Natural polymers for gene delivery and tissue engineering☆
Introduction
The field of tissue engineering has evolved greatly since the advent of the idea of combining cells and scaffolds to create artificial tissues. Over the past several years, the definition of a tissue engineering matrix has changed dramatically from a material that functioned solely as an inert structural support for cell attachment, to serving as a more complex, dynamic environment for tissue development. This, along with continuing discoveries in areas of stem cell biology and development of bioreactor technology have set the stage for a future of research that emphasizes the creation of a biomimetic microenvironment for artificial tissue development [1], [2], [3], [4], [5], [6].
As more is known of the environment conducive to multi-cellular tissue development, the more it is evident how bioreactive and dynamic an artificial environment must be in order to provide support to neo-tissue growth [7]. This includes the need to accommodate multiple cell types, each very distinct in function, present within a single tissue. There is also the requirement for the matrix itself to respond to changes dictated by the cells, such as remodeling. Another critical component is the ability to introduce signals and cues to these cells in a spatial and temporal manner for tissue growth and maintenance. Incorporation of these properties in scaffold development has generally relied on the development of novel polymers with reactive sites, amenable to modification for engraftment of bioactive elements, or with sites incorporated in the backbone for enzymatic degradation. Additionally, the incorporation of gene delivery elements into the scaffold has great potential to enhance the interplay between cells and the extracellular milieu.
Many polymeric carriers are amenable to conjugation of cell-specific ligands, theoretically allowing for targeted transgene expression. Coordinated delivery of multiple genes can be used to aid in multi-cellular tissue development, with each gene affecting different aspects and stages of tissue growth and development. Therapeutic genes can also be utilized to enhance incorporation of a tissue construct once implanted in vivo and enhance growth and assimilation with neighboring tissues.
This review will discuss the current status of use of natural polymers for gene delivery, with a special focus towards research with applications in tissue engineering. Although a majority of gene delivery systems are based on synthetic polymers, natural polymers have the advantage of having the intrinsic property of environmental responsiveness via degradation and remodeling by cell-secreted enzymes. They are also generally non-toxic, even at high concentrations, and therefore can readily be incorporated into oral delivery or bolus matrix delivery systems.
Natural polymers have been applied to a wide range of gene therapeutics, from nanoparticulates to three-dimensional scaffolds. Nano- and micro-scale particles have been applied to oral and intramuscular delivery successfully as non-viral gene therapy systems. These particulates can be modified with proteins, such as KNOB or transferrin, or antibodies/antigens to allow for cell-specific targeting and enhanced gene transfer. As derivatives of extracellular matrix components, natural polymers can function as not only DNA complexing agents but structural scaffolds for tissue engineering applications as well. This combination of gene therapy and tissue engineering within a single system can result in a powerful synergism of treatment options for regenerative medicine.
Section snippets
Cationic polymers as DNA complexing agents
A DNA complexing agent is commonly used in non-viral gene therapy systems [8], [9]. Although naked DNA transfer is feasible, especially in vivo [10], there are many benefits to complexation of DNA by a cationic lipid or polymer. This review will focus on natural polymers as gene carriers. In condensing the anionic DNA into compact nanoparticles, the polymeric gene carrier can provide protection from DNAses and prolong the bioavailability of the incorporated DNA, upon introduction into an
Utility of matrix-mediated gene therapy
The delivery of gene therapeutics within a matrix allows for the provision of a unique opportunity to control the environment in which gene transfer occurs. Foremost, the matrix allows for localized delivery and retention at the site of implantation. This is valuable in controlling the types of cells that will come into contact with this matrix and eventually receive the transgene. Systemic delivery may not be favorable, for example, in cases where the given gene is tissue specific. In
Discussion and concluding remarks
The application of gene therapy towards tissue engineering holds great promise. Genetic modification of cells can allow for control of cell fate and function, especially in light of the current explosion of the use of stem cells in tissue engineering applications. Sequential, transient control of gene expression in these stem cells and other supportive cells, one can, in theory, simulate an environment akin to the cascade of growth factor and transcription factor induction that occurs during
Acknowledgments
The authors acknowledge the support of NIH (EB003447) and Division of Johns Hopkins in Singapore (A⁎STAR of Singapore).
