Permselectivity of Silk Fibroin Hydrogels for Advanced Drug Delivery Neurotherapies.

A promising trend in tissue engineering is using biomaterials to improve the control of drug concentration in targeted tissue. These vehicular systems are of specific interest when the required treatment time window is higher than the stability of therapeutic molecules in the body. Herein, the capacity of silk fibroin hydrogels to release different molecules and drugs in a sustained manner was evaluated. We found that a biomaterial format, obtained by an entirely aqueous-based process, could release molecules of variable molecular weight and charge with a preferential delivery of negatively charged molecules. Although the theoretical modeling suggested that drug delivery was more likely to be driven by Fickian diffusion, the external media had a considerable influence on the release, with lipophilic organic solvents such as acetonitrile-methanol (ACN-MeOH) intensifying the release of hydrophobic molecules. Second, we found that silk fibroin could be used as a vehicular system to treat a variety of brain disorders as this biomaterial sustained the release of different factors with neurotrophic (brain-derived neurotrophic factor) (BDNF), chemoattractant (C-X-C motif chemokine 12) (CXCL12), anti-inflammatory (TGF-ß-1), and angiogenic (VEGF) capacities. Finally, we demonstrated that this biomaterial hydrogel could release cholesteronitrone ISQ201, a nitrone with antioxidant capacity, showing neuroprotective activity in an in vitro model of ischemia-reoxygenation. Given the slow degradation rate shown by silk fibroin in many biological tissues, including the nervous system, our study expands the restricted list of drug delivery-based biomaterial systems with therapeutic capacity for both short- and especially long-term treatment windows and has merit for use with brain pathologies.

Resistance to Degradation of Silk Fibroin Hydrogels Exposed to Neuroinflammatory Environments.

Central nervous system (CNS) diseases represent an extreme burden with significant social and economic costs. A common link in most brain pathologies is the appearance of inflammatory components that can jeopardize the stability of the implanted biomaterials and the effectiveness of therapies. Different silk fibroin scaffolds have been used in applications related to CNS disorders. Although some studies have analyzed the degradability of silk fibroin in non-cerebral tissues (almost exclusively upon non-inflammatory conditions), the stability of silk hydrogel scaffolds in the inflammatory nervous system has not been studied in depth. In this study, the stability of silk fibroin hydrogels exposed to different neuroinflammatory contexts has been explored using an in vitro microglial cell culture and two in vivo pathological models of cerebral stroke and Alzheimer's disease. This biomaterial was relatively stable and did not show signs of extensive degradation across time after implantation and during two weeks of in vivo analysis. This finding contrasted with the rapid degradation observed under the same in vivo conditions for other natural materials such as collagen. Our results support the suitability of silk fibroin hydrogels for intracerebral applications and highlight the potentiality of this vehicle for the release of molecules and cells for acute and chronic treatments in cerebral pathologies.

Silk Fibroin: An Ancient Material for Repairing the Injured Nervous System.

Silk refers to a family of natural fibers spun by several species of invertebrates such as spiders and silkworms. In particular, silkworm silk, the silk spun by Bombyx mori larvae, has been primarily used in the textile industry and in clinical settings as a main component of sutures for tissue repairing and wound ligation. The biocompatibility, remarkable mechanical performance, controllable degradation, and the possibility of producing silk-based materials in several formats, have laid the basic principles that have triggered and extended the use of this material in regenerative medicine. The field of neural soft tissue engineering is not an exception, as it has taken advantage of the properties of silk to promote neuronal growth and nerve guidance. In addition, silk has notable intrinsic properties and the by-products derived from its degradation show anti-inflammatory and antioxidant properties. Finally, this material can be employed for the controlled release of factors and drugs, as well as for the encapsulation and implantation of exogenous stem and progenitor cells with therapeutic capacity. In this article, we review the state of the art on manufacturing methodologies and properties of fiber-based and non-fiber-based formats, as well as the application of silk-based biomaterials to neuroprotect and regenerate the damaged nervous system. We review previous studies that strategically have used silk to enhance therapeutics dealing with highly prevalent central and peripheral disorders such as stroke, Alzheimer's disease, Parkinson's disease, and peripheral trauma. Finally, we discuss previous research focused on the modification of this biomaterial, through biofunctionalization techniques and/or the creation of novel composite formulations, that aim to transform silk, beyond its natural performance, into more efficient silk-based-polymers towards the clinical arena of neuroprotection and regeneration in nervous system diseases.