Live adaptation of organ models in the OR

The non-deformed liver model (red) adapts to the deformed surface profile (blue). Credit: Graphics: Dr. Stefanie Speidel, KIT, in Medical Physics, 41

During minimally invasive operations, a surgeon has to trust the information displayed on the screen: A virtual 3D model of the respective organ shows where a tumor is located and where sensitive vessels can be found. Soft tissue, such as the tissue of the liver, however, deforms during breathing or when the scalpel is applied. Endoscopic cameras record in real time how the surface deforms, but do not show the deformation of deeper structures such as tumors. Young scientists of the Karlsruhe Institute of Technology (KIT) have now developed a real-time capable computation method to adapt the virtual organ to the deformed surface profile.

The principle appears to be simple: Based on computer tomography image data, the scientists construct a virtual 3D model of the respective organ, including the tumor, prior to operation. During the operation, cameras scan the surface of the organ and generate a stiff profile mask. To this virtual mold, the 3D model then is to fit snuggly, like jelly to a given form. The Young Investigator Group of Dr. Stefanie Speidel analyzed this geometrical problem of shape adaptation from the physical perspective. "We model the surface profile as electrically negative and the volume model of the organ as electrically positive charged," Speidel explains. "Now, both attract each other and the elastic volume model slides into the immovable profile mask." The adapted 3D model then reveals to the surgeon how the tumor has moved with the deformation of the organ.

Simulations and experiments using a close-to-reality phantom liver have demonstrated that the electrostatic-elastic method even works when only parts of the deformed surface profile are available. This is the usual situation at the hospital. The human liver is surrounded by other organs and, hence, only partly visible by endoscopic cameras. "Only those structures that are clearly identified as parts of the liver by our system are assigned an electric charge," says Dr. Stefan Suwelack who, as part of Speidel's group, wrote his Ph.D. thesis on this subject. Problems only arise, if far less than half of the deformed surface is visible. To stabilize computation in such cases, the KIT researchers can use clear reference points, such as crossing vessels. Their method, however, in contrary to others does not rely on such references from the outset.

In addition, the model of the KIT researchers is more precise than conventional methods, because it also considers biomechanical factors of the liver, such as the elasticity of the tissue. So for instance, the phantom liver used by the scientists consists of two different silicones: A harder material for the capsule, i.e. the outer shell of the liver, and a softer material for the inner liver tissue.

As a result of their physical approach, the young scientists also succeeded in accelerating the computation process. As shape adaptation was described by electrostatic and elastic energies, they found a single mathematical formula. Using this formula, even conventional computers equipped with a single processing unit only work so quickly that the method is competitive. Contrary to conventional computation methods, however, the new method is also suited for parallel computers. Using such a computer, the Young Investigator Group now plans to model organ deformations stably in real time.

Source: Karlsruhe Institute of Technology

Mechanics of cells' long-range communication modeled by researchers

As fibrosis progresses, "bridges" of extracellular matrix appear between cells. Credit: Image courtesy of University of Pennsylvania

Interdisciplinary research at the University of Pennsylvania is showing how cells interact over long distances within fibrous tissue, like that associated with many diseases of the liver, lungs and other organs.

By developing mathematical models of how the collagen matrix that connects cells in tissue stiffens, the researchers are providing insights into the pathology of fibrosis, cirrhosis of the liver and certain cancers.

Tissue stiffness has long been know to be clinically relevant in these diseases, but the underlying changes that alter the mechanics of tissues are poorly understood. Consisting of a complex network of fibers, tissues have proven difficult to simulate and model beyond local, neighbor-to-neighbor interactions.

Developing a better understanding of the large-scale mechanical changes that occur over longer distances, specifically the process by which the extracellular matrix is pulled into compact, highly-aligned "bridges," could eventually form the basis of treatments for related diseases.

Vivek Shenoy, professor in the Department of Materials Science and Engineering in Penn's School of Engineering and Applied Science, has led an interdisciplinary research team to tackle this problem, authoring a pair of papers that were published in Biophysical Journal.

