Horst A. von Recum

Electrospinning: Applications in drug delivery and tissue engineering

Despite its long history and some preliminary work in tissue engineering nearly 30 years ago, electrospinning has not gained widespread interest as a potential polymer processing technique for applications in tissue engineering and drug delivery until the last 5-10 years. This renewed interest can be attributed to electrospinnings relative ease of use, adaptability, and the ability to fabricate fibers with diameters on the nanometer size scale. Furthermore, the electrospinning process affords the opportunity to engineer scaffolds with micro to nanoscale topography and high porosity similar to the natural extracellular matrix (ECM). The inherently high surface to volume ratio of electrospun scaffolds can enhance cell attachment, drug loading, and mass transfer properties. Various materials can be electrospun including: biodegradable, non-degradable, and natural materials. Electrospun fibers can be oriented or arranged randomly, giving control over both the bulk mechanical properties and the biological response to the scaffold. Drugs ranging from antibiotics and anticancer agents to proteins, DNA, and RNA can be incorporated into electrospun scaffolds. Suspensions containing living cells have even been electrospun successfully. The applications of electrospinning in tissue engineering and drug delivery are nearly limitless. This review summarizes the most recent and state of the art work in electrospinning and its uses in tissue engineering and drug delivery.

Degradation of polydispersed poly(l-lactic acid) to modulate lactic acid release

Polydispersed poly(L-lactic acid) (PLLA) membranes comprised of blends of monodispersed PLLA of weight average molecular weight of 82,500 and 7600 were fabricated to investigate the effect of polydispersity on degradation characteristics. The PLLA blends exhibited large spherulites of high molecular weight chains embedded in a low molecular weight matrix. During degradation in phosphate buffer at pH 7.4 and 37 degrees C for 28 d, the release rate of lactic acid increased as the percentage of the low molecular weight component in the blend was increased. For low molecular weight compositions larger than 50%, voids were created in the degrading blends due to the degradation of low molecular weight chains and the concurrent dissolution of lactic acid, and also the release of undegraded particles of high molecular weight. These studies demonstrate the feasibility of modulating lactic acid release during in vivo degradation of PLLA implants by adjusting the polymer polydispersity.

Cyclodextrin-based device coatings for affinity-based release of antibiotics

Cyclodextrin-based hydrogels were synthesized to create robust networks with tunable mechanical properties capable of serving as device coatings. The CD networks were able to swell and load drug in aqueous and organic solvents. The rheological properties of the swollen gels were investigated using stress and frequency sweeps, with both demonstrating high storage modulus, indicating strong elastic gels. The ability of the gels to swell in numerous solvents allowed for the separate loading and release of different antibiotic drug molecules with varying hydrophilicities. Based on FTIR and TGA studies, each drug was found to form an inclusion complex with CD. For comparison, dextran gels were prepared similarly. As expected for affinity-based mechanisms, the release of drugs from the CD-based gels was slower than diffusion-based release from the dextran gels, and could be sustained for more than 200 h. Coating potential was tested by coating two different medical devices: metal screws and polymer meshes. The meshes were characterized by SEM, revealing that CD-based coatings resulted in a uniform thin film, whereas the dextran gels only partly coated the device and showed delamination. Considerably longer bactericidal activity against Staphylococcus aureus was observed for both the CD hydrogels and coatings, as compared to dextran-based ones. The slow, sustained, affinity-based release of antibiotics from the CD-based networks reflects their potential as a delivery platform.

Endothelial Stem Cells and Precursors for Tissue Engineering: Cell Source, Differentiation, Selection, and Application

Endothelial cells are of great interest because of their potential in cell therapy for vascular diseases and ischemic tissue, tissue engineering for vascular grafts and vascularized tissue beds, and modeling for pharmaceutical transport across endothelial barriers. However, limited availability and proliferation capability of mature endothelial cells hampers development of these applications. Recent advances in stem cell technology have enabled researchers to derive endothelial or endothelial-like cells from stem cells or other precursor populations. The current state of these cell sources and their in vitro differentiation, selection, and applications are discussed in this review.

Affinity-Based Drug Delivery

Affinity-based drug delivery systems utilize interactions between the therapeutic drug and the delivery system to manipulate drug loading and to control drug release. In this paper, affinity-based drug delivery system syntheses, types of therapeutic factors delivered, and delivery system loading and release are discussed in detail. The paper is divided into three subsections, based on the type of delivery system: molecular imprinting systems, growth-factor delivery, and cyclodextrin-based delivery. The objective of this paper is to examine the current state of research, highlight the breakthroughs and challenges, point out potential impacts of this relatively new technology, and explore future developmental areas.

