Controlled delivery of therapeutics from microporous membranes. I. Fabrication and characterization of microporous polyurethane membranes containing polymeric microspheres.

This paper describes a process for the inclusion of polymer microspheres in microporous polyurethane tubes and membranes. These composites were fabricated via a spray, phase-inversion technique using Cardiothane 51, a medical grade polyurethane, and either spray-dried poly(D,L-lactide-co-glycolide 50:50) microspheres or commercially available fluorescent polystyrene-latex microspheres. Characterization of the polyurethane membranes was performed using Fouriertransform infrared spectroscopy, differential scanning calorimetry, dynamic mechanical analysis, hydraulic permeability testing, scanning electron microscopy, and visible and fluorescence light microscopy. The results indicated the feasibility of layering microspheres throughout the microporous membrane or wall of the microporous tube, and the potential of such composite structures for local delivery of bioactive substances.

Penetrating micropores increase patency and achieve extensive endothelialization in small diameter polymer skin coated vascular grafts.

This article points to the importance of penetrating micropores through the graft wall to minimize thrombosis and to enhance endothelialization in small diameter polymer skin coated vascular grafts. Four types of spongy polyurethane-polydimethylsiloxane vascular grafts (PUG) fabricated by a spray, phase-inversion technique, 1.5 mm inner diameter, 1.5-1.9 cm in length, were implanted end-to-end in the infrarenal aorta of 26 adult rats. Some had a continuous inner skin and a hydraulic permeability (HP) of 0 ml/min/cm2/ 120 mmHg (PUG-S-O). Some had an inner skin with varying amounts of isolated penetrating micropores and a mean hydraulic permeability of 11 (PUG-S-11), 37 (PUG-S-37), or 58 ml/min/cm2/120 mmHg (PUG-S-58). Twelve PUG-S-O, 6 PUG-S-11, 4 PUG-S-11, and 4 PUG-S-58 were evaluated between 2 hr and 3 months after implantation. All PUG-S-O occluded soon after implantation. The PUG that had a HP of more than 11 ml/min/cm2 showed acceptable patency. However, endothelialization was limited to anastomoses in patent PUG-S-11. In contrast, the patent PUG-S-37 and PUG-S-58 were largely endothelialized. In all patent grafts at 3 months, numerous host cells had migrated, and newly formed capillaries were seen in the voids of the graft wall, which appeared moderately to highly cellular. In conclusion, it appears that penetrating micropores through the graft wall increase patency and that a highly porous structure is needed to achieve extensive endothelialization in small diameter polymer skin coated vascular grafts.

Gas transport in the intracorporeal oxygenator with woven tubes.

The woven tubes membrane oxygenator is a suitable configuration for the intracorporeal membrane oxygenator because of a high gas exchange performance and a compact packing of tubing. In this study the oxygen transfer performance of woven tubes was evaluated by an in vitro experiment with an external perfusion mode; the blood flow is outside of the tubes in order to reveal the feasibility of designing the intravascular oxygenator (IVOX) by the woven tubes. The oxygen transfer efficiency of the external perfusion mode is superior to that with the internal perfusion mode because of the larger convective mixing effect on the external surface of the tubes. Thus the use of the external perfusion mode results in the shorter necessary tube length for the rated condition, which enables making the oxygenator unit more compact. All of these features encourage the adoption of the woven tubes for use in the intravascular oxygenator.

Cardiopulmonary bypass: a historical perspective.

Cardiopulmonary bypass in the clinical setting is barely 40 years old. Yet worldwide, it is used in the operating room in more than 500,000 cases a year. This broad acceptance is a tribute to the vision of gifted investigators who could see beyond the mere technical problems of perfused isolated organs. They integrated mechanical concepts, knowledge of materials, and sheer inventiveness with an appreciation of physiological issues to address the clinical needs of open-heart surgery.

Very small-diameter polyurethane vascular prostheses with rapid endothelialization for coronary artery bypass grafting.

