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LONG-TERM IN VIVO DELIVERY OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-1 BY TISSUE-ENGINEERED SKELETAL MUSCLE IMPLANTS FOR TREATING DISUSE MUSCLE ATROPHY IN MICE. P.H.U. Lee, X.Y. Wang, H.H. Vandenburgh. Dept. of Pathobiology, Brown Univ. School of Medicine, Providence RI.

It is well known that space flight causes significant muscle atrophy in both humans and animals. Long-term systemic delivery of therapeutic growth factors, such as insulin-like growth factor-1 (IGF-1), at pharmacological levels may be an effective countermeasure for attenuating or preventing space flight-induced skeletal muscle atrophy. The goal of this study was to demonstrate that recombinant human IGF-1 (rhIGF-1) can be delivered long-term in vivo in a murine model using tissue-engineered skeletal muscles made from genetically modified primary mouse myoblasts. A retroviral vector was used to stably transduce primary mouse myoblasts (PMM) with the rhIGF-1 gene under the control of a constitutively expressed promoter. These cells (PMM-IGF1) were tissue-engineered into bioartifical muscles that secreted 673.8+/-146 ng/implant/day in vitro. These rhIGF-1 secreting bioartificial muscles were implanted subcutaneously into mice while sham operated mice served as controls. Serum rhIGF-1 levels were assayed every two weeks for 65 days. rhIGF-1 was detected in the serum as soon as 23 days after implantation. By 51 days, serum levels had reached as high as 565 ng/ml, whereas sham control animals had no detectable levels for the duration of the study. Sustained or increased rhIGF-1 levels were detected in implanted mice until the end of the study at 65 days post-implantations. This study demonstrates the feasibility of long-term sustained delivery of rhIGF-1 in mice using tissue-engineered skeletal muscle. rhIGF-1 delivered in this manner can be used in a hindlimb suspension model for demonstrating its potential application for treating space flight-induced skeletal muscle atrophy. 

(Supported by AG15415, HL60502, and NASA NAG2-1205.)