Age-Related ECM Stiffness Mediates TRAIL Activation in Muscle Stem Cell Differentiation.

The stiffening of the extracellular matrix (ECM) with age hinders muscle regeneration by causing intrinsic muscle stem cell (MuSC) dysfunction through a poorly understood mechanism. Here, the study aims to study those age-related molecular changes in the differentiation of MuSCs due to age and/or stiffness. Hence, young and aged MuSCs are seeded onto substrates engineered to mimic a soft and stiff ECM microenvironment to study those molecular changes using single-cell RNA sequencing (scRNA).

Diffusion Models in De Novo Drug Design.

Diffusion models have emerged as powerful tools for molecular generation, particularly in the context of 3D molecular structures. Inspired by nonequilibrium statistical physics, these models can generate 3D molecular structures with specific properties or requirements crucial to drug discovery. Diffusion models were particularly successful at learning the complex probability distributions of 3D molecular geometries and their corresponding chemical and physical properties through forward and reverse diffusion processes.

The geometric evolution of aortic dissections: Predicting surgical success using fluctuations in integrated Gaussian curvature.

Clinical imaging modalities are a mainstay of modern disease management, but the full utilization of imaging-based data remains elusive. Aortic disease is defined by anatomic scalars quantifying aortic size, even though aortic disease progression initiates complex shape changes. We present an imaging-based geometric descriptor, inspired by fundamental ideas from topology and soft-matter physics that captures dynamic shape evolution.

Predicting Young's Modulus of Linear Polyurethane and Polyurethane-Polyurea Elastomers: Bridging Length Scales with Physicochemical Modeling and Machine Learning.

Predicting the properties of complex polymeric materials based on monomer chemistry requires modeling physical interactions that bridge molecular, interchain, microstructure, and bulk length scales. For polyurethanes, a polymer class with global commercial and industrial significance, these multiscale challenges are intrinsic due to the thermodynamic incompatibility of the urethane and polyol-rich domains, resulting in heterogeneities from molecular to microstructural length scales. Machine learning can model patterns in data to establish a relationship between the monomer chemistry and bulk material properties, but this is made difficult by small data sets and a diverse set of monomers.

Hierarchical Machine Learning for High-Fidelity 3D Printed Biopolymers.

A hierarchical machine learning (HML) framework is presented that uses a small dataset to learn and predict the dominant build parameters necessary to print high-fidelity 3D features of alginate hydrogels. We examine the 3D printing of soft hydrogel forms printed with the freeform reversible embedding of suspended hydrogel method based on a CAD file that isolated the single-strand diameter and shape fidelity of printed alginate. Combinations of system variables ranging from print speed, flow rate, ink concentration to nozzle diameter were systematically varied to generate a small dataset of 48 prints.

Elucidating the Physicochemical Basis of the Glass Transition Temperature in Linear Polyurethane Elastomers with Machine Learning.

The glass transition temperature () is a fundamental property of polymers that strongly influences both mechanical and flow characteristics of the material. In many important polymers, configurational entropy of side chains is a dominant factor determining it. In contrast, the thermal transition in polyurethanes is thought to be determined by a combination of steric and electronic factors from the dispersed hard segments within the soft segment medium.

Adsorption kinetics, thermodynamics, and isotherm studies for functionalized lanthanide-chelating resins.

Conventional ion exchange resins are widely utilized to remove metals from aqueous solutions, but their limited selectivity precludes dilute ion extraction. This research investigated the adsorption performance of ligand-functionalized resins towards rare earth elements (REE). Functionalized resin particles were synthesized by grafting different ligands (diethylenetriaminepentaacetic dianhydride (DTPADA), phosphonoacetic acid (PAA), or N,N-bis(phosphonomethyl)glycine (BPG)) onto pre-aminated polymeric adsorbents (diameter ∼ 0.

Transport patterns of anti-TNF-α in burn wounds: Therapeutic implications of hyaluronic acid conjugation.

A central complication in burn injuries is progression of the zone of necrosis, which is associated with intense inflammatory responses. Conjugation of monoclonal antibodies against tumor necrosis factor-α (TNF-α), a central mediator of inflammation, to high molecular weight hyaluronic acid (HA) has been shown to be an effective treatment in reducing secondary necrosis in rodent models of deep partial-thickness burns. Here the transport of conjugated and non-conjugated antibodies in burn injuries was investigated to explore the effects of antibody tethering on the spatiotemporal distribution of anti-TNF-α.

Tip-Loaded Dissolvable Microneedle Arrays Effectively Deliver Polymer-Conjugated Antibody Inhibitors of Tumor-Necrosis-Factor-Alpha Into Human Skin.

