Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair

Philip J Hanwright; Chenhu Qiu; Jennifer Rath; Yang Zhou; Nicholas von Guionneau; Karim A Sarhane; Thomas G W Harris; Gregory P Howard; Harsha Malapati; Michael J Lan; Sashank Reddy; Ahmet Hoke; Hai-Quan Mao; Sami H Tuffaha

doi:10.1016/j.biomaterials.2021.121244

Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair

Biomaterials. 2022 Jan:280:121244. doi: 10.1016/j.biomaterials.2021.121244. Epub 2021 Nov 12.

Authors

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
² Department of Materials Science and Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA.
³ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁴ Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁵ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
⁶ Department of Materials Science and Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address: hmao@jhu.edu.
⁷ Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address: stuffah1@jhmi.edu.

PMID: 34794826
DOI: 10.1016/j.biomaterials.2021.121244

Abstract

Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

Keywords: Chronic denervation; IGF-1; Nanoparticles; Nerve regeneration; Peripheral nerve injury.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Denervation
Insulin-Like Growth Factor I / metabolism
Insulin-Like Growth Factor I / therapeutic use
Muscle, Skeletal / metabolism
Nerve Regeneration
Peripheral Nerve Injuries* / drug therapy
Rats
Recovery of Function / physiology
Schwann Cells / metabolism

Substances

Insulin-Like Growth Factor I