Drug Delivery and Translational Research

, Volume 5, Issue 2, pp 168–186

Integration of drug, protein, and gene delivery systems with regenerative medicine

  • Elizabeth R. Lorden
  • Howard M. Levinson
  • Kam W. Leong
Review Article


Regenerative medicine has the potential to drastically change the field of health care from reactive to preventative and restorative. Exciting advances in stem cell biology and cellular reprogramming have fueled the progress of this field. Biochemical cues in the form of small molecule drugs, growth factors, zinc finger protein transcription factors and nucleases, transcription activator-like effector nucleases, monoclonal antibodies, plasmid DNA, aptamers, or RNA interference agents can play an important role to influence stem cell differentiation and the outcome of tissue regeneration. Many of these biochemical factors are fragile and must act intracellularly at the molecular level. They require an effective delivery system, which can take the form of a scaffold (e.g., hydrogels and electrospun fibers), carrier (viral and nonviral), nano- and microparticle, or genetically modified cell. In this review, we will discuss the history and current technologies of drug, protein, and gene delivery in the context of regenerative medicine. Next, we will present case examples of how delivery technologies are being applied to promote angiogenesis in nonhealing wounds or prevent angiogenesis in age related macular degeneration. Finally, we will conclude with a brief discussion of the regulatory pathway from bench to bedside for the clinical translation of these novel therapeutics.


Regeneration Drug delivery Gene delivery Protein delivery Biomedical engineering Angiogenesis 


  1. 1.
    Hasetine W. A brave new medicine. A conversation with William Haseltine. Interview by Joe Flower. Health Forum J. 1999;42(4):28–30. 61–5.PubMedGoogle Scholar
  2. 2.
    Chen FM, Zhao YM, Jin Y, Shi S. Prospects for translational regenerative medicine. Biotechnol Adv. 2012;30(3):658–72. doi:10.1016/j.biotechadv.2011.11.005.PubMedCrossRefGoogle Scholar
  3. 3.
    Couto DS, Perez-Breva L, Cooney CL. Regenerative medicine: learning from past examples. Tissue Eng Part A. 2012;18(21–22):2386–93. doi:10.1089/ten.TEA.2011.0639.PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024.PubMedCrossRefGoogle Scholar
  5. 5.
    Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51(6):987–1000.PubMedCrossRefGoogle Scholar
  6. 6.
    Rai BNV, Cool SM. Heparan sulfate-based treatments for regenerative medicine. Crit Rev Eukaryot Gene Expr. 2011;21(1):1–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Cherry ABC, Daley GQ. Reprogramming cellular identity for regenerative medicine. Cell. 2012;148(6):1110–22. doi:10.1016/j.cell.2012.02.031.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nat. 2012;481(7381):295–305. doi:10.1038/nature10761.CrossRefGoogle Scholar
  9. 9.
    Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet. 2011;12(4):243–52. doi:10.1038/nrg2938.PubMedCrossRefGoogle Scholar
  10. 10.
    Jopling C, Boue S, Belmonte JCI. Dedifferentiation, transdifferentiation, and reprogramming: three routes to regeneration. Nat Rev. 2011;12:79–89.CrossRefGoogle Scholar
  11. 11.
    Smith HO, Wilcox KW. A restriction enzyme from Hemophilus influenzae. I. Purification and general properties. J Mol Biol. 1970;51(2):379–91.PubMedCrossRefGoogle Scholar
  12. 12.
    Brown LR. Commercial challenges of protein drug delivery. Expert Opin Drug Deliv. 2005;2(1):29–42. doi:10.1517/17425247.2.1.29.PubMedCrossRefGoogle Scholar
  13. 13.
    Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, et al. Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990;323(9):570–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA−SCID: initial trial results after 4 years. Sci. 1995;270(5235):475–80. doi:10.1126/science.270.5235.475.CrossRefGoogle Scholar
  15. 15.
    Egermann M, Baltzer AW, Adamaszek S, Evans C, Robbins P, Schneider E, et al. Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep. Hum Gene Ther. 2006;17(5):507–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Kliem MA, Heeke BL, Franz CK, Radovitskiy I, Raore B, Barrow E, et al. Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats. Amyotroph Lateral Scler. 2011;12(5):331–9. doi:10.3109/17482968.2011.574142.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31. doi:10.1056/NEJMoa054481.PubMedCrossRefGoogle Scholar
  18. 18.
    Jeschke MG, Herndon DN. The combination of IGF-I and KGF cDNA improves dermal and epidermal regeneration by increased VEGF expression and neovascularization. Gene Ther. 2007;14(16):1235–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Wetterau M, George F, Weinstein A, Nguyen PD, Tutela JP, Knobel D, et al. Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. Wound Repair Regen. 2011;19(4):481–6. doi:10.1111/j.1524-475X.2011.00697.x.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805–16. doi:10.1056/NEJMoa042760.PubMedCrossRefGoogle Scholar
  21. 21.
