Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Effect of Blending and Degradation on the Morphology of Polyferrocenylsilane Block Copolymer Micelles

This thesis describes the study of the self-assembly of polyferrocenylsilane (PFS) block copolymers in solution, with a focus on how the length and nature of the corona forming block affected the nature and properties of micelles formed. Most experiments were carried out with four samples: PFS50-PI1000, PFS48-PI264, PFS53-PDMS285, and PFS80-PDMS960, where PI = polyisoprene, PDMS = polydimethylsiloxane, and the subscripts refer to the degree of polymerization. When each polymer was added to a suspension of short pre-formed seed micelles, long uniform fiber-like micelles formed. Polymers with long corona and core forming blocks had the lowest linear aggregation numbers (micelles per nm). When binary blends of these polymers were added to the seed micelles, the micelle length varied with polymer composition in the blend. Complex structures were formed from the self-assembly of blends of PFS homopolymer and PFS48-PI264. These structures had a central lamella with fibers attached to both short ends of the lamella. The physical dimensions of the structures did not change with increasing homopolymer loadings for blends containing PFS20. However the area of the lamellar structures increased, and the fiber length decreased, with increased loading of PFS50. I infer that PFS homopolymer cocrystallized with PFS48-PI264 to decrease the grafting density of the PI corona chains in the blend structure. I used intense sonication to produce a new type of seed micelle that formed multiarm-star (multipod) micelles when additional block copolymer was added. These stars have fiber-like micelles attached to a small central point. Stars with more than 4 arms become more prevalent iii for regrowth after longer sonication times. These stars have multiple fiber-like arms growing from a large dark central structure. In order to understand the origin of this phenomenon, I undertook a detailed study of polymer degradation during sonication. I found cleavage of the corona chains from the micelles, some crosslinking, but less degradation of PFS in the semicrystalline micelle core. I learned that polymer degradation is the main driving force for star formation in star-shaped structures with fewer than 4 arms, and that aggregates of small micelle fragments nucleate stars with more than 4 arms.Ph

Reversible Cross-Linking of Polyisoprene Coronas in Micelles, Block Comicelles, and Hierarchical Micelle Architectures Using Pt(0)–Olefin Coordination

Previous work has established that polyisoprene (PI) coronas in cylindrical block copolymer micelles with a poly(ferrocenyldimethylsilane) (PFS) core can be irreversibly cross-linked by hydrosilylation using (HSiMe₂)₂O in the presence of Karstedt’s catalyst. We now show that treatment of cylindrical PI-<i>b</i>-PFS micelles with Karstedt’s catalyst alone, in the absence of any silanes, leads to PI coronal cross-linking through Pt(0)–olefin coordination. The cross-linking can be reversed through the addition of 2-bis(diphenylphosphino)ethane (dppe), a strong bidentate ligand, which removes the platinum from the PI to form Pt(dppe)₂. The Pt(0) cross-linking of PI was studied with self-assembled cylindrical PI-<i>b</i>-PFS block copolymer micelles, where the cross-linking was found to dramatically increase the stability of the micellar structures. The Pt(0)–alkene coordination-induced cross-linking can be used to provide transmission electron microscopy contrast between PI and poly(dimethylsiloxane) (PDMS) corona domains in block comicelles as the process selectively increases the electron density of the PI regions. Moreover, following the assembly of a hierarchical scarf-shaped comicelle consisting of a PFS-<i>b</i>-PDMS platelet template with PI-<i>b</i>-PFS tassels, Pt(0)-induced cross-linking of the PI coronal regions allowed for the selective removal of the PFS-<i>b</i>-PDMS center, leaving behind an unprecedented hollowed-out scarf structure. The addition of Karstedt’s catalyst to PI or polybutadiene homopolymer toluene/xylene solutions resulted in the formation of polymer gels which underwent de-gelation upon the addition of dppe

Evaluation of the Cross Section of Elongated Micelles by Static and Dynamic Light Scattering

We describe simultaneous static (SLS) and dynamic light scattering (DLS) measurements on dilute solutions of a series of poly­(ferrocenyldimethylsilane-<i>b</i>-isoprene) (PFS₅₀–PI₁₀₀₀) block copolymer micelles of uniform length in <i>tert</i>-butyl acetate (<i>t</i>BA) and in decane. The subscripts in the term PFS₅₀–PI₁₀₀₀ refer to the mean degree of polymerization of each block. The SLS experiments show that in both solvents the micelles formed are elongated and rigid. We also observed that the large length of the PI block (1000 units) contributes to the SLS signal. From the SLS data, we calculated the mass per unit length (linear aggregation number), as well as the cross section of the micelles in both solvents. Interestingly, the linear aggregation number and the micelle cross sections, as deduced by SLS, were the same in decane and in <i>t</i>BA. However, the fitting of DLS data indicates that the hydrodynamic cross section of the micelles in <i>t</i>BA is much larger than that in decane, and both values are larger than the values determined by SLS. We hypothesize that the difference between cross sections deduced from SLS and DLS data fitting is related to the shape of the segment density profile of the corona. In <i>t</i>BA, the PI chains are more stretched than in decane, increasing the hydrodynamic radius of the micelle cross section

