Controlled Release of a Therapeutic Peptide in Sprayable Surgical Sealant for Prevention of Postoperative Abdominal Adhesions.

Formation of asymmetric, rigid scar tissue known as surgical adhesions is caused by traumatic disruption of mesothelial-lined surfaces in surgery. A widely adopted prophylactic barrier material (Seprafilm) for the treatment of intra-abdominal adhesions is applied operatively as a pre-dried hydrogel sheet but has reduced translational efficacy due its brittle mechanical properties. Topically administered peritoneal dialysate (Icodextrin) and anti-inflammatory drugs have failed to prevent adhesions due to an uncontrolled release profile. Hence, inclusion of a targeted therapeutic into a solid barrier host matrix with improved mechanical properties could provide dual utility in adhesion prevention and as a surgical sealant. Spray deposition of poly(lactide-co-caprolactone) (PLCL) polymer fibers through solution blow spinning has yielded a tissue-adherent barrier material with previously reported adhesion prevention efficacy due to a surface erosion mechanism that inhibits deposition of inflamed tissue. However, such an approach uniquely presents an avenue for controlled therapeutic release through mechanisms of diffusion and degradation. Such a rate is kinetically tuned via facile blending of "high" molecular weight (HMW) and "low" molecular weight (LMW) PLCL with slow and fast biodegradation rates, respectively. Here, we explore viscoelastic blends of HMW PLCL (70% w/v) and LMW PLCL (30% w/v) as a host matrix for anti-inflammatory drug delivery. In this work, COG133, an apolipoprotein E (ApoE) mimetic peptide with potent anti-inflammatory properties was selected and tested. In vitro studies with PLCL blends presented low (∼30%) and high (∼80%) percent release profiles over a 14-day period based on the nominal molecular weight of the HMW PLCL component. Two independent mouse models of cecal ligation and cecal anastomosis significantly reduced adhesion severity versus Seprafilm, COG133 liquid suspension, and no treatment control. The synergy of physical and chemical methods in a barrier material with proven preclinical studies highlights the value of COG133-loaded PLCL fiber mats in effectively dampening the formation of severe abdominal adhesions.

Sprayable tissue adhesive with biodegradation tuned for prevention of postoperative abdominal adhesions.

Adhesions are dense, fibrous bridges that adjoin tissue surfaces due to uncontrolled inflammation following postoperative mesothelial injury. A widely used adhesion barrier material in Seprafilm often fails to prevent transverse scar tissue deposition because of its poor mechanical properties, rapid degradation profile, and difficulty in precise application. Solution blow spinning (SBS), a polymer fiber deposition technique, allows for the placement of in situ tissue-conforming and tissue-adherent scaffolds with exceptional mechanical properties. While biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA) have desirable strength, they exhibit bulk biodegradation rates and inflammatory profiles that limit their use as adhesion barriers and result in poor tissue adhesion. Here, viscoelastic poly(lactide-co-caprolactone) (PLCL) is used for its pertinent biodegradation mechanism. Because it degrades via surface erosion, spray deposited PLCL fibers can dissolve new connections formed by inflamed tissue, allowing them to function as an effective, durable, and easy-to-apply adhesion barrier. Degradation kinetics are tuned to match adhesion formation through the design of PLCL blends comprised of highly adhesive "low"-molecular weight (LMW) constituents in a mechanically robust "high"-molecular weight (HMW) matrix. In vitro studies demonstrate that blending LMW PLCL (30% w/v) with HMW PLCL (70% w/v) yields an anti-fibrotic yet tissue-adhesive polymer sealant with a 14-day erosion rate countering adhesion formation. PLCL blends additionally exhibit improved wet tissue adhesion strength (~10 kPa) over a 14-day period versus previously explored biodegradable polymer compositions, such as PLGA. In a mouse cecal ligation model, select PLCL blends significantly reduce abdominal adhesions severity versus no treatment and Seprafilm-treated controls.

Biodegradable, Tissue Adhesive Polyester Blends for Safe, Complete Wound Healing.

