Degradation of partially oxidized alginate and its potential application for tissue engineering.

Alginate has been widely used in a variety of biomedical applications including drug delivery and cell transplantation. However, alginate itself has a very slow degradation rate, and its gels degrade in an uncontrollable manner, releasing high molecular weight strands that may have difficulty being cleared from the body. We hypothesized that the periodate oxidation of alginate, which cleaves the carbon-carbon bond of the cis-diol group in the uronate residue and alters the chain conformation, would result in promoting the hydrolysis of alginate in aqueous solutions. Alginate, oxidized to a low extent (approximately 5%), degraded with a rate depending on the pH and temperature of the solution. This polymer was still capable of being ionically cross-linked with calcium ions to form gels, which degraded within 9 days in PBS solution. Finally, the use of these degradable alginate-derived hydrogels greatly improved cartilage-like tissue formation in vivo, as compared to alginate hydrogels.

Hydrogels for combination delivery of antineoplastic agents.

The systemic delivery of anticancer agents has been widely investigated during the past decade but localized delivery may offer a safer and more effective delivery approach. We have designed and synthesized a novel hydrogel to locally deliver antineoplastic agents, and demonstrate the different types of release that can be achieved from these hydrogels using three model drugs: methotrexate, doxorubicin, and mitoxantrone. Alginate was chemically modified into low molecular weight oligomers and cross-linked with a biodegradable spacer (adipic dihydrazide) to form biodegradable hydrogels. The model antineoplastic agents were loaded into the hydrogel via three different mechanisms. Methotrexate was incorporated within the pores of the hydrogel and was released by diffusion into the surrounding medium. Doxorubicin was covalently attached to the polymer backbone via a hydrolytically labile linker and was released following the chemical hydrolysis of the linker. Mitoxantrone was ionically complexed to the polymer and was released after the dissociation of this complex. These three release mechanisms could potentially be used to deliver a wide selection of antineoplastic agents, based on their chemical structure. This novel delivery system allows for the release of single or combinations of antineoplastic agents, and may find utility in localized antineoplastic agent delivery.

Promoting angiogenesis in engineered tissues.

There is a tremendous need for organs and tissues to replace those lost due to diseases or trauma. In theory, transplanting cells on biomaterial matrices can create functional tissue. A critical question, however, is how to supply cells embedded within large cell-polymer constructs with sufficient oxygen and nutrients to sustain their survival and proliferation, and allow for the integration of the developing tissue with the surrounding tissue. A rapid and high level of vascularization of transplanted polymer-cell matrices is essential in tissue engineering approaches to meet these challenges. This review summarizes the current approaches and materials under development in our laboratory to promote angiogenesis in engineered tissues.

Sustained and controlled release of daunomycin from cross-linked poly(aldehyde guluronate) hydrogels.

We have incorporated daunomycin, an antineoplastic agent, into a biodegradable hydrogel through a labile covalent bond. In brief, sodium alginate was chemically broken down to low molecular weight and followed by oxidation to prepare poly(aldehyde guluronate). Adipic dihydrazide was used to incorporate the drug into the polymer backbone and cross-link the polymer to form hydrogels. Daunomycin can be released from the hydrogel after the hydrolysis of the covalent linkage between the drug and the polymer. A wide range of release profiles of daunomycin (e.g., from 2 days to 6 weeks) has been achieved using these materials, and the biological activity of the released daunomycin was maintained.

In vitro and in vivo models for the reconstruction of intercellular signaling.

A critical need in both tissue-engineering applications and basic cell culture studies is the development of synthetic extracellular matrices (ECMs) and experimental systems that reconstitute three-dimensional cell-cell interactions and control tissue formation in vitro and in vivo. We have fabricated synthetic ECMs in the form of fiber-based fabrics, highly porous sponges, and hydrogels from biodegradable polymers (e.g., polyglycolic acid) and tested their ability to regulate tissue formation. Both cell seeding onto these synthetic ECMs and subsequent culture conditions can be varied to control initial cell-cell interactions and subsequent cell growth and tissue development. Three-dimensional tissues composed of cells of interest, matrix produced by these cells, and the synthetic ECM (until it degrades) can be created with these systems. For example, smooth muscle cells can be grown on polyglycolic acid fiber-based synthetic ECMs to produce tissues with cell densities in excess of 10(8) cells/mL. These tissues contain extensive elastin and collagen, and the smooth muscle cells within the tissue express the contractile phenotype (e.g., alpha-actin staining). Similar approaches can be used to grow a number of other tissues (e.g., dental pulp) that resemble the native tissue. These engineered tissues may provide novel experimental systems to study the role of three-dimensional intercellular signaling in tissue development and may also find clinical application as replacements to lost or damaged tissues.