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In this concept article, we review recent works on the use of biologically-derived materials, including biomolecules, hybrid biomolecular composites, and natural tissues for achieving stimuli-responsiveness, adaptability, and memory storage for potential neuromorphic computing applications. Unlike solid-state materials, bioderived platforms are often intrinsically modular, including possessing the ability to leverage the diversity of naturally multifunctional biomolecules, cornerstones in biological transduction, signaling, and learning. The primary neuromorphic functionality of bioderived systems considered here is memory resistance, as obtained through combinations of resistive switching, activity-dependent plasticity, and memory storage. In some cases, these capabilities are achieved in bio-derived systems by closely emulating the structure, function, or signaling mechanisms found in living neurons. Our review considers bioderived systems that span multiple length scales and levels of hierarchical complexity: from single-molecule enabled devices to intact tissues, interrogated either in vitro or in vivo on living organisms. Through this exercise, we offer our perspective on research opportunities in the development and use of synapse- and neuron-inspired bioderived systems, including the prospect of biocompatible, and even tissue-like, neuromorphic materials to smartly monitor and treat injury and disease, deliver therapeutics, and interpret neural activity. These capabilities could unlock a new generation of smart, adaptable bioderived composites that autonomously report, learn (i.e., classify, forecast), compute, and actuate in the direct vicinity of living cells and tissues, i.e. at the edge of biology.

Providing AI platforms with perceptual capabilities at low energy cost is imperative to making them more human-like. This goal is contingent on developing stimuli-responsive materials that closely ...

Biomolecular assemblies of phospholipids and the pore forming species monazomycin were constructed using the droplet interface bilayer technique to mimic synaptic properties. Electrical characterization of the interface confirms the existence of multiple forms of short-term synaptic plasticity in response to constant stimuli. Memory of prior stimulation can last up to 20 minutes suggesting an unaccounted mechanism of longer term memory retention, termed “medium-term synaptic plasticity.” Monazomycin doped biomembranes were stimulated by a series of step voltage inputs with varying off-times ranging from one to twenty minutes. Percentage of peak current obtained inactivation percentage, and change in inactivation percentage were compared. Peak current is reduced in subsequent stimulations and gradually restores back to 100% after 20 minutes. Inactivation percentage is also reduced but recovers at 20 minutes. Initial current right after application increases and remains elevated up to 20 minutes. Multiple sinusoidal voltage inputs were performed with −80 mV step inputs in between. I-V hysteresis for these inputs were compared. The peak negative current of the hysteresis decreased while the positive peak increased after each cycle. Medium term synaptic plasticity is believed to be the result of lingering concentration differences at the interfaces and lingering presence of nonconducting monazomycin in the bilayer.

Coronary microvascular function and blood flow responses during acute exercise are impaired in the aged heart but can be restored by exercise training. Coronary microvascular resistance is directly dependent on vascular smooth muscle function in coronary resistance arterioles; therefore, we hypothesized that age impairs contractile function and alters the phenotype of vascular smooth muscle in coronary arterioles. We further hypothesized that exercise training restores contractile function and reverses age-induced phenotypic alterations of arteriolar smooth muscle. Young and old Fischer 344 rats underwent 10 wk of treadmill exercise training or remained sedentary. At the end of training or cage confinement, contractile responses, vascular smooth muscle proliferation, and expression of contractile proteins were assessed in isolated coronary arterioles. Both receptor- and non-receptor-mediated contractile function were impaired in coronary arterioles from aged rats. Vascular smooth muscle shifted from a differentiated, contractile phenotype to a secretory phenotype with associated proliferation of smooth muscle in the arteriolar wall. Expression of smooth muscle myosin heavy chain 1 (SM1) was decreased in arterioles from aged rats, whereas expression of phospho-histone H3 and of the synthetic protein ribosomal protein S6 (rpS6) were increased. Exercise training improved contractile responses, reduced smooth muscle proliferation and expression of rpS6, and increased expression of SM1 in arterioles from old rats. Thus age-induced contractile dysfunction of coronary arterioles and emergence of a secretory smooth muscle phenotype may contribute to impaired coronary blood flow responses, but arteriolar contractile responsiveness and a younger smooth muscle phenotype can be restored with late-life exercise training.NEW & NOTEWORTHY Aging impairs contractile function of coronary arterioles and induces a shift of the vascular smooth muscle toward a proliferative, noncontractile phenotype. Late-life exercise training reverses contractile dysfunction of coronary arterioles and restores a young phenotype to the vascular smooth muscle.

