In vivo bioresponses to silk proteins

Abstract

Silks are appealing materials for numerous biomedical applications involving drug delivery, tissue engineering, or implantable devices, because of their tunable mechanical properties and wide range of physical structures. In addition to the functionalities needed for specific clinical applications, a key factor necessary for clinical success for any implanted material is appropriate interactions with the body in vivo. This review summarizes our current understanding of the in vivo biological responses to silks, including degradation, the immune and inflammatory response, and tissue remodeling with particular attention to vascularization. While we focus in this review on silkworm silk fibroin protein due to the large quantity of in vivo data thanks to its widespread use in medical materials and consumer products, spider silk information is also included if available. Silk proteins are degraded in the body on a time course that is dependent on the method of silk fabrication and can range from hours to years. Silk protein typically induces a mild inflammatory response that decreases within a few weeks of implantation. The response involves recruitment and activation of macrophages and may include activation of a mild foreign body response with the formation of multinuclear giant cells, depending on the material format and location of implantation. The number of immune cells present decreases with time and granulation tissue, if formed, is replaced by endogenous, not fibrous, tissue. Importantly, silk materials have not been demonstrated to induce mineralization, except when used in calcified tissues. Due to its ability to be degraded, silk can be remodeled in the body allowing for vascularization and tissue ingrowth with eventual complete replacement by native tissue. The degree of remodeling, tissue ingrowth, or other specific cell behaviors can be modulated with addition of growth or other signaling factors. Silk can also be combined with numerous other materials including proteins, synthetic polymers, and ceramics to enhance its characteristics for a particular function. Overall, the diverse array of silk materials shows excellent bioresponses in vivo with low immunogenicity and the ability to be remodeled and replaced by native tissue making it suitable for numerous clinical applications.

Biocompatibility and immunogenic response to recombinant honeybee silk material

“…34 Along with measuring humoral responses to antigens, the inflammatory responses to an implanted material can also be assessed by monitoring the cellular immune response at the implant site. 31 These histological observations are consistent with an expected acute foreign body reaction that follows implantation. 35 We observed mild granuloma formation and mild fibrous encapsulation associated with implantation of recombinant honeybee silk materials (Figs.…”

“…These results demonstrate that, like nearly all protein therapeutics tested, [26][27][28][29][30] low but detectable levels of IgG against Amel3F are produced in animals after implantation of the silk materials (Fig. [31][32][33] These materials are deemed acceptable biomaterials. Similarly, silk from silkworms induces a low immune response 30 and collagen from animal sources a moderate response.…”

Bioengineered silkworms with butterfly cytotoxin-modified silk glands produce sericin cocoons with a utility for a new biomaterial

“…Moreover, the production of these transgenic silkworms can be easily and economically scaled, particularly given the strong industrial foundation of the silk industry in Japan. Numerous studies have evaluated the use of manufactured silk proteins as implantable materials that mimic extracellular matrices, because proteinaceous silk materials can be physically and chemically manipulated, are biocompatible and biodegradable, and are already used as silk fibers for surgical sutures (16,35). Our findings demonstrate that bioengineering by the targeted P1A expression successfully produced silkworms with a biologically useful trait that has significant application potential.…”

Carboxylated Agarose (CA)-Silk Fibroin (SF) Dual Confluent Matrices Containing Oriented Hydroxyapatite (HA) Crystals: Biomimetic Organic/Inorganic Composites for Tibia Repair

“…46 According to the structural analysis of SF in the composites, the sufficient crystalline β-sheets in the fibroin could significantly increase the stability and mechanical properties of SF. 41 Therefore, the composites containing SF showed 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24 great compressive strengths and elastic moduli, suggesting the SF actually reinforced the organic matrices and even the whole composite system. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 Cell adhesion was the first importan...…”

“…40 The processing methods of SF could also induce the hydrophobic domains to form the β-sheet regions. 41 That is, the presence of β-sheets had a protective effect on the degradation rate. In this work, sufficient β-sheets were provided via the crosslinking and mineralization processes such that the CA-SF/HA composites presented relatively slow degradation rate compared with the other samples.…”