Document Detail


Balancing cell migration with matrix degradation enhances gene delivery to cells cultured three-dimensionally within hydrogels.
MedLine Citation:
PMID:  20450944     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In regenerative medicine, hydrogels are employed to fill defects and support the infiltration of cells that can ultimately regenerate tissue. Gene delivery within hydrogels targeting infiltrating cells has the potential to promote tissue formation, but the delivery efficiency of non-viral vectors within hydrogels is low, hindering their applicability in tissue regeneration. To improve their functionality, we have conducted a mechanistic study to investigate the contribution of cell migration and matrix degradation on gene delivery. In this report, lipoplexes were entrapped within hydrogels based on poly(ethylene glycol) (PEG) crosslinked with peptides containing matrix metalloproteinase degradable sequences. The mesh size of these hydrogels is substantially less than the size of the entrapped lipoplexes, which can function to retain vectors. Cell migration and transfection were simultaneously measured within hydrogels with varying density of cell adhesion sites (Arg-Gly-Asp peptides) and solids content. Increasing RGD density increased expression levels up to 100-fold, while greater solids content sustained expression levels for 16days. Increasing RGD density and decreasing solids content increased cell migration, which indicates expression levels increase with increased cell migration. Initially exposing cells to vector resulted in transient expression that declined after 2days, verifying the requirement of migration to sustain expression. Transfected cells were predominantly located within the population of migrating cells for hydrogels that supported cell migration. Although the small mesh size retained at least 70% of the lipoplexes in the absence of cells after 32days, the presence of cells decreased retention to 10% after 16days. These results indicate that vectors retained within hydrogels contact migrating cells, and that persistent cell migration can maintain elevated expression levels. Thus, matrix degradation and cell migration are fundamental design parameters for maximizing gene delivery within hydrogels.
Authors:
Jaclyn A Shepard; Alyssa Huang; Ariella Shikanov; Lonnie D Shea
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-05-05
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  146     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-02     Completed Date:  2010-12-20     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  128-35     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Adhesion
Cell Culture Techniques
Cell Movement*
Cross-Linking Reagents / chemistry
DNA / administration & dosage,  genetics
Extracellular Matrix / chemistry*
Gene Transfer Techniques*
Hydrogels / chemistry*
Matrix Metalloproteinases / chemistry
Mice
NIH 3T3 Cells
Oligopeptides / chemistry
Plasmids
Polyethylene Glycols / chemistry
Tissue Engineering
Transfection
Transgenes
Grant Support
ID/Acronym/Agency:
PL1 EB008542/EB/NIBIB NIH HHS; PL1 EB008542-01/EB/NIBIB NIH HHS; PL1EB008542/EB/NIBIB NIH HHS; R01 EB005678/EB/NIBIB NIH HHS; R01 EB005678-04/EB/NIBIB NIH HHS; R01EB005678/EB/NIBIB NIH HHS; R21 EB006520/EB/NIBIB NIH HHS; R21 EB006520-02/EB/NIBIB NIH HHS; R21EB006520/EB/NIBIB NIH HHS
Chemical
Reg. No./Substance:
0/Cross-Linking Reagents; 0/Hydrogels; 0/Oligopeptides; 0/Polyethylene Glycols; 9007-49-2/DNA; 99896-85-2/arginyl-glycyl-aspartic acid; EC 3.4.24.-/Matrix Metalloproteinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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