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  • Print publication year: 2014
  • Online publication date: February 2015

14 - Polysaccharide hydrogels for regenerative medicine applications

from Part III - Hydrogel scaffolds for regenerative medicine

Summary

Introduction

This chapter begins by reviewing the structure and origin of polysaccharides commonly used in hydrogels and then moves on to a brief discussion of the role of structural polysaccharides throughout tissues in the body. Common chemical modification techniques are discussed, followed by approaches used to crosslink polysaccharides into insoluble hydrogels. The authors will also describe recent research approaches for polysaccharide hydrogel materials as scaffolds for tissue engineering, vehicles for drug delivery, and tissue adhesives. The goal of this chapter is to provide the reader with an overview of the exciting potential of polysaccharide-based hydrogels in medicine.

Structure and origin of common polysaccharides

Polysaccharides are large linear or branched carbohydrate molecules composed of repeating monomer units. They can perform structurally, as in the extracellular matrix of animals and cell walls of plants [1], or provide energy storage capacity in the instances of glycogen and starch [2]. Every organism on the planet has the ability to produce polysaccharides. Solubilities of polysaccharides in water vary depending on the chemical structure [3]. Monomer units often contain chemical groups that can be functionalized chemically in order to modify their material properties. Important structural polysaccharides in the human body are known as glycosaminoglycans (GAGs), which are anionic, linear polysaccharides composed of repeating disaccharide units. The repeat unit is comprised of a hexosamine and either a hexose or hexuronic acid.

References
Buckeridge, M. S. 2010. Seed cell wall storage polysaccharides: models to understand cell wall biosynthesis and degradation. Plant Physiol., 154(3), 1017–23.
Robyt, J. F. 2001. Polysaccharides: Energy Storage. In eLS. New York: John Wiley & Sons, Ltd.
Whistler, R. L. 1973. Solubility of Polysaccharides and Their Behavior in Solution, in Carbohydrates in Solution. Washington, DC: American Chemical Society, pp. 242–55.
Hadler, N. M. and Napier, M. A. 1977. Structure of hyaluronic acid in synovial fluid and its influence on the movement of solutes. Semin Arthritis Rheum., 7(2), 141–52.
Chong, B. F., Blank, L. M., McLaughlin, R., Nielsen, L. K. 2005. Microbial hyaluronic acid production. Appl. Microbiol. Biotechnol., 66(4), 341–51.
Shimada, E. and Matsumura, G. 1975. Viscosity and molecular weight of hyaluronic acids. J. Biochem., 78(3), 513–17.
Schulz, T., Schumacher, U. and Prehm, P. 2007. Hyaluronan export by the ABC transporter MRP5 and its modulation by intracellular cGMP. J. Biol. Chem., 282(29), 20999–1004.
Gandhi, N. S. and Mancera, R. L. 2008. The structure of glycosaminoglycans and their interactions with proteins. Chem. Biol. Drug Des., 72(6), 455–82.
Nandini, C. D. and Sugahara, K. 2006. Role of the sulfation pattern of chondroitin sulfate in its biological activities and in the binding of growth factors. Adv. Pharmacol., 53, 253–79.
Desaire, H., Sirich, T. L. and Leary, J. A. 2001. Evidence of block and randomly sequenced chondroitin polysaccharides: sequential enzymatic digestion and quantification using ion trap tandem mass spectrometry. Anal. Chem., 73(15), 3513–20.
Barnhill, J. G., Fye, C. L., Williams, D. W. et al. 2006. Chondroitin product selection for the glucosamine/chondroitin arthritis intervention trial. J. Am. Pharm. Assoc., 46(1), 14–24.
Cox, M. N. and Lehninger, D. 2004. Principles of Biochemistry. New York: Freeman.
Gatti, G., Casu, B., Hamer, G. K. and Perlin, A. S. 1979. Studies on the conformation of heparin by 1H and 13C NMR spectroscopy. Macromolecules, 12(5), 1001–7.
Triplett, D. A. 1979. Heparin: biochemistry, therapy, and laboratory monitoring. Ther. Drug Monit., 1(2), 173–97.
Linhardt, R. J. and Gunay, N. S. 1999. Production and chemical processing of low molecular weight heparins. Semin. Thromb. Hemost., 25(Suppl. 3), 5–16.
