longitudinal-micro-computed-tomography-image-analysis-for-user

Longitudinal Micro-Computed Tomography Image Analysis for User-Defined Region of Interest in Critical-Sized Bone Defects

Micro-computed tomography (&#181;CT) imaging analysis of bone volume is a necessary quantitative tool for investigating bone regeneration potential and ...

University of Rochester

University of Rochester Medical Center

Despite decades of progress, developing minimally invasive bone-specific drug delivery systems (DDS) to improve fracture healing remains a significant clinical challenge. To address this critical therapeutic need, nanoparticle (NP) DDS comprised of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) functionalized with a peptide that targets tartrate-resistant acid phosphatase (TRAP) and achieves preferential fracture accumulation has been developed. The delivery of AR28, a glycogen synthase kinase-3 beta (GSK3β) inhibitor, via the TRAP binding peptide-NP (TBP-NP) expedites fracture healing. Interestingly, however, NPs are predominantly taken up by fracture-associated macrophages rather than cells typically associated with fracture healing. Therefore, the underlying mechanism of healing via TBP-NP is comprehensively investigated herein. TBP-NP promotes M2 macrophage polarization and enhances osteogenesis in preosteoblast-macrophage co-cultures in vitro. Longitudinal analysis of TBP-NP -mediated fracture healing reveals distinct spatial distributions of M2 macrophages, an increased M2/M1 ratio, and upregulation of anti-inflammatory and downregulated pro-inflammatory genes compared to controls. This work demonstrates the underlying therapeutic mechanism of bone-targeted NP DDS, which leverages macrophages as druggable targets and modulates M2 macrophage polarization to enhance fracture healing, highlighting the therapeutic benefit of this approach for fractures and bone-associated diseases.

Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing.

Regenerating critical-sized long bone defects poses substantial challenges due to limitations of autografts and processed allografts. Biomaterial scaffolds offer versatile alternatives, yet their effectiveness is often constrained by their limited innate osteoinductivity. While growth factors and cells can enhance osteoinduction, the inclusion of biologics in biomaterial scaffolds creates regulatory challenges for clinical translation. To address this, here we describe three-dimensional (3D) printed polycaprolactone (PCL) scaffolds for temporally controlled delivery of osteoimmunomodulatory amorphous calcium phosphate-chitosan nanoparticles (ACPC-NP). , the ACPC-NP exhibit concentration dependent effects on osteoblasts, monocytes, and osteoclasts. At increasing concentrations up to 500 μg/ml, these nanoparticles stimulate osteogenesis, modulate M2/M1 macrophage polarization, and inhibit osteoclast maturation and activity. Leveraging these concentration-dependent effects  through temporally controlled release of ACPC-NP from 3D-printed PCL scaffolds, we observe the complete regeneration and the restoration of biomechanical strength of critically sized radial defects in rats. Such healing is absent in defects implanted with bare PCL scaffolds or those loaded with calcium-phosphate microparticles. The tunable osteoimmunomodulation by the NP underscores the translational potential of this technology to yield structurally sound and functionally robust bone regeneration outcomes.

Article	Year
Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 37797180	2024
Dose-dependent osteoimmunomodulatory effects of amorphous calcium phosphate nanoparticles promote 3D-printed scaffold-mediated bone regeneration. Bioactive materials\| PubMed ID: 40487242	2025

Ming Yan

Biography

JoVE Journal Publications

Other Publications