Faculty Bibliography

4-Vinyl pyridine was grafted to the surface of the cellulosic membrane Cuprophan, and subsequently alkylated with both C10 and C16 aliphatic chains. Complement activation of heparinized human blood, corrected for anaphylatoxin adhesion, was measured by radioimmunoassay. The surface treatments both yielded substantial reductions in C5a activity, with a lessor reduction in C3a and C4a activity. Alkylation with 10 and 16 carbon chains resulted both in enhancements of albumin adsorption and stability. These enhancements as well as the reductions in complement activation were statistically indistinguishable between the two treatments. The reduction in complement activation was influenced more by adsorption of endogenous albumin and possibly by the vinyl pyridine graft, than the removal of surface active hydroxyl groups from Cuprophan.

Tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and streptokinase were evaluated for their ability to reduce postsurgical adhesion formation in a rat uterine horn devascularization and serosal injury model in a blinded, randomized study. Small doses of tPA, uPA, or streptokinase were delivered over approximately a 4-day period either from a biodegradable hydrogel matrix or as four daily intraperitoneal injections. The hydrogel was formed upon the uterine horns by photopolymerization of an aqueous precursor solution containing dissolved drug. A control group that received no treatment had an average extent of adhesion formation of 72 +/- 15% (mean +/- SEM, percentage of the length of the uterine horns involved in adhesions). Application of this formulation of the hydrogel alone reduced the extent of adhesion formation to 22 +/- 10% by functioning as a mechanical barrier. When tPA was released from the hydrogel, adhesion formation was reduced to 4 +/- 3%, while when tPA was given by intraperitoneal injection, adhesion formation was only reduced to 49 +/- 8%. Local delivery of urokinase reduced adhesion formation to 6 +/- 6%, but intraperitoneal injection of urokinase did not reduce adhesion formation. Streptokinase did not reduce adhesion formation when administered by intraperitoneal injection and increased adhesion formation to 45 +/- 9% when locally released relative to the hydrogel alone. These results suggest that both tPA and uPA may be used to prevent adhesion formation when delivered locally.

A covalently and a physicochemically cross-linked hydrogel, both based primarily on polyethylene glycol and both formed in situ, were compared side by side in a rat uterine horn devascularization and serosal injury model for efficacy in adhesion prevention. The primary difference between the two materials was the nature of their cross-linking. The covalently cross-linked hydrogel was a photopolymerized polyethylene glycol-co-lactic acid diacrylate, and the physically cross-linked hydrogel was a polyethylene glycol-co-polypropylene glycol, Poloxamer 407. In the surgical model employed, application of the covalently cross-linked hydrogel reduced the extent of adhesion formation from 75 +/- 10% in the control group to 16 +/- 6% (mean +/- s.d., P < 0.001). Application of the physically cross-linked hydrogel reduced adhesion formation to 38 +/- 19% (P < 0.01). Retention of the two hydrogels upon the site of application was also evaluated. The covalently cross-linked hydrogel formed a continuous barrier upon the uterine horns for more than 4 d, while the physicochemically cross-linked hydrogel was present upon the uterine horns for less than 2 d. This difference in retention was probably the cause of the difference in efficacy and may be attributed to the nature of the cross-linking.

The time between intravenous injection of a glucose bolus and the time the glucose concentration peaked in the subcutaneous tissue was measured in pentobarbital-anesthetized rats with implanted 290-microns-diameter amperometric sensors. Boluses of 100, 200, and 400 mg/kg body wt were injected. The glucose concentration in the jugular vein was monitored by frequent withdrawal and analysis of samples. The glucose concentration in the subcutaneous tissue was continuously monitored with the sensors. The times required for the subcutaneously implanted sensor to reach its maximum current, corrected for sensor response times, were 7.5 +/- 3.9, 9.8 +/- 5.5, and 10.0 +/- 4.4 min for the smallest to the largest dose, respectively. The shorter delay in response to the smallest dose was statistically significant (P < 0.03). The results were consistent with dilution of the bolus in the cardiovascular system and transport of glucose by both diffusion and facilitated transport via a saturable mediator. An understanding of the differences in the dynamics of venous vs. subcutaneous response to a glucose dose is important in developing algorithms for the control of blood glucose based on a subcutaneous measurement.

Biomaterials play a pivotal role in field of tissue engineering. Biomimetic synthetic polymers have been created to elicit specific cellular functions and to direct cell-cell interactions both in implants that are initially cell-free, which may serve as matrices to conduct tissue regeneration, and in implants to support cell transplantation. Biomimetic approaches have been based on polymers endowed with bioadhesive receptor-binding peptides and mono- and oligosaccharides. These materials have been patterned in two- and three-dimensions to generate model multicellular tissue architectures, and this approach may be useful in future efforts to generate complex organizations of multiple cell types. Natural polymers have also played an important role in these efforts, and recombinant polymers that combine the beneficial aspects of natural polymers with many of the desirable features of synthetic polymers have been designed and produced. Biomaterials have been employed to conduct and accelerate otherwise naturally occurring phenomena, such as tissue regeneration in wound healing in the otherwise healthy subject; to induce cellular responses that might not be normally present, such as healing in a diseased subject or the generation of a new vascular bed to receive a subsequent cell transplant; and to block natural phenomena, such as the immune rejection of cell transplants from other species or the transmission of growth factor signals that stimulate scar formation. This review introduces the biomaterials and describes their application in the engineering of new tissues and the manipulation of tissue responses.

A new nonbiologic photopolymerizable glue, polyethyleneglycol 400 diacrylate, was studied with respect to its mechanical and biochemical interaction with human blood vessels. Using the human placental artery model, we tested the ability of polyethyleneglycol 400 diacrylate to prevent leakage of blood at the site of vascular anastomoses, which are made porous by the presence of tissue gaps and suture puncture sites. Fibrin glue is known to augment local vessel thrombogenicity through the presence of the coagulation enzyme thrombin. We tested the effect of externally applied polyethyleneglycol 400 diacrylate (which does not contain thrombin) on luminal thrombin activity and platelet deposition from flowing human blood. At a shear rate of 312 per second and a transmural pressure of 80 cm H2O, the leakage rate of saline from human placental artery anastomoses was 1.0 +/- 1.2 ml/min (n = 8). When the same anastomoses were then glued, 7 of 8 of the anastomoses leaked less than 0.05 ml/min (p < 0.05). Platelet deposition to human vessels was not influenced by the external application of polyethyleneglycol 400 diacrylate either on intact vessels (no polyethyleneglycol 400 diacrylate, 0.51 +/- 0.28 x 10(6) platelets/cm2; with polyethyleneglycol 400 diacrylate, 0.47 +/- 0.26 x 10(6) platelets/cm2; n = 7) or at anastomoses (no polyethyleneglycol 400 diacrylate, 0.69 +/- 0.36 x 10(6) platelets/cm2; with polyethyleneglycol 400 diacrylate, 0.53 +/- 0.33 x 10(6) platelets/cm2; n = 8), p > 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)