Two types of spongy polyurethane-polydimethylsiloxane blend (Cardiothane 51, Kontron Instruments, Inc., Everett, Mass.) vascular grafts with an internal diameter of 1.5 mm were fabricated by a spray, phase-inversion technique. Low-porosity grafts with hydraulic permeability of 2.7 +/- 0.4 ml/min per square centimeter and medium-porosity grafts with hydraulic permeability of 39 +/- 8 ml/min per square centimeter displayed good handling properties and suturability. Twelve straight low-porosity grafts, 17 straight medium-porosity grafts (1.5 to 2.0 cm in length), and one loop medium-porosity graft (10 cm in length) were implanted by the same surgeon end to end in the infrarenal aorta of 30 male Sprague-Dawley rats. Three months after implantation, patency was 8% for low-porosity grafts (1/12) and 76% for straight medium-porosity grafts (13/17). The loop medium-porosity graft was also patent. The sole patent low-porosity graft showed neointimal hyperplasia and incomplete endothelialization. All but one of the patent straight medium-porosity grafts showed a glistening and transparent neointima with complete endothelialization and no anastomotic hyperplasia. The loop medium-porosity graft displayed endothelialization from each anastomosis and in many islands in the middle portion of the graft, totalling 47% of the luminal surface by morphometric analysis. Thick mural thrombus, anastomotic hyperplasia, or aneurysm formation were not observed in any patent medium-porosity graft. These data indicate that in the rat aortic replacement model it is possible to achieve patency and a high degree of endothelialization in very small-diameter prostheses of appropriate porosity.

Microporous small diameter PVDF-TrFE vascular grafts fabricated by a spray phase inversion technique.

Microporous prostheses of 1.5 mm internal diameter were fabricated with a polyvinylidene fluoride-trifluoroethylene (PVDF-TrFE)n co-polymer by the spray phase inversion technique. Some of the grafts were made piezoelectric by poling under a high electrical field. Overall, 24 poled grafts (P) and 24 unpoled grafts (UP) (15-22 mm in length) were implanted in the infrarenal aorta of 48 adult rats. Patency rates in P were 100% (8/8) at 2 days, 100% (8/8) at 2 weeks, 75% (6/8) at 6 months, and 92% total (22 of 24). Patency rates in UP were 100% (8/8) at 2 days, 63% (5/8) at 2 weeks, 100% (8/8) at 6 months, and 88% total (21 of 24). Thus there was no significant difference in patency between the two types of grafts. Both showed similar macroscopic and microscopic findings. At 2 days, fibrin deposition was somewhat heavier on the poled grafts, but no difference in surface platelet deposition could be detected. Endothelialization was observed from both anastomoses at 2 weeks and was almost complete at 6 months. The excellent biocompatibility of PVDF-TrFE and the microporous structure of the grafts were probably the dominant factors in success with these grafts. Although piezoelectric activity in excised cleaned poled prostheses remained significantly higher than that in the control UP, the charges developed may have been too small to exert a biologic effect, either because of insufficient dipole orientation or inadequate mechanical deformation.

Pivot design in bileaflet valves.

The design criteria leading to the development of a new bileaflet valve (Sorin Bicarbon) were derived from the analysis of functional requirements, the performance of existing prostheses, and the availability of an advanced carbon coating technology (Carbofilm). The hinge is the critical element affecting fluid dynamics, durability, and thrombus formation in bileaflet valves. A comparative study of three existing models led to a new hinge design that was based on coupling two spheric surfaces with different radii of curvature (leaflet pivot and hinge recess) and obtained by electroerosion into a Carbofilm-coated metallic housing. In this valve, the point of contact moves continuously by rolling, not sliding. This minimizes friction and wear and allows uninterrupted washing of the blood exposed surfaces even during diastole (a finding established in patients using transesophageal echocardiography). Tricuspid implantation without anticoagulation in 33 sheep did not lead to thrombotic events (follow-up, 40-400 days). In the first 36 clinical implants observed for 15 months (mitral position, size 29; two unrelated deaths), the mean diastolic gradient by echo Doppler was 4 +/- 1.25 mmHg; the functional area was 3.2 +/- 0.6 cm2. No leaflet fracture and no thrombotic or embolic complications were observed clinically using a standard anticoagulant regimen.

Bioartificial organs.

Bioartificial organs combine the physical aspects of implantable prostheses with the biological advantages of organ transplantation. Enclosing live cells in a permselective, synthetic envelope avoids rejection by an immunoincompatible host while the geometric limitation of the closed polymer capsule prevents overgrowth of the transplanted material. As a tenet bioartificial organs widen the range of therapeutics based on the biological activity of cell transplants and open an alternative path to gene therapy.

In vivo evaluation of porous versus skinned polyurethane-polydimethylsiloxane small diameter vascular grafts.

