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Bio-Design and Manufacturing

, Volume 2, Issue 4, pp 278–286 | Cite as

Can the venerated silk be the next-generation nanobiomaterial for biomedical-device designing, regenerative medicine and drug delivery? Prospects and hitches

  • Rocktotpal KonwarhEmail author
Review
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Abstract

Of late, the relevance of silk in a myriad of material science and biotechnological realms has been realized, as attested by the incessantly clambering number of reports and patents in the scientific repositories. The write-up is geared off with a scrutiny into the pertinence of the basic nano-structural features of silk, christened as the ‘queen of textile’ for exemplary bioengineering applications including designing and fabrication of devices for microfluidics, optofluidics, chemo/bio sensing, etc. Then, the major thrust of this short review is directed towards comprehending the prospects of using silk-based biomaterials (e.g. scaffolds, electrospun membranes, films, hydrogels, bioinks) for tissue engineering and regenerative medicine as well as targeted delivery of various biomolecular cargoes/therapeutic agents, etc., as vouched by few avant-garde endeavours of the recent years. The write-up is entwined with a discussion on the various factors that could plausibly hinder the realization of silk as the next-generation nanobiomaterial, suggestions for some approaches to dodge and deal with the practical snags and what lies ahead!

Keywords

Drug delivery Microfluidics Nanobiomaterial Regenerative medicine Silk Tissue engineering 

Introduction

Witnessing the continually growing pertinence of silk as a material of choice in the biomedical domain is quite invigorating. In recent years, there has been commendable addition to the records in the scientific repositories, vouching for the immense prospects of silk in the niche of tissue engineering and regenerative medicine (TERM). Revered with the sobriquet of ‘queen of textile’, silk is making a larger-than-life journey from the traditional looms and the ramp walks to the operation theatres as well as its foray into the nano/bioengineering labs for fabrication of innovative optical, electronic, energy and microfluidic devices demand special mention [1, 2, 3]. A myriad of insects (e.g. silkworms, spiders etc.) are known to synthesize silk, the synthesis being dictated by microfluidic principles [4]. Silk represents nature’s quintessential nanotechnological manoeuvre, attesting the evolutionary intricacies of nano-viscoelastic, nano-roughness, nano-stiffness, nano-electric and nano-tribological facets [5, 6]. Dictates of intermediate hydrophobic/hydrophilic block ratios and longer chain lengths have been corroborated with the formation of spider silk fibre and its high strength, as attested by mesoscopic modelling in concert with genetic block copolymer synthesis [7]. Furthermore, functioning of spider silk peptide as linear nano-spring for intracellular tension-sensing has also been proposed [8]. On the other hand, covalently integrated repetitive heavy and non-repetitive light chains as well as the crystalline and amorphous domains (with varied compositional abundance of amino acids) are the signature attributes of silkworm silk [9]. Features of biocompatibility, resilience, mechanical robustness and tunable biodegradation profile as well as ease of processibility into multiple formats (e.g. nanoparticles, films, electrospun mats, hydrogels, etc.) have conferred special niche to silkworm silk (constituted by fibroin (SF) and the sticky hydrophilic sericin (SSC)) in particular in the domains of soft and hard tissue engineering, cosmetics, food preservation, etc. [1, 2, 9, 10]. Perusal of recent publications and patents unveils that exploration of the nanoscale attributes as well as the unique biomaterial properties of silk has paved the way to numerous advanced biomedical applications, amongst others. In the succeeding sections of this article, I have tried to cite a few exemplary endeavours that stand in testimony to the afore-stated statement, interlaced with highlights on the prospects and challenges in the niche of silk-based nanobiomaterials.

From micro/nanofluidics to optofluidics

Pertinently, the early morning sight of condensing water droplets on the spider silk-web’s robust fibres (constituted by hierarchically organized bundles of nano-confined flaw-tolerant fibrils, embodying β-crystallites in specific orientations) may be bracketed together with the nanoscale topography of alternating conical spindle knots and joints [11]. The concert of surface energy gradient and alteration in Laplace pressure in the droplet core dictates the movement of the droplet over the fibre. Elucidation of differential roughness and surface wettability due to such unique nanofibrillar organization has propelled research for the fabrication of microfluidic devices for oil–water separation, filtration, fog-collection as well as cost-effective, easy-to-use and field-deployable devices, particularly for diagnostic and environmental applications [4, 11, 12]. As an exemplary evidence, Bhandari et al. [13] had adeptly evaluated the prospects of a silk fabric-chip for direct immunoassay, based on capillary action mediated sample flow and visual detection. Fabrication of ‘fab-chips’ (zari silk, roughened with silver nanoparticles), impregnated as wearable pathogen sensors in clothing [14] has also been documented. The researchers had used adenine (associated with the major SERS signal of DNA—a pathogenic biomarker) to demonstrate the practical feasibility of the chips in diagnostic applications. In another report, application of microfluidic thread-based analytical device (µTAD) was attested by the facile separation of weak and normal ABO blood type (Fig. 1I), based on antibody treated silk threads [15], circumventing the issues of transfusion inaccuracies as well as facilitating easier migration of erythrocytes, thereby, preventing agglutination in comparison to cotton fibres. At this juncture, it is crucial to note that albeit natural silk spinning has inspired the fabrication of artificial innovative spinning devices, component fine-tuning still remains elusive [4]. Furthermore, achieving optimal solution flow-attributes as well as enhanced user control of the microfluidic devices demands simulation and optimization studies. On the other hand, high fidelity nano-patterned optical arrangements (with tunable signature-spectral profile for sensing bioactive substances) in silk have paved the way to fabrication of number of optofluidic devices, permitting straightforward readout [16]. Embossed photonic nanometre scale patterns into fibroin films and haemoglobin, incorporated into silk diffraction gratings for oxygen sensing [17]; highly sensitive silk plasmonic absorber sensor (SPAS) (based on silk-gold nanostructure) (Fig. 1II) for glucose sensing [18], etc. merit special mention. In this backdrop, investigation of the optical attributes of non-mulberry (e.g. Philosamia ricini, Anatheraea assama) silk proteins with unique amino acid sequences [9] is expected to open up new avenues to explore.
Fig. 1

I Silk thread-based microfluidics assay for weak ABO blood typing. (Reproduced from [15], Copyright© 2014, American Chemical Society). II Silk-based nanoplasmonic optical sensor (Reproduced from [18], Copyright© 2015, American Chemical Society). III Downregulation of oxidative stress confers sericin-mediated protection against UV-induced skin damage (Reproduced from [20], Copyright© 2018, American Chemical Society). IV Hybrid silk-protein matrix as bioactive wound dressings and skin grafts (Reproduced from [21], Copyright© 2018, American Chemical Society). V Immunomodulatory injectable silk hydrogels for functional islets’ maintenance (Reproduced from [23], Copyright© 2018, Elsevier)

Prospects for TERM and biocargo-delivery

As mentioned in the introductory section, silk has received an unprecedented impetus in the domain of TERM and allied biomedical applications. Some of the exemplary reports are cited underneath. To start off, silk-based approaches to address skin damage has been at the forefront of research in the last few years [19]. As an exemplary evidence, Jadi et al. [20] had demonstrated that non-mulberry silk sericin could function as an effective antioxidant in ameliorating UV A and UV B radiation-induced skin damage, thereby raising the prospects of its inclusion in skin care products (Fig. 1III). Needless to say that a number of pathophysiological conditions (e.g. burns, diseases like diabetes, etc.) perturb the otherwise highly orchestrated process of wound healing. In situ 3D printing, in situ forming hydrogels, electrospraying, use of microRNA (miRNA) and small interfering RNA (siRNA)-based skin therapeutics and so on have been investigated for accelerated wound healing [19]. Amongst others, electrospun silk-based mats have garnered considerable research thrust in the recent years. Lately, a simple coating technique was employed for functionalization of silkworm silk fibroin-based electrospun matrices with recombinant spider silk fusion proteins [21]. Functionalization of the spider silk fusion proteins with cell-binding RGD (Arg-Gly-Asp) peptide, growth factor peptide and antimicrobial peptide conferred multifaceted features to the fabricated SF-based wound dressings (Fig. 1IV). In an extended work to this report, the researchers had recently demonstrated substantial skin tissue regeneration (in comparison to commercial Duoderm dressing and untreated wounds), mediated by spider silk fusion proteins functionalized silkworm silk-based skin dressings in alloxan-treated diabetic rabbit model [22]. Thus, these studies attest the prospective candidature of such hybrid silk matrices to address diabetic wounds and burns.