Precision Epitaxy for Aqueous 1D and 2D Poly(-caprolactone) Assemblies

The fabrication of monodisperse nanostructures of highly controlled size and morphology with spatially distinct functional regions is a current area of high interest in materials science. Achieving this control directly in a biologically relevant solvent, without affecting cell viability, opens the door to a wide range of biomedical applications, yet this remains a significant challenge. Herein, we report the preparation of biocompatible and biodegradable poly(ε-caprolactone) 1D (cylindrical) and 2D (platelet) micelles in water and alcoholic solvents via crystallization-driven self-assembly. Using epitaxial growth in an alcoholic solvent, we show exquisite control over the dimensions and dispersity of these nanostructures, allowing access to uniform morphologies and predictable dimensions based on the unimer-to-seed ratio. Furthermore, for the first time, we report epitaxial growth in aqueous solvent, achieving precise control over 1D nanostructures in water, an essential feature for any relevant biological application. Exploiting this further, a strong, biocompatible and fluorescent hydrogel was obtained as a result of living epitaxial growth in aqueous solvent and cell culture medium. MC3T3 and A549 cells were successfully encapsulated, demonstrating high viability (&gt;95% after 4 days) in these novel hydrogel materials.</p

Solution Self-Assembly of Blends of Crystalline-Coil Polyferrocenylsilane-<i>block</i>-polyisoprene with Crystallizable Polyferrocenylsilane Homopolymer

The self-assembly of block copolymers in solution leads to micellar structures with various morphologies. One way to modify the morphology of these micelles is to blend the block copolymer with a homopolymer corresponding to the core-forming block. Although the self-assembly of blends of amorphous homopolymers and block polymers has been extensively studied, there are few examples of solution self-assembly of blends of a core-crystalline block copolymer with a semicrystalline homopolymer. Here we describe a systematic study of the assembly in decane of blends of a polyferrocenylsilane-<i>block</i>-polyisoprene sample (PFS₄₈-<i>b</i>-PI₂₆₄) with two different PFS homopolymer samples (PFS₅₀ and PFS₂₀). We examine the structures formed as a function of blend composition and compare them to the structures formed from the individual components. PFS₄₈-<i>b</i>-PI₂₆₄ itself forms long cylindrical micelles, while the two homopolymer samples form stacks of lamellar crystals. Self-assembly of block copolymer mixtures leads to structures with an elongated planar core and fiber-like protrusions from the ends. The details of the structure vary in an interesting and systematic way as the ratio of homopolymer/block copolymer is increased, with important differences seen for the PFS50 and PFS20 homopolymer samples. This study demonstrates that cocrystallization plays a crucial role in determining the structures formed from these mixtures

Polyferrocenylsilane Crystals in Nanoconfinement: Fragmentation, Dissolution, and Regrowth of Cylindrical Block Copolymer Micelles with a Crystalline Core

Two samples of rod-like micelles in decane were prepared by seeded growth from a sample of a poly­(isoprene-<i>b</i>-ferrocenyldimethylsilane) diblock copolymer (PI₁₀₀₀–PFS₅₀, where the subscripts indicate the degree of polymerization). These micelles were uniform in length with a mass/length of 1.9 molecules/nm. The longer micelles (L-1250) had a number-average length <i>L</i>_n = 1243 nm, whereas the shorter micelles (L-250) had <i>L</i>_n = 256 nm. We used transmission electron microscopy (TEM) to examine the behavior of these micelles when dilute solutions of L-1250 or L-250 or their mixtures were heated at temperatures ranging from 40 to 75 °C and then cooled to room temperature. At 55 °C, the L-1250 sample underwent kinetically controlled fragmentation to give a broad distribution of micelle lengths. At this temperature, fragmentation was much less prominent in the L-250 sample. At higher temperatures, micelles with narrow distributions of lengths were obtained in each case (<i>L</i>_w/<i>L</i>_n ≈ 1.01). This process operates under thermodynamic control, and <i>L</i>_n values increased strongly with an increase in temperature. These results indicate that the micelles fragment, and polymer molecules dissolve, as the samples were heated. The fraction of surviving fragments decreased significantly at elevated temperatures, presumably reflecting a distribution of crystallinity in the cores of the micelle precursor. When the solutions were cooled, the surviving fragments served as seeds for the epitaxial growth of the micelles as the polymer solubility decreased. The most striking result of these experiments was the finding that fragments formed from the L-1250 micelles had a distribution of dissolution temperatures shifted by about 5 °C to higher temperature than the shorter L-250 micelles