Digital light processing printed hydrogel scaffolds with adjustable modulus.

Hydrogels are extensively explored as biomaterials for tissue scaffolds, and their controlled fabrication has been the subject of wide investigation. However, the tedious mechanical property adjusting process through formula control hindered their application for diverse tissue scaffolds. To overcome this limitation, we proposed a two-step process to realize simple adjustment of mechanical modulus over a broad range, by combining digital light processing (DLP) and post-processing steps. UV-curable hydrogels (polyacrylamide-alginate) are 3D printed via DLP, with the ability to create complex 3D patterns. Subsequent post-processing with Fe3+ ions bath induces secondary crosslinking of hydrogel scaffolds, tuning the modulus as required through soaking in solutions with different Fe3+ concentrations. This innovative two-step process offers high-precision (10 µm) and broad modulus adjusting capability (15.8-345 kPa), covering a broad range of tissues in the human body. As a practical demonstration, hydrogel scaffolds with tissue-mimicking patterns were printed for cultivating cardiac tissue and vascular scaffolds, which can effectively support tissue growth and induce tissue morphologies.

Architecture design and advanced manufacturing of heart-on-a-chip: scaffolds, stimulation and sensors.

Heart-on-a-chip (HoC) has emerged as a highly efficient, cost-effective device for the development of engineered cardiac tissue, facilitating high-throughput testing in drug development and clinical treatment. HoC is primarily used to create a biomimetic microphysiological environment conducive to fostering the maturation of cardiac tissue and to gather information regarding the real-time condition of cardiac tissue. The development of architectural design and advanced manufacturing for these "3S" components, scaffolds, stimulation, and sensors is essential for improving the maturity of cardiac tissue cultivated on-chip, as well as the precision and accuracy of tissue states. In this review, the typical structures and manufacturing technologies of the "3S" components are summarized. The design and manufacturing suggestions for each component are proposed. Furthermore, key challenges and future perspectives of HoC platforms with integrated "3S" components are discussed. Architecture design concepts of scaffolds, stimulation and sensors in chips.

A quick paster type of soluble nanoparticle microneedle patch for the treatment of obesity.

Obesity is a major public burden on the working population and induces chronic diseases. Its treatment often requires long-term medication, which makes patient compliance difficult. In this study, we reported the value of HORN-MN, which comprised a fast-soluble hyaluronic acid microneedle matrix and a weak acid-degradable oleanolic acid dimer of rosiglitazone nanoparticles. The results showed that the microneedles easily punctured the stratum corneum and dissolved in the dermis of the abdominal wall within 5 min, followed by the release of rosiglitazone nanoparticles. Thereafter, the nanoparticles were endocytosed by macrophages and white adipocytes, then degraded to oleanolic acid in the lysosomes, thereby, releasing rosiglitazone. Oleanolic acid significantly improved the inflammatory status of obese adipose tissue and promoted white adipocyte browning, and rosiglitazone significantly potentiated WAC browning. Accordingly, the patch demonstrated a remarkable obesity-reducing efficacy in mice. In conclusion, this study developed a quick paster type of soluble rosiglitazone nanoparticle microneedle for the treatment of obesity. This patch can be suitable for working people, with an evident obesity-reducing efficacy but no effect on skin integrity despite multiple administrations.

Timing Matters: Time of Day Impacts the Ergogenic Effects of Caffeine-A Narrative Review.

Caffeine has attracted significant attention from researchers in the sports field due to its well-documented ergogenic effects across various athletic disciplines. As research on caffeine continues to progress, there has been a growing emphasis on evaluating caffeine dosage and administration methods. However, investigations into the optimal timing of caffeine intake remain limited. Therefore, this narrative review aimed to assess the ergogenic effects of caffeine administration at different times during the morning (06:00 to 10:00) and evening (16:00 to 21:00). The review findings suggest that circadian rhythms play a substantial role in influencing sports performance, potentially contributing to a decline in morning performance. Caffeine administration has demonstrated effectiveness in mitigating this phenomenon, resulting in ergogenic effects and performance enhancement, even comparable to nighttime levels. While the specific mechanisms by which caffeine regulates circadian rhythms and influences sports performance remain unclear, this review also explores the mechanisms underlying caffeine's ergogenic effects, including the adenosine receptor blockade, increased muscle calcium release, and modulation of catecholamines. Additionally, the narrative review underscores caffeine's indirect impact on circadian rhythms by enhancing responsiveness to light-induced phase shifts. Although the precise mechanisms through which caffeine improves morning performance declines via circadian rhythm regulation necessitate further investigations, it is noteworthy that the timing of caffeine administration significantly affects its ergogenic effects during exercise. This emphasizes the importance of considering caffeine intake timing in future research endeavors to optimize its ergogenic potential and elucidate its mechanisms.