Suh, J. K. and Matthew, H. W. 2000. Application of chitosan-based polysaccharide biomaterials in cartilage tissue engineering: a review. Biomaterials, 21(24), 2589–98.
Chandy, T. and Sharma, C. P. 1990. Chitosan – as a biomaterial. Biomater. Artif. Cells Artif. Organs, 18(1), 1–24.
Kumar, G., Smith, P. J. and Payne, G. F. 1999. Enzymatic grafting of a natural product onto chitosan to confer water solubility under basic conditions. Biotechnol. Bioeng., 63(2), 154–65.
Baldwin, A. D. and Kiick, K. L. 2010. Polysaccharide-modified synthetic polymeric biomaterials. Biopolymers, 94(1), 128–40.
Lansdown, A. B. and Payne, M. J. 1994. An evaluation of the local reaction and biodegradation of calcium sodium alginate (Kaltostat) following subcutaneous implantation in the rat. J. R. Coll. Surg. Edinb., 39(5), 284–8.
Gilchrist, T. and Martin, A. M. 1983. Wound treatment with Sorbsan – an alginate fibre dressing. Biomaterials, 4(4), 317–20.
Augst, A. D., Kong, H. J. and Mooney, D. J. 2006. Alginate hydrogels as biomaterials. Macromol. Biosci., 6(8), 623–33.
Rowley, J. A., Madlambayan, G. and Mooney, D. J. 1999. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 20(1), 45–53.
Naessens, M., Cerdobbel, A., Soetaert, W. and Vandamme, E. J. 2005. Leuconostoc dextransucrase and dextran: production, properties and applications. J. Chem. Technol. Biotechnol., 80(8), 845–60.
Kamath, K. R. and Park, K. 1995. Study on the release of invertase from enzymatically degradable dextran hydrogels. Polymer Gels Networks, 3(3), 243–54.
Massia, S. P., Stark, J. and Letbetter, D. S. 2000. Surface-immobilized dextran limits cell adhesion and spreading. Biomaterials, 21(22), 2253–61.
Franssen, O., van Ooijen, R. D., de Boer, D., Maes, R. A. A. and Hennink, W. E. 1999. Enzymatic degradation of cross-linked dextrans. Macromolecules, 32(9), 2896–902.
Kiani, C., Chen, L., Wu, Y. J., Yee, A. J. and Yang, B. B. 2002. Structure and function of aggrecan. Cell Res., 12(1), 19–32.
Fthenou, E., Zafiropoulos, A., Tsatsakis, A. et al. 2006. Chondroitin sulfate A chains enhance platelet derived growth factor-mediated signalling in fibrosarcoma cells. Int. J. Biochem. Cell Biol., 38(12), 2141–50.
Swann, D. A., Radin, E. L., Nazimiec, M. et al. 1974. Role of hyaluronic acid in joint lubrication. Ann. Rheum. Dis., 33(4), 318–26.
Damus, P. S., Hicks, M. and Rosenberg, R. D. 1973. Anticoagulant action of heparin. Nature, 246(5432), 355–7.
Lindahl, U. and Roden, L. 1966. The chondroitin 4-sulfate-protein linkage. J. Biol. Chem., 241(9), 2113–19.
Doege, K. J., Sasaki, M., Kimura, T. and Yamada, Y. 1991. Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J. Biol. Chem., 266(2), 894–902.
Mow, V. C., Radcliffe, A. and Poole, A. R. 1992. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials, 13, 67–97.
Sanchez-Adams, J., Willard, V. P. and Athanasiou, K. A. 2011. Regional variation in the mechanical role of knee meniscus glycosaminoglycans. J. Appl. Physiol., 111(6), 1590–6.
Le Maitre, C. L., Pockert, A., Buttle, D. J., Freemont, A. J. and Hoyland, J. A. 2007. Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem. Soc. Trans., 35(Part 4), 652–5.
Lapčík, L., Lapčík, L., De Smedt, S., Demeester, J. and Chabrecek, P. 1998. Hyaluronan: preparation, structure, properties, and applications. Chem. Rev., 98(8), 2663–84.
van der Harst, M. R., Brama, P. A., van de Lest, C. H. et al. 2004. An integral biochemical analysis of the main constituents of articular cartilage, subchondral and trabecular bone. Osteoarthritis Cartilage, 12(9), 752–61.
Prince, C. W. and Navia, J. M. 1983. Glycosaminoglycan alterations in rat bone due to growth and fluorosis. J. Nutr., 113(8), 1576–82.
