Influence of Nanogel Amphiphilicity on Dermal Delivery: Balancing Surface Hydrophobicity and Network Rigidity.

Polymeric nanogels are promising nonirritating nanocarriers for topical delivery applications. However, conventional hydrophilic networks limit encapsulation of hydrophobic therapeutics and hinder tailored interactions with the amphiphilic skin barrier. To address these limitations, we present amphiphilic nanogels containing hydrophilic networks with hydrophobic domains. Two competing factors determine favorable nanogel-skin interactions and need to be balanced through network composition: suitable surface hydrophobicity and low network rigidity (through physical hydrophobic cross-links). To ensure comparability in such investigations, we prepared a library of nanogels with increasing hydrophobic cholesteryl amounts but similar colloidal features. By combining mechanical and surface hydrophobicity tests (atomic force microscopy (AFM)) with dermal delivery experiments on excised human skin, we can correlate an increased delivery efficacy of Nile red to the viable epidermis with a specific network composition, i.e., 20-30 mol % cholesterol. Thus, our nanogel library identifies a specific balance between surface amphiphilicity and network rigidity to guide developments of advanced dermal delivery vehicles.

Dual-reactive nanogels for orthogonal functionalization of hydrophilic shell and amphiphilic network.

Amphiphilic nanogels (NGs) combine a soft, water-swollen hydrogel matrix with internal hydrophobic domains. While these domains can encapsulate hydrophobic cargoes, the amphiphilic particle surface can reduce colloidal stability and/or limit biological half-life. Therefore, a functional hydrophilic shell is needed to shield the amphiphilic network and tune interactions with biological systems. To adjust core and shell properties independently, we developed a synthetic strategy that uses preformed dual-reactive nanogels. In a first step, emulsion copolymerization of pentafluorophenyl methacrylate (PFPMA) and a reduction-cleavable crosslinker produced precursor particles for subsequent network modification. Orthogonal shell reactivity was installed by using an amphiphilic block copolymer (BCP) surfactant during this particle preparation step. Here, the hydrophilic block poly(polyethylene glycol methyl ether methacrylate) (PPEGMA) contains a reactive alkyne end group for successive functionalization. The hydrophobic block (P(PFPMA-co-MAPMA) contains random methacryl-amido propyl methacrylamide (MAPMA) units to covalently attach the surfactant to the growing PPFPMA network. In the second step, orthogonal modification of the core and shell was demonstrated. Network functionalization with combinations of hydrophilic (acidic, neutral, or basic) and hydrophobic (cholesterol) groups gave a library of pH- and redox-sensitive amphiphilic NGs. Stimuli-responsive properties were demonstrated by pH-dependent swelling and reduction-induced degradation via dynamic light scattering. Subsequently, copper-catalyzed azide-alkyne cycloaddition was used to attach azide-modified rhodamine as model compound to the shell (followed by UV-Vis). Overall, this strategy provides a versatile platform to develop multi-functional amphiphilic nanogels as carriers for hydrophobic cargoes.

Regioselective Seeded Polymerization in Block Copolymer Nanoparticles: Post-Assembly Control of Colloidal Features.

Post-assembly modifications are efficient tools to adjust colloidal features of block copolymer (BCP) particles. However, existing methods often address particle shape, morphology, and chemical functionality individually. For simultaneous control, we transferred the concept of seeded polymerization to phase separated BCP particles. Key to our approach is the regioselective polymerization of (functional) monomers inside specific BCP domains. This was demonstrated in striped PS-b-P2VP ellipsoids. Here, polymerization of styrene preferably occurs in PS domains and increases PS lamellar thickness up to 5-fold. The resulting asymmetric lamellar morphology also changes the particle shape, i.e., increases the aspect ratio. Using 4-vinylbenzyl azide as co-monomer, azides as chemical functionalities can be added selectively to the PS domains. Overall, our simple and versatile method gives access to various multifunctional BCP colloids from a single batch of pre-formed particles.

Shape-based separation of synthetic microparticles.

