Silk Devices Research Articles

Superb Silk Hydrogels with High Adaptability, Bioactivity, and Versatility Enabled by Photo-Cross-Linking.

The exceptional biocompatibility and adaptability of hydrogels have garnered significant interest in the biomedical field for the fabrication of biomedical devices. However, conventional synthetic hydrogels still exhibit relatively weak and fragile properties. Drawing inspiration from the photosynthesis process, we developed a facile approach to achieve a harmonious combination of superior mechanical properties and efficient preparation of silk fibroin hydrogel through photo-cross-linking technology, accomplished within 60 s. The utilization of riboflavin and H2O2 enabled a sustainable cyclic photo-cross-linking reaction, facilitating the transformation from tyrosine to dityrosine and ultimately contributing to the formation of highly cross-linked hydrogels. These photo-cross-linking hydrogels exhibited excellent elasticity and restorability even after undergoing 1000 cycles of compression. Importantly, our findings presented that hydrogel-encapsulated adipose stem cells possess the ability to stimulate cell proliferation along with stem cell stemness. This was evidenced by the continuous high expression levels of OCT4 and SOX2 over 21 days. Additionally, the utilization of photo-cross-linking hydrogels can be extended to various material molding platforms, including microneedles, microcarriers, and bone screws. Consequently, this study offered a significant approach to fabricating biomedical hydrogels capable of facilitating real-time cell delivery, thereby introducing an innovative avenue for designing silk devices with exceptional machinability and adaptability in biomedical applications.

Tuning the Biodegradation Rate of Silk Materials via Embedded Enzymes.

Conventional thinking when designing biodegradable materials and devices is to tune the intrinsic properties and morphological features of the material to regulate their degradation rate, modulating traditional factors such as molecular weight and crystallinity. Since regenerated silk protein can be directly thermoplastically molded to generate robust dense silk plastic-like materials, this approach afforded a new tool to control silk degradation by enabling the mixing of a silk-degrading protease into bulk silk material prior to thermoplastic processing. Here we demonstrate the preparation of these silk-based devices with embedded silk-degrading protease to modulate the degradation based on the internal presence of the enzyme to support silk degradation, as opposed to the traditional surface degradation for silk materials. The degradability of these silk devices with and without embedded protease XIV was assessed both in vitro and in vivo. Ultimately, this new process approach provides direct control of the degradation lifetime of the devices, empowered through internal digestion via water-activated proteases entrained and stabilized during the thermoplastic process.

Engineering Natural and Recombinant Silks for Sustainable Biodevices.

Silk fibroin (SF) is a structural protein derived from natural silkworm silks. Materials fabricated based on SF usually inherit extraordinary physical and biological properties, including high mechanical strength, toughness, optical transparency, tailorable biodegradability, and biocompatibility. Therefore, SF has attracted interest in the development of sustainable biodevices, especially for emergent bio-electronic technologies. To expand the function of current silk devices, the SF characteristic sequence has been used to synthesize recombinant silk proteins that benefit from SF and other functional peptides, such as stimuli-responsive elastin peptides. In addition to genetic engineering methods, innovated chemistry modification approaches and improved material processing techniques have also been developed for fabricating advanced silk materials with tailored chemical features and nanostructures. Herein, this review summarizes various methods to synthesize functional silk-based materials from different perspectives. This review also highlights the recent advances in the applications of natural and recombinant silks in tissue regeneration, soft robotics, and biosensors, using B. mori SF and silk-elastin-like proteins (SELPs) as examples.

Safety and efficacy of the Silk flow diverter: Insight from the DIVERSION prospective cohort study

