A soft microrobot uses light driven motion, temperature sensing, and localized heating to control single cells inside 3D cancer microtissues, improving precision in drug testing and tissue engineering.
(Nanowerk Spotlight) The search for better laboratory models of human tissue pushed researchers toward systems that act more like real tumors and organs. Early studies relied on flat layers of cells on rigid plastic where conditions were uniform and predictable. These cultures revealed basic biology but could not reproduce the uneven structures and shifting chemical conditions that shape disease. When scientists turned to spheroids and organoids, they gained access to small three-dimensional clusters of cells with crowded interiors and realistic gradients.
These constructs created more lifelike behavior, yet they formed through chance contact among cells. Sizes varied. Interiors could lose oxygen and fail while outer layers kept growing. Experiments built on these systems often changed in unpredictable ways because the underlying structures did not form in a consistent manner.
Engineers introduced tools that helped but did not fully solve the problem. Hydrogels offered soft networks that support cells. Three-dimensional printing arranged living cells and biomaterials in controlled layouts. Microfluidic systems delivered steady flows and shaped chemical changes. These methods improved structure and environment but did not allow a researcher to reach inside a dense spheroid and act on one cell without altering the rest. They also lacked a practical way to sense temperature or heat a tiny region inside crowded tissue.
Early microrobots moved through liquid and carried cells or particles, yet many relied on rigid materials or required magnetic fields and other conditions that did not work well inside tight cellular spaces. They could manipulate cells or apply force, but they could not sense the environment or control local temperature with fine precision.
A research team at Technical University of Munich published a study in Advanced Materials (“A Soft Microrobot for Single‐Cell Transport, Spheroid Assembly, and Dual‐Mode Drug Screening”) that introduces a soft microrobot that addresses these limitations by combining motion, cell transport, controlled heating, and temperature sensing inside realistic 3D cancer microtissues. This device, called TACSI which stands for thermally activated cell signal imaging, is a sphere of alginate hydrogel about 30 micrometers wide.
Conceptual overview of the microgel and microrobot biointegration process for single- and 3D-cell experiments. A fluorescence microscope is set up with a 785 nm laser source for photothermal actuation. TACSI microrobots and scaffold microgels enable single-cell adhesion, subsequent transport, and manipulation. Self-assembledmicrotumors facilitate 3D cell experiments for thermally gated ion channel activation, cell-to-cell communication, and cancer invasion studies. (Image: Reproduced from DOI:10.1002/adma.202508807, CC BY) (click on image to enlarge)
Alginate is a natural polymer that forms a soft network in the presence of calcium. Part of its structure is modified with a short protein fragment known as RGD that helps cells attach. Another part carries Rhodamine B which is a fluorescent dye that brightens or dims with temperature. Gold nanorods embedded in the sphere absorb near infrared light and convert it into heat. This blend of materials turns TACSI into a soft microrobot that can warm its surroundings and measure temperature changes with spatial resolution on the scale of single cells.
The team makes these microrobots using a microfluidic device. A water solution with alginate, RGD modified alginate, Rhodamine B modified alginate, and fine calcium carbonate particles flows through a narrow channel and forms droplets. These droplets enter an oil phase that contains acetic acid. The acid dissolves calcium carbonate. Calcium ions then crosslink the alginate and form a stable hydrogel sphere. Some spheres remain transparent and serve as scaffold microgels. Others contain gold nanorods and become active TACSI microrobots.
A version called μTACSI adds a thin coating of poly L lysine which carries positive charge and binds to the negatively charged surface of cells. This coating enables single-cell pickup that occurs as soon as the microrobot touches a target.
Motion occurs through light induced heating. A 785-nanometer laser warms the microrobot and the fluid near it. The temperature difference creates thermophoretic convection which is a flow that moves liquid from cooler areas toward warmer ones. This flow pushes or lifts the microrobot depending on where the laser is aimed. Steering the laser along different parts of the microrobot surface shifts its direction of travel. The paper describes upward motion and planar motion but does not quantify exact speeds, so the effect is kept qualitative here. The same flow pattern allows indirect control of nearby scaffold microgels which move in response to the fluid currents.
The μTACSI variant attaches to cells through both electrostatic attraction from the poly L lysine coating and receptor binding from the RGD sequence. In tests with human fibrosarcoma cells, the microrobot approaches a target, makes contact, and forms a stable link without external force. It can then gather additional cells and reposition them within the workspace. TACSI without the coating cannot hold cells under the same conditions. Attached cells remain healthy, later detach, and migrate in normal patterns observed in control samples.
These microrobots also support the assembly of spheroids that contain built in sensing and actuation. The team mixes cells, scaffold microgels, and TACSI in a tube and lets the mixture settle. Cells attach to the microgels to a depth of almost 7 micrometers which creates a firm mechanical connection. The mixture compacts into spheroids with smooth circular outlines once it includes at least 20 microgels and 400 cells. When the spheroids are dissociated with enzymes, the microgels return to their original size which shows that they were compressed by surrounding cells but not damaged. Cell viability stays above 95 percent in spheroids built with scaffold microgels, TACSI, or combinations of both for at least 72 hours.
Rhodamine B provides real-time temperature sensing. Its brightness changes in a linear way between 37 and 60 degrees Celsius. Adjusting laser current raises TACSI core temperature from about 47.5 degrees to about 78 degrees. Inside spheroids, a single microrobot heated to about 60 to 65 degrees produces a steep gradient. The temperature drops by about 15 degrees at a distance of 20 micrometers from its surface. This pattern forms a narrow region of high heat close to the microrobot and much cooler layers only a short distance away. The gradient makes it possible to expose cells to precise thermal doses inside complex living structures.
The researchers then measure cell responses using a calcium sensitive dye. A short heating pulse that lifts nearby cells to almost 49 degrees produces a marked rise in intracellular calcium followed by a return to baseline within several seconds. Scans across a broad temperature range reveal thresholds near 46 and 52 degrees that align with known activation points of heat sensitive ion channels.
Temperatures above about 54 degrees produce stronger calcium changes and slower recovery. Cells near TACSI often lose normal function under these conditions while cells farther away continue to respond and regain function.
Experiments in flat cultures show related patterns. Brief heating at about 50 to 53 degrees produces mild stress. Heating at 59 degrees triggers strong heat shock responses and slows cell division. Higher temperatures or longer exposure drive clear signs of apoptosis. These findings give a detailed map of how thermal dose shapes cell behavior.
The researchers also test TACSI in combination with chemotherapy. Spheroids placed in collagen gels extend invasive branches into the surrounding matrix. Short heating periods at 53, 56, or 59 degrees reduce this movement slightly. A low dose of doxorubicin produces a similar effect. When the treatments act together, invasion distance and cell viability drop more sharply.
Longer mild heating at 53 degrees causes invasive structures to pull back even in areas below direct thermal stress which suggests that stressed cells influence neighboring cells. When μTACSI is placed on the spheroid surface and heated during drug exposure, it forms a pocket in the collagen and kills adjacent cells while distant cells respond according to the local thermal dose.
This study presents a soft microrobot able to reposition cells, shape spheroids, map temperature at micrometer resolution, and deliver controlled heating inside dense microtissues. The platform works with standard microscopes and culture plates and connects physical manipulation with biological signaling. Its capabilities point toward practical tools that organize cell structures and test therapies inside living models with spatial precision that current methods cannot match.
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