Sustained spatiotemporal release of TGF‐β1 confers enhanced very early chondrogenic differentiation during osteochondral repair in specific topographic patterns

Abstract

The continuous presence of TGF-β is critically important to induce effective chondrogenesis. To investigate chondrogenesis in a cartilage defect, we tested the hypothesis that the implantation of TGF-β1-releasing scaffolds improves very early cartilage repair in vivo. Spatiotemporal controlled release of TGF-β1 was achieved from multiblock scaffolds that were implanted in osteochondral defects in the medial femoral condyles of adult minipigs. We observed a sustained presence of TGF-β1 at 4 wk in vivo, which significantly promoted structural aspects of early overall cartilage repair, especially cellularity, cellular morphology, and safranin O staining intensity. Furthermore, early aggrecan and type II collagen production were both increased in specific topographic patterns in cartilaginous repair tissue. Sustained release of TGF-β1 also increased cell numbers and proliferation, staining intensities for the stem cell surface marker, CD105, and number of stromal cell-derived factor-1 (SDF-1) -positive cells within cartilaginous repair tissue. These data identify a mechanism by which TGF-β1 modulates early chondrogenesis by primarily increasing the number of progenitor cells arising from the subchondral bone marrow compartment via the SDF-1/chemokine (CXC motif) receptor 4 pathway, their proliferation, differentiation, and extracellular matrix deposition in specific topographic patterns, highlighting the pivotal role played by TGF-β1 during this crucial phase.-Asen, A.-K., Goebel, L., Rey-Rico, A., Sohier, J., Zurakowski, D., Cucchiarini, M., Madry, H. Sustained spatiotemporal release of TGF-β1 confers enhanced very early chondrogenic differentiation during osteochondral repair in specific topographic patterns.

Hydrogel‐Guided, rAAV‐Mediated IGF‐I Overexpression Enables Long‐Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large‐Animal Full‐Thickness Chondral Defect Model at One Year In Vivo

“…The minimal sample size of 8 was calculated as previously described. [31,56] Healthy, skeletally mature female Aachener minipigs (age 18-22 months, average body weight (BW): 42.75 ± 6.54 kg; Gerd Heinrichs, Heinsberg, Germany) were fed by standard diet and received water ad libitum. After 12 h fasting, sedation was induced with an intramuscular injection of 30 mg ketamin per animal (Ketanest S, Pfizer, Berlin, Germany), 2 mg xylazine per animal (Rompun, Bayer, Leverkusen, Germany), and 1 mg atropine per animal (B. Braun, Melsungen, Germany).…”

Efficient TGF-β1 Delivery to Articular Chondrocytes In Vitro Using Agro-Based Liposomes

“…Furthermore, bioactive agents are well protected once encapsulated in liposomes from the external harsh in vivo environment [ 10 , 11 , 12 ]. This could solve the short half-life, low stability and poor penetration into cartilage of transforming growth factor (TGF)-β1, which has shown positive effects on chondrocytes [ 13 , 14 , 15 , 16 ] by binding to their receptors and activating signaling pathways among which the best known are extracellular signal-regulated kinase (ERK), p38-mitogen-activated protein kinase (p38-MAPK) and Smad [ 17 , 18 , 19 ]. Indeed, TGF-β1 is known to retain chondrocyte articular phenotype by inducing the genes coding for Col 2, ACAN and Sox-9 [ 16 , 20 ], as well as the release of inorganic pyrophosphate (PPi) [ 21 , 22 ].…”

rAAV-Mediated Human FGF-2 Gene Therapy Enhances Osteochondral Repair in a Clinically Relevant Large Animal Model Over Time In Vivo

“…It is likely that undifferentiated MSCs that migrated from the bone marrow into the defect 54 represent the major reparative cell population, as reported in a previous study 2 (although that work did not specifically assess their source), whereas MSCs of synovial or other origins could contribute. 2,28 Although Correa et al 7 reported that FGF-2 is an early activator of the chondrogenic machinery in MSCs, those investigators also identified accelerated hypertrophic changes after FGF-2 exposure in vitro. A hypertrophic phenotype reflects degeneration and therefore is undesirable for chondral repair.…”