    Sooriakumaran P, Coley HM, Fox SB, Macanas-Pirard P, Lovell DP, Henderson A, et al. A randomized controlled trial investigating the effects of celecoxib in patients with localized prostate cancer. Anticancer Res. 2009;29(5):1483–8.PubMedGoogle Scholar
  22. 22.
    Blumenthal GM, Cortazar P, Zhang JJ, Tang SH, Sridhara R, Murgo A, et al. FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncol. 2012;17(8):1108–13. doi:10.1634/theoncologist.2012-0044.CrossRefGoogle Scholar
  23. 23.
    Russell JL, Goetsch SC, Aguilar HR, Frantz DE, Schneider JW. Targeting native adult heart progenitors with cardiogenic small molecules. ACS Chem Biol. 2012;7(6):1067–76. doi:10.1021/cb200525q.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov. 2010;9(3):203–14.PubMedGoogle Scholar
  25. 25.
    Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci U S A. 2004;101(23):8786–90. doi:10.1073/pnas.0402595101.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Downing TL, Wang AJ, Yan ZQ, Nout Y, Lee AL, Beattie MS, et al. Drug-eluting microfibrous patches for the local delivery of rolipram in spinal cord repair. J Control Release. 2012;161(3):910–7. doi:10.1016/j.jconrel.2012.05.034.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, et al. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004;24(29):6590–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Wu F, Xing DM, Peng ZR, Rao T. Enhanced rat sciatic nerve regeneration through silicon tubes implanted with valproic acid. J Reconstr Microsurg. 2008;24(4):267–76. doi:10.1055/s-2009-1078696.PubMedCrossRefGoogle Scholar
  29. 29.
    Ferrer-Miralles N, Domingo-Espin J, Corchero JL, Vazquez E, Villaverde A. Microbial factories for recombinant pharmaceuticals. Microb Cell Fact. 2009;8:17. doi:10.1186/1475-2859-8-17.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Graslund S, Nordlund P, Weigelt J, Hallberg BM, Bray J, Gileadi O, et al. Protein production and purification. Nat Methods. 2008;5(2):135–46. doi:10.1038/nmeth.f.202.PubMedCrossRefGoogle Scholar
  31. 31.
    Goodman M. Market watch: Sales of biologics to show robust growth through to 2013. Nat Rev Drug Discov. 2009;8(11):837-. http://www.nature.com/nrd/journal/v8/n11/suppinfo/nrd3040_S1.html.
  32. 32.
    Martínez JL, Liu L, Petranovic D, Nielsen J. Pharmaceutical protein production by yeast: towards production of human blood proteins by microbial fermentation. Curr Opin Biotechol. 2012;23(6):965–71.CrossRefGoogle Scholar
  33. 33.
    Redwan EL, Wormald MR. Cumulative updating of approved biopharmaceuticals. Hum Antib. 2007;16(3/4):138–56.Google Scholar
  34. 34.
    Hariawala MD, Esakof D. VEGF improves myocardial blood flow but produces EDRF-mediated hypotensionin porcine hearts. J Surg Res. 1996;63:77–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, et al. The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circ. 2003;107(10):1359–65. doi:10.1161/01.cir.0000061911.47710.8a.CrossRefGoogle Scholar
  36. 36.
    Lazarous DF, Shou M, Scheinowitz M, Hodge E, Thirumurti V, Kitsiou AN, et al. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circ. 1996;94(5):1074–82.CrossRefGoogle Scholar
  37. 37.
    Eppler SM, Combs DL, Henry TD, Lopez JJ, Ellis SG, Yi JH, et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther. 2002;72(1):20–32. doi:10.1067/mcp.2002.126179.PubMedCrossRefGoogle Scholar
  38. 38.
    Ramakrishna S, Kim Y-H, Kim H. Stability of zinc finger nuclease protein is enhanced by the proteasome inhibitor MG132. PLoS One. 2013;8(1):e54282. doi:10.1371/journal.pone.0054282.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Choo Y, Sanchez-Garcia I, Klug A. In vivo repression by a site-specific DNA-binding protein designed against an oncogenic sequence. Nature. 1994;372(6507):642–5. doi:10.1038/372642a0.PubMedCrossRefGoogle Scholar
  40. 40.
    Kang JS, Kim J-S. Zinc finger proteins as designer transcription factors. J Biol Chem. 2000;275(12):8742–8. doi:10.1074/jbc.275.12.8742.PubMedCrossRefGoogle Scholar
  41. 41.
    Li-Shan L, Yao-Guo Y, Wei L, Li-Long G, Heng G, Chang-Wei L, et al. Zinc finger protein-activating transcription factor upregulates vascular endothelial growth factor-A expression in vitro. Chin Med Sci J. 2012;27(3):171–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Dai Q, Huang J, Klitzman B, Dong C, Goldschmidt-Clermont PJ, March KL, et al. Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia. Circ. 2004;110(16):2467–75. doi:10.1161/01.CIR.0000145139.53840.49.CrossRefGoogle Scholar
  43. 43.
    Tsang SH. Stem cell biology and regenerative medicine. Stem cell biology and regenerative medicine in ophthalmology. New York, NY: Humana Press; 2012.Google Scholar
  44. 44.
