Microspheres of biodegradable polymers as a drug-delivery system in the vitreous.

Microspheres of biodegradable polymers were evaluated as a potential controlled-release drug-delivery system in the vitreous. The microspheres were prepared with polymers of poly(lactic acid) or copolymers of glycolic acid and lactic acid. The release of 5-fluorouracil (5-FU) from the microspheres was studied in vitro. Poly(lactic acid) microspheres released 70-85% of total 5-FU over 7 days. Microspheres of polymers with a smaller molecular weight released the drug more rapidly. Copolymer microspheres released 98% of 5-FU over 2 days. The rate of drug release was controllable by changing the molecular weight of the polymers or using a matrix of copolymer. The intravitreal kinetics of the microspheres were studied in ten rabbits in vivo. A suspension of microspheres was injected into the vitreous cavity of five normal eyes and five vitrectomized eyes. By 48 +/- 5.2 days after injection, the microspheres disappeared from the vitreous cavity in the five normal eyes. Clearance from the vitreous cavity was accelerated in the five rabbits that underwent vitrectomy (14 +/- 2.4 days; P less than 0.001). No difference was found in the b waves of electroretinograms before and after injection of the microspheres. The histologic study showed no abnormal findings as a result of the injection. These results suggested that microspheres of biodegradable polymers may be a potential delivery system for the controlled release of drugs in the vitreous.

Bioabsorbable struts made from poly-L-lactide and their application for treatment of chest deformity.

Poly-L-lactide, a polymer of lactic acid, shows slow degradation in living tissue. Poly-L-lactide plate of high molecular weight maintains more than 90% of its initial mechanical properties for more than 3 months after implantation. Using struts made from poly-L-lactide plate, we performed chest wall reconstruction in 56 patients: for postoperative chronic sternal dehiscence in 23 and sternal elevation for pectus excavatum in 33 cases. The postoperative external appearances of the anterior chest were improved in comparison with the preoperative state in all cases. The internal features were evaluated by computed tomographic scan. Neither postoperative wound infection nor respiratory complication was observed, and no tendency for regression of the anterior chest occurred in any of the patients. In 3 of 56 cases (5.4%; one in the sternal dehiscence group and two in the pectus excavatum group), it was necessary to remove part of the strut because of overgrowth of granulation tissue around the implanted material after 4, 12, and 13 postoperative months, respectively. In the pectus excavatum group, the computed tomographic evaluations showed that poly-L-lactide strut maintained sufficient strength to support the thoracic wall 5 months after implantation. These findings suggest that the bioabsorbable poly-L-lactide strut is a promising material for surgical treatment of chest deformity.

Modification of synthesis and investigation of properties for 2-cyanoacrylates.

The conventional method for synthesis of 2-cyanoacrylate monomers was modified and the adhesive properties were studied for the cyanoacrylate monomers and the resultant polymers. Toluene was found to be better as reaction solvent than methyl alcohol or xylene. The higher the molecular weight of the condensation oligomer before pyrolysis and the narrower the molecular weight distribution, the higher the yield of cyanoacrylate monomer. Ethoxyethyl cyanoacrylate with an ether side chain was shown to be a soft and biodegradable adhesive. The softening and glass transition temperatures of ethoxyethyl cyanoacrylate polymer were much lower than those of cyanoacrylate polymers with methyl, ethyl or isobutyl side chains. Hydrolysis of poly(ethoxyethyl cyanoacrylate), evaluated from formaldehyde generation and mass loss, was faster than that of ethyl cyanoacrylate and isobutyl cyanoacrylate polymer. Hydrolysis of the ethoxyethyl cyanoacrylate polymers was greatly affected by the molecular weight of the polymers. The morphological change of the cyanoacrylate polymer films was studied by scanning electron microscopy.

Degradation of high molecular weight poly(L-lactide) in alkaline medium.

