BonoFill-II, from bench to bedside: A novel autologous cell-based, tissue-engineered product in line to replace bone autografts for large segmental bone defect applications

Abstract

Background & Aim Significant losses of bone tissues that are often too large to heal occur in >10% of all open fractures and present an urgent clinical challenge associated with grave morbidities and huge healthcare costs. Bone autografting, the therapeutic standard in such cases, has a 50% complication rate, with persistent infection or non-union present in 18% of the patients, and further surgery required in 36% of them. Bone tissue engineering technologies have been widely suggested as an alternative to autografts. Such technologies were tested in segmental animal bone defects up to 5 cm long, with success reported mostly for defects under 2.5 cm. This size (or equivalent product volume) is also the upper limit for tissue-engineered bone grafts in clinical development. Considering that much larger defects, with a mean of 5.5 cm, are encountered in the clinic, Bonus is developing autologous tissue-engineered bone grafts for the treatment of defects larger than 2.5 cm. Methods, Results & Conclusion Bonus utilizes proprietary procedures to isolate adipose tissue-derived mesenchymal cells from patients’ lipoaspirates, seed them on mineral scaffold particles, and culture them in a specially designed bioreactor (Fig. 1). The expansion of the cells on this scaffold increases their osteo-inducibility, allowing a controlled osteoinduction process that possibly also retains some of these cells’ additional regenerative functions. This possibility is exemplified by the higher levels of osteogenic and other genes related to angiogenesis and ECM remodeling expressed by 3D-osteoinduced cells, compared to the 2D ones. After their osteoinduction, the cells and scaffold are washed and formulated into the final product—BonoFill-II. In a preclinical study, BonoFill-II applied to a 3.2 cm defect in a sheep tibia led to a full recovery in 12 weeks (N=7), as well as a full bridging of a 10.5 cm defect (Fig. 2). A phase I/II clinical trial is currently underway testing BonoFill-II in patients with bone defects ≥2.5 cm. So far, we have treated patients with defects up to 8.5 cm long and a history of 2-7 failed prior interventions, with a few representatives that can exemplify this study safety and efficacy (Fig. 3). The performance of BonoFill-II was also tested in Phase I/II trial in patients in need of a bone transplant in the upper maxilla with complete success reported. Overall, the solid underlying science and innovative technologies developed by Bonus position BonoFill-II as a promising alternative to bone autografts.