Skip to main content

Advertisement

Log in

Polycaprolactone scaffold as targeted drug delivery system and cell attachment scaffold for postsurgical care of limb salvage

  • Research Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

In this paper, a dual-function drug-laden polycaprolactone scaffold, which can serve as both targeted drug delivery system and attachment platform for tissue regeneration for the postsurgical care of limb salvage procedure, was developed with a simple and solvent-free molding technique. Scaffolds of varying surface architecture were created using poly(ethylene glycol) diacrylate microneedle arrays. A model drug, rhodamine B, was incorporated homogenously into the scaffold. In vitro drug release studies showed that rhodamine B was released in a slow and sustained manner for 112 days. Its release rate was affected by drug loading and scaffold surface architecture. Release of rhodamine B from the scaffolds followed the Higuchi diffusion model. Other drugs, namely, doxorubicin and lidocaine hydrochloride, were also effectively loaded into and released from the scaffolds. Cell attachment study demonstrated potential for the scaffolds to provide attachment platforms for tissue regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lindell EB, Carroll NC. Limb salvage tumor surgery in children. Iowa Orthop J. 1993;13:124–35.

    PubMed  CAS  Google Scholar 

  2. Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ. Osteosarcoma. J Am Acad Orthop Surg. 2009;17(8):515–27.

    PubMed  Google Scholar 

  3. Carty CP, Dickinson IC, Watts MC, Crawford RW, Steadman P. Impairment and disability following limb salvage procedures for bone sarcoma. Knee. 2009;16(5):405–8..

    Article  PubMed  Google Scholar 

  4. Agins HJ, Alcock NW, Bansal M, Salvati EA, Wilson Jr PD, Pellicci PM, et al. Metallic wear in failed titanium-alloy total hip replacements. A histological and quantitative analysis. J Bone Joint Surg Am. 1988;70(3):347–56.

    PubMed  CAS  Google Scholar 

  5. Lalor PA, Revell PA, Gray AB, Wright S, Railton GT, Freeman MA. Sensitivity to titanium. A cause of implant failure? J Bone Joint Surg Br. 1991;73(1):25–8.

    PubMed  CAS  Google Scholar 

  6. Uhthoff HK, Finnegan M. The effects of metal plates on post-traumatic remodelling and bone mass. J Bone Joint Surg Br. 1983;65(1):66–71.

    PubMed  CAS  Google Scholar 

  7. Yaremchuk MJ, Fiala TG, Barker F, Ragland R. The effects of rigid fixation on craniofacial growth of rhesus monkeys. Plast Reconstr Surg. 1994;93(1):1–10. discussion 1–5.

    Article  PubMed  CAS  Google Scholar 

  8. Sullivan PK, Smith JF, Rozzelle AA. Cranio-orbital reconstruction: safety and image quality of metallic implants on CT and MRI scanning. Plast Reconstr Surg. 1994;94(5):589–96.

    Article  PubMed  CAS  Google Scholar 

  9. Dhillon MS, Prabhakar S, Prasanna C. Preliminary experience with biodegradable implants for fracture fixation. Indian J Orthop. 2008;42(3):319–22.

    Article  PubMed  Google Scholar 

  10. Mankin HJ, Gebhardt MC, Jennings LC, Springfield DS, Tomford WW. Long-term results of allograft replacement in the management of bone tumors. Clin Orthop Relat Res. 1996;324:86–97.

    Article  PubMed  Google Scholar 

  11. Moore WR, Graves SE, Bain GI. Synthetic bone graft substitutes. ANZ J Surg. 2001;71(6):354–61.

    Article  PubMed  CAS  Google Scholar 

  12. Kurz LT, Garfin SR, Booth Jr RE. Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine (Phila Pa 1976). 1989;14(12):1324–31.

    Article  CAS  Google Scholar 

  13. Schantz JT, Lim TC, Ning C, Teoh SH, Tan KC, Wang SC, et al. Cranioplasty after trephination using a novel biodegradable burr hole cover: technical case report. Neurosurgery. 2006;58(1 Suppl):ONS-E176. discussion ONS-E176.

    PubMed  Google Scholar 

  14. Schuckert KH, Jopp S, Teoh SH. Mandibular defect reconstruction using three-dimensional polycaprolactone scaffold in combination with platelet-rich plasma and recombinant human bone morphogenetic protein-2: de novo synthesis of bone in a single case. Tissue Eng Part A. 2009;15(3):493–9.

    Article  PubMed  CAS  Google Scholar 

  15. Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, et al. Preoperative chemotherapy for osteogenic-sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982;49(6):1221–30.

