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

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.

Engineered full-length Fibronectin-based hydrogels sequester and present growth factors to promote regenerative responses in vitro and in vivo

“…The ulna was left intact to provide mechanical stabilisation and to avoid the use of additional external fixation plates. Hydrogel-filled implant tubes, 4 mm in length and that contain multiple pores along their sides 21,22,71 , were placed inside the bone defect.…”

“…Taking into account that 70% of BMP2 (not bound to FN) is released during the first hours, the amount of BMP2 that remained within the FNPEG+ hydrogels was only 4.5 ng per implant tube for an initial loading of 5 µg/mL (providing an actual BMP2 concentration of 1.5 µg/mL retained within the hydrogel), and for FNPEG++ hydrogels, 67.5 ng of BMP2 per implant tube for an initial loading of 75 µg/mL (providing an actual BMP2 concentration of retained 22.5 µg/mL within the hydrogel). We note that 4.5 ng of BMP2 in this model is considered to be an ultralow dose 21,22 .…”

“…It has been used to expose the FNIII 9-10 and FNIII [12][13][14] binding sites to cells to enable the delivery of ultra-low doses of BMP2 [19][20][21] . This PEAbased system has been used to present BMP2 in a murine non-healing (critical-size) bone defect model 22 and in a veterinary case of a dog with a humeral fracture 21 . It has also been used to present VEGF in an in vivo wound healing murine model 20 .…”

Gelatin Nanoparticle‐Injectable Platelet‐Rich Fibrin Double Network Hydrogels with Local Adaptability and Bioactivity for Enhanced Osteogenesis

“…In case of complex bone defects with critically sized defect area, irregular shape, and mechanical stimuli due to human's physiological activities presents as a limiting factor to achieve bone regeneration. To overcome this, bone grafts containing osteoinductive growth factors especially BMP‐2 and BMP‐7 have been extensively used for clinical treatment of bone defects . However, severe side effects, high cost, and off‐label use of inappropriate dose of these growth factors have restricted further applications in clinics .…”

“…To overcome this, bone grafts containing osteoinductive growth factors especially BMP‐2 and BMP‐7 have been extensively used for clinical treatment of bone defects . However, severe side effects, high cost, and off‐label use of inappropriate dose of these growth factors have restricted further applications in clinics . Thus, to achieve sustained release of, preferably autologous, growth factors at a physiologically relevant dose is an important key to realize successful bone regeneration.…”