William L. Murphy, Jennifer M. Umhoefer, Xiaohua Yu, Adam H. Biedrzycki, Andrew S. Khalil, Mark D. Markel, Dalton Hess
Proteins tend to lose their biological activity due to their fragile structural conformation during formulation, storage, and delivery. Thus, the inability to stabilize proteins in controlled-release systems represents a major obstacle in drug delivery. Here, a bone mineral inspired protein stabilization strategy is presented, which uses nanostructured mineral coatings on medical devices. Proteins bound within the nanostructured coatings demonstrate enhanced stability against extreme external stressors, including organic solvents, proteases, and ethylene oxide gas sterilization. The protein stabilization effect is attributed to the maintenance of protein conformational structure, which is closely related to the nanoscale feature sizes of the mineral coatings. Basic fibroblast growth factor (bFGF) released from a nanostructured mineral coating maintains its biological activity for weeks during release, while it maintains activity for less than 7 d during release from commonly used polymeric microspheres. Delivery of the growth factors bFGF and vascular endothelial growth factor using a mineral coated surgical suture significantly improves functional Achilles tendon healing in a rabbit model, resulting in increased vascularization, more mature collagen fiber organization, and a two fold improvement in mechanical properties. The findings of this study demonstrate that biomimetic interactions between proteins and nanostructured minerals provide a new, broadly applicable mechanism to stabilize proteins in the context of drug delivery and regenerative medicine.
Proteins bound on the nanostructured coatings that mimic the structure of bone mineral demonstrate enhanced stability even against extreme external stressors, including organic solvents and ethylene oxide gas sterilization. This feature of these coatings, while used to stabilize growth factors, has demonstrated remarkably enhanced activity of growth factors both in vitro and in vivo, indicating its great potential in drug delivery and regenerative medicine.