Bridging the Gap

The world can be a dangerous place. With more than 41 million visits to US emergency rooms due to trauma each year, it is crucial to study the process of wound healing and how medical intervention might facilitate it. A study led by Christopher Chen, a professor of biomedical engineering and materials science and engineering at the Boston University College of Engineering, points to a promising new direction researchers could use to better understand wound healing.

Chen and his research team, whose study was published in Nature Communications, have developed a three-dimensional microtissue culture that mimics the healing process more closely than the traditional two-dimensional culture of cells that researchers have long used.

“Healing wounds requires the human body to fill 3D spaces, so we reasoned that healing of wounded 3D microtissues would more closely resemble wound healing in the human body,” says Chen. “This finding has the potential to become the new standard to study wound healing in vitro.”

First, the research team bioengineered a unique cell culture system in which 3D microtissues are formed from wound-repairing cells called fibroblasts embedded in a matrix of collagen fibers, similar to how they exist in the human body. Next, the leading authors of the study—Selman Sakar from the Swiss Federal Institute of Technology in Lausanne and Jeroen Eyckmans, senior postdoctoral associate in Chen’s Tissue Microfabrication Lab—cut tiny holes in the microtissues and captured time-lapse videos of the reaction under a microscope. The images showed the fibroblast cells closing the gap and healing the tissue without any signs of scarring. The process of healing observed in these microtissues was surprisingly different from healing previously observed in cells cultured on traditional 2D surfaces.

“When we did the same molecular manipulations in a single-layer sheet of cells, key players that sped up healing in 3D actually slowed healing of the sheet,” says Eyckmans. “Also, the restoration of 3D tissue architecture that is absent in 2D but occurs in our microtissues is of high interest when thinking about how to induce tissue regeneration rather than scarring.”

Digging deeper, they looked at what might be happening with another scaffolding molecule called fibronectin, which plays a large role in wound healing. They found that the fibroblast cells were dismantling fibronectin present in microtissue and towing it into the wound, using it to build a bridge to connect to the opposite side of the gap. The fibroblast cells flocked to the bridge and began producing their own fibronectin, completely filling in the wound until the defect returned to its three-dimensional form, completely restoring the wounded tissue.

“What was most surprising was that the cells didn’t just move in to close up the hole; they remodeled the entire matrix, modifying their environment to close the gap,” says Eyckmans. “This provides a new approach to studying wound healing and standardizing this practice in research could lead to many important insights in this field.”

While this technology would not be directly incorporated into patient care, future work could be done to develop this model into a research tool to explore a variety of questions, from scar formation to how the process could impact the speed of wound healing to the role various stresses play in the healing process.