    Sebastiano V, Maeder ML, Angstman JF, Haddad B, Khayter C, Yeo DT, et al. In situ genetic correction of the sickle-cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells (Dayton, Ohio). 2011;29(11):1717–26. doi:10.1002/stem.718.CrossRefGoogle Scholar
  45. 45.
    Soldner F, Laganiere J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell. 2011;146(2):318–31. doi:10.1016/j.cell.2011.06.019.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Phase 1 Dose Escalation Study of Autologous T-cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases in HIV-Infected Patients [database on the Internet]. ClinicalTrials.gov Identifier: NCT01044654. 2012. AccessedGoogle Scholar
  47. 47.
    Joung JK, Sander JD. TALENs: a widely applicable technology for targeted genome editing. Nat Rev Mol Cell Biol. 2013;14(1):49–55. http://www.nature.com/nrm/journal/v14/n1/suppinfo/nrm3486_S1.html.
  48. 48.
    Ding Q, Lee Y-K, Schaefer EAK, Peters DT, Veres A, Kim K, et al. A TALEN genome-editing system for generating human stem cell-based disease models. Cell Stem Cell. 2013;12:238–51.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P, Kaeppel C et al. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat Biotech. 2011;29(9):816–23. http://www.nature.com/nbt/journal/v29/n9/abs/nbt.1948.html#supplementary-information.Google Scholar
  50. 50.
    Pattanayak V, Ramirez CL, Joung JK, Liu DR. Revealing off-target cleavage specificities of zinc-finger nucleases by in vitro selection. Nat Meth. 2011;8(9):765–70. http://www.nature.com/nmeth/journal/v8/n9/abs/nmeth.1670.html#supplementary-information.Google Scholar
  51. 51.
    Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9(10):767–74. doi:10.1038/nrd3229.PubMedCrossRefGoogle Scholar
  52. 52.
    Dhoot DS, Kaiser PK. Ranibizumab for age-related macular degeneration. Expert Opin Biol Ther. 2012;12(3):371–81. doi:10.1517/14712598.2012.660523.PubMedCrossRefGoogle Scholar
  53. 53.
    Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493–507. doi:10.2165/11531280-000000000-00000.PubMedCrossRefGoogle Scholar
  54. 54.
    Ng CM, Bruno R, Combs D, Davies B. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J Clin Pharmacol. 2005;45(7):792–801. doi:10.1177/0091270005277075.PubMedCrossRefGoogle Scholar
  55. 55.
    Getts DR, Getts MT, McCarthy DP, Chastain EML, Miller SD. Have we overestimated the benefit of human(ized) antibodies? MAbs. 2010;2(6):682–94. doi:10.4161/mabs.2.6.13601.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Kormann MS, Hasenpusch G, Aneja MK, Nica G, Flemmer AW, Herber-Jonat S, et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol. 2011;29(2):154–7. doi:10.1038/nbt.1733.PubMedCrossRefGoogle Scholar
  57. 57.
    Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nat. 2001;411(6836):494–8. doi:10.1038/35078107.CrossRefGoogle Scholar
  58. 58.
    Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A, et al. SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth. Cancer Res. 2003;63(14):3919–22.PubMedGoogle Scholar
  59. 59.
    Kaiser PK, Symons RC, Shah SM, Quinlan EJ, Tabandeh H, Do DV et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am J Ophthalmol. 2010;150(1):33–9 e2. doi:10.1016/j.ajo.2010.02.006.Google Scholar
  60. 60.
    Bumcrot D, Manoharan M, Koteliansky V, Sah DWY. RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol. 2006;2(12):711–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science. 1990;249(4968):505–10. doi:10.1126/science.2200121.PubMedCrossRefGoogle Scholar
  62. 62.
    Ellington A, Keefe AD, Pai S. Aptamers as therapeutics. Nat Rev Drug Discov. 2010;9(7):537–50.PubMedCrossRefGoogle Scholar
  63. 63.
    Ng EWM, Shima DT, Calias P, Cunningham ET, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006;5(2):123–32.PubMedCrossRefGoogle Scholar
  64. 64.
    White RR, Sullenger BA, Rusconi CP. Developing aptamers into therapeutics. J Clin Investigation. 2000;106(8):929–34. doi:10.1172/jci11325.CrossRefGoogle Scholar
  65. 65.
    Cao J, Sun C, Zhao H, Xiao Z, Chen B, Gao J, et al. The use of laminin-modified linear ordered collagen scaffolds loaded with laminin-binding biliary neurotrophic factor for sciatic nerve regeneration in rats. Biomaterials. 2011;32(16):3939–48. doi:10.1016/j.biomaterials.2011.02.020.PubMedCrossRefGoogle Scholar
  66. 66.
    Piantino J, Burdick JA, Goldberg D, Langer R, Benowitz LI. An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp Neurol. 2006;201(2):359–67. doi:10.1016/j.expneurol.2006.04.020.PubMedCrossRefGoogle Scholar
  67. 67.
