Topical Delivery of Senicapoc Nanoliposomal Formulation for Ocular Surface Treatments.

Topical ophthalmologic treatments have been facing great challenges with main limitations of low drug bioavailability, due to highly integrative defense mechanisms of the eye. This study rationally devised strategies to increase drug bioavailability by increasing ocular surface residence time of drug-loaded nanoliposomes dispersed within thermo-sensitive hydrogels (Pluronic F-127). Alternatively, we utilized sub-conjunctival injections as a depot technique to localize nanoliposomes. Senicapoc was encapsulated and sustainably released from free nanoliposomes and hydrogels formulations in vitro. Residence time increased up to 12-fold (60 min) with 24% hydrogel formulations, as compared to 5 min for free liposomes, which was observed in the eyes of Sprague-Dawley rats using fluorescence measurements. Pharmacokinetic results obtained from flushed tears, also showed that the hydrogels had greater drug retention capabilities to that of topical viscous solutions for up to 60 min. Senicapoc also remained quantifiable within sub-conjunctival tissues for up to 24 h post-injection.

Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

Migration and Phenotype Control of Human Dermal Fibroblasts by Electrospun Fibrous Substrates.

Electrospun fibrous matrices, mimicking extracellular matrix (ECM) hierarchical structures, are potential scaffolds for wound healing. To design functional scaffolds, it is important to explore the interactions between scaffold topographic features and cellular responses, especially directional migration and phenotypic changes, which are critical functional aspects during wound healing. Here, accelerated and persistent migration of human dermal fibroblasts (HDFs) is observed on fibers with aligned orientation. Furthermore, aligned fibers can induce fibroblast-to-myofibroblast differentiation of HDFs. During wound healing, the presence of myofibroblasts advances wound repair by rendering contractile force and ECM deposition within the early and middle courses, but its continuous persistence in the later event may not be desired due to the contribution in pathological scarring. To tune the balance, it is noted in this work that the introduction of matricellular protein angiopoietin-like 4 (ANGPTL4) is capable of reversing the phenotypic alteration induced by aligned fibers, in a time-dependent manner. These results indicate fibrous matrices with oriented configuration are functional in mediating directional cell migration and phenotypic change. The discoveries further suggest that tissue-engineered fibrous grafts with precise alignment modulation and ANGPTL4 releasing properties may thus be promising to promote wound repair with minimizing scar formation.

4D printing and stimuli-responsive materials in biomedical aspects.

Three-dimensional (3D) printing has revolutionized the world manufacturing production. In biomedical applications, however, 3D printed constructs fell short of expectations mainly due to their inability to adequately mimic the dynamic human tissues. To date, most of the 3D printed biomedical structures are largely static and inanimate as they lack the time-dependant dimension. To adequately address the dynamic healing and regeneration process of human tissues, 4D printing emerges as an important development where "time" is incorporated into the conventional concept of 3D printing as the fourth dimension. As such, additive manufacturing (AM) evolves from 3D to 4D printing and in the process putting stimulus-responsive materials in the limelight. In this review, the state-of-the-art efforts in integrating the time-dependent behaviour of stimulus-responsive materials in 4D printing will be discussed. In addition, current literatures on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials will be the major focus in this review. Lastly, potential usage of 4D printing in biomedical applications will also be discussed, followed by technical considerations as well as outlook for future discoveries. STATEMENT OF SIGNIFICANCE: In this Review, we have demonstrated the significance of 4D printing in biomedical applications, in which "time" has been incorporated into the conventional concept of 3D printing as the 4th dimension. As such, 4D printing differentiates and evolves from 3D printing using stimulus-responsive materials which can actively respond to external stimuli and more sophisticated "hardware"-printer which can achieve multi-printing via mathematical-predicted designs that are programmed to consider the transformation of 3D constructs over time. The emphasize will be on the interactions between various types of stimuli (categorized under physical, chemical and biological signals) with the associated stimulus-responsive materials, followed by technical considerations as well as outlook for future discoveries.

