Nanofiber matrix formulations for the delivery of Exendin-4 for tendon regeneration: In vitro and in vivo assessment

Tendon and ligament injuries are the most common musculoskeletal injuries,which not only impact the quality of life but result in a massive economic burden.Surgical interventions for tendon/ligament injuries utilize biological and/or engineered grafts to reconstruct damaged tissue,but these have limitations.Engineered matrices confer superior physicochemical properties over biological grafts but lack desirable bioactivity to promote tissue healing.While incorporating drugs can enhance bioactivity,large matrix surface areas and hydrophobicity can lead to uncontrolled burst release and/or incomplete release due to binding.To overcome these limitations,we evaluated the delivery of a peptide growth factor(exendin-4;Ex-4)using an enhanced nanofiber matrix in a tendon injury model.To overcome drug surface binding due to matrix hydrophobicity of poly(caprolactone)(PCL)-which would be expected to enhance cell-material interactions-we blended PCL and cellulose acetate(CA)and electrospun nanofiber matrices with fiber diameters ranging from 600 to 1000 nm.To avoid burst release and protect the drug,we encapsulated Ex-4 in the open lumen of halloysite nanotubes(HNTs),sealed the HNT tube endings with a polymer blend,and mixed Ex-4-loaded HNTs into the polymer mixture before electrospinning.This reduced burst release from~75%to~40%,but did not alter matrix morphology,fiber diameter,or tensile properties.We evaluated the bioactivity of the Ex-4 nanofiber formulation by culturing human mesenchymal stem cells(hMSCs)on matrix surfaces for 21 days and measuring tenogenic differentiation,compared with nanofiber matrices in basal media alone.Strikingly,we observed that Ex-4 nanofiber matrices accelerated the hMSC proliferation rate and elevated levels of sulfated glycosaminoglycan,tendon-related genes(Scx,Mkx,and Tnmd),and ECM-related genes(Col-Ⅰ,Col-Ⅲ,and Dcn),compared to control.We then assessed the safety and efficacy of Ex-4 nanofiber matrices in a full-thickness rat Achilles tendon defect with histology,marker expression,functional walking track analysis,and mechanical testing.Our analysis confirmed that Ex-4 nanofiber matrices enhanced tendon healing and reduced fibrocartilage formation versus nanofiber matrices alone.These findings implicate Ex-4 as a potentially valuable tool for tendon tissue engineering.

EXPLAINING THE CHANGES IN ALPS BY IDENTIFYING ALPS-IMPORTANT COEFFICIENTS:AN EMPIRICAL APPLICATION OF CHINA

This paper establishes the relation between APLs and direct input coefficients through Sherman-Morrison formulation.On such a basis,elasticity matrix can be calculated for each element of the APLs matrix,which measures the percentage change in the APLs-matrix element brought by one percentage change in every direct input coefficient.Hence,the percentage change in each APLs-matrix element caused by the real percentage change in each coefficient with other coefficients fixed can be drawn,from which it is easily to find out the APLs-important coefficients and is useful to explain the reason for change in the matrix.The empirical application studies the Chinese economy.What's more,the method is applied under different level of aggregation.The comparison between the APLs matrix of 1997 and 2002 allows the authors to visualize the elements that change dramatically.Then the methodology above is applied to explain the change from the perspective of direct input coefficients and find out the important coefficients to the Chinese APLs matrix.