Localized BMP-4 release improves the enthesis of engineered bone-to-bone ligaments

Abstract

Successful anterior cruciate ligament (ACL) reconstruction requires a functional enthesis, the interface between a bone and ligament or tendon. The enthesis normally exhibits a gradient of tissue phenotypes to smooth the transition from the compliant ligament to stiff bone and decrease stress concentrations between the 2 tissues. However, this structure does not fully regenerate after surgical repair leading to increased rupture rates and incidence of osteoarthritis. We have previously engineered ligaments between 2 cylindrical brushite cement anchors using human ACL fibroblasts entrapped in a fibrin gel. Using this model, we hypothesized that the local application and release of growth factors from the brushite cement anchors will promote fibrocartilage formation and improve interface failure load. Of 5 chondrogenic growth factors (BMP‐2, BMP‐4, and BMP‐7 and TGF‐β1 and TGF‐β3) tested, we identified TGF‐β1 as having a significant negative effect (P = .0001), while the local release of BMP‐4 at the enthesis of engineered ligaments improved the interface failure load by up to 38% compared to control conditions. BMP‐4 treatment increased the expression of the enthesis‐related genes Sox9, aggrecan, and tenascin C and the inhibitor of mineralization osteopontin. These data suggest that BMP‐4 drives a shift toward a fibrocartilaginous phenotype resulting in a stronger engineered enthesis.

Natural, synthetic and commercially-available biopolymers used to regenerate tendons and ligaments

“…Basic fibroblast growth factor (bFGF) [ 95 ] (also known as fibroblast growth factor 2 (FGF-2) [ 163 ]), growth differentiation factor (GDF) [ [163] , [164] , [165] , [166] , [167] ], transforming growth factor-beta 3 (TGF-β3) [ 168 ], and platelet-derived growth factor (PDGF) [ 169 , 170 ] have been commonly used for TL tissue engineering [ 171 , 172 ]. Considering interfacial regeneration, several factors including transforming growth factor-beta 1 (TGF-β1) [ 173 ], TGF-β3 [ 173 ], different bone morphogenetic proteins (BMPs, e.g.…”

“…Considering interfacial regeneration, several factors including transforming growth factor-beta 1 (TGF-β1) [ 173 ], TGF-β3 [ 173 ], different bone morphogenetic proteins (BMPs, e.g. BMP-12, BMP-7,BMP-2) [ 164 , [174] , [175] , [176] , [177] ], PDGF-BB [ 178 ], FGF-2 [ 179 ] and F2A (peptide mimetic of FGF-2) [ 172 ] have been used to signal stem cells for interfacial regeneration, in both in vitro and in vivo studies [ 8 ].…”

Biofabrication and Signaling Strategies for Tendon/Ligament Interfacial Tissue Engineering

“…Several parameters, such as the type of the cells and scaffold phases, determine the appropriate growth factor type and strategy. For instance, growth factor gradients, in type, concentration, and/or releasing time, are required to promote a differential proliferation for seeded cells in interface tendon scaffolds. ,,, Basic fibroblast growth factor (bFGF) (also known as fibroblast growth factor 2 (FGF-2)), growth differentiation factor (GDF), − platelet-derived growth factor (PDGF), , and transforming growth factor-beta 3 (TGF-β3) are commonly used in TL tissue engineering. , When the interfacial regeneration is considered, several factors including transforming growth factor-beta 1 (TGF-β1), TGF-β3, different bone morphogenetic proteins (BMPs; e.g., BMP-12, BMP-7, BMP-2), ,− PDGF-BB, FGF-2, and F2A (peptide mimetic of FGF-2) have been employed to enhance insertional healing and improve the interfacial strength both in vitro and in animal models. Thus, the optimization of cell culture medium supplementation has attracted much interest; however, there are limited reports on growth factor signal using biodegradable scaffolds.…”

Nanofibrous scaffolds for the healing of the fibrocartilaginous enthesis: advances and prospects

“…10,89 It is estimated that there are over 100 000 cases of ACL reconstruction in the United States alone each year, with a cost of over $1.5 billion. 11 As the gold standard for treating rotator cuff tears, the incidence of retearing can even reach 94%. 12,13 Surgical repair and reconstruction typically only restore the anatomical structure of the fibrocartilaginous enthesis, and the scar tissue formed after healing lacks natural gradient structure and collagen fiber arrangement, resulting in poor mechanical properties that do not promote fibrocartilaginous enthesis regeneration.…”