    Censi R, Di Martino P, Vermonden T, Hennink WE. Hydrogels for protein delivery in tissue engineering. J Control Release. 2012;161(2):680–92. doi:10.1016/j.jconrel.2012.03.002.PubMedCrossRefGoogle Scholar
  68. 68.
    Sill TJ, von Recum HA. Electrospinning: applications in drug delivery and tissue engineering. Biomaterials. 2008;29(13):1989–2006. doi:10.1016/j.biomaterials.2008.01.011.PubMedCrossRefGoogle Scholar
  69. 69.
    Curtin CM, Cunniffe GM, Lyons FG, Bessho K, Dickson GR, Duffy GP, et al. Innovative collagen nano-hydroxyapatite scaffolds offer a highly efficient nonviral gene delivery platform for stem cell-mediated bone formation. Adv Mater. 2012;24(6):749–54.PubMedCrossRefGoogle Scholar
  70. 70.
    Macaya D, Spector M. Injectable hydrogel materials for spinal cord regeneration: a review. Biomed Mater. 2012;7(1):012001. doi:10.1088/1748-6041/7/1/012001.PubMedCrossRefGoogle Scholar
  71. 71.
    Liao IC, Chew SY, Leong KW. Aligned core–shell nanofibers delivering bioactive proteins. Nanomedicine. 2006;1(4):465–71. doi:10.2217/17435889.1.4.465.PubMedCrossRefGoogle Scholar
  72. 72.
    Chew SY, Mi R, Hoke A, Leong KW. Aligned protein–polymer composite fibers enhance nerve regeneration: a potential tissue-engineering platform. Adv Funct Mater. 2007;17(8):1288–96. doi:10.1002/adfm.200600441.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Marchesi C, Pluderi M, Colleoni F, Belicchi M, Meregalli M, Farini A, et al. Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection. Glia. 2007;55(4):425–38. doi:10.1002/glia.20470.PubMedCrossRefGoogle Scholar
  74. 74.
    Kloxin AM, Kasko AM, Salinas CN, Anseth KS. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Sci. 2009;324:59–63.CrossRefGoogle Scholar
  75. 75.
    Sershen SR, Westcott SL, Halas NJ, West JL. Temperature-sensitive polymer–nanoshell composites for photothermally modulated drug delivery. J Biomed Mater Res. 2000;51(3):293–8. doi:10.1002/1097-4636(20000905)51:3<293::aid-jbm1>3.0.co;2-t.PubMedCrossRefGoogle Scholar
  76. 76.
    Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA. Hydrogels in regenerative medicine. Adv Mater. 2009;21(32–33):3307–29. doi:10.1002/adma.200802106.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ehrbar M, Schoenmakers R, Christen EH, Fussenegger M, Weber W. Drug-sensing hydrogels for the inducible release of biopharmaceuticals. Nat Mater. 2008;7(10):800–4. doi:10.1038/nmat2250.PubMedCrossRefGoogle Scholar
  78. 78.
    Tang M, Zhang R, Bowyer A, Eisenthal R, Hubble J. A reversible hydrogel membrane for controlling the delivery of macromolecules. Biotechnol Bioeng. 2003;82(1):47–53. doi:10.1002/bit.10539.PubMedCrossRefGoogle Scholar
  79. 79.
    Zhang R, Tang M, Bowyer A, Eisenthal R, Hubble J. Synthesis and characterization of a D-glucose sensitive hydrogel based on CM-dextran and concanavalin A. React Funct Polym. 2006;66(7):757–67. doi:10.1016/j.reactfunctpolym.2005.11.003.CrossRefGoogle Scholar
  80. 80.
    Wang F, Li Z, Khan M, Tamama K, Kuppusamy P, Wagner WR, et al. Injectable, rapid gelling, and highly flexible hydrogel composites as growth factor and cell carriers. Acta Biomater. 2010;6(6):1978–91. doi:10.1016/j.actbio.2009.12.011.PubMedCrossRefGoogle Scholar
  81. 81.
    Banerjee I, Mishra D, Das T, Maiti TK. Wound pH-responsive sustained release of therapeutics from a poly(NIPAAm-co-AAc) hydrogel. J Biomater Sci Polym Ed. 2012;23(1–4):111–32. doi:10.1163/092050610x545049.PubMedCrossRefGoogle Scholar
  82. 82.
    Gao SQ, Maeda T, Okano K, Palczewski K. A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids. Investig Ophthalmol Vis Sci. 2012;53(10):6314–23. doi:10.1167/iovs.12-10279.CrossRefGoogle Scholar
  83. 83.
    Bidarra SJ, Barrias CC, Fonseca KB, Barbosa MA, Soares RA, Granja PL. Injectable in situ crosslinkable RGD-modified alginate matrix for endothelial cells delivery. Biomaterials. 2011;32(31):7897–904.PubMedCrossRefGoogle Scholar
  84. 84.
    Hastings CL, Kelly HM, Murphy MJ, Barry FP, O'Brien FJ, Duffy GP. Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischemia. J Control Release. 2012;161(1):73–80. doi:10.1016/j.jconrel.2012.04.033.PubMedCrossRefGoogle Scholar
  85. 85.
