Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based on tissue engineering principles, was performed in six sheep with papain-induced experimental emphysema (EMPH). Physiologic measurements, at baseline, after generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes, diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest wall, pleural pressures generated during active respiratory muscle contraction, lung resistance and dynamic elastance. The animal model displayed hyperinflation (change in total lung capacity +8%; change in residual volume +66%), reduced DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced human EMPH. BLVR was well tolerated without complications, and it reduced lung volumes (change in total lung capacity -16%; change in residual volume -55%) in a pattern that resulted in significant improvements in vital capacity (10%). At autopsy, well-organized, peripheral scars associated with tissue contraction were observed at 33 of the 36 (91%) treated sites. There was no evidence of infection, abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved respiratory function safely and consistently. The BLVR technology employed in this study addresses the limitations identified in our prior attempt at BLVR therapy and appears safe and effective enough to justify a trial in humans.