decades as a biomedical material. It can be de- signed as a bioactive material, besides it is similar com- position with natural bone, osteoconducive, osteoinduc- tivity, biodegra-dability, high mechanical strength and their medical products such as screws, plates and rods have been commercial forms a strong bond to natural bone in vivo [31,32,33]. Moreover, the introduction of HA can regulate the pH of biomaterials. Above proper- ties of hydroxyapatite and other inorganic phosphate can induct the growth of bone and prevent the inflammatory reaction [31,32,33,34]. Rezwan, K. et al [13] reviewed the function of bioac- tive glasses, glass-ceramics and the calcium phosphates or HA in the enhancement of the bioactivity of polyure- thanes. It has been found that reactions on bioactive glass surfaces can release critical concentrations of solu- ble Si, Ca, P and Na ions, depending on the processing route and particle size. The released ions induce intra- cellular and extracellular responses. One key reason that makes bioactive glassed-correlation material is the pos- sibility of controlling a range of chemical properties and thus the rate of bioresorption. Park, Y.S. et al [35] inves- tigated the fabrication method of a three-dimensional reticulated scaffold with interconnected pores of several hundred micrometers using calcium phosphate glass in the system of CaO-CaF2-P2O5-MgO-ZnO and a polyure- thane sponge as a template. It is thought that this kind of biodegradable glass scaffold combined with osteogenic cells has potential to be studied further as a tissue engi- neered bone substitute. The structure and chemistry of glasses, in particular sol-gel derived glasses, can be tai- lored at a molecular level by varying either composition, or thermal or environmental processing history. Above inorganic phosphate is important bioactive modification material, however, current technology is difficult to solve the compatibility between inorganic phosphate and polyurethanes. It is difficult to make a uniform matrix, particularly, the current coating/blending methods,which result in that it is difficult to form a uniform matrix, particularly, the content of inorganic ceramic is high [36,37]. Some researches found that some of HA/PLA composites lost their strengths rapidly in physiological environment and failures occur mainly at the interface of HA and the polymer matrix. Two main reasons may take responsibility for these interfacial fail- ures: one is lack of effective adhesion between ceramic phase and polymer matrix; the other is self-catalytic degradation of hydroxyl groups on HA surfaces to poly- mer main chains. The structure of polyurethanes/HA is similar to HA/PLA, which may result in the same inter- face separation. For solving the problem, Xian, Y.M adopted chemical reaction to produce HA crystal on the polymer surface, the chemical reaction to make inorganic phosphate in the surface polymer can solve the interface separation, however, another problem appeared [30]. The reaction of making HA/polymers crystal is similar to the biomimetic calcification, which lasted for more than one week, and then make negative effect on the polymers. Moreover, the products can not ensure the crystal struc- ture. ![]() 38 M. N. Huang et al. / J. Biomedical Science and Engineering 2 (2009) 36-40 SciRes Copyright © 2009 JBiSE Introducing inorganic phosphate can not wholly solve the bioactivity problem. Some researchers use bioactive factor, which can react with polymers to enhance their bioactivity [38,39,40], such as RGD, moreover, the bio- active factors is important for cell homing. 2.2. Surface Modification of Porous Polyure- thanes Scaffold with Bioactive Factors 2.2.1. Arg-Gly-Asp(RGD) Modified Biomimetic Polyurethanes In an effort to improve the adhesion and retention of cells to polymer scaffolds, researches typically coated with various extracellular matrix proteins [40,41,42]. These studies highlight that extracellular proteins played an important role in attachment and spreading of cells to surface, where specific domains on cell membrane bind directly with extracellular matrix moleculaes via in- tegrins [43,44]. A number of specific cell-recognition sequences have been identified, the most extensively studied sequence being the arginine-glycine-aspartic acid (RGD) motif present in matrix molecules such as vi- tronectin, fibronectin, laminin and collagen, fibrillin [40,45,46,47]. RGD peptide is one of the major bioactive factor to design biomimetic polyurethanes and has been widely researched in recent years [38,39,40]. In order to provide a stable linking, RGD peptides should be covalently at- tached to polymer via functional groups like hydroxyl-, amino-, or carboxyl-groups. Some polyurethanes are amino-terminated [4,38], which can react with the car- boxyl-groups of RGD, with 1,3-Dicyclohexylcar- bodiimide (DCC) as catalyst. Other polyurethanes are hydroxyl-terminated, the hydroxyl-also can react with the carboxyl-group of RGD [48]. Moreover, in order to enhance the surface functionali- zation, polymeric materials, such as polyurethane must be functionalized before bioactive peptides or proteins are immobilized on their surfaces [44]. In general, the functionalization can be realized by a variety of means, either by introduced the multi-functional groups mono- mer or polymer[39], or by subsequent surface modifica- tion by plasma treatment [45] ozone oxidation [46] sur- face graft polymerization [40] or site-specific reactions [47]. Here, we put emphasis on two examples to demon- strate the successful application of linking group in sur- face modification. One example [39], the difunctional spacer molecule-diisocyanate is introduced as the linking group of polyurethane film and RGD, realizing the sur- face functionalization of polyurethane. Another example, Jozwiak, A.B [40] used two steps to enhance the intro- duction rate. First, the multi-amino group-polyethyle- neimine (PEI) is introduced, a medium sized molecular weight branched form of PEI was used here in order to provide a large number of reactive primary amine groups and enhance its entrapment within the polyurethane sur- face. Second, introducing the dextran, which is func- tional spacer molecule and can link the RGD easily. 