    Sun J, Jiang G, Qiu T, Wang Y, Zhang K, Ding F. Injectable chitosan-based hydrogel for implantable drug delivery: body response and induced variations of structure and composition. J Biomed Mater Res A. 2010;95A(4):1019–27. doi:10.1002/jbm.a.32923.CrossRefGoogle Scholar
  86. 86.
    Choi JS. In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF). Biomaterials. 2007;29:587–96.PubMedCrossRefGoogle Scholar
  87. 87.
    Liao IC, Leong KW. Efficacy of engineered FVIII-producing skeletal muscle enhanced by growth factor-releasing coaxial electrospun fibers. Biomaterials. 2011;32(6):1669–77. doi:10.1016/j.biomaterials.2010.10.049.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Cui W, Zhou Y, Chang J. Electrospun nanofibrous materials for tissue engineering and drug delivery. Sci Technol Adv Mater. 2010;11(1):14109–19.CrossRefGoogle Scholar
  89. 89.
    Fu Y-C, Nie H, Ho M-L, Wang C-K, Wang C-H. Optimized bone regeneration based on sustained release from three-dimensional fibrous PLGA/HAp composite scaffolds loaded with BMP-2. Biotechnol Bioeng. 2008;99(4):996–1006. doi:10.1002/bit.21648.PubMedCrossRefGoogle Scholar
  90. 90.
    Chew SY, Wen J, Yim EKF, Leong KW. Sustained release of proteins from electrospun biodegradable fibers. Biomacromolecules. 2005;6(4):2017–24. doi:10.1021/bm0501149.PubMedCrossRefGoogle Scholar
  91. 91.
    Xu XL, Yang LX, Xu XY, Wang X, Chen XS, Liang QZ, et al. Ultrafine-medicated fibers electrospun from W/O emulsions. J Control Release. 2005;108(1):33–42. doi:10.1016/j.jconrel.2005.07.021.PubMedCrossRefGoogle Scholar
  92. 92.
    Xu XL, Zhuang XL, Chen XS, Wang XR, Yang LX, Jing XB. Preparation of core–sheath composite nanofibers by emulsion electrospinning. Macromol Rapid Commun. 2006;27(19):1637–42. doi:10.1002/marc.200600384.CrossRefGoogle Scholar
  93. 93.
    Zhang H, Zhao C, Zhao Y, Tang G, Yuan X. Electrospinning of ultrafine core/shell fibers for biomedical applications. Sci China Chem. 2010;53(6):1246–54. doi:10.1007/s11426-010-3180-3.CrossRefGoogle Scholar
  94. 94.
    Sun ZC, Zussman E, Yarin AL, Wendorff JH, Greiner A. Compound core–shell polymer nanofibers by co-electrospinning. Adv Mater. 2003;15(22):1929–32. doi:10.1002/adma.200305136.CrossRefGoogle Scholar
  95. 95.
    Liao IC, Chen S, Liu JB, Leong KW. Sustained viral gene delivery through core–shell fibers. J Control Release. 2009;139(1):48–55. doi:10.1016/j.jconrel.2009.06.007.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jiang H, Hu Y, Zhao P, Li Y, Zhu K. Modulation of protein release from biodegradable core–shell structured fibers prepared by coaxial electrospinning. J Biomed Mater Res B Appl Biomater. 2006;79B(1):50–7. doi:10.1002/jbm.b.30510.CrossRefGoogle Scholar
  97. 97.
    Bowman K, Leong KW. Chitosan nanoparticles for oral gene delivery. Int J Nanomedicine. 2006;1(2):117–28.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Pan J, Chan SY, Lee WG, Kang LF. Microfabricated particulate drug-delivery systems. Biotechnol J. 2011;6(12):1477–87. doi:10.1002/biot.201100237.PubMedCrossRefGoogle Scholar
  99. 99.
    Kohane D. Microparticles and nanoparticles for drug delivery. Biotechnol Bioeng. 2007;1(96):203–9.CrossRefGoogle Scholar
  100. 100.
    Lee J, Bhang S, Park H, Kim B-S, Lee K. Active blood vessel formation in the ischemic hindlimb mouse model using a microsphere/hydrogel combination system. Pharm Res. 2010;27(5):767–74. doi:10.1007/s11095-010-0067-0.PubMedCrossRefGoogle Scholar
  101. 101.
    Ise M, Ise H, Shiba Y, Kobayashi S, Goto M, Takahashi M, et al. Targeting N-acetylglucosamine-bearing polymer-coated liposomes to vascular smooth muscle cells. J Artif Organs. 2011;14(4):301–9. doi:10.1007/s10047-011-0595-3.PubMedCrossRefGoogle Scholar
  102. 102.
    Auricchio A. Fighting blindness with adeno-associated virus serotype 8. Hum Gene Ther. 2011;22(10):1169–70. doi:10.1089/hum.2011.2521.PubMedCrossRefGoogle Scholar
  103. 103.
    Tang Y, Cummins J, Huard J, Wang B. AAV-directed muscular dystrophy gene therapy. Expert Opin Biol Ther. 2010;10(3):395–408. doi:10.1517/14712591003604690.PubMedCrossRefGoogle Scholar
  104. 104.
