Superiority of a Silk Surgical Site Wound Closure Device Over Synthetic Dressings.

BACKGROUND: Silk fibroin is an emerging biomaterial with enhanced properties of cellular regeneration, growth and proliferation. The use of a silk fibroin wound dressing has the potential to decrease the incidence of wound healing complications and to improve patient outcomes compared to synthetic dressing alternatives. METHODS: A prospective, randomized, single-blinded clinical trial was conducted on 50 patients who were dressed with a silk fibroin dressing on one side of their body and on the contralateral side with 3M Steri-Strips® after undergoing abdominoplasty, reduction mammaplasty, or brachioplasty procedures. Data was collected over 5 postoperative visits using photographs and an investigator administered questionnaire to monitor erythema, skin irritation, skin discomfort, the need for pharmaceutical intervention, wound dehiscence and mechanical skin injury. A comprehensive 75 patient statistical analysis was conducted combining the results with a previously published study comparing Dermabond® Prineo® to the silk dressing. RESULTS: 20.8% (10/48) of patients were assessed by surgeons as having skin erythema (7-10) on the Steri-Strip® control side and 0% (0/48) on the silk dressing side (p=0.002). The frequency of breast triple point separation in 43 cases was 30.2% (13/43) on the Steri-Strip® side and 9.3% (4/43) on the silk side (p=0.012). 75% (36/48) of patients had partial or total detachment of Steri-Strips® while 0% (0/48) had total detachment of the silk dressing and 18.8% (9/48) had partial detachment of the silk dressing within the first two weeks (p<0.001). CONCLUSION: A silk fibroin wound dressing significantly reduces the incidence of wound healing complications throughout the postoperative period.Clinical Relevance Statement: The adoption of a silk fibroin wound dressing into clinical practice has the potential to improve patient outcomes, decrease medical adhesive related skin injuries and reduce the rate of wound healing complications.

Silk Bioprotein as a Novel Surgical-Site Wound Dressing: A Prospective, Randomized, Single-Blinded, Superiority Clinical Trial.

Background: Medical adhesive-related skin injuries (MARSIs) affect about 1.5 million patients annually in the United States. Complications include allergic contact dermatitis, skin blistering, skin tears, and surgical-site infections (SSIs). The authors hypothesize that a natural hypoallergenic silk bioprotein wound dressing will decrease the incidence of MARSI in comparison to a synthetic alternative. Objectives: This study aimed to assess the efficacy and safety of a silk bioprotein wound dressing compared to the Dermabond Prineo (Ethicon, Inc., Somerville, NJ) skin closure system. Methods: This prospective, randomized, single-blinded trial studied 25 patients who were dressed with Dermabond Prineo on one side of their body and on the contralateral side with the silk bioprotein dressing after undergoing abdominoplasty or reduction mammaplasty procedures. Data were collected over 5 postoperative visits using photographs and an investigator administered questionnaire to track rash, itch, discomfort, erythema, edema, SSIs, need for pharmaceutical intervention, mechanical injury, removal time, and bathing routines. Results: Sixty-four percent (16/25) of patients characterized the severity of discomfort as a score of 4 out of 10 or greater on the Dermabond Prineo control side and only 4% (1/25) for the silk-dressing side (P < .001). Fifty-two percent (13/25) had a visible rash of 4 or higher on the Dermabond Prineo side of their incision and 0% (0/25) had a rash on the silk side (P < .001). Fifty-two percent (13/25) required steroids or antibiotics to treat MARSI to Dermabond Prineo and 0% (0/25) required pharmaceutical intervention on the silk side (P < .001). Conclusions: The use of a silk bioprotein wound dressing significantly reduces the incidence of MARSI throughout the postoperative period.

Recent progress of redox-responsive polymeric nanomaterials for controlled release.

