A team from the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has published a new method for encapsulating single cells within tunable microgels based on alginates from brown seaweed.1 This, it is hoped, could greatly boost the efficacy of cell-based therapies and tissue engineering.
These hydrogels were already known as an effective material for manipulating cells and tissues due to their biocompatibility and the ability to tune their mechanical and biochemical properties to match physiological conditions inside the body. Past studies have shown them to influence the differentiation of stem cells, incite immune attacks on cancer cells, and weaken tumors' resistance to chemotherapy, among other things.
However, because the hydrogels are several millimetres wide, they are prone to becoming surrounded by thick scar tissue that blocks the biological signals of islet cells and renders the implant ineffective. For this reason, their use has been largely restricted to controlling groups of cells at large rather than individual ones.
What is new here is the use of a microfluidic method for encapsulating single cells in microscale hydrogels. As a result, the encapsulated cells consist of 40% cell and 60% hydrogel layer and are only 4% of the volume of the larger capsules. The process leads to far fewer empty capsules and is also very fast, encapsulating 1,000 cells/second inside one microfluidic channel.
The researchers claim multiple advantages. Smaller cells like these can be delivered intravenously, which opens up new vistas for the treatment cancers, tissue injuries and some immune disorders. The thinner hydrogel layer means that the cells can get into action faster and they also have a better chance of surviving against the body’s attempts to clear itself of them after injection. All this, the team claims, “sets the stage for a dramatic increase in the specificity of control that can be exerted upon cells and their ability to survive implantation.”
The breakthrough came by combining the expertise of David Mooney, Professor of Bioengineering at SEAS, in tissue engineering and biocompatible hydrogels with that of Professor David Weitz, Professor of Physics and Applied Sciences at Harvard and SEAS, in using 'designer' emulsions inside microfluidic devices to encapsulate active materials.
As with previous techniques, they coated cells in calcium carbonate nanoparticles to facilitate cell encapsulation when mixed with an alginate polymer solution. A new next step, washing away those nanoparticles that had not adhered to cells using a water and oil emulsion inside a microfluidic device before mixing with a polymer solution, left mainly microgel-encapsulated single cells behind.
As a result, Mooney claims, researchers will be able to study the ability of biomaterials to determine cell function and fate at single-cell level rather than on entire populations of cells, as in the past, thus enabling them to influence cell behavior at a totally different scale. Consequently, the method could improve cell-based therapies, help explore heterogeneity between cell populations or even revolutionise tissue engineering in treatments for conditions like diabetes and Parkinson's disease, enabling mini-tissues to be formed via cell-by-cell construction, with greater control over their composition than was hitherto possible.
There will certainly be more to come soon, because tunable microgels have been the subject of considerable research in academia in recent years. In Ireland, for instance, teams from multiple universities led by Dr Dilip Thomas of National University of Ireland Galway have recently published research concluding that a tunable, shape-controlled, collagen-based microgel platform can be used to deliver human mesenchymal stem cells at a low cell dose for angiogenesis in vivo.3
Meanwhile, inter-disciplinary researchers from the world of physics and material science, functional photonics and mechanical engineering at two universities in Hong Kong last year published a paper on the use of microgel beads for the co-delivery of multiple and sometimes incompatible drugs at individual release rates.4
This claimed to be one of the first studies to adopt microfluidic electrospray technology to generate microgel beads of such versatility. The technique was used to fabricate alginate-based multi-compartment microgel beads, using cadmium-telluride quantum dots and a quenching agent as a model pair. The beads effectively separated incompatible drugs during co-delivery and significantly prolong the time of observable fluorescence emission from the dots. Moreover, the drug release rates from different compartments can be tuned using the polymer blending technique to achieve a variety of drug release patterns.
- Mooney, D. Weitz, A. Mao & J.-W. Shin, Nature Materials
- Wyss Institute, Press release: Making Every Cell Matter, 31 October 2016
- D. Thomas et al., 10th World Biomaterials Congress, Montréal, Canada, 17-22 May 2016 (http://www.frontiersin.org/10.3389/conf.fbioe.2016.01.00756/event_abstract)
- W.-Fu Lai, A.S. Susha & A.L. Rogach, ACS Appl. Mater. Interfaces 2016, 8(1), 871–880