To study the effect of molecular weight and morphology on hydrolytic degradation, four poly(L-lactide)s (PLLAs) with average molecular weight of 3.0 x 10(5), 4.5 x 10(5), 6.5 x 10(5) and 3 x 10(6) were used. PLLA films with different morphologies were obtained by solution casting. Degradation of the films was performed at 37 degrees C in 0.01 N NaOH solution and this alkaline hydrolysis seemed to simulate well the real case while offering significant acceleration of the degradation process. Diverse microscopy techniques (light, polarizing and scanning electron) were used to study the surface change of morphology and erosion of the PLLA films. Swelling was visualized by scanning electron microscopy, particularly on the spherulites, which were eroded from the centre by hydrolysis. In the case of highly amorphous film, crystallization took place as degradation proceeded. The reduction in transparency of PLLA films, measured by a spectrophotometer at 570 nm, was ascribed to the increased density of spherulites. Differential scanning calorimetry revealed that the crystallinity of PLLA increased with degradation time, in accordance with accelerated spherulite formation.

Synthesis of polylactides with different molecular weights.

The synthesis of poly(lactic acid) through polycondensation of the lactic acid monomer gave weight average molecular weights (Mw) lower than 1.6 x 10(4), whereas ring-opening polymerization of lactides in bulk at 130 degrees C for 72 h using stannous octoate as catalyst in the concentration range from 0.003 to 0.8 wt% produced polylactides with viscosity average molecular weight (Mv) ranging from 2 x 10(4) to 6.8 x 10(5). The monomer conversion and Mv showed a maximum at a catalyst concentration around 0.05 wt%. The monomer conversion and Mv increased almost linearly with polymerization time up to a monomer conversion of 80%, but both the conversion and Mv decreased after passing through a maximum, when the polymerization reaction was allowed to proceed for longer periods of time. This time dependence was pronounced at higher polymerization temperatures. The decrease in Mv at prolonged polymerization and higher polymerization temperatures was attributed to thermal depolymerization of resultant polylactides, but no significant optical rotation of poly(L-lactide) was noticed.

Controlled cisplatin delivery system using poly(D,L-lactic acid).

Cisplatin (CDDP)-containing poly(D,L-lactic acid) microspheres (CDDP-MS) and beads (CDDP-B) with an average molecular weight of the oligomer of 1.2 x 10(4) and 4% CDDP loading were prepared. In Tris buffer, 95% of CDDP disappeared from CDDP-MS within 3 d. In vitro and in vivo, CDDP-B released CDDP for 30-57 d, and for 21-42 d, respectively. The other CDDP-B with an average oligomer molecular weight of 9.6 x 10(3) with 5% lactic acid monomers, that contained 4% CDDP, showed a two-phase CDDP release pattern and CDDP disappeared within 41 d in vitro, and within 21 d in vivo. Histologically, tissue necrosis surrounding the CDDP-B was not severe.

Evaluation of a bilayer artificial skin capable of sustained release of an antibiotic.

A bilayer artificial skin, composed of an upper silicone sheet and a lower collagen sponge, has been developed by modifying a technique proposed by Yannas and Burke. We have applied it clinically with success, but infection sometimes occurred in the area where the artificial skin was placed. To use it safely in an infected wound, we developed a new type of artificial skin capable of sustained release of antibiotic. Microspheres of poly-L-lactic acid containing an antibiotic, were installed in the upper silicone sheet. The usefulness of the new type of artificial skin was suggested by in vitro studies.

Polymer-hydroxyapatite composites for biodegradable bone fillers.

A number of composites made from biodegradable polymers and hydroxyapatite were studied in vivo and in vitro in an attempt to develop biodegradable artificial bone fillers. Histological observation in rats revealed that polylactic acid, of low molecular weight (PLAoligomer), was rapidly resorbed and replaced by newly formed bone tissue when incorporated with hydroxyapatite and this suggested that the incorporated hydroxyapatite seemed to play an active role in the new bone formation. In vitro testing revealed that the solubility of hydroxyapatite was markedly enhanced when mixed with PLAoligomer.