The functional properties of colloidal materials can be tailored by tuning the shape of their constituent particles. Unfortunately, a reliable, general methodology for purifying colloidal materials solely based on shape is still lacking. Here we exploit the single-particle analysis and sorting capabilities of the fluorescence-activated cell sorting (FACS) instrument, a commonly used tool in biomedical research, and demonstrate the ability to separate mixtures of synthetic microparticles based solely on their shape with high purity. We achieve this by simultaneously obtaining four independent optical scattering signals from the FACS instrument to create shape-specific 'scattering signatures' that can be used for particle classification and sorting. We demonstrate that these four-dimensional signatures can overcome the confounding effects of particle orientation on shape-based characterization. Using this strategy, robust discrimination of particles differing only slightly in shape and an efficient selection of desired shapes from mixtures comprising particles of diverse sizes and materials is demonstrated.

Amphiphilic Nanogels: Fuzzy Spheres with a Pseudo-Periodic Internal Structure.

Amphiphilic polymer nanogels (NGs) are promising drug delivery vehicles that extend the application of conventional hydrophilic NGs to hydrophobic cargoes. By randomly introducing hydrophobic groups into a hydrophilic polymer network, loading and release profiles as well as surface characteristics of these colloids can be tuned. However, very little is known about the underlying internal structure of such complex colloidal architectures. Of special interest is the question how the amphiphilic network composition influences the internal morphology and the "fuzzy" surface structure. To shine light into the influence of varying network amphiphilicity on these structural features, we investigated a small library of water-swollen amphiphilic NGs using small-angle X-ray scattering (SAXS). It was found that overall hydrophilic NGs, consisting of pure poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA), display a disordered internal structure as indicated by the absence of a SAXS peak. In contrast, a SAXS peak is present for amphiphilic NGs with various amounts of incorporated hydrophobic groups such as cholesteryl (CHOLA) or dodecyl (DODA). The internal composition of the NGs is considered structurally homologous to microgels. Application of the Teubner-Strey model reveals that hydrophilic PHPMA NGs have a disordered internal structure (positive amphiphilicity factor) while CHOLA and DODA samples have an ordered internal structure (negative amphiphilicity factor). From the SAXS data it can be derived that the internal structure of the amphiphilic NGs consists of regularly alternating hydrophilic and hydrophobic domains with repeat distances of 3.45-5.83 nm.

Spinal vascular malformations: treatment strategies and outcome.

Spinal vascular malformations (SVMs) are a heterogeneous group that can cause acute, subacute, or chronic spinal cord dysfunction. The majority of the patients present to neurosurgical attention after a protracted course with severe neurological dysfunction. Spinal vascular lesions comprise approximately 3-4 % of all intradural spinal lesions. They are pathologically similar to their intracranial counterparts, but their clinical impact is often comparatively worse. Early, correct recognition of the pathology is mandatory to halt the progression of the disease and minimize permanent spinal cord injury. The first clinical observation of a SVM was published in 1890, but it was not until 1914 that the first successful surgical treatment of a spinal vascular malformation was reported. Intervention-either by microsurgical or endovascular means-aims to halt or reverse the progressive neurological deterioration by eliminating flow through the abnormal fistulous or nidal connections, and restoring normal spinal cord perfusion and intravascular pressures. In fact, complex spinal arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs) frequently require a multimodality approach that utilizes both microsurgery and endovascular embolization effectively. The goal of this review is to describe the various types of vascular malformations of the spine, their pathophysiology, clinical presentation, treatment strategies, and outcome. For purposes of discussion on the current manuscript, vascular malformations of the spine were divided into arteriovenous fistulas (AVFs) and arteriovenous malformations (AVMs). Spinal cord aneurysms are extremely rare, and the majority of the lesions that come to the neurosurgeon's attention are concomitant to a spinal AVM.

Fully Aromatic High Performance Thermoset via Sydnone-Alkyne Cycloaddition.

We have developed an efficient synthetic platform for the preparation of a new class of high performance thermosets based on the 1,3-dipolar cycloaddition of a bifunctional sydnone with a trifunctional alkyne. These processable materials possess outstanding thermal stability, with Td5% of 520 °C and a weight loss of <0.1% per day at 225 °C (both in air). Key to this performance is the stability of the starting functional groups that allows for reactive B-staging via simple thermal activation to give fully aromatic and highly cross-linked polypyrazole-based thermosets.

