Hostname: page-component-7c8c6479df-ph5wq Total loading time: 0 Render date: 2024-03-28T16:30:16.028Z Has data issue: false hasContentIssue false

Poly(lactide-co-glycolide)-Hydroxyapatite Composites: The Development of Osteoinductive Scaffolds for Bone Regenerative Engineering

Published online by Cambridge University Press:  23 April 2012

Meng Deng
Affiliation:
Institute for Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A. Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A.
Emily K. Cushnie
Affiliation:
Institute for Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A.
Qing Lv
Affiliation:
Institute for Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A.
Cato T. Laurencin
Affiliation:
Institute for Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A. Department of Orthopaedic Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3711, U.S.A. Department of Chemical, Materials and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, U.S.A.
Get access

Abstract

Regenerative engineering represents a new multidisciplinary paradigm to engineer complex tissues, organs, or organ systems through the integration of tissue engineering with advanced materials science, stem cell science and developmental biology. While possessing elements of tissue engineering, regenerative medicine, and morphogenesis, regenerative engineering is distinct from these individual disciplines since it specifically focuses on the integration and subsequent response of stem cells to biomaterials. One goal of regenerative engineering is the design of materials capable of inducing associated cells toward highly specialized functions. For example, the interaction of cells with calcium phosphate surfaces has proven to be an important signaling modality in promoting osteogenic differentiation. A biodegradable polymer-ceramic composite system has been developed from poly(lactide-co-glycolide) and in situ synthesized hydroxyapatite based on the three-dimensional sintered microsphere matrix platform. We have systematically optimized scaffold physico-chemical, mechanical, and structural properties for bone tissue regeneration applications by varying several parameters such as solution pH, polymer:ceramic ratio, sintering time and sintering temperature. The bioactivity of composite scaffolds is attributed to their ability to deliver calcium ions to surrounding medium and allow for reprecipitation of calcium phosphate on the scaffold surface. Furthermore, the composite scaffolds have demonstrated increased loading capacity of osteoinductive growth factor (BMP-2) and a more sustained release profile due to a greater number of adsorption sites provided by the ionic calcium and phosphate groups as well as a larger matrix surface area. In vitro cell studies were performed to investigate the efficacy of this composite system to induce osteogenic differentiation of human adipose-derived stem cells. Cells cultured on the ceramic containing scaffolds exhibited significantly higher expression of osteoblastic markers and greater extracellular matrix mineralization than non-ceramic containing scaffolds, indicating the potential for the ceramic phase to promote osteogenic differentiation. In addition, loaded BMP-2 retained its bioactivity as a mitogen and osteoinductive agent during the differentiation of adipose-derived stem cells into mature osteoblasts. In vivo evaluation using a critical-sized ulnar defect model in New Zealand white rabbits demonstrated the ability of composite scaffolds to support cellular infiltration throughout the scaffold pore structure and vascularization of new tissue, as well as facilitate formation of newly mineralized bone tissue. The work described herein provides strong evidence for the potential of polymer-ceramic composite scaffolds to function as osteoinductive bone graft substitutes, and paves the way for future development of advanced tissue-inducing materials.

