Multimodal Biological Augmentation with Umbilical Cord Mesenchymal Stem Cell Secretome, Recombinant Human Bone Morphogenetic Protein-2, and Allogeneic Umbilical Cord Mesenchymal Stem Cells in Neurofibromatosis Type 1-Confirmed Congenital Pseudarthrosis of the Distal Tibia and Fibula: A Case Report with Mechanistic Scoping Review.

INTRODUCTION: Congenital pseudarthrosis of the tibia (CPT) associated with neurofibromatosis type 1 (NF1) is characterized by convergent dysregulation of three molecular pathways - transforming growth factor-beta/Smad-driven fibrogenesis, RAS-MEK-ERK hyperactivation, and Wnt/β-catenin blockade - none of which is addressed by conventional surgical fixation alone. This case explores the clinical feasibility of a multimodal biological protocol targeting all three pathways simultaneously.

CASE REPORT: A 6-year-old male with histopathologically confirmed NF1-associated Crawford type IV CPT of the distal tibia and concurrent distal fibular pseudarthrosis underwent radical hamartoma excision combined with quadruple biological augmentation: Allogeneic umbilical cord mesenchymal stem cells (UC-MSC) (20 million cells), UC-MSC conditioned medium (secretome; first injection intraoperatively post-graft), recombinant human bone morphogenetic protein-2 (rhBMP-2) (Novosys), and synthetic hydroxyapatite scaffold (Bongros), stabilized with an Ilizarov trans-ankle external fixator. A second secretome injection (1.4 mL, fluoroscopy-guided) was administered percutaneously at 8 months, targeting the distal tibial union site during frame removal.

CONCLUSION: Tibial callus measured 9.88 mm at 6 months (equalling diaphyseal width) with no graft resorption. At 8 months, tibial bridging callus was sufficient to permit Ilizarov frame removal without refracture. The distal tibial pseudarthrosis was stabilized with retained K-wires; the fibula received no internal fixation and showed no ongoing healing. No infection or hardware complication occurred. This case is, to our knowledge, the first to describe this quadruple augmentation protocol and a two-stage secretome delivery strategy in CPT, providing a hypothesis-generating proof of concept for future translational investigation.