Salt gradient enhanced sensitivity in nanopores for intracellular calcium ion detection.

Intracellular calcium ion detection is of great significance for understanding the cell metabolism and signaling pathways. Most of the current ionic sensors either face the size issue or sensitivity limit for the intracellular solution with high background ion concentrations. In this paper, we proposed a calmodulin (CaM) functionalized nanopore for sensitive and selective Ca2+ detection inside living cells. A salt gradient was created when the nanopore sensor filled with a low concentration electrolyte was in contact with a high background concentration solution, which enhanced the surface charge-based detection sensitivity. The nanopore sensor showed a 10 × sensitivity enhancement by application of a 100-fold salt gradient, and a detection limit of sub nM. The sensor had a wide detection range from 1 nM to 1 mM, and allowed for quick calcium ion quantification in a few seconds. The sensor was demonstrated for intracellular Ca2+ detection in A549 cells in response to ionomycin.

3D Aligned Nanofiber Scaffold Fabrication with Trench-Guided Electrospinning for Cardiac Tissue Engineering.

Constructing three-dimensional (3D) aligned nanofiber scaffolds is significant for the development of cardiac tissue engineering, which is promising in the field of drug discovery and disease mechanism study. However, the current nanofiber scaffold preparation strategy, which mainly includes manual assembly and hybrid 3D printing, faces the challenge of integrated fabrication of morphology-controllable nanofibers due to its cross-scale structural feature. In this research, a trench-guided electrospinning (ES) strategy was proposed to directly fabricate 3D aligned nanofiber scaffolds with alternative ES and a direct ink writing (DIW) process. The electric field effect of DIW poly(dimethylsiloxane) (PDMS) side walls on guiding whipping ES nanofibers was investigated to construct trench design rules. It was found that the width/height ratio of trenches greatly affected the nanofiber alignment, and the trench width/height ratio of 1.5 provided the nanofiber alignment degree over 60%. As a proof of principle, 3D nanofiber scaffolds with controllable porosity (60-80%) and alignment (30-60%) were fabricated. The effect of the scaffolds was verified by culturing human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which resulted in the uniform 3D distribution of aligned hiPSC-CMs with ∼1000 µm thickness. Therefore, this printing strategy shows great potential for the efficient engineered tissue construction.

Facile and Cost-Effective Fabrication of Highly Sensitive, Fast-Response Flexible Humidity Sensors Enabled by Laser-Induced Graphene.

The need to simplify fabrication processes and reduce costs for high-performance humidity sensors is increasingly vital, especially in fields such as healthcare and agriculture. This study introduces a simple and cost-effective approach using laser-induced graphene (LIG) on a polyimide film to create highly sensitive and fast-response flexible humidity sensors. The LIG acts as the electrode, while the porous polyimide between the interdigital LIG electrodes serves as the humidity sensing material, showing changes in electrical conductivity based on the humidity levels. The LIG humidity sensor, an ionic-conduction type, exhibits remarkable sensitivity, with a 28,231-fold increase in current as relative humidity changes from 26.1 to 90.2%. It also boasts of ultrashort response/recovery times (less than 0.5/7 s), providing significant advantages in detecting rapid and subtle humidity variations compared to a commercially available MEMS humidity sensor. We successfully demonstrated the LIG humidity sensor's capabilities in ultrafast breathing monitoring (≈174 times per minute), moisture detection of grains, and detection of sudden water pipe leakage. Due to its straightforward and cost-effective fabrication process, the LIG humidity sensor holds immense practical value for affordable, widespread use across various applications.

Hot-Pressed Super-Elastic Graphene Aerogel with Bidirectional Thermal Conduction Properties as Thermal Interface Materials.

