Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

Abstract

Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

Strategies for controlling egress of therapeutic cells from hydrogel microcapsules

“…Following 48 hr of encapsulation, hMSCs remain viable (>70%). However, HUVEC and rEPC viability drops dramatically after 24 hr, similar to reports in agarose–gelatin cocoons (Mak et al, ). HUVECs are regulated by a number of growth factors and signalling proteins and do not fare well cultured in isolation (Heng et al, ).…”

“…Large‐volume cell‐encapsulation methods (vortex and macroscale droplet formation; Karoubi et al, ; Mak et al, ; Mak et al, ) produce highly heterogeneous microcapsules that result in a large number of free (non‐encapsulated) cells, limiting the protection offered by encapsulation prior to injection in a therapeutic application. In contrast, droplet microfluidic systems offer reproducible encapsulation of therapeutic cells by allowing for control over size, enhanced yield, and increased consistency from batch to batch.…”

“…Recently, microcapsules of agarose incorporating fibrinogen and fibronectin have been shown to increase the viability of therapeutically delivered mesenchymal stromal cells (Hakimzadeh, Stewart, & Courtman, ; Karoubi, Ormiston, Stewart, & Courtman, ) and cardiac stem cells (Davis & Stewart, ; Kanda et al, ; Mayfield et al, ) in animal models. Combinations of agarose and gelatin have also been exploited for their different phase transition temperatures in an effort to improve cell viability and egress (Mak et al, ; Mak, Magne, Cheung, Atanasova, & Griffith, ). Whether or not agarose encapsulation alone can be effectively tuned for controlling egress efficiency and timed release of various therapeutic cells remains to be seen.…”

Development of a tunable method to generate various three-dimensional microstructures by replenishing macromolecules such as extracellular matrix components and polysaccharides

“…With the emulsion method, many capsules can be produced simultaneously, but some cells are damaged due to contact with oil. The encapsulation process resulted in cell death rates of approximately 20% and 30% in human fibroblasts and human umbilical vein endothelial cells, respectively 42 . Because encapsulation using MC medium was able to significantly prevent cytotoxicity (Fig.…”

Correction: W.C. Mak, et al. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules. J. Funct. Biomater. 2015, 6, 439–453

“…Recently, we found a mistake in Figure 4D in our previously published paper [ 1 ], which we would like to correct. In brief, the images for Figure 4D at time 12 h are incorrect and should be replaced as shown below ( Figure 1 ).…”