Healing of ligaments after rupture and ligament grafts after reconstruction remains a great challenge. Healing involves a complex, coordinated series of events that form a neo-ligament which is more scar-like in character than the native tissue. The repair process extends from months to years and the injured ligament never fully recovers its original mechanical properties. Reconstructed knees are often less stable and fail to restore normal joint kinematics. These deficiencies are likely the cause of premature joint degeneration and osteoarthritis. Preliminary data from our lab strongly suggest that ligament healing can become much more regenerative by modulation of the inflammatory processes. Preliminary data also suggest that microspheres can be designed to release proteins that will spatially and temporally modulate inflammation for regenerative healing. We propose to investigate inflammatory processes during ligament healing (rat MCL model) and during ligament graft healing (rat ACL model) to study their role in scar formation and/or tissue regeneration. We will modulate inflammation with interleukin-4 (IL-4), interleukin-1 receptor antagonist (IL-1Ra) and neutralizing antibody for interleukin-17 (1-IL-17). Through these, we expect to induce more regenerative healing in ligaments and ligament grafts. Clinical translation requires a localized delivery system. We therefore propose to develop two methods, first, a "sustained" release of inflammatory mediators from microspheres that can be injected into the torn ends of a ruptured ligament or into a ligament graft prior to reconstruction, and second, protein release from microspheres that is "controlled" by local pH changes due to inflammation. Treatments will be optimized (via dosage and time) and outcomes will be compared at two healing times. Parameters of evaluation will be: size of wound, ECM composition, ECM microstructural morphology and organization, mechanical behavior, cellularity, and cell types. Changes in signaling factors relevant to healing/regeneration will be explored. The closer to an intact ligament the above parameters are, the more healing will be considered regenerative. If successful, five very significant outcomes will arise from this study: 1) an improved understanding of inflammatory processes and their role in ligament "scar" formation, 2) a highly developed sustained microsphere delivery system to locally modulate healing 3) a sophisticated pH-developed microsphere delivery system to locally control healing, 4) an improved method to induce regenerative ligament healing, and 5) an advanced technique to induce regenerative ALC graft healing. Each one of these would be of great significance and each would have much broader applications than those explored herein.

Public Health Relevance

Ligament injuries frequently occur, but healing is problematic. The ACL, with relatively little healing potential, must be reconstructed to recover function, but ACL grafts usually lengthen and their strength can drop by ~50% after remodeling. Even with ligaments that heal well (e.g. the MCL) the resulting scar-like tissue is mechanically inferior and compositionally abnormal years after injury. And, these healed ligaments are usually longer than the native tissue. Therefore, ligament graft healing and ligament healing frequently result in laxity, joint instability, and abnormal joint motion, which correlate with an early onset of osteoarthritis. New methods to induce regenerative healing of ligaments or ligament grafts would then be very significant. Developing these methods (via controlled delivery of inflammatory mediators from biomineral coatings on injectable microspheres) is the goal of this application.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-C (02))
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Tyree, Bernadette
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University of Wisconsin Madison
Physical Medicine & Rehab
Schools of Medicine
United States
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Yu, Xiaohua; Suárez-González, Darilis; Khalil, Andrew S et al. (2015) How does the pathophysiological context influence delivery of bone growth factors? Adv Drug Deliv Rev 84:68-84
Frisch, Kayt E; Marcu, David; Baer, Geoffrey S et al. (2014) Influence of tendon tears on ultrasound echo intensity in response to loading. J Biomech 47:3813-9
Chamberlain, Connie S; Leiferman, Ellen M; Frisch, Kayt E et al. (2014) Interleukin-1 receptor antagonist modulates inflammation and scarring after ligament injury. Connect Tissue Res 55:177-86
Saether, Erin E; Chamberlain, Connie S; Leiferman, Ellen M et al. (2014) Enhanced medial collateral ligament healing using mesenchymal stem cells: dosage effects on cellular response and cytokine profile. Stem Cell Rev 10:86-96
Frisch, Kayt E; Marcu, David; Baer, Geoffrey S et al. (2014) The influence of partial and full thickness tears on infraspinatus tendon strain patterns. J Biomech Eng 136:051004
Pensalfini, Marco; Duenwald-Kuehl, Sarah; Kondratko-Mittnacht, Jaclyn et al. (2014) Evaluation of global load sharing and shear-lag models to describe mechanical behavior in partially lacerated tendons. J Biomech Eng 136:091006
Duenwald-Kuehl, Sarah; Bates, Melissa L; Cortes, Sonia Y et al. (2014) Ultrasound assessment of ex vivo lung tissue properties using a fluid-filled negative pressure bath. J Biomech Eng 136:
Wu, Mon-Ju; Karls, Joseph; Duenwald-Kuehl, Sarah et al. (2014) Spatial and frequency-based super-resolution of ultrasound images. Comput Methods Biomech Biomed Eng Imaging Vis 2:146-156
Suárez-González, Darilis; Lee, Jae Sung; Diggs, Alisha et al. (2014) Controlled multiple growth factor delivery from bone tissue engineering scaffolds via designed affinity. Tissue Eng Part A 20:2077-87
Yu, Xiaohua; Khalil, Andrew; Dang, Phuong Ngoc et al. (2014) Multilayered Inorganic Microparticles for Tunable Dual Growth Factor Delivery. Adv Funct Mater 24:3082-3093

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