Abstract
Purpose. Tissue engineering seeks to replace and regrow damaged or diseased tissues and organs from either cells resident in the surrounding tissue or cells transplanted to the tissue site. The purpose of this review is to present the application of polymeric delivery systems for growth factor delivery in tissue engineering.
Methods. Growth factors direct the phenotype of both differentiated and stem cells, and methods used to deliver these molecules include the development of systems to deliver the protein itself, genes encoding the factor, or cells secreting the factor.
Results. Results in animal models and clinical trials indicate that these approaches may be successfully used to promote the regeneration of numerous tissue types.
Conclusions. Controlling the dose, location, and duration of these factors through polymeric delivery strategies will dictate their utility in tissue regeneration.
Similar content being viewed by others
REFERENCES
D. J. Mooneyand and A. G. Mikos. Growing new organs. Sci. Am. 280:60-65 (1999).
P. Aebischer and J. Ridet. Recombinant proteins for neurodegenerative diseases: the delivery issue. Trends Neurosci. 24:533-540 (2001).
F. C. Payumo, H. D. Kim, M. A. Sherling, L. P. Smith, C. Powell, X. Wang, H. S. Keeping, R. F. Valentini, and H. H. Vandenburgh. Tissue engineering skeletal muscle for orthopaedic applications. Clin. Orthop. Oct:S228-S242 (2002).
E. Pimentel. Handbook of Growth Factors I: General Basic Aspects. CRC Press, Boca Raton, Florida, 1994.
D. F. Bowen-Pope, T. W. Malpass, D. M. Foster, and R. Ross. Platelet-derived growth factor in vivo: levels, activity, and rate of clearance. Blood 64:458-469 (1984).
E. R. Edelman, M. A. Nugent, and M. J. Karnovsky. Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition. Proc. Natl. Acad. Sci. USA 90:1513-1517 (1993).
D. F. Lazarous, M. Shou, M. Scheinowitz, E. Hodge, V. Thirumurti, A. N. Kitsiou, J. A. Stiber, A. D. Lobo, S. Hunsberger, E. Guetta, S. E. Epstein, and E. F. Unger. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation 94:1074-1082 (1996).
G. D. Yancopoulos, S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash. Vascular-specific growth factors and blood vessel formation. Nature 407:242-248 (2000).
J. B. Murray, L. Brown, R. Langer, and M. Klagsburn. A micro sustained release system for epidermal growth factor. In Vitro 19:743-748 (1983).
V. Moulin. Growth factors in skin wound healing. Eur. J. Cell Biol. 68:1-7 (1995).
K. Hashimoto. Regulation of keratinocyte function by growth factors. J. Dermatol. Sci. 24(ppl 1):S46-S50 (2000).
C. H. Heldin and B. Westermark. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol. Rev. 79:1283-1316 (1999).
M. H. Branton and J. B. Kopp. TGF-#x0392 and fibrosis. Microbes Infect. 1:1349-1365 (1999).
T. G. Terrell, P. K. Working, C. P. Chow, and J. D. Green. Pathology of recombinant human transforming growth factor-#x0392 1 in rats and rabbits. Int. Rev. Exp. Pathol. 34(Pt B):43-67 (1993).
A. Buckley, J. M. Davidson, C. D. Kamerath, T. B. Wolt, and S. C. Woodward. Sustained release of epidermal growth factor accelerates wound repair. Proc. Natl. Acad. Sci. USA 82:7340-7344 (1985).
T. A. Mustoe, G. F. Pierce, A. Thomason, P. Gramates, M. B. Sporn, and T. F. Deuel. Accelerated healing of incisional wounds in rats induced by transforming growth factor-#x0392. Science 237:1333-1336 (1987).
M. K. Nagau and J. M. Embil. Becaplermin: recombinant platelet derived growth factor, a new treatment for healing diabetic foot ulcers. Expert. Opin. Biol. Ther. 2:211-218 (2002).
R. J. Rohrich, S. A. Trott, M. Love, S. J. Beran, and H. H. Orenstein. Mersilene suture as a vehicle for delivery of growth factors in tendon repair. Plast. Reconstr. Surg. 104:1713-1717 (1999).
K. Ulubayram, A. Nur Cakar, P. Korkusuz, C. Ertan, and N. Hasirci. EGF containing gelatin-based wound dressings. Biomaterials 22:1345-1356 (2001).
