A scaffold-free graft for large critical size bone defect: preclinical evidence to clinical proof of concept


Theys, Nicolas (Novadip Biosciences)


"Introduction. Large critical size bone defect is one of the most challenging pathologies in orthopaedic surgery. NVD‑003 is an autologous scaffold-free cell-based osteogenic implant intended to improve bone healing in severe pathophysiological conditions. This study aims to investigate the therapeutic potential of NVD-003, an osteogenic graft derived from human adipose stem cells.
Methods. NVD-003 consists of autologous osteogenic cells cultured from adipose tissue derived stem cells embedded in their extracellular matrix with hydroxyapatite/beta-tricalcium phosphate (HA/TCP) particles. The bioactivity of NVD-003 was studied in nude rat models: (i) to compare the impact of fresh or decellularized grafts in term of angiogenesis (up to 1 month) in a fibrotic tissue (in a cauterized muscular pocket); (ii) to assess its in vivo osteogenicity (in comparison to HA/TCP particles alone), at 1/2/3 months post-implantation, in an irreversible femoral critical size bone defect. The angiogenesis was quantified by histomorphometry while the osteogenesis was studied by micro-CTscan, histomorphometry and Q-RT-PCR on graft explants. Four paediatric patients (5 to 15 years old) suffering from a congenital pseudarthrosis of the tibia were treated in a compassionate use program. Three months after the adipose tissue procurement, the 3D-grafts were placed into the defect and followed clinically and radiologically.
Results. (i)- Preclinical: After 1-mo of intra-muscular implantation, cellular survival of human cells and the promotion of angiogenesis were observed. The number of blood vessels number per tissue area at 12 weeks post-implantation and the blood vessels area per tissue area at 8 weeks post-implantation were noticeably increased in NVD-003 implants as compared to HA/TCP particles. Quantitative analysis of µCT images at successive imaging time points (4, 8 and 12 weeks) showed that a similar level of mineralization was observed at each time point, indicating the absence of resorption of the test item up to 3 months post-implantation. A complete integration and bone fusion were found for the 3D graft in comparison to HA/TCP alone which revealed a lack of tissue remodelling and osteogenesis. Specific genes of the skeletal development were overexpressed in the bone defect treated with the NVD-003 (at 4/8 weeks post-implantation) while no osteoinduction was found for the HA/TCP particles alone. Changes in bone formation were assessed using histomorphometry measurements of the entire implant site. Bone area showed a trend towards an increase with NVD-003 already at 8 weeks post-implantation, while a noticeable increase in bone area was observed with NVD-003 as compared to HA/βTCP samples at 12 weeks post-implantation.
(ii) Clinical: A large volume (>15cm3) of the autologous 3D graft was manufactured in aseptic areas under GMP requirements for each patient and then implanted without any modification of the surgical procedure. The graft was easily handled, shaped, and implanted. NVD-003 implant demonstrated a continuous remodelling (with bone formation) up to 14 months post-implantation to obtain a sufficient bone fusion (allowing walk without pain) and no recurrence of the disease.
Conclusion. The NVD-003 graft plays a major role to induce angio- and osteogenesis in a complex environment and to recover a bone fusion in a critical-sized bone defect."


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