Management of intracranial aneurysms associated with arteriovenous malformations.

Intracranial or brain arteriovenous malformations (BAVMs) are some of the most interesting and challenging lesions treated by the cerebrovascular neurosurgeon. It is generally believed that the combination of BAVMs and intracranial aneurysms (IAs) is associated with higher hemorrhage rates at presentation and higher rehemorrhage rates and thus with a more aggressive course and natural history. There is wide variation in the literature on the prevalence of BAVM-associated aneurysms (range 2.7%-58%), with 10%-20% being most often cited in the largest case series. The risk of intracranial hemorrhage in patients with unruptured BAVMs and coexisting IAs has been reported to be 7% annually, compared with 2%-4% annually for those with BAVM alone. Several different classification systems have been applied in an attempt to better understand the natural history of this combination of lesions and implications for treatment. Independent of the classification used, it is clear that a few subtypes of aneurysms have a direct hemodynamic correlation with the BAVM itself. This is exemplified by the fact that the presence of a distal flow-related or an intranidal aneurysm appears to be associated with an increased hemorrhage risk, when compared with an aneurysm located on a vessel with no direct supply to the BAVM nidus. Debate still exists regarding the etiology of the association between those two vascular lesions, the subsequent implications for patients' risk of hemorrhagic stroke, and finally the determination of which patients warrant treatment and when. The ultimate goals of the treatment of a BAVM associated with an IA are to prevent hemorrhage, avoid stepwise neurological deterioration, and eliminate the mortality risk associated with recurrent hemorrhagic events. The treatment is only justifiable if the risks associated with an intervention are lower than or equivalent to the long-term risks of disability or mortality caused by the lesion itself. When faced with this difficult decision, a few questions need to be answered by the treating neu-rosurgeon: What is the mode of presentation? What is the symptomatic lesion? Which one of the lesions bled? What is the relationship between the BAVM and IA? Is it possible to safely treat both BAVM and IA? The objective of this review is to discuss the demographics, natural history, classification, and strategies for management of BAVMs associated with IAs.

A facile synthesis of dynamic, shape-changing polymer particles.

We herein report a new facile strategy to ellipsoidal block copolymer nanoparticles that exhibit a pH-triggered anistropic swelling profile. In a first step, elongated particles with an axially stacked lamellae structure are selectively prepared by utilizing functional surfactants to control the phase separation of symmetric polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) in dispersed droplets. In a second step, the dynamic shape change is realized by cross-linking the P2VP domains, thereby connecting glassy PS discs with pH-sensitive hydrogel actuators.

Optically monitoring the microenvironment of a hydrophobic cargo in amphiphilic nanogels: influence of network composition on loading and release.

Amphiphilic nanogels (ANGs) are promising carriers for hydrophobic cargos such as drugs, dyes, and catalysts. Loading content and release kinetics of these compounds are controlled by type and number of hydrophobic groups in the amphiphilic copolymer network. Thus, understanding the interactions between cargo and colloidal carrier is mandatory for a tailor-made and cargo-specific ANG design. To systematically explore the influence of the network composition on these interactions, we prepared a set of ANGs of different amphiphilicity and loaded these ANGs with varying concentrations of the solvatochromic dye Nile Red (NR). Here, NR acts as a hydrophobic model cargo to optically probe the polarity of its microenvironment. Analysis of the NR emission spectra as well as measurements of the fluorescence quantum yields and decay kinetics revealed a decrease in the polarity of the NR microenvironment with increasing hydrophobicity of the hydrophobic groups in the ANG network and dye-dye interactions at higher loading concentrations. At low NR concentrations, the hydrophobic cargo NR is encapsulated in the hydrophobic domains. Increasing NR concentrations resulted in probe molecules located in a more hydrophilic environment, i.e., at the nanodomain border, and favored dye-dye interactions and NR aggregation. These results correlate well with release experiments, indicating first NR release from more hydrophilic network locations. Overall, our findings demonstrate the importance to understand carrier-drug interactions for efficient loading and controlled release profiles in amphiphilic nanogels.