    Hacein-Bey-Abina S et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Sci. 2003;302(5644):415–9.CrossRefGoogle Scholar
  105. 105.
    Felgner JH, Kumar R, Sridhar CN, Wheeler CJ, Tsai YJ, Border R, et al. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J Biol Chem. 1994;269(4):2550–61.PubMedGoogle Scholar
  106. 106.
    Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization, and transfection efficiency. J Control Release. 2001;70(3):399–421. doi:10.1016/s0168-3659(00)00361-8.PubMedCrossRefGoogle Scholar
  107. 107.
    Boussif O, Lezoualc'h F, Zanta MA, Mergny MD, Scherman D, Demeneix B, et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc Natl Acad Sci U S A. 1995;92(16):7297–301.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Su XF, Fricke J, Kavanagh DG, Irvine DJ. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. Molec Pharm. 2011;8(3):774–87. doi:10.1021/mp100390w.CrossRefGoogle Scholar
  109. 109.
    Zhang Y, Satterlee A, Huang L. In vivo gene delivery by nonviral vectors: overcoming hurdles. Mol Ther. 2012;20(7):1298–304.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Romero NB, Braun S, Benveniste O, Leturcq F, Hogrel JY, Morris GE, et al. Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. Hum Gene Ther. 2004;15(11):1065–76. doi:10.1089/hum.2004.15.1065.PubMedCrossRefGoogle Scholar
  111. 111.
    Guo X, Huang L. Recent advances in nonviral vectors for gene delivery. Acc Chem Res. 2012;45(7):971–9. doi:10.1021/ar200151m.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Elsabahy M, Nazarali A, Foldvari M. Nonviral nucleic acid delivery: key challenges and future directions. Curr Drug Deliv. 2011;8(3):235–44.PubMedCrossRefGoogle Scholar
  113. 113.
    Garcia L, Urbiola K, Duzgunes N, de Ilarduya CT. Lipopolyplexes as nanomedicines for therapeutic gene delivery. In: Duzgunes N, editor. Nanomedicine: Infectious Diseases, Immunotherapy, Diagnostics, Antifibrotics, Toxicology and Gene Medicine. Methods in Enzymology. San Diego: Elsevier Academic Press Inc; 2012. p. 327–38.CrossRefGoogle Scholar
  114. 114.
    Grigsby CL, Leong KW. Balancing protection and release of DNA: tools to address a bottleneck of nonviral gene delivery. J R Soc Interface. 2010;7:S67–82. doi:10.1098/rsif.2009.0260.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Grigsby CL, Ho YP, Leong KW. Understanding nonviral nucleic acid delivery with quantum dot-fret nanosensors. Nanomedicine (Lond). 2012;7(4):565–77.CrossRefGoogle Scholar
  116. 116.
    Green JJ, Langer R, Anderson DG. A combinatorial polymer library approach yields insight into nonviral gene delivery. Accounts Chem Res. 2008;41(6):749–59. doi:10.1021/ar7002336.CrossRefGoogle Scholar
  117. 117.
    Anderson DG, Lynn DM, Langer R. Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery. Angew Chem. 2003;115(27):3261–6. doi:10.1002/ange.200351244.CrossRefGoogle Scholar
  118. 118.
    Pelet J, Putnam D. A combinatorial library of bifunctional polymeric vectors for siRNA delivery in vitro. Pharm Res. 2013;30(2):362–76. doi:10.1007/s11095-012-0876-4.PubMedCrossRefGoogle Scholar
  119. 119.
    Scudellari M. The Delivery Dilemma. Nat Rep Stem Cells. 2009:1754–8705.Google Scholar
  120. 120.
    Elbjeirami WM, West JL. Angiogenesis-like activity of endothelial cells co-cultured with VEGF-producing smooth muscle cells. Tissue Eng. 2006;12(2):381–90.PubMedCrossRefGoogle Scholar
  121. 121.
    Cyranoski D. Stem cells cruise to clinic: Japanese study of induced pluripotent stem cells aims to demonstrate safety in humans. Nature News. 2013;494. doi:10.1038/494413a.
  122. 122.
    Murry CE, Pu WT. Reprogramming fibroblasts into cardiomyocytes. N Engl J Med. 2011;364(2):177–8.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    T V, A O, ZP P, Y K, TC S, M. W. Direct conversion of fibroblasts to functional neurons by defined factors. Nat. 2010;463(7284):1035–41.Google Scholar
  124. 124.
    Abdullah A, Pollock A, Sun T. The path from skin to brain: generation of functional neurons from fibroblasts. Mol Neurobiol. 2012;45(3):586–95. doi:10.1007/s12035-012-8277-6.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Yim EKF, Darling EM, Kulangara K, Guilak F, Leong KW. Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of human mesenchymal stem cells. Biomaterials. 2009;31:1299–306.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Murugan R, Ramakrishna S. Design strategies of tissue engineering scaffolds with controlled fiber orientation. Tissue Eng. 2007;13(8):1845–66. doi:10.1089/ten.2006.0078.PubMedCrossRefGoogle Scholar
  127. 127.