On the other hand, although islet transplantation is projected as an apt strategy to address type 1 diabetes, however, islet dysfunction in long-term culture hinders the clinical success of the approach [23]. In this backdrop, Kumar et al. [23] had reported mulberry and non-mulberry silk fibroin blend-based immuno-informed biomimetic, injectable hydrogel, exhibiting local modulation of in vivo inflammatory responses, for islet encapsulation and prospective transplantation for insulin-dependent type 1 diabetes (Fig. 1V). Pertinently, the 3D micro-niche of the hydrogels (compatible with endothelial cells) supported a persistent islet viability and insulin secretion. On a similar vein, mulberry (Bombyx mori) and non-mulberry (Philosamia ricini and Antheraea assamensis) silkworm silk protein were exploited through sequential rolling of cell-laden patterned films for a simple biofabrication of an affordable and biodegradable vascular graft (Fig. 2I) [24]. Translating research of such biofabricated small diameter graft into an ‘off the shelf’ product for replacement of occluded/diseased coronary artery and arteriovenous fistula for hemodialysis access, as proposed in the study, demand further in vivo assessments. Similarly, gold nanoparticle-doped electrospun silk protein-based nerve conduit, pre-seeded with Schwann cells has been adroitly employed for structural and functional regeneration of severed sciatic nerves in Sprague–Dawley rats, further vouched by the restoration of stretching and jumping capacity as well as muscular regeneration in them [25].
Fig. 2

I Patterned silk films-based small diameter vascular conduits (Reproduced from [24], Copyright© 2016, American Chemical Society). II Engineered silk-based angle-ply intervertebral disc construct (Reproduced from [26], Copyright© 2018, Elsevier). III Mimicking of the hierarchical complexity at the osteochondral interface using mulberry and non-mulberry silk-bioactive glass composites (Reproduced from Ref. [27] under Creative Commons Attribution (CC-BY) License, Copyright© 2017, American Chemical Society)

In another recent endeavour, a bioengineered silk-blend-based full thickness angle-ply construct (Fig. 2II) was reported to mimic the native intervertebral disc (IVD) complexity [26]. Proliferation, alignment and maturation of primary annulus fibrosus (AF) cells (porcine-origin) and differential mechanical features mediated guidance of extracellular matrix turnover were documented. This study is pertinent in the context of the fact that the conventional surgical interventions (which are highly case-dependent and not applicable to all patients) are good enough only in symptomatic pain relief, with no restitution of the biomechanical functions [26] and possibly eventual degeneration of adjacent parts.

On a similar note, the current treatment approaches of autologous chondrocyte implantation, matrix-assisted chondrocyte implantation or mosaicplasty to address osteochondral defects (OCD) are challenged in the context of obtainability of suitable donor tissue, donor site morbidity and the consequential poor resistance of the fibrocartilage towards shear and clinical robustness [27]. In this regard, exploitation of biphasic scaffolds for OCD has been envisaged as a prospective solution. At this juncture, I would like to cite one of our works wherein, we had demonstrated that a silk–bioglass-based inexpensive, implantable biphasic electrospun nanofibrous composite, mimicking the osteochondral interfacial micro-niche (Fig. 2III) could offer a plausible solution for conditions like osteochondral degeneration and arthritis [27]. The biphasic scaffold provided a bioactive, mechanically robust and porous bioglass-based osteogenic matrix to emulate the micro-milieu of the subchondral bone (that assisted directional alignment of osteoblasts) while chondrocyte condensation into functional clusters was evident on the silk mats.