M. Centrella, T. L. McCarthy, and E. Canalis. Effects of transforming growth factors on bone cells. Connect. Tissue Res. 20:267-275 (1989).
L. Lu, M. J. Yaszemski, and A. G. Mikos. TGF-#x03921 release from biodegradable polymer microparticles: its effects on marrow stromal osteoblast function. J. Bone Joint. Surg. Am. 83-A(ppl 1):S82-S91 (2001).
K. Elima. Osteoinductive proteins. Ann. Med. 25:395-402 (1993).
G. Li, M. L. Bouxsein, C. Luppen, X. J. Li, M. Wood, H. J. Seeherman, J. M. Wozney, and H. Simpson. Bone consolidation is enhanced by rhBMP-2 in a rabbit model of distraction osteogenesis. J. Orthop. Res. 20:779-788 (2002).
S. D. Boden, J. Kang, H. Sandhu, and J. G. Heller. Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in Clinical Studies. Spine 27:2662-2673 (2002).
K. Bessho, D. L. Carnes, R. Cavin, and J. L. Ong. Experimental studies on bone induction using low-molecular-weight poly (DL-lactide-co-glycolide) as a carrier for recombinant human bone morphogenetic protein-2. J. Biomed. Mater. Res. 61:61-65 (2002).
M. Mori, M. Isobe, Y. Yamazaki, K. Ishihara, and N. Nakabayashi. Restoration of segmental bone defects in rabbit radius by biodegradable capsules containing recombinant human bone morphogenetic protein-2. J. Biomed. Mater. Res. 50:191-198 (2000).
J. A. Burdick, M. N. Mason, A. D. Hinman, K. Thorne, and K. S. Anseth. Delivery of osteoinductive growth factors from degradable PEG hydrogels influences osteoblast differentiation and mineralization. J Control. Release 83:53-63 (2002).
B. H. Woo, B. F. Fink, R. Page, J. A. Schrier, Y. W. Jo, G. Jiang, M. DeLuca, H. C. Vasconez, and P. P. DeLuca. Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein-2 in a polymeric matrix. Pharm. Res. 18:1747-1753 (2001).
W. L. Murphy, M. C. Peters, D. H. Kohn, and D. J. Mooney. Sustained release of vascular endothelial growth factor from mineralized poly(lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials 21:2521-2527 (2000).
A. Minamide, M. Kawakami, H. Hashizume, R. Sakata, and T. Tamaki. Evaluation of carriers of bone morphogenetic protein for spinal fusion. Spine 26:933-939 (2001).
J. Street, M. Bao, L. deGuzman, S. Bunting, F. V. Peale Jr., N. Ferrara, H. Steinmetz, J. Hoeffel, J. L. Cleland, A. Daugherty, N. van Bruggen, H. P. Redmond, R. A. Carano, and E. H. Filvaroff. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl. Acad. Sci. USA 99:9656-9661 (2002).
K. K. Hirschi, T. C. Skalak, S. M. Peirce, and C. D. Little. Vascular assembly in natural and engineered tissues. Ann. NY Acad. Sci. 961:223-242 (2002).
S. B. Freedman and J. M. Isner. Therapeutic angiogenesis for coronary artery disease. Ann. Intern. Med. 136:54-71 (2002).
R. Laham. Angiogenesis (clinical trials). Can. J. Cardiol. 17(ppl A):29A-32A (2001).
A. B. Ennett and D. J. Mooney. Tissue engineering strategies for in vivo neovascularisation. Expert. Opin. Biol. Ther. 2:805-818 (2002).
R. J. Laham, F. W. Sellke, E. R. Edelman, J. D. Pearlman, J. A. Ware, D. L. Brown, J. P. Gold, and M. Simons. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 100:1865-1871 (1999).
M. C. Peters, P. J. Polverini, and D. J. Mooney. Engineering vascular networks in porous polymer matrices. J. Biomed. Mater. Res. 60:668-678 (2002).
Y. Kawakami, H. Iwata, Y. J. Gu, M. Miyamoto, Y. Murakami, A. N. Balamurugan, M. Imamura, and K. Inoue. Successful subcutaneous pancreatic islet transplantation using an angiogenic growth factor-releasing device. Pancreas 23:375-381 (2001).
