Low back pain is a major cause of disability and is heavily associated with intervertebral disc degeneration. Osteogenic protein 1 (OP-1) is a growth factor that has shown potential to regenerate the intervertebral disc in human cells and animal models. However, high doses are required, presumably due to clearance from the tissue; controlled release may be a solution to this problem. In this study, we developed a preclinical, pathophysiological human tissue explant culture model of degenerated nucleus pulposus (NP). The NP explants were cultured for 28 days and injected with 100 µg OP-1 as a bolus, or with sustained-release biodegradable microspheres loaded with 16 or 1.6 µg OP-1. After culture, the tissue explants were analysed for biochemical content [water, sulphated glycosaminoglycans (GAGs), hydroxyproline and DNA], histology, cell viability and gene expression (disc matrix anabolic and catabolic markers). Untreated degenerated NP explants lost some of their GAG content when cultured for 4 weeks, but maintained other tissue constituents. Gene expression levels were close to native values. A bolus injection of OP-1 partially restored GAG content to the native level in half of the donors, while the sustained release of OP-1 did not affect the NP explants. No effect of treatment was observed on anabolic or catabolic gene expression at day 28. These results demonstrated that the regenerative potential of OP-1 is donor dependent, and only at very high doses. This questions the clinical use of OP-1 as a regenerative agent, as these high doses may increase the incidence of complications. Copyright © 2015 John Wiley & Sons, Ltd.