Background and purposeFlow diverters are considered as an essential tool in the stent-based treatment of complex intracranial aneurysms. We report here a subgroup analysis of the nationwide prospective DIVERSION study to investigate the safety and efficacy of the Silk flow diverter at 12 months follow-up. MethodsWe performed a subgroup analysis of patients included in the DIVERSION, a national prospective cohort study including all flow diverters placement between 2012 and 2014 in France, and treated with the Silk. The primary outcome was the morbi-mortality at 12 months, including death, morbidity event and aneurysm retreatment within 12 months post-treatment. All reported serious events were adjudicated by an independent Data Safety and Monitoring Board. Satisfactory occlusion was defined as 3 or 4 on Kamran's scale by an independent imaging core laboratory during follow-up. ResultsA total of 102 procedures involving 101 patients (mean age±standard deviation, 54.3±13.5 years) harbouring 118 aneurysms (113/118 located in the anterior circulation; mean size 8.2±7.1mm) were included. During the 12-month follow-up, 34 (33.3%) procedures experienced at least one morbi-mortality event: 3 deaths, 27 morbidity events and 4 retreatments. Overall, 1/3 deaths and 10/27 morbidity events were related to the device and/or the procedure, leading to a specific survival rate and a specific free-morbidity survival rate at 12 months of 98.98% [95% confidence interval, 92.98%–99.86%] and 89.73% [95%CI, 81.71%–94.36%], respectively. The rate of permanent-related neurological deficit was 5.9% within 12 months. One year follow-up imaging showed satisfactory occlusion in 82.2% of cases. ConclusionFlow diversion with the Silk device has a reasonable safety and effectiveness profile for the endovascular treatment of intracranial aneurysms.

Silk Biomaterials-Mediated miRNA Functionalized Orthopedic Devices.

Silk-based bioresorbable medical devices, such as screws, plates, and rods, have been under investigation due to their promising properties for orthopedic repairs. Options to functionalize these new devices for enhanced control of bone regeneration would also exploit the compatible processing methods used to generate the devices. MicroRNAs are important regulators of bone maintenance and formation, and miRNA-based therapeutics have the potential to aid bone repair, utilizing a transient therapeutic approach with local bioactivity. We hypothesized that silk-based orthopedic devices could be used for the local delivery of miRNAs, using anti-sense miR-214 (AS-miR-214), to inhibit endogenous expression of osteoinductive antagonist and thereby supporting the upregulation of osteoinductive target molecules activating transcription factor 4 (ATF4) and Osterix (Osx). AS-miR-214 silk devices, prepared using surface coating, demonstrated continuous release of miRNA inhibitors up to 7 days in vitro. Additionally, human mesenchymal stem cells seeded on AS-miR-214 silk films expressed higher levels of osteogenic genes ATF4, Osx, Runx2, and Osteocalcin. Interestingly, these cells exhibited lower cell viability and DNA content over 21 days. Conversely, the cells demonstrated significantly higher levels of alkaline phosphatase expression and calcium deposition compared with cells seeded on silk films with nontargeting miRNA controls. The study demonstrated that the silk-based orthopedic devices, in conjunction with bioactive miRNA-based therapeutics, may serve as a novel system for localized bone tissue engineering, enhancing osteogenesis at the implant interface while avoiding detrimental systematic side effects.

Relationships and redundancies of selected hemodynamic and structural parameters for characterizing virtual treatment of cerebral aneurysms with flow diverter devices

Background and purposeTo quantify the relationship and to demonstrate redundancies between hemodynamic and structural parameters before and after virtual treatment with a flow diverter device (FDD) in cerebral aneurysms. MethodsSteady computational fluid dynamics (CFD) simulations were performed for 10 cerebral aneurysms where FDD treatment with the SILK device was simulated by virtually reducing the porosity at the aneurysm ostium. Velocity and pressure values proximal and distal to and at the aneurysm ostium as well as inside the aneurysm were quantified. In addition, dome-to-neck ratios and size ratios were determined. Multiple correlation analysis (MCA) and hierarchical cluster analysis (HCA) were conducted to demonstrate dependencies between both structural and hemodynamic parameters. ResultsVelocities in the aneurysm were reduced by 0.14m/s on average and correlated significantly (p<0.05) with velocity values in the parent artery (average correlation coefficient: 0.70). Pressure changes in the aneurysm correlated significantly with pressure values in the parent artery and aneurysm (average correlation coefficient: 0.87). MCA found statistically significant correlations between velocity values and between pressure values, respectively. HCA sorted velocity parameters, pressure parameters and structural parameters into different hierarchical clusters. HCA of aneurysms based on the parameter values yielded similar results by either including all (n=22) or only non-redundant parameters (n=2, 3 and 4). ConclusionHemodynamic and structural parameters before and after virtual FDD treatment show strong inter-correlations. Redundancy of parameters was demonstrated with hierarchical cluster analysis.

