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The technology of synthesis, extraction and modification of biodegradable polyhydroxybutyrate (PHB) is introduced briefly in this article. It is also summarized that the research progress in application of PHB in drug delivery and tissue engineering.
Hormone release rates from biodegradable cylindrical implants consisting of a physical matrix of [14C]levonorgestrel and copolymers of [3H]lactic and glycolic acids have been monitored in rats. Two copolymers were evaluated: one consisted of 90 parts L-lactide/10 parts glycolide (90L/10G) containing 33 or 50% hormone by weight, and the other of 50 parts DL-lactide/50 parts L-lactide (50DL/50L) containing 50% hormone. For each system, 4-6 rods (0.8 x 16 mm) providing 19 mg of steroid per rat were subcutaneously implanted into the scapular regions of 5 rats, and 14C and 3H in faeces and urine were determined weekly for 90-724 days. An initial burst of hormone release, peaking at approximately 90 microgram day-1, occurred in the first two weeks. This was followed by an approximately 10-30 microgram day-1 for the 90L/10G system containing 33% hormone, a more uniform rate of approximately 25 microgram day-1 for the 50DL/50L system and the highest rate of approximately 40 microgram day-1 for the 90L/10G system containing 50% hormone. 3H and 14C in residual implants of 90L/10G with 33% hormone removed from animals dying of natural causes during the test were assayed. For this system 3H activity decreased by over 50% within 250 days, compared with < 25% loss in 14C activity. The amounts of 3H and 14C released were similar over much of the subsequent test period. At the end of the test both polymer and drug were essentially depleted. All animals with the 50DL/50L system died late in the test period. Between days 609 and 724 from 13.7-27.2% initial 14C and from 10.0-22.1% initial 3H was measured in recovered rods. Microscopic inspection of recovered rods showed a loss of core material and tissue encapsulation. There were no signs of local tissue irritation or systemic toxicity.
The requirements of ideal extracellular matrix materials for bone tissue engineering were stated, and the advantages and disadvantages of bioceramics, biodegradable synthetic polymers and natural polymers were analyzed. Based on these, we highlight a point that the ideal extracellular matrix materials for bone tissue engineering should be made up of bioceramics materials, synthetic polymers or natural polymers. These materials should possess a morphological structure of three-dimensional foam and have a self-mediated drug delivery system of bone growth factors. The design and manufacture of such compound extracellular matrix materials for bone tissue engineering is a very important and urgent challenge.
This study was focused on the utilization of a recombinant expression system to produce a unique modified subunit vaccine possessing a self-contained delivery system which could potentially improve the uptake and delivery of vaccine products as well their immunogenic potential. For this purpose the A-layer protein (At-R) associated with the fish pathogen atypical Aeromonas salmonicida was cloned and modified by the genetic fusion of the protein transduction domain (MTS) derived from Kaposi fibroblast growth factor (At-MTS). The potential for these proteins to be employed as antigens for oral immunization of goldfish was examined by encapsulation of At-R, At-MTS and the control, BSA, into biodegradable alginate gel macrospheres which were fed to goldfish in place of standard pellet fish feed. The bead physical properties were modified only in the presence of At-R and the temporal release of proteins was significantly less when At-MTS was employed. Western blot analysis of serum samples collected from fish following intubation with the recombinant proteins determined that the rate of protein uptake from the digestive tract into the blood system improved considerably when MTS was fused to At-R. Experimental fish were fed one of three protein-alginate formulae on a schedule of 3 days/week or 5 days/month for a period of 2 months. After 1 month, animals fed on the 5-day protocol demonstrated increased serum antibody titers while following an additional month of feeding this level decreased and titers were found to be higher in fish maintained on the 3-day regime. Fish fed At-MTS maintained the highest titer at the end of 2-month period. To determine whether the diminished antibody titers were a result of oral tolerance fish were injected intraperitoneally with the At-R antigen. Only experimental groups which had been fed At-R or At-MTS demonstrated increased antibody titers which paralleled a typical secondary humoral response. In spite of the presence of an increased titer to A-protein, vaccinated fish did not demonstrate resistance to infection with atypical A. salmonicida.