Traditional graphene-based films normally possess high thermal conductivity (TC) only along a single direction, which is not suitable for thermal interface materials (TIMs). Here, a graphene film with excellent bidirectional TC and mechanical properties was prepared by hot-pressing super-elastic graphene aerogel (SEGA). Thermal annealing at 1800 °C improves the further restacking of graphene sheets, bringing high structure stability to SEGA for enduring the hot-pressing process. The junctions and nodes between the graphene layers in the hot-pressed SEGA (HPSEGA) film provide bidirectional heat transport paths. The in-plane TC and through-plane TC of HPSEGA film with a thickness of 101 µm reach 740 Wm-1K-1 and 42.5 Wm-1K-1, respectively. In addition, HPSEGA film with higher thickness still maintains excellent thermal transport properties due to the interconnected structure reducing the effect of the defects. The infrared thermal images visually manifest the excellent thermal-transfer capability and thermal-dissipation efficiency of the HPSEGA films, indicating the great potential as advanced bidirectional TIMs.

Temperature-Immune, Wide-Range Flexible Robust Pressure Sensors for Harsh Environments.

Flexible pressure sensors possess vast potential for various applications such as new energy batteries, aerospace engines, and rescue robots owing to their exceptional flexibility and adaptability. However, the existing sensors face significant challenges in maintaining long-term reliability and environmental resilience when operating in harsh environments with variable temperatures and high pressures (∼MPa), mainly due to possible mechanical mismatch and structural instability. Here, we propose a composite scheme for a flexible piezoresistive pressure sensor to improve its robustness by utilizing material design of near-zero temperature coefficient of resistance (TCR), radial gradient pressure-dividing microstructure, and flexible interface bonding process. The sensing layer comprising multiwalled carbon nanotubes (MWCNTs), graphite (GP), and thermoplastic polyurethane (TPU) was optimized to achieve a near-zero temperature coefficient of resistance over a temperature range of 25-70 °C, while the radial gradient microstructure layout based on pressure division increases the range of pressure up to 2 MPa. Furthermore, a flexible interface bonding process introduces a self-soluble transition layer by direct-writing TPU bonding solution at the bonding interface, which enables the sensor to achieve signal fluctuations as low as 0.6% and a high interface strength of up to 1200 kPa. Moreover, it has been further validated for its capability of monitoring the physiological signals of athletes as well as the long-term reliable environmental resilience of the expansion pressure of the power cell. This work demonstrates that the proposed scheme sheds new light on the design of robust pressure sensors for harsh environments.

Bioorthogonal Engineered Virus-Like Nanoparticles for Efficient Gene Therapy.

Gene therapy offers potentially transformative strategies for major human diseases. However, one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissue. Here, we report a novel virus-like nanoparticle, the bioorthgonal engineered virus-like recombinant biosome (reBiosome), for efficient gene therapies of cancer and inflammatory diseases. The mutant virus-like biosome (mBiosome) is first prepared by site-specific codon mutation for displaying 4-azido-L-phenylalanine on vesicular stomatitis virus glycoprotein of eBiosome at a rational site, and the reBiosome is then prepared by clicking weak acid-responsive hydrophilic polymer onto the mBiosome via bioorthogonal chemistry. The results show that the reBiosome exhibits reduced virus-like immunogenicity, prolonged blood circulation time and enhanced gene delivery efficiency to weakly acidic foci (like tumor and arthritic tissue). Furthermore, reBiosome demonstrates robust therapeutic efficacy in breast cancer and arthritis by delivering gene editing and silencing systems, respectively. In conclusion, this study develops a universal, safe and efficient platform for gene therapies for cancer and inflammatory diseases.

Integrated Manufacturing of Suspended and Aligned Nanofibrous Scaffold for Structural Maturation and Synchronous Contraction of HiPSC-Derived Cardiomyocytes.

Electrospun nanofiber constructs represent a promising alternative for mimicking the natural extracellular matrix in vitro and have significant potential for cardiac patch applications. While the effect of fiber orientation on the morphological structure of cardiomyocytes has been investigated, fibers only provide contact guidance without accounting for substrate stiffness due to their deposition on rigid substrates (e.g., glass or polystyrene). This paper introduces an in situ fabrication method for suspended and well aligned nanofibrous scaffolds via roller electrospinning, providing an anisotropic microenvironment with reduced stiffness for cardiac tissue engineering. A fiber surface modification strategy, utilizing oxygen plasma treatment combined with sodium dodecyl sulfate solution, was proposed to maintain the hydrophilicity of polycaprolactone (PCL) fibers, promoting cellular adhesion. Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), cultured on aligned fibers, exhibited an elongated morphology with extension along the fiber axis. In comparison to Petri dishes and suspended random fiber scaffolds, hiPSC-CMs on suspended aligned fiber scaffolds demonstrated enhanced sarcomere organization, spontaneous synchronous contraction, and gene expression indicative of maturation. This work demonstrates the suspended and aligned nano-fibrous scaffold provides a more realistic biomimetic environment for hiPSC-CMs, which promoted further research on the inducing effect of fiber scaffolds on hiPSC-CMs microstructure and gene-level expression.

