[show abstract][hide abstract] ABSTRACT: The use of tissue adhesives for internal clinical applications is limited due to a lack of materials that balance strong adhesion with biocompatibility. The use of substrate topography is explored to reduce the volume of a highly reactive and toxic glue without compromising adhesive strength. Micro-textured patches coated with a thin layer of cyanoacrylate glue achieve similar adhesion levels to patches employing large amounts of adhesive, and is superior to the level of adhesion achieved when a thin coating is applied to a non-textured patch. In vivo studies demonstrate reduced tissue inflammation and necrosis for patterned patches with a thinly coated layer of reactive glue, thus overcoming a significant challenge with existing tissue adhesives such as cyanoacrylate. Closure of surgical stomach and colon defects in a rat model is achieved without abdominal adhesions. Harnessing the synergy between surface topography and reactive chemistry enables controlled tissue adhesion with an improved biocompatibility profile without requiring changes in the chemical composition of reactive tissue glues.
[show abstract][hide abstract] ABSTRACT: Prodrug-based self-assembled hydrogels represent a new class of active biomaterials that can be harnessed for medical applications, in particular the design of stimuli responsive drug delivery devices. In this approach, a promoiety is chemically conjugated to a known-drug to generate an amphiphilic prodrug that is capable of forming self-assembled hydrogels. Prodrug-based self-assembled hydrogels are advantageous as they alter the solubility of the drug, enhance drug loading, and eliminate the use of harmful excipients. In addition, self-assembled prodrug hydrogels can be designed to undergo controlled drug release or tailored degradation in response to biological cues. Herein we review the development of prodrug-based self-assembled hydrogels as an emerging class of biomaterials that overcome several common limitations encountered in conventional drug delivery.
Current opinion in biotechnology 03/2013; · 7.82 Impact Factor
[show abstract][hide abstract] ABSTRACT: This tutorial review could serve as an introduction of cardanol into the world of soft nanomaterials; it is a biobased lipid-mixture obtained from the plant Anacardium occidentale L. Cardanol is a renewable raw material derived from a byproduct of cashew nut processing industry: Cashew Nut Shell Liquid (CNSL). Cardanol is a rich mixture of non-isoprenoic phenolic compounds that is a valuable raw material for generating a variety of soft nanomaterials such as nanotubes, nanofibers, gels and surfactants. These nanostructures may then serve as templates for the synthesis of additional nanomaterials. The wealth and diversity of cardanol-derived functional nanomaterials has urged us to present an article that will give readers a taste of a new class of cardanol-derived functional amphiphiles, along with their ability to generate hierarchical functional nanomaterials through non-covalent soft-chemical routes. In this concise review, we discuss selected examples of novel biobased surfactants, glycolipids, and polymers derived from cardanol, and their subsequent self-assembly into functional soft materials.
Chemical Society Reviews 11/2012; · 24.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Monitoring the location, distribution and long-term engraftment of administered cells is critical for demonstrating the success of a cell therapy. Among available imaging-based cell tracking tools, magnetic resonance imaging (MRI) is advantageous due to its noninvasiveness, deep penetration, and high spatial resolution. While tracking cells in preclinical models via internalized MRI contrast agents (iron oxide nanoparticles, IO-NPs) is a widely used method, IO-NPs suffer from low iron content per particle, low uptake in nonphagocytotic cell types (e.g., mesenchymal stem cells, MSCs), weak negative contrast, and decreased MRI signal due to cell proliferation and cellular exocytosis. Herein, we demonstrate that internalization of IO-NP (10 nm) loaded biodegradable poly(lactide-co-glycolide) microparticles (IO/PLGA-MPs, 0.4-3 μm) in MSCs enhances MR parameters such as the r(2) relaxivity (5-fold), residence time inside the cells (3-fold) and R(2) signal (2-fold) compared to IO-NPs alone. Intriguingly, in vitro and in vivo experiments demonstrate that internalization of IO/PLGA-MPs in MSCs does not compromise inherent cell properties such as viability, proliferation, migration and their ability to home to sites of inflammation.