    Article  PubMed  CAS  Google Scholar 

  16. Susa M, Iyer AK, Ryu K, Hornicek FJ, Mankin H, Amiji MM, et al. Doxorubicin loaded polymeric nanoparticulate delivery system to overcome drug resistance in osteosarcoma. BMC Cancer. 2009;9:399.

    Google Scholar 

  17. Hogendoorn PC, Athanasou N, Bielack S, De Alava E, Dei Tos AP, Ferrari S, et al. Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v204–13.

    Article  PubMed  Google Scholar 

  18. Matsumine A, Takegami K, Asanuma K, Matsubara T, Nakamura T, Uchida A, et al. A novel hyperthermia treatment for bone metastases using magnetic materials. Int J Clin Oncol. 2011;16(2):101–8.

    Article  PubMed  Google Scholar 

  19. Gaur AH, Liu T, Knapp KM, Daw NC, Rao BN, Neel MD, et al. Infections in children and young adults with bone malignancies undergoing limb-sparing surgery. Cancer. 2005;104(3):602–10.

    Article  PubMed  Google Scholar 

  20. Goff BJ, Castillo R, Raja SN. Painful sequelae following limb salvage: etiology and management. J Am Acad Orthop Surg. 2011;19 Suppl 1:S23–7.

    PubMed  Google Scholar 

  21. Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces. 2010;75(1):1–18.

    Article  PubMed  CAS  Google Scholar 

  22. Gou M, Zheng X, Men K, Zhang J, Zheng L, Wang X, et al. Poly(epsilon-caprolactone)/poly(ethylene glycol)/poly(epsilon-caprolactone) nanoparticles: preparation, characterization, and application in doxorubicin delivery. J Phys Chem B. 2009;113(39):12928–33.

    Article  PubMed  CAS  Google Scholar 

  23. Li X, Li R, Qian X, Ding Y, Tu Y, Guo R, et al. Superior antitumor efficiency of cisplatin-loaded nanoparticles by intratumoral delivery with decreased tumor metabolism rate. Eur J Pharm Biopharm. 2008;70(3):726–34.

    Article  PubMed  CAS  Google Scholar 

  24. Teo EY, Ong SY, Chong MS, Zhang Z, Lu J, Moochhala S, et al. Polycaprolactone-based fused deposition modeled mesh for delivery of antibacterial agents to infected wounds. Biomaterials. 2011;32(1):279–87.

    Article  PubMed  CAS  Google Scholar 

  25. Takada K. Microfabrication-derived DDS: from batch to individual production. Drug Discov Ther. 2008;2(3):140–55.

    PubMed  CAS  Google Scholar 

  26. Lin W-J, Flanagan DR, Linhardt RJ. A novel fabrication of poly(ε-caprolactone) microspheres from blends of poly(ε-caprolactone) and poly(ethylene glycol)s. Polymer. 1999;40(7):1731–5.

    Article  CAS  Google Scholar 

  27. Khademhosseini A, Vacanti JP, Langer R. Progress in tissue engineering. Sci Am. 2009;300(5):64–71.

    Article  PubMed  CAS  Google Scholar 

  28. Kim GH, Son JG. 3D polycarprolactone (PCL) scaffold with hierarchical structure fabricated by a piezoelectric transducer (PZT)-assisted bioplotter. Appl Phys A Mater. 2009;94(4):781–5.

    Article  CAS  Google Scholar 

  29. Park SA, Lee SH, Kim WD. Fabrication of porous polycaprolactone/hydroxyapatite (PCL/HA) blend scaffolds using a 3D plotting system for bone tissue engineering. Bioprocess Biosyst Eng. 2011;34(4):505–13.

    Article  PubMed  Google Scholar 

  30. Baroli B. From natural bone grafts to tissue engineering therapeutics: brainstorming on pharmaceutical formulative requirements and challenges. J Pharm Sci. 2009;98(4):1317–75.

    Article  PubMed  CAS  Google Scholar 

  31. Mouriño V, Boccaccini AR. Bone tissue engineering therapeutics: controlled drug delivery in three-dimensional scaffolds. J R Soc Interface. 2010;7(43):209–27.

    Article  PubMed  Google Scholar 

  32. Kochhar JS, Goh WJ, Chan SY, Kang L. A simple method of microneedle array fabrication for transdermal drug delivery. Drug Dev Ind Pharm. 2012; in press.

  33. Zhang JT, Keller TF, Bhat R, Garipcan B, Jandt KD. A novel two-level microstructured poly(N-isopropylacrylamide) hydrogel for controlled release. Acta Biomater. 2010;6(10):3890–8.