Miyazaki, T., Miyauchi, S., Tawada, A., Anada, T. and Matsuzaka, S. 2010. Effect of chondroitin sulfate-E on the osteoclastic differentiation of RAW264 cells. Dent. Mater. J., 29(4), 403–10.
Fujii, Y., Fujii, K., Nakano, K. and Tanaka, Y. 2003. Crosslinking of CD44 on human osteoblastic cells upregulates ICAM-1 and VCAM-1. FEBS Lett., 539(1–3), 45–50.
Pivetta, E., Scapolan, M., Wassermann, B. et al. 2011. Blood-derived human osteoclast resorption activity is impaired by hyaluronan–CD44 engagement via a p38-dependent mechanism. J. Cell Physiol., 226(3), 769–79.
Miyazaki, T., Miyauchi, S., Tawada, A. et al. 2008. Oversulfated chondroitin sulfate-E binds to BMP-4 and enhances osteoblast differentiation. J. Cell Physiol., 217(3), 769–77.
Nikitovic, D., Zafiropoulos, A., Tzanakakis, G. N., Karamanos, N. K. and Tsatsakis, A. M. 2005. Effects of glycosaminoglycans on cell proliferation of normal osteoblasts and human osteosarcoma cells depend on their type and fine chemical compositions. Anticancer Res., 25(4), 2851–6.
Bernstein, E. F., Underhill, C. B., Hahn, P. J., Brown, D. B. and Uitto, J. 1996. Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans. Br. J. Dermatol., 135(2), 255–62.
Witt, D. P. and Lander, A. D. 1994. Differential binding of chemokines to glycosaminoglycan subpopulations. Curr. Biol., 4(5), 394–400.
Termeer, C., Benedix, F., Sleeman, J. et al. 2002. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med., 195(1), 99–111.
West, D. C., Shaw, D. M., Lorenz, P., Adzick, N. S. and Longaker, M. T. 1997. Fibrotic healing of adult and late gestation fetal wounds correlates with increased hyaluronidase activity and removal of hyaluronan. Int. J. Biochem. Cell Biol., 29(1), 201–10.
Novak, U. and Kaye, A. H. 2000. Extracellular matrix and the brain: components and function. J. Clin. Neurosci., 7(4), 280–90.
Pratt, R. M., Larsen, M. A. and Johnston, M. C. 1975. Migration of cranial neural crest cells in a cell-free hyaluronate-rich matrix. Dev. Biol., 44(2), 298–305.
Yamaguchi, Y. 2000. Lecticans: organizers of the brain extracellular matrix. Cell Mol. Life Sci., 57(2), 276–89.
Prabhakar, V., Capila, I., Bosques, C. J., Pojasek, K. and Sasisekharan, R. 2005. Chondroitinase ABC I from Proteus vulgaris: cloning, recombinant expression and active site identification. Biochem. J., 386(Part 1), 103–12.
Silver, J. and Miller, J. H. 2004. Regeneration beyond the glial scar. Nature Rev. Neurosci., 5(2), 146–56.
Hassell, J. R., Cintron, C., Kublin, C. and Newsome, D. A. 1983. Proteoglycan changes during restoration of transparency in corneal scars. Arch. Biochem. Biophys., 222(2), 362–9.
Chakravarti, S., Petroll, W. M., Hassell, J. R. et al. 2000. Corneal opacity in lumican-null mice: defects in collagen fibril structure and packing in the posterior stroma. Invest. Ophthalmol. Vis. Sci., 41(11), 3365–73.
Hart, G. W. 1976. Biosynthesis of glycosaminoglycans during corneal development. J. Biol. Chem., 251(21), 6513–21.
Trochon, V., Mabilat, C., Bertrand, P. et al. 1996. Evidence of involvement of CD44 in endothelial cell proliferation, migration and angiogenesis in vitro. Int. J. Cancer, 66(5), 664–8.
Ausprunk, D. H. 1982. Synthesis of glycoproteins by endothelial cells in embryonic blood vessels. Dev. Biol., 90(1), 79–90.
Ofosu, F. A., Modi, G. J., Smith, L. M. et al. 1984. Heparan sulfate and dermatan sulfate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood, 64(3), 742–7.
Wight, T. N. 2002. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr. Opin. Cell Biol., 14(5), 617–23.
