Affinity-based release of glial-derived neurotrophic factor from fibrin matrices enhances sciatic nerve regeneration

Department of Biomedical Engineering, Washington University, Campus Box 1097, One Brookings Drive, St. Louis, MO 63130, USA.
Acta biomaterialia (Impact Factor: 6.03). 05/2009; 5(4):959-68. DOI: 10.1016/j.actbio.2008.11.008
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Glial-derived neurotrophic factor (GDNF) promotes both sensory and motor neuron survival. The delivery of GDNF to the peripheral nervous system has been shown to enhance regeneration following injury. In this study, we evaluated the effect of affinity-based delivery of GDNF from a fibrin matrix in a nerve guidance conduit on nerve regeneration in a 13 mm rat sciatic nerve defect. Seven experimental groups were evaluated which received GDNF or nerve growth factor (NGF) with the delivery system within the conduit, control groups excluding one or more components of the delivery system, and nerve isografts. Nerves were harvested 6 weeks after treatment for analysis by histomorphometry and electron microscopy. The use of the delivery system (DS) with either GDNF or NGF resulted in a higher frequency of nerve regeneration vs. control groups, as evidenced by a neural structure spanning the 13 mm gap. The GDNF DS and NGF DS groups were also similar to the nerve isograft group in measures of nerve fiber density, percent neural tissue and myelinated area measurements, but not in terms of total fiber counts. In addition, both groups contained a significantly greater percentage of larger diameter fibers, with GDNF DS having the largest in comparison to all groups, suggesting more mature neural content. The delivery of GDNF via the affinity-based delivery system can enhance peripheral nerve regeneration through a silicone conduit across a critical nerve gap and offers insight into potential future alternatives to the treatment of peripheral nerve injuries.

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    • "In addition, RT-PCR analysis has indicated that some AF cells express a number of neurotrophic factors, such as BDNF, GDNF, CNTF, NGF, and NT-3 (Pan et al. 2007). Since neurotrophic factors have frequently been shown to be neuroprotective in ischemic stroke models (Beck et al. 1994; Duarte et al. 2012; Ferrer et al. 1998; Kiprianova et al. 1999; Kitagawa et al. 1998a, 1998b; Miyazaki et al. 1999; Schabitz et al. 1997; Wang et al. 1997; Yamashita et al. 1997), traumatic brain injury (Minnich et al. 2010), and peripheral nerve injury (Fine et al. 2002; Kokai et al. 2011; Wood et al. 2009), it is possible that some of the beneficial effects of AF cells may be explained by the release of trophic factors. AF cells have also been shown to secrete a number of immune-modulating cytokines such as Il-6, and growth related oncogene (GRO) and monocyte chemotactic protein (MCP) family members (Moorefield et al. 2011), which might serve to limit the damage after nervous system injury. "
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    ABSTRACT: There is a need for improved therapy for acquired brain injury, which has proven resistant to treatment by numerous drugs in clinical trials and continues to represent one of the leading causes of disability worldwide. Research into cell-based therapies for the treatment of brain injury is growing rapidly, but the ideal cell source has yet to be determined. Subpopulations of cells found in amniotic fluid, which is readily obtained during routine amniocentesis, can be easily expanded in culture, have multipotent differentiation capacity, are non-tumourigenic, and avoid the ethical complications associated with embryonic stem cells, making them a promising cell source for therapeutic purposes. Beneficial effects of amniotic fluid cell transplantation have been reported in various models of nervous system injury. However, evidence that amniotic fluid cells can differentiate into mature, functional neurons in vivo and incorporate into the existing circuitry to replace lost or damaged neurons is lacking. The mechanisms by which amniotic fluid cells improve outcomes after experimental nervous system injury remain unclear. However, studies reporting the expression and release of neurotrophic, angiogenic, and immunomodulatory factors by amniotic fluid cells suggest they may provide neuroprotection and (or) stimulate endogenous repair and remodelling processes in the injured nervous system. In this paper, we address recent research related to the neuronal differentiation of amniotic fluid-derived cells, the therapeutic efficacy of these cells in animal models of nervous system injury, and the possible mechanisms mediating the positive outcomes achieved by amniotic fluid cell transplantation.
    Biochemistry and Cell Biology 10/2013; 91(5):271-86. DOI:10.1139/bcb-2013-0019 · 2.15 Impact Factor
    • "Natural biomaterials, such as fibrin gels, work well as peripheral nerve drug delivery systems due to their ease of placement (Jubran and Widenfalk, 2003) and lack of inhibitory effects on nerve regeneration (Sameem et al., 2011). Their utility as extended-release delivery devices is limited, however, because typically, drug release is limited to a few days in vivo (Jubran and Widenfalk, 2003; Wood et al., 2009, 2010, 2012). By combining materials, such as polymer microspheres , with fibrin gels or glue to construct a drug delivery device may allow tailoring for drug release profiles ranging from days, weeks, or months (Baumann et al., 2009; Garbayo et al., 2008, 2009; Wood et al., 2012). "
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    ABSTRACT: The majority of bioengineering strategies to promote peripheral nerve regeneration after injury have focused on therapies to bridge large nerve defects while fewer therapies are being developed to treat other nerve injuries, such as nerve transection. We constructed delivery systems using fibrin gels containing either free GDNF or polylactide-glycolic acid (PLGA) microspheres with GDNF to treat delayed nerve repair, where ELISA verified GDNF release. We determined the formulation of microspheres containing GDNF that optimized nerve regeneration and functional recovery in a rat model of delayed nerve repair. Experimental groups underwent delayed nerve repair and treatment with GDNF microspheres in fibrin glue at the repair site or control treatments (empty microspheres or free GDNF without microspheres). Contractile muscle force, muscle mass, and MUNE were measured 12 weeks following treatment, where GDNF microspheres (2 week formulation) were superior compared to either no GDNF or short-term release of free GDNF to nerve. Nerve histology distal to the repair site demonstrated increased axon counts and fiber diameters due to GDNF microspheres (2 week formulation). GDNF microspheres partially reversed the deleterious effects of chronic nerve injury, and recovery was slightly favored with the 2 week formulation compared to the 4 week formulation. Biotechnol. Bioeng. © 2012 Wiley Periodicals, Inc.
    Biotechnology and Bioengineering 05/2013; 110(5). DOI:10.1002/bit.24800 · 4.13 Impact Factor
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    • "In subsequent studies, the system has been used to deliver lower affinity heparin-binding growth factors, such as NGF (Sakiyama-Elbert & Hubbell, 2000b; Wood et al., 2007, 2009), NT-3 (Taylor et al., 2004; Willerth et al., 2008), glial-derived neurotrophic growth factor (Wood et al., 2008, 2009), platelet-derived growth factor (Willerth et al., 2008) and sonic hedgehog (Willerth et al., 2008). Wood et al. (2009) investigated the repair of a 13 mm gap in a rat sciatic nerve using a silicone nerve guidance conduit containing the delivery system loaded with GDNF; see Fig. 2. It was found that systems that contained the delivery system resulted in a higher frequency of nerve regeneration compared with control groups without the delivery system. "
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