One, "Remodeling of Fibrous Extracellular Matrices by Contractile Cells: Predictions from Discrete Fiber Network Simulations" involved developing simulations that extrapolated the overall remodeling of the extracellular matrix based on the behavior of neighboring pairs of cells. The other, "Long Range Force Transmission in Fibrous Matrices Enabled by Tension-Driven Alignment of Fibers," took a more mathematical approach, producing a coarse-grained model of this remodeling that could be more broadly applied to fibrotic tissue.

"We're trying to understand how force is transmitted in tissues," Shenoy said. "Cells are the ones that generate force, and it has to be transmitted through what surrounds the cell, the extracellular matrix, or ECM. But imagine trying to model the ECM by trying to keep track of each collagen fibril in your liver; there are tens of millions of those. So we're taking what we learn from simulating those networks to turn it into a model that captures the main features with only a few parameters.

"The key here is the mechanics," he said. "In particular, how does ECM, as a fibrous material, differ from solids, gels and other materials that are better studied."

Rebecca Wells, an associate professor in Penn's Perelman School of Medicine and a co-author on the latter paper, provided insight into the clinical relevance of the mechanics that characterize ECM-related disorders.

"Fibrosis occurs when you have an injury and the tissue responds by depositing ECM, forming scar tissue," Wells said. "In liver fibrosis, the liver can stiffen by up to an order of magnitude, so measuring stiffness is a common diagnostic test for the disease. Increased stiffness also occurs in cancer, where tumors are typically stiffer than the surrounding tissue."

Existing experimental evidence showed that mechanical forces were at play in the changes in both fibrosis and cancer and that these forces were important to their development and progression but could not explain the long-ranging changes cells were able to produce to change their environments. When put in tissue-simulating gels, cells can deform their immediate surroundings but are unable to pull on more distant cells. In real, ECM-linked tissue, however, cells' range of influence can be up to 20 times their own diameter.

"If you look at a normal tissue," Shenoy said, "you see the cells are more rounded, and the network of ECM fibers is more random. But as cancer progresses, you see more elliptical cells, more ECM, and you see that the ECM fibers are more aligned. The cells are the ones generating force, so they're contracting and pulling the fibers, stretching them out into bridges."

"That's also the pathology of cirrhosis," Wells said. "My group had been looking at the early mechanical changes associated with liver fibrosis, which progresses to cirrhosis, but then, by collaborating with Vivek, we started to wonder if these large scale changes in the architecture of the liver could have a mechanical basis and if something similar to what is seen in gels might be occurring in the liver. This is a new way of approaching the problem, which has largely been thought of as biochemical in origin. And there are other tissues where it is probably the same thing, the lung, for example."

The researchers found that the critical difference between the existing models and ECM's long-range behavior was rooted in its elastic properties. Materials with linear elasticity cannot transmit force over the distances observed, but the team's simulations showed that nonlinear elasticity could arise from the ECM's fibrous structure.

"In our model, every component is linearly elastic," Shenoy said, "but the collective behavior is nonlinear; it emerges because of the connectivity. When you deform the network, it's easy to bend the 'sticks' that represent collagen fibers but hard to stretch them. When you deform it to a small extent, it's all the bending of the fibers, but, as you deform further, it can't accommodate bending any more and moves over to stretching, forming the bridges we see in the tissue."

Such simulations can't predict which fibers will end up in which bridge, necessitating the coarser-grained model the researchers described in their second paper. By showing the point at which linear elasticity gives way to its nonlinear counterpart, the team produced a more complete picture of how the alignment of collagen bridges under tension transmit force between distant cells.

Further studies are needed to elucidate the feedback loops between ECM stiffening and cell contraction strength. The team is conducting physical experiments to confirm and refine their in silico findings.

"Right now," Wells said," we're hypothesizing that the mechanical interactions modeled by the Shenoy lab explain aspects of cancer and fibrosis, and we're developing the experimental systems to confirm it with real cells."

Source: University of Pennsylvania