Hinek, A., Wrenn, D. S., Mecham, R. P. and Barondes, S. H. 1988. The elastin receptor: a galactoside-binding protein. Science, 239(4847), 1539–41.
Hocking, A. M., Shinomura, T. and McQuillan, D. J. 1998. Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol., 17(1), 1–19.
Lee, Y., Chung, H. J., Yeo, S. et al. 2010. Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol–thiol reaction. Soft Matter, 6(5), 977–83.
Ryu, J. H., Lee, Y., Kong, W. H. et al. 2011. Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials. Biomacromolecules, 12(7), 2653–9.
Bhattarai, N., Ramay, H. R., Gunn, J., Matsen, F. A. and Zhang, M. 2005. PEG-grafted chitosan as an injectable thermosensitive hydrogel for sustained protein release. J. Control. Release, 103(3), 609–24.
Huang, X., Zhang, Y., Donahue, H. J. and Lowe, T. L. 2007. Porous thermoresponsive-co-biodegradable hydrogels as tissue-engineering scaffolds for 3-dimensional in vitro culture of chondrocytes. Tissue Eng., 13(11), 2645–52.
Mørch, Y. A., Donati, I., Strand, B. L. and Skjåk-Braek, G. 2006. Effect of Ca2+, Ba2+, and Sr2+ on alginate microbeads. Biomacromolecules, 7(5), 1471–80.
Hoffman, A. S. 2002. Hydrogels for biomedical applications. Adv. Drug Deliv. Rev., 54(1), 3–12.
Denuzière, A., Ferrier, D., Damour, O. and Domard, A. 1998. Chitosan–chondroitin sulfate and chitosan–hyaluronate polyelectrolyte complexes: biological properties. Biomaterials, 19(14), 1275–85.
Villanueva, I., Gladem, S. K., Kessler, J. and Bryant, S. K. 2010. Dynamic loading stimulates chondrocyte biosynthesis when encapsulated in charged hydrogels prepared from poly(ethylene glycol) and chondroitin sulfate. Matrix Biol., 29(1), 51–62.
Gerecht, S., Burdick, J. A., Ferreira, L. S. et al. 2007. Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc. Nat. Acad. Sci. USA, 104(27), 11298–303.
Zhang, Y. and Chu, C. C. 2001. Biodegradable dextran–polylactide hydrogel network and its controlled release of albumin. J. Biomed. Mater. Res., 54(1), 1–11.
Kolb, H. C., Finn, M. G. and Sharpless, K. B. 2001. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl., 40(11), 2004–21.
Manzl, C., Enrich, J., Ebner, H., Dallinger, R. and Krumschnabel, G. 2004. Copper-induced formation of reactive oxygen species causes cell death and disruption of calcium homeostasis in trout hepatocytes. Toxicology, 196(1–2), 57–64.
Hu, X., Li, D., Zhou, F. and Gao, C. 2011. Biological hydrogel synthesized from hyaluronic acid, gelatin and chondroitin sulfate by click chemistry. Acta Biomater., 7(4), 1618–26.
Tan, H., Rubin, J. P. and Marra, K. G. 2009. Injectable in situ forming biodegradable chitosan–hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials, 30(13), 2499–506.
Hiemstra, C., Aa, L. J., Zhong, Z., Dijkstra, P. J. and Feijen, J. 2007. Rapidly in situ-forming degradable hydrogels from dextran thiols through Michael addition. Biomacromolecules, 8(5), 1548–56.
Strehin, I., Ambrose, W. M., Schein, O., Salahuddin, A. and Elisseeff, A. 2009. Synthesis and characterization of a chondroitin sulfate–polyethylene glycol corneal adhesive. J. Cataract Refract. Surg., 35(3), 567–76.
Jin, R., Moreira Teixeira, L. S., Dijkstra, P. J. 2009. Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials, 30(13), 2544–51.
Chen, T., Embree, H. D., Brown, E. M., Taylor, M. M. and Payne, G. F. 2003. Enzyme-catalyzed gel formation of gelatin and chitosan: potential for in situ applications. Biomaterials, 24(17), 2831–41.
Kurisawa, M., Chung, J. E., Yang, Y. Y., Gao, S. J. and Uyama, H. 2005. Injectable biodegradable hydrogels composed of hyaluronic acid–tyramine conjugates for drug delivery and tissue engineering. Chem. Commun., (34), 4312–14.