Autoinflammatory skin diseases are characterized by a disequilibrium of cytokines in the local skin microenvironment, suggesting that local delivery of therapeutics, including anticytokine antibodies, may provide benefit without the unwanted off-target effects of systemically delivered therapies. Rapid diffusion of therapeutics away from the target site has been a challenge to the development of local therapies. Conjugation of high molecular weight hydrophilic polymers to cytokine neutralizing mAbs has been shown to be an effective strategy for local control of inflammation in healing burn wounds.

Tunable Pickering emulsions with polymer-grafted lignin nanoparticles (PGLNs).

Lignin is an abundant biopolymer that has native interfacial functions but aggregates strongly in aqueous media. Polyacrylamide was grafted onto kraft lignin nanoparticles using reversible addition-fragmentation chain transfer (RAFT) chemistry to form polymer-grafted lignin nanoparticles (PGLNs) that tune aggregation strength while retaining interfacial activities in forming Pickering emulsions. Polymer graft density on the particle surface, ionic strength, and initial water and cyclohexane volume fractions were varied and found to have profound effects on emulsion characteristics, including emulsion volume fraction, droplet size, and particle interfacial concentration that were attributed to changes in lignin aggregation and hydrophobic interactions.

Lignopolymers as viscosity-reducing additives in magnesium oxide suspensions.

Lignopolymers are a new class of polymer additives with the capability to be used as dispersants in cementitious pastes. Made with kraft lignin cores and grafted polymer side-chains, the custom-synthesized lignopolymers were examined in terms of the molecular architecture for viscosity reducing potential in inert model suspensions. Lignin-poly(acrylic acid) (LPAA) and lignin-polyacrylamide (LPAm) have been found to vary the rheology of magnesium oxide (MgO) suspensions based on differences in chain architecture and particle-polymer interactions.

Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays.

Unlabelled: Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here, we evaluated the use of tip-loaded dissolvable microneedle arrays (MNAs) for localized intradermal delivery of anti-TNF-α Ab.

Molecular architecture requirements for polymer-grafted lignin superplasticizers.

Superplasticizers are a class of anionic polymer dispersants used to inhibit aggregation in hydraulic cement, lowering the yield stress of cement pastes to improve workability and reduce water requirements. The plant-derived biopolymer lignin is commonly used as a low-cost/low-performance plasticizer, but attempts to improve its effects on cement rheology through copolymerization with synthetic monomers have not led to significant improvements. Here we demonstrate that kraft lignin can form the basis for high-performance superplasticizers in hydraulic cement, but the molecular architecture must be based on a lignin core with a synthetic-polymer corona that can be produced via controlled radical polymerization.

Local delivery of antitumor necrosis factor-α through conjugation to hyaluronic acid: dosing strategies and early healing effects in a rat burn model.

The objective of this study was to measure dose-response effects of topical delivery of inhibitors of tumor necrosis factor-α (TNF-α) through conjugation to hyaluronic acid in a rat burn model to determine effects on inflammatory responses, burn progression, and early stages of healing. Monoclonal antibodies against TNF-α were conjugated to hyaluronic acid and applied topically in a rat partial-thickness burn model. Metrics of inflammatory responses and tissue necrosis were measured as well as the quantitative analysis of collagen composition and organization.

Polymer-grafted lignin surfactants prepared via reversible addition-fragmentation chain-transfer polymerization.

Kraft lignin grafted with hydrophilic polymers has been prepared using reversible addition-fragmentation chain-transfer (RAFT) polymerization and investigated for use as a surfactant. In this preliminary study, polyacrylamide and poly(acrylic acid) were grafted from a lignin RAFT macroinitiator at average initiator site densities estimated to be 2 per particle and 17 per particle. The target degrees of polymerization were 50 and 100, but analysis of cleaved polyacrylamide was consistent with a higher average molecular weight, suggesting not all sites were able to participate in the polymerization.

Reducing protein adsorption with polymer-grafted hyaluronic acid coatings.

We report a thermoresponsive chemical modification strategy of hyaluronic acid (HA) for coating onto a broad range of biomaterials without relying on chemical functionalization of the surface. Poly(di(ethylene glycol) methyl ether methacrylate) (PMEO2MA), a polymer with a lower critical solution temperature of 26 °C in water, was grafted onto HA to allow facile formation of biopolymer coatings. While the mechanism for film formation appears to involve a complex combination of homogeneous nucleation followed by heterogeneous film growth, we demonstrate that it resulted in hydrophilic coatings that significantly reduce protein adsorption despite the high fraction of hydrophobic (PMEO2MA).

Electrocatalytic oxygen evolution with an immobilized TAML activator.

Iron complexes of tetra-amido macrocyclic ligands are important members of the suite of oxidation catalysts known as TAML activators. TAML activators are known to be fast homogeneous water oxidation (WO) catalysts, producing oxygen in the presence of chemical oxidants, e.g.

Polymer-conjugated inhibitors of tumor necrosis factor-α for local control of inflammation.

Burns, chronic wounds, osteoarthritis, and uveitis are examples of conditions characterized by local, intense inflammatory responses that can impede healing or even further tissue degradation. The most powerful anti-inflammatory drugs available are often administered systemically, but these carry significant side effects and are not compatible for patients that have underlying complications associated with their condition. Conjugation of monoclonal antibodies that neutralize pro-inflammatory cytokines to high molecular weight hydrophilic polymers has been shown to be an effective strategy for local control of inflammation.

Effects of hyaluronic acid conjugation on anti-TNF-α inhibition of inflammation in burns.

Biomaterials capable of neutralizing specific cytokines could form the basis for treating a broad range of conditions characterized by intense, local inflammation. Severe burns, spanning partial- to full-thickness of the dermis, can result in complications due to acute inflammation that contributes to burn progression, and early mediation may be a key factor in rescuing thermally injured tissue from secondary necrosis to improve healing outcomes. In this work, we examined the effects on burn progression and influence on the inflammatory microenvironment of topical application of anti-tumor necrosis factor-α (anti-TNF-α) alone, mixed with hyaluronic acid (HA) or conjugated to HA.

Reduction of burn progression with topical delivery of (antitumor necrosis factor-α)-hyaluronic acid conjugates.

In this study, we explored whether topical application of antibodies targeting tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) conjugated to hyaluronic acid (HA) could reduce the extension of necrosis by modulating inflammation locally in a partial-thickness rat burn model. Partial-thickness to deep partial-thickness burn injuries present significant challenges in healing, as these burns often progress following the initial thermal insult, resulting in necrotic expansion and increased likelihood of secondary complications. Necrotic expansion is driven by a microenvironment with elevated levels of pro-inflammatory mediators, and local neutralization of these using antibody conjugates could reduce burn progression.

Improved lignin polyurethane properties with Lewis acid treatment.

Chemical modification strategies to improve the mechanical properties of lignin-based polyurethanes are presented. We hypothesized that treatment of lignin with Lewis acids would increase the concentration of hydroxyl groups available to react with diisocyanate monomers. Under the conditions used, hydrogen bromide-catalyzed modification resulted in a 28% increase in hydroxyl group content.

Conjugation of β-sheet peptides to modify the rheological properties of hyaluronic acid.

Hyaluronic acid (HA) is a naturally occurring polysaccharide that is commonly used in cosmetic, wound healing, and tissue regeneration applications because of its biocompatibility and intrinsic biological activities. However, the rheological behavior of unmodified HA is not ideal for many of these. In particular, whereas chain entanglements result in an increase in viscosity, they do not prevent flow from delivery sites under zero-shear conditions.

Enhanced adhesion of dopamine methacrylamide elastomers via viscoelasticity tuning.

We present a study on the effects of cross-linking on the adhesive properties of bio-inspired 3,4-dihydroxyphenylalanine (DOPA). DOPA has a unique catechol moiety found in adhesive proteins in marine organisms, such as mussels and polychaete, which results in strong adhesion in aquatic conditions. Incorporation of this functional group in synthetic polymers provides the basis for pressure-sensitive adhesives for use in a broad range of environments.

Teaching technological innovation and entrepreneurship in polymeric biomaterials.

A model for incorporating an entrepreneurship module has been developed in an upper-division and graduate-level engineering elective on Polymeric Biomaterials (27-311/42-311/27-711/42-711) at Carnegie Mellon University. A combination of lectures, assignments, and a team-based project were used to provide students with a framework for applying their technical skills in the development of new technologies and a basic understanding of the issues related to translational research and technology commercialization. The specific approach to the project established in the course, which represented 20% of the students' grades, and the grading rubric for each of the milestones are described along with suggestions for generalizing this approach to different applications of biomaterials or other engineering electives.

Enhanced wet adhesion and shear of elastomeric micro-fiber arrays with mushroom tip geometry and a photopolymerized p(DMA-co-MEA) tip coating.

Using principles inspired by the study of naturally occurring sticky systems such as the micro- and nanoscale fibers on the toes of geckos and the adhesive proteins secreted by marine animals such as mussels, this study describes the development and evaluation of a novel patterned and coated elastomeric microfibrillar material for enhanced repeatable adhesion and shear in wet environments. A multistep fabrication process consisting of optical lithography, micromolding, polymer synthesis, dipping, stamping, and photopolymerization is described to produce uniform arrays of polyurethane elastomeric microfibers with mushroom-shaped tips coated with a thin layer of lightly cross-linked p(DMA-co-MEA), an intrinsically adhesive synthetic polymer. Adhesion and shear force characterization of these arrays in contact with a glass hemisphere is demonstrated, and significant pull-off force, overall work of adhesion, and shear force enhancements in submerged aqueous environments are shown when compared to both unpatterned and uncoated samples, as well as previously evaluated patterned and coated arrays with differing geometry.