    Article  PubMed  CAS  Google Scholar 

  34. Tanaka N, Imai K, Okimoto K, Ueda S, Tokunaga Y, Ibuki R, et al. Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II): in vivo evaluation. J Control Release. 2006;112(1):51–6.

    Article  PubMed  CAS  Google Scholar 

  35. Mulye NV, Turco SJ. A simple-model based on first-order kinetics to explain release of highly water-soluble drugs from porous dicalcium phosphate dihydrate matrices. Drug Dev Ind Pharm. 1995;21(8):943–53.

    Article  CAS  Google Scholar 

  36. Hixson AW, Crowell JH. Dependence of reaction velocity upon surface and agitation: I—theoretical consideration. Ind Eng Chem. 1931;23:923–31.

    Article  CAS  Google Scholar 

  37. Rodrigues MR, Lanzarini CM, Ricci E. Preparation, in vitro characterization and in vivo release of naproxen loaded in poly-caprolactone nanoparticles. Pharm Dev Technol. 2011;16(1):12–21.

    Article  PubMed  CAS  Google Scholar 

  38. Chang HI, Perrie Y, Coombes AG. Delivery of the antibiotic gentamicin sulphate from precipitation cast matrices of polycaprolactone. J Control Release. 2006;110(2):414–21.

    Article  PubMed  CAS  Google Scholar 

  39. Gou M, Shi H, Guo G, Men K, Zhang J, Zheng L, et al. Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles. Nanotechnology. 2011;22(9):095102.

    Article  PubMed  Google Scholar 

  40. Hee CK, Nicoll SB. Induction of osteoblast differentiation markers in human dermal fibroblasts: potential application to bone tissue engineering. Conf Proc IEEE Eng Med Biol Soc. 2006;1:521–4.

    PubMed  Google Scholar 

  41. Notingher I, Jell G, Lohbauer U, Salih V, Hench LL. In situ non-invasive spectral discrimination between bone cell phenotypes used in tissue engineering. J Cell Biochem. 2004;92(6):1180–92.

    Article  PubMed  CAS  Google Scholar 

  42. Ramsey WS, Hertl W, Nowlan ED, Binkowski NJ. Surface treatments and cell attachment. In Vitro Cell Dev B. 1984;20(10):802–8.

    Article  CAS  Google Scholar 

  43. Anselme K. Osteoblast adhesion on biomaterials. Biomaterials. 2000;21(7):667–81.

    Article  PubMed  CAS  Google Scholar 

  44. Sun HF, Mei L, Song CX, Cui XM, Wang PY. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27(9):1735–40.

    Article  PubMed  CAS  Google Scholar 

  45. Morcuende JA, Gomez P, Stack J, Oji G, Martin J, Fredericks DC, et al. Effect of chemotherapy on segmental bone healing enhanced by rhBMP-2. Iowa Orthop J. 2004;24:36–42.

    PubMed  Google Scholar 

  46. Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R. Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am. 1984;66(4):602–7.

    PubMed  CAS  Google Scholar 

  47. Bramwell VH, Steward WP, Nooij M, Whelan J, Craft AW, Grimer RJ, et al. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: a European Osteosarcoma Intergroup study. J Clin Oncol. 1999;17(10):3260–9.

    PubMed  CAS  Google Scholar 

  48. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997;350(9082):911–7.

    Article  PubMed  CAS  Google Scholar 

  49. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voute PA, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992;10(10):1579–91.

    PubMed  CAS  Google Scholar 

  50. Salerno M, Cenni E, Fotia C, Avnet S, Granchi D, Castelli F, et al. Bone-targeted doxorubicin-loaded nanoparticles as a tool for the treatment of skeletal metastases. Curr Cancer Drug Targets. 2010;10(7):649–59.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to express his gratitude to Dr. Alexandre Chan and Dr. Richard Quek from the National Cancer Center Singapore for their comments and inputs. The authors also thank Jaspreet S. Kochhar for his assistance in microneedle fabrication.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lifeng Kang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 18 kb)

Supplementary Figure

Drug loading and drug loading efficiency. (a) Microscopic and fluorescence images of rhodamine B loaded PCL scaffolds. Rhodamine B was uniformly distributed throughout the scaffold. (b) Drug loading efficiencies over different multiple molding attempts using a single microneedle array. Near 100 % drug loading efficiencies were observed. (JPEG 38 kb)

High-resolution image (TIFF 2028 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, B.S., Teoh, SH. & Kang, L. Polycaprolactone scaffold as targeted drug delivery system and cell attachment scaffold for postsurgical care of limb salvage. Drug Deliv. and Transl. Res. 2, 272–283 (2012). https://doi.org/10.1007/s13346-012-0096-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-012-0096-9

Keywords

Navigation