The anterior cruciate ligament (ACL) is the most frequently injured knee ligament, with over 100,000 reconstruction surgeries performed annually. Currently, the biological fixation of soft tissue-based grafts for ACL reconstruction poses a significant clinical challenge. Our approach to biological fixation centers on the regeneration of the anatomic insertion site between soft tissue and bone. Given the characteristic spatial variation in cell type, matrix composition and mineral content inherent at the enthesis, it is expected that interface regeneration will require multiple cell types and a stratified scaffold capable of supporting multi-tissue formation. Therefore, we have developed a biomimetic, multi-phased scaffold consisting of three distinct yet continuous phases, each designed for the formation of the ligament, fibrocartilage or bone regions found at the ACL-to-bone insertion. The objective of this proposal is to optimize multi-cell culture and scaffold design parameters for interface regeneration and multi-tissue formation.
Aim 1 will test the hypothesis that osteoblast-fibroblast interactions can promote chondrocyte-mediated fibrocartilage formation on the scaffold.
Aim 2 will optimize scaffold phase-specific mineral content and distribution.
Aim 3 will focus on the formation of four distinct yet continuous tissue regions (ligament, non-mineralized fibrocartilage, mineralized fibrocartilage, and bone) through the tri-culture of fibroblasts, chondrocytes and osteoblasts on the stratified scaffold.
Aim 4 will determine whether these biomimetic tissue regions formed in vitro can be maintained in vivo. Our effort to regenerate the anatomic fibrocartilage interface on ACL reconstruction grafts represents an innovative departure from the traditional focus on the non-physiologic fibrocartilage found within the bone tunnel. Moreover, the multi-phased scaffold design and tri-culture methods proposed here for multi-tissue formation are highly original. It is anticipated that the successful completion of our studies will facilitate the development of a new generation of integrative fixation devices, and our findings can be applied to many other conditions in which soft tissue-to-bone integration is also critical.

Public Health Relevance

Biological fixation of soft tissue-based grafts for Anterior Cruciate Ligament (ACL) reconstruction poses a significant clinical challenge. We propose that the regeneration of the soft tissue-to-bone interface is a prerequisite for the functional integration of biological and synthetic grafts for ACL reconstruction. This project focuses on the design and optimization of a novel biomimetic scaffold for interface tissue engineering, using both in vitro and in vivo studies. Findings from the planned studies will have a significant impact on public health due to the large number of ACL reconstruction procedures performed nationally and worldwide. In addition, this project can have broad impact for the translation of tissue engineered grafts to the clinical setting, by enabling the formation of complex tissue systems through graft integration with each other as well as with the host environment.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
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Columbia University (N.Y.)
Biomedical Engineering
Schools of Engineering
New York
United States
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Bogdanowicz, Danielle R; Lu, Helen H (2017) Designing the stem cell microenvironment for guided connective tissue regeneration. Ann N Y Acad Sci 1410:3-25
Boushell, Margaret K; Khanarian, Nora T; LeGeros, Raquel Z et al. (2017) Effect of ceramic calcium-phosphorus ratio on chondrocyte-mediated biosynthesis and mineralization. J Biomed Mater Res A 105:2694-2702
Qu, Dovina; Subramony, Siddarth D; Boskey, Adele L et al. (2017) Compositional mapping of the mature anterior cruciate ligament-to-bone insertion. J Orthop Res 35:2513-2523
Lee, Nancy M; Erisken, Cevat; Iskratsch, Thomas et al. (2017) Polymer fiber-based models of connective tissue repair and healing. Biomaterials 112:303-312
Lee, Nancy; Robinson, Jennifer; Lu, Helen (2016) Biomimetic strategies for engineering composite tissues. Curr Opin Biotechnol 40:64-74
Wang, I-Ning E; Bogdanowicz, Danielle R; Mitroo, Siddarth et al. (2016) Cellular interactions regulate stem cell differentiation in tri-culture. Connect Tissue Res 57:476-487
Patel, Sahishnu; Gualtieri, Anthony P; Lu, Helen H et al. (2016) Advances in biologic augmentation for rotator cuff repair. Ann N Y Acad Sci 1383:97-114
Mosher, Christopher Z; Spalazzi, Jeffrey P; Lu, Helen H (2015) Stratified scaffold design for engineering composite tissues. Methods 84:99-102
Qu, Dovina; Mosher, Christopher Z; Boushell, Margaret K et al. (2015) Engineering complex orthopaedic tissues via strategic biomimicry. Ann Biomed Eng 43:697-717
Subramony, Siddarth D; Su, Amanda; Yeager, Keith et al. (2014) Combined effects of chemical priming and mechanical stimulation on mesenchymal stem cell differentiation on nanofiber scaffolds. J Biomech 47:2189-96

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