Biodegradation and antitumour effect of adriamycin-containing poly(L-lactic acid) microspheres.

Adriamycin-containing poly (L-lactic acid) microspheres were prepared to develop a slow-releasing and long-acting adriamycin delivery system. An almost constant release of adriamycin from the adriamycin-containing poly(L-lactic acid) was achieved in Tris buffer and adriamycin disappeared within 20 d. Adriamycin was not detected in serum for up to 14 d, when the suspension of the adriamycin-containing poly(L-lactic acid) microspheres was injected into lung parenchyma, the femoral muscles of rabbits or the peritoneal cavity of mice. However, adriamycin remained in the rabbit muscles for up to 10 d under formation of scar tissue. When free adriamycin was added to P815 tumour cells in culture, the cell survival rate decreased with the exposure time. The treatment with the adriamycin-containing poly(L-lactic acid) microspheres showed a higher survival rate for mice bearing P815 tumour cells than with free adriamycin. In addition, the systemic side effects were insignificant when the adriamycin-containing poly(L-lactic acid) microspheres were given to mice instead of free adriamycin.

Scleral plug of biodegradable polymers for controlled drug release in the vitreous.

We designed a new device, a scleral plug, that releases drugs into the vitreous after being implanted and fixed at the pars plana. Use of the plug for provision of doxorubicin hydrochloride was evaluated in rabbits. The scleral plug (8.5 mg) was made of poly(lactic-glycolic acid) (molecular weight, 40,000 daltons) containing 1% doxorubicin. Vitreous concentrations of doxorubicin were measured after the implantation. In vitro studies showed that the plug released 26% of the drug during 4 weeks. In vivo studies demonstrated that the concentration in the vitreous humor was maintained at a therapeutic range for longer than 4 weeks. No substantial toxic reactions were observed by electroretinographic and histopathologic evaluations. Our findings suggested that a scleral plug made of biodegradable polymers is a promising device for a controlled drug-release system in the vitreous.

Long-term preservation of rat pancreatic islets under physiological conditions.

In this study, we found that islet cells treated with polyphenol could be preserved for over 2 months under physiological conditions retaining their original function and maintaining their spherical shapes without any insulin secretion. When islets were treated at higher concentration than 250 microg ml(-1), these islets could retain their compact spherical shape over 65 days whereas non-treated islets were scattered ease to break within 2 weeks. The secretional capacity from treated islets in the initial stage is also lower than untreated islets. However, in the case of untreated islets, insulin release rapidly lowered with the progress in the culture time and secretion completely disappeared after 9 days. On the contrary, islets treated with polyphenol (250 microg ml(-1)) in RPMI culture medium showed significant enhancement of insulin secretion on 40th day. The secretional capacity of islets was greatly dependent on the treating concentration. Polyphenol treatment may be a useful method for preservation of mammalian islet cells. By changing the concentration of polyphenol, it is possible to control the preservation duration and insulin secretion of islets.

One-knot microvascular anastomosis. An experimental study in rats.

Experimental microvascular anastomosis using a glutide copolymer (lactide:glycolide, 80:20) as an external splint was undertaken in 33 rats between the carotid artery and the jugular vein. Both vessels were dissected free over a 1-cm length and cut at the cranial end of the dissected part. The carotid artery was then introduced into a glutide pipe-splint. The arterial wall was turned 180 degrees over the edge of the splint. This reflected artery wall and the glutide were covered by the freed-up jugular vein. One stitch was made around the vein, the artery, and the glutide in a manner similar to binding steel wire over a barrel. Thus, the "one-knot anastomosis" was completed. The patency rate at the anastomosed site was 100%, confirmed by angiography in 30 rats and by direct surgery in three. The time required to produce the anastomosis was between 5 and 7 minutes. Light microscopic observation showed that there was no obstruction by thrombus formation at 1 and 5 weeks after the anastomotic surgery. This technique may be clinically applicable for extracranial-intracranial bypass surgery, reconstruction of venous sinuses, and other vascular procedures.

