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.

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.

The tunability of biomaterials is crucial for optimising their performance in medical applications. Silk fibroin, derived from the silkworm Bombyx mori, stands out due to its inherent biocompatibility, mechanical strength, and biodegradability. Among its various formats, silk fibroin hydrogels are particularly significant due to their three-dimensional network structure, high water content, and biomechanical properties analogous to human soft tissues. This study explores the creation of tuneable silk fibroin hydrogels by modulating parameters such as sonication time as a physical crosslinking method, hydrogel concentration, and degumming time without altering the chemical composition of the silk fibroin. By adjusting these factors, we precisely control critical properties, including gelation time, mechanical strength, degradation rates, hydrophobicity, and microstructural attributes. Our findings demonstrate that the synergistic manipulation of these parameters enables the development of hydrogels with tailored properties suited for various biomedical applications. The resulting hydrogels maintain their biocompatibility while offering customisable biodegradation rates (tissue context-dependent), controlled gelation times, and molecular delivery capabilities. These tuneable hydrogels have shown promising results in controlling the shape and spatial distribution of silk fibroin implants in murine models. In conclusion, this study underscores the potential of tuning silk fibroin hydrogels' physical properties to create advanced biomaterials that, firstly, limit the load of toxic elements in the final biomaterial product and, secondly, allow for the modification of its properties according to specific biomedical requirements. Our results have significant implications for the development of drug carriers, potentially enabling them to overcome regulatory frameworks more effectively prior to the use of silk fibroin as an implantable biomaterial in humans. RESUMEN La capacidad de ajuste de los biomateriales es crucial para optimizar su rendimiento en aplicaciones médicas. La fibroína de seda, derivada del gusano de seda Bombyx mori, destaca por su biocompatibilidad inherente, su resistencia mecánica y su biodegradabilidad. Entre sus diversos formatos, los hidrogeles de fibroína de seda son particularmente significativos debido a su estructura de red tridimensional, su alto contenido de agua y sus propiedades biomecánicas análogas a los tejidos blandos humanos. Este estudio explora la creación de hidrogeles de fibroína de seda ajustables mediante la modulación de parámetros como el tiempo de sonicación como método de entrecruzamiento físico, la concentración de hidrogel y el tiempo de desgomado, sin alterar la composición química de la fibroína de seda. Al ajustar estos factores, controlamos con precisión propiedades críticas, como el tiempo de gelificación, la resistencia mecánica, la hidrofobicidad y los atributos microestructurales. Nuestros hallazgos demuestran que la manipulación sinérgica de estos parámetros permite el desarrollo de hidrogeles con propiedades ajustadas para diversas aplicaciones biomédicas. Los hidrogeles resultantes mantienen su biocompatibilidad y ofrecen tasas de biodegradación personalizables (dependientes del contexto tisular), tiempos de gelificación controlados y capacidades de liberación molecular. Estos hidrogeles ajustables han mostrado resultados prometedores en el control de la forma y la distribución espacial de los implantes de fibroína de seda en modelos murinos. En conclusión, este estudio subraya el potencial de ajustar las propiedades físicas de los hidrogeles de fibroína de seda para crear biomateriales avanzados que, en primer lugar, limiten la carga de elementos tóxicos en el producto final del biomaterial y, en segundo lugar, permitan la modificación de sus propiedades de acuerdo con requisitos biomédicos específicos. Nuestros resultados tienen implicaciones significativas para el desarrollo de transportadores de fármacos, lo que podría permitirles superar de manera más efectiva los marcos regulatorios antes del uso de fibroína de seda como biomaterial implantable en humanos.