Surface modification of stainless steel for biomedical applications: Revisiting a century-old material.

Stainless steel (SS) has been widely used as a material for fabricating cardiovascular stents/valves, orthopedic prosthesis, and other devices and implants used in biomedicine due to its malleability and resistance to corrosion and fatigue. Despite its good mechanical properties, SS (as other metals) lacks biofunctionality. To be successfully used as a biomaterial, SS must be made resistant to the biological environment by increasing its anti-fouling properties, preventing biofilm formation (passive surface modification), and imparting functionality for eluting a specific drug or capturing selected cells (active surface modification); these features depend on the final application. Various physico-chemical techniques, including plasma vapor deposition, electrochemical treatment, and attachment of different linkers that add functional groups, are used to obtain SS with increased corrosion resistance, improved osseointegration capabilities, added hemocompatibility, and enhanced antibacterial properties. Existing literature on this topic is extensive and has not been covered in an integrated way in previous reviews. This review aims to fill this gap, by surveying the literature on SS surface modification methods, as well as modification routes tailored for specific biomedical applications. STATEMENT OF SIGNIFICANCE: Stainless steel (SS) is widely used in many biomedical applications including bone implants and cardiovascular stents due to its good mechanical properties, biocompatibility and low price. Surface modification allows improving its characteristics without compromising its important bulk properties. SS with improved blood compatibility (blood contacting implants), enhanced ability to resist bacterial infection (long-term devices), better integration with a tissue (bone implants) are examples of successful SS surface modifications. Existing literature on this topic is extensive and has not been covered in an integrated way in previous reviews. This review paper aims to fill this gap, by surveying the literature on SS surface modification methods, as well as to provide guidance for selecting appropriate modification routes tailored for specific biomedical applications.

Flow of Tunable Elastic Microcapsules through Constrictions.

We design and fabricate elastically tunable monodisperse microcapsules using microfluidics and cross-linkable polydimethylsiloxane (PDMS). The overall stiffness of the microcapsules is governed by both the thickness and cross-link ratio of the polymer shell. Flowing suspensions of microcapsules through constricted spaces leads to transient blockage of fluid flow, thus altering the flow behavior. The ability to tune microcapsule mechanical properties enables the design of elastic microcapsules that can be tailored for desired flow behavior in a broad range of applications such as oil recovery, reactor feeding, red blood cell flow and chemical targeted delivery.

Perfluoroalkyl-Functionalized Hyperbranched Polyglycerol as Pore Forming Agents and Supramolecular Hosts in Polymer Microspheres.

Perfluoroalkyl-functionalized, hyperbranched polyglycerols that produce stable microbubbles are integrated into a microfluidic emulsion to create porous microspheres. In a previously-presented work a dendrimer with a perfluorinated shell was used. By replacing this dendrimer core with a hyperbranched core and evaluating different core sizes and degrees of fluorinated shell functionalization, we optimized the process to a more convenient synthesis and higher porosities. The new hyperbranched polyglycerol porogens produced more pores and can be used to prepare microspheres with porosity up to 12% (v/v). The presented preparation forms pores with a perfluoroalkyl-functionalized surface that enables the resulting microspheres to act as supramolecular host systems. The microspheres can incorporate gases into the pores and actives in the polymer matrix, while the perfluoroalkylated pore surface can be used to immobilize perfluoro-tagged molecules onto the pores by fluorous-fluorous interaction.

Microfluidic fabrication and micromechanics of permeable and impermeable elastomeric microbubbles.

We use droplet microfluidics to produce monodisperse elastomeric microbubbles consisting of gas encapsulated in a polydimethylsiloxane shell. These microbubbles withstand large, repeated deformations without rupture. We perform µN-scale compression tests on individual microbubbles and find their response to be highly dependent on the shell permeability; during deformation, the pressure inside impermeable microbubbles increases, resulting in an exponential increase in the applied force. Finite element models are used to interpret and extend these experimental results enabling the design and development of deformable microbubbles with a predictable mechanical response. Such microbubbles can be designed to repeatedly transit through the narrow constrictions found in a porous medium functioning as probes of the local pressure.

Microfluidic fabrication of perfluorohexane-shelled double emulsions for controlled loading and acoustic-triggered release of hydrophilic agents.

The ability of low boiling point liquid perfluorocarbons (PFCs) to undergo a phase change from a liquid to a gas upon ultrasound irradiation makes PFC-based emulsions promising vehicles for triggered delivery of payloads. However, loading hydrophilic agents into PFC-based emulsions is difficult due to their insolubility in PFC. Here, we address this challenge by taking advantage of microfluidic technologies to fabricate double emulsions consisting of large aqueous cores and a perfluorohexane (PFH) shell, thus yielding high loading capacities for hydrophilic agents. Using this technology, we efficiently encapsulate a model hydrophilic agent within the emulsions and study its response to ultrasound irradiation. Using a combination of optical and acoustic imaging methods, we observe payload release upon acoustic vaporization of PFH. Our work demonstrates the utility of microfluidic techniques for controllably loading hydrophilic agents into PFH-based emulsions, which have great potential for acoustically triggered release.

Microfluidic fabrication of stable gas-filled microcapsules for acoustic contrast enhancement.

