Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease exception policy and outcomes in pediatric patients with hepatopulmonary syndrome requiring liver transplantation.

Hepatopulmonary syndrome (HPS) is associated with increased waitlist mortality in liver transplantation (LT) candidates. Children with HPS are granted Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) exception points for waitlist prioritization in the United States based on criterion developed for adults. In this study, the impact of this MELD/PELD exception policy on post-LT survival in children was examined. A retrospective cohort of patients aged younger than 18 years with a MELD/PELD exception request who underwent LT between 2007 and 2018 were identified in the Scientific Registry of Transplant Recipients. Patients were stratified by waitlist partial pressure of arterial oxygen (PaO 2 ) to assess risk factors for waitlist mortality and post-LT survival. Among 3082 pediatric LT recipients included in the study, 124 patients (4%) received MELD/PELD exception points for HPS. Patients with HPS were a median age of 9 years (interquartile range: 6, 12 years), 54.8% were girls, and 54% were White. Most patients (87.9%) were listed with laboratory MELD/PELD scores <15. Waitlist mortality for patients with HPS exception points was rare and not different from patients without HPS. When stratified by pre-LT PaO 2 , hypoxemia severity was not associated with differences in 1-, 3-, or 5-year survival rates after LT ( p = 0.13). However, patients with HPS showed a slightly lower survival rate at 5 years compared with patients without HPS (88.7% vs. 93.4%; p = 0.04). MELD/PELD exceptions for children with HPS mitigated waitlist mortality, and recipients with HPS experienced excellent 5-year survival after LT, although slightly lower than in patients without HPS. Unlike adults with HPS, the severity of pre-LT hypoxemia in children does not impact post-LT survival. These data suggest that adult criteria for granting MELD/PELD exception points may not appropriately capture HPS severity in pediatric patients. Further prospective multicenter studies to examine the risk factors predicting negative survival outcomes in children with HPS are warranted.

CAQ Corner: Surgical evaluation for liver transplantation.

The evaluation of a liver transplantation candidate is a complex and detailed process that in many cases must be done in an expedited manner because of the critically ill status of some patients with end-stage liver disease. It involves great effort from and the collaboration of multiple disciplines, and during the evaluation several studies and interventions are performed to assess and potentially prepare a patient for liver transplant. Here we review the liver transplantation evaluation from a surgical perspective.

The development of artificial livers.

PURPOSE OF REVIEW: While liver transplantation is an established treatment for liver failure, the number of patients with liver failure amenable to such intervention far outnumbers the donor supply of livers. Technologies serving to bridge this gap are required. Artificial livers may serve as an alternative. In this review, we discuss the development of artificial liver technologies. RECENT FINDINGS: The accrued clinical data suggest that current liver assist devices may serve a role in specific liver diseases, but for the most part no survival benefit has been demonstrated. More clinical trials are expected to elucidate their utilization. Simultaneously, recent advances in materials and tissue engineering are allowing for exciting developments for novel artificial livers. SUMMARY: As there continues to be more clinical data regarding the use of current liver devices, new intricate artificial liver technologies, with the use of sophisticated three-dimensional materials, are being developed that may help improve outcomes of liver failure patients.

Progress of Multicompartmental Particles for Medical Applications.

Particulate materials are becoming increasingly used in the literature for medical applications, but translation to the clinical setting has remained challenging as many particle systems face challenges from in vivo barriers. Multicompartmental particles that can incorporate several materials in an individual particle may allow for more intricate control and addressing of issues that otherwise standard particles are unable to. Here, some of the advances made in the use of multicompartmental particles for medical applications are briefly described.

Long-circulating Janus nanoparticles made by electrohydrodynamic co-jetting for systemic drug delivery applications.

