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Synthesis of poly(propylene fumarate)

Nature Protocols volume 4, pages 518–525 (2009)Cite this article

Abstract

This protocol describes the synthesis of 500–4,000 Da poly(propylene fumarate) (PPF) by a two-step reaction of diethyl fumarate and propylene glycol through a bis(hydroxypropyl) fumarate diester intermediate. Purified PPF can be covalently cross-linked to form degradable polymer networks, which have been widely explored for biomedical applications. The properties of cross-linked PPF networks depend upon the molecular properties of the constituent polymer, such as the molecular weight. The purity of the reactants and the exclusion of water from the reaction system are of utmost importance in the generation of high-molecular-weight PPF products. Additionally, the reaction time and temperature influence the molecular weight of the PPF product. The expected time required to complete this protocol is 3 d.

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Figure 1
Figure 2: Apparatus for PPF synthesis.
Figure 3: Washing of PPF solution during product purification.
Figure 4

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References

  1. Coombes, D.M., Shelley, M.J., McKenzie, J. & Sneddon, K.J. Biodegradable fixation in oral and maxillofacial surgery. Dent Update 34, 641–644 (2007).

    Article  PubMed  Google Scholar 

  2. Guelcher, S.A. Biodegradable polyurethanes: synthesis and applications in regenerative medicine. Tissue Eng. Part B Rev. 14, 3–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Houchin, M.L. & Topp, E.M. Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J. Pharm. Sci. 97, 2395–2404 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Hutmacher, D.W., Schantz, J.T., Lam, C.X., Tan, K.C. & Lim, T.C. State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. J. Tissue Eng. Regen. Med. 1, 245–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Tsuji, H. Poly(lactide) stereocomplexes: formation, structure, properties, degradation, and applications. Macromol. Biosci. 5, 569–597 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Venugopal, J., Low, S., Choon, A.T. & Ramakrishna, S. Interaction of cells and nanofiber scaffolds in tissue engineering. J. Biomed. Mater Res. B Appl. Biomater 84, 34–48 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Fisher, J.P., Holland, T.A., Dean, D. & Mikos, A.G. Photoinitiated cross-linking of the biodegradable polyester poly(propylene fumarate). Part II. In vitro degradation. Biomacromolecules 4, 1335–1342 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Timmer, M.D., Ambrose, C.G. & Mikos, A.G. In vitro degradation of polymeric networks of poly(propylene fumarate) and the crosslinking macromer poly(propylene fumarate)-diacrylate. Biomaterials 24, 571–577 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Timmer, M.D., Ambrose, C.G. & Mikos, A.G. Evaluation of thermal- and photo-crosslinked biodegradable poly(propylene fumarate)-based networks. J. Biomed. Mater Res. A 66, 811–818 (2003).

    Article  PubMed  Google Scholar 

  10. Fisher, J.P., Holland, T.A., Dean, D., Engel, P.S. & Mikos, A.G. Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds. J. Biomater Sci. Polym. Ed. 12, 673–687 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Peter, S.J., Kim, P., Yasko, A.W., Yaszemski, M.J. & Mikos, A.G. Crosslinking characteristics of an injectable poly(propylene fumarate)/beta-tricalcium phosphate paste and mechanical properties of the crosslinked composite for use as a biodegradable bone cement. J. Biomed. Mater. Res. 44, 314–321 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. He, S., Yaszemski, M.J., Yasko, A.W., Engel, P.S. & Mikos, A.G. Injectable biodegradable polymer composites based on poly(propylene fumarate) crosslinked with poly(ethylene glycol)-dimethacrylate. Biomaterials 21, 2389–2394 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. He, S. et al. Synthesis of biodegradable poly(propylene fumarate) networks with poly(propylene fumarate)-diacrylate macromers as crosslinking agents and characterization of their degradation products. Polymer 42, 1251–1260 (2001).

    Article  CAS  Google Scholar 

  14. Fisher, J.P., Dean, D. & Mikos, A.G. Photocrosslinking characteristics and mechanical properties of diethyl fumarate/poly(propylene fumarate) biomaterials. Biomaterials 23, 4333–4343 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Timmer, M.D., Carter, C., Ambrose, C.G. & Mikos, A.G. Fabrication of poly(propylene fumarate)-based orthopaedic implants by photo-crosslinking through transparent silicone molds. Biomaterials 24, 4707–4714 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Cooke, M.N., Fisher, J.P., Dean, D., Rimnac, C. & Mikos, A.G. Use of stereolithography to manufacture critical-sized 3D biodegradable scaffolds for bone ingrowth. J. Biomed. Mater. Res. B Appl. Biomater. 64, 65–69 (2003).

