Feb.11, 2014

Biomedical engineers in the United States have announced a unique micro-robotic technique to assemble the components of complex materials, bringing 3D-printed replacement organs even closer to reality.

The shortage of available organs for transplantation leaves many patients on lengthy waiting lists for life-saving treatment. Therefore tissue engineering and 3D printing have become vitally important to the future of medicine. Being able to engineer organs using a patient's own cells can not only alleviate this shortage, but also address issues related to rejection of donated organs. Tissue engineering allows researchers to study cell behavior, such as cancer cell resistance to therapy, and test new drugs or combinations of drugs to treat many diseases.

Researchers at Brigham and Women's Hospital (BWH) and Carnegie Mellon University, led by Savas Tasoglu, PhD, in the BWH Division of Renal Medicine, presented an approach that uses untethered magnetic micro-robotic coding for precise construction of individual cell-encapsulating hydrogels (such as cell blocks).

Micro-robotic creation of (ag) a three-layer heterogeneous pyramid structure consisting of 16, 4 and 1 gel on each layer, and (hl) a heterogeneous structure consisting of poly(ethylene glycol) dimethacrylate (PEG) hydrogels, which totally encase 100μm diameter copper cylinders and 200μm diameter polystyrene spheres. All the experiments were performed in a 20mm × 20mm × 4mm chamber in phosphate-buffered saline (PBS). Snapshots of manipulation stages are shown in each subfigure, with the completed structure shown in schematic form in (g) and (l), corresponding to panes (e) and (k), respectively. Gels were placed on the second layer by moving them over a polyester plateau, which is the same thickness as the first layer of gels. The third layer was reached in (d) by pushing the gels up a polyester ramp. The time points of images are: 2:45 (a), 12:48 (b), 19:24 (c), 21:19 (d), 22:28 (e), 25:22 (f), 0:00 (h), 3:40 (i), 13:36 (j) and 15:39 (k) in minutes:seconds format. Scale bar, 1mm.

The micro-robot, which is remotely controlled by magnetic fields, can move one hydrogel at a time to build structures. This is critical in tissue engineering, as human tissue architecture is complex, with different types of cells at various levels and locations. When building these structures, the location of the cells is significant in that it will impact how the structure will ultimately function.

"Compared with earlier techniques, this technology enables true control over bottom-up tissue engineering," explains Tasoglu.

Tasoglu and Utkan Demirci, PhD, MS, associate professor of Medicine in the Division of Biomedical Engineering also demonstrated that micro-robotic construction of cell-encapsulating hydrogels can be performed without affecting cell vitality and proliferation.

Further benefits may be realized by using numerous micro-robots together in bioprinting, the creation of a design that can be utilized by a bioprinter to generate tissue and other complex materials in the laboratory environment.

Micro-robotic coding of (af) square silicon chiplets into square and rod patterns, and (gl) hexagonal polydimethylsiloxane blocks into triangle and rod patterns. All the experiments were performed in a 20mm × 20mm × 4mm chamber. Snapshots of manipulation of 1mm × 1mm square silicon chiplets at different time points (shown at the left corner). The time stamp format is minutes:seconds. The magnetic micro-robots are shown in a blue circle (af). Black object in each image (gl) is top-view of the crawling magnetic micro-robot. Scale bar, 1mm.

"Our work will revolutionize three-dimensional precise assembly of complex and heterogeneous tissue engineering building blocks and serve to improve complexity and understanding of tissue engineering systems," said Metin Sitti, professor of Mechanical Engineering and the Robotics Institute and head of CMU's NanoRobotics Lab.

"We are really just beginning to explore the many possibilities in using this micro-robotic technique to manipulate individual cells or cell-encapsulating building blocks." says Demirci. "This is a very exciting and rapidly evolving field that holds a lot of promise in medicine."

Fluorescence images of National Institutes of Health (NIH) 3T3 mouse embryonic fibroblast cell-encapsulating hydrogels after the assembly of (a) T-shape, (b) square-shape, (c) L-shape and (d) rod-shape constructs. Scale bar, 500μm for (ad). Green represents live cells and red represents dead cells. (eg) Immunocytochemistry of proliferating cells stained with Ki67 (red), DAPI (blue) and Phalloidin (green) at day 4. (e) Cells stained with DAPI and Phalloidin at × 20 magnification. Scale bar, 100μm. (f) Cells stained with Ki67 and Phalloidin at × 20 magnification. Scale bar, 100μm. (g) Cells stained with Ki67, DAPI and Phalloidin at × 40 magnification. Scale bar, 40μm. (ag) Stainings were performed following the assembly of hydrogels. (hq) Two- and three-dimensional heterogeneous assemblies of human umbilical vein endothelial cells, 3T3 and cardiomyocyte-encapsulating hydrogels. HUVECs, 3T3s and cardiomyocytes are stained with Alexa 488 (green), DAPI (blue) and propidium iodide (red), respectively. (h) Bright field and (i) fluorescence images of an assembly composed of circular and triangular gels. (jo) Fluorescence images of several two-dimensional heterogeneous assemblies of HUVEC, 3T3 and cardiomyocyte-encapsulating hydrogels. (p) Schematic form and (q) fluorescence image of three-dimensional heterogeneous assembly of HUVEC, 3T3 and cardiomyocyte encapsulating hydrogels. Scale bar, 500μm for (hq). Stainings were performed before the assembly of hydrogels for (hq). Teleoperated assembly durations of (ad, hq) are ~10s to 5min depending on the complexity of the final shape. (r) MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a yellow tetrazole) assay results of 3T3 cell suspensions in which micro-robots were kept for 5, 20 and 60min durations. The positive control represents the cells that were incubated without any micro-robot presence. Results are normalized with day 0 absorbance values. Statistical analysis was only performed between positive control and (5, 20, 60) min cases. Brackets connecting groups indicate statistically significant difference (n=6, P<0.05). Error bars represent standard error of the mean.

Micro-robotic coding and reconfiguration of Poly(ethylene glycol) dimethacrylate hydrogels (ak) and gelatin methacrylate hydrogels (lt) with various shapes into complex planar constructs. The black object in each image is top-view of a crawling micro-robot. To demonstrate the precision of micro-robotic manipulation, gels with several shapes including square, triangle, circle, hexagon, bracket-shape, plus-shape and others were coded. All the experiments were performed in 20mm × 20mm × 4mm chamber in phosphate-buffered saline (PBS). Continuous coding and reconfiguring sequences are shown in panes (af), (g,h), (j,k), (lp) and (rt). Orientation and position control in untethered micro-robotic coding of material composition (uy). Snapshots of ‘tetris’-shaped PEG hydrogels in a rectangular reservoir at different time points: 2:08 (u), 8:32 (v), 16:12 (w), 31:39 (x), 48:00 (y) in minutes:seconds format. Orientation and position of incoming hydrogels were dynamically changed as the geometry of cavities dynamically changed. All the experiments were performed in a 20mm × 20mm × 4mm chamber. Scale bar, 1mm.


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