Effects of age on the repair ability of mesenchymal stem cells in rabbit tendon

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Abstract
Successful tissue engineered repair in the aging adult requires an abundant source of autologous, multipotent mesenchymal stem cells (MSCs). Although the number of bone marrow-derived MSCs declines dramatically with aging, their effectiveness in repair with increasing age has not been studied. We tested the hypothesis that MSCs harvested from geriatric rabbits would not repair patellar tendon defects as well as MSCs harvested from younger adult rabbits. In a novel within-subjects experiment, autologous MSCs were isolated from 1-year old rabbits, culture expanded, and cryogenically preserved. After housing the rabbits for 3 years, MSCs were re-harvested from the 4-year old rabbits and expanded. Five hundred thousand thawed and fresh MSCs were each separately mixed with type I collagen gel (333.3 x 10(3) cells/mg collagen) 24 h before surgery, and the resulting constructs implanted in bilateral full-length central third tendon defects. Twelve weeks post-surgery, the bone-tendon repair-bone units were failed in tension. Intra-animal (paired) comparisons between repair tissue treated with 1-year old MSCs and repair tissue treated with 4-year old MSCs resulted in no significant differences (alpha=0.05) in material properties including maximum stress (10.8 MPa vs. 9.9 MPa; p=0.762), modulus (139.8 MPa vs. 146.2 MPa; p=0.914), and strain energy density (0.52 N mm/mm(3) vs. 0.53 N mm/mm(3); p=0.966). Despite an age-related trend, there were also no significant differences in structural properties including maximum force (62.9 N vs. 27.0 N; p=0.070), stiffness (24.9 N/mm vs. 12.0 N/mm; p=0.111), and strain energy (87.2 N mm vs. 31.4 N mm; p=0.061). A subset of the rabbits (n=4 1 yrMSC, n=2 4 yrMSC) showed the presence of ectopic bone in the repair region and were not included in the mechanical analyses. We conclude that in the rabbit model MSCs do not lose their benefit as a tendon repair therapy with aging and that MSCs can be cryogenically stored for 3 years and still effectively repair soft tissue injuries.