Tissue Engineering, Regenerative Medicine, and Clinical Applications in Orthopedics: From Bench to Bedside

Abstract

Osteosarcoma (OS) is the most common bone tumor in the pediatric population, representing >50% of bone malignancies in patients <20 years old. Following surgical resection of the tumor, allografts or metal endoprostheses are used to reconstruct bone voids. In addition, patients with OS undergo systemic chemotherapy to prevent micro-metastases and recurrence. However, treatment is suboptimal; allografts are obtained from tissue banks and need to be matched for major histocompatibility complexes, limiting availability, and though prosthetic materials have been utilized in the clinic for years, they cause incomplete healing, extended time to heal, prolonged non-weight bearing periods, increased fracture risk, infections, degenerative arthritis, and joint instability. This evidence demonstrates a gap in the current standard of care and urges the development of novel treatment options for the regeneration of bone loss in following tumor excision in pediatric OS. Though it is known that a previously developed biomimetic magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) can regenerate bone, it is unclear if MHA/Coll is oncologically safe and can promote bone regeneration in the presence of chemotherapy. We were able to determine that MHA/Coll can promote bone regeneration when exposed to chemotherapy and that MHA/Coll has properties that suggest oncologic safety. In vitro, we demonstrated that human mesenchymal stem cells (hMSCs) seeded on MHA/Coll had significantly less migration towards TCCC-OS cells or PDX-derived conditional media. Moreover, hMSCs on MHA/Coll had increased expression of osteogenic genes (BGLAP, SPP1, ALP), even when exposed chemotherapeutics. In a critical size defect murine model, we proved that MHA/Coll promotes a generation of a higher volume of bone if systemic chemotherapy is given before or after surgery compared to mice not given chemotherapy. This is the first study to demonstrate that a highly osteogenic scaffold can be oncologically safe and hMSCs recruited to the scaffold are able to undergo osteogenesis in vitro and are unaffected by chemotherapy in vitro and in vivo. The possibility to repair bone voids utilizing a highly osteogenic scaffold following tumor excision could lead to improved outcomes and fewer complications for patients affected by OS.