Three-Dimensional Porous Scaffolds at the Crossroads of Tissue Engineering and Cell-Based Gene Therapy Daniel L. Coutu, 1 Azizeh-Mitra Yousefi, 2 and Jacques Galipeau 3 * 1 Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada 2 Industrial Material Institute, National Research Council of Canada, Boucherville, Quebec, Canada 3 Division of Hematology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada ABSTRACT In the last 20 years, more than 1,500 gene therapy clinical trials have been approved worldwide targeting a variety of indications, from inherited monogenic diseases to acquired conditions such as cancer, cardiovascular and infectious diseases. However, concerns about the safety and efficacy of gene therapy pharmaceuticals justify the development of alternative strategies to ensure the clinical translation of this still promising field. In particular, ex vivo gene therapy strategies using autologous adult stem cells coupled to three-dimensional (3D) porous scaffolds show great promises in preclinical studies. Developments in the fields of biomaterial sciences and tissue engineering have already helped understanding how we can harness to regenerative potential of many cell types to create artificial tissues and organs and vastly improve the engraftment of ex vivo manipulated adult stem cells. In this article, we will review the current state of the art in tissue engineering by exploring the various types of clinically available biomaterials and the methods used to process them into complex 3D scaffolds. We will then review how these technologies are applied in cell-based gene therapy and identify novel avenues of research that may benefit patients in the near future. J. Cell. Biochem. 108: 537–546, 2009. ß 2009 Wiley-Liss, Inc. KEY WORDS: GENE THERAPY; CELL THERAPY; 3D POROUS SCAFFOLDS; BIOMATERIALS; TISSUE ENGINEERING; ADULT STEM CELLS G ene therapy is defined by the use of recombinant genetic material therapeutically to correct the genotypic defect causing a disease or to modulate a pathological response. Since the first human treated by gene therapy in 1989, 1,537 clinical trials had been approved worldwide as of March 2009 (see http://www. wiley.co.uk/genmed/clinical/). Despite the fact that gene therapy was first conceptualized as a treatment option for inherited monogenic diseases, a large fraction of those studies targeted acquired conditions such as cardiovascular, neurological, and infectious diseases, as well as cancer. As a result of this broad application of gene therapy, we now have 20 years of clinical experience with gene therapy targeting various types of cells or tissues with different vectors (viral and non-viral) and different strategies (ex vivo and in vivo gene transfer) [Edelstein et al., 2007]. The implementation of standard clinical gene therapy protocols in routine clinical practice has, however, been slower than first expected due to the very few clinically meaningful gene therapy successes and the risks associated with platform-specific immuno- genicity and genotoxicity. Nevertheless, this clinical experience allows us to draw certain conclusions about how gene therapists should direct future research to facilitate clinical translation of this still extremely promising field. In its simplest form, gene therapy consists of either local or systemic delivery of a gene transfer vector. This approach has a number of inherent limitations that include: (1) inadequate gene transfer efficiency and gene expression, (2) inefficient targeting of appropriate cells or tissues, and (3) poor overall safety profile of the vectors (fatal immune responses, insertional mutagenesis, detection of viral vectors in semen) [Thomas et al., 2003; Nathwani et al., 2005; Porteus et al., 2006]. Another approach consists of using ex vivo modified cells, autologous or allogeneic, to be grafted into the patient. Although this avoids systemic dissemination vectors in subjects, it is also limited by the safety, low engraftment, and immunogenicity of ex vivo gene-engineered cells. The lack of safety and efficiency of these approaches to gene therapy justifies on-going development of alternative cell and gene delivery strategies addressing these specific issues. The integration of biomaterial engineering, tissue engineering, and stem cell research provides us with innovative tools for developing delivery platforms maximizing safety and efficacy. Journal of Cellular Biochemistry PROSPECT Journal of Cellular Biochemistry 108:537–546 (2009) 537 *Correspondence to: Dr. Jacques Galipeau, MD, Jewish General Hospital, McGill University, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2. E-mail: jacques.galipeau@mcgill.ca Received 1 July 2009; Accepted 6 July 2009  DOI 10.1002/jcb.22296  ß 2009 Wiley-Liss, Inc. Published online 13 August 2009 in Wiley InterScience (www.interscience.wiley.com).