Pressure-sensitive adhesives typically used for bandages are nonbiodegradable, inhibiting healing, and may cause an allergic reaction. Here, we investigated the effect of biodegradable copolymers with promising thermomechanical properties on wound healing for their eventual use as biodegradable, biocompatible adhesives. Blends of low molecular weight (LMW) and high molecular weight (HMW) poly(lactide-co-caprolactone) (PLCL) are investigated as tissue adhesives in comparison to a clinical control. Wounds treated with PLCL blend adhesives heal completely with similar vascularization, scarring, and inflammation indicators, yet require fewer dressing changes due to integration of the PLCL adhesive into the wound. A blend of LMW and HMW PLCL produces an adhesive material with significantly higher adhesive strength than either neat polymer. Wound adhesion is comparable to a polyurethane bandage, utilizing conventional nonbiodegradable adhesives designed for extremely strong adhesion.

Pressure-Sensitive Tissue Adhesion and Biodegradation of Viscoelastic Polymer Blends.

Viscoelastic blends of biodegradable polyesters with low and high molecular weight distributions have remarkably strong adhesion (significantly greater than 1 N/cm2) to soft, wet tissue. Those that transition from viscous flow to elastic, solidlike behavior at approximately 1 Hz demonstrate pressure-sensitivity yet also have sufficient elasticity for durable bonding to soft, wet tissue. The pressure-sensitive tissue adhesive (PSTA) blends produce increasingly stronger pull-apart adhesion in response to compressive pressure application, from 10 to 300 s. By incorporating a stiffer high molecular weight component, the PSTA exhibits dramatically improved burst pressure (greater than 100 kPa) when used as a tissue sealant. The PSTA's biodegradation mechanism can be switched from erosion (occurring primarily over the first 10 days) to bulk chemical degradation (and minimal erosion) depending on the chemistry of the high molecular weight component. Interestingly, fibrosis toward the PSTA is reduced when fast-occurring erosion is the dominant biodegradation mechanism.

Sprayable and biodegradable, intrinsically adhesive wound dressing with antimicrobial properties.

Conventional wound dressings are difficult to apply to large total body surface area (TBSA) wounds, as they typically are prefabricated, require a layer of adhesive coating for fixation, and need frequent replacement for entrapped exudate. Large TBSA wounds as well as orthopedic trauma and low-resource surgery also have a high risk of infection. In this report, a sprayable and intrinsically adhesive wound dressing loaded with antimicrobial silver is investigated that provides personalized fabrication with minimal patient contact. The dressing is composed of adhesive and biodegradable poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) blend fibers with or without silver salt (AgNO3). in vitro studies demonstrate that the PLGA/PEG/Ag dressing has antimicrobial properties and low cytotoxicity, with antimicrobial silver controllably released over 7-14 days. In a porcine partial-thickness wound model, the wounds treated with both antimicrobial and nonantimicrobial PLGA/PEG dressings heal at rates similar to those of the clinical, thin film polyurethane wound dressing, with similar scarring. However, PLGA/PEG adds a number of features beneficial for wound healing: greater exudate absorption, integration into the wound, a 25% reduction in dressing changes, and tissue regeneration with greater vascularization. There is also modest improvement in epidermis thickness compared to the control wound dressing.

Rapid and Tunable Method To Fabricate Angle-Independent and Transferable Structurally Colored Films.

The assembly of monodisperse particles into colloidal arrays that diffract visible light through constructive interference is of considerable interest due to their resilience against color fading. In particular, noniridescent structurally colored materials are promising as a means of coloration for paints, inks, cosmetics, and displays because their color is angle independent. A rapid and tunable assembly method for producing noniridescent structurally colored colloidal-based materials that are pliable after fabrication is described. Structurally colored particle arrays were fabricated by centrifuging highly charged silica particles suspended in deionized water. By tuning the particle diameter, the colors displayed by the arrays spanned the visible spectrum while retaining angle-independent structural color. The color of centrifuged colloids of a single particle diameter was precisely controlled within 50 nm by modulating the particle concentration. The peak wavelength diffracted by the material was further tuned by altering the centrifugal rate and assembly time. Centrifugation assembly of particles in a polymer solution also produces noniridescent colloidal films, and the control of their color is reported. Together, these results offer design considerations for the centrifugation-based assembly of colloidal films with tunable structural color that are transferable after fabrication and are angle independent.

Structurally colored protease responsive nanoparticle hydrogels with degradation-directed assembly.

