The human intervertebral disc (IVD) is a complex organ composed of fibrous and cartilaginous connective tissues, and it serves as a boundary between 2 adjacent vertebrae. It provides a limited range of motion in the torso as well as stability during axial compression, rotation, and bending. Adult IVDs have poor innate healing potential due to low vascularity and cellularity. Degenerative disc disease (DDD) generally arises from the disruption of the homeostasis maintained by the structures of the IVD, and genetic and environmental factors can accelerate the progression of the disease. Impaired cell metabolism due to pH alteration and poor nutrition may lead to autophagy and disruption of the homeostasis within the IVD and thus plays a key role in DDD etiology. To develop regenerative therapies for degenerated discs, future studies must aim to restore both anatomical and biomechanical properties of the IVDs. The objective of this review is to give a detailed overview about anatomical, radiological, and biomechanical features of the IVDs as well as discuss the structural and functional changes that occur during the degeneration process.
Tissue-engineered intervertebral disc (TE-IVD) constructs are an attractive therapy for treating degenerative disc disease and have previously been investigated in vivo in both large and small animal models. The mechanical environment of the spine is notably challenging, in part due to its complex anatomy, and implants may require additional mechanical support to avoid failure in the early stages of implantation. As such, the design of suitable support implants requires rigorous validation.
Diabetes has long been implicated as a major risk factor for intervertebral disc (IVD) degeneration, interfering with molecular signaling and matrix biochemistry, which ultimately aggravates the progression of the disease. Glucose content has been previously shown to influence structural and compositional changes in engineered discs in vitro, impeding fiber formation and mechanical stability.
Abstract Invasion is a critical step in the metastatic process during which cells dissociate from the primary tumor to breach the basement membrane and migrate through the stroma. Successful invasion can then lead to other steps in the metastatic cascade such as intravasation through the vascular system to secondary sites, ultimately resulting in the spread of tumors throughout the body as well as a dramatic decrease in patient survival. Efficient migration through the extracellular matrix is a key determinant of a tumor cell's ability to invade local tissue and eventually metastasize to secondary sites. Previous work has indicated that the ability of cancer cells to migrate and therefore invade efficiently through the stroma is dependent on the microenvironment, which differs from its normal state in the presence of non-cancerous cells. Alterations to matrix properties such as fiber alignment, stiffness, and density may facilitate this migration. We have focused on how these properties impact the migratory abilities of cancer cells in in vitro models of the tumor microenvironment. There is significant evidence to suggest that the molecular mechanisms governing 2D migration are significantly different than those dictating migration in 3D matrices. In recent work, we have shown that in vivo, cells also migrate in pseudo-3D environments where they utilize preformed tunnels and interstitial spaces in the tissue to navigate through the stroma. To recreate these tunnels in vitro, we created and utilized a micromolded 3D system of patterned collagen microtracks to gain a more complete understanding of invasive migration. The consequences of altering matrix properties on cell behavior were then examined using this system and compared to the more commonly utilized 3D collagen matrix model. Results indicate that increasing collagen density affected single cell migration in 3D matrices but did not have a significant impact on average cell velocity in the microtracks, suggesting these cells migrate independently of density. These findings then raise the question of how important extracellular cues are in determining the behavior of cancer cells during track migration and how this influence changes depending on the state of the microenvironment. Since changes in collagen density affected migration in 3D matrices but not microtracks, it is worth determining if a similar trend is seen for stiffness. To this end, we utilized the in vitro microtrack system described above to investigate how single cell migration through tracks is affected by changes in extracellular stiffness. Collagen gels of varying stiffness were made through non-enzymatic glycation by allowing the gels to incubate in ribose solutions of different concentrations. The migration of cells through the tracks was quantified based on average cell velocities across the various conditions. Interestingly, the data indicate there is no significant difference in velocity with increasing stiffness. This is in contrast to 2D migration, where a similar change in stiffness causes an increase in cell velocity. These results suggest that either the change in stiffness is too subtle for the cells to detect within the tracks or they behave as they did in response to density, insensitive to alterations to either of these properties. When taken together with our previous published findings, the data suggest that while the tumor microenvironment is important in mediating malignancy and metastasis, it varies in its influence. Cells moving in microtracks, which offer the least resistance as they navigate through the extracellular matrix, may migrate independently of a variety of mechanical cues from the microenvironment that more closely regulate their migration in other contexts. Citation Format: Marianne Lintz. The role of extracellular stiffness in metastatic cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A51.
Public confidence in education has eroded. The authors discuss conceptual bases for school/community relations and, using data from a national study, describe how administrators of 181 “high-confidence” schools get and hold the public’s confidence in their schools. These administrators do nearly the opposite of what selected literature and studies suggest.
Metastasis is a dynamic process in which cancer cells navigate the tumor microenvironment, largely guided by external chemical and mechanical cues. Our current understanding of metastatic cell migration has relied primarily on studies of single cell migration, most of which have been performed using two-dimensional (2D) cell culture techniques and, more recently, using three-dimensional (3D) scaffolds. However, the current paradigm focused on single cell movements is shifting toward the idea that collective migration is likely one of the primary modes of migration during metastasis of many solid tumors. Not surprisingly, the mechanics of collective migration differ significantly from single cell movements. As such, techniques must be developed that enable in-depth analysis of collective migration, and those for examining single cell migration should be adopted and modified to study collective migration to allow for accurate comparison of the two. In this review, we will describe engineering approaches for studying metastatic migration, both single cell and collective, and how these approaches have yielded significant insight into the mechanics governing each process.
