Effect of dose and release rate of CTGF and TGFβ3 on avascular meniscus healing

Abstract

Meniscus tears in the avascular region rarely functionally heal due to poor intrinsic healing capacity, frequently resulting in tear propagation, followed by meniscus deterioration. Recently, we have reported that time-controlled application of connective tissue growth factor (CTGF) and transforming tissue growth factor β3 (TGFβ3) significantly improved healing of avascular meniscus tears by inducing recruitment and step-wise fibrocartilaginous differentiation of mesenchymal stem/progenitor cells (MSCs). In this study, we investigated effects of the dose of CTGF and the release rate of TGFβ3 on avascular meniscus healing in our existing explant model. Our hypothesis was that dose and release rate of CTGF and TGFβ3 are contributing factors for functional outcome in avascular meniscus healing by stem cell recruitment. Low (100ng/ml) and high (1,000 ng/ml) doses of CTGF as well as fast (0.46 ± 0.2ng/day) and slow (0.29 ± 0.1 ng/day) release rates of TGFβ3 were applied to our established meniscus explant model for meniscus tears in the inner-third avascular region. The release rate of TGFβ3 was controlled by varying compositions of poly(lactic-co-glycolic acids) (PLGA) microspheres. The meniscus explants were then cultured for 8 weeks on top of mesenchymal stem/progenitor cells (MSCs). Among the tested combinations, we found that a high CTGF dose and slow TGFβ3 release are most effective for integrated healing of avascular meniscus, demonstrating improvements in alignment of collagen fibers, fibrocartilaginous matrix elaboration and mechanical properties. This study may represent an important step toward the development of a regenerative therapy to improve healing of avascular meniscus tears by stem cell recruitment.

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

“…Interestingly, Yin et al (2016) have combined CTGF and TGF-β1 in a step-wise manner, which led to augmented tenogenic differentiation of MSCs, as well as to tendon-like tissue formation in the repair process of rat patella tendon defect. CTGF alone or in combination with TGF-β has also been associated with fibrocartilage formation in meniscal injury models (Lee et al, 2014;Tarafder et al, 2019). Therefore, as well as to minimize costs, we designed our study with administration of only one growth factor from the TGFβ family.…”

Advances in the Mechanisms Affecting Meniscal Avascular Zone Repair and Therapies

“…The avascular meniscal defect was completely filled with type 1 and 2 collagen as well as newly formed capillaries (He et al, 2011). Another in vitro study reported enhanced alignment of collagen fibers, fibrocartilaginous matrix elaboration and mechanical properties after supplementation with high-dose CTGF (1,000 ng/ml) and a slowed release rate of TGFβ3 (0.29 ± 0.1 ng/day) in a bovine meniscal explant tear model (Tarafder et al, 2019)…”

Meniscal Regenerative Scaffolds Based on Biopolymers and Polymers: Recent Status and Applications

“…For example, Zhang et al (2016) demonstrated that a 3D-printed PCL scaffold with a mean pore size of 215 μm significantly enhanced seeded cell colonization and further improved meniscal regeneration. Aside from changing the scaffold porosity, the incorporation of chemotactic chemokines could be a promising avenue ( Tarafder et al, 2019 ; Baek et al, 2020 ; Zhu et al, 2020 ).…”