Brian G. Amsden

Biodegradable injectable in situ forming drug delivery systems

The ability to inject a drug incorporated into a polymer to a localized site and have the polymer form a semi-solid drug depot has a number of advantages. Among these advantages is ease of application and localized, prolonged drug delivery. For these reasons a large number of in situ setting polymeric delivery systems have been developed and investigated for use in delivering a wide variety of drugs. In this article we introduce the various strategies that have been used to prepare in situ setting systems, and outline their advantages and disadvantages as localized drug delivery systems.

Camptothecin Delivery Methods

Camptothecin has shown significant antitumor activity to lung, ovarian, breast, pancreas, and stomach cancers. Camptothecin, however, like a number of other potent anticancer agents such as paclitaxel, is extremely water insoluble. Furthermore, pharmacology studies have determined that prolonged schedules of administration given continuously are required. Thus, this insolubility has restricted its clinical application. For these reasons, a number of water-soluble analogs have been synthesized and a number of different formulation approaches have been investigated. In this review, we examine each of these approaches and discuss their advantages and limitations.

Diffusion characteristics of calcium alginate gels

The diffusivity of a protein solute (bovine serum albumin) within calcium alginate gels made from sodium alginate of different guluronic acid content was determined. It was found that protein diffusion within alginate gels, prepared to be isotropic in structure, was greatest for gels prepared from sodium alginate of low guluronic acid content as opposed to those prepared from sodium alginate of high guluronic acid content. This finding was explained in terms of the difference in flexibility of the polymer backbone of the two alginates. The greater the polymer backbone flexibility, the greater the solute diffusivity within the gel.

Curable, biodegradable elastomers: emerging biomaterials for drug delivery and tissue engineering

Biodegradable elastomers have a number of potential applications in the biomedical area, especially in the emerging field of soft-tissue engineering where the mechanical properties of the polymer scaffold should match those of the tissue to be grown. An increasing number of synthesis strategies have been employed in order to prepare such elastomers. In this review, these synthesis strategies and the properties of these elastomers are outlined. The factors that influence the characteristics of these elastomers including mechanical properties, degradation rate, and mechanical property change during degradation, are discussed in terms of the design of the elastomer and their advantages and disadvantages for the biomedical applications considered.

An Obstruction-Scaling Model for Diffusion in Homogeneous Hydrogels

A mathematical description of the restricted movement a solute experiences while diffusing in a homogeneous hydrogel is presented. The model is based on the premise that physical obstruction effects dominate the diffusive process, and a scaling law expression is incorporated to describe the distance between cross-links in the polymer network. The model was compared to experimental data taken from literature sources and found to provide good agreement to the effects of both polymer volume fraction and solute size on the diffusivity of a solute within the hydrogel.

Solute diffusion in hydrogels.: An examination of the retardation effect

Abstract A new expression which describes the retardation of solutes within stiff-chained, swollen hydrogels was developed based on the idea that solute transport is determined by the probability of the solute finding an opening between the polymer chains greater than the radius of the solute molecule. The retardation factor expression derived was tested against experimentally determined diffusivities of globular proteins released from protein-loaded calcium alginate hydrogels, as well as from experimental and simulation data from the literature. The expression provided close agreement with the observed effects of polymer volume fraction, solute hydrodynamic radius, and polymer chain radius on solute diffusivity.

An examination of factors affecting the size, distribution and release characteristics of polymer microbeads made using electrostatics

A new technique of generating polymeric monolithic microbeads containing solid protein particles has been developed. The method involves extruding a suspension of protein particles within a polymer solution through a needle and into an electric field. The electric field force effectively pulls the forming droplet off the end of the needle, producing a series of smaller droplets. A factorial design investigation of the extrusion process using bovine serum albumin particles suspended in ethylene vinyl acetate dissolved in dichloromethane, illustrated that the size of the microbead was controlled primarily by the strength of the electric field and the gauge of the needle used. Smaller microbeads were formed by increasing the applied electric field and using a higher gauge (smaller internal diameter) needle. However, the reduction in microbead average diameter came at the expense of a much broader distribution of microbead diameters. Release studies using the microbeads illustrated the ability of the process to encapsulate and slowly release protein. From these studies, the critical volumetric loading of the microbeads was determined and found to be dependent on the size of the incorporated protein particles.

Composite hydrogel scaffolds incorporating decellularized adipose tissue for soft tissue engineering with adipose-derived stem cells.