Type
Research Article
Copyright
Copyright © Materials Research Society 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. Braddock, M., Houston, P., Campbell, C. and Ashcroft, P., News Physiol Sci 16, 208213 (2001).Google Scholar
2. Einhorn, T. A., Clin Orthop Relat Res 355, S721 (1998).Google Scholar
3. McKibbin, B., J Bone Joint Surg Br 60-B, 150-162 (1978).Google Scholar
4. Carano, R. A. D. and Filvaroff, E. H., Drug Discov Today 8, 980989 (2003).Google Scholar
5. Schindeler, A., McDonald, M. M., Bokko, P. and Little, D. G., Semin Cell Dev Biol 19, 459466 (2008).Google Scholar
6. Laurencin, C., Khan, Y. and El-Amin, S. F., Expert Rev Med Devices 3, 4957 (2005).Google Scholar
7. Goulet, J. A., Senunas, L. E., DeSilva, G. L. and Greenfield, M. L., Clin Orthop Relat Res 339, 7681 (1997).Google Scholar
8. Albrektsson, T. A. and Johansson, C. J., Eur Spine J 10, S96101 (2001).Google Scholar
9. Urist, M. R., Science 150, 893899 (1965).Google Scholar
10. Bessa, P. C., Casal, M. and Reis, R. L., J Tissue Eng Regen Med 2, 113 (2008).Google Scholar
11. Urist, M. R. and Strates, B. S., J Dent Res 50, 13921406 (1971).Google Scholar
12. Bostrom, M. P. G. and Camacho, N. P., Clin Orthop Relat Res 355, S274282 (1998).Google Scholar
13. Laurencin, C. T., Attawia, M. A., Lu, L. Q., Borden, M. D., Lu, H. H., Gorum, W. J. and Lieberman, J. R., Biomaterials 22, 12711277 (2001).Google Scholar
14. Lieberman, J., Daluiski, A. and Einhorn, T., J Bone Joint Surg Am 84-A, 1032-1044 (2002).Google Scholar
15. Yamaguchi, A., Ishizuya, T., Kintou, N., Wada, Y., Katagiri, T., Wozney, J. M., Rosen, V. and Yoshiki, S., Biochem Biophys Res Commun 220, 366371 (1996).Google Scholar
16. White, A. P., Vaccaro, A. R., Hall, J. A., Whang, P. G., Friel, B. C. and McKee, M. D., Int Orthop 31, 735741 (2007).Google Scholar
17. McKay, W. F., Peckham, S. M. and Badura, J. M., Int Orthop 31, 729734 (2007).Google Scholar
18. Habibovic, P. and de Groot, K., J Tissue Eng Regen Med 1, 2532 (2007).Google Scholar
19. Lv, Q., Lo, K. W. H., Nair, L. S. and Laurencin, C. T., in Biodegradable Polymers in Clinical Use and Clinical Development, edited by Domb, A. J., Kumar, N. and Ezra, A. (John Wiley & Sons, Inc., Hoboken, NJ, USA, 2011), pp. 495517.Google Scholar
20. LeGeros, R. Z., Chem Rev 108, 47424753 (2008).Google Scholar
21. Chai, Y. C., Roberts, S. J., Schrooten, J. and Luyten, F. P., Tissue Eng Part A 17, 10831097 (2010).Google Scholar
22. Müller, P., Bulnheim, U., Diener, A., Lüthen, F., Teller, M., Klinkenberg, E.-D., Neumann, H.-G., Nebe, B., Liebold, A., Steinhoff, G. and Rychly, J., J Cell Mol Med 12, 281291 (2008).Google Scholar
23. Ripamonti, U., J Bone Joint Surg Am 73, 692703 (1991).Google Scholar
24. Yamasaki, H. and Sakai, H., Biomaterials 13, 308312 (1992).Google Scholar
25. van Eeden, S. P. and Ripamonti, U., Plast Reconstr Surg 93, 959966 (1994).Google Scholar
26. Pollick, S., Shors, E. C., Holmes, R. E. and Kraut, R. A., J Oral Maxillofac Surg 53, 915922 (1995).Google Scholar
27. Magan, A. and Ripamonti, U., J Craniofac Surg 7, 7178 (1996).Google Scholar
28. Ripamonti, U., Biomaterials 17, 3135 (1996).Google Scholar
29. Yuan, H., Kurashina, K., de Bruijn, J. D., Li, Y., De Groot, K. and Zhang, X., Biomaterials 20, 17991806 (1999).Google Scholar
30. Ripamonti, U., Crooks, J., Khoali, L. and Roden, L., Biomaterials 30, 14281439 (2009).Google Scholar
