This exploratory bioengineering research proposal seeks to develop innovative methods for anterior cruciate ligament (ACL) repair utilizing novel biohybrid constructs and a physiologic loading environment to generate functional tissue equivalents. The ACL is a soft connective tissue comprised of fibroblasts in a dense collagenous matrix designed to transmit tensile loads and stabilize the knee joint. Approximately 150,000 ACL replacements are performed annually in the United States as a result of the poor healing capacity of the tissue. Environmental stimuli such as mechanical stresses and extracellular matrix (ECM) signaling molecules have been shown to regulate the behavior of ligament fibroblasts and the ACL healing response. In particular, both tensile loading and collagen-based materials have been reported to enhance ECM elaboration and organization as well as the alignment and proliferation of ligament fibroblasts. However, the precise mechanical loading parameters that stimulate anabolic processes conducive to ligament healing have not been well characterized. In addition, mechanically functional materials that effectively present native collagen ligands have not been fully developed. The lack of a viable healing response in the ACL may be due to multiple factors including the limited proliferative and biosynthetic activity of ACL fibroblasts in comparison to those of other fibrous tissues. The overall objective of this proposal is to determine specific environmental cues that may be utilized to engineer functional ligament tissue from a novel, adult human dermal fibroblast cell source. These cells will be seeded on scaffold materials surface-modified with collagen-mimetic peptides and exposed to cyclic tensile loading to control ECM elaboration, structural organization, and the mechanical properties of engineered ligament constructs. Successful completion of the proposed studies will provide valuable insight into the regulation of fibroblast behavior by environmental stimuli. Specifically, this work will improve our understanding of the role that both mechanical forces and ECM ligands play in directing fibroblast growth and remodeling. Moreover, the translational component of this research will aid in the development of new treatment modalities for ACL repair, and future studies will utilize these approaches in an in vivo animal model.
| Brink, Hallie E; Bernstein, Joseph; Nicoll, Steven B (2009) Fetal dermal fibroblasts exhibit enhanced growth and collagen production in two- and three-dimensional culture in comparison to adult fibroblasts. J Tissue Eng Regen Med 3:623-33 |
| Stalling, Simone S; Nicoll, Steven B (2008) Fetal ACL fibroblasts exhibit enhanced cellular properties compared with adults. Clin Orthop Relat Res 466:3130-7 |
| Chao, Pen-Hsiu Grace; Lu, Helen H; Hung, Clark T et al. (2007) Effects of applied DC electric field on ligament fibroblast migration and wound healing. Connect Tissue Res 48:188-97 |
| Brink, Hallie E; Stalling, Simone S; Nicoll, Steven B (2005) Influence of serum on adult and fetal dermal fibroblast migration, adhesion, and collagen expression. In Vitro Cell Dev Biol Anim 41:252-7 |