Striped, ellipsoidal particles by controlled assembly of diblock copolymers.

Control of interfacial interactions leads to a dramatic change in shape and morphology for particles based on poly(styrene-b-2-vinylpyridine) diblock copolymers. Key to these changes is the addition of Au-based surfactant nanoparticles (SNPs) which are adsorbed at the interface between block copolymer-containing emulsion droplets and the surrounding amphiphilic surfactant to afford asymmetric, ellipsoid particles. The mechanism of formation for these novel nanostructures was investigated by systematically varying the volume fraction of SNPs, with the results showing the critical nature that the segregation of SNPs to specific interfaces plays in controlling structure. A theoretical description of the system allows the size distribution and aspect ratio of the asymmetric block copolymer colloidal particles to be correlated with the experimental results.

The treatment of cavernous sinus meningiomas: evolution of a modern approach.

Cavernous sinus meningiomas (CSMs) are challenging lesions for the skull base neurosurgeon to manage given their close association with cranial nerves II-VI and the internal carotid artery. In the 1980s and early 1990s, with advancements in microsurgical techniques, increasing knowledge of the relevant microsurgical neuroanatomy, and the advent of advanced skull base surgical approaches, the treatment of CSMs involved attempts at gross-total resection (GTR). Initial fervor for a surgical cure waned, however, as skull base neurosurgeons demonstrated the limits of complete resection in this region, the ongoing issue of potential tumor recurrences, and the unacceptably high cranial nerve and vascular morbidity associated with this strategy. The advent of radiosurgery and its documented success for tumor growth control and limited morbidity in cavernous lesions has helped to shift the treatment goals for CSMs from GTR to tumor control and symptom relief while minimizing treatment- and lesion-associated morbidity. The authors review the relevant microanatomy of the cavernous sinus with anatomical and radiographic correlates, as well as the various treatment options. A modernized, multimodality treatment algorithm to guide management of these lesions is proposed.

The far-lateral approach for foramen magnum meningiomas.

Foramen magnum meningiomas (FMMs) are slow growing, most often intradural and extramedullary tumors that pose significant challenges to the skull base neurosurgeon. The indolent clinical course of FMMs and their insidious onset of symptoms are important factors that contribute to delayed diagnosis and relative large size at the time of presentation. Symptoms are often produced by compression of surrounding structures (such as the medulla oblongata, upper cervical spinal cord, lower cranial nerves, and vertebral artery) within a critically confined space. Since the initial pathological description of a FMM in 1872, various surgical approaches have been described with the aim of achieving radical tumor resection. The surgical treatment of FMMs has evolved considerably over the last 4 decades due to the progress in microsurgical techniques and development of a multitude of skull base approaches. Posterior and posterolateral FMMs can be safely resected via a standard midline suboccipital approach. However, controversy still exits regarding the optimal management of anterior or anterolateral lesions. Independently of technical variations and the degree of bone removal, all modern surgical approaches to the lower clivus and anterior foramen magnum derive from the posterolateral (or far-lateral) craniotomy originally described by Roberto Heros and Bernard George. This paper is a review of the surgical management of FMMs, with emphasis on the far-lateral approach and its variations. Clinical presentation, imaging findings, important neuroanatomical correlations, recurrence rates, and outcomes are discussed.

Development of contrast-induced nephropathy in subarachnoid hemorrhage: a single center perspective.