One-step solid-oil-water emulsion for sustained bioactive ranibizumab release.

BACKGROUND: The advent of therapeutic proteins highlights the need for delivery systems that protect and extend the duration of its action. Ranibizumab-VEGF is one such drug used for treating wet AMD. This paper describes a facile method to sustain bioactive ranibizumab release from PLGA-based particles. METHODS: Two emulsion techniques were explored namely: water-in-oil-in-water (WOW) and solid-in-oil-in-water (SOW) emulsion. The bioactivity of ranibizumab was evaluated by comparing its binding capability to VEGF, measured with ELISA to total protein measured by microBCA. RESULTS: During the emulsion process, contact of ranibizumab with the water-oil interface is the main destabilizing factor and this can be prevented with the use of amphiphilic PVA and solid-state protein in WOW and SOW emulsion respectively. In vitro release of the ranibizumab-loaded particles indicated that a 15-day release could be achieved with SOW particles while the WOW particles generally suffered from a burst release. Released ranibizumab was capable of inhibiting endothelial cell growth indicating its retention of bioactivity. The suppression of burst release from the SOW particles was attributed to the relatively smooth surface morphology of the SOW microparticles. CONCLUSIONS: The use of SOW encapsulation in modulating ranibizumab release while maintaining their bioactivity has been highlighted.

Sustained-release of naproxen sodium from electrospun-aligned PLLA-PCL scaffolds.

Spontaneous tendon healing may result in reduced tissue functionality. In view of this, tissue engineering (TE) emerges as a promising approach in promoting proper tendon regeneration. However, unfavourable post-surgical adhesion formations restrict adequate tendon healing through the TE approach. Naproxen sodium (NPS), a non-steroidal anti-inflammatory drug (NSAID), has been demonstrated to prevent adhesions by inhibiting the inflammatory response. Therefore, in this study, various factors, such as polymer composition, i.e. different poly-l-lactic acid (PLLA):polycaprolactone (PCL) ratios, and percentage of water:hexafluoroisopropanol (HFIP; as co-solvent) ratios, were investigated to understand how these can influence the release of NPS from electrospun scaffolds. By adjusting the amount of water as the co-solvent, NPS could be released sustainably for as long as 2 weeks. Scaffold breaking strength was also enhanced with the addition of water as the co-solvent. This NPS-loaded scaffold showed no significant cytotoxicity, and L929 murine fibroblasts cultured on the scaffolds were able to proliferate and align along the fibre orientation. These scaffolds with desirable tendon TE characteristics would be promising candidates in achieving better tendon regeneration in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Materials technology in drug eluting balloons: Current and future perspectives.

The coating material technology is important for the delivery of anti-proliferative drugs from the surface of drug-eluting balloons (DEBs), which are emerging as alternatives to drug-eluting stents (DES) in the field of interventional cardiology. Currently, several shortcomings limit their competition with DES, including low drug transfer efficiency to the arterial tissues and undesirable particulate generation from the coating matrix. In this review, we provide a survey of the materials used in existing DEBs, and discussed the mechanisms of actions of both the drugs and coating materials. The type of drug and the influence of the coating material characteristics on the drug uptake, distribution and retention in arterial tissues are described. We also summarize the novel coating excipients under development and provide our perspective on the possible use of nano-scale carriers to address the shortcomings of current coating technology. The scope of this review includes only materials that have been approved for biomedical applications or are generally recognized as safe (GRAS) for drug delivery.

Calcium phosphate coated Keratin-PCL scaffolds for potential bone tissue regeneration.

