PDGF‐BB released in tendon repair using a novel delivery system promotes cell proliferation and collagen remodeling

Abstract

The purpose of this study was to promote fibroblast proliferation and collagen remodeling in flexor tendon repair through sustained delivery of platelet derived growth factor (PDGF-BB). The release kinetics of PDGF-BB from a novel fibrin matrix delivery system was initially evaluated in vitro. After the in vivo degradation rate of the fibrin matrix was determined using fluorescently tagged fibrin, PDGF-BB was delivered to the site of flexor tendon repair in vivo in a canine model. The effect of PDGF-BB on intrasynovial tendon healing was studied using histology-based assays (cell density, proliferation, and type I collagen expression) and by measuring total DNA levels and reducible collagen crosslink levels. The fibrin matrix delivery system provided sustained release of PDGF-BB in vitro at a rate modulated by the ratio of heparin to growth factor. In vivo, the fibrin matrix remained at the repair site for more than 10 days. Delivery of PDGF-BB led to a qualitative increase in cell density, cell proliferation, and type I collagen mRNA expression. PDGF-BB also led to statistically significant increases in total DNA (20% increase at 7 days, 18% increase at 14 days) and reducible collagen crosslinks (30% increase at 7 days). Sustained delivery of growth factors may be achieved using a novel fibrin-based delivery system. PDGF-BB delivery increased cell proliferation and matrix remodeling and thus may accelerate flexor tendon healing. ß

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

“…The fibrin-based delivery system with heparinimmobilised PDGF-BB is the only one that has been explored for tendon regeneration application (Sakiyama-Elbert and Hubbell, 2000a;SakiyamaElbert and Hubbell, 2000b;Thomopoulos et al, 2007). This delivery system is based on a bi-domain peptide that includes a factor XIIIa substrate, derived from α 2 -plasmin inhibitor, at the N-terminus and a heparin-binding domain at the C-terminus.…”

“…One of the main responses upon addition of PDGF-BB in a dose-dependent manner, either in serum free or complete culture medium, is the increase in proliferation of tenocytes (Table 1) (Banes et al, 1995;Caliari and Harley, 2011;Costa et al, 2006;Evrova et al, 2016;Thomopoulos et al, 2005;Wong et al, 2003). Typically, the increase in cell proliferation has been assessed by metabolic activity assays or DNA synthesis quantification assays, while not exploring which pathway exactly led to the observed response.…”

“…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.…”

“…PDGF attracts inflammatory cells, such as neutrophils and macrophages, responsible for the breakdown and phagocytosis of the debris (Deuel et al, 1982;Inaba et al, 1993;Tzeng et al, 1985). Also, PDGF attracts tenocytes and fibroblasts that migrate to the wound site and start synthesising extracellular matrix components, including collagen (Banes et al, 1995;Siegbahn et al, 1990;Spindler et al, 1995;Thomopoulos et al, 2005).…”

Cell Migration after Synovium Graft Interposition at Tendon Repair Site

“…Although advances in the treatment of flexor tendon injuries have led to improved rehabilitation in patients [21,34,39,40], only small improvements have been made in functional outcomes [23]. Therefore, techniques that modulate the biology of tendon healing at the repair site have been a recent research focus [3,7,18,30,35,36,38].…”