Coarse-grained model of tropoelastin self-assembly into nascent fibrils.

Elastin is the dominant building block of elastic fibers that impart structural integrity and elasticity to a range of important tissues, including the lungs, blood vessels, and skin. The elastic fiber assembly process begins with a coacervation stage where tropoelastin monomers reversibly self-assemble into coacervate aggregates that consist of multiple molecules. In this paper, an atomistically based coarse-grained model of tropoelastin assembly is developed. Using the previously determined atomistic structure of tropoelastin, the precursor molecule to elastic fibers, as the basis for coarse-graining, the atomistic model is mapped to a MARTINI-based coarse-grained framework to account for chemical details of protein-protein interactions, coupled to an elastic network model to stabilize the structure. We find that self-assembly of monomers generates up to ∼70 â€‹nm of dense aggregates that are distinct at different temperatures, displaying high temperature sensitivity. Resulting assembled structures exhibit a combination of fibrillar and globular substructures within the bulk aggregates. The results suggest that the coalescence of tropoelastin assemblies into higher order structures may be reinforced in the initial stages of coacervation by directed assembly, supporting the experimentally observed presence of heterogeneous cross-linking. Self-assembly of tropoelastin is driven by interactions of specific hydrophobic domains and the reordering of water molecules in the system. Domain pair orientation analysis throughout the self-assembly process at different temperatures suggests coacervation is a driving force to orient domains for heterogeneous downstream cross-linking. The model provides a framework to characterize macromolecular self-assembly for elastin, and the formulation could easily be adapted to similar assembly systems.

Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model.

The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry.

Combinatorial molecular optimization of cement hydrates.

Despite its ubiquitous presence in the built environment, concrete's molecular-level properties are only recently being explored using experimental and simulation studies. Increasing societal concerns about concrete's environmental footprint have provided strong motivation to develop new concrete with greater specific stiffness or strength (for structures with less material). Herein, a combinatorial approach is described to optimize properties of cement hydrates. The method entails screening a computationally generated database of atomic structures of calcium-silicate-hydrate, the binding phase of concrete, against a set of three defect attributes: calcium-to-silicon ratio as compositional index and two correlation distances describing medium-range silicon-oxygen and calcium-oxygen environments. Although structural and mechanical properties correlate well with calcium-to-silicon ratio, the cross-correlation between all three defect attributes reveals an indentation modulus-to-hardness ratio extremum, analogous to identifying optimum network connectivity in glass rheology. We also comment on implications of the present findings for a novel route to optimize the nanoscale mechanical properties of cement hydrate.

Vascularized free tissue transfer for reconstruction of ablative defects in oral and oropharyngeal cancer patients undergoing salvage surgery following concomitant chemoradiation.

The purpose of this study was to determine whether chemotherapy delivered concurrently with external beam radiation therapy for loco-regionally advanced head and neck cancer affects the rate or severity of postoperative complications in patients who underwent salvage surgery for recurrent or persistent disease with simultaneous microvascular free flap reconstruction. The primary study group consisted of patients with head and neck malignancies that had undergone surgical salvage with microvascular free flap reconstruction for persistent or recurrent disease following definitive radiation or concomitant chemoradiation treatment. A group of demographically matched patients who underwent microvascular free flap reconstruction for non-malignant and malignant conditions who never received radiation were randomly selected to serve as a control group. The study cohort was divided according to radiation treatment. The overall success rate of flap reconstruction was 92%, with an overall complication rate of 23%. Concurrently administered chemotherapy did not appear to affect the type of or the complication rate. The results of this investigation indicate that microvascular free flap reconstruction of head and neck defects is highly predictable, results in relatively few major complications, and suggests that neither radiation alone nor concomitant chemoradiation has a statistically significant effect on overall flap survival or complication rate.

Serratus fascia "sandwich" free-tissue transfer for complex dorsal hand and wrist avulsion injuries.

The serratus anterior fascia was used as a free-tissue transfer in four patients for the reconstruction of dorsal hand defects. All patients had multiple open metacarpal fractures with extensor tendon injuries. The fascia was used to "sandwich" the extensor tendons in a bed of areolar gliding tissue to avoid adhesions. The mean follow-up was 2 years. There were no complications and all flaps survived completely. All flaps were grafted with meshed split-thickness skin at the time of transfer with a 100 percent take in all cases. A good functional result was noted in all patients. This free-tissue transfer is recommended for complex injuries to the dorsum of the hand associated with soft-tissue defects.

The relationship of functional return to varying methods of nerve repair.

This experimental study correlated varying methods of nerve repair with the degree of functional return using the rat sciatic nerve as a model. Six groups of adult male Sprague-Dawley rats (300 to 350 g) had their left sciatic nerve crushed (Group 1), transected and not repaired (Group 6), or transected and repaired using four methods that varied the degree of axonal alignment (Groups 2, 3, 4, and 5). Functional return was evaluated weekly using the sciatic functional index (SFI) and histology. Group 1 (crush) had a significantly better functional return than the other groups (p less than .001). Group 6 (no repair) had a significantly worse functional return than the other groups (p less than .001). Groups 2, 3, 4, and 5, regardless of the precision of axonal alignment, experienced the same degree of functional return (p less than .05). In all groups, with the exception of Group 1 (crush), the degree of functional return was poor. As multiple modifications in conventional microsurgical neurorrhaphy have not resulted in a significant functional improvement, factors not addressed by current techniques apparently compromise clinical results. Further improvement in the results of neurorrhaphy will require modifications in our techniques beyond presently conventional microsurgical methods.

The elbow flexion test. A clinical test for the cubital tunnel syndrome.

The elbow flexion test is a little known, inadequately standardized, and poorly understood clinical test for the cubital tunnel syndrome. To evaluate and define this test, 13 patients with clinical and electrophysiologic evidence of cubital tunnel syndrome were tested with elbow flexion in a standardized manner. This consisted of full elbow flexion with full extension of the wrists for three minutes. All patients noted the onset of or the increase in one or more of the symptoms of pain, numbness, or tingling with this test. Numbness and tingling followed the sensory distribution of the ulnar nerve, but pain was not limited to the ulnar nerve distribution. The symptom complex, rapid onset, and rapid resolution of symptoms support a locally induced segmental ulnar nerve ischemia as the cause of symptoms. This study demonstrates the elbow flexion test to be a useful, reliable, and provocative test for the cubital tunnel syndrome.