Articular cartilage injury and degeneration are leading causes of disability [1, 2]. Accessing bone marrow cells for cartilage repair through microfracture is commonly performed clinically. However, the frequently fibrous repairs yield mixed results [3, 4]. Safe, localized in vivo use of bioactive factors to improve chondrogenesis in situ of human bone marrow cells (BMC) for cartilage repair therefore has compelling public health impacts. Transforming growth factor-beta-1 (TGF-b1) consistently induces chondrogenesis of hBMC [5, 6]. Major challenges for in vivo administration of TGF-b1 include controlling and containing TGF-b1 effects. TGF-b signaling through its type II receptor (TbR-ll) is important to cellular responsiveness to TGF-b and to cartilage homeostasis . Using chondrogenesis as the desired endpoint, we propose to study an intriguing question as to whether the pattern of TbR-II expression, in particular sustained TbR-II expression, is the mechanism that determines whether bone marrow cells will undergo chondroid differentiation in vivo. The central hypothesis of this proposal is that sustained upregulation of TbR-ll is necessary for in vivo chondrogenesis of bone marrow cells and that this can be achieved through sustained administration of TGF-B1.
The specific aims of this proposal are: 1. To test the hypothesis that sustained upregulation of TbR-II is necessary for chondrogenesis of adult human BMC in vivo, within the diarthrodial environment. 2. To test the hypothesis that controlled release of TGF-b1 from genipin crosslinked polyethylene glycol (PEG-genipin) scaffolds will induce localized, sustained in vivo TbR-ll upregulation, chondrogenesis of host bone marrow cells (BMC), and improve osteochondral repair with minimal joint effects. 3. To test the hypothesis that highly localized, stable and regulatable TGF-b1 gene expression in diarthrodial joints can be achieved by adeno-associated virus (AAV)-TGF-b vectors that are gradually released from PEG-genipin scaffolds. Such gene expression is anticipated to induce localized in vivo upregulation of TbR-ll, chondrogenesis of host bone marrow repair cells, and improve osteochondral repair with minimal joint effects. The unique translational aspects of this proposal include (1) a Clinician-Scientist led multidisciplinary team to optimize related but independent strategies for localized, controlled in vivo delivery of growth factors to improve the cartilage repair potential of bone marrow cells; and (2) provision of a direct pathway for clinical translation of innovative scaffold technology and controlled gene therapy to improve cartilage repair, and the arthroscopic use of novel nondestructive advanced cartilage imaging technologies.
|Williams, Ashley; Winalski, Carl S; Chu, Constance R (2017) Early articular cartilage MRI T2 changes after anterior cruciate ligament reconstruction correlate with later changes in T2 and cartilage thickness. J Orthop Res 35:699-706|
|LaPrade, Robert F; Dragoo, Jason L; Koh, Jason L et al. (2016) AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries. J Am Acad Orthop Surg 24:e62-78|
|Goodrich, Laurie R; Chen, Albert C; Werpy, Natasha M et al. (2016) Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? J Bone Joint Surg Am 98:23-34|
|Chu, Constance R (2015) The Challenge and the Promise of Bone Marrow Cells for Human Cartilage Repair. Cartilage 6:36S-45S|
|Chu, Constance R; Millis, Michael B; Olson, Steven A (2014) Osteoarthritis: From Palliation to Prevention: AOA Critical Issues. J Bone Joint Surg Am 96:e130|
|Braun, Hillary J; Kim, Hyeon Joo; Chu, Constance R et al. (2014) The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med 42:1204-10|
|Grissom, Murray J; Temple-Wong, Michele M; Adams, Matthew S et al. (2014) Synovial Fluid Lubricant Properties are Transiently Deficient after Arthroscopic Articular Cartilage Defect Repair with Platelet-Enriched Fibrin Alone and with Mesenchymal Stem Cells. Orthop J Sports Med 2:|
|Chu, Constance R; Williams, Ashley A; West, Robin V et al. (2014) Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction. Am J Sports Med 42:1847-56|
|Lee, Hannah H; O'Malley, Michael J; Friel, Nicole A et al. (2013) Effects of doxycycline on mesenchymal stem cell chondrogenesis and cartilage repair. Osteoarthritis Cartilage 21:385-393|
|Qian, Yongxian; Williams, Ashley A; Chu, Constance R et al. (2013) Repeatability of ultrashort echo time-based two-component T2* measurements on cartilages in human knee at 3 T. Magn Reson Med 69:1564-72|
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