Development-based In Vivo Bioreactor Strategy for Challenging Senescent Bone Reconstruction

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Orthopedic Surgery

Background:

• Critical segmental bone defects in elderly patients present significant challenges due to aging-related bone dysfunction and limited graft options.
• Fibrous tissue invasion further compromises healing in aged bone, necessitating innovative therapeutic strategies.

Purpose of the Study:

• To develop an in vivo bioreactor strategy using BMP-2 loaded biomaterials to engineer bone (vBR-Bone) that recapitulates native osseous architecture.
• To evaluate the efficacy of vBR-Bone in rejuvenating aged bone and repairing critical-sized femoral defects in aged murine models.

Main Methods:

• An in vivo bioreactor strategy was employed, utilizing BMP-2 loaded biomaterials to trigger intrinsic developmental programs for bone regeneration.
• The engineered vBR-Bone was tested in aged murine models with critical-sized femoral shaft defects, utilizing a compartmentalized approach with a biomimetic periosteum.
• Mechanistic studies investigated the role of TGF-β1 and the PI3K/AKT/mTOR signaling axis in vBR-Bone mediated osteogenesis.

Main Results:

• vBR-Bone successfully recapitulated native bone architecture, including vasculature and marrow niche, and rejuvenated aged bone by reducing senescence and improving stem cell function.
• A 6-week repair of critical-sized femoral defects was achieved in aged mice using vBR-Bone fragments within a biomimetic periosteum, restoring bone mineral density, volume, and microstructure.
• The biomimetic periosteum facilitated vascular ingrowth while inhibiting fibrous invasion, creating an optimal environment for regeneration.

Conclusions:

• The in vivo bioreactor-derived bone (vBR-Bone) strategy offers a promising solution for critical age-related segmental bone defects by overcoming autograft limitations and senescence-associated dysfunction.
• This approach effectively rejuvenates aged bone and promotes robust osteogenesis through a reconstituted bone-remodeling microenvironment.
• vBR-Bone represents a clinically translatable strategy for enhancing bone repair in elderly populations.