BIO-MECHANICAL ENGINEERING: BENCH TO BEDSIDE
The ultimate goal of the mechbio research program is to decipher how cells use mechanical signals, intrinsic to life on Earth, to self-assemble tissues, organs and organisms and to apply that knowledge to improve the quality of life through development of new technologies as well as clinical treatments and prophylactic measures. Previous work focused on mechanically modulated transport in nature. Currently, we are applying insights from our previous two decades of research to understand and harness nature’s development and healing capacities with the ultimate goal to apply nature’s paradigm to develop and manufacture novel mechanoactive materials including tissues. A hallmark of the mechbio research program is its integration of basic science and fundamental mechanical engineering with multiscale biology, physiological applications and clinical translation.
MECHANICALLY MODULATED TRANSPORT IN NATURAL BIOSYSTEMS
Mechanical loads play a key role in maintaining osteocyte viability via bone fluid flow enhanced transport of nutrients and waste products to and from the blood supply. Using innovative methods in an ex vivo sheep model, an in vivo rat model, and an in vitro bone culture model, team mechbio showed experimentally that mechanical loading drives extravascular fluid flow through bone. Furthermore, the mechbio team demonstrated that fluid movement resulting from mechanical loading enhances molecular transport from the blood supply to osteocytes, thus playing a key role in osteocyte viability, which has important clinical implications for healing and aging bone. In addition, the mechbio team developed computer models to predict flow patterns under conditions simulating those applied in in vivo and in vitro experimental models. By comparing the predictions of such models with actual experimental data, we explicated the relationship between mechanical loading parameters and fluid dynamics in bone, bridging the gap in understanding between the fluid and solid mechanobiological environment at the scale of the skeleton, bone tissue, and cells within bone. In sum, this work helped to form a global picture of fluid flow, osteocyte viability and bone remodeling that brought a new perspective in understanding the governance of functional adaptation and repair of bone tissue in health and disease. We continue this work, developing and testing multiscale models, in a collaboration with Professors Iwona Jasiuk and Pratap Vanka at the University of Illinois Champaign-Urbana and Professor Roy Aaron at Brown University.
HARNESSING NATURE’S REGENERATIVE POWER – STEM CELL MECHANICS
Structure – function relationships are ubiquitous throughout Nature, across length and time scales. Our working hypothesis is that already at earliest stages of life, mechanical function inherent to life in Earth’s gravitational environment modulates the self-assembly of structure by cells to form multicellular structures. Similarly, during prenatal development and postnatal healing, mechanical stress modulates tissue modeling and remodeling. Furthermore, prior to and during tissue formation, mechanical stress likely modulates the determination of cell fate, e.g. when multipotent stem cells differentiate to the osteoblast and endothelial cell lineages. However, the role of mechanical cues in driving differentiation (fate determination) of stem cells is largely unknown. Our studies have shown that embryonic mesenchymal stem cells are quite sensitive to mechanical stress. By conditionally knocking out specific constituents of stem cells’ mechanosensing apparatus (beta-catenin, a transmembrane protein that anchors cell-cell adherens junctions to actin in the cytoskeleton), cells lose their capacity to self assemble structure (and hence tissues). Interestingly, studies of mesenchymal stem cells residing in the periosteum of adult sheep show mechanosensitivity similar to embryonic cells. Furthermore, mesenchymal stem cells resident in the periosteum of adult sheep exhibit the capacity to generate bone de novo in critical sized (2.54 cm) defects within two weeks. During development, different cell types, e.g. osteoblasts and endothelial cells, receive distinct mechanical cues. In this research thrust, we are studying the role of mechanics in the cell’s capacity to self-assemble structure. We exploit this knowledge to deliver mechanical signals that drive cell lineage during de novo formation of tissues during prenatal development and postnatal healing. We are continuing this work with targeted collaboration through Ludwig Maximilians University in Munich (Professor Stefan Milz and Dr. Denitsa Docheva), CIC BiomaGUNE in San Sebastian (Dr. Ralf Richter), and University of Paris Est (Professors Vittorio Sansalone, Thibault Lemaire).
APPLYING NATURE’S PARADIGM: NOVEL MECHANOACTIVE MATERIALS
Load-induced fluid flow behavior in bone provided the design inspiration for this novel class of mechanoactive materials. Certain combinations of anisotropic stiffness and permeability coefficients in a fluid-filled solid structure (poroelastic, e.g. bone) result in counterintuitive flow when the structure is subjected to tension or compression. Nonlinearities in flow and transport result when loading is asymmetrical (tension and compression are not balanced over the course of a cycle), boundary conditions are asymmetrical (area available for inflow or outflow) or uptake of the transported agent is factored in (ratchet effect). This R&D thrust area is envisioned as an application of nature’s mechanobiological paradigm for the development of widely applicable mechanoactive materials. We are developing and reducing to practice a new class of mechanically and/or biologically active materials that are tuned to harness the forces generated by natural movement to deliver agents to and route fluid away from the surface to which the material is attached (e.g. the skin). Application examples include mechanoactive wound dressings, biomedical implants, textiles, body armor and microfluidic valves/switches. The technology and associated applications have been protected through multiple Invention Disclosures, two Provisional Patents, and a Full Utility Patent filed through Case TTO.