An experimental study on prevention of postlaminectomy scar formation by the use of new materials.

An experimental study was performed to investigate the prevention of scar formation after lumbar laminectomy, using Elastase and the new polylactic acid (PLA) membrane containing Elastase. The experimental animals consisted of four groups: control group, E group (using intravenous administration of Elastase), P group (covering the laminectomy defect with PLA membrane), and P-E group (covering the laminectomy defect with "PLA" + Elastase" membrane). The animals were killed at varying intervals (2-12 weeks) and changes in the lumbar spines were evaluated histologically. Scar formation was suppressed most significantly in the P-E group, followed in order by the E group, the P group, and the controls.

A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier.

We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.

Partial hemiarthroplasty for the treatment of osteonecrosis of the femoral head. An experimental study in the dog.

The use of a composite osteochondral device for simulating partial hemiarthroplasty was examined. The device was composed of a polyvinyl alcohol hydrogel and a titanium fibre mesh, acting as artificial cartilage and as porous artificial bone, respectively. The titanium fibre mesh was designed to act as an interface material, allowing firm attachment to both the polyvinyl alcohol gel (through injection moulding) and the femoral joint surface (through bony ingrowth). We implanted 22 of these devices into canine femoral heads. Histological findings from the acetabular cartilage and synovial membrane, as well as the attachment of the prosthesis to bone, were examined up until one year after operation. No marked pathological changes were found and firm attachment of the device to the underlying bone was confirmed. The main potential application for this device is for partial surface replacement of the femoral head after osteonecrosis. Other applications could include articular resurfacing and the replacement of intervertebral discs.

Design of a polyvinyl alcohol hydrogen containing phospholipid as controlled-release vehicle for rectal administration of (+/-)-propranolol HCl.

Polyvinyl alcohol hydrogels which contained phospholipid, egg yolk lecithin or hydrogenated soya lecithin were designed as a transrectal delivery system for propranolol hydrochloride. The hydrogel preparations containing phospholipid were prepared by a low-temperature crystallization method. The release profile of propranolol from hydrogel preparations containing phospholipid complied with Fickian diffusion (Higuchi model). The release of propranolol from the hydrogel preparation decreased with higher contents of phospholipid (approximately 2% w/w). In rats plasma concentrations of propranolol after rectal administration of hydrogel preparations containing phospholipid (1 and 2% w/w) were prolonged compared with those of rats receiving preparations without phospholipid.

Biodegradable poly (lactic acid) microspheres for drug delivery systems.

In connection with aim of maximizing the bio-availability of conventional drugs with minimum side-effects, new drug delivery systems (DDS) continue to attracted much attention. The controlled or sustained release of drugs represents one such approach, and in this regard report upon a study of DDS using biodegradable polymers which include poly (lactic acid) (PLA), poly (glycolic acid), and their copolymers (PLGA). Much attention is being paid to the controlled release of bio-active agents from microcapsules and microspheres made of biodegradable polymers, such as lactic acid homopolymers, as well as copolymers of glycolic acid. (11-21) Microcapsules or microspheres are injectable and able to provide pre-programmed durations of action, offering several advantages over the conventional dosage forms. This article reviews the results of a work program conducted in collaboration with a medical doctor upon DDS using biodegradable microspheres, such as PLA and PLGA.

Polyacrylonitrile membrane interposition between a xenograft and an animal in fulminant liver failure. The concept of xenohemodiafiltration.

