Issue I, Winter 2017

Welcome to the first edition of our Progenesis blog discussing the latest developments, applications and concerns pertaining to alginate and its technology. As a disclaimer, Progenesis is a company that is using genetic engineering to commercialize the use of bacterial alginates and to produce custom alginates not found in seaweed, the current commercial source of alginate. All the opinions expressed in these blogs are solely that of the company.

The technology of using alginate in tissue repair and engineering de novo tissue continues to evolve. Rodness, J., et al (Acta Biomater 2016 Nov; 45;169-181) approached the issue of revascularization of heart tissue after a heart attack by using growth factors that were delivered by hydrogel microspheres. They produced a chitosan sheet with compacted calcium alginate microspheres. In vitro, these restrained microspheres release bioactive VEGF into the supernatant for the entire duration of the study (5-days). Using an animal model of heart attacks, they found a 50% degradation of the chitosan patch 25+ days after implantation. What is quite interesting is that both VEGF containing and VEGF – negative alginate microspheres had better cardiac function relative to chitosan sheet only controls. However, the VEGF-containing microsphere patched hearts had higher capillary density around the border than VEGFnegative patches.

These results suggest that the presence of the microspheres, in the absence of any cytokine, improve cardiac function. An important question is whether the material composing the microsphere, in this case calcium alginate, is responsible for improving cardiac function. A comparison of microsphere hydrogels composed of different polymers is needed to answer this question. If the results of this type of experiment point to alginate as being responsible for improved cardiac function, then the exciting possibility is that the composition of the alginate polymer could further enhance cardiac function and most likely would affect the release of cytokines such as VEGF. Many other possibilities exist for development and use of custom design alginates including enhanced tensile strength and resistance to degradation, allowing longer times of release of bioactive material.

Another “hot” area of research is in production of living tissue through 3-D printing technologies. A recent review by Axpe and Oyen (Axpe, E., Oyen ML: Applications of Alginate-Based Bioinks in 3D Bioprinting, Int J Mol Sci 2016; 17:1976; doi:10.3390/ijms17121976) discusses the benefits and disadvantages of using alginate in 3D printing. This new technology allows the automated production of 3D tissues containing living cells in precise spatial locations in the layers of biocompatible material. A variety of hydrogels have been used for fabrication of these layers of artificial tissue including agarose, gelatin, hyaluronic acid, polyethylene glycol-diacrylate and alginate. Due to its cell growth support and biocompatibility, alginate has gained acceptance for use in printing these artificial tissues. However as pointed out by Axpe and Oyen, there are problems with the seaweed alginate used in this application. The hydrogel once printed should degrade in an appropriate time, allowing the cells to produce their own extracellular matrix. The degradation of alginate is slow and difficult to control. This is one of the major issues in using alginate in 3-D bioprinting. In addition, the extrusion process during printing, required the use of low molecular weight alginate gel, which unfortunately have poor mechanical properties.

Table 1 in this review article lists the problems with the use of alginate as a bioink, as well as the author’s suggested solutions. These include the immunogenicity of mannuronic acid, the need for fast gelation, and the slow degradation kinetics of alginate. The authors propose the solutions to these as: use of high G:M ratio alginate, using of multivalent cations such as calcium and tuning the weight percent and oxidation of the alginate respectively. The alterative to these solutions is the development of custom bacterial alginate polymers that have high G:M ratios, shorter in vitro degradation time and increased tensile strength by incorporation G block structure in the polymer. This latter modification could help in applications where the currently used seaweed alginate has poor mechanical properties.

The above discussed reports provide an insight into new applications of alginate in tissue engineering. They also highlight some of the properties of alginate that need to be improved to maximize its use in this field. In our next blog (Spring 2017) we will examine the potential effects of climate change on the current commercial source of alginate, brown seaweed.