11 research outputs found
Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry
Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expres- sion, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, patho- logical behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracel- lular matrix (ECM) proteins. A high-throughput bead-based
ELISA approach and inhibitor studies revealed that differ- entiation marker expression is mediated chiefly via focal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity of in vitro testing platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features of in vivo disease and elucidate potential context-dependent therapeutic targets
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EXTREME INDENTATION AND FRACTURE OF SOFT POLYMER GELS
The mechanical properties of conventional hard materials, such as metals and ceramics, have received widespread attention in the past several decades; however mechanical characterization, failure in particular, of soft materials, such as polymer gels, elastomers, and biological tissues and organs, has largely been ignored. While practical issues such as difficulty in handling, processing, and slippage offer complexities in characterization, the breakdown of the fundamental assumptions of linear elastic fracture mechanics due to large strains prior to failure, significant energy dissipation ahead of a crack tip and rate and time dependent effects makes understanding of failure in soft materials even more challenging. Moreover, most research efforts have primarily focussed on understanding crack propagation in soft polymer materials, and not much attention has been given to the critical force and energy involved in the nucleation of a crack in soft solids. Understanding the mechanics behind crack nucleation is not only vital for advancing soft material fracture mechanics, but is also relevant to numerous healthcare applications such as percutaneous needle insertion (biopsies, blood sampling, and anesthesia); robot-assisted surgeries, and design of advanced surgical instruments. Here, we focus on characterizing the process of crack nucleation via puncture with spherically tipped indenters. This simple method offers ease of implementation without requiring special sample preparation, while also yielding interesting insight into the process of crack nucleation, or fracture initiation, in soft polymer networks. First, we study puncture in a series of acrylic triblock copolymer gels with varying gel concentration at characteristic length scales relevant to intrinsic material properties and network structure. Failure properties namely, fracture initiation energy were characterized via puncture mechanics, and crack propagation energy, was measured via traditional pure shear tests. Crack propagation energy was shown to scale quadratically with polymer volume fraction. The observed scaling is in excellent agreement with the predicted scaling by modifying the classical Lake-Thomas model to incorporate fracture of triblock copolymer gels via chain pull-out and plastic yielding of micelles. Interestingly, our results demonstrate a linear dependence of fracture initiation energy on polymer volume fraction, thus indicating the role played by different fundamental mechanisms governing crack nucleation process in soft gels. Thus, our experimental results proved a new insight into the process of fracture initiation in soft polymer gels. The analysis of puncture tests in gels at the highest concentration showed interesting failure properties, and no longer obeyed the experimentally established scalings for lower gel concentrations. Based on our current understanding, we hypothesize significant enhancement in failure properties due to a change in micelle morphology as indicated by the small-angle X-ray scattering data. Understanding the role played by polymer volume fraction on fracture initiation will significantly contribute towards the molecular design of tough polymer gels for a plethora of innovative applications in soft robotics, tissue engineering, wearable electronics, and soft actuators. Next, we examine the effect of machine loading compliance (or far-field compliance) on the critical force to puncture soft polymer gels. Our results have shown that incorporation of a compliant spring beam in series with the indenter can lead to a reduction in critical puncture force by ~60% when the spring beam compliance is ten times greater than the effective gel-indenter compliance at the point of puncture. The reduction in critical puncture force with increasing beam compliance was varied at deformation rates varied over three orders of magnitude. It was found that varying the spring beam compliance alters the local deformation rate during puncture, thereby affecting fracture initiation in an analogous manner to widely studied crack propagation in soft gels. This work not only contributes towards the mechanistic knowledge of fracture initiation in soft polymer gels but also has an important technological application in the form of a reduced-pain medical device. Lastly, we adopt resilin-based hydrogels as a material system to understand the influence of polymer concentration above and below overlap concentration, c* on fracture initiation via puncture at length scales relevant to biological cells(~10-50 μm). Low strain oscillatory shear rheology enabled bulk mechanical characterization, whereas micro-indentation was used to characterize energy storing capability or resilience as a function of applied strain via micro-indentation at ~mm length scales. A significant enhancement in mechanical properties is observed at higher concentrations reflecting increased network homogeneity above c*. Moreover, the gel at the highest concentration possessed exceptionally high fracture initiation toughness possibly due to the formation of nanoaggregates toughening via a reinforcement mechanism. The lessons learned from this research will significantly advance the current synthetic strategies in the design of soft polymer gels for tissue engineering applications
Swelling and Dye-Adsorption Characteristics of an Amphoteric Superabsorbent Polymer
Amphoteric superabsorbent polymers (SAPs) based on the
anionic
monomer sodium acrylate (SA) and the cationic monomer [2-(methacryloyloxy)ethyl]trimethylammonium
chloride (METAC) were synthesized by solution polymerization using <i>N</i>,<i>N</i>′-methylenebisacrylamide as a
cross-linking agent. The ratio of anionic to cationic repeat units
was varied to obtain anionic, cationic, and amphoteric SAPs. The synthesized
SAPs were characterized by Fourier transform infrared spectroscopy.
