Advances in 3D tissue engineering have helped biomedical researchers design and test therapies for a wide range of diseases with increasing speed and accuracy. Now, a new easily adopted device, developed by a team of University of Washington investigators, will enable scientists to create models of human tissue with even greater control and complexity.
The overarching goal of tissue engineering is to create lab-made environments that recreate the natural habitats of cells. One method that is popular with researchers at the Institute for Stem Cells and Regenerative Medicine (ISCRM) and many other institutions around the world involves suspending cells in a 3D gel between two free standing posts. This modeling platform has been used to grow engineered heart, lung, skin, and musculoskeletal tissues.
While this approach allows cells to behave as they would inside the body, these models are mostly homogeneous and have so far not enabled researchers to easily study multiple tissue types together. More precise control over the composition and spatial arrangement of tissues in an experiment would make it possible for scientists to model complex diseases more accurately and to carefully study border regions where healthy and diseased tissues meet or where bones and ligaments connect.
Mechanical Engineering and Chemistry Labs Team Up to Improve Tissue Engineering
In an exciting breakthrough, researchers from the University of Washington have published a paper in the journal Advanced Science detailing a new platform that provides tissue engineers with the ability to examine how cells respond to various mechanical and physical cues, while creating distinct regions in a suspended tissue. The 3D-printed device unveiled in the study is known as STOMP (Suspended Tissue Open Microfluidic Patterning).
In the paper, a team of scientists led by Ashleigh Theberge, PhD and Nate Sniadecki, PhD show that STOMP, which is designed to be compatible with existing two-post modeling tools developed by the Sniadecki Lab, can be used to recreate important biological interfaces like bone and ligament or fibrotic and healthy heart tissue.
Dr. Sniadecki is a professor of mechanical engineering and an interim co-director of the Institute for Stem Cell and Regenerative Medicine. Dr. Theberge is a professor of chemistry. The first authors of the paper are Lauren Brown, a PhD student, and Amanda Haack, PhD, a postdoc and MD/PhD student. ISCRM faculty members Cole DeForest, PhD, a professor of chemical engineering and bioengineering, and Tracy Popowics, PhD, a professor of oral biology, are also authors of the paper.
According to the researchers, STOMP enhances a method of tissue engineering called casting, which they compare in simple terms to making Jello. Imagine pouring the ingredients into a removable mold which gives the substance its form, then pulling the mold back without altering the shape of the dessert before it is served. In the lab, the “Jello” is a mixture of living and synthetic materials, which are pipetted into a frame rather than poured into a mold. STOMP uses capillary action (think of water flowing up a straw that has been inserted in a glass) to allow scientists to space out different cell types in whatever pattern an experiment requires, similar to someone in a kitchen adding evenly spread pieces of fruit to Jello.
In the investigation, the researchers put STOMP to the test in two experiments. In one aspect of the study, work done by Alex Goldstein, a PhD student, they demonstrated that having diseased and healthy engineered heart tissues led to different contractile dynamics than homogenous tissues. As further proof of concept, Priti Mulimani, MDS, PhD, successfully modeled the periodontal ligament, the fibrous joint that connects the tooth to the surrounding bone in the jaw.
Opening Up New Possibilities in Cell Signaling Research
The STOMP device, which is about the size of a fingertip, docks on to the two-post system originally developed by the Sniadecki Lab to measure the contractile force of heart cells. The tiny piece of hardware contains an open microfluidic channel with geometric features that allow researchers to manipulate the spacing and composition of different cell types, and to create multiple regions within single suspended tissue, all without requiring additional equipment or capabilities.
Additionally, hydrogel technology developed in the DeForest Research Group allowed the team to soup up STOMP with another design feature: degradable walls. Asha Viswanathan and Serena Nguyen, two undergraduate students in the Theberge Lab, adapted a degradable hydrogel known as PEG (polyethylene glycol) as a building material. The upshot is that tissue engineers using STOMP can essentially degrade the walls of the device and leave the tissues intact.
Sniadecki emphasizes the significance of the degradable walls. “Normally when you put cells in a 3D gel, they will use their own contractile forces to pull everything together, which causes the tissue to shrink away from the walls of the mold. But not every cell is super strong and not every biomaterial can get remodeled like that. So that kind of non-stick quality was pretty important to give us more versatility.”
Dr. Theberge is excited for how other teams will use STOMP: “This method opens new possibilities for tissue engineering and cell signaling research. It was a true team effort of multiple groups working across disciplines.”
As a tissue engineering tool, STOMP could be useful for a wide range of topics, including neuromuscular research. ISCRM faculty member Alec Smith, PhD is a research assistant professor of neurobiology and biophysics. Dr. Smith has used the two-post suspension platform to model neuromuscular junctions in his lab’s effort to study neuromuscular diseases. He speaks to the added value that STOMP brings.
“The ability to spatially control the deposition of multiple cell types within a single engineered tissue has great potential for enhancing our ability to generate neuromuscular tissues in vitro. Our lab is excited to work with the STOMP system to see how the technology can be employed to promote greater levels of neuromuscular junction formation, thereby enhancing our capacity to model disease phenotypes and screen novel therapeutics.”
Indeed, the capabilities offered by STOMP meet a demand within the tissue engineering community. “We’ve had a lot of people reach out,” says Brown.” I think something that most people who are using casting techniques are really excited about is the way STOMP integrates into their existing system.”
Acknowledgements:
This publication was supported by the National Institutes of Health (NIH)through R35GM128648 (A.B.T.), R35GM138036 (C.A.D.), R01HL149734, R03DE029827 (T.E.P., N.J.S.), T32CA080416 (I.K.), F30HL158030(A.J.H.), R90DE023059 (P.M.), 5TL1TR002318-08 (L.G.B.), a diversity supplement to R35GM128648 (E.E.B.), and the University of Washington. This work was partially supported by Friends of FSH Research and The Chris Carrino Foundation for FSHD (L.G.B.) and fellowship funds from Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center – Seat-tle (NIAMS P50AR065139) (L.G.B.). This work was also partially funded by a gift to support research from Ionis Pharmaceuticals (A.B.T., L.G.B.,A.J.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders