Biomedical subjects

Brian Amsden

Publications and source records attributed to Brian Amsden.

8 recordsLinked to original sources

PubMed2006

Sustained release of bioactive therapeutic proteins from a biodegradable elastomeric device.

Effective localized delivery of a therapeutic protein requires a biodegradable device capable of delivering active protein at a sustained rate, and at a concentration within its therapeutic window. The objective of this study was to demonstrate that a biodegradable elastomeric device can be made in a cylindrical geometry, and still retain the ability to release a variety of therapeutic proteins at a nearly constant rate in nanomolar concentration with high bioactivity. The elastomers were prepared with cylindrical geometry by photo-cross-linking an acrylated star-poly(epsilon-caprolactone-co-d,l-lactide) macromer. Vascular endothelial growth factor (VEGF), interferon-gamma (IFN-gamma), and interleukin-2 (IL-2) were co-lyophilized with excipients, then entrapped within the elastomer matrix by photo-polymerization. Under identical formulation conditions, these proteins were released at the same, nearly constant rate for a significant part of the release profile (until 70%-80% release depending on formulation characteristics). Decreasing the molecular weight of the acrylated macromer increased the rate of protein release, but did not alter the zero order nature of the release kinetics. Cell based bioactivity assays showed only that 57% of the VEGF released was bioactive. By contrast, both IL-2 and IFN-gamma showed relatively high bioactivity and over 80% of the released proteins were bioactive. The elastomer formulation has potential as a regio-specific protein delivery device.

Cells, Cultured↗

PubMed2006

In vitro release of a water-soluble agent from low viscosity biodegradable, injectable oligomers.

Low-molecular-weight poly(epsilon-caprolactone-co-1,3-trimethylene carbonate) and poly(1,3-trimethylene carbonate) are potential vehicles for the regio-specific delivery of water-soluble agents. In this paper, the characteristics and the mechanism governing the in vitro release of a model water-soluble drug, vitamin B12, from these polymer vehicles were determined. The loading of vitamin B12 was kept to 1 w/w%. The oligomers examined ranged from amorphous, high viscosity to crystalline but low viscosity. The oligomers did not degrade appreciably in vitro. The total fraction of vitamin B12 released increased as the crystallinity of the oligomers decreased, reaching nearly total release only for the completely amorphous oligomers. The rate of release was fastest for the amorphous oligomers and dependent on their viscosity. Inclusion of a more osmotically active agent, trehalose, into the vitamin B12 particles through co-lyophilization resulted in enhanced total fraction released and a faster release rate. The results are consistent with an osmotically driven release mechanism.

Caproates↗

PubMed2006

Maintenance of vascular endothelial growth factor and potentially other therapeutic proteins bioactivity during a photo-initiated free radical cross-linking reaction forming biodegradable elastomers.

Previously, we prepared a biodegradable elastomeric device that can release different therapeutic proteins at a nearly constant rate in nanomolar concentrations with high bioactivity. The elastomer device was fabricated using a photo-initiated free radical cross-linking reaction of acrylated star(epsilon-caprolactone-co-D,L-lactide) in organic solvent in the presence of solid protein particles. The objective of this study was to examine the effect of various parameters used for fabricating the photo-cross-linked elastomeric device on the stability of a therapeutic protein, vascular endothelial growth factor (VEGF), to determine which factor plays the dominant role in protecting VEGF. VEGF was lyophilized with or without bovine serum albumin (BSA) and then suspended in solid state in a macromer (acrylated star-poly(epsilon-caprolactone-co-D,L-lactide)) solution containing different concentrations of a free radical initiator, 2,2-dimethoxy-2-phenylacetophenone (DMPA). The protein suspension was then UV-irradiated at different intensities. UV irradiation with the generation of free radicals was detrimental to VEGF stability. BSA preserved the VEGF bioactivity during UV irradiation but provided little protection in the presence of the photo-initiator DMPA. The acrylated macromer acted as a free radical scavenger and effectively preserved VEGF and BSA stability during UV-initiated photo-polymerization. The detrimental effect of UV radiation with free radical generation on VEGF stability during device manufacture can be eliminated by choosing the proper bulking agents coupled with an efficient photo-polymerization reaction.

1-Octanol↗

PubMed2006

Osmotic-driven release kinetics of bioactive therapeutic proteins from a biodegradable elastomer are linear, constant, similar, and adjustable.

