Overcoming barriers confronting application of protein therapeutics in bone fracture healing.

Bone fracture is a major contributor to debilitation and death among patients with bone diseases. Thus, osteogenic protein therapeutics and their delivery to bone have been extensively researched as strategies to accelerate fracture healing. To prevent morbidity and mortality of fractures, which occur frequently in the aging population, there is a critical need for development of first-line therapeutics. Bone morphogenic protein-2 (BMP-2) has been at the forefront of bone regeneration research for its potent osteoinduction, despite safety concerns and biophysiological obstacles of delivery to bone. However, continued pursuit of osteoinductive proteins as a therapeutic option is largely aided by drug delivery systems, playing an imperative role in enhancing safety and efficacy. In this work, we highlighted several types of drug delivery platforms and their biomaterials, to evaluate the suitability in overcoming challenges of therapeutic protein delivery for bone regeneration. To showcase the clinical considerations for each type of platform, we have assessed the most common route of administration strategies for bone regeneration, classifying the platforms as implantable or injectable. Additionally, we have analyzed the commonly utilized models and methodology for safety and efficacy evaluation of these osteogenic protein-loaded systems, to present clinical opinions for future directions of research in this field. It is hoped that this review will promote research and development of clinically translatable osteogenic protein therapeutics, while targeting first-line treatment status for achieving desired outcomes of fracture healing. Graphical abstract.