Two types of spongy polyurethane-polydimethylsiloxane (PU-PDMS) vascular grafts (1.5 mm ID, 450 microns wall thickness) were fabricated with either a skinned (SG) or a porous (PG) luminal surface and an open mesh filamentous external surface by a spraying, phase-inversion technique. Tubular membranes, 15-20 mm in length, were all implanted by the same surgeon as infrarenal aorta replacements in male Sprague-Dawley rats weighing 250-350 g (SG: n = 12, PG: n = 23). The patency rates at 2 weeks and 3 months were 0% (0/7) and 0% (0/1) for SG, 72% (8/11) and 8% (1/12) for PG. Because the wall structure of these grafts was relatively compact and did not provide enough communicating voids, another series of 15 highly porous luminal surface grafts was fabricated with a higher void to material ratio. These grafts (HPG) exhibited a 73% patency at 3 months, with a fully endothelialized surface. The authors conclude that a very open luminal surface structure, and a high wall porosity, are significant factors of graft patency in small diameter vascular prostheses made of a porous material.

Gas transport in serpentine microporous tubes under steady and pulsatile blood flow conditions.

A serpentine gas exchange unit was built with cylindrical tubular microporous membranes featuring periodic arcs with a fixed curvature ratio (ratio of tube radius to radius of curvature) of 1/14 and circular angles between 30 and 360 deg. Oxygen transfer was measured under steady and pulsatile blood flow conditions in vitro and ex vivo to assess the design features which most effectively augment gas transfer. Under steady blood flow conditions, oxygen transfer increased with circular angles beyond 70 deg. Under pulsatile conditions, a wide range of geometrical and fluid mechanical parameters could be combined to enhance gas transfer performance, which eventually depended upon the secondary Reynolds number and the Womersley parameter.

Bionic organs.

When a lizard loses its tail, a new caudal appendage soon grows to replace the one that is missing. But when a human loses a kidney, severs a peripheral nerve or worse, the spinal cord, that organ is lost forever. Such at least is conventional thinking. But imagine that the victim of an industrial accident with a paralyzed hand could achieve new levels of function by inducing axonal regrowth through a synthetic nerve guidance channel; or that a Parkinsonian patient's symptoms could be relieved by implanting in his brain neural tissue encased in a selectively permeable polymer envelope; or that the inexorable progression of the vascular complications of juvenile diabetes could be stopped, even reversed, by a membrane-protected xenograft of insulin-producing tissue. This is the dream of bionic organ science. It is predicated on two lines of technological achievement: the availability of ultra-thin, biocompatible, selectively permeable polymer membranes which can protect a transplant against immune rejection while allowing solute exchange between the graft and its environment; and the synthesis of novel materials, some biostable, some bioresorbable, which can serve as scaffolding or anchor for tissue regrowth in the geometrically and chemically controlled environment of an implant. The fabrication, growth and survival of composites of living tissues with synthetic polymers, often enhanced by the incorporation of specific cell growth factors or inhibitors, has been demonstrated at the tissue culture level, and extended in vivo to experimental models of human endocrine deficiency or neurological defects. The key to progress with bioartificial organs is the confluence of knowledge ranging from materials science to cell and molecular biology to experimental surgery. Obstacles to clinical implementation of this new therapeutic concept include: large scale procurement of specific tissue structures or isolated postmitotic cells from animal sources; demonstration of safety and efficacy of spontaneously occurring, bioactive tumor cell lines; verification of long-term stability and bio-acceptance of polymer implants; and industrialization of the fabrication process to meet quality control, shelf-life and commercial distribution requirements.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of small-diameter vascular prostheses which release bioactive agents.

A porous, distensible, tubular membrane which incorporates albumin and basic Fibroblast Growth Factor (bFGF), and is potentially utilizable as a bioactive small-diameter vascular prosthesis, was fabricated by a combined spraying, phase-inversion technique using a suspension of albumin and bFGF into a polyetherurethane-urea (Biomer) solution in dimethylacetamide (DMA). Scanning electron microscopy showed a material with an open-cell trabecular structure and small particles of albumin and/or bFGF entrapped in the bulk of the polyurethane trabeculae. The material released albumin and bFGF at an approximately constant rate for at least 2 weeks. The bFGF initially incorporated in the polymer remained biologically active as shown by in-vitro proliferation of human endothelial cells.