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In 2017, cell biologist Penney Gilbert at the University of Toronto in Canada and her colleagues discovered a clue 1. Certain receptor proteins on muscle stem cells respond differently to their binding partners depending on whether the underlying growth substrate is soft or stiff. Cells, it seems, can tune their responses to stimuli according to the physical properties of their environment.

Cells are surrounded by the extracellular matrix (ECM), a cocktail of proteins, signalling molecules and chemicals gas symptoms that cells exude as they grow. Gilbert had previously reported that the stiffness of a cell’s ECM influenced the ability of muscle stem cells to self-renew; the 2017 work suggested a mechanism by which the ECM directed this process.

Cells use the matrix to impart strength and shape to tissues such as bone or brain. As a result, scientists had long dismissed the ECM as just a scaffold — like a garden trellis — that cells use for support. They now know that the matrix plays an active part in cellular behaviour. Cues from the ECM can guide stem cells to repair damaged tissues, re-form blood vessels damaged by a stroke and alter cellular responses to chemotherapy.

“If you asked anybody 25 years ago about the function of the extracellular matrix, they would’ve said it was structural,” says bioengineer Stephen Badylak of the University of Pittsburgh in Pennsylvania. “Now it’s the opposite: it’s recognized as a reservoir of signalling molecules that serves as a sort of information highway between cells.”

The ECM is inspiring developments in cell culture, bioengineering and more, resulting in materials that better reflect how cells live and behave in tissues. Many of the materials are being gas near me app used in the clinic for regenerative medicine. In the laboratory, researchers use them to understand how the matrix can influence cells, and how to improve engineered ECMs. But using them can be tricky. Working out the best matrix for an experiment is one of the biggest hurdles to someone starting out, Gilbert says. “Each synthetic or naturally derived biomaterial has different pros and cons, and homing in on the system that best meets your needs is a current challenge.” Taken from tissues

Until the 1980s, cells were thought to control their surrounding matrix. But to Mina Bissell, a cell biologist now at the Lawrence Berkeley National Laboratory in California, the conversation between cells and matrix seemed more bidirectional. In 1982, she proposed the then-controversial idea that the matrix communicated with a cell’s nucleus to direct its functions 2. The right ECM, she and others found, could drive mouse mammary cells to make milk and rat liver cells to make enzymes. By tweaking the matrix, even mutation-carrying tumour cells could be made to act like healthy cells.

Decellularized materials can be powdered and reconstituted into hydrogels to form potent therapeutics. Once injected into the body, such a hydrogel “reassembles into a structure electricity and magnetism pdf that’s very similar to the original in terms of pore size, fibre diameter and biochemical cues”, Christman says. Such materials have been used to heal tendon tears, rotator-cuff injuries and burned skin, for example.

Matrices from the pig small intestine, bladder or dermis, for example, can all repair human skeletal muscle. But for the oesophagus, only an ECM from the same tissue will suffice. And in the central nervous system, a foreign matrix works better than a nervous system one. Badylak’s team found that urinary bladder ECM stimulates neuronal stem cells to proliferate better than an ECM derived from the central nervous system 3.

Whatever its source, each batch of decellularized material is unique, and must be tested to ensure all cells gas pump heaven have been removed, Christman says, as well as for its mechanical and signalling properties. But that’s sometimes easier said than done: researchers aren’t always sure which properties of decellularized materials — tensile strength, polymer chemistry or ligand composition — actually trigger specific cellular functions.

At the Max Planck Institute for Molecular Biomedicine in Münster, Germany, bioengineer Britta Trappmann has found that matrix stiffness, degradability and ‘stickiness’ can all spur cells that form blood vessels to switch between multicellular and single-cell modes of migration 4. Single cells quickly invade new regions, but the multicellular mode is needed so cells can collectively form a blood vessel. Ideally, bioengineers would be able to design tissue electricity usage by appliance implants that direct which mode cells use.

The chemical palette for such matrices typically includes the natural polymers collagen and hyaluronan, as well as synthetic versions such as polyethylene glycol or polyvinylidenefluoride–trifluoroethylene; the choice depends on the biological question, Gilbert says. When studying whether a matrix made of hyaluronan could improve survival rates for muscle stem cells injected into tissues, Gilbert’s team found that hyaluronan confounded the data because, rather than helping cells adhere to other proteins, the polymer itself bound to cell-surface receptors 5.

How these polymers are turned into scaffolds also varies. Treena Arinzeh, a biomedical engineer at the New Jersey Institute of Technology in Newark, studies how mechanical forces can trigger electric currents that influence stem-cell differentiation. Arinzeh uses electrospinning, in which a voltage is applied to a jet of polymer ejected from a syringe, to create sheets of fibres in which spacing and size can be precisely controlled at the nanoscale level 6. The sheets are stacked to form 3D structures, which Arinzeh has used to study how certain stem cells differentiate in a defined matrix.

Artificial matrices are also being tested for clinical use. Bioengineer Tatiana Segura at Duke University in Durham, North Carolina, developed a material based on hyaluronan that is studded with nanoparticles bearing vascular endothelial growth factor. When injected into mouse brains that had been damaged to replicate a stroke, the gel polymerized into a hydrogel that filled the cavity left by the stroke damage 7. Creating an implant that precisely fits the shape of the cavity is tricky, but injecting a liquid that solidifies in situ could solve the problem. Importantly, the gel promoted blood-vessel formation, which is “really important in the context of brain repair gas or electricity more expensive”, Segura says. Studying cellular functions

Mooney says that when developing an ECM, whether naturally derived or synthetic, researchers need to consider first its composition — which protein ligands should be present, their density and their affinity to cellular receptors — and then its mechanical properties, such as elasticity, stiffness, shape and whether these physical attributes change over time.

Because cells typically grow more slowly in 3D cultures than in 2D ones, Mooney’s team often grows the cells in 2D before moving them to 3D. But Mooney suggests asking yourself whether a 3D culture is even necessary. Cultures grown in 3D are difficult and time-consuming, and from a biological standpoint, certain aspects of cell behaviour “can be very readily b games virus and appropriately modelled in a 2D culture”, he says.

Cells in 2D cultures can be collected from the surface and used in standard protocols for techniques such as gene-expression analyses and enzyme assays; with 3D cultures, “you need to get rid of the matrix to access cells”, Mooney says. Adding a chelating chemical to bind calcium can dissolve some gels, and enzymes can be used to digest matrix materials.

For biomedical engineer Jennifer Leight at Ohio State University in Columbus, matrices are tools for studying the enzymes that cells use to digest and rebuild the ECM. “There are not a lot of ways to study things that cells secrete into the matrix,” says Leight, who works on matrix metalloproteinases (MMP), enzymes that cells secrete to degrade collagen during growth and tissue turnover.

Questions about how implanted materials assemble and degrade in vivo also linger. Segura, for example, can measure the polymer properties of the hydrogel injected into a mouse brain affected by a stroke. But because the dead tissue left behind after a stroke contains cell debris and various fluids, the hydrogel in the lab is “not at all what actually gets polymerized in vivo”, Segura says. And it’s impossible to visualize what happens in the depths of the brain. “We can only make sure that what we inject is the same every time.”

When speaking electricity symbols and meanings to researchers starting out with ECMs, Gilbert says their most frequent question is ‘what’s the best biomaterial for my experiments?’ There’s no easy answer. “You don’t typically see side-by-side comparisons to be able to say, this is the advantage of this material over that one,” she says, “That makes it hard to really home in on the best choice.”