[show abstract][hide abstract] ABSTRACT: One of the greatest challenges in cell therapy is to minimally invasively deliver a large quantity of viable cells to a tissue of interest with high engraftment efficiency. Low and inefficient homing of systemically delivered mesenchymal stem cells (MSCs), for example, is thought to be a major limitation of existing MSC-based therapeutic approaches, caused predominantly by inadequate expression of cell surface adhesion receptors. Using a platform approach that preserves the MSC phenotype and does not require genetic manipulation, we modified the surface of MSCs with a nanometer-scale polymer construct containing sialyl Lewis(x) (sLe(x)) that is found on the surface of leukocytes and mediates cell rolling within inflamed tissue. The sLe(x) engineered MSCs exhibited a robust rolling response on inflamed endothelium in vivo and homed to inflamed tissue with higher efficiency compared with native MSCs. The modular approach described herein offers a simple method to potentially target any cell type to specific tissues via the circulation.
[show abstract][hide abstract] ABSTRACT: Approximately 10% of the population in the USA suffer from nickel allergy, and many are unable to wear jewellery or handle coins and other objects that contain nickel. Many agents have been developed to reduce the penetration of nickel through skin, but few formulations are safe and effective. Here, we show that applying a thin layer of glycerine emollient containing nanoparticles of either calcium carbonate or calcium phosphate on an isolated piece of pig skin (in vitro) and on the skin of mice (in vivo) prevents the penetration of nickel ions into the skin. The nanoparticles capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Approximately 11-fold fewer nanoparticles by mass are required to achieve the same efficacy as the chelating agent ethylenediamine tetraacetic acid. Using nanoparticles with diameters smaller than 500 nm in topical creams may be an effective way to limit the exposure to metal ions that can cause skin irritation.
[show abstract][hide abstract] ABSTRACT: Local delivery of drugs offers the potential for high local drug concentration while minimizing systemic toxicity, which is often observed with oral dosing. However, local depots are typically administered less frequently and include an initial burst followed by a continuous release. To maximize efficiency of therapy, it is critical to ensure that drug is only released when needed. One of the hallmarks of rheumatoid arthritis, for example, is its variable disease activity consisting of exacerbations of inflammation punctuated by periods of remission. This presents significant challenges for matching localized drug delivery with disease activity. An optimal system would be nontoxic and only release drugs during the period of exacerbation, self-titrating in response to the level of inflammation. We report the development of an injectable self-assembled nanofibrous hydrogel, from a generally recognized as safe material, which is capable of encapsulation and release of agents in response to specific enzymes that are significantly upregulated in a diseased state including matrix metalloproteinases (MMP-2 and MMP-9) and esterases. We show that these self-assembled nanofibrous gels can withstand shear forces that may be experienced in dynamic environments such as joints, can remain stable following injection into healthy joints of mice, and can disassemble in vitro to release encapsulated agents in response to synovial fluid from arthritic patients. This novel approach represents a next-generation therapeutic strategy for localized treatment of proteolytic diseases.
Journal of Biomedical Materials Research Part A 03/2011; 97(2):103-10. · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: An implantable MR contrast agent that can be covalently immobilized on tissue during surgery has been developed. The rationale is that a durable increase in tissue contrast using an implantable contrast agent can enhance postsurgical tissue differentiation using MRI. For small-vessel (e.g., vein graft) MRI, the direct benefit of such permanent "labeling" of the vessel wall by modification of its relaxation properties is to achieve more efficient imaging. This efficiency can be realized as either increased contrast leading to more accurate delineation of vessel wall and lesion tissue boundaries, or, faster imaging without penalizing contrast-to-noise ratio, or a combination thereof. We demonstrate, for the first time, stable long-term MRI enhancement using such an exogenous contrast mechanism based on immobilizing a modified diethylenetriaminepentaacetic acid gadolinium(3+) dihydrogen complex on a human vein using a covalent amide bond. Signal enhancement due to the covalently immobilized contrast agent is demonstrated for excised human vein specimens imaged at 3 T, and its long-term stability is demonstrated during a 4-month incubation period.
