Accelerated hermeticity testing of biocompatible moisture barriers used for the encapsulation of implantable medical devices

Barrier layers for the long-term encapsulation of implantable medical devices play a crucial role in the devices’ performance and reliability. Typically, to understand the stability and predict the lifetime of barriers (therefore, the implantable devices), the device is subjected to accelerated testing at higher temperatures compared to its service parameters. Nevertheless, at high temperatures, reaction and degradation mechanisms might be different, resulting in false accelerated test results. In this study, the maximum valid temperatures for the accelerated testing of two barrier layers were investigated: atomic layer deposited (ALD) Al2O3 and stacked ALD HfO2/Al2O3/HfO2, hereinafter referred to as ALD-3. The in-house developed standard barrier performance test is based on continuous electrical resistance monitoring and microscopic inspection of Cu patterns covered with the barrier and immersed in phosphate buffered saline (PBS) at temperatures up to 95 °C. The results demonstrate the valid temperature window to perform temperature acceleration tests. In addition, the optimized ALD layer in combination with polyimide (polyimide/ALD-3/polyimide) works as effective barrier at 60 °C for 1215 days, suggesting the potential applicability to the encapsulation of long-term implants

Polyhexamethylene Biguanide and Nadifloxacin Self-Assembled Nanoparticles: Antimicrobial Effects against Intracellular Methicillin-Resistant Staphylococcus aureus

The treatment of skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA) remains a challenge, partly due to localization of the bacteria inside the host’s cells, where antimicrobial penetration and efficacy is limited. We formulated the cationic polymer polyhexamethylene biguanide (PHMB) with the topical antibiotic nadifloxacin and tested the activities against intracellular MRSA in infected keratinocytes. The PHMB/nadifloxacin nanoparticles displayed a size of 291.3 ± 89.6 nm, polydispersity index of 0.35 ± 0.04, zeta potential of +20.2 ± 4.8 mV, and drug encapsulation efficiency of 58.25 ± 3.4%. The nanoparticles killed intracellular MRSA, and relative to free polymer or drugs used separately or together, the nanoparticles displayed reduced toxicity and improved host cell recovery. Together, these findings show that PHMB/nadifloxacin nanoparticles are effective against intracellular bacteria and could be further developed for the treatment of skin and soft tissue infections

Enzymatic Cross-Linking of Dynamic Thiol-Norbornene Click Hydrogels

Enzyme-mediated in situ forming hydrogels are attractive for many biomedical applications because gelation afforded by enzymatic reactions can be readily controlled not only by tuning macromer compositions, but also by adjusting enzyme kinetics. For example, horseradish peroxidase (HRP) has been used extensively for in situ cross-linking of macromers containing hydroxyl-phenol groups. The use of HRP to initiate thiol-allylether polymerization has also been reported, yet no prior study has demonstrated enzymatic initiation of thiol-norbornene gelation. In this study, we discovered that HRP can generate the thiyl radicals needed for initiating thiol-norbornene hydrogelation, which has only been demonstrated previously using photopolymerization. Enzymatic thiol-norbornene gelation not only overcomes light attenuation issue commonly observed in photopolymerized hydrogels, but also preserves modularity of the cross-linking. In particular, we prepared modular hydrogels from two sets of norbornene-modified macromers, 8-arm poly(ethylene glycol)-norbornene (PEG8NB) and gelatin-norbornene (GelNB). Bis-cysteine-containing peptides or PEG-tetra-thiol (PEG4SH) was used as a cross-linker for forming enzymatically and orthogonally polymerized hydrogel. For HRP-initiated PEG-peptide hydrogel cross-linking, gelation efficiency was significantly improved via adding tyrosine residues on the peptide cross-linkers. Interestingly, these additional tyrosine residues did not form permanent dityrosine cross-links following HRP-induced gelation. As a result, they remained available for tyrosinase-mediated secondary cross-linking, which dynamically increased hydrogel stiffness. In addition to material characterizations, we also found that both PEG- and gelatin-based hydrogels exhibited excellent cytocompatibility for dynamic 3D cell culture. The enzymatic thiol-norbornene gelation scheme presented here offers a new cross-linking mechanism for preparing modularly and dynamically cross-linked hydrogels