    Article  PubMed  Google Scholar 

  17. Dean, D. et al. Poly(propylene fumarate) and poly(DL-lactic-co-glycolic acid) as scaffold materials for solid and foam-coated composite tissue-engineered constructs for cranial reconstruction. Tissue Eng. 9, 495–504 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Dean, D. et al. Effect of transforming growth factor beta 2 on marrow-infused foam poly(propylene fumarate) tissue-engineered constructs for the repair of critical-size cranial defects in rabbits. Tissue Eng. 11, 923–939 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Fisher, J.P. et al. Soft and hard tissue response to photocrosslinked poly(propylene fumarate) scaffolds in a rabbit model. J. Biomed. Mater. Res. 59, 547–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Hedberg, E.L. et al. Methods: a comparative analysis of radiography, microcomputed tomography, and histology for bone tissue engineering. Tissue Eng. 11, 1356–1367 (2005).

    Article  PubMed  Google Scholar 

  21. Hacker, M.C. et al. Biodegradable fumarate-based drug-delivery systems for ophthalmic applications. J. Biomed. Mater Res. A 88, 976–989 (2008).

    Google Scholar 

  22. Haesslein, A., Hacker, M.C. & Mikos, A.G. Effect of macromer molecular weight on in vitro ophthalmic drug release from photo-crosslinked matrices. Acta Biomater. 4, 1–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Haesslein, A. et al. Long-term release of fluocinolone acetonide using biodegradable fumarate-based polymers. J. Control Release 114, 251–260 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Hedberg, E.L. et al. Effect of varied release kinetics of the osteogenic thrombin peptide TP508 from biodegradable, polymeric scaffolds on bone formation in vivo . J. Biomed. Mater. Res. A 72, 343–353 (2005).

    Article  PubMed  Google Scholar 

  25. Hedberg, E.L., Tang, A., Crowther, R.S., Carney, D.H. & Mikos, A.G. Controlled release of an osteogenic peptide from injectable biodegradable polymeric composites. J. Control Release 84, 137–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Ueda, H. et al. Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems. J. Biomed. Mater. Res. A 83, 656–666 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Payne, R.G., McGonigle, J.S., Yaszemski, M.J., Yasko, A.W. & Mikos, A.G. Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 3. Proliferation and differentiation of encapsulated marrow stromal osteoblasts cultured on crosslinking poly(propylene fumarate). Biomaterials 23, 4381–4387 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Payne, R.G., McGonigle, J.S., Yaszemski, M.J., Yasko, A.W. & Mikos, A.G. Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 2. Viability of encapsulated marrow stromal osteoblasts cultured on crosslinking poly(propylene fumarate). Biomaterials 23, 4373–4380 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Porter, B.D. et al. Mechanical properties of a biodegradable bone regeneration scaffold. J. Biomech. Eng. 122, 286–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Timmer, M.D., Horch, R.A., Ambrose, C.G. & Mikos, A.G. Effect of physiological temperature on the mechanical properties and network structure of biodegradable poly(propylene fumarate)-based networks. J. Biomater. Sci. Polym. Ed. 14, 369–382 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Domb, A.J., Cato, T.L., Israeli, O., Gerhart, T.N. & Langer, R. The formation of propylene fumarate oligomers for use in bioerodible bone cement composites. J. Polym. Sci. A 28, 973–985 (1990).

    Article  CAS  Google Scholar 

  32. Shung, A.K., Timmer, M.D., Jo, S., Engel, P.S. & Mikos, A.G. Kinetics of poly(propylene fumarate) synthesis by step polymerization of diethyl fumarate and propylene glycol using zinc chloride as a catalyst. J. Biomater. Sci. Polym. Ed. 13, 95–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Peter, S.J., Suggs, L.J., Yaszemski, M.J., Engel, P.S. & Mikos, A.G. Synthesis of poly(propylene fumarate) by acylation of propylene glycol in the presence of a proton scavenger. J. Biomater. Sci. Polym. Ed. 10, 363–373 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Peter, S.J. et al. Characterization of partially saturated poly(propylene fumarate) for orthopaedic application. J. Biomater. Sci. Polym. Ed. 8, 893–904 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Peter, S.J., Lu, L., Kim, D.J. & Mikos, A.G. Marrow stromal osteoblast function on a poly(propylene fumarate)/beta-tricalcium phosphate biodegradable orthopaedic composite. Biomaterials 21, 1207–1213 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Peter, S.J. et al. Effects of transforming growth factor beta1 released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates. J. Biomed. Mater. Res. 50, 452–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Peter, S.J., Miller, S.T., Zhu, G., Yasko, A.W. & Mikos, A.G. In vivo degradation of a poly(propylene fumarate)/beta-tricalcium phosphate injectable composite scaffold. J. Biomed. Mater. Res. 41, 1–7 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Fisher, J.P. et al. Effect of biomaterial properties on bone healing in a rabbit tooth extraction socket model. J. Biomed. Mater. Res. A 68, 428–438 (2004).