Magnetic Resonance in Medicine 01/2011; 65(1):176-83. · 3.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: Emerging data supports a role for negative wall remodeling in the failure of vascular interventions such as vein grafts, yet clinicians/researchers currently lack the ability to temporally/efficiently investigate adventitial surface topography/total vascular wall anatomy in vivo. We established a strategy of immobilizing commercially available iron oxide magnetic nanoparticles (Fe-NPs) onto the surface of human vein conduits to facilitate high-throughput total vascular wall demarcation with magnetic resonance (MR). Binding of activated Fe-NPs to amine groups on the surface of the veins induced a thin layer of negative contrast that differentiated the adventitia from surrounding saline signal in all MR images, enabling delineation of total wall anatomy; this was not possible in simultaneously imaged unlabeled control veins. Under the conditions of this ex vivo experiment, stable covalent binding of Fe-NPs can be achieved (dose-dependent) on human vein surface for MR detection, suggesting a potential strategy for enhancing the ability of MRI to investigate total wall adaptation and remodeling in vein graft failure.
[show abstract][hide abstract] ABSTRACT: Molecular gels, the macroscopic products of a nanoscale bottom-up strategy, have emerged as a promising functional soft material. The prospects of tailoring the architecture of gelator molecules have led to the formation of unique, highly tunable gels for a wide spectrum of applications from medicine to electronics. Biorefinery is a concept that integrates the processes of converting biomass/renewable feedstock and the associated infrastructure used to produce chemicals and materials, which is analogous to petroleum-based refinery. The current review assimilates the successful efforts to demonstrate the prospects of the biorefinery concept for developing new amphiphiles as molecular gelators. Amphiphiles based on naturally available raw materials such as amygdalin, vitamin C, cardanol, arjunolic acid, and trehalose that possess specific functionality were synthesized using biocatalysis and/or chemical synthesis. The hydrogels and organogels obtained from such amphiphiles were conceptually demonstrated for diverse applications including drug-delivery systems and the templated synthesis of hybrid materials.
[show abstract][hide abstract] ABSTRACT: Cell therapy has the potential to impact the quality of life of suffering patients. Systemic infusion is a convenient method of cell delivery; however, the efficiency of engraftment presents a major challenge. It has been shown that modification of the cell surface with adhesion ligands is a viable approach to improve cell homing, yet current methods including genetic modification suffer potential safety concerns, are practically complex and are unable to accommodate a wide variety of homing ligands or are not amendable to multiple cell types. We report herein a facile and generic approach to transiently engineer the cell surface using lipid vesicles to present biomolecular ligands that promote cell rolling, one of the first steps in the homing process. Specifically, we demonstrated that lipid vesicles rapidly fuse with the cell membrane to introduce biotin moieties on the cell surface that can subsequently conjugate streptavidin and potentially any biotinylated homing ligand. Given that cell rolling is a pre-requisite to firm adhesion for systemic cell homing, we examined the potential of immobilizing sialyl Lewis X (SLeX) on mesenchymal stem cells (MSCs) to induce cell rolling on a P-selectin surface, under dynamic flow conditions. MSCs modified with SLeX exhibit significantly improved rolling interactions with a velocity of 8 microm/s as compared to 61 microm/s for unmodified MSCs at a shear stress of 0.5 dyn/cm(2). The cell surface modification does not impact the phenotype of the MSCs including their viability and multi-lineage differentiation potential. These results show that the transitory modification of cell surfaces with lipid vesicles can be used to efficiently immobilize adhesion ligands and potentially target systemically administered cells to the site of inflammation.
[show abstract][hide abstract] ABSTRACT: We report multi-armed/dendritic molecules having unsaturated side chains for generating scratch-free, self-standing cross-linked transparent films with embedded metal nanoparticles via autoxidation induced in situ synthesis.
Chemical Communications 10/2009; · 6.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: There has been significant interest in the clinical use of adult mesenchymal stem cells (MSCs), which are connective tissue progenitor cells. One of the greatest challenges in traditional stem cell therapy is to deliver a large quantity of viable stem cells with high engraftment efficiency. MSCs home at a low efficiency due to the lack of relevant adhesion molecules on their surface. We have engineered the surface of the MSCs with the sialyl Lewis<sup>x</sup> (SLeX) moiety, found on the surfaces of leukocytes representing the active site of the P-selectin glycoprotein ligand (PSGL-1) for inducing rolling response as the first step in the homing process which involves reversible, adhesive interactions between glycoprotein receptors on specific circulating cells and ligands expressed on the surface of the vascular endothelium. MSCs were covalently modified SLeX through biotin-streptavidin linkage and the rolling response of the modified MSCs were examined on P-selectin surface. Modified MSCs exhibited velocities of 2 mum/sec whereas the unmodified MSCs exhibited velocities of 65 mum/sec at a wall shear stress of 0.366 dynes/cm<sup>2</sup> on P-selectin surface in a parallel plate flow chamber assay. Most importantly, the MSCs' native phenotype including its ability to proliferate and differentiate into multi-lineages was retained after the modification. This platform strategy demonstrates the potential to target MSCs to specific tissues within the body by conjugation of specific targeting ligands.