Ko, C. S., Huang, J. P., Huang, C. W. and Chu, I. M. 2009. Type II collagen–chondroitin sulfate–hyaluronan scaffold cross-linked by genipin for cartilage tissue engineering. J. Biosci. Bioeng., 107(2), 177–82.
Selmi, T. A., Verdonk, P., Chambat, P. et al. 2008. Autologous chondrocyte implantation in a novel alginate–agarose hydrogel: outcome at two years. J. Bone Joint Surg. Br., 90(5), 597–604.
Varghese, S., Hwang, N. S., Canver, A. C. et al. 2008. Chondroitin sulfate based niches for chondrogenic differentiation of mesenchymal stem cells. Matrix Biol., 27(1), 12–21.
Jin, R., Teixeira, L. S., Dijkstra, P. J. et al. 2010. Enzymatically-crosslinked injectable hydrogels based on biomimetic dextran–hyaluronic acid conjugates for cartilage tissue engineering. Biomaterials, 31(11), 3103–13.
Wang, D. A., Varghese, S., Sharma, B. et al. 2007. Multifunctional chondroitin sulphate for cartilage tissue-biomaterial integration. Nature Mater., 6(5), 385–92.
Kon, E., Gobbi, A., Filardo, G. et al. 2011. Second-generation autologous chondrocyte implantation: results in patients older than 40 years. Am. J. Sports Med., 39(8), 1668–75.
Nehrer, S., Domayer, S., Dorotka, R. et al. 2006. Three-year clinical outcome after chondrocyte transplantation using a hyaluronan matrix for cartilage repair. Eur. J. Radiol., 57(1), 3–8.
Buschmann, M. D. H., Hoemann, C. D., Hurtig, M. B. and Shive, M. S. 2007. Cartilage repair with chitosan–glycerol phosphate-stabilized blood clots. In Cartilage Repair Strategies, ed. Williams, R. J.. Totowa, NJ: Humana Press.
Shive, M. S., Hoemann, C. D., Restrepo, A. et al. 2006. BST-CarGel: in situ chondroinduction for cartilage repair. Operative Techniques Orthopaedics, 16(4), 8.
Stephan, S. J., Tholpady, S. S., Gross, B. et al. 2010. Injectable tissue-engineered bone repair of a rat calvarial defect. Laryngoscope, 120(5), 895–901.
Alsberg, E., Anderson, K. W., Albeiruti, A., Franceschi, R. T. and Mooney, D. J. 2001. Cell-interactive alginate hydrogels for bone tissue engineering. J. Dent. Res., 80(11), 2025–9.
Tanaka, K., Goto, T., Miyazaki, T. et al. 2011. Apatite-coated hyaluronan for bone regeneration. J. Dent. Res., 90(7), 906–11.
Yannas, I. V. and Burke, J. F. 1980. Design of an artificial skin. I. Basic design principles. J. Biomed. Mater. Res., 14(1), 65–81.
Sun, G., Zhang, X., Shen, Y. I. et al. 2011. Dextran hydrogel scaffolds enhance angiogenic responses and promote complete skin regeneration during burn wound healing. Proc. Nat. Acad. Sci. USA, 108(52), 20976–81.
Lee, W. R., Park, J. H., Kim, K. H. et al. 2009. The biological effects of topical alginate treatment in an animal model of skin wound healing. Wound Repair Regen., 17(4), 505–10.
Uccioli, L., Giurato, L., Ruotolo, V. et al. 2011. Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up. Int. J. Low Extrem. Wounds, 10(2), 80–5.
Leipzig, N. D., Giurato, L., Ruotolo, V. et al. 2011. Differentiation of neural stem cells in three-dimensional growth factor-immobilized chitosan hydrogel scaffolds. Biomaterials, 32(1), 57–64.
Park, J. S., Chu, J. S., Tsou, A. D. et al. 2011. The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β. Biomaterials, 32(16), 3921–30.
Wei, Y. T., He, Y., Xu, C. L. et al. 2010. Hyaluronic acid hydrogel modified with nogo-66 receptor antibody and poly-l-lysine to promote axon regrowth after spinal cord injury. J. Biomed. Mater. Res. B Appl. Biomater., 95(1), 110–17.
Raines, A. L., Sunwoo, M., Gertzmann, A. A. et al. 2011. Hyaluronic acid stimulates neovascularization during the regeneration of bone marrow after ablation. J. Biomed. Mater. Res. Part A, 96(3), 575–83.