31. Yuan, H., Fernandes, H., Habibovic, P., de Boer, J., Barradas, A., de Ruiter, A., Walsh, W. R., van Blitterswijk, C. A. and de Bruijn, J. D., Proc Natl Acad Sci U S A 107, 1361413619 (2010).Google Scholar
32. Yuan, H., De Bruijn, J., Li, Y., Feng, J., Yang, Z., De Groot, K. and Zhang, X., J Mater Sci Mater Med 12, 713 (2001).Google Scholar
33. Yuan, H., Yang, Z., de Bruijn, J. D., de Groot, K. and Zhang, X., Biomaterials 22, 26172623 (2001).Google Scholar
34. Yang, Z., Yuan, H., Tong, W., Zou, P., Chen, W. and Zhang, X., Biomaterials 17, 21312137 (1996).Google Scholar
35. Gosain, A. K., Song, L., Riordan, P., Amarante, M. T., Nagy, P. G., Wilson, C. R., Toth, J. M. and Ricci, J. L., Plast Reconstr Surg 109, 619630 (2002).Google Scholar
36. Habibovic, P., Gbureck, U., Doillon, C. J., Bassett, D. C., van Blitterswijk, C. A. and Barralet, J. E., Biomaterials 29, 944953 (2008).Google Scholar
37. Habibovic, P., Kruyt, M. C., Juhl, M. V., Clyens, S., Martinetti, R., Dolcini, L., Theilgaard, N. and van Blitterswijk, C. A., J Orthop Res 26, 13631370 (2008).Google Scholar
38. Ripamonti, U., Klar, R. M., Renton, L. F. and Ferretti, C., Biomaterials 31, 64006410 (2010).Google Scholar
39. Hasegawa, S., Neo, M., Tamura, J., Fujibayashi, S., Takemoto, M., Shikinami, Y., Okazaki, K. and Nakamura, T., J Biomed Mater Res A 81, 930938 (2007).Google Scholar
40. Barbieri, D., Renard, A., Bruijn, J. D. and Yuan, H., Eur Cell Mater 19, 252261 (2010).Google Scholar
41. Fujibayashi, S., Neo, M., Kim, H. M., Kokubo, T. and Nakamura, T., Biomaterials 25, 443450 (2004).Google Scholar
42. Yuan, H., de Bruijn, J. D., Zhang, X., van Blitterswijk, C. A. and de Groot, K., J Biomed Mater Res 58, 270276 (2001).Google Scholar
43. Habibovic, P., Yuan, H., Van Der Valk, C. M., Meijer, G., Van Blitterswijk, C. A. and De Groot, K., Biomaterials 26, 35653575 (2005).Google Scholar
44. Ducheyne, P. and Qiu, Q., Biomaterials 20, 22872303 (1999).Google Scholar
45. Habibovic, P., Sees, T. M., van den Doel, M. A., van Blitterswijk, C. A. and de Groot, K., J Biomed Mater Res A 77, 747762 (2006).Google Scholar
46. Klein, C., de Groot, K., Chen, W., Li, Y. and Zhang, X., Biomaterials 15, 3134 (1994).Google Scholar
47. Yamasaki, H., Jpn J Oral Biol 32, 190192 (1990).Google Scholar
48. Ripamonti, U., Crooks, J. and Kirkbride, A., South African J Sci 95, 335343 (1999).Google Scholar
49. Engler, A. J., Sen, S., Sweeney, H. L. and Discher, D. E., Cell 126, 677689 (2006).Google Scholar
50. Dalby, M. J., Gadegaard, N., Tare, R., Andar, A., Riehle, M. O., Herzyk, P., Wilkinson, C. D. W. and Oreffo, R. O. C., Nat Mater 6, 9971003 (2007).Google Scholar
51. James, R., Deng, M., Laurencin, C. T. and Kumbar, S. G., Front Mater Sci 5, 342357 (2011).Google Scholar
52. Kumbar, S. G., Kofron, M., Nair, L. S. and Laurencin, C. T., in Biomedical Nanostructures, edited by Gonsalves, K., Halberstadt, C., Laurencin, C. T. and Nair, L. S. (John Wiley & Sons, New York, 2008), pp. 261295.Google Scholar
53. Stevens, M. M. and George, J. H., Science 310, 11351138 (2005).Google Scholar
54. Laurencin, C. T., Kumbar, S. G. and Nukavarapu, S. P., Wiley Interdiscip Rev Nanomed Nanobiotechnol 1, 610 (2009).Google Scholar
55. Reichert, W. M., Ratner, B. D., Anderson, J., Coury, A., Hoffman, A. S., Laurencin, C. T. and Tirrell, D., J Biomed Mater Res A 96, 275287 (2011).Google Scholar