BACKGROUND AND PURPOSE: The use of iodinated contrast-enhanced imaging studies is increasing in acute cerebrovascular diseases, especially in subarachnoid hemorrhage (SAH). In SAH, such studies are essential for both diagnosis and treatment of the cause and sequela of hemorrhage. These patients are often subjected to multiple contrast studies such as computed tomographic angiography, computed tomographic perfusion, and cerebral angiography. They are also predisposed to intravascular volume depletion as a part of the disease process from cerebral salt wasting (CSW) and as a result of multiple contrast exposure can develop contrast-induced nephropathy (CIN). Data regarding CIN in this population are scarce. We aimed to examine the incidence of CIN in SAH and identify potential associative risk factors. METHODS: We analyzed data from a prospectively collected patient database of patients with SAH admitted to the neurocritical intensive care unit in a single center over a period of 1 year. CIN was defined as an increase in serum creatinine by >1.5 times or >0.3 mg/dl greater than the admission value, or urine output <0.5 ml/kg/h during one 6-h block. RESULTS: In this cohort of 75 patients with SAH who had undergone at least one contrast study, the mean age was 57.3 ± 15.6 years and 70.7% were women. Four percent developed CIN which resolved within 72 h and none required renal replacement therapy or dialysis. Patients older than 75 years (20%, p < 0.05), those with borderline renal function (14.3%, p = 0.26), diabetics (11.1%, p = 0.32), and those with lower recommended "maximum contrast dose" volume (33.3%, p = 0.12) had a trend toward development of CIN, although most were not statistically significant. Twenty-seven patients (36 %) were on 3% hypertonic saline (HTS) for CSW during the contrasted study but none developed CIN. CONCLUSIONS: The incidence of CIN in SAH patients is comparable to previously published reports on non-neurological cohorts. No definite association was noted with any predisposing factors postulated to be responsible for CIN, except for advanced age. Concurrent use of 3% HTS was not associated with CIN in this population.

Rational Design and Development of Polymeric Nanogels as Protein Carriers.

Proteins have gained significant attention as potential therapeutic agents owing to their high specificity and reduced toxicity. Nevertheless, their clinical utility is hindered by inherent challenges associated with stability during storage and after in vivo administration. To overcome these limitations, polymeric nanogels (NGs) have emerged as promising carriers. These colloidal systems are capable of efficient encapsulation and stabilization of protein cargoes while improving their bioavailability and targeted delivery. The design of such delivery systems requires a comprehensive understanding of how the synthesis and formulation processes affect the final performance of the protein. This review highlights critical aspects involved in the development of NGs for protein delivery, with specific emphasis on loading strategies and evaluation techniques. For example, factors influencing loading efficiency and release kinetics are discussed, along with strategies to optimize protein encapsulation through protein-carrier interactions to achieve the desired therapeutic outcomes. The discussion is based on recent literature examples and aims to provide valuable insights for researchers working toward the advancement of protein-based therapeutics.

Solvent Annealing of Striped Ellipsoidal Block Copolymer Particles: Reversible Control over Lamellae Asymmetry, Aspect Ratio, and Particle Surface.

Solvent annealing is a versatile tool to adjust the shape and morphology of block copolymer (BCP) particles. During this process, polar solvents are often used for block-selective swelling. However, such water-miscible solvents can induce (partial) solubilization of one block in the surrounding aqueous medium, thus, causing complex structural variations and even particle disassembly. To reduce the complexity in morphology control, we focused on toluene as a nonpolar polystyrene-selective solvent for the annealing of striped polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) ellipsoids. The selective stretching of PS chains produces unique asymmetric lamellae structures, which translate to an increase in the particle aspect ratio after toluene evaporation. Complete reversibility is achieved by changing to chloroform as a nonselective solvent. Moreover, surfactants can be used to tune block-selective wetting of the particle surface during the annealing; for example, a PS shell can protect the internal lamellae structure from disassembly. Overall, this versatile postassembly process enables the tailoring of the structural features of striped colloidal ellipsoids by only using commercial BCPs and solvents.

Photoreactive nanoparticles as nanometric building blocks for the generation of self-healing hydrogel thin films.

The use of reversible photo-cross-linkable nanoparticles as nano building blocks for the formulation of nanostructured self-healing thin hydrogel films is shown for the first time. This strategy for the fabrication of autonomous self-healing coatings consisted of various microgels bearing surface cinnamate moieties. The nanoparticles were formed by miniemulsion copolymerization, which was followed by surface functionalization with the cinnamate groups. These nanoparticles were then used to form films by drop-casting, followed by interparticle photo-cross-linking polymerization through the light-induced forward dimerization reaction of the previously incorporated cinnamate groups. The reversibility of this macroscopic network formation was also demonstrated by photoinducing the backward dimerization reaction and carrying out several cycles of photoinduced cross-linking and de-cross-linking. The self-healing ability through swelling of these films following surface damage was also demonstrated. Finally, the ability of these self-healing macroscopic films to incorporate additives of different chemical nature before photo-cross-linking was evaluated.