Liu, Y. and Chan-Park, M. B. 2009. Hydrogel based on interpenetrating polymer networks of dextran and gelatin for vascular tissue engineering. Biomaterials, 30(2), 196–207.
Pandis, L., Zavan, B., Abatangelo, B. et al. 2010. Hyaluronan-based scaffold for in vivo regeneration of the rat vena cava: preliminary results in an animal model. J. Biomed. Mater. Res. Part A, 93(4), 1289–96.
Re’em, T., Kaminer-Israeli, Y., Ruvinov, E. and Cohen, S. 2012. Chondrogenesis of hMSC in affinity-bound TGF-β scaffolds. Biomaterials, 33(3), 751–61.
Lee, K. W., Yoon, J. J., Lee, J. H. et al. 2004. Sustained release of vascular endothelial growth factor from calcium-induced alginate hydrogels reinforced by heparin and chitosan. Transplant. Proc., 36(8), 2464–5.
Ruvinov, E., Leor, J. and Cohen, S. 2011. The promotion of myocardial repair by the sequential delivery of IGF-1 and HGF from an injectable alginate biomaterial in a model of acute myocardial infarction. Biomaterials, 32(2), 565–78.
Sánchez, M., Anitua, E., Azofra, J. et al. 2007. Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am. J. Sports Med., 35(2), 245–51.
Fortier, L. A., Potter, H. G., Rickey, E. J. et al. 2010. Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. J. Bone Joint Surg. Am., 92(10), 1927–37.
Gobbi, A., Karnatzikos, G., Scotti, C. 2011. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage, 2(3), 14.
Marx, R. E. 2001. Platelet-rich plasma (PRP): what is PRP and what is not PRP?Implant. Dent., 10(4), 225–8.
Wong, D. A., Kumar, A., Jatana, S., Ghiselli, G. and Wong, K. 2008. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J., 8(6), 1011–18.
Canter, H. I., Vargel, I., Korkusuz, P. et al. 2010. Effect of use of slow release of bone morphogenetic protein-2 and transforming growth factor-β-2 in a chitosan gel matrix on cranial bone graft survival in experimental cranial critical size defect model. Ann. Plast. Surg., 64(3), 342–50.
Kolambkar, Y. M., Dupont, K. M., Boerckel, J. D. et al. 2011. An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials, 32(1), 65–74.
Jeon, O., Powell, C., Solorio, L. D., Krebs, M. D. and Alsberg, E. 2011. Affinity-based growth factor delivery using biodegradable, photocrosslinked heparin-alginate hydrogels. J. Control. Release, 154(3), 258–66.
Wood, M. D., Moore, A. M., Hunter, D. A. et al. 2009. Affinity-based release of glial-derived neurotrophic factor from fibrin matrices enhances sciatic nerve regeneration. Acta Biomater., 5(4), 959–68.
Xu, H., Yan, Y. and Li, S. 2011. PDLLA/chondroitin sulfate/chitosan/NGF conduits for peripheral nerve regeneration. Biomaterials, 32(20), 4506–16.
Marx, R. E., Carlson, E. R., Eichstaedt, R. M. et al. 1998. Platelet-rich plasma: growth factor enhancement for bone grafts. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 85(6), 638–46.
Lu, H. H., Vo, J. M., Chin, H. S. et al. 2008. Controlled delivery of platelet-rich plasma-derived growth factors for bone formation. J. Biomed. Mater. Res. Part A, 86(4), 1128–36.
Oktay, E. O., Demiralp, B., Demiralp, B. et al. 2010. Effects of platelet-rich plasma and chitosan combination on bone regeneration in experimental rabbit cranial defects. J. Oral Implantol., 36(3), 175–84.
Strehin, I., Nahas, Z., Arora, K., Nguyen, T. and Elisseeff, J. 2010. A versatile pH sensitive chondroitin sulfate-PEG tissue adhesive and hydrogel. Biomaterials, 31(10), 2788–97.
Chenault, H. K., Bhatia, S. K., Dimaio, W. G. et al. 2011. Sealing and healing of clear corneal incisions with an improved dextran aldehyde-PEG amine tissue adhesive. Curr. Eye Res., 36(11), 997–1004.
Artzi, N., Shazly, T., Crespo, C. et al. 2009. Characterization of star adhesive sealants based on PEG/dextran hydrogels. Macromolec. Biosci., 9(8), 754–65.