The incorporation of hydroxyapatite (HA) nanoparticles within or on the surface of electrospun polymeric scaffolds is a popular approach for bone tissue engineering. However, the fabrication of osteoconductive composite scaffolds via benign processing conditions still remains a major challenge to date. In this work, a new method was developed to achieve a uniform coating of calcium phosphate (CaP) onto electrospun keratin-polycaprolactone composites (Keratin-PCL). Keratin within PCL was crosslinked to decrease its solubility, before coating of CaP. A homogeneous coating was achieved within a short time frame (~10min) by immersing the scaffolds into Ca(2+) and (PO4)(3-) solutions separately. Results showed that the incorporation of keratin into PCL scaffolds not only provided nucleation sites for Ca(2+) adsorption and subsequent homogeneous CaP surface deposition, but also facilitated cell-matrix interactions. An improvement in the mechanical strength of the resultant composite scaffold, as compared to other conventional coating methods, was also observed. This approach of developing a biocompatible bone tissue engineering scaffold would be adopted for further in vitro osteogenic differentiation studies in the future.

Sustained Release of Hydrophilic l-ascorbic acid 2-phosphate Magnesium from Electrospun Polycaprolactone Scaffold-A Study across Blend, Coaxial, and Emulsion Electrospinning Techniques.

The purpose of this study was to achieve a sustained release of hydrophilic l-ascorbic acid 2-phosphate magnesium (ASP) from electrospun polycaprolactone (PCL) scaffolds, so as to promote the osteogenic differentiation of stem cells for bone tissue engineering (TE). ASP was loaded and electrospun together with PCL via three electrospinning techniques, i.e., coaxial, emulsion, and blend electrospinning. For blend electrospinning, binary solvent systems of dichloromethane-methanol (DCM-MeOH) and dichloromethane-dimethylformamide (DCM-DMF) were used to achieve the desired ASP release through the effect of solvent polarity and volatility. The scaffold prepared via a blend electrospinning technique with a binary solvent system of DCM-MeOH at a 7:3 ratio demonstrated a desirable, sustained ASP release profile for as long as two weeks, with minimal burst release. However, an undesirable burst release (~100%) was observed within the first 24 h for scaffolds prepared by coaxial electrospinning. Scaffolds prepared by emulsion electrospinning displayed poorer mechanical properties. Sustained releasing blend electrospun scaffold could be a good potential candidate as an ASP-eluting scaffold for bone tissue engineering.

Electrospun human keratin matrices as templates for tissue regeneration.

AIM: The aim of this work was to study the feasibility of fabricating human hair keratin matrices through electrospinning and to evaluate the potential of these matrices for tissue regeneration. MATERIALS & METHODS: Keratin was extracted from human hair using Na2S and blended with poly(ethylene oxide) in the weight ratio of 60:1 for electrospinning. Physical morphology and chemical properties of the matrices were characterized using scanning electron microscopy and Fourier transform infrared spectroscopy, respectively. Cell viability and morphology of murine and human fibroblasts cultured on the matrices were evaluated through the Live/Dead(®) assay and scanning electron microscopy. RESULTS: Electrospun keratin matrices were successfully produced without affecting the chemical conformation of keratin. Fibroblasts cultured on keratin matrices showed healthy morphology and penetration into matrices at day 7. CONCLUSION: Electrospun human hair keratin matrices provide a bioinductive and structural environment for cell growth and are thus attractive as alternative templates for tissue regeneration.

Insights into the role of focal adhesion modulation in myogenic differentiation of human mesenchymal stem cells.

We report the establishment of a novel platform to induce myogenic differentiation of human mesenchymal stem cells (hMSCs) via focal adhesion (FA) modulation, giving insights into the role of FA on stem cell differentiation. Micropatterning of collagen type I on a polyacrylamide gel with a stiffness of 10.2 kPa efficiently modulated elongated FA. This elongated FA profile preferentially recruited the ß(3) integrin cluster and induced specific myogenic differentiation at both transcription and translation levels with expression of myosin heavy chain and α-sarcomeric actin. This was initiated with elongation of FA complexes that triggered the RhoA downstream signaling toward a myogenic lineage commitment. This study also illustrates how one could partially control myogenic differentiation outcomes of similar-shaped hMSCs by modulating FA morphology and distribution. This technology increases our toolkit choice for controlled differentiation in muscle engineering.