We introduce a facile approach for the production of gas-filled microcapsules designed to withstand high pressures. We exploit microfluidics to fabricate water-filled microcapsules that are then externally triggered to become gas-filled, thus making them more echogenic. In addition, the gas-filled microcapsules have a solid polymer shell making them resistant to pressure-induced buckling, which makes them more mechanically robust than traditional prestabilized microbubbles; this should increase the potential of their utility for acoustic imaging of porous media with high hydrostatic pressures such as oil reservoirs.

Emulsion templating of poly(lactic acid) particles: droplet formation behavior.

Monodisperse poly(DL-lactic acid) (PLA) particles of diameters between 11 and 121 µm were fabricated in flow focusing glass microcapillary devices by evaporation of dichloromethane (DCM) from emulsion droplets at room temperature. The dispersed phase was 5% (w/w) PLA in DCM containing 0.1-2 mM Nile Red and the continuous phase was 5% (w/w) poly(vinyl alcohol) in reverse osmosis water. Particle diameter was 2.7 times smaller than the diameter of the emulsion droplet template, indicating very low particle porosity. Monodisperse droplets have only been produced under dripping regime using a wide range of dispersed phase flow rates (0.002-7.2 cm(3)·h(-1)), continuous phase flow rates (0.3-30 cm(3)·h(-1)), and orifice diameters (50-237 µm). In the dripping regime, the ratio of droplet diameter to orifice diameter was inversely proportional to the 0.39 power of the ratio of the continuous phase flow rate to dispersed phase flow rate. Highly uniform droplets with a coefficient of variation (CV) below 2% and a ratio of the droplet diameter to orifice diameter of 0.5-1 were obtained at flow rate ratios of 4-25. Under jetting regime, polydisperse droplets (CV > 6%) were formed by detachment from relatively long jets (between 4 and 10 times longer than droplet diameter) and a ratio of the droplet size to orifice size of 2-5.

Microfluidic synthesis of advanced microparticles for encapsulation and controlled release.

We describe droplet microfluidic strategies used to fabricate advanced microparticles that are useful structures for the encapsulation and release of actives; these strategies can be further developed to produce microparticles for advanced drug delivery applications. Microfluidics enables exquisite control in the fabrication of polymer vesicles and thermosensitive microgels from single and higher-order multiple emulsion templates. The strategies used to create the diversity of microparticle structures described in this review, coupled with the scalability of microfluidics, will enable fabrication of large quantities of novel microparticle structures that have potential uses in controlled drug release applications.

Monodisperse gas-filled microparticles from reactions in double emulsions.

We present a strategy for preparing size-controlled gas-filled microparticles using two aqueous components that chemically react to produce the gas. We use a dual-bore microfluidic device to isolate the reactants of two gas-producing reactions until they are encapsulated in the outer droplet. The reactants in the monodisperse droplets merge and produce the gas bubbles, which are stabilized with a surfactant and form the core of the microparticles. The number and size of the generated gas bubbles are governed by the gas-forming reaction used. Our versatile strategy can be applied to a wide range of gas-producing reactions.

Targeted binding of PEG-lipid modified polymer ultrasound contrast agents with tiered surface architecture.

In order for site-directed polymer ultrasound contrast agents (UCAs) to provide acoustic enhancement at disease sites to distinguish normal tissue from diseased tissue, the surface of these agents must be functionalized with mixtures of grafted polymers. Here a combination of longer liganded polyethylene glycol (PEG)-lipids and shorter unliganded PEG-lipids were introduced into the oil phase of a modified solvent evaporation double emulsion method for preparing UCAs. UCAs with different lengths of both liganded and unliganded lipids were imaged under 7.5 MHz ultrasound. The B-mode image brightness of the mixed PEG-lipid UCAs was within 1 dB the brightness of the unliganded surface. After 15 min of continuous insonation, 70% of the contrast signal remained. The peptide arginine-glycine-aspartic acid (RGD) was added to the surface of these UCAs through a biotin-avidin linkage and binding was assessed under static and shear conditions. Binding was significant after 30 min of static incubation and the adherence of the UCA increased under shear flow from 3 UCA/cell (static) to 5 UCA/cell (shear).

Targeted binding of PLA microparticles with lipid-PEG-tethered ligands.

Solid core polymeric particles are an attractive delivery vehicle as they can efficiently encapsulate drugs of different physical and chemical characteristics. However, the effective targeting of such particles for therapeutic purposes has been somewhat elusive. Here, we report novel polymeric particles comprised of poly(lactic acid) (PLA) with incorporated poly(ethylene glycol)-lipids (PEG-lipids). Particles are characterized for morphology, surface charge, and composition with field-emission scanning electron microscopy (FESEM), zeta potential measurements, and proton nuclear magnetic resonance ((1)H NMR) spectroscopy, respectively. The surface densities of PEG lipids determined by (1)H NMR and particle size distributions are consistent with scaling theory for adsorption of chains onto a surface. We observe significant binding of liganded PEG-lipid tethers when the molecular weight is greater than the unliganded PEG-lipids for significant binding events. Importantly, the binding is not completely lost when the unliganded PEG molecular weight is greater than the liganded PEG-lipid tether. We observe a similar trend for the lower affinity ligand (thioctic acid), but the degree of binding is significantly lower than the high affinity ligand (biotin). This novel technique used to fabricate these liganded particles combined with the lipid bilayer binding studies provides a platform for systematic optimization of particle binding.