Inactivating Salmonella Enteritidis on shell eggs by using ozone microbubble water.

The major pathogen associated with eggs is Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) and chlorine washing is the most widely used for sanitization. Microbubble, a novel technique and able to operate in large quantity, has been presented to be an alternative method. Thus, microbubble water combining with ozone (OMB) was applied to disinfect S. Enteritidis spiked on shells at 107 cells per egg. OMB was generated by injecting ozone into a Nikuni microbubble system, then delivered into 10 L of water. After 5, 10, or 20 min of activation time, the eggs were placed into OMB and washed for 30 or 60 s. The controls involved unwashed, water washing, ozone only, and microbubble only (MB). The highest reduction, 5.19 log CFU/egg, was achieved by the combination of 20-min activation and 60-s washing, which was used for following tests of large water quantities. Comparing with the unwashed control, 4.32, 3.73 and 3.07 log CFU/egg reductions were achieved in 25, 80, and 100 L of water, respectively. The other system, Calpeda, with higher motor power was tested in 100 L and obtained a reduction of 4.15 log CFU/egg. The average diameter of bubbles generated by Nikuni and Calpeda pump systems were 29.05 and 36.50 µm, respectively, which both were within the microbubble definition of ISO. Much lower reductions, around 1-2 log10 CFU/egg, were shown with the treatments of ozone only and MB by the same operative parameters. After 15-day storage at ambient temperature, the OMB-treated eggs showed similar sensory quality with the unwashed ones. This is the first study demonstrating that OMB effectively inactivates S. Enteritidis on shell eggs in large quantity of water and does not diminished the sensory characteristics of eggs. Furthermore, bacterial population was under the detection limit in the OMB-treated water.

Local vs Systemic Use of Steroids for Sudden Deafness with Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND: Diabetes is associated with a risk of idiopathic sudden deafness. The main treatment of diabetic sudden deafness is systemic and topical application of steroids. Topical steroid therapy reduces systemic adverse reactions compared with systemic therapy. PURPOSE: The aim of this study was to conduct a meta-analysis design on the improvement value and recovery rate of pure tone mean hearing threshold (PTA).To investigate whether there is difference between local and systemic steroid treatment as the initial treatment for sudden deafness patients with diabetes. METHODS: We searched databases from publication date to October 1, 2022 including PubMed, EMBASE, Cochrane Library, web of science, CNKI, Wan fang Database, China Biomedical Literature Database (CBM), and VIP information resource system. A systematic literature review was conducted on the efficacy and safety of local and systemic steroid therapy for diabetic sudden deafness. RevMan5.4 and stata14 software were used for Meta-analysis. RESULTS: A total of 23 studies were included in this study, covering 1777 patients, including 885 cases in the observation group (local steroid group) and 894 cases in the control group (systemic steroid group). Meta-analysis showed that there was a significant difference in the total effective rate of local and systemic steroid treatment for diabetic sudden deafness between groups (RR = 1.17, 95% CI = 1.11-1.22, P < 0.05). The effective rate in the observation group was higher than that in the control group. For the improvement of PTA, the difference between groups was statistically significant (RR = 6.60, 95% CI = 3.07-10.14, P < 0.05). The improvement of PTA in the local steroid group was higher than that in the systemic steroid group. Subgroup analysis showed that there were significant differences between groups in hormones, drug administration, follow-up time and course of disease. CONCLUSION: Topical steroid therapy is effective in the treatment of diabetic sudden deafness. Hormone methylprednisolone has high effective rate; the shorter the course of disease and the longer the follow-up time are, the higher the total effective rate will be. Tympanic injection is more effective than post-aural injection. Topical steroid injections are safer for hormonal side effect.

Synergistic Effect of Rhodiola rosea and Caffeine Supplementation on the Improvement of Muscle Strength and Muscular Endurance: A Pilot Study for Rats, Resistance Exercise-Untrained and -Trained Volunteers.

