Localized Tacrolimus Delivery Repairs the Damaged Central Nervous System

The central nervous system (CNS) possesses a limited capacity to regenerate in comparison to other tissues with higher regenerative capacities, like the peripheral nervous system and skin. Thus, CNS injuries can be particularly devastating as the body does not repair these wounds in the same manner as these other tissues. Damage to the CNS comes in two waves post-injury. The initial trauma causes the primary injury, disrupting structures of the CNS and leading to cell death. A cascade of events follows this initial injury, causing additional damage and reducing the regenerative capacity of CNS tissue. These events include scarring of the wound induced by astrocytes and infiltration of the injury site by neutrophils and macrophages due to the immune response. Both of these phenomena contribute to the inhibitory environment present after injury. Reducing the effects of the inflammatory response increases the potential for regeneration after such injuries by improving the microenvironment. The Food and Drug Administration (FDA) approved drug tacrolimus, also known as FK506, acts to suppress the immune system. Accordingly, it is delivered either systematically or orally to prevent organ rejection after transplantation. Tacrolimus also promotes nerve regeneration through the aforementioned mechanism by mitigating the effects of inflammation and reactive glia, including astrocytes (Konofaos and Terzis, 2013Konofaos P. Terzis J.K. FK506 and nerve regeneration: past, present, and future.J. Reconstr. Microsurg. 2013; 29: 141-148Crossref PubMed Scopus (60) Google Scholar). However, systematic administration of the levels of tacrolimus necessary for promoting regeneration in CNS results in damage to other organs in the body that take up the drug more readily (Kruh and Foster, 2012Kruh J. Foster C.S. Corticosteroid-sparing agents: conventional systemic immunosuppressants.in: New Treatments in Noninfectious Uveitis. Karger Publishers, 2012Crossref Scopus (32) Google Scholar). Controlled release of tacrolimus from biomaterial scaffolds addresses this issue by providing localized delivery of this agent to the injury site while limiting its exposure to other organs. However, previous biomaterial-based controlled release strategies have focused on tacrolimus delivery to other tissues, like skin, using hydrogels, (Gabriel et al., 2016Gabriel D. Mugnier T. Courthion H. Kranidioti K. Karagianni N. Denis M.C. Lapteva M. Kalia Y. Möller M. Gurny R. Improved topical delivery of tacrolimus: a novel composite hydrogel formulation for the treatment of psoriasis.J. Control. Release. 2016; 242: 16-24Crossref PubMed Scopus (51) Google Scholar) or by using microspheres to promote peripheral nerve regeneration in vitro (Tajdaran et al., 2015Tajdaran K. Shoichet M.S. Gordon T. Borschel G.H. A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506).Biotechnol. Bioeng. 2015; 112: 1948-1953Crossref PubMed Scopus (49) Google Scholar) – instead of attempting to regenerate damaged CNS. The study by van der Merwe et al. featured in this issue of EBioMedicine develops a novel electrospun scaffold for in vivo tacrolimus delivery (van der Merwe et al., 2017van der Merwe Y. Faust A.E. Conner I.P. Gu X. Feturi F. Zhao W. Leonard B. Roy S. Gorantla V.S. Venkataramanan R. Washington K.M. Wagner W.R. Steketee M.B. An elastomeric polymer matrix, PEUU-Tac, delivers bioactive tacrolimus transdurally to the CNS in rat.EBioMedicine. 2017; (TBA)Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Electrospinning serves as a commonly used method for producing defined nanofiber scaffolds with appropriate physical and chemical properties for tissue engineering applications (Villarreal-Gómez et al., 2016Villarreal-Gómez L.J. Cornejo-Bravo J.M. Vera-Graziano R. Grande D. Electrospinning as a powerful technique for biomedical applications: a critically selected survey.J. Biomater. Sci. Polym. Ed. 2016; 27: 157-176Crossref PubMed Scopus (100) Google Scholar). Here, they fabricate these fibrous scaffolds from the low cost, biocompatible elastomeric material poly(ester urethane)urea (PEUU) (Stankus et al., 2004Stankus J.J. Guan J. Wagner W.R. Fabrication of biodegradable elastomeric scaffolds with sub-micron morphologies.J. Biomed. Mater. Res. A. 2004; 70: 603-614Crossref PubMed Google Scholar) and tune the mechanical properties of this electrospun scaffold referred to as PEUU-Tac to replicate the features of the dura, the protective membrane that surrounds the CNS. They first loaded tacrolimus into these scaffolds and showed that these scaffolds deliver the majority (~85%) of the drug within 24 h as indicated by in vitro release studies. These scaffolds remained stable for 5 weeks before starting to degrade. They also showed that tacrolimus modulates the survival of retinal ganglion cells in a dose-dependent fashion in vitro and increases neurite extension in the same cell culture system. These electrospun sheets can function as an artificial dura for repairing the damaged CNS. In particular, this study focused on repairing the optic nerve after an ischemia injury model in rats. These scaffolds were wrapped around damaged optic nerves followed by suturing to ensure they remained in place. The animals were then monitored to determine the effect of these drug releasing scaffolds on nerve regeneration while simultaneously measuring the systemic release of tacrolimus. Controlled delivery of tacrolimus reduced the expression of glial fibrillary acidic protein (GFAP), suggesting a decrease in glial scar formation. It also increased GAP-43 expression, suggesting regeneration of the retinal ganglion was occurring in vivo. These scaffolds were also easily removed after 2 weeks as the majority of the drug was released in the initial 24 h. Thus, they can be easily replaced if necessary to extend the duration of release. Importantly, the authors showed that the levels of tacrolimus in the blood were not significantly elevated, demonstrating the benefits of using this controlled delivery strategy. Future work includes optimizing the release profile of tacrolimus from these scaffolds due to its narrow working range of concentrations, and assessing if these scaffolds can promote functional recovery in pre-clinical CNS injury models. This study demonstrates a novel, clinically-relevant strategy for localized delivery of tacrolimus for repairing the damaged CNS. It achieves an important milestone towards adapting such a strategy for clinical applications. Surgeons could easily use these PEUU-Tac scaffolds as novel patches that mimic the dura and its properties to repair damaged optic nerve in vivo. These novel scaffold properties also suggest that this regeneration-promoting strategy could be implemented throughout the CNS, including for applications in repair of the damaged spinal cord or in the case of traumatic brain injury. Future studies will investigate how to properly balance the necessary delivery of tacrolimus to achieve regeneration while avoiding its negative side effects that occur due to differential uptake by other tissues of the body. The author declared no conflicts of interest. An Elastomeric Polymer Matrix, PEUU-Tac, Delivers Bioactive Tacrolimus Transdurally to the CNS in RatCentral nervous system (CNS) neurons fail to regrow injured axons, often resulting in permanently lost neurologic function. Tacrolimus is an FDA-approved immunosuppressive drug with known neuroprotective and neuroregenerative properties in the CNS. However, tacrolimus is typically administered systemically and blood levels required to effectively treat CNS injuries can lead to lethal, off-target organ toxicity. Thus, delivering tacrolimus locally to CNS tissues may provide therapeutic control over tacrolimus levels in CNS tissues while minimizing off-target toxicity. Full-Text PDF Open Access

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