References (82)
Engineering blood vessels from stem cells: recent advances and applications
Curr. Opin. Biotechnol.
(2005)- et al.
Bioreactor design for tissue engineering
J. Biosci. Bioeng.
(2005) - et al.
Synthetic extracellular matrices for tissue engineering and regeneration
Curr. Top. Dev. Biol.
(2004) - et al.
Recent advances in non-viral gene delivery
Adv. Genet.
(2005) - et al.
Development of non-viral vectors for systemic gene delivery
J. Control. Release
(2002) - et al.
Delivery of plasmid DNA expressing small interference RNA for TGF-beta type II receptor by cationized gelatin to prevent interstitial renal fibrosis
J. Control. Release
(2005) - et al.
Intranasal IFN-gamma gene transfer protects BALB/c mice against respiratory syncytial virus infection
Vaccine
(1999) - et al.
DNA-polycation nanospheres as non-viral gene delivery vehicles
J. Control. Release
(1998) - et al.
Mechanism of cell transfection with plasmid/chitosan complexes
Biochim. Biophys. Acta
(2001) - et al.
In vitro gene delivery mediated by chitosan. effect of pH, serum, and molecular mass of chitosan on the transfection efficiency
Biomaterials
(2001)
Mesenchymal stem cells, MG63 and HEK293 transfection using chitosan–DNA nanoparticles
Biomaterials
Chitosan–DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency
J. Control. Release
Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency
J. Control. Release
Chitosan nanoparticles containing plasmid DNA encoding house dust mite allergen, Der p 1 for oral vaccination in mice
Vaccine
Expression and immunogenicity of the major house dust mite allergen Der p 1 following DNA immunization
Vaccine
Atelocollagen for protein and gene delivery
Adv. Drug Delivery Rev.
Evaluation of collagen and methylated collagen as gene carriers
Int. J. Pharm.
Delivery and expression of pDNA embedded in collagen matrices
J. Control. Release
Gene transfer by DNA–gelatin nanospheres
Arch. Biochem. Biophys.
Tissue engineering via local gene delivery: update and future prospects for enhancing the technology
Adv. Drug Delivery Rev.
Sustained effects of gene-activated matrices after CNS injury
Mol. Cell. Neurosci.
Combination of porous hydroxyapatite and cationic liposomes as a vector for BMP-2 gene therapy
Biomaterials
Enhanced neovasculature formation in ischemic myocardium following delivery of pleiotrophin plasmid in a biopolymer
Biomaterials
Characterization of DNA-hyaluronan matrix for sustained gene transfer
J. Control. Release
Delivery of a vector encoding mouse hyaluronan synthase 2 via a crosslinked hyaluronan film
Biomaterials
Hyaluronan microspheres for sustained gene delivery and site-specific targeting
Biomaterials
Adenovirus encoding human platelet-derived growth factor-B delivered in collagen exhibits safety, biodistribution, and immunogenicity profiles favorable for clinical use
Molec. Ther.
Engineering of tooth-supporting structures by delivery of PDGF gene therapy vectors
Molec. Ther.
BMP gene delivery for alveolar bone engineering at dental implant defects
Molec. Ther.
Delivery of FGF genes to wound repair cells enhances arteriogenesis and myogenesis in skeletal muscle
Molec. Ther.
Barriers to non-viral gene delivery
J. Pharm. Sci.
Endosomes, lysosomes: their implication in gene transfer
Adv. Drug Delivery Rev.
Intracellular trafficking and transgene expression of viral and non-viral gene vectors
Adv. Drug Delivery Rev.
Structure/property studies of polymeric gene delivery using a library of poly(beta-amino esters)
Molec. Ther.
Formation and intracellular trafficking of lipoplexes and polyplexes
Molec. Ther.
Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics
Tissue Eng.
Bioengineered tissues: the science, the technology, and the industry
Orthod. Craniofac. Res.
'Smart' delivery systems for biomolecular therapeutics
Orthod. Craniofac. Res.
Biology of developmental and regenerative skeletogenesis
Clin. Orthop. Relat. Res.
Progress and prospects: naked DNA gene transfer and therapy
Gene Ther.
Gene delivery in bone tissue engineering: progress and prospects using viral and non-viral strategies
Tissue Eng.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Gene Delivery for Tissue Engineering”, Vol. 58/4, 2006.