Development of a Tabletop Soft Gel Encapsulation Machine

Currently, to test new formulations of gel capsules at Pfizer, they must use the large-scale machine that requires a minimum of 25 kg of gel melt and produce hundreds of capsules per run. Production at a smaller scale to enable rapid changeover for research and development is desired. The team’s goal was to achieve continuous production of sealed capsules with 80% fill capacity. Capsule sealing was the prime consideration. Preliminary trials using the existing system and heat transfer analysis indicated localized heating was necessary to promote capsule sealing. To provide localized heating, a brass wedge was designed based on the pilot scale machine. The machined wedge was integrated with a PID control system. Using pre-made gelatin ribbons, the appropriate process parameters to achieve sealed capsules were determined. The critical, coupled parameters were die roll temperature, wedge temperature, wedge height, and die roll speed. Capsule sealing efficiency was highest at a speed of 4 capsules/min. For air-filled capsules, a sealing efficiency of 100% was achieved. For PEG-400-filled capsules, a sealing efficiency of 50% was achieved. Future work will include integration with the gelatin feed system and addition of a vacuum during capsule formation to increase fill capacity.https://scholarscompass.vcu.edu/capstone/1151/thumbnail.jp

Storage effects of gel encapsulation on stability of chokeberry monomeric anthocyanins, procyanidins, color density, and percent polymeric color

Chokeberries (Aronia melanocarpa) are an antioxidant-rich plant product due to their high content of polyphenols, especially anthocyanins and procyanidins. These polyphenols have been shown to provide protection against coronary heart disease, stroke, and lung cancer, as well as against oxidative stress, the main cause behind chronic diseases promoted by free radicals. The objective of this study was to determine the storage effects of gelatin encapsulation on monomeric anthocyanins, procyanidins, color density, and percent polymeric color of three gummy candies of different strengths formulated with a base of 25.4% chokeberry concentrate, 47.6% sucrose, 1.3% Splenda, and 0.025% potassium sorbate. The gum strengths varied by percentages of gelatin and water in the formulations, with 19.1:6.6, 17.8:7.9, and 16.5:9.2 ratios used to produce soft, medium, and hard strength gummies, respectively. Total monomeric anthocyanins, total procyanidins, color density, and percent polymeric color of the gummies were determined 1 day post-processing and after 2, 4, and 6 months of storage at refrigerated and room temperatures. Storage for 6 months at room temperature resulted in dramatic losses of monomeric anthocyanins (80-82%), total procyanidins (48-54%), and color density (76-80%). Anthocyanin losses during storage coincided with marked increases in percent polymeric color values indicating that anthocyanins and procyanidins underwent condensation reactions to form polymers. Refrigerated storage ameliorated losses of monomeric anthocyanins (61-65%), total procyanidins (17-22%), and color density (60-67%) over 6 months of storage compared to samples stored at ambient temperature. Refrigerated storage also ameliorated the increase in polymeric color values observed in samples stored at room temperature indicating condensation reactions responsible for polymer formation were retarded. Gum strength did not have a significant effect on retention of anthocyanins and procyanidins

Classification of analytics, sensorics, and bioanalytics with polyelectrolyte multilayer capsules

Polyelectrolyte multilayer (PEM) capsules, constructed by LbL (layer-by-layer)-adsorbing polymers on sacrificial templates, have become important carriers due to multifunctionality of materials adsorbed on their surface or encapsulated into their interior. They have been also been used broadly used as analytical tools. Chronologically and traditionally, chemical analytics has been developed first, which has long been synonymous with all analytics. But it is not the only development. To the best of our knowledge, a summary of all advances including their classification is not available to date. Here, we classify analytics, sensorics, and biosensorics functionalities implemented with polyelectrolyte multilayer capsules and coated particles according to the respective stimuli and application areas. In this classification, three distinct categories are identified: (I) chemical analytics (pH; K+, Na+, and Pb2+ ion; oxygen; and hydrogen peroxide sensors and chemical sensing with surface-enhanced Raman scattering (SERS)); (II) physical sensorics (temperature, mechanical properties and forces, and osmotic pressure); and (III) biosensorics and bioanalytics (fluorescence, glucose, urea, and protease biosensing and theranostics). In addition to this classification, we discuss also principles of detection using the above-mentioned stimuli. These application areas are expected to grow further, but the classification provided here should help (a) to realize the wealth of already available analytical and bioanalytical tools developed with capsules using inputs of chemical, physical, and biological stimuli and (b) to position future developments in their respective fields according to employed stimuli and application areas

Compound droplet manipulations on fiber arrays

Recent works demonstrated that fiber arrays may constitue the basis of an open digital microfluidics. Various processes, such as droplet motion, fragmentation, trapping, release, mixing and encapsulation, may be achieved on fiber arrays. However, handling a large number of tiny droplets resulting from the mixing of several liquid components is still a challenge for developing microreactors, smart sensors or microemulsifying drugs. Here, we show that the manipulation of tiny droplets onto fiber networks allows for creating compound droplets with a high complexity level. Moreover, this cost-effective and flexible method may also be implemented with optical fibers in order to develop fluorescence-based biosensor