Safety and Efficacy Results of BonoFill First-in-Human, Phase I/IIa Clinical Trial for the Maxillofacial Indication of Sinus Augmentation and Mandibular Bone Void Filling.

PURPOSE: The gold standard for bone regeneration of bone deficiencies is still an autologous bone graft, which has considerable disadvantages; namely, the need for a second major surgery and the limited volume of bone available for harvesting. BonoFill (BF) is a novel, tissue-engineered, bone graft with intrinsic osteoinductive, osteoconductive, and osteogenic properties, consisting of the patient's own adipose tissue-derived mesenchymal stem cells, attached to hydroxyapatite particles. Here, we present the safety and efficacy results of BF first-in-human clinical study for maxillofacial bone tissue regeneration. MATERIALS AND METHODS: Eleven eligible male and female subjects, aged 49-65 years, were enrolled into the clinical study in 2 clinical indications: Bone augmentation and bone void grafting in the jaws. Clinical follow-up was performed throughout a period of 6 months after BF treatment and included clinical examination, blood tests, CT scans, and biopsies collected from the transplantation site to assess chronic bone infection, changes in complete blood count, and adequate bone augmentation for implant placement. RESULTS: The study results demonstrated that BF promoted adequate bone tissue regeneration without complications. Per our evaluation, there were no incidents of chronic bone infection, or significant changes in complete blood count, and the patients reported overall good health for the duration of the study. At trial end, in the sinus augmentation indication, the BF treated sites residual bone was augmented at an average of 6.36 mm (Δ new bone, n = 10) and the total bone height at the treated area was on average 11.44 mm (n = 10). In the indication of filling of bone voids, the patient's average residual bone height of 2.91 mm was 15.76 mm (n = 1) at trial end. CONCLUSIONS: BF treatment was shown to be safe and resulted in newly generated bone, which provided adequate bone height for placement of dental implants. Thus, BF is a promising novel autologous bone graft for bone tissue repair.

Stem cells of the lamina propria of human oral mucosa and gingiva develop into mineralized tissues in vivo.

AIMS: To characterize the mineralized tissue formed constitutively in the supracalvarial region of scid mice by a primitive stem cell population (hOMSC) derived from the lamina propria of the human oral mucosa and gingiva. MATERIAL AND METHODS: Fibrin-hOMSC constructs were cultured for 14 days at which time point they were analysed for the expression of osteoblastic/cementoblastic markers and implanted between the skin and calvaria bones into scid mice. After 8 weeks, the animals were sacrificed and the implantation sites analysed. RESULTS: Two-week-old cultures of fibrin-hOMSC constructs expressed osteogenic/cementogenic markers at the gene level. Macroscopic and radiographic examinations revealed mineralized masses at the implantation sites of fibrin-hOMSC constructs. Histology, histochemistry and immunofluorescence showed mineralized masses consisting of avascular cellular and acellular matrices that stained positively for collagen, Ca, cementum attachment protein, cementum protein 1, bone sialoprotein, alkaline phosphatase, osteocalcin, amelogenin and ameloblastin. Positive anti-human nuclear antigen indicated the human origin of the cells. Atomic force microscopy depicted long prismatic structures organized in lamellar aggregates. CONCLUSIONS: Within the limitation of this study, the results indicate for the first time that fibrin-hOMSC constructs are endowed with the constitutive capacity to develop into mineralized tissues that exhibit certain similarities to cementum and bone.

Autologous cell-coated particles for the treatment of segmental bone defects-a new cell therapy approach.

BACKGROUND: Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are one of the most potent adult stem cells, capable of differentiating into bone, cartilage, adipose, muscle, and others. An innovative autologous AT-MSC-derived cell-based product (BonoFill-II) for bone tissue regeneration was developed to be suited as a bone graft for segmental bone defects. METHODS: BonoFill-II was transplanted into 8 sheep with 3.2-cm full cortex segmental defect formed in the tibia. Bone regeneration was followed by X-ray radiographs for 12 weeks. At experiment termination, the healed tibia bones were analyzed by computed tomography, histology, and mechanical tests. RESULTS: Our results indicate that one dose of BonoFill-II injectable formula led to an extensive bone growth within the transplantation site and to a complete closure of the critical gap in the sheep's tibia in a relatively short time (8-12 weeks), with no inflammation and no other signs of graft rejection. This new and innovative product opens new prospects for the treatment of long bone defects. CONCLUSIONS: Injection of BonoFill-II (an innovative autologous cell therapy product for bone tissue regeneration) into a critical size segmental defect model (3.2 cm), generated in the sheep tibia, achieved full bridging of the gap in an extremely short period (8-12 weeks).