Pertinently, of late, silk-based 3D bio-printing has given a whole new perspective to the endeavours to mimic the microarchitecture of native tissues [28]. In the realm of silk-based 3D bio-printing, rheological adjustment of silk fibroin solution is a serious practical issue. Use of toxic chemical cross-linkers may usher in negative trade-off with respect to the cell-viability while use of organic solvents (e.g. 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)) to augment viscosity could lead to unintended trimming of the fibroin protein [28]. In this context, researchers have fabricated a hybrid silk fibroin–gelatin polymer-based bioink (free from any toxic chemical cross-linker), exhibiting excellent 3D bio-printability for prospective cartilage tissue engineering (Fig. 3) [28]. The work also attested a commendable print fidelity of the bioink for creating anatomical structures, exemplified by printing of a human ear under optimized extrudability. In another recent report, an immunocompatible 3D bio-printed (based on silk–gelatin bioink) scaffold was fabricated to mimic the internal and bulk architecture of the menisci for plausible patient specific implantation [29].
Fig. 3

Cross-linker-free silk–gelatin bioink for 3D bio-printing for prospective application in cartilage tissue engineering. Scheme of the study showing a bioink formulation, b entanglement and interaction of biopolymers, c digital modelling and, d 3D bio-printing and maturation of cell-laden construct (reproduced from [28], Copyright© 2019, American Chemical Society)

In another recent endeavour, researchers have established the prospects of non-invasive magnetic actuation of iron oxide nanoparticles loaded SF nanofibrous matrix to engineer functional cardiac tissue construct and achieving actuation frequency-dependent tuning of drug release [30]. Furthermore, recent endeavours have also been directed towards exploitation of both silk fibroin and sericin nanoparticles for the therapeutic delivery of various bioactive moieties/drugs/anticancer agents like curcumin, insulin, doxorubicin, quercetin, atorvastatin, etc. (Table 1). To cite for evidence, in vivo reduction in tumour size (bracketed together with the plausible reactive oxygen species mediated apoptosis) was registered for curcumin and 5-fluorouracil loaded silk fibroin nanoparticles (in comparison to free drug usage) in an endeavour to address breast cancer [38]. Similarly, a mechanically strong injectable hydrogel system, comprising a blend of silk protein and doxorubicin loaded folic acid functionalized single walled carbon nanotube was fabricated for on-demand, localized, targeted drug release, post intermittent exposure to near- infrared light (Fig. 4) [39]. The pH and temperature responsive hydrogel system was endocytosed by folic acid receptor positive (FR+ve) oral cancer cell line KB, eventually inducing the apoptotic pathway. A qualitative understanding as well as accessibility of quantitate data on intracellular trafficking besides unmasking of the delivery via endosomotropic or lysomotropic ways are pre-requisite for the successful application of such silk-based systems for delivery of therapeutic agents [3, 40].
Table 1

Representative nanoscale silk-based therapeutic agent delivery systems

Therapeutic agent

Silk protein used for fabrication of the nano-delivery system

Outcome, observed at the bio-interface

References

Insulin

Silk fibroin

Bound insulin exhibited augmented resistance to trypsin digestion and prolonged half-life than native insulin; in vitro stability in human serum

[31]

Paclitaxel (PTX)

Silk fibroin

Speedier killing of gastric cancer cell lines BGC-823 and SGC-7901; better antitumor activity than the free PTX

[32]

Cisplatin

Silk fibroin

Apoptosis in A549 lung cancer cells

[33]

Atorvastatin

Silk sericin

Increased hyperlipidemic activity

[34]

Quercetin

Silk fibroin

Quercetin’s sustained release at pH 7.4 (phosphate buffer saline) and pH 6.8 (simulated intestinal fluid)

[35]

Doxorubicin (Dox)

Silk sericin

pH responsive, surface charge reversal nanoparticles with augmented cellular entry and Dox delivery

[36]

Curcumin

Silk fibroin

Increased cytotoxicity in neuroblastoma cells in comparison to hepatocarcinoma cells

[37]

Fig. 4

Carbon nanotube loaded silk hydrogel for on-demand anticancer drug delivery (reproduced from [39], Copyright© 2019, American Chemical Society)

On the other hand, formation of strong complexes of silk with DNA is hindered due to non-cationic nature of the former. In this context, nanoscale complexes of silk chains with poly(l-lysine) copolymers, displaying electrostatic interaction with plasmid DNA (pDNA) were employed for gene-delivery into human embryonic kidney cells [41]. Similarly, Antheraea pernyi silk fibroin (rich in cell-binding RGD sequences)/poly(ethylene imine)/DNA ternary complex exhibited higher transfection efficacy in human colorectal carcinoma (HCT 116) and human embryonic kidney (HEK 293) cells with augmented transfection being displayed in the former, attributed to copiousness of RGD binding integrins [42]. These are just a few representative studies to illustrate the potential of silk for regenerative medicine and allied biomedical applications.

