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The Role of Macrophages in Early Healing of a Tendon Graft in a Bone Tunnel
Peyton L. Hays, MD1; Sumito Kawamura, MD1; Xiang-Hua Deng, MD1; Elias Dagher, MD1; Kai Mithoefer, MD1; Liang Ying, BS1; Scott A. Rodeo, MD1
1 The Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address for S.A. Rodeo: rodeos@hss.edu
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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at The Laboratory for Soft Tissue Research, The Hospital for Special Surgery, New York, NY

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2008 Mar 01;90(3):565-579. doi: 10.2106/JBJS.F.00531
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Background: Macrophages accumulate following tendon-to-bone repair and may contribute to the formation of a scar-tissue interface rather than to the reformation of a normal insertion site. We hypothesized that macrophage depletion may lead to improved insertion site regeneration, in a form of "scar-less" healing rather than reactive scar-tissue formation.

Methods: One hundred and ninety-two Sprague-Dawley rats underwent anterior cruciate ligament reconstruction with use of a flexor tendon autograft and were divided into a control group (ninety-six rats) and a liposomal clodronate-injected group (ninety-six rats). Clodronate is a bisphosphonate that selectively induces macrophage apoptosis. Animals in the liposomal clodronate group received weekly intraperitoneal injections of liposomal clodronate (1.33 mL/100 g of body weight). Rats were killed at serial time points from three to forty-two days. Immunostaining identified macrophages and transforming growth factor-beta (TGF-ß) at the tendon-bone interface. Fibrous interface width, osteoid formation, and collagen fiber continuity were evaluated with use of histomorphometry. Serial fluorochrome labeling was used to measure mineral apposition rate. Additional rats were killed for biomechanical testing at seven, fourteen, twenty-eight, and forty-two days.

Results: Liposomal clodronate significantly decreased macrophages and TGF-ß accumulation at the tendon-bone interface (p < 0.05). Specimens from rats that received liposomal clodronate exhibited a significantly narrower fibrous tissue interface between tendon and bone at all time points compared with specimens from controls (p < 0.05). In specimens from the liposomal clodronate group, healing proceeded at an accelerated rate, characterized by enhanced collagen fiber continuity and a greater degree of interface remodeling between tendon and bone. There were significant increases in osteoid formation (p < 0.05) and mineral apposition rates (p < 0.05) among experimental specimens. At forty-two days, the specimens from the liposomal clodronate group had significantly greater increases than the control specimens with respect to load to failure (mean and standard deviation, 13.5 ± 4.2 N and 9.7 ± 3.9 N, respectively; p < 0.05) and stiffness (mean, 11.5 ± 5.0 N/mm and 7.5 ± 3.2 N/mm; p < 0.05).

Conclusions: Macrophage depletion following anterior cruciate ligament reconstruction resulted in significantly improved morphologic and biomechanical properties at the healing tendon-bone interface, which we hypothesize are due to diminished macrophage-induced TGF-ß production.

Clinical Relevance: Techniques to modulate inflammation, and specifically macrophages, may improve tendon-bone healing and may enhance the structural integrity of healing tendon grafts.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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