A tunable protease responsive nanoparticle hydrogel (PRNH) that demonstrates large non-iridescent color changes due to a degradation-directed assembly of nanoparticles is reported. Structurally colored composites are fabricated with silica particles, 4-arm poly(ethylene glycol) norbornene (4PEGN), and a proteolytically degradable peptide. When placed in a protease solution, the peptide crosslinks degrade causing electrostatic binding and adsorption of the polymer to the particle surface which leads to the assembly of particles into compact amorphous arrays with structural color. The particle surface charge and size is investigated to probe their effect on the assembly mechanism. Interestingly, only PRNHs with highly negative particle surface charge exhibit color changes after degradation. Ultra-small angle X-ray scattering revealed that the particles become coated in polymer after degradation, producing a material with less order compared to the initial state. Altering the particle diameter modulates the composites' color, and all sizes investigated (178-297 nm) undergo the degradation-directed assembly. Varying the amount of 4PEGN adjusts the swollen PRNH color and has no effect on the degradation-directed assembly. Taken together, the effects of surface charge, particle size, and polymer concentration allow for the formulation of new design rules for fabricating tunable PRNHs that display vivid changes in structural color upon degradation.

Improving the adhesion, flexibility, and hemostatic efficacy of a sprayable polymer blend surgical sealant by incorporating silica particles.

Commercially available surgical sealants for internal use either lack sufficient adhesion or produce cytotoxicity. This work describes a surgical sealant based on a polymer blend of poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) that increases wet tissue adherence by incorporation of nano-to-microscale silica particles, without significantly affecting cell viability, biodegradation rate, or local inflammation. In functional studies, PLGA/PEG/silica composite sealants produce intestinal burst pressures that are comparable to cyanoacrylate glue (160 mmHg), ∼2 times greater than the non-composite sealant (59 mmHg), and ∼3 times greater than fibrin glue (49 mmHg). The addition of silica to PLGA/PEG is compatible with a sprayable in situ deposition method called solution blow spinning and decreases coagulation time in vitro and in vivo. These improvements are biocompatible and cause minimal additional inflammation, demonstrating the potential of a simple composite design to increase adhesion to wet tissue through physical, noncovalent mechanisms and enable use in procedures requiring simultaneous occlusion and hemostasis. STATEMENT OF SIGNIFICANCE: Incorporating silica particles increases the tissue adhesion of a polymer blend surgical sealant. The particles enable interfacial physical bonding with tissue and enhance the flexibility of the bulk of the sealant, without significantly affecting cytotoxicity, inflammation, or biodegradation. These studies also demonstrate how silica particles decrease blood coagulation time. This surgical sealant improves upon conventional devices because it can be easily deposited with accuracy directly onto the surgical site as a solid polymer fiber mat. The deposition method, solution blow spinning, allows for high loading in the composite fibers, which are sprayed from a polymer blend solution containing suspended silica particles. These findings could easily be translated to other implantable or wearable devices due to the versatility of silica particles.

Spray-Processed Composites with High Conductivity and Elasticity.

Highly conductive elastic composites were constructed using multistep solution-based fabrication methods that included the deposition of a nonwoven polymer fiber mat through solution blow spinning and nanoparticle nucleation. High nanoparticle loading was achieved by introducing silver nanoparticles into the fiber spinning solution. The presence of the silver nanoparticles facilitates improved uptake of silver nanoparticle precursor in subsequent processing steps. The precursor is used to generate a second nanoparticle population, leading to high loading and conductivity. Establishing high nanoparticle loading in a microfibrous block copolymer network generated deformable composites that can sustain electrical conductivities reaching 9000 S/cm under 100% tensile strain. These conductive elastic fabrics can retain at least 70% of their initial electrical conductivity after being stretched to 100% strain and released for 500 cycles. This composite material system has the potential to be implemented in wearable electronics and robotic systems.

Enzyme Induced Stiffening of Nanoparticle-Hydrogel Composites with Structural Color.