    Article  PubMed  Google Scholar 

  39. Fisher, J.P. et al. Photoinitiated cross-linking of the biodegradable polyester poly(propylene fumarate). Part I. Determination of network structure. Biomacromolecules 4, 1327–1334 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Christenson, E.M., Soofi, W., Holm, J.L., Cameron, N.R. & Mikos, A.G. Biodegradable fumarate-based polyHIPEs as tissue engineering scaffolds. Biomacromolecules 8, 3806–3814 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Hedberg, E.L. et al. In vivo degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds. Biomaterials 26, 4616–4623 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Hedberg, E.L. et al. In vitro degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds. Biomaterials 26, 3215–3225 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Horch, R.A. et al. Nanoreinforcement of poly(propylene fumarate)-based networks with surface modified alumoxane nanoparticles for bone tissue engineering. Biomacromolecules 5, 1990–1998 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Shi, X. et al. In vitro cytotoxicity of single-walled carbon nanotube/biodegradable polymer nanocomposites. J. Biomed. Mater. Res. A 86, 813–823 (2008).

    Article  PubMed  Google Scholar 

  45. Shi, X. et al. Injectable nanocomposites of single-walled carbon nanotubes and biodegradable polymers for bone tissue engineering. Biomacromolecules 7, 2237–2242 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Shi, X. et al. Fabrication of porous ultra-short single-walled carbon nanotube nanocomposite scaffolds for bone tissue engineering. Biomaterials 28, 4078–4090 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Suggs, L.J. et al. Preparation and characterization of poly(propylene fumarate-co-ethylene glycol) hydrogels. J. Biomater. Sci. Polym. Ed. 9, 653–666 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Suggs, L.J. et al. In vitro and in vivo degradation of poly(propylene fumarate-co-ethylene glycol) hydrogels. J. Biomed. Mater Res. 42, 312–320 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Suggs, L.J. & Mikos, A.G. Development of poly(propylene fumarate-co-ethylene glycol) as an injectable carrier for endothelial cells. Cell Transplant 8, 345–350 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Suggs, L.J., Shive, M.S., Garcia, C.A., Anderson, J.M. & Mikos, A.G. In vitro cytotoxicity and in vivo biocompatibility of poly(propylene fumarate-co-ethylene glycol) hydrogels. J. Biomed. Mater. Res. 46, 22–32 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Suggs, L.J., West, J.L. & Mikos, A.G. Platelet adhesion on a bioresorbable poly(propylene fumarate-co-ethylene glycol) copolymer. Biomaterials 20, 683–690 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Shung, A.K., Behravesh, E., Jo, S. & Mikos, A.G. Crosslinking characteristics of and cell adhesion to an injectable poly(propylene fumarate-co-ethylene glycol) hydrogel using a water-soluble crosslinking system. Tissue Eng. 9, 243–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Behravesh, E., Jo, S., Zygourakis, K. & Mikos, A.G. Synthesis of in situ cross-linkable macroporous biodegradable poly(propylene fumarate-co-ethylene glycol) hydrogels. Biomacromolecules 3, 374–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Behravesh, E. & Mikos, A.G. Three-dimensional culture of differentiating marrow stromal osteoblasts in biomimetic poly(propylene fumarate-co-ethylene glycol)-based macroporous hydrogels. J. Biomed. Mater. Res. A 66, 698–706 (2003).

    Article  PubMed  Google Scholar 

  55. Behravesh, E., Timmer, M.D., Lemoine, J.J., Liebschner, M.A. & Mikos, A.G. Evaluation of the in vitro degradation of macroporous hydrogels using gravimetry, confined compression testing, and microcomputed tomography. Biomacromolecules 3, 1263–1270 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Behravesh, E., Zygourakis, K. & Mikos, A.G. Adhesion and migration of marrow-derived osteoblasts on injectable in situ crosslinkable poly(propylene fumarate-co-ethylene glycol)-based hydrogels with a covalently linked RGDS peptide. J. Biomed. Mater. Res. A 65, 260–270 (2003).

    Article  PubMed  Google Scholar 

  57. Jo, S., Shin, H. & Mikos, A.G. Modification of oligo(poly(ethylene glycol) fumarate) macromer with a GRGD peptide for the preparation of functionalized polymer networks. Biomacromolecules 2, 255–261 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work described in this protocol was supported by grants from the US National Institutes of Health to A.G.M. (R01 DE15164 and R01 DE17441).

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Authors and Affiliations

  1. Department of Bioengineering, Rice University, MS 142, P.O. Box 1892, Houston, 77251, Texas, USA

    F Kurtis Kasper, Kazuhiro Tanahashi & Antonios G Mikos

  2. Fischell Department of Bioengineering, University of Maryland, 3238 Jeong H. Kim Engineering Building, College Park, 20742, Maryland, USA

    John P Fisher

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  1. F Kurtis Kasper
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  2. Kazuhiro Tanahashi
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Correspondence to Antonios G Mikos.

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Kasper, F., Tanahashi, K., Fisher, J. et al. Synthesis of poly(propylene fumarate). Nat Protoc 4, 518–525 (2009). https://doi.org/10.1038/nprot.2009.24

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