Neointimal formation after stent implantation can cause luminal narrowing, called restenosis. Restenosis is induced by initial platelet adhesion and thrombus formation followed by immunocyte adhesion on the stent surface and on the injured vessel wall. The thrombus releases factors, which activates the proliferation of smooth muscle cells. Stents, coated with an antithrombotic surface, may prevent platelet adhesion and subsequent smooth muscle cell proliferation. This paper will review stent coating with poly-LD-lactic acid, a biodegradable polymer containing Iloprost, a synthetic prostacycline, and PEG-Hirudin as a method for reducing of restenosis.
Biodegradable microspheres (MS) based on poly(D,L-lactide) and poly(D,L-lactide-coglycolide) have the capacity to release encapsulated antigens over defined lengths of time depending on their composition and to elicit and sustain strong and long-lasting immune responses to protein antigens. In the present study, two synthetic multiple antigenic peptides (MAP), P30B2 and (NANP)6P2P30, were incorporated into MS of different compositions. P30B2 and (NANP)6P2P30 are composed of one or two universal T helper epitopes from tetanus toxin, 947-967 (P30) and 830-843 (P2), and of a B cell epitope derived from the repeat sequence of Plasmodium berghei or Plasmodium falciparum, respectively. BALB/c mice were immunized with these two peptides in different formulations, including individual MS or mixtures of MS with various release properties, Incomplete Freund's adjuvant (IFA) or as soluble peptides. MS formulations elicited strong and sustained proliferative and antibody responses comparable to those obtained with the IFA preparations. Furthermore, MS formulations induced specific isotype/ subclass antibodies similar to those induced by IFA. No significant augmentation of total serum IgE was detected during this study. In addition, a boosting effect was obtained when the immunized mice were reinjected with a small antigen dose in IFA several months later. These results indicate that biodegradable MS may be a suitable vaccine delivery system/adjuvant not only for protein antigens but also for weakly immunogenic synthetic peptides.
BACKGROUND: Bioabsorbable membranes have been successfully used for guided tissue regeneration (GTR) and local delivery systems because they are biocompatible and do not require second surgery for removal. Several studies have demonstrated that metronidazole, when applied topically, produced immediate effects on microbiological and clinical parameters, most notably a reduction in probing depth and loss of attachment. The purpose of this study was to evaluate the regenerative potential of a metronidazole-loaded biodegradable (polylactide/glycolide) (PLGA) GTR membrane in dogs. METHODS: Six male adult dogs with 36 created osseous defects were enrolled. Bilateral dehiscence type defects in 5 mm diameter were created at buccal aspect of the alveolar bone in maxillary premolar teeth. After full thickness flap elevation, exposed root surfaces were thoroughly planed. In the experimental sites, PLGA membranes with or without metronidazole were fitted and placed over the defects. On the control defects only root planing was performed. Gingival flaps were replaced slightly coronal to the cemento-enamel junction. Animals were sacrificed at 60 days. The histometric analysis was evaluated with the following parameters: defect height (DH), apical extension of junctional epithelium (AEJE), new cementum height (NCH), new bone height (NBH), and new gingival connective tissue height (NCTH). RESULTS: Postoperative clinical healing was similar in the 3 groups. There were no statistically significant differences between the 2 experimental groups in any parameters. Statistically significant differences were observed for AEJE, NCH, NBH, and NCTH in experimental groups when compared with the controls. Statistically significantly greater NCH, NBH, and NCTH were seen in the experimental groups than the controls and control defects showed longer AEJE than the experimental defects. CONCLUSIONS: These results suggest that PLGA membranes with and without metronidazole may have a beneficial effect on periodontal regeneration.
