Scaffold-mediated BMP-2 Minicircle DNA Delivery Accelerated Bone Repair in a Mouse Critical-size Calvarial Defect Model

Overview

Journal J Biomed Mater Res A

Specialty Biomedical Engineering

Date 2016 Apr 10

PMID 27059085

Citations 11

Authors

Michael Keeney

Michael T Chung

Elizabeth R Zielins

Kevin J Paik

Adrian McArdle

Shane D Morrison

Ryan C Ransom

Namrata Barbhaiya

David Atashroo

Gunilla Jacobson

Richard N Zare

Michael T Longaker

Derrick C Wan

Fan Yang

Affiliations

Soon will be listed here.

Abstract

Scaffold-mediated gene delivery holds great promise for tissue regeneration. However, previous attempts to induce bone regeneration using scaffold-mediated non-viral gene delivery rarely resulted in satisfactory healing. We report a novel platform with sustained release of minicircle DNA (MC) from PLGA scaffolds to accelerate bone repair. MC was encapsulated inside PLGA scaffolds using supercritical CO2 , which showed prolonged release of MC. Skull-derived osteoblasts transfected with BMP-2 MC in vitro result in higher osteocalcin gene expression and mineralized bone formation. When implanted in a critical-size mouse calvarial defect, scaffolds containing luciferase MC lead to robust in situ protein production up to at least 60 days. Scaffold-mediated BMP-2 MC delivery leads to substantially accelerated bone repair as early as two weeks, which continues to progress over 12 weeks. This platform represents an efficient, long-term nonviral gene delivery system, and may be applicable for enhancing repair of a broad range of tissues types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2099-2107, 2016.

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References

Hosseinkhani H, Yamamoto M, Inatsugu Y, Hiraoka Y, Inoue S, Shimokawa H . Enhanced ectopic bone formation using a combination of plasmid DNA impregnation into 3-D scaffold and bioreactor perfusion culture. Biomaterials. 2005; 27(8):1387-98. DOI: 10.1016/j.biomaterials.2005.08.017. View

Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z . Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene Ther. 2007; 15(4):257-66. DOI: 10.1038/sj.gt.3303070. View

Wong D, Kumar A, Jatana S, Ghiselli G, Wong K . Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J. 2007; 8(6):1011-8. DOI: 10.1016/j.spinee.2007.06.014. View

Li S, Quarto N, Senarath-Yapa K, Grey N, Bai X, Longaker M . Enhanced Activation of Canonical Wnt Signaling Confers Mesoderm-Derived Parietal Bone with Similar Osteogenic and Skeletal Healing Capacity to Neural Crest-Derived Frontal Bone. PLoS One. 2015; 10(10):e0138059. PMC: 4592195. DOI: 10.1371/journal.pone.0138059. View

Darquet A, Cameron B, Wils P, Scherman D, Crouzet J . A new DNA vehicle for nonviral gene delivery: supercoiled minicircle. Gene Ther. 1998; 4(12):1341-9. DOI: 10.1038/sj.gt.3300540. View

Tservistas M, Levy M, OKennedy R, York P, Humphrey G, Hoare M . The formation of plasmid DNA loaded pharmaceutical powders using supercritical fluid technology. Biotechnol Bioeng. 2000; 72(1):12-8. DOI: 10.1002/1097-0290(20010105)72:1<12::aid-bit2>3.0.co;2-z. View

Heyde M, Partridge K, Howdle S, Oreffo R, Garnett M, Shakesheff K . Development of a slow non-viral DNA release system from PDLLA scaffolds fabricated using a supercritical CO2 technique. Biotechnol Bioeng. 2007; 98(3):679-93. DOI: 10.1002/bit.21446. View

Itaka K, Ohba S, Miyata K, Kawaguchi H, Nakamura K, Takato T . Bone regeneration by regulated in vivo gene transfer using biocompatible polyplex nanomicelles. Mol Ther. 2007; 15(9):1655-62. DOI: 10.1038/sj.mt.6300218. View

Shimoda M, Chen S, Noguchi H, Matsumoto S, Grayburn P . In vivo non-viral gene delivery of human vascular endothelial growth factor improves revascularisation and restoration of euglycaemia after human islet transplantation into mouse liver. Diabetologia. 2010; 53(8):1669-79. PMC: 3804430. DOI: 10.1007/s00125-010-1745-5. View

10.

Mooney D, Baldwin D, Suh N, Vacanti J, Langer R . Novel approach to fabricate porous sponges of poly(D,L-lactic-co-glycolic acid) without the use of organic solvents. Biomaterials. 1996; 17(14):1417-22. DOI: 10.1016/0142-9612(96)87284-x. View

11.

Chang C, Christensen L, Lee M, Kim S . Efficient expression of vascular endothelial growth factor using minicircle DNA for angiogenic gene therapy. J Control Release. 2007; 125(2):155-63. PMC: 2677388. DOI: 10.1016/j.jconrel.2007.10.014. View

12.

Barry J, Silva M, Popov V, Shakesheff K, Howdle S . Supercritical carbon dioxide: putting the fizz into biomaterials. Philos Trans A Math Phys Eng Sci. 2007; 364(1838):249-61. PMC: 1855442. DOI: 10.1098/rsta.2005.1687. View

13.

Jang J, Rives C, Shea L . Plasmid delivery in vivo from porous tissue-engineering scaffolds: transgene expression and cellular transfection. Mol Ther. 2005; 12(3):475-83. PMC: 2648405. DOI: 10.1016/j.ymthe.2005.03.036. View

14.

Sykaras N, Opperman L . Bone morphogenetic proteins (BMPs): how do they function and what can they offer the clinician?. J Oral Sci. 2003; 45(2):57-73. DOI: 10.2334/josnusd.45.57. View

15.

Wang X, Seed B . A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003; 31(24):e154. PMC: 291882. DOI: 10.1093/nar/gng154. View

16.

Holladay C, Keeney M, Greiser U, Murphy M, OBrien T, Pandit A . A matrix reservoir for improved control of non-viral gene delivery. J Control Release. 2009; 136(3):220-5. DOI: 10.1016/j.jconrel.2009.02.006. View

17.

Sunshine J, Green J, Mahon K, Yang F, Eltoukhy A, Nguyen D . Small-Molecule End-Groups of Linear Polymer Determine Cell-type Gene-Delivery Efficacy. Adv Mater. 2014; 21(48):4947-4951. PMC: 4143259. DOI: 10.1002/adma.200901718. View

18.

Chen Z, Riu E, He C, Xu H, Kay M . Silencing of episomal transgene expression in liver by plasmid bacterial backbone DNA is independent of CpG methylation. Mol Ther. 2008; 16(3):548-56. DOI: 10.1038/sj.mt.6300399. View

19.

Li S, Meyer N, Quarto N, Longaker M . Integration of multiple signaling regulates through apoptosis the differential osteogenic potential of neural crest-derived and mesoderm-derived Osteoblasts. PLoS One. 2013; 8(3):e58610. PMC: 3607600. DOI: 10.1371/journal.pone.0058610. View

20.

Sung H, Meredith C, Johnson C, Galis Z . The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. Biomaterials. 2004; 25(26):5735-42. DOI: 10.1016/j.biomaterials.2004.01.066. View