Injuries to the rotator cuff (RC) joint account for over 4 million physician visits and 300,000 surgical repairs in the U.S. annually. Surgical treatment options are limited and often ineffective, however, with re-tear rates as high as 90%. These failures are due in part to the limited healing potential of the injured tissue, a scarcity of graf material, and an inability of currently available biologic tendon grafts to develop relevant mechanical properties. A potential solution to this problem is the use of tissue-engineered grafts that more closely recapitulate the structure and function of healthy native tendon. For tendon tissue engineering applications, aligned nanofiber scaffolds with topographical cues that mimic the collagen fibers of native tendon have been shown to promote tendon-specific differentiation, cell morphologies, and matrix organization. Although these nanofibrous scaffolds have shown considerable promise, there remains a limited understanding of how specific microenvironmental cues within these scaffolds affect and direct tendon tissue formation, and the precise combination of cues necessary to promote optimal cell and matrix organization and generate functional tendon tissues is not well understood. The goal of this study is to identify specific scaffold microenvironmental features that promote tendon neo- tissue formation, and to understand cellular mechanisms that underlie tendon tissue formation. We hypothesize that aligned scaffold architectural cues at both nano- and micro-scale levels synergize to direct tendon neo-tissue formation by promoting directed cell migration and high intracellular tension.
In Specific Aim 1, we will determine the role of specific microenvironmental architectural features in promoting tendon neo-tissue formation using a highly adaptable micro-photopatterning (?PP) model system that permits precise and independent manipulation of microenvironmental variables.
In Specific Aim 2, will measure cell migration behaviors and molecular-level intracellular tension in response to culture on ?PP architectures and determine how cell migration and tension relate to tendon neo-tissue formation. This study will allow us to identify and understand the parameters that lead to improved tendon tissue formation and incorporate these features into biomaterial scaffold designs. This fellowship will not only equip me with new knowledge and tools to facilitate my career as a productive independent scientist in the field of orthopaedic bioengineering, but also simultaneously contribute key information towards the goal of improving tendon surgical outcomes.
Tendon injuries are a common cause of pain and disability, with limited treatment options and high surgical failure rates. Tissue-engineered tendon grafts provide a possible solution to this problem;however, there is currently a limited understanding of the biomaterial scaffold microenvironmental cues critical for directing tendon neo-tissue formation. We aim to identify the specific scaffold microenvironmental features that promote tendon neo-tissue formation, and to understand the cellular mechanisms that underlie this tissue formation. This information will be used to inform tendon scaffold design and improve tendon tissue engineering functional outcomes.
| Lozoya, Oswaldo A; Gilchrist, Christopher L; Guilak, Farshid (2016) Universally Conserved Relationships between Nuclear Shape and Cytoplasmic Mechanical Properties in Human Stem Cells. Sci Rep 6:23047 |
| Orr, Steven B; Chainani, Abby; Hippensteel, Kirk J et al. (2015) Aligned multilayered electrospun scaffolds for rotator cuff tendon tissue engineering. Acta Biomater 24:117-26 |
| Gilchrist, Christopher L; Ruch, David S; Little, Dianne et al. (2014) Micro-scale and meso-scale architectural cues cooperate and compete to direct aligned tissue formation. Biomaterials 35:10015-24 |
