Impaired biomechanical properties correlate with neoangiogenesis as well as VEGF and MMP‐3 expression during rat patellar tendon healing

Abstract

Recent studies reveal an important role of vascular endothelial growth factor (VEGF)-induced angiogenesis in degenerative tendon diseases. The way how VEGF influences mechanical properties of the tendons is not well understood yet. We here hypothesized that tendinopathy results in a hypoxia-mediated stimulation of VEGF and that the mechanical stability of the tendon is impaired in an angiogenic process by VEGF-induced matrix metalloproteinases (MMPs). A modified in situ freezing model of patellar tendon was used to create a tendinopathy. 0, 7, 14, and 28 days post-surgical animals were sacrificed and patellar tendons were dissected for biomechanical and immunohistochemical analysis. Native tendons were used as controls. Immunohistochemical staining revealed a peak in HIF-1a stabilization immediately after surgery. Both VEGF and MMP-3 were increased 7 days after surgery. Angiogenesis was also abundant 7 days after surgery. In contrast, biomechanical stability of the tendon was decreased 7 days after surgery. The current results reveal a time-dependent correlation of HIF-1/VEGF-induced and MMP-3-supported angiogenesis with decreased biomechanical properties during tendon healing. The therapeutical modulation of neoangiogenesis by influencing the level of VEGF and MMP-3 might be a promising target for new approaches in degenerative tendon diseases. ß

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

“…Tested in vitro on canine tenocytes, fibrin matrices with PDGF-BB led to a significant increase in total DNA, compared to martices without PDGF-BB or matrices with PDGF-BB but without the delivery system. After 6 d in culture, collagen synthesis was enhanced to a greater extent by controlled delivery of PDGF-BB, rather than by PDGF-BB in fibrin matrices without delivery system, suggesting a need for its sustained delivery over time (Sakiyama-Elbert et al, 2008). In a subsequent study, sustained delivery of PDGF-BB from the fibrin system resulted in downregulation of collagen (Col I and Col III) and lubrican gene expression at day 5.…”

“…Since tendons are hypovascular, in the long run, this can be a drawback for the healing process, where some vascularisation can provide extrinsic factors for a better healing (Barrientos et al,20 www.ecmjournal.org O Evrova et al PDGF-BB delivery for tendon healing Fenwick et al, 2002). In this regard, application of PDGF-BB can prove beneficial, rather than VEGF, which has been shown to have deleterious effect on tendon healing, resulting in abundant hypoxiainducible factor 1 (HIF-1)/VEGF-induced and matrix metallopeptidase 3 (MMP-3)-supported angiogenesis with inferior biomechanical properties of the tendons (Sahin et al, 2012). The clinical efficacy of PDGF-BB (rhPDGF-BB) use in wound healing has been shown in several phase III studies, where its application is well tolerated and safe (Smiell et al, 1999).…”

“…So far, the most widely characterised delivery device for in vitro conditions has been a fibrinbased delivery system that allows immobilisation of heparin-binding growth factors, such as PDGF-BB, thus protecting them from degradation prior to release at the tendon injury site (Sakiyama-Elbert and Hubbell, 2000a;Sakiyama-Elbert et al, 2008) (Table 2). This system, allowing for a sustained PDGF-BB delivery over a period of 10 d, has significant advantages compared to the bolus application of growth factors (growth factors are cleared within 48 h) (Robinson and Talmadge, 2002) or traditional synthetic polymeric delivery systems that can create acidic environment during degradation (Zisch et al, 2003).…”

“…The release kinetics of PDGF-BB from the fibrinmatrix-based delivery system can be modulated by different molar ratios of PDGF-BB to heparin, different amounts of PDGF-BB loading and also different gel size (Sakiyama-Elbert et al, 2008). In in vitro conditions, decreasing the molar ratio of PDGF-BB to heparin, from 1 : 10 to 1 : 10,000, led to significantly more sustained delivery of PDGF-BB within 10 d (Sakiyama-Elbert et al, 2008;Thomopoulos et al, 2007).…”

“…In in vitro conditions, decreasing the molar ratio of PDGF-BB to heparin, from 1 : 10 to 1 : 10,000, led to significantly more sustained delivery of PDGF-BB within 10 d (Sakiyama-Elbert et al, 2008;Thomopoulos et al, 2007). Three different doses of PDGF-BB loading were evaluated (0.125, 0.25 and 1.25 μg/mL), where increase in the amount loaded led to more sustained release.…”