In fulminant liver failure (FLF) there is need for support as a bridge to liver transplantation. Based on the concepts of hemofiltration and xenotransplantation, the authors present a model of liver support in FLF. The authors performed a portacaval shunt and ligature of the hepatic artery in 12 pigs. In six pigs (Group A) continuous hemofiltration through a polyacrylonitrile membrane was performed. Six isolated dog's livers were catheterized through the portal vein and perfused with autologous erythrocytes, albumin, and electrolytes in a closed circuit. With the use of the auxiliary liver, the circuit was connected to one of the lateral outlets of the hemofilter, while the other lateral outlet was connected to the portal vein through the pump. Thus, a polyacrylonitrile exchange membrane was created between the blood of the pig with FLF and the auxiliary liver's circulation. In Group B (controls), six pigs were connected directly to the auxiliary liver through a pump. In Group A, the auxiliary liver worked for 8 hr, without evidence of macroscopic or histologic damage. Lactic acid and ammonia levels improved: lactic acid, 8.2 +/- 6 mmol/L to 1.6 +/- 1 mmol/L; ammonia 487 +/- 110 micrograms/dl to 117 +/- 13 micrograms/dl, p < 0.1. The lidocaine clearing (MEGX) test results remained at functional levels (> 90 ng/ml) at the end of the perfusion. In Group B, the perfusion was discontinued at 60 +/- 15 min because of evidence of necrosis of the auxiliary liver. Lactic acid levels increased from 8.19 +/- 1.1 mmol/L to 13 +/- 4 mmol/L, ammonia levels remained high (390 +/- 15 micrograms/dl to 480 +/- 80 micrograms/dl), and the MEGX test results showed levels below functional activity by the end of the perfusion (45 +/- 30 ng/ml). The authors conclude that the concept of xenohemodiafiltration based on the interposition of a polyacrylonitrile membrane between a xenograft and an animal in FLF is adequate to support functions of detoxification and could be used in the future in the support of patient with FLF.

Polyacrylonitrile membrane interposition between a xenograft and a patient in fulminant liver failure: the concept of xenohemodiafiltration in clinical practice.

Fulminant hepatic failure is an important cause of morbidity and mortality in intensive care units. Conventional therapies are not sufficiently effective. Liver transplantation may be life saving, but a "bridge therapy" is needed until transplantation is performed. Hepatic extracorporeal xenohemodiafiltration (XHDF) is aimed at the transitory support of a patient with fulminant hepatic failure. The first clinical case of XHDF is presented. The system consisted of cross-circulation between a porcine liver and a patient with fulminant liver failure through a polyacrylonitrile membrane. The procedure lasted for 5 hours and produced hemodynamic, biochemical, and metabolic improvements. Intracranial pressure decreased from 34 to 5 cm H2O, serum ammonia fell from 673 to 370 ng/dl, lactic acid from 11 to 5.3 mmol/L, and bilirubin from 7.4 to 2.5 mg/dl. Hemodynamic values were maintained stable throughout the procedure. The patient was able to undergo transplantation and remains alive 11 months later. XHDF is a clinical experimental method that can constitute an alternative clinical therapy to support patients with fulminant hepatic failure until an organ is available for transplantation.

Clinical evaluation of uniaxially oriented poly-L-lactide rod for fixation of experimental femoral diaphyseal fracture in immature cats.

Transverse diaphyseal fractures of the femur were experimentally made in immature cats, and were fixed by an intramedullary pinning technique using an uniaxially oriented poly-L-lactide (PLLA) rod, a biodegradable polymer. The healing process was evaluated radiographically and histologically. Formation of bony callus was completed in 8 weeks, and cortical bony union followed. The remodeling process was then observed form 12 to 16 weeks. The healing process was almost the same as when a metallic implant was used. Abundant periosteal callus formation may be attributable to the lower elasticity of the PLLA rod compared with metallic implants. Since no other abnormalities such as growth deformities were detected, it was concluded that the combined use of a uniaxially oriented PLLA rod and an external splint is clinically useful for the repair of diaphyseal fractures in immature cats.