An injectable tissue-engineered adipose substitute that could be used to deliver adipose-derived stem cells (ASCs), filling irregular defects and stimulating natural soft tissue regeneration, would have significant value in plastic and reconstructive surgery. With this focus, the primary aim of the current study was to characterize the response of human ASCs encapsulated within three-dimensional bioscaffolds incorporating decellularized adipose tissue (DAT) as a bioactive matrix within photo-cross-linkable methacrylated glycol chitosan (MGC) or methacrylated chondroitin sulphate (MCS) delivery vehicles. Stable MGC- and MCS-based composite scaffolds were fabricated containing up to 5 wt% cryomilled DAT through initiation with long-wavelength ultraviolet light. The encapsulation strategy allows for tuning of the 3-D microenvironment and provides an effective method of cell delivery with high seeding efficiency and uniformity, which could be adapted as a minimally-invasive in situ approach. Through in vitro cell culture studies, human ASCs were assessed over 14 days in terms of viability, glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, adipogenic gene expression and intracellular lipid accumulation. In all of the composites, the DAT functioned as a cell-supportive matrix that enhanced ASC viability, retention and adipogenesis within the gels. The choice of hydrogel also influenced the cell response, with significantly higher viability and adipogenic differentiation observed in the MCS composites containing 5 wt% DAT. In vivo analysis in a subcutaneous Wistar rat model at 1, 4 and 12 weeks showed superior implant integration and adipogenesis in the MCS-based composites, with allogenic ASCs promoting cell infiltration, angiogenesis and ultimately, fat formation.

The role of oxidation and enzymatic hydrolysis on the in vivo degradation of trimethylene carbonate based photocrosslinkable elastomers.

The in vivo degradation of trimethylene carbonate (TMC) containing elastomers was investigated, and the mechanism of degradation explored through in vitro degradation under enzymatic and oxidative conditions. The elastomers were prepared via UV initiated crosslinking of prepolymers of TMC and equimolar amounts of TMC and epsilon-caprolactone (CL). The degradation process was followed by investigating the changes in the mechanical properties, mass loss, water uptake, sol content, differential scanning calorimetry, and surface chemistry through attenuated total reflectance infrared (ATR-FTIR) spectroscopy. During in vivo degradation, TMC and TMCCL elastomers exhibited surface erosion. The tissue response was of greater intensity in the case of the TMC elastomer. Both elastomers exhibited degradation in cholesterol esterase containing solutions in vitro, but no parallels were found between the rate of in vivo degradation and the rate of in vitro degradation. Only the TMCCL elastomer degraded in lipase. Degradation in a stable superoxide anion in vitro medium was consistent with the observed in vivo degradation results, indicating a dominant role of oxidation through the secretion of this reactive oxygen species by adherent phagocytic cells in the degradation of these elastomers.

Hydrogel/electrospun fiber composites influence neural stem/progenitor cell fate

Cell replacement therapy with multi-potent neural stem/progenitor cells (NSPCs) into the injured spinal cord is limited by poor survival and host tissue integration. An injectable and biocompatible polymeric cell delivery system serves as a promising strategy to facilitate cell delivery, promote cell survival and direct cell behaviour. We developed and characterized the use of a physical hydrogel blend of hyaluronan (HA) and methylcellulose (MC) for NSPC delivery, and incorporated electrospun fibers of either collagen or poly(e-caprolactone-co-D,L-lactide) (P(CL:DLLA)) to promote cell–matrix interactions and influence cell behaviour. The shear-thinning and thermally reversible HAMC had a zero-shear viscosity of 1.2 Pa s at 25 °C, formed a weak gel at 37 °C with a yield stress of 0.5 Pa, and swelled to 115% of its original volume after one day. HAMC was both cytocompatible and allowed NSPC differentiation in vitro, similar to what one would observe in media. Interestingly, cells cultured in HAMC remained homogeneously dispersed over the 7 d culture period, unlike those cultured in media controls where significant cell aggregation was observed. Inclusion of electrospun fibers in the HAMC hydrogel further influenced cell behaviour. Composite systems of collagen fibers in HAMC resulted in reduced survival/proliferation and differentiation relative to HAMC itself whereas composites of P(CL:DLLA) fibers in HAMC maintained cell survival/proliferation and enhanced neuronal and oligodendrocytic differentiation similar to HAMC. In this study, the importance of the cell delivery vehicle to NSPC survival and cell fate was demonstrated in vitro and is being tested in on-going studies in vivo.