56. Deng, M., Kumbar, S. G., Lo, K. W. H., Ulery, B. D. and Laurencin, C. T., Recent Pat Biomed Eng 4, 168184 (2011).Google Scholar
57. Ambrosio, A. M. A., Sahota, J. S., Khan, Y. and Laurencin, C. T., J Biomed Mater Res 58, 295301 (2001).Google Scholar
58. Khan, Y. M., Katti, D. S. and Laurencin, C. T., J Biomed Mater Res A 69A, 728737 (2004).Google Scholar
59. Borden, M., Attawia, M., Khan, Y., El-Amin, S. F. and Laurencin, C. T., J Bone Joint Surg Br 86, 12001208 (2004).Google Scholar
60. Borden, M., Attawia, M., Khan, Y. and Laurencin, C. T., Biomaterials 23, 551559 (2002).Google Scholar
61. Jiang, T., Nukavarapu, S. P., Deng, M., Jabbarzadeh, E., Kofron, M. D., Doty, S. B., Abdel-Fattah, W. I. and Laurencin, C. T., Acta Biomater 6, 34573470 (2010).Google Scholar
62. Cushnie, E. K., Khan, Y. M. and Laurencin, C. T., J Biomed Mater Res A 84A, 5462 (2008).Google Scholar
63. Khan, Y., Cushnie, E., Kelleher, J. and Laurencin, C., J Mater Sci 42, 41834190 (2007).Google Scholar
64. Cushnie, E. K., Khan, Y. M. and Laurencin, C. T., J Biomed Mater Res A 94A, 568575 (2010).Google Scholar
65. Khan, Y., El-Amin, S. F. and Laurencin, C. T., in Conf Proc IEEE Eng Med Biol Soc (2006), Vol. 1, pp. 529530.Google Scholar
66. Lu, H. H., El-Amin, S. F., Scott, K. D. and Laurencin, C. T., J Biomed Mater Res A 64A, 465474 (2003).Google Scholar
67. Lv, Q., Nair, L. and Laurencin, C. T., J Biomed Mater Res A 91A, 679691 (2009).Google Scholar
68. Yu, X., Botchwey, E. A., Levine, E. M., Pollack, S. R. and Laurencin, C. T., Proc Natl Acad Sci U S A 101, 1120311208 (2004).Google Scholar
69. Deng, M., Kumbar, S. G., Nair, L. S., Weikel, A. L., Allcock, H. R. and Laurencin, C. T., Adv Funct Mater 21, 26412651 (2011).Google Scholar
70. Deng, M., Kumbar, S. G., Wan, Y., Toti, U. S., Allcock, H. R. and Laurencin, C. T., Soft Matter 6, 31193132 (2010).Google Scholar
71. Deng, M., Nair, L. S., Nukavarapu, S. P., Jiang, T., Kanner, W. A., Li, X., Kumbar, S. G., Weikel, A. L., Krogman, N. R., Allcock, H. R. and Laurencin, C. T., Biomaterials 31, 48984908 (2010).Google Scholar
72. Deng, M., Nair, L. S., Nukavarapu, S. P., Kumbar, S. G., Jiang, T., Krogman, N. R., Singh, A., Allcock, H. R. and Laurencin, C. T., Biomaterials 29, 337349 (2008).Google Scholar
73. Deng, M., Nair, L. S., Nukavarapu, S. P., Kumbar, S. G., Brown, J. L., Krogman, N. R., Weikel, A. L., Allcock, H. R. and Laurencin, C. T., J Biomed Mater Res A 92A, 114125 (2010).Google Scholar
74. Nukavarapu, S. P., Kumbar, S. G., Brown, J. L., Krogman, N. R., Weikel, A. L., Hindenlang, M. D., Nair, L. S., Allcock, H. R. and Laurencin, C. T., Biomacromolecules 9, 18181825 (2008).Google Scholar
75. Bhattacharyya, S., Kumbar, S. G., Khan, Y. M., Nair, L. S., Singh, A., Krogman, N. R., Brown, P. W., Allcock, H. R. and Laurencin, C. T., J Biomed Nanotechnol 5, 6975 (2009).Google Scholar
76. Bhattacharyya, S., Nair, L. S., Singh, A., Krogman, N. R., Greish, Y. E., Brown, P. W., Allcock, H. R. and Laurencin, C. T., J Biomed Nanotechnol 2, 3645 (2006).Google Scholar
77. Greish, Y. E., Bender, J. D., Lakshmi, S., Brown, P. W., Allcock, H. R. and Laurencin, C. T., Biomaterials 26, 19 (2005).Google Scholar
78. Greish, Y. E., Sturgeon, J. L., Singh, A., Krogman, N. R., Touny, A. H., Sethuraman, S., Nair, L. S., Laurencin, C. T., Allcock, H. R. and Brown, P. W., J Mater Sci Mater Med 19, 31533160 (2008).Google Scholar