How the Environment Around Collagen Shapes Its Growth

Collagen is ubiquitous in the human body, forming the fibrous scaffolding that gives tissues — from skin and bone to tendons and fascia — much of their strength and structure. Collagen also plays a role in the progression of diseases such as fibrosis and cancer, making an increased understanding of its formation critical in fighting these conditions.

But collagen doesn’t assemble in isolation. Its ability to form the large, organized fibers that shape tissues depends in part on the physical environment around it. 

In order to better understand the environmental factors that influence collagen formation, a team led by Kyle Vining, Assistant Professor in Preventative and Restorative Science at Penn Dental Medicine with a secondary appointment in Materials Science and Engineering (MSE) at Penn Engineering, together with co-first authors Asal Tavakoli Joorabi, a doctoral student in MSE, and Nicholas Derr, a former instructor in Applied Mathematics at Massachusetts Institute of Technology (MIT), conducted experiments that offer a new way to think about how the extracellular matrix (ECM), the complex network of proteins and other molecules surrounding cells, participates in tissue formation and remodeling. 

The group’s discovery was published in Science Advances and included work by collaborators from the University of Wisconsin-Madison and Lawrence Berkeley National Laboratory.

“Collagen is the most abundant structural protein in the human body, so understanding how it builds the scaffolding of our tissues is fundamental,” says Vining. “What we show is that collagen doesn’t just assemble on its own, it has to grow within the physical environment around it, and properties like how easily that environment can deform or allow things to move through it can determine how large and organized those collagen structures become.”

“Our bodies are full of incredibly complicated systems that arise through complex processes,” adds Derr. “It is often difficult to understand how cell and tissue properties arise from first principles, much less reproduce those effects. This work shows that collagen formation, despite its complexity, can be indirectly controlled by tuning the properties of its surroundings.”

The findings offer a new way to think about how collagen remodeling contributes to diseases like fibrosis and cancer, while also providing principles for designing biomaterials that can control collagen structure for tissue engineering and regenerative medicine.

Building Collagen Inside a Molecular Mesh

The team wanted to understand how an existing extracellular matrix affects collagen assembly. Rather than changing the collagen itself, as previous studies have often done, the researchers kept the collagen constant and changed only the properties of the material surrounding it.

They built an artificial ECM using alginate, a natural material that forms a soft, water-rich gel. By controlling how the alginate molecules were connected, the researchers could create environments that were relatively permissive, allowing the network to rearrange and relax, or more restrictive, making it harder for the material to move and accommodate growing collagen structures.

The experimental design was particularly important. The researchers first formed the alginate network at 4 degrees Celsius, when collagen remains unassembled. They then raised the temperature to 37 degrees Celsius, triggering collagen assembly inside the already-existing network.

“Collagen doesn’t assemble in empty space,” says Tavakoli. “It has to grow within tissue that is already there. We found that when the surrounding material could move and make room, collagen formed larger fiber networks. But when the surrounding material was more restricted and couldn’t easily rearrange, collagen fiber formation was limited.”

Growing Inside a Molecular Cage

The researchers’ results can be understood by imagining collagen trying to build a tree inside a crowded net.

Individual collagen molecules are long compared with the tiny spaces in the surrounding network. As they join together into larger structures, the growing collagen fibers eventually become much larger than those pores, forcing them to push against and deform the material around them.

“If the mesh can stretch, shift and loosen, the branches can continue growing outward and eventually form a large network,” says Tavakoli. “But if the mesh has been tightly tied together and cannot move, the growing branches become trapped and their growth is restricted.”

The experiments showed this effect. More permanently crosslinked alginate networks were more restrictive and suppressed the formation of large collagen fibers, while more dynamic networks allowed collagen to assemble into larger, thicker structures.

Importantly, stiffness alone did not tell the whole story. The researchers found that materials that could relax and allow water and molecules to move through the network were more supportive of collagen growth. More restrictive materials retained stress and limited collagen assembly.

Mechanical confinement shapes collagen assembly. In this mechanically restrictive environment, collagen was unable to extend into the long fibers we typically observe. Instead, the surrounding matrix constrained its growth, causing the collagen to assemble locally into this heart-shaped structure.

A Two-Way Relationship

The findings suggest that collagen and the extracellular matrix have a more dynamic relationship than the traditional picture of collagen simply being deposited into a passive scaffold.

That two-way relationship could be particularly important in diseases such as fibrosis and cancer, where the ECM is extensively remodeled. In fibrosis, excessive collagen deposition and crosslinking can stiffen tissue. In tumors, changes in collagen organization can influence how cancer cells move through surrounding tissue.

“The way collagen and its scaffolding interact is a feedback loop,” says Tavakoli. “The matrix remodeling changes tissue mechanics, those mechanics influence how new collagen can assemble, and the resulting collagen architecture can further change the mechanics of the tissue.”

While this study does not directly test this process in cancer or living tissue, it provides a mechanistic hypothesis that can now be investigated in more biologically complex systems.

From Materials Science to Cancer Biology

“This project really required several interdisciplinary fields because the question sits at the intersection of biology, materials science, mechanics, imaging and mathematical modeling,” says Tavakoli. “No single technique could have answered the question. We needed to connect what we saw in the collagen to what the material was doing mechanically and then ask whether a physical model could explain both.”

The team also developed computer simulations to test whether the physical restrictions of the surrounding network could explain the experimental results. The model simulated how growing collagen interacts with the surrounding network and predicted that more restrictive environments would slow collagen assembly and limit the size of the structures that form.

The model matched the experimental observations, providing a physical explanation for why changing the surrounding material — without changing the collagen itself — could dramatically alter collagen organization.

“The interesting thing about this work is how we are showing that the collagen structure can be programmed into the material just by tuning the properties of the gel,” says Vining. “This means we have a knob to turn off collagen fibers or increase collagen fibers without needing input from cells or other external cues.”

Asal Tavakoli Joorabi presenting the foundations of this work at the American Cancer Society Fall meeting in August, 2025.

What Happens in Living Tissue?

The next challenge is determining whether the same mechanism operates in actual tissues, where cells are constantly producing, degrading and reorganizing the ECM. The researchers are particularly interested in whether cells actively remodel their surroundings to make them permissive for new collagen assembly.

“The biggest remaining question is how cells reorganize their matrix in response to biophysical cues,” says Vining. “There are no cells in this study. The next step would be investigating how cells, organoids or tumors remodel and reorganize the matrix.”

Learn more about the work being done in Kyle Vining’s lab here.

The Vining Lab group

This work was supported by the National Institute of Dental & Craniofacial Research of the National Institutes of Health (NIH) under Award Numbers R00DE030084 and L70DE035343, the National Institute of General Medical Sciences of the NIH under Award Number R35GM157079 and the National Science Foundation (NSF) through the University of Pennsylvania Materials Research Science and Engineering Center were partially supported by the NSF under Grant Nos. DMS-1753203 and DMS-2427204. This work was carried out in part at the Singh Center for Nanotechnology, which is supported by the NSF National Nanotechnology Coordinated Infrastructure Program under grant NNCI-2025608.