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

20 - Growth factor delivery on scaffolds

from Part IV - Biological factor delivery



Traditionally tissue engineering entails the seeding and culturing of differentiated somatic cells onto biodegradable scaffolds, with subsequent implantation of the cell–scaffold constructs into the defective or damaged sites to regenerate tissues [1]. In this approach, the scaffold acts as a three-dimensional (3D) framework to provide physical support and accommodate cell growth and deposition of extracellular matrices, and its biodegradability allows the scaffold material to be resorbed in pace with new tissue formation. Despite some encouraging successes in clinical trials [2, 3], two key limitations with this approach include the limited source of exogenous donor cells and the lack of adequate vascularity to maintain vitality of the newly regenerated tissues. To address these limitations, current advanced tissue engineering techniques gear toward harnessing a biomimetic scaffold that provides a synthetic regenerative microenvironment to support natural tissue regeneration and angiogenesis [4]. In addition to providing physical support, the ideal biomimetic scaffold would preferably also deliver bioactive factors, which instruct endogenous stem cell recruitment and differentiation three-dimensionally and in a controlled manner [5] (Figure 20.1). Various bioactive factors, including growth factors [6–8], nucleic acids [9], and integrin-binding ligands [10], have successfully been delivered or presented on biodegradable scaffolds. Among these, growth factors are the most important soluble signals in the natural regenerative microenvironment, being actively involved in stem cell recruitment, proliferation, and differentiation, angiogenesis, and tissue morphogenesis. Although they are potent, growth factors are expensive and have short half-lives in vivo. Therefore, scaffolds with controlled-release capacity are desired in order to preserve growth factor bioactivity and to prolong their function at therapeutic levels over an extended time period. However, there remain significant challenges in delivering growth factors effectively from scaffolds, including the need to preserve the bioactivity of growth factors during the possibly harsh incorporation process, the control of their release over an extended period during tissue regeneration, and the need for release to be restricted locally so as to avoid toxic or unwanted systemic side effects. Additionally, each individual delivery strategy is related, and sometimes restricted, to the type of scaffold utilized.

Langer, R. and Vacanti, J. P. 1993. Tissue engineering. Science, 260(5110), 920–6.
Shin’oka, T., Imai, Y. and Ikada, Y. 2001. Transplantation of a tissue-engineered pulmonary artery. New Engl. J. Med., 344(7), 532–3.
Raya-Rivera, A., Esquiliano, D. R., Yoo, J. J. et al. 2011. Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet, 377(9772), 1175–82.
Ma, P. X. 2008. Biomimetic materials for tissue engineering. Adv. Drug Delivery Rev., 60(2), 184–98.
Zhang, Z., Hu, J. and Ma, P. X. 2012. Nanofiber-based delivery of bioactive agents and stem cells to bone sites. Adv. Drug Delivery Rev., 64(22), 1129–41.
Whang, K., Tsai, D. C., Nam, E. K. et al. 1998. Ectopic bone formation via rhBMP-2 delivery from porous bioabsorbable polymer scaffolds. J. Biomed. Mater. Res., 42(4), 491–9.
Oldham, J. B., Lu, L., Zhu, X. et al. 2000. Biological activity of rhBMP-2 released from PLGA microspheres. J. Biomech. Eng. Trans. ASME, 122(3), 289–92.
Peter, S. J., Lu, L., Kim, D. J. et al. 2000. Effects of transforming growth factor beta 1 released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates. J. Biomed. Mater. Res., 50(3), 452–62.
Shea, L. D., Smiley, E., Bonadio, J. and Mooney, D. J. 1999. DNA delivery from polymer matrices for tissue engineering. Nature Biotechnol., 17(6), 551–4.
Hern, D. L. and Hubbell, J. A. 1998. Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing. J. Biomed. Mater. Res., 39(2), 266–76.
Asahina, I., Sampath, T. K., Nishimura, I. and Hauschka, P. V. 1993. Human osteogenic protein-1 induces both chondroblastic and osteoblastic differentiation of osteoprogenitor cells derived from newborn rat calvaria. J. Cell Biol., 123(4), 921–33.