This work draws inspiration from totipotent cellular systems to design smart materials whose compositions and properties can be learned or evolved. Totipotency refers to the inherent genetic potential of a single cell to adapt and produce all types of differentiated cells within an organism. To study this principal and apply it synthetically, tissue-like compartmentalized assemblies are constructed via lipid membrane-separated aqueous droplets in a hydrophobic medium through the droplet interface bilayer (DIB) method. Within our droplets, we explore synthetic totipotency via cell-free reactions including actin polymerization and cell free protein synthesis (CFPS). The transcription and translation of our CFPS reactions are controlled by stimuli-responsive riboswitches (RS). Via this scheme, adaptable material properties and functions are achieved in vitro via protein production from cell-free machinery administered through RS governance. Here, we present thermally or chemically-triggered riboswitches for orthogonal production of representative fluorescent protein products, as well functional proteins. To characterize the material properties of target proteins, we study the formation of polymerized actin shells to stabilize organically-encased droplets and span DIBs. We present a modified protocol for chemically-triggered actin polymerization as well as a thermally triggered actin RS. We characterize theophylline (TP)-triggered production of alpha hemolysin (α-HL) through CFPS and synthesized an organic-soluble trigger that can be sensed from the oil phase by a RS in an aqueous bioreactor droplet. We also demonstrate increased droplet conductivity when CFPS α-HL products are incorporated in DIBs. This interdisciplinary work involves cell culture, gene expression, organic synthesis, vesicle formation, protein quantification, tensiometry, droplet aspiration, microplate fluorescence/absorption experiments, fluorescent microscopy, and electrophysiology. This project is an essential design analysis for creating smart, soft materials using synthetic biology and provides motivation for artificial tissues capable of adapting in response to external stimuli.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that is crucial in maintaining cellular redox homeostasis. Aerobic exercise training has been reported to enhance vasodi...

KEY POINTS: In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium‐dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. ABSTRACT: Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium‐dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day(–1), 5 days week(–1), for 4 weeks. Blood flow to the stretched limb and the non‐stretched contralateral limb was determined at rest and during treadmill exercise. Endothelium‐dependent/independent vasodilatation was evaluated in soleus muscle arterioles. Levels of hypoxia‐induced factor‐1α, vascular endothelial growth factor A and neuronal nitric oxide synthase were determined in soleus muscle fibres. Levels of endothelial nitric oxide synthase and superoxide dismutase were determined in soleus muscle arterioles, and microvascular volume and capillarity were evaluated by microcomputed tomography and lectin staining, respectively. During exercise, blood flow to plantar flexor muscles was significantly higher in the stretched limb. Endothelium‐dependent vasodilatation was enhanced in arterioles from the soleus muscle from the stretched limb. Microvascular volume, number of capillaries per muscle fibre, and levels of hypoxia‐induced factor‐1α, vascular endothelial growth factor and endothelial nitric oxide synthase were significantly higher in the stretched limb. These results indicate that daily passive stretching of muscle enhances endothelium‐dependent vasodilatation and induces angiogenesis. These microvascular adaptations may contribute to increased muscle blood flow during exercise in muscles that have undergone daily passive stretch.

Age is known to induce remodeling and stiffening of large-conduit arteries; however, little is known of the effects of age on remodeling and mechanical properties of coronary resistance arteries. We employed a rat model of aging to investigate whether 1) age increases wall thickness and stiffness of coronary resistance arteries, and 2) exercise training reverses putative age-induced increases in wall thickness and stiffness of coronary resistance arteries. Young (4 mo) and old (21 mo) Fischer 344 rats remained sedentary or underwent 10 wk of treadmill exercise training. Coronary resistance arteries were isolated for determination of wall-to-lumen ratio, effective elastic modulus, and active and passive responses to changes in intraluminal pressure. Elastin and collagen content of the vascular wall were assessed histologically. Wall-to-lumen ratio increased with age, but this increase was reversed by exercise training. In contrast, age reduced stiffness, and exercise training increased stiffness in coronary resistance arteries from old rats. Myogenic responsiveness was reduced with age and restored by exercise training. Collagen-to-elastin ratio (C/E) of the wall did not change with age and was reduced with exercise training in arteries from old rats. Thus age induces hypertrophic remodeling of the vessel wall and reduces the stiffness and myogenic function of coronary resistance arteries. Exercise training reduces wall-to-lumen ratio, increases wall stiffness, and restores myogenic function in aged coronary resistance arteries. The restorative effect of exercise training on myogenic function of coronary resistance arteries may be due to both changes in vascular smooth muscle phenotype and expression of extracellular matrix proteins.

Conditions during spaceflight, such as the loss of the head-to-foot gravity vector, are thought to potentially alter cerebral blood flow and vascular resistance. The purpose of the present study was to determine the effects of long-term spaceflight on the functional, mechanical, and structural properties of cerebral arteries. Male C57BL/6N mice were flown 30 days in a Bion-M1 biosatellite. Basilar arteries isolated from spaceflight (SF) ( n = 6), habitat control (HC) ( n = 6), and vivarium control (VC) ( n = 16) mice were used for in vitro functional and mechanical testing and histological structural analysis. The results demonstrate that vasoconstriction elicited through a voltage-gated Ca2+ mechanism (30–80 mM KCl) and thromboxane A2 receptors (10−8 − 3 × 10−5 M U46619) are lower in cerebral arteries from SF mice. Inhibition of Rho-kinase activity (1 μM Y27632) abolished group differences in U46619-evoked contractions. Endothelium-dependent vasodilation elicited by acetylcholine (10 μM, 2 μM U46619 preconstriction) was virtually absent in cerebral arteries from SF mice. The pressure-diameter relation was lower in arteries from SF mice relative to that in HC mice, which was not related to differences in the extracellular matrix protein elastin or collagen content or the elastin/collagen ratio in the basilar arteries. Diameter, medial wall thickness, and medial cross-sectional area of unpressurized basilar arteries were not different among groups. These results suggest that the microgravity-induced attenuation of both vasoconstrictor and vasodilator properties may limit the range of vascular control of cerebral perfusion or impair the distribution of brain blood flow during periods of stress.