Environmental cues to guide stem cell fate decision for tissue engineering applications

The human body contains a variety of stem cells capable of both repeated self-renewal and production of specialised, differentiated progeny. Critical to the implementation of these cells in tissue engineering strategies is a thorough understanding of which external signals in the stem cell microenvironment provide cues to control their fate decision in terms of proliferation or differentiation into a desired, specific phenotype. These signals must then be incorporated into tissue regeneration approaches for regulated exposure to stem cells. The precise spatial and temporal presentation of factors directing stem cell behaviour is extremely important during embryogenesis, development and natural healing events, and it is possible that this level of control will be vital to the success of many regenerative therapies. This review covers existing tissue engineering approaches to guide the differentiation of three disparate stem cell populations: mesenchymal, neural and endothelial. These progenitor cells will be of central importance in many future connective, neural and vascular tissue regeneration technologies.

Cyclodextrin complexation for affinity-based antibiotic delivery.

Novel beta-cyclodextrin polymer (CD)-based drug delivery hydrogels were prepared by varying type and concentration of crosslinkers and optimizing the gel synthesis conditions. For comparison, dextrose gels were prepared using the same crosslinkers. The optimized gels were characterized by Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM), and X-ray diffraction (XRD) as well as swelling and release studies. For drug release studies, the gels were loaded with three different model antibiotics varying in size and hydrophobicity: rifampin (RM), novobiocin (NB), and vancomycin (VM), using a common solvent method. The loading efficiency was calculated and release kinetics were determined in vitro. As expected for affinity-based mechanisms, the release of drugs, from CD-based gels, was slower than release from dextrose gels which indicated that the antibiotics all form inclusion complexes with CD. Release kinetics were also more linear in the observed time frame when using CD-based hydrogels versus dextrose hydrogels. This modification in release depended on the affinity-between CD and drug, such that larger drugs and more hydrophilic ones had their release profiles altered less than small hydrophobic ones. In conclusion, affinity-based mechanisms can be used to load antibiotics and obtain longer, more linear release profiles than purely diffusion-based mechanisms.

The Role of Nanomaterials in Translational Medicine

There are a range of definitions for nanomaterials and a range of length scales that are considered nano, but one thing is consistent among fields: nanomaterials are small and special. Nanomaterials have the potential to have tremendous impact on medical treatments. In one example, nanomaterials are permitting the tracking of cells via magnetic resonance imaging (MRI) in clinical trials to assess the efficacy and safety of cellular therapies. In a second example, nanomaterials are acting as drug delivery vehicles for the targeted delivery of therapies to increase efficacy and to reduce side effects. However, there are distinct challenges that must be considered in the development and application of these materials, including careful analysis of the distribution and clearance of nanomaterials and their potential off-target effects. By carefully assessing materials early in their development at the bench, one may be able to move successful approaches through to the clinic more rapidly, which is indeed the goal of the field. For far too many conditions and diseases, the tools we have are less than adequate, and nanomaterials have the potential to fill that void. To realize this potential, investigators must be willing to invest time and resources to develop and to translate these technologies to the point where the risk is low enough that they have real commercial possibilities. Working collaboratively and leveraging resources and experience play important roles in moving technologies through preclinical and clinical testing. It requires incredible dedication of teams of researchers, but the result is new treatments and therapies.

Toward potential supramolecular tissue engineering scaffolds based on guanosine derivatives

We report the synthesis and study of a new guanosine-based hydrogelator, 8-methoxy-2′,3′,5′-tri-O-acetylguanosine, that can not only gel aqueous solutions at biologically relevant salt concentrations, but can also gel cell media. Studies suggest that this hydrogelator forms helical assemblies, rather than the macrocyclic quartet assemblies commonly found in guanosine hydrogels, which allow it to form hydrogels at as low as 0.5 wt% in 100mM NaCl. Furthermore, we show that this gelator is non-toxic to cells, injectable and that by simply mixing with 2′,3′,5′-tri-O-acetylguanosine, we can systematically vary the modulus and shear sensitivity of the gel over orders of magnitude.

A biodegradable thermoset polymer made by esterification of citric acid and glycerol.

A new biomaterial, a degradable thermoset polymer, was made from simple, economical, biocompatable monomers without the need for a catalyst. Glycerol and citric acid, nontoxic and renewable reagents, were crosslinked by a melt polymerization reaction at temperatures from 90 to 150°C. Consistent with a condensation reaction, water was determined to be the primary byproduct. The amount of crosslinking was controlled by the reaction conditions, including temperature, reaction time, and ratio between glycerol and citric acid. Also, the amount of crosslinking was inversely proportional to the rate of degradation. As a proof-of-principle for drug delivery applications, gentamicin, an antibiotic, was incorporated into the polymer with preliminary evaluations of antimicrobial activity. The polymers incorporating gentamicin had significantly better bacteria clearing of Staphylococcus aureus compared to non-gentamicin gels for up to 9 days.