Torii, Y., Hitomi, K. and Tsukagoshi, N. 1996. Synergistic effect of BMP-2 and ascorbate on the phenotypic expression of osteoblastic MC3T3-E1 cells. Molec. Cellular Biochem., 165(1), 25–9.
Wozney, J. M. and Rosen, V. 1998. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin. Orthopaedics Related Res., 346, 26–37.
Neubuser, A., Peters, H., Balling, R. and Martin, G. R. 1997 Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell, 90(2), 247–55.
Servold, S. A. 1991. Growth factor impact on wound healing. Clinics Podiatric Med. Surg., 8(4), 937–53.
Robson, M. C., Mustoe, T. A. and Hunt, T. K. 1998. The future of recombinant growth factors in wound healing. Am. J. Surg., 176(Suppl. 2A), 80–2.
Gerwins, P., Skoldenberg, E. and Claesson-Welsh, L. 2000. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit. Rev. Oncol. Hematol., 34(3), 185–94.
Lee, K. Y. and Mooney, D. J. 2001. Hydrogels for tissue engineering. Chem. Rev., 101(7), 1869–79.
Nguyen, K. T. and West, J. L. 2002. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials, 23(22), 4307–14.
Siepmann, J. and Peppas, N. A. 2001. Mathematical modeling of controlled drug delivery. Adv. Drug Delivery Rev., 48(2–3), 137–8.
Mellott, M. B., Searcy, K. and Pishko, M. V. 2001. Release of protein from highly cross-linked hydrogels of poly(ethylene glycol) diacrylate fabricated by UV polymerization. Biomaterials, 22(9), 929–41.
Cadee, J. A., de Groot, C. J., Jiskoot, W., den Otter, W. and Hennink, W. E. 2002. Release of recombinant human interleukin-2 from dextran-based hydrogels. J. Controll. Release, 78(1–3), 1–13.
Tabata, Y., Ishii, T., Muniruzzaman, M., Hirano, Y. and Ikada, Y. 2000. Influence of gelatin complexation on cell proliferation activity and proteolytic resistance of basic fibroblast growth factor. J. Biomater. Sci. – Polymer Edition, 11(6), 571–82.
Ungaro, F., Biondi, M., d’Angelo, I. et al. 2006. Microsphere-integrated collagen scaffolds for tissue engineering: effect of microsphere formulation and scaffold properties on protein release kinetics. J. Controll. Release, 113(2), 128–36.
Maschke, A., Becker, C., Eyrich, D. et al. 2007. Development of a spray congealing process for the preparation of insulin-loaded lipid microparticles and characterization thereof. Eur. J. Pharmaceutics Biopharmaceutics, 65(2), 175–87.
Holland, T. A., Tabata, Y. and Mikos, A. G. 2003. In vitro release of transforming growth factor-β1 from gelatin microparticles encapsulated in biodegradable, injectable oligo(poly(ethylene glycol) fumarate) hydrogels. J. Controll. Release, 91(3), 299–313.
Holland, T. A., Tabata, Y. and Mikos, A. G. 2005. Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. J. Controll. Release, 101(1–3), 111–25.
DeLong, S. A., Moon, J. J. and West, J. L. 2005. Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration. Biomaterials, 26(16), 3227–34.
Rizzi, S. C., Ehrbar, M., Halstenberg, S. et al. 2006. Recombinant protein-co-PEG networks as cell-adhesive and proteolytically degradable hydrogel matrixes. Part II: biofunctional characteristics. Biomacromolecules, 7(11), 3019–29.
Park, K. E., Kang, H. K., Lee, S. J., Min, B. M. and Park, W. H. 2006. Biomimetic nanofibrous scaffolds: preparation and characterization of PGA/chitin blend nanofibers. Biomacromolecules, 7(2), 635–43.
