Geometrically anisotropic tissues present architectural and biochemical cues critical for tissue morphogenesis and remodeling but also pose unique challenges for the field of tissue engineering. Tendons are specialized connective tissues that transmit tensile loads between muscle and bone whose functional capacity derives from native tenocytes (TCs) embedded within a highly anisotropic extracellular matrix (ECM). A primary concern for current approaches to tendon regeneration is the rapid TC de-differentiation observed in vitro, making strategies to support long-term culture of TC populations within a tissue engineered construct critically important. Further complicating this issue, like the body's response to injury, a cell's response to a biomaterial is dynamic. It is therefore important to define the initial microstructural and biochemical properties of a biomaterial but essential to control the evolution (remodeling) of these properties with time. However, the tools available to design, implement, and characterize such temporally-variable biomaterials are currently extremely limited. To address this unmet need we propose to demonstrate an innovative biomaterial approach to temporally regulate the initial presentation and remodeling of structural and biochemical cues within a model collagen biomaterial to drive long-term TC bioactivity. This approach will establish a platform for developing a functional tendon regeneration template as well as probing how the evolution of scaffold biophysical properties can be a critical design parameter for bioactive biomaterials. To accomplish these goals we have married temporally-selective biomolecule sequestration strategies with a unique fabrication process to precisely control the geometric anisotropy and structural remodeling of a clinically approved collagen-GAG (CG) scaffold system. The objective of this proposal is to demonstrate the potential for using both initial scaffold properties and subsequent remodeling as dual rheostats for optimizing TC bioactivity.
Aim 1 will test the hypothesis that scaffold geometric anisotropy and strut flexura rigidity co-regulate long-term maintenance of the tenocyte phenotype.
Aim 2 will test the hypothesis that temporally-organized biomolecule immobilization and release can enhance tenocyte bioactivity. Our approach represents a paradigm shift because it seeks to integrate temporal control over two key classes of extrinsic signals - matrix anisotropy as well as biomolecule sequestration and release - within a single biomaterial, making it both unique and ideally-suited for addressing our hypotheses. The capabilities and insight to be developed by this proposal do not currently exist, but offer the tantalizing potential to transform clinical treatments for a wide range of load-bearing tissue injuries through the use of temporally-ordered biomaterial substrates. Results from this project will significantly inform subsequent studies that explicitly test the regenerative potential of these biomaterials in a range of clinically-significat craniofacial and extremity tendon defects. Findings from these studies are expected to have significant impact on human health due to the large numbers of tendon repairs performed annually as well as the substantial costs, both financial and quality-of-life related, associated with failed repairs.
The research described in this proposal will tether biomolecules into geometrically anisotropic (aligned) collagen biomaterials to create a dynamic platform for tendon regeneration. The body's response to injury is dynamic, making it important to define the initial properties of a biomaterial to be implanted into a wound, but essential to control the evolution (remodeling) of these properties with time. This project will develop an improved understanding of how tenocytes mediate and subsequently respond to biomaterial remodeling and is expected to elucidate critical design parameters regarding the presentation of temporally-ordered structural and biochemical signals within a biomaterial to induce tendon regeneration.
|Pence, Jacquelyn C; Clancy, Kathryn B H; Harley, Brendan A C (2017) Proangiogenic Activity of Endometrial Epithelial and Stromal Cells in Response to Estradiol in Gelatin Hydrogels. Adv Biosyst 1:|
|Grier, William K; Iyoha, Ehiremen M; Harley, Brendan A C (2017) The influence of pore size and stiffness on tenocyte bioactivity and transcriptomic stability in collagen-GAG scaffolds. J Mech Behav Biomed Mater 65:295-305|
|Grier, W G; Moy, A S; Harley, B A (2017) Cyclic tensile strain enhances human mesenchymal stem cell Smad 2/3 activation and tenogenic differentiation in anisotropic collagen-glycosaminoglycan scaffolds. Eur Cell Mater 33:227-239|
|Hortensius, Rebecca A; Ebens, Jill H; Harley, Brendan A C (2016) Immunomodulatory effects of amniotic membrane matrix incorporated into collagen scaffolds. J Biomed Mater Res A 104:1332-42|
|Hortensius, Rebecca A; Harley, Brendan Ac (2016) Naturally derived biomaterials for addressing inflammation in tissue regeneration. Exp Biol Med (Maywood) 241:1015-24|
|Hortensius, Rebecca A; Becraft, Jacob R; Pack, Daniel W et al. (2015) The effect of glycosaminoglycan content on polyethylenimine-based gene delivery within three-dimensional collagen-GAG scaffolds. Biomater Sci 3:645-54|
|Pence, Jacquelyn C; Clancy, Kathryn B H; Harley, Brendan A C (2015) The induction of pro-angiogenic processes within a collagen scaffold via exogenous estradiol and endometrial epithelial cells. Biotechnol Bioeng 112:2185-94|
|Caliari, Steven R; Gonnerman, Emily A; Grier, William K et al. (2015) Collagen scaffold arrays for combinatorial screening of biophysical and biochemical regulators of cell behavior. Adv Healthc Mater 4:58-64|
|Caliari, Steven R; Mozdzen, Laura C; Armitage, Oliver et al. (2014) Award Winner in the Young Investigator Category, 2014 Society for Biomaterials Annual Meeting and Exposition, Denver, Colorado, April 16-19, 2014: Periodically perforated core-shell collagen biomaterials balance cell infiltration, bioactivity, and mechani J Biomed Mater Res A 102:917-27|
|Caliari, Steven R; Harley, Brendan A C (2014) Structural and biochemical modification of a collagen scaffold to selectively enhance MSC tenogenic, chondrogenic, and osteogenic differentiation. Adv Healthc Mater 3:1086-96|
Showing the most recent 10 out of 12 publications