[show abstract][hide abstract] ABSTRACT: Utilization of enzyme catalysis as a tool to disassemble self-assembled hydrogels to control the release encapsulated drug provides an opportunity to design a wide range of enzyme-specific low-molecular-weight hydrogelators (LMWGs). Herein, we report a novel approach for controlled delivery of multiple drugs by an enzyme triggered hydrogel degradation mechanism. In this proof-of-concept work, we report the synthesis of LMWGs (amphiphiles) from well-known drug acetaminophen (which is known as Tylenolreg), and their ability to self-assemble into nanoscale structures in aqueous solutions to form hydrogels that subsequently encapsulate a second drug such as curcumin which is a known chemopreventive hydrophobic drug. Upon enzyme triggered degradation, hydrogels showed single and double drug delivery at physiological conditions in vitro. After treating with prodrug amphiphiles, mesenchymal stem cells (MSCs) retain their stem cell properties such as maintaining their adhesive and proliferation capacities with high viability. This new platform approach will have prospective effect on hydrogel based drug delivery research through developing drug delivery vehicles from a wide range of prodrug-based gelators.
[show abstract][hide abstract] ABSTRACT: Covalently conjugated sialyl Lewis X (SLeX) on the mesenchymal stem cell (MSC) surface through a biotin-streptavidin bridge imparts leukocyte-like rolling characteristics without altering the cell phenotype and the multilineage differentiation potential. We demonstrate that the conjugation of SLeX on the MSC surface is stable, versatile, and induces a robust rolling response on P-selectin coated substrates. These results indicate the potential to increase the targeting efficiency of any cell type to specific tissue.
[show abstract][hide abstract] ABSTRACT: Enzyme catalysis as a tool to disassemble supramolecular hydrogels to control the release of encapsulated drugs provides an opportunity to design a wide range of enzyme-specific low-molecular-weight hydrogelators. In this proof-of-concept work, we report the synthesis of low-molecular-weight amphiphilic prodrugs as hydrogelators from a well-known drug acetaminophen (which belongs to a class of drugs called analgesics (pain relievers) and antipyretics (fever reducers)). We have shown the ability of prodrugs to self-assemble to form hydrogels that could subsequently encapsulate a second drug such as curcumin, which is a known chemopreventive and anti-inflammatory hydrophobic drug. Upon enzyme-triggered degradation, the hydrogel released single or multiple drugs at physiologically simulated conditions in vitro. Given that the degradation products consist of the drug and a fatty acid, this approach has an advantage over polymer-based prodrugs that generate polymer fragments with heterogeneous chain lengths upon degradation that may present complex toxicity profiles. Additionally, drug-release occurred without burst release. Spectrophotometric experiments supported the drug-release, and the rate was controlled by modulation of temperature and enzyme concentration. Mesenchymal stem cells treated with prodrugs retained their stem cell properties including the capacity of multi-lineage differentiation, and maintained their adhesive and proliferation capacities with high viability. The present biomaterials could have broad applications as drug-delivery vehicles and cell invasive matrices.
[show abstract][hide abstract] ABSTRACT: Design and synthesis of organic-inorganic hybrid materials from biobased monomers/polymers have a tremendous impact on industry and the environment. Our earlier successful demonstration of in situ synthesis of metal nanoparticles using various forms of self-assembled organic soft materials such as molecular gels and liquid crystals proved to be an efficient approach in preparing hybrid materials. The present study shows the successful extension of previous strategies to generate metal nanoparticles (MNPs) in polymeric systems, another form of soft matter. We have synthesized a biobased polymer, poly(cardanyl acrylate) (PCA) from cardanol. Autoxidation (cross-linking) of PCA produced various free-radicals which were used as a tool to reduce metal salts to prepare and stabilize the gold and silver nanoparticles in situ. This sustainable approach enabled us to avoid external hazardous reducing and stabilizing agents.
Journal of Biobased Materials and Bioenergy 08/2008; 2(3):218-222. · 0.83 Impact Factor