Redox-responsive polymeric nanomaterials (PNMs) have been attractive research targets for drug delivery systems because disturbed levels of redox molecules are associated with the progression of various diseases. To enable PNMs to target biorelevant redox molecules, including reactive oxygen species (ROS), glutathione (GSH) and hydrogen sulfide (H2S), appropriate responsive moieties have to be installed within the polymer structure. Upon application of redox stimuli, redox-responsive PNMs undergo structural changes to release encapsulated payloads. Chalcogen ether, thioketal and arylboronic ester have been widely incorporated into the structure of ROS-responsive PNMs. While disulfide is commonly utilized in GSH-responsive PNMs, azide is a newly explored responsive motif targeting H2S selectively. Diselenide, on the other hand, is a group susceptible to both oxidative and reducing conditions and therefore it has been exploited in dual redox-responsive PNMs. Here, we review PNMs, mainly reported in the last four years, that contain these redox-responsive moieties for controlled payload release.

Highly responsive and rapid hydrogen peroxide-triggered degradation of polycaprolactone nanoparticles.

We synthesized an oxidation-responsive polycaprolactone (O-PCL) bearing pendant arylboronic esters as H2O2-responsive motifs. H2O2 induces fast depolymerization of O-PCL within days. Nanoparticles formulated from O-PCL disintegrate and release payload in response to concentrations of H2O2 (50 µM) that are relevant to human disease.

The Chemistry of Boronic Acids in Nanomaterials for Drug Delivery.

Interest in increasing drug delivery efficiency has risen over the past decade both as a means to improve efficacy of already clinically available drugs and due to the increased difficulties of approving new drugs. As a functional group for targeted drug delivery, boronic acids (BAs) have been incorporated in polymeric particles both as a stimuli-responsive functional group and as a targeting ligand. Here, BA chemistry presents a wealth of opportunities for biological applications. It not only reacts with several chemical markers of disease such as reactive oxygen species (ROS), adenosine triphosphate (ATP), glucose, and reduced pH, but it also acts as ligands for diols such as sialic acid. These stimuli-responsive drug delivery systems optimize delivery of therapeutics based on rational design and precise molecular engineering. When designing materials containing BA, the unique chemical properties are important to take into consideration such as its vacant p-orbital, its molecular geometry, and the designed acid's pKa. Instead of behaving as most carboxylic acids that donate protons, BAs instead primarily act as Lewis acids that accept electrons. In aqueous solution, most polymers containing BA exist in an equilibrium between their triangular hydrophobic form and a tetrahedral hydrophilic form. The most common pKa's are in the nonphysiological range of 8-10, and much ongoing research focuses on modifying BAs into materials sensitive to a more physiologically relevant pH range. So far, BA moieties have been incorporated into a stunning array of materials, ranging from small molecules that can self-assemble into higher order structures such as micelles and polymeric micelles, via larger polymeric assemblies, to large scale hydrogels. With the abundance of biological molecules containing diols and polyhydroxy motifs, BA-containing materials have proven valuable in several biomedical applications such as treatment of cancer, diabetes, obesity, and bacterial infections. Both materials functionalized with BA and boronic esters display good safety profiles in vitro and in vivo; thus, BA-containing materials represent promising carriers for responsive delivery systems with great potential for clinical translation. The intention of this Account is to showcase the versatility of BA for biomedical applications. We first discuss the chemistry of BA and what to consider when designing BA-containing materials. Further, we review how its chemistry recently has been applied to nanomaterials for enhanced delivery efficiency, both as a stimuli-responsive group and as a targeting ligand. Lastly, we discuss the current limitations and further perspectives of BA in biomaterials, based on the great benefits that can come from utilizing the unique BA chemistry to enhance drug delivery efficiency.

A Bioelectronic Platform Modulates pH in Biologically Relevant Conditions.

Bioelectronic devices that modulate pH can affect critical biological processes including enzymatic activity, oxidative phosphorylation, and neuronal excitability. A major challenge in controlling pH is the high buffering capacity of many biological media. To overcome this challenge, devices need to be able to store and deliver a large number of protons on demand. Here, a bioelectronic modulator that controls pH using palladium nanoparticles contacts with high surface area as a proton storage medium is developed. Reversible electronically triggered acidosis (low pH) and alkalosis (high pH) in physiologically relevant buffer conditions are achieved. As a proof of principle, this new platform is used to control the degradation and fluorescence of acid sensitive polymeric microparticles loaded with a pH sensitive fluorescent dye.

Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H2O2. The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNFα 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.

Disease-Triggered Drug Release Effectively Prevents Acute Inflammatory Flare-Ups, Achieving Reduced Dosing.

For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.

Delivery of Cargo with a Bioelectronic Trigger.

Biological systems exchange information often with chemical signals. Here, we demonstrate the chemical delivery of a fluorescent label using a bioelectronic trigger. Acid-sensitive microparticles release fluorescin diacetate upon low pH induced by a bioelectronic device. Cardiac fibroblast cells (CFs) uptake fluorescin diacetate, which transforms into fluorescein and emits a fluorescent signal. This proof-of-concept bioelectronic triggered delivery may be used in the future for real-time programming and control of cells and cell systems.

A Single-Blind Study Evaluating the Efficacy of Gold Nanoparticle Photothermal-Assisted Liposuction in an Ex Vivo Human Tissue Model.

BACKGROUND: Liposuction is one of the most performed cosmetic surgery procedures. In a previously reported study, gold-nanoparticle (GNP) laser-assisted liposuction (NanoLipo) was shown to improve procedure parameters and outcomes in a porcine model. OBJECTIVES: An ex vivo human liposuction model was developed to assess the ease, efficacy, and outcomes of NanoLipo, and to further explore its mechanism of action in facilitating liposuction. METHODS: NanoLipo was compared to a control without GNPs in sets of fresh, nonperfused, anatomically symmetric, matched tissue specimens from 12 patients. A subset of three experiments was performed under single-blinded conditions. Intraoperative assessments included lipoaspirate volume, percentage of free oil, ease of removal, and temperature rise. Specimens were palpated, visualized for evenness, and graded with and without skin. Postoperative assessment included viability staining of the lipoaspirate and remaining tissues. Microcomputed tomography was used to assess the distribution of infused GNPs within the tissues. RESULTS: NanoLipo consistently removed more adipose tissue with more liberated triglycerides compared to control. NanoLipo specimens were smoother, thinner, and had fewer and smaller irregularities. Infused solutions preferentially distributed between fibrous membranes and fat pearls. After NanoLipo, selective structural-tissue disruptions, indicated by loss of metabolic activity, were observed. Thus, NanoLipo likely creates a bimodal mechanism of action whereby fat lobules are dislodged from surrounding fibro-connective tissue, while lipolysis is simultaneously induced. CONCLUSIONS: NanoLipo showed many advantages compared to control under blinded and nonblinded conditions. This technology may be promising in facilitating fat removal.

Chemical amplification accelerates reactive oxygen species triggered polymeric degradation.

Chemical amplification is a known strategy for improving the sensitivity of stimuli-responsive polymers. However, the chemical amplification effect has never been fully examined. Many questions remain about its mechanism and efficacy, obstructing its further implementation. Here, we design and demonstrate a reactive oxygen species (ROS) responsive polymer (ROS-ARP) with a chemical amplification strategy to dismiss these concerns. The ROS-ARP is designed to change the hydrophilicity by ROS, revealing a carboxylic acid, which also catalyzes ketal hydrolysis along the polymer backbone. The chemical amplification strategy of ROS-ARP accelerated the polymer degradation up to 17 fold compared to a previously reported ROS-responsive polymer. To investigate the mechanism behind this increased acceleration, we compared the degradation kinetics in various environments. Additionally, other effects such as hydrophilicity changes were excluded. The accelerated degradation of ROS-ARP is evaluated as a potential drug delivery system, demonstrating on-demand cargo release from the formulated polymeric particles.

Review of the progress toward achieving heat confinement-the holy grail of photothermal therapy.

