Large-scale bicortical skull bone regeneration using ex vivo replication-defective adenoviral-mediated bone morphogenetic protein-2 gene-transferred bone marrow stromal cells and composite biomaterials

Sophia Chia Ning Chang, Tsung Min Lin, Hui Ying Chung, Philip Kuo Ting Chen, Feng Huei Lin, Jeuren Lou, Long Bin Jeng

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

OBJECTIVE: Bone marrow stromal cells (BMSCs) have great potential in bone repair. We developed an animal model to test the hypothesis that ex vivo gene transfer of human bone morphogenetic protein (BMP)-2 to BMSCs via a replication-defective (E1A-deleted) adenovirus vector (AdV) with appropriate biopolymers would enhance autologous bone formation during repair of a large-scale skull defect. METHODS: Eighteen miniature swine were treated with AdV BMP-2-transduced BMSCs in biopolymer (group 1), BMSCs in biopolymer (group 2), or biopolymer alone (group 3). After 6 months, the swine were killed, and the skull repair was examined by gross pictures, histology, 3-dimensional computed tomography, and biomechanical study. RESULTS: Group 1 showed complete solid bone formation after 6 months, and hematoxylin and eosin staining demonstrated the presence of mature, woven, well-mineralized bone. Computed tomography showed wholesome repair of the skull defect. Statistical analysis demonstrated a significant difference in bone thickness between groups 1 and 2. Biomechanical testing showed a statistically significant difference in the stiffness of new bone formed in group 1 compared with group 2. CONCLUSION: The Ad5 E1A-deleted AdV may be the optimal starting vector in ex vivo gene therapy for benign skeletal diseases. Additionally, the use of the gelatin/tricalcium phosphate ceramic/glutaraldehyde biopolymer with AdV BMP-2 gene transfer strongly enhances the bony healing of critical-size bicortical craniofacial defects. This method can be used by modifying the delivery of constructs to malunion treatment, in regional osteoporosis therapy, and spinal fusion.

Original languageEnglish
JournalNeurosurgery
Volume65
Issue number6 SUPPL. 1
DOIs
Publication statusPublished - Dec 1 2009
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein 2
Biopolymers
Bone Regeneration
Biocompatible Materials
Mesenchymal Stromal Cells
Skull
Adenoviridae
Bone and Bones
Genes
Osteogenesis
Tomography
Miniature Swine
Spinal Fusion
Glutaral
Gelatin
Hematoxylin
Eosine Yellowish-(YS)
Genetic Therapy
Osteoporosis
Histology

Keywords

  • Bone marrow mesenchymal stem cells
  • E1A-deleted adenovirus
  • Ex vivo gene therapy

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Large-scale bicortical skull bone regeneration using ex vivo replication-defective adenoviral-mediated bone morphogenetic protein-2 gene-transferred bone marrow stromal cells and composite biomaterials. / Chang, Sophia Chia Ning; Lin, Tsung Min; Chung, Hui Ying; Chen, Philip Kuo Ting; Lin, Feng Huei; Lou, Jeuren; Jeng, Long Bin.

In: Neurosurgery, Vol. 65, No. 6 SUPPL. 1, 01.12.2009.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVE: Bone marrow stromal cells (BMSCs) have great potential in bone repair. We developed an animal model to test the hypothesis that ex vivo gene transfer of human bone morphogenetic protein (BMP)-2 to BMSCs via a replication-defective (E1A-deleted) adenovirus vector (AdV) with appropriate biopolymers would enhance autologous bone formation during repair of a large-scale skull defect. METHODS: Eighteen miniature swine were treated with AdV BMP-2-transduced BMSCs in biopolymer (group 1), BMSCs in biopolymer (group 2), or biopolymer alone (group 3). After 6 months, the swine were killed, and the skull repair was examined by gross pictures, histology, 3-dimensional computed tomography, and biomechanical study. RESULTS: Group 1 showed complete solid bone formation after 6 months, and hematoxylin and eosin staining demonstrated the presence of mature, woven, well-mineralized bone. Computed tomography showed wholesome repair of the skull defect. Statistical analysis demonstrated a significant difference in bone thickness between groups 1 and 2. Biomechanical testing showed a statistically significant difference in the stiffness of new bone formed in group 1 compared with group 2. CONCLUSION: The Ad5 E1A-deleted AdV may be the optimal starting vector in ex vivo gene therapy for benign skeletal diseases. Additionally, the use of the gelatin/tricalcium phosphate ceramic/glutaraldehyde biopolymer with AdV BMP-2 gene transfer strongly enhances the bony healing of critical-size bicortical craniofacial defects. This method can be used by modifying the delivery of constructs to malunion treatment, in regional osteoporosis therapy, and spinal fusion.",
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AU - Lin, Tsung Min

AU - Chung, Hui Ying

AU - Chen, Philip Kuo Ting

AU - Lin, Feng Huei

AU - Lou, Jeuren

AU - Jeng, Long Bin

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AB - OBJECTIVE: Bone marrow stromal cells (BMSCs) have great potential in bone repair. We developed an animal model to test the hypothesis that ex vivo gene transfer of human bone morphogenetic protein (BMP)-2 to BMSCs via a replication-defective (E1A-deleted) adenovirus vector (AdV) with appropriate biopolymers would enhance autologous bone formation during repair of a large-scale skull defect. METHODS: Eighteen miniature swine were treated with AdV BMP-2-transduced BMSCs in biopolymer (group 1), BMSCs in biopolymer (group 2), or biopolymer alone (group 3). After 6 months, the swine were killed, and the skull repair was examined by gross pictures, histology, 3-dimensional computed tomography, and biomechanical study. RESULTS: Group 1 showed complete solid bone formation after 6 months, and hematoxylin and eosin staining demonstrated the presence of mature, woven, well-mineralized bone. Computed tomography showed wholesome repair of the skull defect. Statistical analysis demonstrated a significant difference in bone thickness between groups 1 and 2. Biomechanical testing showed a statistically significant difference in the stiffness of new bone formed in group 1 compared with group 2. CONCLUSION: The Ad5 E1A-deleted AdV may be the optimal starting vector in ex vivo gene therapy for benign skeletal diseases. Additionally, the use of the gelatin/tricalcium phosphate ceramic/glutaraldehyde biopolymer with AdV BMP-2 gene transfer strongly enhances the bony healing of critical-size bicortical craniofacial defects. This method can be used by modifying the delivery of constructs to malunion treatment, in regional osteoporosis therapy, and spinal fusion.

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