Natural polymers for gene delivery and tissue engineering

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Abstract

Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.

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).

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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.

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