    Kosen Y, Miyaji H, Kato A, Sugaya T, Kawanami M. Application of collagen hydrogel/sponge scaffold facilitates periodontal wound healing in class II furcation defects in beagle dogs. J Periodontal Res. 2012;47(5):626–34. doi:10.1111/j.1600-0765.2012.01475.x.PubMedCrossRefGoogle Scholar
  128. 128.
    Archibald SJ, Krarup C, Shefner J, Li ST, Madison RD. A collagen-based nerve guide conduit for peripheral nerve repair: an electrophysiological study of nerve regeneration in rodents and nonhuman primates. J Comp Neurol. 1991;306(4):685–96. doi:10.1002/cne.903060410.PubMedCrossRefGoogle Scholar
  129. 129.
    Lin YC, Marra KG. Injectable systems and implantable conduits for peripheral nerve repair. Biomed Mater. 2012;7(2):024102. doi:10.1088/1748-6041/7/2/024102.PubMedCrossRefGoogle Scholar
  130. 130.
    Rodriguez FJ, Gomez N, Perego G, Navarro X. Highly permeable polylactide–caprolactone nerve guides enhance peripheral nerve regeneration through long gaps. Biomaterials. 1999;20(16):1489–500. doi:10.1016/s0142-9612(99)00055-1.PubMedCrossRefGoogle Scholar
  131. 131.
    Jeffries EM, Wang YD. Biomimetic micropatterned multichannel nerve guides by templated electrospinning. Biotechnol Bioeng. 2012;109(6):1571–82. doi:10.1002/bit.24412.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Wang HB, Mullins ME, Cregg JM, McCarthy CW, Gilbert RJ. Varying the diameter of aligned electrospun fibers alters neurite outgrowth and Schwann cell migration. Acta Biomater. 2010;6(8):2970–8. doi:10.1016/j.actbio.2010.02.020.PubMedCrossRefGoogle Scholar
  133. 133.
    Cellot G, Cilia E, Cipollone S, Rancic V, Sucapane A, Giordani S, et al. Carbon nanotubes might improve neuronal performance by favoring electrical shortcuts. Nat Nanotechnol. 2009;4(2):126–33. doi:10.1038/nnano.2008.374.PubMedCrossRefGoogle Scholar
  134. 134.
    Patel ZS, Mikos AG. Angiogenesis with biomaterial-based drug- and cell-delivery systems. J Biomater Sci Polym Ed. 2004;15(6):701–26. doi:10.1163/156856204774196117.PubMedCrossRefGoogle Scholar
  135. 135.
    De Coppi P, Delo D, Farrugia L, Udompanyanan K, Yoo JJ, Nomi M, et al. Angiogenic gene-modified muscle cells for enhancement of tissue formation. Tissue Eng. 2005;11(7–8):1034–44.PubMedCrossRefGoogle Scholar
  136. 136.
    Incontinent Urinary Diversion Using an Autologous Neo-Urinary Conduit [database on the Internet]. ClinicalTrials.gov Identifier: NCT01087697. 2012. Accessed:Google Scholar
  137. 137.
    Reiffel AJ, Kafka C, Hernandez KA, Popa S, Perez JL, Zhou S, et al. High-fidelity tissue engineering of patient-specific auricles for reconstruction of pediatric microtia and other auricular deformities. PLoS One. 2013;8(2):e56506. doi:10.1371/journal.pone.0056506.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Risau W. Mechanisms of angiogenesis. Nat. 1997;386(6626):671–4.CrossRefGoogle Scholar
  139. 139.
    Naderi H, Matin MM, Bahrami AR. Review paper: critical issues in tissue engineering: biomaterials, cell sources, angiogenesis, and drug delivery systems. J Biomater Appl. 2011;26(4):383–417. doi:10.1177/0885328211408946.PubMedCrossRefGoogle Scholar
  140. 140.
    Chen RR, Silva EA, Yuen WW, Mooney DJ. Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation. Pharm Res. 2007;24(2):258–64. doi:10.1007/s11095-006-9173-4.PubMedCrossRefGoogle Scholar
  141. 141.
    Matsui T, Nishino Y, Maeda S, Yamagishi S-i. PEDF-derived peptide inhibits corneal angiogenesis by suppressing VEGF expression. Microvasc Res. 2012;84(1):105–8. doi:10.1016/j.mvr.2012.02.006.PubMedCrossRefGoogle Scholar
  142. 142.
    Bowers DT, Chhabra P, Langman L, Botchwey EA, Brayman KL. FTY720-loaded poly(DL-lactide-co-glycolide) Electrospun Scaffold Significantly Increases Microvessel Density over 7 Days in Streptozotocin-Induced Diabetic C57b16/J Mice: Preliminary Results. Transplant Proc. 2011;43(9):3285–7. doi:10.1016/j.transproceed.2011.09.008.PubMedCrossRefGoogle Scholar
  143. 143.
