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Purpose <p>Congenital pseudarthrosis of the tibia (CPT) is a rare genetic disease characterized by impaired periosteal bone tissue requiring multiple surgeries to achieve union. We present the first-in-human study assessing the safety of using a tissue-engineered bone construct with osteoinductive mesenchymal stem cells (MSCs) for the treatment of CPT.</p> Methods <p>MSCs were osteogenically primed on hydroxyapatite, tricalcium phosphate and silicate scaffolds, transplanted into children (<i>n</i> = 9) with CPT and monitored during a 2-year follow-up period for adverse events and union at either end.</p> Results <p>During the 2-year period, three patients experienced serious adverse events unrelated to stem cell transplantation. One had a seroma, while the other two had Rush rod fixation at the distal end, one of whom required graft removal for infection at 1&#xa0;year. All patients were full weight-bearing at a mean of 4.5&#xa0;months (3 to 7.5). At 3.17&#xa0;months (3–4.5), all patients showed radiological union of the graft. The bone mineral density in the region of the scaffold at 1&#xa0;year showed a mean increase of 0.235 ± 0.21&#xa0;g/cm<sup>2</sup> from 0.117 ± 0.1&#xa0;g/cm<sup>2</sup>; however, no improvement was observed in four children with neurofibromatosis type 1. The refractures occurred progressively from 9&#xa0;months onwards in seven patients over the next 4–6-year period requiring bone grafting.</p> Conclusion <p>In sum, contrast to traumatic bone defects, a more pragmatic approach is required to target the disease pathology with defective bone formation and mineralization to prevent refractures and deforming of the bones. This trial was registered at the Clinical Trials Registry — India (CTRI/2014/09/005027).</p> Lay Summary <p>Congenital pseudarthrosis of tibia (CPT) is a rare orthopaedic condition, often occurring in children with genetic mutations in neurofibromin gene. The disease is difficult to manage because once a bone breaks, it does not heal on its own unlike regular bone fractures. Treating CPT often requires multiple rounds of corrective surgeries, including the use of metal rod inside the bone, bone grafts, or external supports, along with removal of abnormal tissue. This study explores a new treatment strategy using a specially engineered bone graft with patient’s own stem cells to help the bone heal better. A total of nine children with CPT underwent transplantation with stem cells loaded with bone graft and monitored for 2&#xa0;years to assess for any complications and progressive healing. The initial results showed improvement but unlike regular bone injuries, treating CPT requires a more careful approach to address the underlying genetic issues with bone formation to prevent future fractures and deformities.</p>

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Safety Evaluation of Autologous Human Bone Marrow-derived MSCs on Hydroxyapatite-based Scaffold for Congenital Pseudarthrosis of the Tibia: A Pilot Clinical Trial

  • 期刊论文

  • 发表日期：

    2025年3月21日

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  • Vrisha Madhuri,
  • Sowmya Ramesh,
  • Bibhudutta Sahoo,
  • Suresh Babu Sivadasan,
  • Karthikeyan Rajagopal,
  • Madhavi Kandagaddala,
  • Francis. B. Fernandez,
  • Sridhar Gibikote,
  • Balakumar Balasubramanian,
  • Sanjay K. Chilbule,
  • Vivek Dutt Dinesh,
  • Augustine Thambaiah,
  • Aleya Tabasum,
  • Alok Srivastava,
  • Vikram Mathews,
  • Annie John,
  • Harikrishna Varma

摘要

Purpose

Congenital pseudarthrosis of the tibia (CPT) is a rare genetic disease characterized by impaired periosteal bone tissue requiring multiple surgeries to achieve union. We present the first-in-human study assessing the safety of using a tissue-engineered bone construct with osteoinductive mesenchymal stem cells (MSCs) for the treatment of CPT.

Methods

MSCs were osteogenically primed on hydroxyapatite, tricalcium phosphate and silicate scaffolds, transplanted into children (n = 9) with CPT and monitored during a 2-year follow-up period for adverse events and union at either end.

Results

During the 2-year period, three patients experienced serious adverse events unrelated to stem cell transplantation. One had a seroma, while the other two had Rush rod fixation at the distal end, one of whom required graft removal for infection at 1 year. All patients were full weight-bearing at a mean of 4.5 months (3 to 7.5). At 3.17 months (3–4.5), all patients showed radiological union of the graft. The bone mineral density in the region of the scaffold at 1 year showed a mean increase of 0.235 ± 0.21 g/cm2 from 0.117 ± 0.1 g/cm2; however, no improvement was observed in four children with neurofibromatosis type 1. The refractures occurred progressively from 9 months onwards in seven patients over the next 4–6-year period requiring bone grafting.

Conclusion

In sum, contrast to traumatic bone defects, a more pragmatic approach is required to target the disease pathology with defective bone formation and mineralization to prevent refractures and deforming of the bones. This trial was registered at the Clinical Trials Registry — India (CTRI/2014/09/005027).

Lay Summary

Congenital pseudarthrosis of tibia (CPT) is a rare orthopaedic condition, often occurring in children with genetic mutations in neurofibromin gene. The disease is difficult to manage because once a bone breaks, it does not heal on its own unlike regular bone fractures. Treating CPT often requires multiple rounds of corrective surgeries, including the use of metal rod inside the bone, bone grafts, or external supports, along with removal of abnormal tissue. This study explores a new treatment strategy using a specially engineered bone graft with patient’s own stem cells to help the bone heal better. A total of nine children with CPT underwent transplantation with stem cells loaded with bone graft and monitored for 2 years to assess for any complications and progressive healing. The initial results showed improvement but unlike regular bone injuries, treating CPT requires a more careful approach to address the underlying genetic issues with bone formation to prevent future fractures and deformities.