BACKGROUND: Nanoparticles with controlled physical properties have been widely used for controlled release applications. In addition to shape, the anisotropic nature of the particles can be an important design criterion to ensure selective surface modification or independent release of combinations of drugs. PURPOSE: Electrohydrodynamic (EHD) co-jetting is used for the fabrication of uniform anisotropic nanoparticles with individual compartments and initial physicochemical and biological characterization is reported. METHODS: EHD co-jetting is used to create nanoparticles, which are characterized at each stage with scanning electron microscopy (SEM), structured illumination microscopy (SIM), dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Surface immobilization techniques are used to incorporate polyethylene glycol (PEG) and I(125) radiolabels into the nanoparticles. Particles are injected in mice and the particle distribution after 1, 4 and 24 hours is assessed. RESULTS AND DISCUSSION: Nanoparticles with an average diameter of 105.7 nm are prepared by EHD co-jetting. The particles contain functional chemical groups for further surface modification and radiolabeling. The density of PEG molecules attached to the surface of nanoparticles is determined to range between 0.02 and 6.04 ligands per square nanometer. A significant fraction of the nanoparticles (1.2% injected dose per mass of organ) circulates in the blood after 24 h. CONCLUSION: EHD co-jetting is a versatile method for the fabrication of nanoparticles for drug delivery. Circulation of the nanoparticles for 24 h is a pre-requisite for subsequent studies to explore defined targeting of the nanoparticles to a specific anatomic site.

Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis.

Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MTX equivalent dose of 4.95 µmol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.

CXCR4-Targeted Nanocarriers for Triple Negative Breast Cancers.

CXCR4 is a cell membrane receptor that is overexpressed in triple-negative breast cancers and implicated in growth and metastasis of this disease. Using electrohydrodynamic cojetting, we prepared multicompartmental drug delivery carriers for CXCR4 targeting. The particles are comprised of a novel poly(lactide-co-glycolide) derivative that allows for straightforward immobilization of 1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (Plerixafor), a small molecule with affinity for CXCR4. Targeted nanocarriers are selectively taken up by CXCR4-expressing cells and effectively block CXCR4 signaling. This study suggests that CXCR4 may be an effective target for nanocarrier-based therapies.

Cardiomyocyte-Driven Actuation in Biohybrid Microcylinders.

Biohybrid microcylinders are fabricated using electrohydrodynamic cojetting followed by a surface chemistry approach to maximize cell-adhesive characteristics. As proper cell alignment and mechanical stiffness are important components of bioactuator design, spatial cell selectivity and stress/strain properties of microcylinders are characterized to demonstrate their capability of response to rat cardio-myocyte contraction. These microcylinders can find applications in a host of micromechanical systems.

Dual-stimuli-responsive microparticles.

The need for smart materials in the area of biotechnology has fueled the development of numerous stimuli-responsive polymers. Many of these polymers are responsive to pH, light, temperature, or oxidative stress, and yet very few are responsive toward multiple stimuli. Here we report on the synthesis of a novel dual-stimuli-responsive poly(ethylene glycol)-based polymer capable of changing its hydrophilic properties upon treatment with UV light (exogenous stimulus) and markers of oxidative stress (endogenous stimulus). From this polymer, smart microparticles and fibers were fabricated and their responses to either stimulus separately and in conjunction were examined. Comparison of the degradation kinetics demonstrated that the polymer became water-soluble only after both oxidation and irradiation with UV light, which resulted in selective degradation of the corresponding particles. Furthermore, in vitro experiments demonstrated successful uptake of these particles by Raw 264.7 cells. Such dual-stimuli-responsive particles could have potential applications in drug delivery, imaging, and tissue engineering.

Chemically orthogonal three-patch microparticles.

Compared to two-dimensional substrates, only a few methodologies exist for the spatially controlled decoration of three-dimensional objects, such as microparticles. Combining electrohydrodynamic co-jetting with synthetic polymer chemistry, we were able to create two- and three-patch microparticles displaying chemically orthogonal anchor groups on three distinct surface patches of the same particle. This approach takes advantage of a combination of novel chemically orthogonal polylactide-based polymers and their processing by electrohydrodynamic co-jetting to yield unprecedented multifunctional microparticles. Several micropatterned particles were fabricated displaying orthogonal click functionalities. Specifically, we demonstrate novel two- and three-patch particles. Multi-patch particles are highly sought after for their potential to present multiple distinct ligands in a directional manner. This work clearly establishes a viable route towards orthogonal reaction strategies on multivalent micropatterned particles.

Controlled microstructuring of janus particles based on a multifunctional poly(ethylene glycol).