The equilibrium swelling capacity of the SAPs was found to be dependent
on the nature and extent of the net charge on the SAPs but independent
of pH. The equilibrium swelling capacity was lowest for the SAP whose
ratio of anionic to cationic repeat units was unity. The equilibrium
swelling capacity increased as this ratio deviated from unity. The
adsorption of an anionic dye (orange G) and a cationic dye (methylene
blue) was carried out from the individual solution as well as from
their mixture. The adsorption of the dyes was found to be dependent
on the nature and amount of net charge on the SAPs but independent
of pH. The amount of the dye adsorbed decreased as the net charge
on the amphoteric SAPs decreased. The amphoteric SAPs with net negative
or positive charge selectively adsorbed oppositely charged dyes from
the mixture, but the amounts adsorbed were lower than those adsorbed
from the individual dye solutions
Polyanhydrides of Castor Oil-Sebacic Acid for Controlled Release Applications
A family of high molecular weight castor oil (CO)-based biodegradable polyanhydrides was synthesized by a catalyst-free melt-condensation reaction between prepolymers of CO and sebacic acid (SA). The structure of the polymers was characterized by H-1 NMR and Fourier transform infrared spectroscopy, which indicated the formation of the anhydride bond along the polymer backbone. Thermal analysis and X-ray diffraction confirmed the semicrystalline nature of the polymers. Incorporation of SA enhanced the crystallinity of the polymer. The hydrophobic nature of these polymers was revealed by contact angle goniometry. Water wettability decreased with increase in SA content. Compressive tests demonstrated a sharp increase in strength and decrease in ductility with increasing SA content. In vitro hydrolytic degradation studies indicated surface-eroding behavior. The degradation rate decreased with an increase of SA content in the polymers because of increased crystallinity. The release studies of both hydrophobic and hydrophilic dyes followed zero-order kinetics. In vitro cell studies to assess the cytotoxicity of the polymer confirmed minimal toxicity of the degradation products. Thus, a family of CO-SA polyanhydrides have been synthesized and characterized for controlled release applications where the physical, mechanical, and degradation kinetics can be modulated by varying the weight fraction of the prepolymers
Lef Congenital Mesoblasti Nephroma in a Term Male Neonate: A Case Report
Congenital mesoblasticnephroma (CMN) is a benign and very rare renal tumor, typically occurring in utero or during infancy. We are reporting a very young case of left sided classical congenital mesoblasticnephroma in a full term, small for gestational age, male neonate; who was detected with left sided flank mass immediately after birth. The patient was managed successfully by total nephrectomy. The diagnosis of CMN-classical type was confirmed on histopathological examination
Polyanhydrides of Castor Oil–Sebacic Acid for Controlled Release Applications
A family
of high molecular weight castor oil (CO)-based biodegradable
polyanhydrides was synthesized by a catalyst-free melt–condensation
reaction between prepolymers of CO and sebacic acid (SA). The structure
of the polymers was characterized by <sup>1</sup>H NMR and Fourier
transform infrared spectroscopy, which indicated the formation of
the anhydride bond along the polymer backbone. Thermal analysis and
X-ray diffraction confirmed the semicrystalline nature of the polymers.
Incorporation of SA enhanced the crystallinity of the polymer. The
hydrophobic nature of these polymers was revealed by contact angle
goniometry. Water wettability decreased with increase in SA content.
Compressive tests demonstrated a sharp increase in strength and decrease
in ductility with increasing SA content. In vitro hydrolytic degradation
studies indicated surface-eroding behavior. The degradation rate decreased
with an increase of SA content in the polymers because of increased
crystallinity. The release studies of both hydrophobic and hydrophilic
dyes followed zero-order kinetics. In vitro cell studies to assess
the cytotoxicity of the polymer confirmed minimal toxicity of the
degradation products. Thus, a family of CO-SA polyanhydrides have
been synthesized and characterized for controlled release applications
where the physical, mechanical, and degradation kinetics can be modulated
by varying the weight fraction of the prepolymers
Antimicrobial Agents Based on Metal Complexes: Present Situation and Future Prospects
The rise in antimicrobial resistance is a cause of serious concern since the ages. Therefore, a dire need to explore new antimicrobial entities that can combat against the increasing threat of antibiotic resistance is realized. Studies have shown that the activity of the strongest antibiotics has reduced drastically against many microbes such as microfungi and bacteria (Gram-positive and Gram-negative). A ray of hope, however, was witnessed in early 1940s with the development of new drug discovery and use of metal complexes as antibiotics. Many new metal-based drugs were developed from the metal complexes which are potentially active against a number of ailments such as cancer, malaria, and neurodegenerative diseases. Therefore, this review is an attempt to describe the present scenario and future development of metal complexes as antibiotics against wide array of microbes
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Smooth Muscle Stiffness Sensitivity is Driven by Soluble and Insoluble ECM Chemistry
Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble factors are major drivers of several critical SMC behaviors, such as motility, proliferation, invasion, and differentiation marker expres- sion, and these factors modulated the effect of stiffness on proliferation and migration. Overall, modulus only modestly affected behaviors other than proliferation, relative to integrin binding and soluble factors. Surprisingly, patho- logical behaviors (proliferation, motility) are not inversely related to SMC marker expression, in direct conflict with previous studies on substrates coupled with single extracel- lular matrix (ECM) proteins. A high-throughput bead-based ELISA approach and inhibitor studies revealed that differ- entiation marker expression is mediated chiefly via focal adhesion kinase (FAK) signaling, and we propose that integrin binding and FAK drive the transition from a migratory to a proliferative phenotype. We emphasize the importance of increasing the complexity of in vitro testing platforms to capture these subtleties in cell phenotypes and signaling, in order to better recapitulate important features of in vivo disease and elucidate potential context-dependent therapeutic targets