Engineered Healing of Avascular Meniscus Tears by Stem Cell Recruitment

Abstract

Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone. Upon injury, the outer zone of the meniscus can be repaired and expected to functionally heal but tears in the inner avascular region are unlikely to heal. To date, no regenerative therapy has been proven successful for consistently promoting healing in inner-zone meniscus tears. Here, we show that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) can induce seamless healing of avascular meniscus tears by inducing recruitment and step-wise differentiation of synovial mesenchymal stem/progenitor cells (syMSCs). A short-term release of CTGF, a selected chemotactic and profibrogenic cue, successfully recruited syMSCs into the incision site and formed an integrated fibrous matrix. Sustain-released TGFβ3 then led to a remodeling of the intermediate fibrous matrix into fibrocartilaginous matrix, fully integrating incised meniscal tissues with improved functional properties. Our data may represent a novel clinically relevant strategy to improve healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells.

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

“…Cadaveric allografts or synthetic materials can be transplanted to lower the joint contact pressure after meniscectomy; however, such meniscus grafts are limited by donor availability, testing and discarding to avoid pathogen transmission, potential immune responses, structural mismatch, access, capabilities, and costs . Tissue engineering and regenerative medicine approaches have recently emerged with the hope to overcome the current limitations associated with the existing meniscus repair and replacement strategies . Various biomaterials, bioactive cues, and/or stem/progenitor cells have been applied to improve healing of avascular meniscus tears in vitro and in vivo, and have shown promising progress …”

“…Tissue engineering and regenerative medicine approaches have recently emerged with the hope to overcome the current limitations associated with the existing meniscus repair and replacement strategies . Various biomaterials, bioactive cues, and/or stem/progenitor cells have been applied to improve healing of avascular meniscus tears in vitro and in vivo, and have shown promising progress …”

“…Recently, we devised an in situ tissue engineering approach to promote healing of avascular meniscus tears by endogenous stem/progenitor cells. We have demonstrated that time‐controlled application of connective tissue growth factor (CTGF) and transforming tissue growth factor beta 3 (TGFβ3) successfully improved healing of avascular meniscus tears by inducing recruitment and step‐wise fibrocartilaginous differentiation of mesenchymal stem/progenitor cells (MSCs) . Among several growth factors and cytokines tested for meniscus healing, the selection of CTGF and TGFβ3 is based on our previous studies .…”

“…We have demonstrated that time‐controlled application of connective tissue growth factor (CTGF) and transforming tissue growth factor beta 3 (TGFβ3) successfully improved healing of avascular meniscus tears by inducing recruitment and step‐wise fibrocartilaginous differentiation of mesenchymal stem/progenitor cells (MSCs) . Among several growth factors and cytokines tested for meniscus healing, the selection of CTGF and TGFβ3 is based on our previous studies . Moreover, a single application of CTGF‐loaded fibrin glue mixed with poly(lactic‐co‐glycolic acids) (PLGA) microspheres (μS)‐encapsulating TGFβ3 successfully recruited MSCs into the defect sites, resulting in integrated healing with fibrocartilaginous tissue .…”

“…Among several growth factors and cytokines tested for meniscus healing, the selection of CTGF and TGFβ3 is based on our previous studies . Moreover, a single application of CTGF‐loaded fibrin glue mixed with poly(lactic‐co‐glycolic acids) (PLGA) microspheres (μS)‐encapsulating TGFβ3 successfully recruited MSCs into the defect sites, resulting in integrated healing with fibrocartilaginous tissue . Our previous work showed that CTGF, through short‐term release from a fibrin gel, functions as a chemotactic, profibrogenic factor that recruits MSCs into the defect site, followed by constructing intermediate fibrous repair tissue .…”