Mechanical Reinforcement of Polymeric Fibers through Peptide Nanotube Incorporation

High aspect ratio nanotubular assemblies can be effective fillers in mechanically reinforced composite materials. However, most existing nanotubes used for structural purposes are limited in their range of mechanical, chemical, and biological properties. We demonstrate an alternative approach to mechanical reinforcement of polymeric systems by incorporating synthetic d,l-cyclic peptide nanotube bundles as a structural filler in electrospun poly d-, l-lactic acid fibers. The nanotube bundles self-assemble through dynamic hydrogen bonding from synthetic cyclic peptides to yield structures whose dimensions can be altered based on processing conditions, and can be up to hundreds of micrometers long and several hundred nanometers wide. With 8 wt % peptide loading, the composite fibers are >5-fold stiffer than fibers composed of the polymer alone, according to atomic force microscopy-based indentation experiments. This represents a new use for self-assembling cyclic peptides as a load-bearing component in biodegradable composite materials.Engineering and Applied Science

Modeling the influence of gravity and the mechanical properties of elastin and collagen fibers on alveolar and lung pressure–volume curves

Abstract The relationship between pressure (P) and volume (V) in the human lung has been extensively studied. However, the combined effects of gravity and the mechanical properties of elastin and collagen on alveolar and lung P–V curves during breathing are not well understood. Here, we extended a previously established thick-walled spherical model of a single alveolus with wavy collagen fibers during positive pressure inflation. First, we updated the model for negative pressure-driven inflation that allowed incorporation of a gravity-induced pleural pressure gradient to predict how the static alveolar P–V relations vary spatially throughout an upright human lung. Second, by introducing dynamic surface tension and collagen viscoelasticity, we computed the hysteresis loop of the lung P–V curve. The model was tested by comparing its predicted regional ventilation to literature data, which offered insight into the effects of microgravity on ventilation. The model has also produced novel testable predictions for future experiments about the variation of mechanical stresses in the septal walls and the contribution of collagen and elastin fibers to the P–V curve and throughout the lung. The model may help us better understand how mechanical stresses arising from breathing and pleural pressure variations affect regional cellular mechanotransduction in the lung

Effects of Chondroadherin on Cartilage Nanostructure and Biomechanics via Murine Model

While small leucine rich proteins/proteoglycans (SLRPs) are present in very low concentrations in the extracellular matrix (ECM), they have been shown to be critical determinants of the proper ECM assembly and function in connective tissues [1] including bone [2], cornea [3], and cartilage [4]. However, their direct and indirect roles in matrix biomechanics and the potential for osteoarthritis-related dysfunction of cartilage remain unclear. With the advent of new high resolution nanotechnological tools, the direct quantification of cartilage biomechanical properties using murine models can provide important insights into how secondary ECM molecules, such as SLRPs, affect the function and pathology of cartilage [5]. Previous nanoindentation studies of murine cartilage have assessed the effects of maturation and osteoarthritis-like degradation of cartilage on its biomechanical properties [6, 7]. Recently, murine models have received increased attention because of the availability of specific gene-knockout and gene alteration technologies [8]. For example, chondroadherin (CHAD) is a non-collagenous small leucine-rich proteoglycan (SLRP) with α-helix and β-sheet secondary structure, spatially localized in the territorial matrix (MW = 38 kDa) [9]. In articular cartilage, CHAD is distributed non-uniformly with depth [10], and binds to type II collagen and the α2β1 integrin and is hypothesized to function in the communication between chondrocytes and their surrounding matrix, as well as in the regulation of collagen fibril assembly [11, 12] (Fig. 1). The objective of the present study is to explore the role of CHAD and its depletion on the structure and nanomechanical properties of both superficial and middle/deep zone cartilage. The current methods thereby enabled depth-dependent analysis of cartilage nanostructure and dynamic energy-dissipative mechanisms

High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis

a b s t r a c t Murine models of osteoarthritis (OA) and post-traumatic OA have been widely used to study the development and progression of these diseases using genetically engineered mouse strains along with surgical or biochemical interventions. However, due to the small size and thickness of murine cartilage, the relationship between mechanical properties, molecular structure and cartilage composition has not been well studied. We adapted a recently developed AFM-based nano-rheology system to probe the dynamic nanomechanical properties of murine cartilage over a wide frequency range of 1 Hz to 10 kHz, and studied the role of glycosaminoglycan (GAG) on the dynamic modulus and poroelastic properties of murine femoral cartilage. We showed that poroelastic properties, highlighting fluid-solid interactions, are more sensitive indicators of loss of mechanical function compared to equilibrium properties in which fluid flow is negligible. These fluid-flow-dependent properties include the hydraulic permeability (an indicator of the resistance of matrix to fluid flow) and the high frequency modulus, obtained at high rates of loading relevant to jumping and impact injury in vivo. Utilizing a fibril-reinforced finite element model, we estimated the poroelastic properties of mouse cartilage over a wide range of loading rates for the first time, and show that the hydraulic permeability increased by a factor $ 16 from k normal ¼7.80 Â 10 À 16 71.3 Â 10 À 16 m 4 /N s to k GAG-depleted ¼1.26 Â 10 À 14 76.73 Â 10 À 15 m 4 /N s after GAG depletion. The high-frequency modulus, which is related to fluid pressurization and the fibrillar network, decreased significantly after GAG depletion. In contrast, the equilibrium modulus, which is fluid-flow independent, did not show a statistically significant alteration following GAG depletion

Mechanical Reinforcement of Polymeric Fibers through Peptide Nanotube Incorporation

High aspect ratio nanotubular assemblies can be effective fillers in mechanically reinforced composite materials. However, most existing nanotubes used for structural purposes are limited in their range of mechanical, chemical, and biological properties. We demonstrate an alternative approach to mechanical reinforcement of polymeric systems by incorporating synthetic d,l-cyclic peptide nanotube bundles as a structural filler in electrospun poly d-, l-lactic acid fibers. The nanotube bundles self-assemble through dynamic hydrogen bonding from synthetic cyclic peptides to yield structures whose dimensions can be altered based on processing conditions, and can be up to hundreds of micrometers long and several hundred nanometers wide. With 8 wt % peptide loading, the composite fibers are >5-fold stiffer than fibers composed of the polymer alone, according to atomic force microscopy-based indentation experiments. This represents a new use for self-assembling cyclic peptides as a load-bearing component in biodegradable composite materials

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

OBJECTIVE Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. DESIGN We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. RESULTS PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.ConclusionPlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC