Self-assembling Peptide Hydrogels Facilitate Vascularization in Two-Component Scaffolds.

One of the major constraints against using polymeric scaffolds as tissue-regenerative matrices is a lack of adequate implant vascularization. Self-assembling peptide hydrogels can sequester small molecules and biological macromolecules, and they can support infiltrating cells in vivo. Here we demonstrate the ability of self-assembling peptide hydrogels to facilitate angiogenic sprouting into polymeric scaffolds after subcutaneous implantation. We constructed two-component scaffolds that incorporated microporous polymeric scaffolds and viscoelastic nanoporous peptide hydrogels. Nanofibrous hydrogels modified the biocompatibility and vascular integration of polymeric scaffolds with microscopic pores (pore diameters: 100-250 µm). In spite of similar amphiphilic sequences, charges, secondary structures, and supramolecular nanostructures, two soft hydrogels studied herein had different abilities to aid implant vascularization, but had similar levels of cellular infiltration. The functional difference of the peptide hydrogels was predicted by the difference in the bioactive moieties inserted into the primary sequences of the peptide monomers. Our study highlights the utility of soft supramolecular hydrogels to facilitate host-implant integration and control implant vascularization in biodegradable polyester scaffolds in vivo. Our study provides useful tools in designing multi-component regenerative scaffolds that recapitulate vascularized architectures of native tissues.

Risk Factors Associated With Atrial Fibrillation in Elderly Patients.

Background: Atrial fibrillation (AF) is the most common arrhythmia with a growing prevalence worldwide, especially in the elderly population. Patients with AF are at higher risk of serious life-threatening events and complications that may lead to long-term sequelae and reduce quality of life. The aim of our study was to examine the association of additional risk factors and comorbid medical conditions with AF in patients 65 years, or older. Methods: We performed a retrospective electronic medical record review of patients aged 65 years and older, who visited our internal medicine office between July 1, 2020 and June 30, 2021. Results: Among 2,433 patients, 418 patients (17.2%) had AF. Our analysis showed that for each unit increased in age, there was a 4.5% increase in the odds of AF (95% confidence interval (CI) 2.2-6.9%; P < 0.001). Compared to patients of Caucasian descent, African-American patients had significantly decreased odds of AF (odds ratio (OR) 0.274, 95% CI 0.141 - 0.531; P < 0.001). Patients with hypertension had 2.241 greater odds of AF (95% CI 1.421 - 3.534; P = 0.001). Additional comorbidities with significantly greater odds of AF included other cardiac arrhythmias (OR 2.523, 95% CI 1.720 - 3.720; P < 0.001), congestive heart failure (OR 3.111, 95% CI 1.674 - 5.784; P < 0.001), osteoarthritis (OR 3.014, 95% CI 2.138 - 4.247; P < 0.001), liver disease (OR 2.129, 95% CI 1.164 - 3.893; P = 0.014), and colorectal disease (OR 1.500 95% CI 1.003 - 2.243; P = 0.048). Comorbidities with significantly decreased odds of AF included other rheumatological disorder (OR 0.144, 95% CI 0.086 - 0.243; P < 0.001), non-steroidal anti-inflammatory drugs (NSAIDs) use (OR 0.206, 95% CI 0.125 - 0.338; P < 0.001), and corticosteroid use (OR 0.553, 95% CI 0.374 - 0.819; P = 0.003). Conclusions: Increasing age, hypertension, presence of other cardiac arrhythmias, congestive heart failure, osteoarthritis, liver disease, and colorectal disease are associated with increased odds of having AF.

Angiogenic hydrogels for dental pulp revascularization.