Multi-level studies have shown that Rhodiola rosea (RHO) and Caffeine (CAF) have the potential to be nutritional supplements to enhance physical performance in resistance exercise-untrained and -trained subjects. This study examined the synergistic effects of RHO (262.7 mg/kg for rats and 2.4 g for volunteers) and CAF (19.7 mg/kg for rats and 3 mg/kg for volunteers) supplementation on improving physical performance in rats, resistance exercise-untrained volunteers and resistance exercise-trained volunteers. Rats and volunteers were randomly grouped into placebo, CAF, RHO and CAF+RHO and administered accordingly with the nutrients during the training procedure, and pre- and post-measures were collected. We found that RHO+CAF was effective in improving forelimb grip strength (13.75%), erythropoietin (23.85%), dopamine (12.65%) and oxygen consumption rate (9.29%) in the rat model. Furthermore, the current results also indicated that the combination of RHO+CAF significantly increased the bench press one-repetition maximum (1RM) (16.59%), deep squat 1RM (15.75%), maximum voluntary isometric contraction (MVIC) (14.72%) and maximum repetitions of 60% 1RM bench press (22.15%) in resistance exercise-untrained volunteers. Additionally, despite the excellent base level of the resistance exercise-trained volunteers, their deep squat 1RM and MVIC increased substantially through the synergistic effect of RHO and CAF. In conclusion, combined supplementation of RHO+CAF is more beneficial in improving the resistance exercise performance for both resistance exercise-untrained and -trained volunteers. The present results provide practical evidence that the synergies of RHO and CAF could serve as potential supplementary for individuals, especially resistance exercise-trained subjects, to ameliorate their physical performances effectively and safely.

Nanofiber self-consistent additive manufacturing process for 3D microfluidics.

3D microfluidic devices have emerged as powerful platforms for analytical chemistry, biomedical sensors, and microscale fluid manipulation. 3D printing technology, owing to its structural fabrication flexibility, has drawn extensive attention in the field of 3D microfluidics fabrication. However, the collapse of suspended structures and residues of sacrificial materials greatly restrict the application of this technology, especially for extremely narrow channel fabrication. In this paper, a 3D printing strategy named nanofiber self-consistent additive manufacturing (NSCAM) is proposed for integrated 3D microfluidic chip fabrication with porous nanofibers as supporting structures, which avoids the sacrificial layer release process. In the NSCAM process, electrospinning and electrohydrodynamic jet (E-jet) writing are alternately employed. The porous polyimide nanofiber mats formed by electrospinning are ingeniously applied as both supporting structures for the suspended layer and percolating media for liquid flow, while the polydimethylsiloxane E-jet writing ink printed on the nanofiber mats (named construction fluid in this paper) controllably permeates through the porous mats. After curing, the resultant construction fluid-nanofiber composites are formed as 3D channel walls. As a proof of concept, a microfluidic pressure-gain valve, which contains typical features of narrow channels and movable membranes, was fabricated, and the printed valve was totally closed under a control pressure of 45 kPa with a fast dynamic response of 52.6 ms, indicating the feasibility of NSCAM. Therefore, we believe NSCAM is a promising technique for manufacturing microdevices that include movable membrane cavities, pillar cavities, and porous scaffolds, showing broad applications in 3D microfluidics, soft robot drivers or sensors, and organ-on-a-chip systems.

Finger-inspired rigid-soft hybrid tactile sensor with superior sensitivity at high frequency.

Among kinds of flexible tactile sensors, piezoelectric tactile sensor has the advantage of fast response for dynamic force detection. However, it suffers from low sensitivity at high-frequency dynamic stimuli. Here, inspired by finger structure-rigid skeleton embedded in muscle, we report a piezoelectric tactile sensor using a rigid-soft hybrid force-transmission-layer in combination with a soft bottom substrate, which not only greatly enhances the force transmission, but also triggers a significantly magnified effect in d31 working mode of the piezoelectric sensory layer, instead of conventional d33 mode. Experiments show that this sensor exhibits a super-high sensitivity of 346.5 pC N-1 (@ 30 Hz), wide bandwidth of 5-600 Hz and a linear force detection range of 0.009-4.3 N, which is ~17 times the theoretical sensitivity of d33 mode. Furthermore, the sensor is able to detect multiple force directions with high reliability, and shows great potential in robotic dynamic tactile sensing.

Nanostructure of Functional Larotaxel Liposomes Decorated with Guanine-Rich Quadruplex Nucleotide-Lipid Derivative for Treatment of Resistant Breast Cancer.