The passive monitoring of biological environments by soft materials has a variety of nanobiotechnology applications; however, invoking distinct transitions in geometric, mechanical or optical properties remains a prevalent design challenge. We demonstrate here that close-packed nanoparticle-hydrogel composites can progress through a substantial shift in such properties by the use of a chemical-to-physical cross-link transition mediated by the catalytic activity of different proteases. Catalytic cleavage of the original hydrogel network structure initiates the self-assembled formation of a secondary, physically cross-linked network, causing a 1200% increase in storage modulus. Furthermore, this unique mechanism can be fabricated as a 3D photonic crystal with broad (∼240 nm), visible responses to the targeted enzymes. Moreover, the material provided threshold responses, requiring a certain extent of proteolytic activity before the transition occurred. This allowed for the fabrication of Boolean logic gates (OR and AND), which responded to a specific assortment of proteases. Ultimately, this mechanism enables the design of stimuli-responsive hydrogels, which can proceed through a secondary network formation, after an energetic barrier has been breached. Protease responsive hydrogel nanocomposites, described here, could offer avenues in degradation-stiffening and collapsing materials for a variety of biomaterial applications.

Simple and inexpensive quantification of ammonia in whole blood.

Quantification of ammonia in whole blood has applications in the diagnosis and management of many hepatic diseases, including cirrhosis and rare urea cycle disorders, amounting to more than 5 million patients in the United States. Current techniques for ammonia measurement suffer from limited range, poor resolution, false positives or large, complex sensor set-ups. Here we demonstrate a technique utilizing inexpensive reagents and simple methods for quantifying ammonia in 100 µL of whole blood. The sensor comprises a modified form of the indophenol reaction, which resists sources of destructive interference in blood, in conjunction with a cation-exchange membrane. The presented sensing scheme is selective against other amine containing molecules such as amino acids and has a shelf life of at least 50 days. Additionally, the resulting system has high sensitivity and allows for the accurate reliable quantification of ammonia in whole human blood samples at a minimum range of 25 to 500 µM, which is clinically for rare hyperammonemic disorders and liver disease. Furthermore, concentrations of 50 and 100 µM ammonia could be reliably discerned with p = 0.0001.

Sprayable elastic conductors based on block copolymer silver nanoparticle composites.

Block copolymer silver nanoparticle composite elastic conductors were fabricated through solution blow spinning and subsequent nanoparticle nucleation. The reported technique allows for conformal deposition onto nonplanar substrates. We additionally demonstrated the ability to tune the strain dependence of the electrical properties by adjusting nanoparticle precursor concentration or localized nanoparticle nucleation. The stretchable fiber mats were able to display electrical conductivity values as high as 2000 ± 200 S/cm with only a 12% increase in resistance after 400 cycles of 150% strain. Stretchable elastic conductors with similar and higher bulk conductivity have not achieved comparable stability of electrical properties. These unique electromechanical characteristics are primarily the result of structural changes during mechanical deformation. The versatility of this approach was demonstrated by constructing a stretchable light emitting diode circuit and a strain sensor on planar and nonplanar substrates.

Self-assembled block copolymer photonic crystal for selective fructose detection.

The use of one-dimensional photonic crystals fabricated from a self-assembled lamellar block copolymer as a sensitive and selective fructose sensor is investigated. The polystyrene-b-poly(2-vinyl pyridine) (PS-b-P2VP) films are functionalized with 2-(bromomethyl)phenylboronic acid. The boronic acid moiety confined within the lamellar morphology can reversibly bind to sugars such as fructose, imparting the photonic properties of the PS-b-P2VP film. The films exhibit a detection limit of 500 µM in water and 1mM in phosphate buffered saline. Exposure to a 50 mM solution of fructose invokes a highly visible color change from blue to orange. The films are also able to selectively recognize and respond to fructose in competitive studies in the presence of glucose, mannose and sucrose.

Color changing block copolymer films for chemical sensing of simple sugars.

We investigated the use of functionalized photonic block copolymer films for the detection of glucose. Polystyrene-b-poly(2-vinyl pyridine) (PS-b-P2VP) block copolymers were chemically functionalized with 2-(bromomethyl)phenylboronic acid and cast into films that reflect a visible color when exposed to aqueous media. The 2-(bromomethyl)phenylboronic acid functionality can reversibly bind to glucose. When exposed to high concentrations of glucose the polymer responded with a red shift in color. Low concentration exposure of glucose caused the polymer films to blue shift in color. The BCP films also exhibited a selective response to fructose, mannose or galactose, giving a different response depending on which sugar is present. The color of the polymer was tuned to blue, green, yellow or orange by varying the film's crosslink density. The color change can be visually observed without the use of equipment such as a spectrometer.