Editors' ChoiceBone Regeneration

Biomaterials-based biologic burst release builds better bone

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Science Translational Medicine  23 Nov 2016:
Vol. 8, Issue 366, pp. 366ec189
DOI: 10.1126/scitranslmed.aal2797

Trauma results in over 6 million bone fractures per year. Although most can be repaired through bone setting with internal or external fixation, 5 to 13% fail to regenerate, leading to nonunions. Grafts comprised of a patient’s own bone tissue (autografts) or cadaver tissue (allografts) are the gold standard therapies used to repair nonunions, but they have significant drawbacks, including donor site morbidity and potential disease transmission, respectively. Synthetic and biological–based materials that release bioactive molecules hold tremendous promise for improving regenerative outcomes without the drawbacks of current gold standard graft technology. Parathyroid hormone (PTH) is known to modify bone homeostasis and is a U.S. Food and Drug Administration–approved biologic therapeutic for the systemic treatment of osteoporosis. Interestingly, PTH must be delivered in a pulsatile fashion to enhance bone deposition, since continuous delivery can lead to bone resorption. The current PTH treatment regimen for osteoporosis requires daily injections; although helpful for facilitating systemic bone deposition, this strategy is likely not optimal for site-specific bone regeneration.

In a recent study, Dang et al. developed a multilayered biomaterial that produced localized burst release of PTH and showed significantly enhanced bone regeneration in a calvarial defect model in mice. The biodegradable biomaterial was comprised of a three-dimensional (3D) porous nanofibrous poly(L-lactic acid) scaffold coupled with a poly(caprolactone) shell with internal alternating layers of surface-eroding polyanhydride and alginate/PTH. The authors showed that this construct achieved pulsatile release of PTH for a few hours each day for up to 21 days. The biomaterial was implanted into a calvarial defect in mice and compared with animals given a similar device that delivered bioinactive bovine serum albumin (BSA) protein control, a continuous-release PTH scaffold, or daily injections of PTH. The results showed that localized pulsatile delivery of PTH effectively regenerated bone tissue, whereas daily injections of PTH, continuous BSA release, and continuous PTH release showed partial, minimal, and no regeneration, respectively. As expected, localized PTH delivery also obviated some of the off-target effects associated with systemic PTH delivery, as demonstrated by the minimal mineralization seen in the tibia.

Additional studies need to be conducted to investigate whether these effects can be recapitulated in long bones like the ulna or the femur because the calvarial defect model utilizes a 2D fracture plane rather than the 3D region present in the majority of nonunion fractures. Nevertheless, the work by Dang et al. provides strong support for the utility of their pulsatile PTH delivery system for localized bone regeneration.

M. Dang et al., Local pulsatile PTH delivery regenerates bone defects via enhanced bone remodeling in a cell-free scaffold. Biomaterials 114, 1–9 (2017). [Full Text]

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