Printed GelMA Hydrogel Construct

Hydrogel Chemistry & Crosslinking – Part 3

Although it’s instantly recognized from the food industry, gelatin is used in a wide variety of applications – from photography to food to pharmaceuticals.  Industrially, gelatin is produced on a large scale and in tightly controlled processes – annual global production is over 300 million kilograms (Transparency Market Research 2013).

Thermally crosslinked hydrogels

It’s thermal gelation properties are well known from Jell-O, and this responsiveness to temperature change is also a useful property for certain biomedical applications. When a solution of gelatin cools, the protein polymers coil together to form twisted, helical structures, which results in the mixture solidifying. Other naturally-derived and synthetic hydrogel materials show similar temperature sensitivity – for example gellan gum (which can also be crosslinked ionically), agarose, polymers of N-isopropylacrylamide (NiPAAM) and Poloaxomer 407, which is more commonly known from its trade name, Pluronic F127. In the case of Pluronic F127, sol-gel transition occurs during heating – that is, the polymer solution is in a liquid state at low temperatures, and forms a thermally crosslinked hydrogel as it is warmed.

Relevance for additive biomanufacturing

Thermal crosslinking of hydrogels is reversible, and normally thermal crosslinking is not strong enough to be used on its own – other, more stable crosslinking mechanisms are normally also required. In the field of 3D bioprinting, in which a hydrogel structure is built using additive manufacturing, thermoresponsive hydrogels are commonly used. An example using modified gelatin, called GelMA is shown above. In this example, the 3D structure is built by extruding a GelMA solution through a needle, and is mixed with hyaluronic acid (HA) to increase the viscosity. As the GelMA/HA solution passes through the needle and onto the build stage, it cools, and in doing so, forms a solid gel structure. Mixing with HA or other high viscosity additives is not essential – Billiet et al have demonstrated printing of GelMA on its own (Billiet et al. 2014).

Permanent Crosslinking

Once the structure is complete, it can be further crosslinked using light to make the printed 3D structure retain its shape permanently. So if the structure is heated, the permanent crosslinks hold the structure together – so, for example, if it was then implanted, it would retain its printed shape and structure.

Read the previous article in this series. Next Up: Enzymatic Crosslinking


Billiet, Thomas, Elien Gevaert, Thomas De Schryver, Maria Cornelissen and Peter Dubruel. 2014. “The 3D printing of gelatin methacrylamide cell-laden tissue-engineered constructs with high cell viability.” Biomaterials 35: 49-62.

Schuurman, Wouter, Peter A. Levett, Michiel W. Pot, Paul René van Weeren, Wouter J. A. Dhert, Dietmar W. Hutmacher, Ferry P. W. Melchels, Travis J. Klein and Jos Malda. 2013. “Gelatin-Methacrylamide Hydrogels as Potential Biomaterials for Fabrication of Tissue-Engineered Cartilage Constructs.” Macromolecular Bioscience 13 (5): 551-561. doi: 10.1002/mabi.201200471.

Transparency Market Research. 2013. Gelatin Market by Raw Material (Pig Skin, Bovine Hide, Bones and Others) for Food & Beverage, Nutraceuticals, Pharmaceuticals, Photography, Cosmetics and Other Applications – Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2012 – 2018.