A novel water insoluble, multifunctional poly(ethylene glycol), poly(hydrazide ethylene glycol-co-benzyl glycidyl ether) (P(HZ-co-BnGE)), is synthesized via thiol-ene click reaction of poly(allyl glycidyl ether-co-benzyl glycidyl ether) (P(AGE-co-BnGE)). The base polymer P(AGE-co-BnGE) is previously prepared by anionic ring-opening copolymerization of the corresponding monomers. To demonstrate utility, bicompartmental microspheres and microcylinders containing P(HZ-co-BnGE) in one of the compartments are prepared via electrohydrodynamic (EHD) co-jetting. Next, spatially controlled surface reactivity toward sugars is demonstrated by selective binding of 2α-mannobiose to the P(HZ-co-BnGE) compartment only, as confirmed by a carbohydrate-lectin-binding assay. These sugar-reactive hydrazide-presenting microparticles have potential applications for glyco-targeted drug delivery.

Photoswitchable particles for on-demand degradation and triggered release.

On-demand degradable polymer particles are fabricated via electrospraying of a solution of acetal-protected dextran that further includes 2-(4-methoxystyryl)-4,6-bis(trichloromethyl)-1,3,5-triazine as a photoacid generator. The illumination of UV light gives rise to photoacid and activates the catalytic deprotection of hydroxyl groups of dextran, leading to controlled dissolution of the microparticles in water.

Biocompatibility of biodegradable semiconducting melanin films for nerve tissue engineering.

The advancement of tissue engineering is contingent upon the development and implementation of advanced biomaterials. Conductive polymers have demonstrated potential for use as a medium for electrical stimulation, which has shown to be beneficial in many regenerative medicine strategies including neural and cardiac tissue engineering. Melanins are naturally occurring pigments that have previously been shown to exhibit unique electrical properties. This study evaluates the potential use of melanin films as a semiconducting material for tissue engineering applications. Melanin thin films were produced by solution processing and the physical properties were characterized. Films were molecularly smooth with a roughness (R(ms)) of 0.341 nm and a conductivity of 7.00+/-1.10 x 10(-5)S cm(-1) in the hydrated state. In vitro biocompatibility was evaluated by Schwann cell attachment and growth as well as neurite extension in PC12 cells. In vivo histology was evaluated by examining the biomaterial-tissue response of melanin implants placed in close proximity to peripheral nerve tissue. Melanin thin films enhanced Schwann cell growth and neurite extension compared to collagen films in vitro. Melanin films induced an inflammation response that was comparable to silicone implants in vivo. Furthermore, melanin implants were significantly resorbed after 8 weeks. These results suggest that solution-processed melanin thin films have the potential for use as a biodegradable semiconducting biomaterial for use in tissue engineering applications.

Microfabrication of poly (glycerol-sebacate) for contact guidance applications.

Controlling cell orientation and morphology through topographical patterning is a phenomenon that is applicable to a wide variety of medical applications such as implants and tissue engineering scaffolds. Previous work in this field, termed contact guidance, has demonstrated the application of this cellular response on a wide variety of material substrates such as silicon, quartz, glass, and poly(di-methyl siloxane) typically using ridge-groove geometries with sharp feature edges. One limitation of these studies in terms of biomedical applications is the choice of material. Therefore, demonstrating contact guidance and topography in a biodegradable material platform is a promising strategy for controlling cellular arrangements in tissue engineering scaffolds. This study investigates several strategies to advance contact guidance strategies and technology to more practical applications. Flexible biodegradable substrates with rounded features were fabricated by replica-molding poly(glycerol-sebacate) on sucrose-coated microfabricated silicon. Bovine aortic endothelial cells were cultured on substrates with microstructures between 2 and 5 microm in wavelength and with constant feature depth of 0.45 microm. Cells cultured on substrates with smaller pitches exhibited a substantially higher frequency of cell alignment and smaller circularity index. This work documents the first known use of using a flexible, biodegradable substrate with rounded features for use in contact guidance applications. The replica-molding technique described here is a general process that can be used to fabricate topographically patterned substrates with rounded features for many biomaterials. Furthermore, these results may lead to further elucidation of the mechanism of cell alignment and contact guidance on microfabricated substrates.