2.2.2. Growth Factors Modified Biomimetic Poly- urethanes Chemotaxis, proliferation, differentiation and matrix synthesis are essential in natural tissue/organ develop- ment and wound healing [45]. Owing to the rapid ad- vances in recombinant technology and the availability of large scale manufacturing of cytokines and growth fac- tors, many recent tissue engineering strategies have turned to specific growth factors to stimulate cellular activity in vitro and to improve functional neotissue formation in vivo [47,48]. Characteristic of these bioac- tive factors is that they can effective release at specific site and realize the function of improving cell prolifera- tion and recruitment [46,49]. Incorporation of angiogenic growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), among others, into scaffolds for controlled release has been shown to promote lacal angiogenesis [50]. Plate- let-derived growth factor (PDGF) has been demonstrated to stimulate proliferation and recruitment of both perio- dontal ligament and bone cells in vitro. In vivo study also showed that PDGF-BB enhances the ability of heal- ing [46]. There are many methods to incorporate growth factors into synthetic scaffolds, such as absorbing growth factor to scaffold, and blending growth factor containing mi- crospheres into the scaffold [46], or directly mixing growth factor containing protein powder into the scaffold during processing [50]. However, absorbing growth fac- tors onto the scaffold has the drawback of low loading efficiency and rapid releasing, which may be associated with in bioactivity due to harsh solvents such as hexane [46] or methylene chloride [51]. Incorporating growth factor directly into the scaffold can potentially avoid these shortcomings. Whether or not has bioactivity of the released bioac- tive factors is an essential problem. Bioactivity of the factors can be assessed in two methods [47,50,52]. First, bioactivity of the released factor can be determined through the direct method-human gingival fibroblase DNA synthesis as measured by specific composition [46]. Second, the bioactivity is assessed in terms of its ability to stimulate the growth of cells [50,52]. 3. CONCLUTION AND PRESPECT 3.1. Possibility and Challenge of Bulk Modi- fication for Polyurethanes Besides above methods, how can we improve bioactivity of polymers? Now, a great wealth of knowledge about the biology of integrin mediated cell adhesion has proved that the modification of polyurethanes with RGD peptides or other bioactive factors are useful tool to de- sign bioactive porous scaffolds that can provide biologi- cal cues elicit specific cellular responses and direct new tissue formation. However, the surface modification has some limitations. Since surface modification has been performed on well-defined model surfaces and the ![]() M. N. Huang et al. / J. Biomedical Science and Engineering 2 (2009) 36-40 39 SciRes Copyright © 2009 JBiSE evaluation of cell behavior on material has been con- ducted under serum free media, the results may not properly indicate complicated events associated with in vivo environments. Even though some model surfaces may be useful to provide fundamental knowledge to un- derstand cell behavior through specific binding, they may not be directly used as tissue engineering scaffolds. If we use bulk designing of polyurethanes, incorpo- rated RGD or collagen may result in recognition sites is present not only on the surfaces but also in the bulk of the materials. Niu, X.F. et al [53] review the bulk modi- fication, which describe the bulk modification of bioma- terials is beneficial to tissue engineering applications where injectable biomimetic materialsare required to match the complex HA of native tissue at defect sites. Cook et al [54] and Barrera et al [55] conducted a lot of investigations in understanding the effects of bulk modi- fication via RGD peptides. They synthesized RGD bulk modified poly (lactic acid-co-lysine) and successfully blended it with PLA to fabricate a thin film. When this film was exposed to endothelial cell suspended media for 4 h, the specific function of RGD was maintained to fa- cilitate cell spreading. Polyurethanes are the biomaterials with hydroxyl- terminated and amine-terminated. The RGD or other peptide can react with the terminal group of polyure- thanes, which may result in bioactive polyurethanes. My laboratory chose the bulk modification to introduce the bioactive factor, such as RGD/MGF, and then emul- sion/freeze drying mean was adopted to make porous polyurethane scaffold with bioactivity polyurethane. 3.2. The Possibility of Introduction of Inor- ganic Phosphate by Chemical Reaction Inorganic phosphate is important component of natural bone, however, current technology is difficult to solve the compatibility between the inorganic phosphate and polyurethanes. How to introduce the inorganic phosphate, and at the same time avoid above disadvantage is a key problem for enhancing the stability of polyurethane/inorganic phos- phate composition. In order to overcome these limita- tions of composite, covalently attached the inorganic phosphate to polyurethanes by linking group may be a feasible method. Linking group should easily react with the hydroxyl-from inorganic phosphate and the carboxyl- or amino-group from polyurethanes. Silane derivatives are used as modification molecular to link hydroxyl groups (-OH) in HA surface to polymer main chain, which is carried out via direct reactions of –OR groups on HA surfaces. At the same time, other functional groups (-NH2) of silane derivatives may further react towards the terminal groups carboxylic group or hy- droxyl group. Moreover, glutaraldehyde [43] may be the important cross-linking agent. In addition, in order to ensure the homogeneity of composite, the effective con- nection of emulsion blending-chemical crosslinking may be an efficient method [44]. For realizing biodegradation, bioactivity and me- chanical property of the bone repair materials, the paper puts forward two methods to make the biodegradable materials, which are equipped with the uniform structure and bioactive components. 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