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Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds. We have shown that the tumor necrosis factor-α (TNF-α)-stimulated protein 6 (TSG-6) released from MSCs in co-culture with activated Mφ or following injection into wound margins suppressed the release of TNF-α from activated Mφ and concomitantly induced a switch from a high to an anti-fibrotic low transforming growth factor-β1 (TGF-β1)/TGF-β3 ratio. This study provides insight into what we believe to be a previously undescribed multifaceted role of MSC-released TSG-6 in wound healing. MSC-released TSG-6 was identified to improve wound healing by limiting Mφ activation, inflammation, and fibrosis. TSG-6 and MSC-based therapies may thus qualify as promising strategies to enhance tissue repair and to prevent excessive tissue fibrosis.

We know it is important to avoid excessive strain on reconstructed ligaments, but we do not know how individual muscles affect cruciate ligament strain. To answer this, we studied the effect of muscle forces and external loads on cruciate ligament strain. Nine cadaveric knee joints were tested in an apparatus that allowed unconstrained knee joint motion. Quadriceps, hamstring, and gastrocnemius muscle forces were simulated. Additionally, external loads were applied such as varus-internal or valgus-external rotation forces. Cruciate ligament strain was recorded at different knee flexion angles. Activation of the gastrocnemius muscle significantly (P < 0.05) strained the posterior cruciate ligament at flexion angles larger than 40 degrees. Quadriceps muscle activation significantly strained the anterior cruciate ligament when the knee was flexed 20 degrees to 60 degrees (P < 0.01) and reduced the strain on the posterior cruciate ligament in the same flexion range (P < 0.05). Activation of the hamstring muscles strained the posterior cruciate ligament when the knee was flexed 70 degrees to 110 degrees (P < 0.05). Combined varus and internal rotation forces significantly increased anterior cruciate ligament strain throughout the flexion range (P < 0.05). The results suggest that to minimize strain on the ligament after posterior cruciate ligament surgery, strong gastrocnemius muscle contractions should be avoided beyond 30 degrees of knee flexion. The study also calls into question the use of vigorous quadriceps exercises in the range of 20 degrees to 60 degrees of knee flexion after anterior cruciate ligament reconstruction.

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