Our studies on the application of hormone-polymer composites in urological field are discussed in this review. We first studied the modes of in vivo and in vitro release of testosterone from vinyl polymer-testosterone composites prepared by radiation-induced polymerization. It was ascertained by our group that in vivo and in vitro release of testosterone from biodegradable copolypeptide -testosterone composites as well as vinyl polymer composites was well controlled. Using this system, we were successful in preparing a testicular prosthesis, which was made of vinyl polymer-testosterone composites and was ascertained to release testosterone constantly for a long period in the dose range of clinical usage. We also applied this sustained release drug delivery system to the method of administration of an LH x RH agonist, which was one of the best therapeutic drugs for androgen dependent prostatic cancer. Sustained release of the LH x RH agonist in the dose range of clinical usage over a period of several months from copolymer-LH x RH agonist composites was confirmed in both male rats and in prostatic cancer patients. Prostatic cancer cells contain a major secretion protein (alpha-protein or estramustine-binding protein) and estramustine has a high affinity for alpha-protein. Therefore, we examined the effect of an estramustine-microsphere containing anticancer drugs, namely, the missile therapy for prostatic cancer. The missile therapy should open the way to specific and selective chemotherapy for prostatic cancer.
OBJECTIVE: Local delivery of carmustine (BCNU) from biodegradable polymers prolongs survival against experimental brain tumors. Moreover, paracrine administration of interleukin-2 (IL-2) has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models. We report the use of a novel polymeric microsphere delivery vehicle to release IL-2. We demonstrate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from the microspheres in the rat brain. These microspheres are used to deliver IL-2, and biodegradable polymer wafers are used to deliver BCNU, directly at the site of an intracranially implanted glioma in the rat. The two agents administered locally show a synergistic effect. METHODS: Fischer 344 rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2 (IL-2 MS). Five days later, animals in each group were randomized to receive polymer implants loaded with 0, 3.8, or 10% BCNU at the tumor site. RESULTS: Animals that received the combination of IL-2 MS and 3.8% BCNU polymer (median survival, 28.5 d) or IL-2 MS and 10% BCNU polymer (median survival, 45.5 d) showed significantly improved survival compared with animals that received monotherapy with IL-2 microspheres (median survival, 24 d), 3.8% BCNU polymer (median survival, 24 d), or 10% BCNU polymer (median survival, 32.5 d). Control animals had a median survival of 18 days. The combination of either 3.8 or 10% BCNU polymer with IL-2 MS resulted in 7 and 25% long-term survivors, respectively. CONCLUSION: By showing synergy of IL-2 and BCNU in an animal glioma model and using a reproducible synthetic delivery system for each agent (i.e., one that did not rely on genetically engineered cells or viruses), we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical application in patients with malignant brain tumors.
The aim of this study was to develop delivery systems for administration of CSF-1 to remedy the systemic deficiency of this cytokine in osteopetrotic op/op mice and to study the microglial response and neuronal survival in op/op mice following cerebral cortex ischemic lesion. Unilateral cerebral cortex ischemic lesions were produced in homozygous op/op mice and either microencapsulated rhCSF-1 or LM-10 fibroblast-like cells producing CSF-1 were administered either locally, at the site and time of the lesioning, or into the peritoneum 2 weeks before the lesion was made. Physical properties (shape, size, integrity) and kinetics of rhCSF-1 release were assessed prior to the experiments in situ. Depending on the characteristics of the biodegradable polymer (e.g., chitosan with different densities or poly-L-lactic-poly-glycolic acid), remarkable differences in survival of encapsulated cells were observed. Cellular integrity following encapsulation and metabolic activity was regularly assessed for a period of 1 month. The best level of viability was achieved with highly viscous chitosan (311). The results from these studies demonstrate that: (1) rhCSF-1 incorporated into biodegradable spheres can be released and retain its biological activity; (2) microencapsulated LM-10 cells which produce CSF-1 can survive and constitutively release CSF-1 in alginate-chitosan spheres for different lengths of time depending on the physical properties of the chitosan used; and (3) CSF-1 is an important growth factor in the central nervous system where it can both strongly alter morphological changes of microglia and enhance survival of neurons in injured brain.