H. Lee, R. A. Cusick, F. Browne, T. Ho Kim, P. X. Ma, H. Utsunomiya, R. Langer, and J. P. Vacanti. Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices. Transplantation 73:1589-1593 (2002).
T. P. Richardson, M. C. Peters, A. B. Ennett, and D. J. Mooney. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19:1029-1034 (2001).
J. M. Isner. Myocardial gene therapy. Nature 415:234-239 (2002).
H. Kuwahara, A. T. Mitchell, M. D. Macklin, J. Zhao, D. Listengarten, and L. G. Phillips. Transfer of platelet-derived growth factor-BB gene by gene gun increases contraction of collagen lattice by fibroblasts in diabetic and non-diabetic human skin. Scand. J. Plast. Reconstr. Surg. Hand Surg. 34:301-307 (2000).
C. K. Byrnes, F. H. Khan, P. H. Nass, C. Hatoum, M. D. Duncan, and J. W. Harmon. Success and limitations of a naked plasmid transfection protocol for keratinocyte growth factor-1 to enhance cutaneous wound healing. Wound Repair Regen. 9:341-346 (2001).
D. S. Musgrave, P. Bosch, S. Ghivizzani, P. D. Robbins, C. H. Evans, and J. Huard. Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 24:541-547 (1999).
D. F. Lazarous, M. Shou, J. A. Stiber, E. Hodge, V. Thirumurti, L. Goncalves, and E. F. Unger. Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovasc. Res. 44:294-302 (1999).
T. Reid, R. Warren, and D. Kirn. Intravascular adenoviral agents in cancer patients: Lessons from clinical trials. Cancer Gene Ther. 9:979-986 (2002).
L. D. Shea, E. Smiley, J. Bonadio, and D. J. Mooney. DNA delivery from polymer matrices for tissue engineering. Nat. Biotechnol. 17:551-554 (1999).
V. Labhasetwar, J. Bonadio, S. Goldstein, W. Chen, and R. J. Levy. A DNA controlled-release coating for gene transfer: transfection in skeletal and cardiac muscle. J. Pharm. Sci. 87:1347-1350 (1998).
D. Wang, D. R. Robinson, and G. S. Kwon. and J. Samuel. Encapsulation of plasmid DNA in biodegradable poly(D, L-lactic-co-glycolic acid) microspheres as a novel approach for immunogene delivery. J. Control. Release 57:9-18 (1999).
S. A. Audouy, L. F. de Leij, D. Hoekstra, and G. Molema. In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm. Res. 19:1599-1605 (2002).
J. A. Andrades, M. E. Nimni, B. Han, D. C. Ertl, F. L. Hall, and J. Becerra. Type I collagen combined with a recombinant TGF-#x0392 serves as a scaffold for mesenchymal stem cells. Int. J. Dev. Biol. (ppl 1):107S-108S (1996).
E. Alsberg, K. W. Anderson, A. Albeiruti, J. A. Rowley, and D. J. Mooney. Engineering growing tissues. Proc. Natl. Acad. Sci. USA 99:12025-12030 (2002).
K. Partridge, X. Yang, N. M. Clarke, Y. Okubo, K. Bessho, W. Sebald, S. M. Howdle, K. M. Shakesheff, and R. O. Oreffo. Adenoviral BMP-2 gene transfer in mesenchymal stem cells: in vitro and in vivo bone formation on biodegradable polymer scaffolds. Biochem. Biophys. Res. Commun. 292:144-152 (2002).
S. T. Boyce, R. J. Kagan, K. P. Yakuboff, N. A. Meyer, M. T. Rieman, D. G. Greenhalgh, and G. D. Warden. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann. Surg. 235:269-279 (2002).
X. Chen, M. Katakowski, Y. Li, D. Lu, L. Wang, L. Zhang, J. Chen, Y. Xu, S. Gautam, A. Mahmood, and M. Chopp. Human bone marrow stromal cell cultures conditioned by traumatic brain tissue extracts: growth factor production. J. Neurosci. Res. 69:687-691 (2002).
A. S. Breitbart, J. M. Mason, C. Urmacher, M. Barcia, R. T. Grant, R. G. Pergolizzi, and D. A. Grande. Gene-enhanced tissue engineering: applications for wound healing using cultured dermal fibroblasts transduced retrovirally with the PDGF-B gene. Ann. Plast. Surg. 43:632-639 (1999).
