Scientists develop acellular nanocomposite living hydrogels

A biomaterial that can mimic certain behaviors within biological tissues could advance regenerative medicine, disease modeling, soft robotics and more, according to researchers at Penn State.

Materials created up to this point to mimic tissues and extracellular matrices (ECMs)—the body’s biological scaffolding of proteins and molecules that surrounds and supports tissues and cells—have all had limitations that hamper their practical applications, according to the team. To overcome some of those limitations, the researchers developed a bio-based, “living” material that encompasses self-healing properties and mimics the biological response of ECMs to mechanical stress.

They published their results in Materials Horizons, where the research was also featured on the cover of the journal.

“We developed a cell-free—or acellular—material that dynamically mimics the behavior of ECMs, which are key building blocks of mammalian tissues that are crucial for tissue structure and cell functions,” said corresponding author Amir Sheikhi, associate professor of chemical engineering and the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biomaterials and Regenerative Engineering.

According to the researchers, previous iterations of their material—a hydrogel, or water-rich polymer network—were synthetic and lacked the desired combination of mechanical responsiveness and biological mimicry of ECMs.

“Specifically, these materials need to replicate nonlinear strain-stiffening, which is when ECM networks stiffen under strain caused by physical forces exerted by cells or external stimuli,” Sheikhi said, explaining nonlinear strain-stiffening is important for providing structural support and facilitating cell signaling.

“The materials also need to replicate the self-healing properties necessary for tissue structure and survival. Prior synthetic hydrogels had difficulties in balancing material complexity, biocompatibility and mechanical mimicry of ECMs.”

The team addressed these limitations by developing acellular nanocomposite living hydrogels (LivGels) made from “hairy” nanoparticles. The nanoparticles are composed of nanocrystals, or “nLinkers,” with disordered cellulose chains, or “hairs,” at the ends.

These hairs introduce anisotropy, meaning the nLinkers have different properties depending on their directional orientation and allow dynamic bonding with biopolymer networks. In this case, the nanoparticles bonded with a biopolymeric matrix of modified alginate, which is a natural polysaccharide found in brown algae.

“These nLinkers form dynamic bonds within the matrix that enable strain-stiffening behavior, that is, mimicking ECM’s response to mechanical stress; and self-healing properties, which restore integrity after damage,” Sheikhi said, noting that the researchers used rheological testing, which measures how material behaves under various stressors, to measure how rapidly the LivGels recovered their structure after high strain. “This design approach allowed fine-tuning of the material’s mechanical properties to match those of natural ECMs.”

Critically, Sheikhi said, this material is entirely made of biological materials and avoids synthetic polymers with potential biocompatibility issues. Beyond mitigating the limitations of previously developed materials, LivGels achieve the dual traits of nonlinear mechanics and self-healing without sacrificing structural integrity. The nLinkers specifically facilitate dynamic interactions that allow precise control of stiffness and strain-stiffening properties. Taken together, the design approach converts bulk, static hydrogels to dynamic hydrogels that closely mimic ECMs.

The potential applications include scaffolding for tissue repair and regeneration within regenerative medicine, simulating tissue behavior for drug testing and creating realistic environments for studying disease progression. The researchers said it could also be used for 3D bioprinting customizable hydrogels or for developing soft robotics with adaptable mechanical properties.

“Our next steps include optimizing LivGels for specific tissue types, exploring in vivo applications for regenerative medicine, integrating LivGels with 3D bioprinting platforms and investigating potential in dynamic wearable or implantable devices,” Sheikhi said.

Roya Koshani, a chemical engineering post-doctoral scholar at Penn State, and Sina Kheirabadi, a doctoral candidate in chemical engineering at Penn State, were co-authors on the paper. Sheikhi is also affiliated with the Departments of Biomedical Engineering, of Chemistry and of Neurosurgery, and with the Huck Institutes of the Life Sciences.