Nanoscale Coatings for Ultralow Dose BMP-2-Driven Regeneration of Critical-Sized Bone Defects.

Zhe A Cheng,David W Shields,Manuel Salmeron‐Sanchez,Laura Ruiz‐Cantu,James F C Windmill,Matthew J Dalby,Peter Childs,Cristina Gonzalez‐Garcia,Elena S Addison,Hannah Donnelly,Andrew Reid,Marco Cantini,Sandra Corr,Andres Alba‐Perez,Virginia Llopis‐Hernandez,William G Marshall,Vineetha Jayawarna

doi:10.1002/advs.201800361

Abstract

While new biomaterials for regenerative therapies are being reported in the literature, clinical translation is slow. Some existing regenerative approaches rely on high doses of growth factors, such as bone morphogenetic protein‐2 (BMP‐2) in bone regeneration, which can cause serious side effects. An ultralow‐dose growth factor technology is described yielding high bioactivity based on a simple polymer, poly(ethyl acrylate) (PEA), and mechanisms to drive stem cell differentiation and bone regeneration in a critical‐sized murine defect model with translation to a clinical veterinary setting are reported. This material‐based technology triggers spontaneous fibronectin organization and stimulates growth factor signalling, enabling synergistic integrin and BMP‐2 receptor activation in mesenchymal stem cells. To translate this technology, plasma‐polymerized PEA is used on 2D and 3D substrates to enhance cell signalling in vitro, showing the complete healing of a critical‐sized bone injury in mice in vivo. Efficacy is demonstrated in a Münsterländer dog with a nonhealing humerus fracture, establishing the clinical translation of advanced ultralow‐dose growth factor treatment.

Highlights

While new biomaterials for regenerative therapies are being reported in the musculoskeletal injuries at a cost of $9.8 billion annually in the USA.[5]
Changes in plasma settings resulted in coatings of different thicknesses but with similar X-ray photoelectron spectroscopy (XPS) spectra, indicating that the properties of the plasmapolymerized PEA (pPEA) deposited at different conditions were comparable (Figure S2, Supporting Information)
We looked at the FN(III9–10) domain, which includes the RGD (Arg-GlyAsp) sequence for integrin binding,[30,31,32] and the FN(III12–14) domain,[17] which binds a variety of growth factor (GF) families including bone morphogenetic proteins (BMPs)-2.[16,23] The availability of both domains was significantly higher on pPEA coatings than on SC-poly(ethyl acrylate) (PEA) surfaces (p < 0.05)

Summary

Introduction

While new biomaterials for regenerative therapies are being reported in the musculoskeletal injuries at a cost of $9.8 billion annually in the USA.[5]. Therapeutic approaches for the treatment of nonunion fractures defect model with translation to a clinical veterinary setting are reported This material-based technology triggers spontaneous fibronectin organization and stimulates growth factor signalling, enabling synergistic integrin and BMP-2 receptor activation in mesenchymal stem cells. Plasma-polymerized PEA is used on 2D and 3D substrates to enhance cell include growth factor (GF)-based treatments,[6,7] stem cell therapies,[7] and magnetic field treatments.[7,8] GFs, in particular bone morphogenetic proteins (BMPs), are commonly used in fracture treatments They are not without limitations, signalling in vitro, showing the complete healing of a critical-sized bone including partial efficacy[9]; uncontrolled injury in mice in vivo. Rates of nonunions from 2 to are being developed to replace existing GF-based treatments by

Results

Discussion

Conclusion