The challenges and the future direction

Albeit, there exist tremendous prospects for bench-to-bed side technology transfer of silk-based nanobiomaterials, a number of pertinent issues need to be addressed tactfully. The prime requisite lies for a scalable, economically feasible-production protocol (with quality-control) for the silk-based nanobiomaterials, propelling clinical trials and applications. In particular, some of the practical snags while resorting to wild non-mulberry silk (endowed with RGD sequence that promotes cell adhesion and proliferation) are the slow-paced seed production and assaults to the worms by a myriad of pests, predators and diseases. Indoor rearing of such worms could be a safer alternative. From the laboratory-experiments’ perspective, the conventional (toxic) lithium salts (used for mulberry silk fibroin extraction) do not hold good enough for cocoon-solubilization for non-mulberry silk protein extraction while harvesting of gland proteins is challenged by concerns of rapid aggregation and precipitation. Anionic detergents like sodium dodecyl sulphate have been forwarded as effective substitutes [9]. On the other hand, territorial nature and hostile attribute of spiders obstruct the collection of ample volumes of their silk proteins. In this context, seri-informatics, complemented by genomic/molecular tools would be instrumental in conservation and improvement in the production of silk of superior quality. In a similar vein, deeper insight into the biochemical machinery of the silk worms (particularly the endemic varieties) and the spiders along with metabolic and cellular engineering of appropriate hosts in the context of genetic engineering could pave the way to the production of novel silk-based nanobiomaterials. Needless to say that comprehending the physicochemical characteristics of the silk proteins with respect to the genomic and proteomic information of the silkworms is of utmost importance [1, 43]. Another issue is the current incipient status of the clinical trials of silk-based nanobiomaterials [3, 44]. There lies a plethora of reports on the successful in vitro or preclinical assessments of silk-based nanobiomaterials for regenerative medicine as well as prospective delivery of biomolecular cargoes; however, in vivo studies and clinical trials are just a handful. Detailed unveiling of the pharmacokinetics, pharmacodynamics and off-target outcomes in bench studies is pre-requisite for commercial translation of silk-based nanobiomaterials.

Amalgamation of bioreactors and stem cell technology is envisaged to pave the way to more realistic applications of silk-based nanobiomaterials for TERM. What next? Possibly, the simulation and optimization strategies to fabricate transplantable bioengineered organs with befitting performance/price equilibrium. Furthermore, silk-based scaffold systems could be possibly employed for the enhanced production of medically important biocatalysts like urokinase under optimized media in bioreactors. Current research also seems to be buoyant towards organ-on-a-chip/multichannel 3D microfluidic silk-based cell culture chip platforms in near future. The realization would imply a route to evade the use of animals in drug assessments and toxin evaluation. As a conclusive statement, I would like to stress upon the fact that silk-based nanobiomaterial-research demands inter-institutional concerted activities and incentives for an innovation ecosystem to ensure a ‘silken-health for all’.

Notes

Acknowledgements

I would like to offer a note of gratitude to Dr. Biman B. Mandal, IIT Guwahati, India, for introducing me to the awe-inspiring niche of silk-bioengineering.

Funding

The author did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors while compiling this article.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

Ethical approval

No studies with human or animal subjects were conducted afresh by the author for inclusion in this review article.

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Copyright information

© Zhejiang University Press 2019

Authors and Affiliations

  1. 1.Department of BiotechnologyAddis Ababa Science and Technology UniversityAkaki Kality, Addis AbabaEthiopia
  2. 2.Centre of Excellence- NanotechnologyAddis Ababa Science and Technology UniversityAkaki Kality, Addis AbabaEthiopia

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