PURPOSE: Pancreatic resection for pancreatic cancer is the only curative modality, but the high incidence of local recurrence after surgery results in a very poor prognosis. This study aims to develop a new therapeutic tool that could inhibit the growth of remnant cancer cells, which is based on local delivery of NK4 (hepatocyte growth factor antagonist) secreted from an NK4 gene-transduced oral mucosal epithelial cell (OMEC) sheet (NK4-sheet), which is adhered to the resected surface. EXPERIMENTAL DESIGN: OMECs, harvested and cultured according to 3T3 feeder layer technique, were seeded on a collagen mesh-overlayered, biodegradable VICRYL mesh to produce an OMEC sheet. NK4 gene transduction was mediated by recombinant adenovirus (Ad-NK4). Applicability of OMECs for cell-based NK4 delivery was examined. An experimental model using nude mice was established to determine the effect of an NK4-sheet on both tumor growth and angiogenesis. RESULTS: NK4 secreted from Ad-NK4-transduced OMECs suppressed MRC-5-induced invasion of pancreatic cancer cell lines. Heterotopically implanted gene-transduced OMECs remained for >/==" BORDER="0">10 days while gradually decreasing. NK4-sheets inhibited both angiogenesis and tumor growth in vivo. CONCLUSION: Autologous OMEC was found to be suited to this purpose because of no secretion of hepatocyte growth factor, ease in harvesting from a patient, reasonably high proliferation potential, and no immune reaction. Although NK4-sheets under development exhibited a low level and short period of NK4 secretion, it is expected that this system may have a great potentiality of protein delivery system to target tissue at clinical situations when it is loaded with multilayered OMECs.
In many cases only the temporary presence of a biomaterial is needed in tissue support, augmentation or replacement. In such cases biodegradable materials are better alternatives than biostable ones. At present, biodegradable polymers are widely used in the field of maxillofacial surgery as sutures, fracture fixation devices and as absorbable membranes. The most often used polymers are aliphatic polyesters, such as polyglycolic acid (PGA) and polylactic acid (PLA). Poly(ortho ester) is a surface eroding polymer, which has been under development since 1970, but is used mostly in drug delivery systems in semisolid form. The aim of this study was to evaluate the tissue reactions of solid poly(ortho ester) (POE), histologically and immunohistochemically. Resorption times and the effect of 2 different sterilization methods (gamma radiation and ethylene oxide) upon resorption were also evaluated. Material was implanted into the tibia and subcutaneously into the mandibular ramus area of 24 rabbits. Follow-up times were 1-10, 14 and 24 weeks. Histological studies showed that POE induces a moderate inflammation in soft tissue and in bone. At 24 week follow-up, inflammation was mild in soft tissue and moderate in bone. In immunohistochemical studies, no highly fluorescent layer of tenascin or fibronectin was found adjacent to the implant. Resorption of gamma-sterilized rods was faster than ethylene oxide-sterilized rods. The total resorption time was more than 24 weeks in both groups. Clinically the healing was uneventful and the implants the well tolerated by the living tissue. This encourages these authors to continue studies with this interesting new material to search for the ideal material for bone filling and fracture fixation.
The authors emphasize the possible pharmacological enhancement of axonal regeneration using a specific growth factor/ extracellular media incorporated in a biodegradable nonneural nerve conduit material. They investigated the early effects on nerve regeneration of continuous local delivery of nerve growth factor (NGF) and the local incorporation of hyaluronic acid (HA) inside a newly manufactured nerve conduit material from fresh human amnionic membrane. Human amnionic membrane contains important biochemical factors that play a major neurotrophic role in the nerve regeneration process. The process of manufacturing a nerve conduit from fresh human amnionic membrane is described. This nerve conduit system was used in rabbits to bridge a 25-mm nerve gap over 3 months. NGF was released locally, over 28 days, at the distal end of the tube via a system of slow release, and HA was incorporated inside the lumen of the tube at the time of surgery. NGF/HA treatment promoted axonal regeneration across the amnionic tube nerve conduit (8,962 +/- 383 myelinated axons) 45% better than the nontreated amnionic tube group (6,180 +/- 353 myelinated axons). The authors demonstrate that NGF/HA media enhances additional axonal regeneration in the amnionic tube nerve conduit. This result is secondary to the effect of the amnion promoting biochemical factors, in combination with the NGF/HA effect on facilitating early events in the nerve regeneration process.
