Meniscal Fibrocartilage Repair Based on Developmental Characteristics: A Proof-of-Concept Study

Background: Unlike the adult meniscus, the fetal meniscus possesses robust healing capacity. The dense and stiff matrix of the adult meniscus provides a biophysical barrier for cell migration, which is not present in the fetal meniscus. Inspired by developmental characteristics, modifying the matrix of the adult meniscus into a fetal-like, loose and soft microenvironment holds opportunity to facilitate repair, especially in the avascular zone. Hypothesis: Modifying the dense and stiff matrix of the adult meniscus into a fetal-like, loose and soft microenvironment could enhance cell migration to the tear interface and subsequent robust healing capacity. Study Design: Controlled laboratory study. Methods: Fresh porcine menisci were treated with hyaluronidase or collagenase. The density and arrangement of collagen fibers were assessed. The degradation of proteoglycans and collagen was evaluated histologically. Cell migration within the meniscus or the infiltration of exogenous cells into the meniscus was examined. Dendritic silica nanoparticles with relatively large pores were used to encapsulate hyaluronidase for rapid release. Mesoporous silica nanoparticles with relatively small pores were used to encapsulate transforming growth factor-beta 3 (TGF-beta 3) for slow release. A total of 24 mature male rabbits were included. A longitudinal vertical tear (0.5 cm in length) was prepared in the avascular zone of the medial meniscus. The tear was repaired with suture, repaired with suture in addition to blank silica nanoparticles, or repaired with suture in addition to silica nanoparticles releasing hyaluronidase and TGF-beta 3. Animals were sacrificed at 12 months postoperatively. Meniscal repair was evaluated macroscopically and histologically. Results: The gaps between collagen bundles increased after hyaluronidase treatment, while collagenase treatment resulted in collagen disruption. Proteoglycans degraded after hyaluronidase treatment in a dose-dependent manner, but collagen integrity was maintained. Hyaluronidase treatment enhanced the migration and infiltration of cells within meniscal tissue. Last, the application of fibrin gel and the delivery system of silica nanoparticles encapsulating hyaluronidase and TGF-beta 3 enhanced meniscal repair responses in an orthotopic longitudinal vertical tear model. Conclusion: The gradient release of hyaluronidase and TGF-beta 3 removed biophysical barriers for cell migration, creating a fetallike, loose and soft microenvironment, and enhanced the fibrochondrogenic phenotype of reparative cells, facilitating the synthesis of matrix and tissue integration. Clinical Relevance: Modifying the adult matrix into a fetal-like, loose and soft microenvironment via the local gradient release of hyaluronidase and TGF-beta 3 enhanced the healing capacity of the meniscus.