Matrix-tethered gene delivery from hydrogel scaffolds

Non-viral gene delivery strategies from hydrogel scaffolds typically involve the encapsulation of naked or ionically complexed DNA into the tissue engineering matrix and its subsequent hydrolysis mediated release into the surrounding tissue (right panel). This approach provides limited control over the location and time where gene transfer takes place. We are currently investigating an alternative strategy, termed tethered delivery. In this approach complex DNA is immobilized to the tissue engineering scaffold via a liable bond, whereby gene transfer only occurs after the tether bond is broken (left panel). Because the complexes are immobilized to the biomaterial, a greater level of control is achieved allowing for temporal and spatial delivery of DNA and/or siRNA. Furthermore, tethered delivery allows for the investigation of the role of the matrix itself on gene transfer, which was not previously possible since the cells did not need to be in direct physical contact with the scaffold for gene transfer to occur. We believe that the matrix itself can be engineered to enhance the process of gene transfer.

Scaffolds for tissue regeneration

Tissue engineering scaffolds must be able to support progenitor cell infiltration and provide the infiltrating cells with the necessary biochemical signals to guide morphogenesis. Our current knowledge of tissue development and adult wound healing must be implemented in the scaffold design in order to develop materials that have the required biochemical signals to guide proper tissue formation. In our laboratory, we are currently investigating novel chemistries to crosslink synthetic and biologically derived polymers to form hydrogels that are biologically active. The hydrogels formed will be used to (i) guide tissue formation in vivo , guiding residing cells, progenitor or stem cells, to regenerate the affected area and (ii) as stem cell niches to study and develop strategies to facilitate the use of stem cells in tissue engineering

Materials for gene delivery

Materials for gene delivery must be able to (i) encapsulate or self-assemble with DNA or siRNA - highly charged and hydrophilic molecules - to form nanoparticles (50-200nm), (ii) protect the nucleic acids from degradation and (iii) aide in trafficking. Thus, the nanopartilces must be able to move efficiently through the different compartments of the cell - which are chemically and biologically different - and be able to efficiently deliver the DNA and siRNA to their site of action, nucleus or cytosol respectively. Research in our laboratory focuses on developing polymers that can immobilize the nanoparticles to biomaterials (for tethered delivery) and exploit the different environments encountered in the cell to achieve efficient gene delivery