    Loyd CM, Diaconu D, Fu W, Adams GN, Brandt E, Knutsen DA, et al. Transgenic overexpression of keratinocyte-specific VEGF and Ang1 in combination promotes wound healing under nondiabetic but not diabetic conditions. Int J Clin Exp Pathol. 2012;5(1):1–11.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Cho S-W, Yang F, Son SM, Park H-J, Green JJ, Bogatyrev S, et al. Therapeutic angiogenesis using genetically engineered human endothelial cells. J Control Release. 2012;160(3):515–24. doi:10.1016/j.jconrel.2012.03.006.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Keeney M, van den Beucken JJJP, van der Kraan PM, Jansen JA, Pandit A. The ability of a collagen/calcium phosphate scaffold to act as its own vector for gene delivery and to promote bone formation via transfection with VEGF(165). Biomaterials. 2010;31(10):2893–902. doi:10.1016/j.biomaterials.2009.12.041.PubMedCrossRefGoogle Scholar
  146. 146.
    Said SS, Pickering JG, Mequanint K. Advances in growth factor delivery for therapeutic angiogenesis. J Vasc Res. 2013;50(1):35–51. doi:10.1159/000345108.PubMedCrossRefGoogle Scholar
  147. 147.
    Amsden BG. Delivery approaches for angiogenic growth factors in the treatment of ischemic conditions. Expert Opin Drug Deliv. 2011;8(7):873–90. doi:10.1517/17425247.2011.577412.PubMedCrossRefGoogle Scholar
  148. 148.
    Schiffelers RM, van Rooy I, Storm G. siRNA-mediated inhibition of angiogenesis. Expert Opin Biol Ther. 2005;5(3):359–68. doi:10.1517/14712598.5.3.359.PubMedCrossRefGoogle Scholar
  149. 149.
    Park H-J, Yang F, Cho S-W. Nonviral delivery of genetic medicine for therapeutic angiogenesis. Adv Drug Deliv Rev. 2012;64(1):40–52. doi:10.1016/j.addr.2011.09.005.PubMedCrossRefGoogle Scholar
  150. 150.
    Mitsos S, Katsanos K, Koletsis E, Kagadis GC, Anastasiou N, Diamantopoulos A, et al. Therapeutic angiogenesis for myocardial ischemia revisited: basic biological concepts and focus on latest clinical trials. Angiogenesis. 2012;15(1):1–22. doi:10.1007/s10456-011-9240-2.PubMedCrossRefGoogle Scholar
  151. 151.
    Chu H, Wang Y. Therapeutic angiogenesis: controlled delivery of angiogenic factors. Ther Deliv. 2012;3(6):693–714.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Bhise NS, Shmueli RB, Sunshine JC, Tzeng SY, Green JJ. Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis. Expert Opin Drug Deliv. 2011;8(4):485–504. doi:10.1517/17425247.2011.558082.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Margolis D, Malay D, Hoffstad O, Leonard C, T M, Lopez de Nava K et al. Prevalence of diabetes, diabetic foot ulcer, and lower extremity amputation among Medicare beneficiaries, 2006 to 2008: Data Points #1. In: Quality AfHRa, editor. Data points publication series. http://www.ncbi.nlm.nih.gov/books/NBK63602/2011.
  154. 154.
    Pham HT, Economides PA, Veves A. The role of endothelial function on the foot: microcirculation and wound healing in patients with diabetes. Clin Podiatr Med Surg. 1998;15(1):85–93.PubMedGoogle Scholar
  155. 155.
    Reddy MA, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011;90(3):421–9. doi:10.1093/cvr/cvr024.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Gene Therapy to Improve Wound Healing in Patients With Diabetes [database on the Internet]. Tissue Repair Company. 2007. Accessed:Google Scholar
  157. 157.
    G M, AJ T, VT M, D M, L P, GF P et al. Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial. Wound Repair Regen. 2009;17(6):772–9.Google Scholar
  158. 158.
    Doukas J, Chandler LA, Gonzalez AM, Gu D, Hoganson DK, Ma C, et al. Matrix immobilization enhances the tissue repair activity of growth factor gene therapy vectors. Hum Gene Ther. 2001;12(7):783–98.PubMedCrossRefGoogle Scholar
  159. 159.
    Study of AdGVPEDF.11D in Neovascular Age-related Macular Degeneration (AMD) [database on the Internet]. ClinicalTrials.gov Identifier: NCT00109499. 2011. Accessed:Google Scholar
  160. 160.
    GenVec. AdPEDF for Macular Degeneration. In: http://www.genvec.com/go.cfm?do=Page.View&pid=30, editor.: Internet; 2013.

Copyright information

© Controlled Release Society 2013

Authors and Affiliations

  • Elizabeth R. Lorden
    • 1
  • Howard M. Levinson
    • 2
  • Kam W. Leong
    • 1
    • 3
  1. 1.Department of Biomedical EngineeringDuke UniversityDurhamUSA
  2. 2.Division of Plastic and Reconstructive Surgery, Department of SurgeryDuke University Medical CenterDurhamUSA
  3. 3.King Abdulaziz UniversityJeddahSaudi Arabia

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