Angiogenesis is critical for tissue healing and regeneration. Promoting angiogenesis in materials implanted within dental pulp after pulpectomy is a major clinical challenge in endodontics. We demonstrate the ability of acellular self-assembling peptide hydrogels to create extracellular matrix mimetic architectures that guide in vivo development of neovasculature and tissue deposition. The hydrogels possess facile injectability, as well as sequence-level functionalizability. We explore the therapeutic utility of an angiogenic hydrogel to regenerate vascularized pulp-like soft tissue in a large animal (canine) orthotopic model. The regenerated soft tissue recapitulates key features of native pulp, such as blood vessels, neural filaments, and an odontoblast-like layer next to dentinal tubules. Our study establishes angiogenic peptide hydrogels as potent scaffolds for promoting soft tissue regeneration in vivo. STATEMENT OF SIGNIFICANCE: A major challenge to endodontic tissue engineering is the lack of in situ angiogenesis within intracanal implants, especially after complete removal of the dental pulp. The lack of a robust vasculature in implants limit integration of matrices with the host tissue and regeneration of soft tissue. We demonstrate the development of an acellular material that promotes tissue revascularization in vivo without added growth factors, in a preclinical canine model of pulp-like soft-tissue regeneration. Such acellular biomaterials would facilitate pulp revascularization approaches in large animal models, and translation into human clinical trials.

Evaluation of Injectable Naloxone-Releasing Hydrogels.

The opioid epidemic in the United States is a serious public health crisis affecting over 1.7 million Americans. In the last two decades, almost 450 000 people have died from an opioid overdose, with nearly 20% of these deaths occurring in 2017 and 2018 alone. During an overdose, overstimulation of the µ-opioid receptor leads to severe and potentially fatal respiratory depression. Naloxone is a competitive µ-opioid-receptor antagonist that is widely used to displace opioids and rescue from an overdose. Here, we describe the development of a slow-release, subcutaneous naloxone formulation for potential management of opioid overdose, chronic pain, and opioid-induced constipation. Naloxone is loaded into self-assembling peptide hydrogels for controlled drug release. The mechanical, chemical, and structural properties of the nanofibrous hydrogel enable subcutaneous administration and slow, diffusion-based release kinetics of naloxone over 30 days in vitro. The naloxone hydrogel scaffold showed cytocompatibility and did not alter the ß-sheet secondary structure or thixotropic properties characteristic of self-assembling peptide hydrogels. Our results show that this biocompatible and injectable self-assembling peptide hydrogel may be useful as a vehicle for tunable, sustained release of therapeutic naloxone. This therapy may be particularly suited for preventing renarcotization in patients who refuse additional medical assistance following an overdose.

Membrane-Disrupting Nanofibrous Peptide Hydrogels.

Self-assembled peptide nanofibers can form biomimetic hydrogels at physiological pH and ionic strength through noncovalent and reversible interactions. Inspired by natural antimicrobial peptides, we designed a class of cationic amphiphilic self-assembled peptides (CASPs) that self-assemble into thixotropic nanofibrous hydrogels. These constructs employ amphiphilicity and high terminal charge density to disrupt bacterial membranes. Here, we focus on three aspects of the self-assembly of these hydrogels: (a) the material properties of the individual self-assembled nanofibers, (b) emergence of bulk-scale elasticity in the nanofibrous hydrogel, and (c) trade-off between the desirable material properties and antimicrobial efficacy. The design of the supramolecular nanofibers allows for higher-order noncovalent ionic cross-linking of the nanofibers into a viscoelastic network. We determine the stiffness of the self-assembled nanofibers via the peak force quantitative nanomechanical atomic force microscopy and the bulk-scale rheometry. The storage moduli depend on peptide concentration, ionic strength, and concentration of multivalent ionic cross-linker. CASP nanofibers are demonstrated to be effective against Pseudomonas aeruginosa colonies. We use nanomechanical analysis and microsecond-time scale coarse-grained simulation to elucidate the interaction between the peptides and bacterial membranes. We demonstrate that the membranes stiffen, contract, and buckle after binding to peptide nanofibers, allowing disruption of osmotic equilibrium between the intracellular and extracellular matrix. This is further associated with dramatic changes in cell morphology. Our studies suggest that self-assembled peptide nanofibrils can potentially acts as membrane-disrupting antimicrobial agents, which can be formulated as injectable hydrogels with tunable material properties.