Nitschke, M., Schmack, G., Janke, A. et al. 2002. Low pressure plasma treatment of poly(3-hydroxybutyrate): toward tailored polymer surfaces for tissue engineering scaffolds. J. Biomed. Mater. Res., 59(4), 632–8.
Wan, Y. Q., Yang, J., Yang, J. L., Bei, J. Z. and Wang, S. G. 2003. Cell adhesion on gaseous plasma modified poly-(l-lactide) surface under shear stress field. Biomaterials, 24(21), 3757–64.
Gao, J. M., Niklason, L. and Langer, R. 1998. Surface hydrolysis of poly(glycolic acid) meshes increases the seeding density of vascular smooth muscle cells. J. Biomed. Mater. Res., 42(3), 417–24.
Park, G. E., Pattison, M. A., Park, K. and Webster, T. J. 2005. Accelerated chondrocyte functions on NaOH-treated PLGA scaffolds. Biomaterials, 26(16), 3075–82.
Duckworth, B. P., Xu, J. H., Taton, T. A., Guo, A. and Distefano, M. D. 2006. Site-specific, covalent attachment of proteins to a solid surface. Bioconjugate Chem., 17(4), 967–74.
Kim, T. G. and Park, T. G. 2006. Surface functionalized electrospun biodegradable nanofibers for immobilization of bioactive molecules. Biotechnol. Prog., 22(4), 1108–13.
Shi, Q., Chen, X. S., Lu, T. C. and Jing, X. B. 2008. The immobilization of proteins on biodegradable polymer fibers via click chemistry. Biomaterials, 29(8), 1118–26.
Fu, G. D., Xu, L. Q., Yao, F., Li, G. L. and Kang, E. T. 2009. Smart nanofibers with a photoresponsive surface for controlled release. ACS Appl. Mater. Interfaces, 1(11), 2424–7.
Killops, K. L., Campos, L. M. and Hawker, C. J. 2008. Robust, efficient, and orthogonal synthesis of dendrimers via thiol-ene “click” chemistry. J. Am. Chem. Soc., 130(15), 5062–4.
Ehrbar, M., Rizzi, S. C., Hlushchuk, R. et al. 2007. Enzymatic formation of modular cell-instructive fibrin analogs for tissue engineering. Biomaterials, 28(26), 3856–66.
Sohier, J., Haan, R. E., de Groot, K. and Bezemer, J. M. 2003. A novel method to obtain protein release from porous polymer scaffolds: emulsion coating. J. Controll. Release, 87(1–3), 57–68.
Whang, K., Goldstick, T. K. and Healy, K. E. 2000. A biodegradable polymer scaffold for delivery of osteotropic factors. Biomaterials, 21(24), 2545–51.
Elsdale, T. and Bard, J. 1972. Collagen substrata for studies on cell behavior. J. Cell Biol., 54(3), 626–37.
Franceschi, R. T. 1999. The developmental control of osteoblast-specific gene expression: role of specific transcription factors and the extracellular matrix environment. Crit. Rev. Oral Biol. Med., 10(1), 40–57.
Xiao, G. Z., Gopalakrishnan, R., Jiang, D. et al. 2002. Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J. Bone Mineral Res., 17(1), 101–10.
Li, W. J., Laurencin, C. T., Caterson, E. J., Tuan, R. S. and Ko, F. K. 2002. Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J. Biomed. Mater. Res., 60(4), 613–21.
Matthews, J. A., Wnek, G. E., Simpson, D. G. and Bowlin, G. L. 2002. Electrospinning of collagen nanofibers. Biomacromolecules, 3(2), 232–8.
Yoshimoto, H., Shin, Y. M., Terai, H. and Vacanti, J. P. 2003. A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. Biomaterials, 24(12), 2077–82.
Li, C. M., Vepari, C., Jin, H. J., Kim, H. J. and Kaplan, D. L. 2006. Electrospun silk-BMP-2 scaffolds for bone tissue engineering. Biomaterials, 27(16), 3115–24.
