Biomedical subjects

J T Hinson

Publications and source records attributed to J T Hinson.

3 recordsLinked to original sources

PubMed2001

High reactivity of alkyl sulfides towards epoxides under conditions of collagen fixation--a convenient approach to 2-amino-4-butyrolactones.

Epoxy crosslinking agents have been investigated for use in the fabrication of bioprosthetic devices, such as heterograft heart valve prostheses. It has been generally assumed that epoxy crosslinking takes place via amino-epoxy reactions. The present study investigated the hypothesis that the reactions of methionine residues with epoxides also can occur in biomaterial crosslinking. A series of model reactions were studied in which a mono-epoxide was combined with individual alkyl sulfides. In the present studies epoxides rapidly alkylate aliphatic sulfides, including methionine derivatives, in buffered aqueous solutions at room temperature and pH close to neutral, forming sulfonium compounds, which are stable at pH 5-7 at temperatures up to 50 degrees C, except for cases in which methionine derivatives with non-protected carboxy groups are used. The rate of reaction remains practically unchanged within the range of pH from 5 to 12, whereas in strongly alkaline media the reverse reaction occurs. This discovery can provide a better understanding of processes occurring in the fixation of bioprosthetic tissues with polyepoxides. It can also develop into a site-specific method to label methionine residues in proteins. The carboxy group-containing sulfonium betaines derived from N-protected methionines undergo cyclization in unexpectedly mild conditions, which can be used as an efficient method for preparation of N-protected 2-amino-4-butyrolactones with sensitive protective groups.

4-Butyrolactone↗

PubMed2001

Bisphosphonate derivatized polyurethanes resist calcification.

Calcification of polyurethane cardiovascular implants is an important disease process that has the potential to compromise the long-term function of devices such as polymer heart valves and ventricular assist systems. In this study we report the successful formulation and characterization of bisphosphonate-derivatized polyurethanes, hypothesized to resist implant calcification based on the pharmacologic activity of the immobilized bisphosphonate. Fully polymerized polyurethanes (a polyurea-polyurethane and a polycarbonate polyurethane) were modified (post-polymerization) with bromoalkylation of the hard segments followed by attachment of a bisphosphonate group at the bromine site. These bisphosphonate-polyurethanes resisted calcification in rat 60 day subdermal implants compared to nonmodified control polyurethane implants, that calcify. Bisphosphonates-modified polyurethanes were also studied in circulatory implants using a pulmonary valve cusp replacement model in sheep. Polyurethane cusps modified with bisphosphonate did not calcify in 90 day implants. compared to control polyurethane cusps implants, that demonstrated nodular surface oriented calcific deposits. It is concluded that bisphosphonate modified polyurethanes resist calcification both in subdermal implants and in the circulation. This novel biomaterial approach offers great promise for long-term blood stream implantation with calcification resistance.

Animals↗

PubMed2001

Localized adenovirus gene delivery using antiviral IgG complexation.

Gene therapy with viral vectors has progressed to clinical trials. However, the localization of viral vector delivery to diseased target sites remains a challenge. We tested the hypothesis that an adenoviral vector could be successfully delivered by complexation with a specific antibody that is bound to a biodegradable matrix designed for achieving localized gene transduction. We report the first successful delivery system based upon antibody immobilization of virions in a type I collagen-avidin gel using a polyclonal biotinylated IgG specific for the adenovirus hexon. In vitro stability studies demonstrated retention of viral vector activity with antibody-complexed adenovirus collagen gel preparations, in comparison to loss of vector activity from collagen gels prepared with nonspecific biotinylated IgG. Cell culture investigations using this antibody-controlled release system for adenoviral vector transduction of rat aortic smooth muscle cells (A10) demonstrated a significantly more localized reporter expression (beta-galactosidase) compared with non-antibody-complexed controls. Herpes simplex thymidine kinase (HSVtk) adenoviral vectors were immobilized on avidin-collagen gels via this antibody-complexation approach, and ganciclovir was added to rat smooth muscle cells (A10) in culture with the gels. With complexed HSVtk adenovirus, only cells either in contact with the virus-containing gel or within 50 microm were killed. By comparison, at the same adenovirus and ganciclovir dose, non-antibody-complexed HSVtk adenoviral delivery with ganciclovir resulted in the death of virtually all cells. Myocardial gene transfer studies in pigs demonstrated significantly more efficient right ventricular adenoviral GFP expression with anti-hexon antibody-complexed matrix injections, compared with direct vector injections. Thus, our results show that matrix formulations based on antibody-complexation delivery of adenovirus resulted in site-specific localization of transgene expression that enhances the efficiency of therapeutic vector strategies and provides a potent means for localization, to avoid distal side-effects. This approach has therapeutic potential as an implantable preparation that through the means of antibody-complexation, can localize and optimize viral vector gene therapy.

Adenoviridae↗