Breast cancer is the most common malignant disease in women all over the world and its chemotherapy outcome is restricted by multidrug resistance. Here, a nanostructure by functional larotaxel liposomes decorated with guanine-rich quadruplex nucleotide-lipid derivative for treatment of resistant breast cancer is developed. The studies are performed on the resistant breast cancer cells and the cancer-bearing mice. The nucleotide-lipid derivative (DSPE-PEG2000 -C6 -GT28nt) is synthesized by introducing a hydrophobic hexyl linkage between GT-28nt (containing 17 guanines and 11 thymidines) and DSPE-PEG2000 -NHS, and is incorporated on the functional larotaxel liposomes for specific binding with nucleolin receptor on the resistant cancer cells. The studies demonstrate that the liposomes had long circulatory effect, targeted capability, and significant anticancer efficacy in resistant cancer-bearing mice. The studies further reveal their action mechanism, consisting of blocking depolymerization of microtubules, arresting cell cycle, blocking JAK-STAT signaling pathway, and inhibiting activity of antiapoptotic proteins. In conclusion, the functional larotaxel liposomes can be used for effective treatment of drug-resistant breast cancer, and this study also offers a novel targeted nanomedicine based on nucleotide-lipid derivative.

Surface Potential/Charge Sensing Techniques and Applications.

Surface potential and surface charge sensing techniques have attracted a wide range of research interest in recent decades. With the development and optimization of detection technologies, especially nanosensors, new mechanisms and techniques are emerging. This review discusses various surface potential sensing techniques, including Kelvin probe force microscopy and chemical field-effect transistor sensors for surface potential sensing, nanopore sensors for surface charge sensing, zeta potentiometer and optical detection technologies for zeta potential detection, for applications in material property, metal ion and molecule studies. The mechanisms and optimization methods for each method are discussed and summarized, with the aim of providing a comprehensive overview of different techniques and experimental guidance for applications in surface potential-based detection.

A glass nanopore ionic sensor for surface charge analysis.

Surface charge-based nanopore characterization techniques unfold unique properties and provide a powerful platform for a variety of sensing applications. In this paper, we have proposed a nanoconfined inner wall surface charge characterization method with glass nanopores. The glass nanopores were functionalized with DNA aptamers that were designed for mercury (Hg2+) ion immobilization by forming thymine-Hg2+-thymine structures. The surface charge of the nanopores was modulated by surface chemistry and Hg2+ ion concentrations and analysed by combining zeta potential measurements on glass slides and the ionic current rectification ratio of the nanopores. Also, 1 pM Hg2+ ions could be detected by the nanopores.

Trends in statin utilization among adults with severe peripheral artery disease including critical limb ischemia in an integrated healthcare delivery system.

Evidence suggests that statin therapy in patients with peripheral artery disease (PAD) is beneficial yet use remains suboptimal. We examined trends in statin use, intensity, and discontinuation among adults aged ⩾ 40 years with incident severe PAD and a subset with critical limb ischemia (CLI) between 2002 and 2015 within an integrated healthcare delivery system. Discontinuation of statin therapy was defined as the first 90-day gap in treatment within 1 year following PAD diagnosis. We identified 11,059 patients with incident severe PAD: 31.1% (n = 3442) with CLI and 68.9% (n = 7617) without CLI. Mean (SD) age was 68.6 (11.3) years, 60.5% were male, 54.2% white, 23.2% Hispanic, and 16.2% black. Statin use in the year before diagnosis increased from 50.4% in 2002 to 66.0% in 2015 (CLI: 43.7% to 68.0%; without CLI: 53.1% to 64.2%, respectively). The proportion of patients on high-intensity statins increased from 7.3% in 2002 to 41.9% in 2015 (CLI: 7.2% to 39.4%; without CLI: 7.4% to 44.2%, respectively). Of the 40.5% (n = 4481) who were not on a statin in the year before diagnosis, 13.5% (n = 607) newly initiated therapy within 1 month (CLI: 10.1% (n = 150); without CLI: 15.3% (n = 457)). Following diagnosis, 12.5% (n = 660) discontinued statin therapy within 1 year (CLI: 15.5% (n = 202); without CLI: 11.5% (n = 458)). Although use of statins increased from 2002 to 2015, a substantial proportion of the overall PAD and CLI subpopulation remained untreated with statins, representing a significant treatment gap in a population at high risk for cardiovascular events and adverse limb outcomes.