PURPOSE: The aim of the study is to determine whether a biodegradable elastomeric device that uses an osmotic pressure delivery mechanism can release different therapeutic proteins at a nearly constant rate in nanomolar concentrations with high bioactivity, given the same formulation conditions. Vascular endothelial growth factor (VEGF) and interleukin-2 (IL-2) were embedded in the device as sample therapeutic proteins, and their release and bioactivity were compared to that achieved previously with interferon-gamma (IFN-gamma). METHODS: A photo-cross-linkable biodegradable macromer consisting of acrylated star(epsilon-caprolactone-co-D,L-lactide) was prepared. VEGF, IL-2, and IFN-gamma were co-lyophilized with serum albumin and trehalose at different ratios and were then embedded into the elastomer by photo-cross-linking the lyophilized particles in a macromer solution. The protein mass and the bioactivity in the release supernatant were measured by enzyme-linked immunosorbent and cell-based assays. RESULTS: VEGF, IL-2, and IFN-gamma were released at the same, nearly constant rate of 25.4 ng/day for over 18 days. Using the optimum elastomer formulation, the release profiles of the proteins were essentially identical, and their rates were linear and constant. Cell-based bioactivity assays showed that 70 and 88% of the released VEGF and IL-2, respectively, were bioactive. The rate of protein release can be adjusted by changing the trehalose loading concentration in the elastomer matrix without altering the linear nature of the protein release kinetics. The elastomeric device degraded in PBS buffer within 85 days. CONCLUSIONS: The elastomer formulation shows promising potential as a sustained protein drug delivery vehicle for local delivery applications.

Cells, Cultured↗

PubMed2006

Initiator structure influence on thermal and rheological properties of oligo(epsilon-caprolactone).

Biodegradable thermoplastic oligomers have potential as biomaterials for tissue augmentation and drug-delivery applications. One means of obtaining such a biomaterial is through the ring-opening polymerization of epsilon-caprolactone using an alcohol initiator. In this paper we continue to examine the influence of the structure of the initiator used on the thermal and rheological properties of oligo(epsilon-caprolactone). Specifically, primary and secondary pentanol, and cis- and trans-pentenol were studied as initiators in the preparation of oligomers of constant molecular weight. In agreement with previous work, the secondary conformer yielded higher melt viscosities, lower degrees of crystallinity and lower glass transition temperatures. The cis conformer produced the lowest melt viscosity; however, the activation energy for flow was higher than obtained previously with oleyl alcohol. This result was attributed to the alkane chain lengths on either side of the cis double bond in the initiator. The order of melt viscosity increased with initiator conformer as follows: cis, trans, primary and secondary. The results were explained in terms of oligomer chain flexibility in the melt.

Biocompatible Materials↗

PubMed2004

Sustained delivery of vascular endothelial growth factor with alginate beads.

Therapeutic angiogenesis is the growth of blood vessels from a pre-existing vasculature for clinical applications such as treating myocardial and limb ischemia. Vascular endothelial growth factor (VEGF) is a potent signal transduction molecule that acts specifically on vascular endothelial cells. Encapsulation of VEGF in a polymer matrix not only protects protein against enzymatic degradation in the body, but also allows proteins to be released at a controllable rate into a localized area. In this study, VEGF was encapsulated in calcium alginate beads by the extrusion/external gelation method, and was subsequently released in PBS and in serum media. The objective was to optimize VEGF encapsulation yield and obtain VEGF release at a constant rate from alginate matrices in vitro. The incorporation of low concentrations of VEGF and NaCl can increase encapsulation yield to 97%. The rate of VEGF release from alginate beads was higher in serum than in PBS, which was due to the capacity of the serum in reducing the electrostatic interaction between alginate and VEGF. The presence of CaCl(2) in the release supernatant can shield the alginate interaction with VEGF, and a constant release rate of 6 ng/ml/day may be sustained for 14 days. These results suggest that the alginate-VEGF delivery system may be useful in the development of vascular tissue engineering and wound healing applications.

Alginates↗

PubMed2003

A model for osmotic pressure driven release from cylindrical rubbery polymer matrices.

Osmotic pressure-driven drug release from rubbery polymer matrices in a cylindrical geometry has been shown to produce a period of nearly constant release. In order to explain this behavior and in an effort to produce a tool for device design, a mathematical model of the release was developed. The model was tested by application to literature data of the release of NaI from poly(dimethylsiloxane) cylinders and found to provide good agreement with the data. The model demonstrates that, although there is a decrease in solute concentration as one moves from the exterior to the center of the cylinder, a period of nearly constant release is produced, lasting until about 60% of the initial drug load has been released.

Models, Theoretical↗

PubMedDate not supplied

Tailoring the swelling pressure of degrading dextran hydroxyethyl methacrylate hydrogels.

Swelling pressure measurements were performed on degrading dextran hydroxyethyl methacrylate (dex-HEMA) hydrogels. In these networks, the cross-links are hydrolyzable carbonate ester bonds formed between methacrylate groups and dextran molecules. It is demonstrated that dex-HEMA gels made in the presence of a known amount of free dextran chains exhibit osmotic properties similar to those of partially degraded dex-HEMA gels. The swelling pressure, Pi(sw), of degrading dex-HEMA gels is controlled primarily by the cross-linked dex-HEMA polymer and the free dextran molecules, while the contribution of short poly-HEMA fragments (produced in the degradation process) is negligible. It is found that Pi(sw) only slightly changes during the first 15 days of degradation. Close to the end of the degradation process, however, a much faster increase in Pi(sw) is observed. The swelling pressure profile of these gels strongly depends on the concentration of the cross-linked dex-HEMA and its chemical composition (amount of HEMA groups per 100 glucose units).

Biodegradation, Environmental↗