Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair

Frontiers in Bioengineering and Biotechnology

Bioengineering and Biotechnology

Kelsey M. O’Hara¹  Victoria R. Duke¹  Joel A. Finbloom²  Bhushan N. Kharbikar²  Nafisa A. Elghazali³  Justin X. Zhong³  Theodore Miclau⁴  Ralph S. Marcucio⁴  Darnell L. Cuylear⁵  Tejal A. Desai⁶  Chelsea S. Bahney⁷  Kevin O. Rivera⁸  Alex N. Kryger⁹ 

[1] Center for Regenerative and Personalized Medicine, The Steadman Philippon Research Institute (SPRI), Vail, CO, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United States;UC Berkeley—UCSF Graduate Program in Bioengineering, San Francisco, CA, United States;Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United States;Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United States;Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Bioengineering, University of California, Berkeley (UC Berkeley), Berkeley, CA, United States;School of Engineering, Brown University, Providence, RI, United States;Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United States;Center for Regenerative and Personalized Medicine, The Steadman Philippon Research Institute (SPRI), Vail, CO, United States;UC Berkeley—UCSF Graduate Program in Bioengineering, San Francisco, CA, United States;Graduate Program in Oral and Craniofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco (UCSF), San Francisco, CA, United States;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), San Francisco, CA, United States;School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, United States;

关键词: fracture repair;    endochondral ossification;    beta-nerve growth factor;    drug delivery;    sustained release;    poly (ethylene) glycol dimethacrylate;   

DOI  :  10.3389/fbioe.2023.1190371

 received in 2023-03-20, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (β-NGF) for the purpose of promoting fracture repair.Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with β-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the β-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble β-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry.Results: In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of β-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble β-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that β-NGF promotes endochondral conversion of cartilage to bone to accelerate healing.Discussion: We demonstrate a novel and translational method wherein β-NGF can be encapsulated within PEGDMA microrods for local delivery and that β-NGF bioactivity is maintained resulting in improved bone fracture repair.

【 授权许可】

Unknown   
Copyright © 2023 Rivera, Cuylear, Duke, O’Hara, Zhong, Elghazali, Finbloom, Kharbikar, Kryger, Miclau, Marcucio, Bahney and Desai.