Photothermal therapy (PTT) involves the application of normally benign light wavelengths in combination with efficient photothermal (PT) agents that convert the absorbed light to heat to ablate selected cancers. The major challenge in PTT is the ability to confine heating and thus direct cellular death to precisely where PT agents are located. The dominant strategy in the field has been to create large libraries of PT agents with increased absorption capabilities and to enhance their delivery and accumulation to achieve sufficiently high concentrations in the tissue targets of interest. While the challenge of material confinement is important for achieving "heat and lethality confinement," this review article suggests another key prospective strategy to make this goal a reality. In this approach, equal emphasis is placed on selecting parameters of light exposure, including wavelength, duration, power density, and total power supplied, based on the intrinsic properties and geometry of tissue targets that influence heat dissipation, to truly achieve heat confinement. This review highlights significant milestones researchers have achieved, as well as examples that suggest future research directions, in this promising technique, as it becomes more relevant in clinical cancer therapy and other noncancer applications.

Simultaneous Enhancement of Photoluminescence, MRI Relaxivity, and CT Contrast by Tuning the Interfacial Layer of Lanthanide Heteroepitaxial Nanoparticles.

Nanoparticle (NP) based exogenous contrast agents assist biomedical imaging by enhancing the target visibility against the background. However, it is challenging to design a single type of contrast agents that are simultaneously suitable for various imaging modalities. The simple integration of different components into a single NP contrast agent does not guarantee the optimized properties of each individual components. Herein, we describe lanthanide-based core-shell-shell (CSS) NPs as triple-modal contrast agents that have concurrently enhanced performance compared to their individual components in photoluminescence (PL) imaging, magnetic resonance imaging (MRI), and computed tomography (CT). The key to simultaneous enhancement of PL intensity, MRI r1 relaxivity, and X-ray attenuation capability in CT is tuning the interfacial layer in the CSS NP architecture. By increasing the thickness of the interfacial layer, we show that (i) PL intensity is enhanced from completely quenched/dark state to brightly emissive state of both upconversion and downshifting luminescence at different excitation wavelengths (980 and 808 nm), (ii) MRI r1 relaxivity is enhanced by 5-fold from 11.4 to 52.9 mM-1 s-1 (per Gd3+) at clinically relevant field strength 1.5 T, and (iii) the CT Hounsfield Unit gain is 70% higher than the conventional iodine-based agents at the same mass concentration. Our results demonstrate that judiciously designed contrast agents for multimodal imaging can achieve simultaneously enhanced performance compared to their individual stand-alone structures and highlight that multimodality can be achieved without compromising on individual modality performance.

Distinct ON/OFF fluorescence signals from dual-responsive activatable nanoprobes allows detection of inflammation with improved contrast.

Visualization of biochemical changes associated with disease is of great clinical significance, as it should allow earlier, more accurate diagnosis than structural imaging, facilitating timely clinical intervention. Herein, we report combining stimuli-responsive polymers and near-infrared fluorescent dyes (emission max: 790 nm) to create robust activatable fluorescent nanoprobes capable of simultaneously detecting acidosis and oxidative stress associated with inflammatory microenvironments. The spectrally-resolved mechanism of fluorescence activation allows removal of unwanted background signal (up to 20-fold reduction) and isolation of a pure activated signal, which enables sensitive and unambiguous localization of inflamed areas; target-to-background ratios reach 22 as early as 3 h post-injection. This new detection platform could have significant clinical impact in early detection of pathologies, individual tailoring of drug therapy, and image-guided tumor resection.

Direct Evidence for Coupled Surface and Concentration Quenching Dynamics in Lanthanide-Doped Nanocrystals.