Silk Device for the Treatment of Intracranial Aneurysms. Part 1: Peri-Procedural Results, Technical Aspects and Learning Curve.

We evaluated the procedural outcomes of intracranial aneurysm treatment with the Silk device and its relation with operator experience. We also detailed some technical points we learned throughout our experience. One hundred and six consecutive patients with intracranial aneurysms treated using Silk (BaltExtrusion, Montmorency, France) stent between October 2010 and November 2013 were included. Patients were evaluated in terms of age, sex, aneurysm size, location, technical success, and adverse events. There were 106 patients (71 female) undergoing 116 procedures with a mean age of 49.8 (range: 3-78 years). Mean aneurysm size was 10.7±8.0 (range, 2-40 mm). Technical success of the procedures was 96.5%. Adverse event rate was 11.2%. Among adverse events, there were 4 adverse events without complications, 2 mild complications, 7 severe complications, 4 of which resulted with death. The adverse event rate was significantly higher during the first half of the operator's experience. The rate of adverse events seemed to stabilize after around 50 patients. Adverse events, regardless of the presence or absence of a clinical complication, were more frequent in aneurysms larger than 18.5 mm. Safety of flow-diverter (FD) placement for intracranial aneurysms increases with operator experience. Training programs in endovascular management of cerebrovascular diseases and relevant fellowship curricula must be adapted to include sufficient flow diverter experience. The learning curve needs to be kept in mind when studies comparing different FD devices or those comparing other treatments to FDS are planned.

Silk Device for the Treatment of Intracranial Aneurysms, Part 2: Factors Related to Clinical and Angiographic Outcome.

To report patient and procedure-related factors affecting the angiographic and clinical outcome in patients treated with the Silk device. All patients with intracranial aneurysms in whom treatment was attempted with the Silk flow diverter by our neurovascular team between October 2010 and November 2013 were included consecutively. The data was analyzed by an independent stroke neurologist not involved in the treatment of the patients. A total of 96 patients (64 female) with ages range from 3 to 78 were included in this study. We found that 54 of the patients were asymptomatic and 42 of them symptomatic, while 21 had a prior history of subarachnoid hemorrhage (SAH). Mean aneurysm size was 10.2 mm (range 2 to 40 mm). 2 patients died due to consequences of SAH. 3 patients developed visual decline on the follow-up, 2 of these were procedure-related. Symptomatic thromboembolic events were noted in 7 cases. Patients with aneurysms smaller than 13 mm had significantly less complications and higher occlusion rates. The complication rate was significantly high in patients admitted with symptoms. Adjunctive coiling had no impact on outcome. Safety and efficacy of flow diversion in this series was closely related to aneurysm size and presenting symptoms. A size cut-off for safety and efficacy has not been reported before and will be useful not only for future studies but also for patient counseling in daily practice. The futility of adjunctive coiling in this series calls for reappraisal of the current recommendations for this specific device.

Delayed complications after flow-diverter stenting: Reactive in-stent stenosis and creeping stents

We assessed the frequency and severity of changes in stent configuration and location after the treatment of intracranial aneurysms, and patterns of in-stent stenosis. We retrospectively reviewed data for consecutive aneurysm patients managed with endovascular implantation of flow-diverter stents (Silk Flow Diverter [Balt Extrusion, Montmorency, France] and Pipeline Embolization Device [ev3/Coviden, Minneapolis, MN, USA]) from October 2011 to July 2012. Routine 2, 6, 9–12, and 16–20month follow-up angiograms were compared, with a focus on changes in stent configuration and location from immediately after deployment to angiographic follow-up, and the incidence and development of in-stent stenosis. Thirty-four patients with 42 aneurysms met inclusion criteria. The Silk device was implanted in 16 patients (47%, single device in 15), the Pipeline device in 18 (53%, single device in 16). On first follow-up angiography, in-stent stenosis was observed in 38% of Silk devices and 39% of Pipeline devices. In-stent stenosis was asymptomatic in 12 of 13 patients. One woman presented with transient ischemic attacks and required stent angioplasty due to end tapering and mild, diffuse in-stent stenosis. Configuration and location changes, including stent creeping and end tapering were seen in 2/16 patients (13%) with Silk devices, and 0/18 patients with Pipeline devices. We describe stent creeping and end tapering as unusual findings with the potential for delayed clinical complications. In-stent stenosis, with a unique behavior, is a frequent angiographic finding observed after flow-diverter stent implant. The stenosis is usually asymptomatic; however, close clinical and angiographic monitoring is mandatory for individualized management.