J. M. Mason, A. S. Breitbart, M. Barcia, D. Porti, R. G. Pergolizzi, and D. A. Grande. Cartilage and bone #x00AEeneration using gene-enhanced tissue engineering. Clin. Orthop. Oct:S171-S178 (2000).
H. Iwaguro, J. Yamaguchi, C. Kalka, S. Murasawa, H. Masuda, S. Hayashi, M. Silver, T. Li, J. M. Isner, and T. Asahara. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular #x00AEeneration. Circulation 105:732-738 (2002).
Y. Lu, J. Shansky, M. Del Tatto, P. Ferland, S. McGuire, J. Marszalkowski, M. Maish, R. Hopkins, X. Wang, P. Kosnik, M. Nackman, A. Lee, B. Creswick, and H. Vandenburgh. Therapeutic potential of implanted tissue-engineered bioartificial muscles delivering recombinant proteins to the sheep heart. Ann. NY Acad. Sci. 961:78-82 (2002).
H. Peng, V. Wright, A. Usas, B. Gearhart, H. C. Shen, J. Cummins, and J. Huard. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J. Clin. Invest. 110:751-759 (2002).
A. S. Breitbart, D. A. Grande, J. Laser, M. Barcia, D. Porti, S. Malhotra, A. Kogon, R. T. Grant, and J. M. Mason. Treatment of ischemic wounds using cultured dermal fibroblasts transduced retrovirally with PDGF-B and VEGF121 genes. Ann Plast Surg 46:555-561 (2001).
R. B. Rutherford, M. Moalli, R. T. Franceschi, D. Wang, K. Gu, and P. H. Krebsbach. Bone morphogenetic protein-transduced human fibroblasts convert to osteoblasts and form bone in vivo. Tissue Eng. 8:441-452 (2002).
J. Y. Lee, S. H. Nam, S. Y. Im, Y. J. Park, Y. M. Lee, Y. J. Seol, C. P. Chung, and S. J. Lee. Enhanced bone formation by controlled growth factor delivery from chitosan-based biomaterials. J. Control. Release 78:187-197 (2002).
K. A. Hildebrand, S. L. Woo, D. W. Smith, C. R. Allen, M. Deie, B. J. Taylor, and C. C. Schmidt. The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. An in vivo study. Am. J. Sports Med. 26:549-554 (1998).
D. M. Arm, A. F. Tencer, S. D. Bain, and D. Celino. Effect of controlled release of platelet-derived growth factor from a porous hydroxyapatite implant on bone ingrowth. Biomaterials 17:703-709 (1996).
C. M. Mierisch, S. B. Cohen, L. C. Jordan, P. G. Robertson, G. Balian, and D. R. Diduch. Transforming growth factor-#x0392 in calcium alginate beads for the treatment of articular cartilage defects in the rabbit. Arthroscopy 18:892-900 (2002).
M. Raschke, B. Wildemann, P. Inden, H. Bail, A. Flyvbjerg, J. Hoffmann, N. P. Haas, and G. Schmidmaier. Insulin-like growth factor-1 and transforming growth factor-#x03921 accelerates osteotomy healing using polylactide-coated implants as a delivery system: a biomechanical and histological study in minipigs. Bone 30:144-151 (2002).
J. W. Vehof, M. T. Haus, A. E. de Ruijter, P. H. Spauwen, and J. A. Jansen. Bone formation in transforming growth factor #x0392-I-loaded titanium fiber mesh implants. Clin. Oral Implants Res. 13:94-102 (2002).
P. A. Puolakkainen, D. R. Twardzik, J. E. Ranchalis, S. C. Pankey, M. J. Reed, and W. R. Gombotz. The enhancement in wound healing by transforming growth factor-#x0392 1 (TGF-#x0392 1) depends on the topical delivery system. J. Surg. Res. 58:321-329 (1995).
