Rapid Cancer Diagnosis and Early Prognosis of Metastatic Risk Based on Mechanical Invasiveness of Sampled Cells.

We provide an innovative, bioengineering, mechanobiology-based approach to rapidly (2-h) establish the in vivo metastatic likelihood of patient tumor-samples, where results are in direct agreement with clinical histopathology and patient outcomes. Cancer-related mortality is mostly due to local recurrence or to metastatic disease, thus early prediction of tumor-cell-fate may critically affect treatment protocols and survival rates. Metastasis and recurrence risks are currently predicted by lymph-node status, tumor size, histopathology and genetic testing, however, these are not infallible and results may require days/weeks. We have previously observed that subpopulations of invasive cancer-cells will rapidly (1-2 h) push into the surface of physiological-stiffness, synthetic polyacrylamide gels, reaching to cell-scale depths, while normal or noninvasive cells do not considerably indent gels. Here, we evaluate the mechanical invasiveness of established breast and pancreatic cell lines and of tumor-cells from fresh, suspected pancreatic cancer tumors. The mechanical invasiveness matches the in vitro metastatic potential in cell lines as determined with Boyden chamber assays. Moreover, the mechanical invasiveness directly agrees with the clinical histopathology in primary-site, pancreatic-tumors. Thus, the rapid, patient-specific, early prediction of metastatic likelihood, on the time-scale of initial resection/biopsy, can directly affect disease management and treatment protocols.

Injectable hydrogels with high fixed charge density and swelling pressure for nucleus pulposus repair: biomimetic glycosaminoglycan analogues.

The load-bearing biomechanical role of the intervertebral disc is governed by the composition and organization of its major macromolecular components, collagen and aggrecan. The major function of aggrecan is to maintain tissue hydration, and hence disc height, under the high loads imposed by muscle activity and body weight. Key to this role is the high negative fixed charge of its glycosaminoglycan side chains, which impart a high osmotic pressure to the tissue, thus regulating and maintaining tissue hydration and hence disc height under load. In degenerate discs, aggrecan degrades and is lost from the disc, particularly centrally from the nucleus pulposus. This loss of fixed charge results in reduced hydration and loss of disc height; such changes are closely associated with low back pain. The present authors developed biomimetic glycosaminoglycan analogues based on sulphonate-containing polymers. These biomimetics are deliverable via injection into the disc where they polymerize in situ, forming a non-degradable, nuclear "implant" aimed at restoring disc height to degenerate discs, thereby relieving back pain. In vitro, these glycosaminoglycan analogues possess appropriate fixed charge density, hydration and osmotic responsiveness, thereby displaying the capacity to restore disc height and function. Preliminary biomechanical tests using a degenerate explant model showed that the implant adapts to the space into which it is injected and restores stiffness. These hydrogels mimic the role taken by glycosaminoglycans in vivo and, unlike other hydrogels, provide an intrinsic swelling pressure, which can maintain disc hydration and height under the high and variable compressive loads encountered in vivo.