Osteogenic efficiency of in situ gelling poloxamine systems with and without bone morphogenetic protein-2

Abstract

In situ gelling solutions for minimally invasive local application of bone growth factors are attracting increasing attention as efficient and patient-friendly alternative to bone grafts and solid scaffolds for repairing bone defects. Poloxamines, i.e., X-shaped poly(ethylene oxide)-poly(propylene oxide) block copolymers with an ethylenediamine core (Tetronic ® ), were evaluated both as an active osteogenic component and as a vehicle for rhBMP-2 injectable implants. After cytotoxicity screening of various poloxamine varieties, Tetronic 908, 1107, 1301 and 1307 solutions were chosen as the most cytocompatible and their sol-to-gel transitions were rheologically characterized. Viscoelastic gels, formed at 37 ºC, sustained protein release under physiological-like conditions. Formulations of rhBMP-2 led to differentiation of mesenchymal stem cells to osteoblasts, quantifi ed as alkaline phosphatase activity with a maximum at day 7, and to mineralized nodules. Interestingly, poloxamine solely gels led to an initial proliferation of the mesenchymal stem cells (fi rst week), followed by differentiation to osteoblasts (second to third week). Histochemical analysis revealed that Tetronic 908 is only osteoinductive; Tetronic 1107 is mostly osteoinductive, although its use leads to a minor differentiation to adipocytes; Tetronic 1307, solely or loaded with rhBMP-2, causes differentiation of both osteoblasts and adipocytes. Enhanced expression levels of CBFA-1 and collagen type I were observed for Tetronic 908, 1107 and 1307, both solely and combined with rhBMP-2. The intrinsic osteogenic activity of poloxamines (not observed for Pluronic F127) offers novel perspectives for bone regeneration using minimally invasive procedures (i.e., injectable scaffolds) and overcoming the safety and the cost/ effectiveness concerns associated with large scale clinical use of recombinant growth factors.

Poloxamine–Cyclodextrin–Simvastatin Supramolecular Systems Promote Osteoblast Differentiation of Mesenchymal Stem Cells

“…Currently, bone morphogenetic proteins (BMPs), mainly rhBMP‐2 and/or rhBMP‐7, are clinically used in the form of collagen sponges for non‐union, open tibial fractures and spinal fusions 3, 4. Alternative carriers/depots that can be applied in the critical defect using minimally invasive techniques, while combining stabilization and slow clearance of BMPs from the application site are under study 5–7. Nevertheless, the rapid local metabolization and the high cost of recombinant proteins make necessary the finding of more affordable and stable osteogenic/osteoinductive synthetic molecules that can mimic the biochemical stimuli that mesenchymal stem cells (MSCs) receive in their native bone niche to differentiate to bone precursors 1, 7…”

Evaluation of the donor cell contribution in rhBMP‐2 mediated bone formation with chitosan thermogels using fluorescent protein reporter mice

“…Injectable scaffolds have recently gained attention due to the growing popularity of minimally invasive arthroscopic and orthopaedic procedures . Moreover, injectable hydrogels are highly advantageous for growth factor and cellular delivery due to their hydrophilic nature, viscoelasticity and stimuli‐responsiveness .…”

Cyclodextrin-Mediated Hierarchical Self-Assembly and Its Potential in Drug Delivery Applications

“…120 Like poloxamers, they undergo a sol-gel transition at 37 C and appropriate pH and concentration conditions. Despite being injectable into bone-degenerative defect sites, the resulting hydrogels lack in consistency and are not able to remain in the injection site long enough to provide a sustained release of auxiliary low molecular weight osteoblast growth-inducing agents.…”