Transdermal Delivery Devices: Fabrication, Mechanics and Drug Release from Silk

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post-fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk-based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.

Panacea or problem: flow diverters in the treatment of symptomatic large or giant fusiform vertebrobasilar aneurysms

The use of flow-diverting stents has gained momentum as a curative approach in the treatment of complex proximal anterior circulation intracranial aneurysms. There have been some reported attempts of treating formidable lesions in the posterior circulation. Posterior circulation giant fusiform aneurysms have a particularly aggressive natural history. To date, no one approach has been shown to be comprehensively effective or low risk. The authors report the initial results, including the significant morbidity and mortality encountered, with flow diversion in the treatment of large or giant fusiform vertebrobasilar aneurysms at Millard Fillmore Gates Circle Hospital. The authors retrospectively reviewed their prospectively collected endovascular database to identify patients with intracranial aneurysms who underwent treatment with flow-diverting devices and determined that 7 patients had presented with symptomatic large or giant fusiform vertebrobasilar aneurysms. The outcomes of these patients, based on the modified Rankin Scale (mRS), were tabulated, as were the complications experienced. Among the 7 patients, Pipeline devices were placed in 6 patients and Silk devices in 1 patient. At the last follow-up evaluation, 4 patients had died (mRS score of 6), all of whom were treated with the Pipeline device. The other 3 patients had mRS scores of 5 (severe disability), 1, and 0. The deaths included posttreatment aneurysm ruptures in 2 patients and lack of improvement in neurological status related to presenting brainstem infarcts and subsequent withdrawal of care in the other 2 patients. Whether flow diversion will be an effective strategy for treatment of large or giant fusiform vertebrobasilar aneurysms remains to be seen. The authors' initial experience suggests substantial morbidity and mortality associated with the treatment and with the natural history. As outcomes data slowly become available for patients receiving these devices for fusiform posterior circulation aneurysms, practitioners should use these devices judiciously.

Flow Diversion for Cerebral Aneurysms: A Cautionary Tale

The article by Kulcsar et al[1][1] in this issue of the American Journal of Neuroradiology represents a sobering view of the potential pitfalls of flow-diversion therapy for cerebral aneurysms. Flow-diversion therapy of aneurysms has been available in Europe for some time, with the Silk device (

Prey-holding abilities of the nests and webs of jumping spiders (Araneae, Salticidae)

Three characteristics of the silk devices of 12 species of Salticidae and three species of spiders from conventional web-building families (Dipluridae, Eresidae and Stiphidiidae) were investigated: macrostructure; prey-holding ability (measured by escape time for five types of insects); and the structure of the silk itself, as revealed by SEM. Five types of salticid nests were recognized, and a few salticids build webs. The webs of the eresid Stegodyphus mimosarum consist of thick structural threads and fine cribellate fibres. Disparity of thread diameter, although not as extreme, was observed in the webs and nests of the other species. In the webs and nests of all species, there were threads that merely rode one over the other without forming junctions and secure ‘naked’ junctions lacking accessory fibres and ‘sleeves’. Ensheathed junctions, which had ‘sleeves’, were found only in webs of Portia (Salticidae) and Cambridgea antipodiana (Amaurobiidae). The cribellate webs of Stegodyphus mimosarum (Eresidae) had greater prey-holding ability than any other webs or nests tested, but all webs and nests were capable of detaining insects at least briefly. The distinctions between spider webs and nests and between sticky and non-sticky webs are discussed.