Casper, C. L., Yamaguchi, N., Kiick, K. L. and Rabolt, J. F. 2005. Functionalizing electrospun fibers with biologically relevant macromolecules. Biomacromolecules, 6(4), 1998–2007.
Nie, H., Soh, B. W., Fu, Y. C. and Wang, C. H. 2008. Three-dimensional fibrous PLGA/HAp composite scaffold for BMP-2 delivery. Biotechnol. Bioeng., 99(1), 223–34.
Zhang, Y. Z., Wang, X., Feng, Y. et al. 2006. Coaxial electrospinning of (fluorescein isothiocyanate-conjugated bovine serum albumin)-encapsulated poly(ε-caprolactone) nanofibers for sustained release. Biomacromolecules, 7(4), 1049–57.
Jiang, H. L., Hu, Y. Q., Zhao, P. C., Li, Y. and Zhu, K. J. 2006. Modulation of protein release from biodegradable core–shell structured fibers prepared by coaxial electrospinning. J. Biomed. Mater. Res. Part B – Appl. Biomater., 79(1), 50–7.
Chen, V. J. and Ma, P. X. 2004. Nano-fibrous poly(l-lactic acid) scaffolds with interconnected spherical macropores. Biomaterials, 25(11), 2065–73.
Wei, G. B. and Ma, P. X. 2006. Macroporous and nanofibrous polymer scaffolds and polymer/bone-like apatite composite scaffolds generated by sugar spheres. J. Biomed. Mater. Res. Part A, 78(2), 306–15.
Chen, V. J., Smith, L. A. and Ma, P. X. 2006. Bone regeneration on computer-designed nano-fibrous scaffolds. Biomaterials, 27(21), 3973–9.
Wang, P., Hu, J. and Ma, P. X. 2009. The engineering of patient-specific, anatomically shaped, digits. Biomaterials, 30(14), 2735–40.
Woo, K. M., Jun, J. H., Chen, V. J. et al. 2007. Nano-fibrous scaffolding promotes osteoblast differentiation and biomineralization. Biomaterials, 28(2), 335–43.
Hu, J. A., Sun, X. A., Ma, H. Y. et al. 2010. Porous nanofibrous PLLA scaffolds for vascular tissue engineering. Biomaterials, 31(31), 7971–7.
Wei, G. B., Jin, Q. M., Giannobile, W. V. and Ma, P. X. 2006. Nano-fibrous scaffold for controlled delivery of recombinant human PDGF-BB. J. Controll. Release, 112(1), 103–10.
Langer, R. 1990. New methods of drug delivery. Science, 249(4976), 1527–33.
Woodrow, K. A., Cu, Y., Booth, C. J. et al. 2009. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nature Mater., 8(6), 526–33.
Wei, G. B., Pettway, G. J., McCauley, L. K. and Ma, P. X. 2004. The release profiles and bioactivity of parathyroid hormone from poly(lactic-co-glycolic acid) microspheres. Biomaterials, 25(2), 345–52.
Wei, G. B., Jin, Q. M., Giannobile, W. V. and Ma, P. X. 2007. The enhancement of osteogenesis by nano-fibrous scaffolds incorporating rhBMP-7 nanospheres. Biomaterials, 28(12), 2087–96.
Jin, Q. M., Wei, G. B., Lin, Z. et al. 2008. Nanofibrous scaffolds incorporating PDGF-BB microspheres induce chemokine expression and tissue neogenesis in vivo. PLOS One, 3(3), e1729.
Ripamonti, U., VandenHeever, B., Sampath, T. K. et al. 1996. Complete regeneration of bone in the baboon by recombinant human osteogenic protein-1 (hOP-1, bone morphogenetic protein-7). Growth Factors, 13(3–4), 273–89.
Cook, S. D. 1999. Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony sites. Orthopedics, 22(7), 669–71.
Xie, Y. C., Yin, T., Wiegraebe, W. et al. 2009. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature, 457(7225), U97–102.
Miura, Y., Gao, Z. G., Miura, M. et al. 2006. Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource. Stem Cells, 24(11), 2428–36.