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Biomaterials. 2018 Jun;168:24-37. doi: 10.1016/j.biomaterials.2018.03.044. Epub 2018 Mar 26.

Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats.

Author information

1
Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
2
The Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China.
3
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
4
Department of Peripheral Neurosurgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
5
Department of Neurosurgery, Orthopaedics, Anatomy Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biomedical Engineering, Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: xjia@som.umaryland.edu.
6
Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: xfxj2000@126.com.

Abstract

Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p < 0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.

KEYWORDS:

Basic fibroblast growth factor; Diabetes; Heparin-poloxamer; Nerve growth factor; Nerve regeneration; Peripheral nerve injury

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