Polymeric photoresist nanoparticles: light-induced degradation of hydrophobic polymers in aqueous dispersion.

Nanoparticles consisting of a photoreactive polymer able to radically switch its hydrophobicity are successfully prepared by miniemulsion polymerization. Irradiation with UV light causes degradation of the particles where at complete dissolution is achieved by changing the initial hydrophobic photoresist polymer into hydrophilic poly(methacrylic acid). Incorporation of the fluorescence-sensitive Nile red serves as a solvatochromic probe to study the particle degradation. Diffusion of either Nile red out from or water into the former hard spherical nanoparticles is studied and not only renders the described material an ideal system for applications, where in situ dissolution of nanoparticles may be needed, but also bears the additional advantage of performing controlled burst release.

Sulfoxide-functionalized nanogels inspired by the skin penetration properties of DMSO.

Among polymeric nanocarriers, nanogels are especially promising non-irritating delivery vehicles to increase dermal bioavailability of therapeutics. However, accurately tailoring defined interactions with the amphiphilic skin barrier is still challenging. To address this limited specificity, we herein present a new strategy to combine biocompatible nanogels with the outstanding skin interaction properties of sulfoxide moieties. These chemical motifs are known from dimethyl sulfoxide (DMSO), a potent chemical penetration enhancer, which can often cause undesired skin damage upon long-term usage. By covalently functionalizing the nanogels' polymer network with such methyl sulfoxide side groups, tailor-made dermal delivery vehicles are developed to circumvent the skin disrupting properties of the small molecules. Key to an effective nanogel-skin interaction is assumed to be the specific nanogel amphiphilicity. This is examined by comparing the delivery efficiency of sulfoxide-based nanogels (NG-SOMe) with their corresponding thioether (NG-SMe) and sulfone-functionalized (NG-SO2Me) analogues. We demonstrate that the amphiphilic sulfoxide-based NG-SOMe nanogels are superior in their interaction with the likewise amphipathic stratum corneum (SC) showing an increased topical delivery efficacy of Nile red (NR) to the viable epidermis (VE) of excised human skin. In addition, toxicological studies on keratinocytes and fibroblasts show good biocompatibility while no perturbation of the complex protein and lipid distribution is observed via stimulated Raman microscopy. Thus, our NG-SOMe nanogels show high potential to effectively emulate the skin penetration enhancing properties of DMSO without its negative side effects.

CABG With Internal Thoracic Artery in Children With Congenital Heart Defects: A Good Option When It Is the Only One.

OBJECTIVE: Coronary complications may present during or after repair of congenital heart defects. We report coronary artery bypass grafting (CABG) by internal thoracic artery (ITA) grafts to either coronary artery in children with congenital anomalies. METHODS: Four cases who underwent CABG with ITA grafts from March 2016 to March 2020 were retrospectively reviewed. RESULTS: At the time of operation, patient's ages and weight were 7 and 20 months old and 14 and 15 years old and 6.5, 10, 40, and 45 kg, respectively. Diagnosis were anomalous origin of the left coronary artery from the pulmonary artery with leftward lateral ostial origin (n = 1), neopulmonary annulus hypoplasia post arterial switch with contiguous right coronary artery (RCA) arising from the left facing sinus (n = 1), RCA stenosis after the Ross procedure (n = 1), and right coronary ostial obstruction after aortic valve replacement in truncus arteriosus (n = 1). Procedures included left ITA to left coronary ostium (n = 1), right ventricular outflow tract (RVOT) enlargement with pulmonary valve replacement with left ITA to RCA (n = 1), RVOT enlargement with pulmonary valve replacement with right ITA to RCA (n = 1), and aortic valve re-replacement, pulmonary valve replacement, and right ITA to RCA (n = 1). At last follow-up, all four patients were asymptomatic, with normal ventricular function, and all grafts were patent. CONCLUSIONS: The use of CABG in children is valuable alternative when dealing with complex coronary anatomy not suitable for classic repairs. In children, graft patency is required to be longer than 50 years; therefore, use of arterial grafts seems mandatory.