S. Govender, C. Csimma, H. K. Genant, A. Valentin-Opran, Y. Amit, R. Arbel, H. Aro, D. Atar, M. Bishay, M. G. Borner, P. Chiron, P. Choong, J. Cinats, B. Courtenay, R. Feibel, B. Geulette, C. Gravel, N. Haas, M. Raschke, E. Hammacher, D. Van Der Velde, P. Hardy, M. Holt, C. Josten, R. L. Ketterl, B. Lindeque, G. Lob, H. Mathevon, G. McCoy, D. Marsh, R. Miller, E. Munting, S. Oevre, L. Nordsletten, A. Patel, A. Pohl, W. Rennie, P. Reynders, P. M. Rommens, J. Rondia, W. C. Rossouw, P. J. Daneel, S. Ruff, A. Ruter, S. Santavirta, T. A. Schildhauer, C. Gekle, R. Schnettler, D. Segal, H. Seiler, R. B. Snowdowne, J. Stapert, G. Taglang, R. Verdonk, L. Vogels, A. Weckbach, A. Wentzensen, and T. Wisniewski. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J. Bone Joint. Surg. Am. 84-A:2123-2134. (2002).
K. A. Selvig, R. G. Sorensen, J. M. Wozney, and U. M. Wikesjo. Bone repair following recombinant human bone morphogenetic protein-2 stimulated periodontal #x00AEeneration. J. Periodontol. 73:1020-1029 (2002).
S. Itoh, M. Kikuchi, K. Takakuda, K. Nagaoka, Y. Koyama, J. Tanaka, and K. Shinomiya. Implantation study of a novel hydroxyapatite/collagen (HAp/col) composite into weight-bearing sites of dogs. J. Biomed. Mater. Res. 63:507-515 (2002).
N. Saito, T. Okada, H. Horiuchi, N. Murakami, J. Takahashi, M. Nawata, H. Ota, K. Nozaki, and K. Takaoka. A biodegradable polymer as a cytokine delivery system for inducing bone formation. Nat. Biotechnol. 19:332-335 (2001).
T. R. Blattert, G. Delling, P. S. Dalal, C. A. Toth, H. Balling, and A. Weckbach. Successful transpedicular lumbar interbody fusion by means of a composite of osteogenic protein-1 (rhBMP-7) and hydroxyapatite carrier: a comparison with autograft and hydroxyapatite in the sheep spine. Spine 27:2697-2705 (2002).
J. N. Grauer, T. C. Patel, J. S. Erulkar, N. W. Troiano, M. M. Panjabi, and G. E. Friedlaender. 2000 Young Investigator Research Award winner. Evaluation of OP-1 as a graft substitute for intertransverse process lumbar fusion. Spine 26:127-33 (2001).
U. Ripamonti, J. Crooks, and D. C. Rueger. Induction of bone formation by recombinant human osteogenic protein-1 and sintered porous hydroxyapatite in adult primates. Plast. Reconstr. Surg. 107:977-988 (2001).
K. Mizuno, K. Yamamura, K. Yano, T. Osada, S. Saeki, N. Takimoto, T. Sakurau, and Y. Nimura. Effect of chitosan film containing basic fibroblast growth factor on wound healing in genetically diabetic mice. J. Biomed. Mater. Res. 64:177-181 (2003).
J. J. Lopez, E. R. Edelman, A. Stamler, M. G. Hibberd, P. Prasad, K. A. Thomas, J. DiSalvo, R. P. Caputo, J. P. Carrozza, P. S. Douglas, F. W. Sellke, and M. Simons. Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia. Am. J. Physiol. 274:H930-H936 (1998).
N. Fournier and C. J. Doillon. Biological molecule-imp#x00AEnated polyester: an in vivo angiogenesis study. Biomaterials 17:1659-1665 (1996).
J. L. Cleland, E. T. Duenas, A. Park, A. Daugherty, J. Kahn, J. Kowalski, and A. Cuthbertson. Development of poly-(D,L-lactide-coglycolide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis. J. Control. Release 72:13-24 (2001).
N. Kipshidze, P. Chawla, and M. H. Keelan. Fibrin meshwork as a carrier for delivery of angiogenic growth factors in patients with ischemic limb. Mayo Clin. Proc. 74:847-848 (1999).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, R.R., Mooney, D.J. Polymeric Growth Factor Delivery Strategies for Tissue Engineering. Pharm Res 20, 1103–1112 (2003). https://doi.org/10.1023/A:1025034925152
Issue Date:
DOI: https://doi.org/10.1023/A:1025034925152