Luminescence quenching at high dopant concentrations generally limits the dopant concentration to less than 1-5 mol% in lanthanide-doped materials, and this remains a major obstacle in designing materials with enhanced efficiency/brightness. In this work, we provide direct evidence that the major quenching process at high dopant concentrations is the energy migration to the surface (i.e., surface quenching) as opposed to the common misconception of cross-relaxation between dopant ions. We show that after an inert epitaxial shell growth, erbium (Er3+) concentrations as high as 100 mol% in NaY(Er)F4/NaLuF4 core/shell nanocrystals enhance the emission intensity of both upconversion and downshifted luminescence across different excitation wavelengths (980, 800, and 658 nm), with negligible concentration quenching effects. Our results highlight the strong coupling of concentration and surface quenching effects in colloidal lanthanide-doped nanocrystals, and that inert epitaxial shell growth can overcome concentration quenching. These fundamental insights into the photophysical processes in heavily doped nanocrystals will give rise to enhanced properties not previously thought possible with compositions optimized in bulk.

Biorthogonal click chemistry on poly(lactic-co-glycolic acid)-polymeric particles.

Biodegradable polymeric materials are a key area of investigation in drug delivery and disease treatment. This is due to their proven clinical potential for payload protection, responsivity, and surface modification imparted by the versatile array of polymers available for their formulation. Here, we employ a novel biodegradable azide containing polymer in the formulation of polymeric nanoparticles and show that these particles can then be functionalized, with biorthogonal click reactions, to alter their surface appearance and their ability to interact with biological systems.

Compact Micellization: A Strategy for Ultrahigh T1 Magnetic Resonance Contrast with Gadolinium-Based Nanocrystals.

Paramagnetic gadolinium (Gd(3+))-based nanocrystals (NCs) with a large number of confined gadolinium ions can be expected to heavily enhance the longitudinal (T1) relaxation of water protons compared to clinical gadolinium complexes with only a single paramagnetic center. However, paramagnetic Gd(3+)-NCs reported to date show only a modest T1 relaxivity of ∼10 mM(-1) s(-1) per Gd(3+) at 1.5 T, only about 3-times higher than clinical Gd(3+) complexes. Here we demonstrate a strategy that achieves ultrahigh T1 relaxivity that is about 25-times higher than clinical Gd(3+) complexes by controlling the proximity of water protons to a paramagnetic NC surface. Using NaGdF4 NCs (∼3 nm) coated with PEG-ylated phospholipid (DSPE-PEG) micelles, we show that the distance of water protons to the NCs surface can be tuned by controlling the NC-micelle sizes. Increasing the ratio of DSPE-PEG to NCs during micellization decreases the size of NC-micelles, enhancing the proximity of water to the NC surface. Using this strategy, we have achieved compact NC-micelles (hydrodynamic diameter, HD ∼ 5 nm) with ultrahigh T1 relaxivity of ∼80 mM(-1) s(-1) per Gd(3+) at 1.41 T. The findings reported here demonstrate a nanostructured Gd(3+)-contrast agent (CA) that simultaneously achieves an ultrahigh T1 relaxivity approaching theoretical predictions, extremely compact size (HD < 5 nm), and a biocompatible surface. Our results show the hitherto unknown ultrahigh T1 relaxation enhancement of water protons in close proximity to a colloidal gadolinium-NC surface that is achievable by precise control of their surface structure.

Nanogels as imaging agents for modalities spanning the electromagnetic spectrum.

In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents.

Enhanced UV upconversion emission using plasmonic nanocavities.

Upconversion of near infrared (NIR) into ultraviolet (UV) radiation could lead to a number of applications in bio-imaging, diagnostics and drug delivery. However, for bare nanoparticles, the conversion efficiency is extremely low. In this work, we experimentally demonstrate strongly enhanced upconversion emission from an ensemble of ß-NaYF4:Gd3+/Yb3+/Tm3+ @NaLuF4 core-shell nanoparticles trapped in judiciously designed plasmonic nanocavities. In doing so, different metal platforms and nanostructures are systematically investigated. Our results indicate that using a cross-shape silver nanocavity, a record high enhancement of 170-fold can be obtained in the UV band centered at a wavelength of 345 nm. The observed upconversion efficiency improvement may be attributed to the increased absorption at NIR, the tailored photonic local density of states, and the light out-coupling characteristics of the cavity.

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction.

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.