Controlled release from fibers of polyelectrolyte complexes

https://doi.org/10.1016/j.jconrel.2005.02.013Get rights and content

Abstract

Controlled release systems for delicate compounds, such as proteins, often suffer the drawbacks of decreased bioactivity and low encapsulation efficiency. This study introduces the concept of producing drug-loaded fibers from interfacial polyelectrolyte complexation. Chitosan–alginate fibers were produced by pulling from the interface between two polyelectrolyte solutions at room temperature. Depending on the component properties, the release time of encapsulated components from these fibers can range from hours to weeks. Dexamethasone was completely released within 2 h, whereas charged compounds such as BSA, PDGF-bb, and avidin showed sustained release for 3 weeks. The fibers were able to release PDGF-bb in a steady fashion for over 3 weeks without an initial burst. Furthermore, the bioactivity of PDGF-bb was retained over this period. Release kinetics could be controlled by the inclusion of heparin, which contains specific binding sites for various growth factors. By varying the alginate/heparin ratios in the anionic polyelectrolyte solution, the release of PDGF-bb could be significantly altered. In this study, interfacial polyelectrolyte complexation has been demonstrated to be a promising technique for producing drug-loaded fibers with high encapsulation efficiency, sustained release kinetics, and capacity to retain the bioactivity of the encapsulants.

Introduction

The choice of scaffolds in engineering tissues in vitro often determines the degree of success in achieving the functional properties of the tissue of interest. A scaffold should ideally promote attachment, migration, proliferation, and differentiation of cells uniformly throughout the scaffold [1]. To achieve this, scaffolds must have certain physical characteristics such as high porosity, structural integrity, defined pore size, and controlled degradability. Furthermore, the scaffold should provide the optimal biochemical microenvironment for the seeded cells. Many of the bioactive agents critical to stimulating cellular activities are delicate proteins that are difficult to incorporate into a scaffold.

Proteins can be delivered in a local and sustained manner in biomaterials through the use of microparticles, emulsion coating, and hydrophobic or charge interactions with the scaffold [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Poly(lactic-co-glycolic acid) (PLGA) microspheres, one of the most widely studied delivery systems, for example, can achieve adjustable burst release of hormones, growth factors, and DNA [4], [5], [7], [8]. Polyphosphoester (PPE) microspheres have also been used to release nerve growth factor for over 70 days in vitro and shown to enhance the regeneration of sciatic nerve in a rat model [2]. However, development of protein delivery systems faces the challenges of low incorporation efficiencies [2], [4], high burst kinetics [5], [8], loss of bioactivity [4], and multi-step synthesis processes [5], [9], [10]. Specific to cell culture and tissue engineering applications is the difficulty of uniform distribution of the controlled release microspheres in a 3D scaffold. If the protein can be uniformly encapsulated in a fiber, then such fibrous scaffolds would be able to present the biological signal in a temporally and spatially controlled manner.

Typical fiber fabrication techniques involve the use of high temperature or organic solvents, rendering them undesirable for protein encapsulation. Yamamoto et al. has described the process of interfacial polyelectrolyte complexation in forming fibers, where they produced fibers based on chitosan and gellan for textile applications [14] and as adsorbers of endocrine disruptors [15]. Polyelectrolyte complexation (PEC) is a self-assembly process that occurs when two oppositely charged polyelectrolytes come together. The removal of the complex from the interface of the polyelectrolyte solutions can result in the formation of a fiber. This fiber formation takes place under aqueous conditions and at room temperature, rendering encapsulation of bioactive agents feasible. Recent publication shows that this process of fiber formation is applicable for the encapsulation of various biologically active agents as well as cells [16].

The interaction between chitosan and alginate has been exploited to produce different biomaterials in the form of microcapsules, hydrogels, films and foams [17], [18], [19]. Iwasaki et al. has produced fibers from the complexation of chitosan and alginate for cartilage tissue engineering [20]. However, no effort has been made to study the drug delivery capability from polyelectrolyte fibers. This study proposes to control the release properties of drugs and proteins from polyelectrolyte complex fibers composed of chitosan and alginate. Protein encapsulation efficiency and release kinetics are function of the complex composition and fiber drawing condition and inclusion of heparin. The encapsulation process does not require complicated processing steps. However, the molecule of interest must have ionic charge groups in order to achieve sustained drug delivery. This study indicates that the polyelectrolyte complex fiber could be an effective drug carrier with the potential advantages of high encapsulation efficiency, high loading level, sustained release profile and retention of the activity of biomacromolecules.

Section snippets

Materials

Three types of polyelectrolytes were used in this experiment. Chitosan derived from crab shells (Mη = 3 × 105, degree of deacetylation = 85%) was used as the cationic polyelectrolyte. Low viscosity alginic acid sodium salt from brown algae (60 M: 40 G units) and heparin sodium salt (MW = 4000–6000) derived from porcine intestinal mucosa were used as the anionic polyelectrolytes. Five different encapsulants were studied: dexamethasone (min. 98%, HPLC grade), recombinant human platelet derived growth

Mechanism of drug incorporation

Drugs were incorporated into the chitosan–alginate fiber during the fiber production process via polyelectrolyte interactions. As the two polyelectrolytes formed a complex at the solution interface and were mechanically drawn into a fiber, the drug of interest could be trapped in the fibers via electrostatic interaction. Chitosan and alginate each have two ionic groups in their repeating units and the controlled drug releasing capability relies on the incomplete charge interactions between the

Discussion

Biomaterials in the form of fibers find applications in surgical sutures, woven medical devices such as vascular grafts, and tissue engineering scaffolds, among others. In particular, fibrous scaffolds are attractive for tissue engineering with inherent advantages of high surface area for cell attachment, controlled porous architecture, and a 3-D microenvironment for cell–cell contact. Optimal tissue engineering requires more than an inert scaffold to serve merely as a substrate for cell

Conclusion

Chitosan–alginate polyelectrolyte complex fibers have been shown to be a promising drug-releasing material that exhibits high encapsulation efficiency and sustained release of charged molecules. Electrostatic interaction between the fiber components and the charged encapsulants controls the release kinetics from the fiber. The exceptional characteristic of the chitosan–alginate polyelectrolyte complex fibers as a drug carrier for hydrophilic and charged molecules such as growth factors suggests

Acknowledgements

We would like to thank Catherine Le Visage for assistance with HPLC and Shawn H. Lim for helpful discussions.

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    Current address: Institute of Bioengineering and Nanotechnology 31 Biopolis Way, Singapore 13866.

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