To reduce the thrombogenic properties of coronary artery stents, a biodegradable polylactic acid (PLA) stent coating with an incorporated thrombin inhibitor and a platelet aggregation inhibitor has been developed. In an ex vivo human stasis model, its effect on platelets, plasmatic coagulation and its release characteristics were studied using whole blood. Bare steel and bare gold-surface stents were compared to steel and gold-surface stents coated with PLA (30 kDa) containing 5% polyethyleneglycol (PEG)-hirudin and 1% iloprost, with an empty tube as control. Markers of activated coagulation (prothrombin fragment F1-2 and thrombin-antithrombin III complex, TAT), were assayed and the release of drugs from the coating was assessed by aPTT and collagen-induced platelet aggregation. Bare steel and gold stents were completely covered by a blood clot, and high levels of coagulation markers (F1-2 fragment and TAT) were detected. No differences in the thrombogenic properties were found between bare gold or steel stents. Coated stents were free of blood clots and only minor elevations of markers were detected. Release data from in-vitro studies over 90 days showed a gradual release of the drugs with an initial exponential release characteristic for PEG-hirudin, slow release of iloprost and a 10% degradation of the PLA carrier. This drug releasing biodegradable coating effectively reduced thrombus formation independent of the metallic surface.
This exploratory laboratory study was undertaken to develop and test an in situ bioremediation system intended to point the way toward a possible field application. The proposed method uses a water table management (WTM) system to deliver nutrients or other amendments to subsoil microorganisms for biostimulation and subsequent biodegradation of pollutants in the saturated and unsaturated zones of the soil. The study was carried out on packed soil columns and bioremediation of residual fertilizer nitrate was attempted. Different levels of organic carbon supplement (glucose C) were introduced into these columns via subirrigation in order to supplement the readily available organic carbon levels in the soil. The study was carried out in two experimental setups. The first setup investigated (i) the effect of addition of a high (970 mg L(-1)) and a low (120 mg L(-1)) glucose C level and (ii) the efficacy of using the subirrigation system as a method for nutrient delivery in bioremediation of leached nitrate. This setup was monitored with time, depth, and with reference to the nitrate residue in the soil solution. Leached nitrate was denitrified to less than 10 mg L(-1) nitrate N at both glucose levels. The second setup investigated the effect of a range of low levels of glucose C on nitrate decontamination, soil pH, and total microbial count in order to find out an optimal glucose C level that reduced the most nitrate and maintained the pH homeostasis of soil.
Biodegradable amphiphilic graft copolymers poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(epsilon-caprolactone) (PHEA-g-PCL) with different branch lengths were synthesized through the ring-opening polymerization of epsilon-caprolactone initiated by the macroinitiator PHEA bearing hydroxyl groups. With use of the graft copolymers with different compositions, nanoparticle drug delivery systems with sizes smaller than 100 nm were prepared by a dialysis method, and microparticle drug delivery systems with sizes smaller than 5 microm were fabricated by a melting-emulsion method. The regularly spherical shapes of the drug-loaded nano- and microparticles were verified by transmission electron microscopy and scanning electron microscopy. In vitro drug release properties of nano- and microparticle drug delivery systems were investigated, with the emphasis on the effects of polymer composition, particle size, and drug-loading content on the release behaviors.
Various comb-type copolymer containing a polycation as a main chain was design to construct delivery systems of DNAs. The comb-type copolymers having cell-specific polysaccharides were proved to be useful to deliver DNA to the target cells in vivo. Of interest, the copolymers with abundant side chains of hydrophilic polymers are capable of stabilizing DNA triplex. Further, injectable nanoparticles for controlled releases of DNAs were fabricated from the copolymer and a biodegradable polymer.
Short-lived gamma emitting radioisotopes can be incorporated into polylactide/glycolide polymeric microspheres with various specific activities for possible use in understanding the in-vivo deposition, distribution and clearance of microparticulate drug carrier systems. The incorporated radiolabel is stable with negligible leaching out of the microspheres. These microspheres are suitable for studying the oral uptake of particles, lung distribution after inhalation delivery and evaluation of in-vivo fate following parenteral administration in systemic circulation or in specific tissue compartments.