Donald L. Wise

Antibiotic Release from Biodegradable PHBV Microparticles

For the treatment of periodontal diseases, design of a controlled release system seemed very appropriate for an effective, long term result. In this study a novel, biodegradable microbial polyester, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), PHBV of various valerate contents containing a well established antibiotic, tetracycline, known to be effective against many of the periodontal disease related microorganisms, was used in the construction of a controlled release system. Tetracycline was loaded in the PHBV microspheres and microcapsules both in its acidic (TC) and in neutral form (TCN). Microcapsules of PHBV were prepared under different conditions using w/o/w double emulsion and their properties such as encapsulation efficiency, loading, release characteristics, and morphological properties were investigated. It was found that concentration of emulsifiers polyvinyl alcohol (PVA) and gelatin (varied between 0-4%) influenced the encapsulation efficiency appreciably. In order to increase encapsulation efficiency (from the obtained range of 18.1-30.1%) and slow down the release of the highly soluble tetracycline.HCl, it was neutralized with NaOH. Encapsulation efficiency of neutralized tetracycline was much higher (51.9-65.3%) due to the insoluble form of the drug used during encapsulation. The release behaviour of neither of the drugs was found to be of zero order. Rather the trends fitted reasonably well to Higuchis approach for release from spherical micropheres. Biodegradability was not an appreciable parameter in the release from microcapsules because release was complete before any signs of degradation were observed.

Biomaterials in orthopedics

Biocompatibility and the biomaterial/tissue interface: hard tissue-biomaterial interactions, Petek Korkusuz, Feza Korkusuz material characteristics and biocompatibility of low ridigity titanium alloys for biomedical applications, Mitsuo Niinomi,Tomokazu Hattori and Shigeo Niwa the corrosion and biocompatibility of orthopaedic implants, Nadim James Hallab, Robert M. Urban and Joshua J. Jacobs technologies for the surface modification of biomaterials, Aron B. Anderson, Anthony W. Dallmier,Stephen J. Chudzik, Lise W. Duran, Patrick E. Guire, Robert W. Hergenrother, Muhammad A. Lodhi, Amy E. Noval, Ronald F. Ofstead and Klaus R. Wormuth. Bioabsorbable biomaterials for bone repair: rational design of absorbable polymers for orthopaedicrepair, James B. Beil, Jorge Heller and Kirk P. Adriano synthesis and evaluation of a poly(propylene glycol-co-fumaric acid) bone graft extender, Stephen A. Doherty, David D. Hile, Donald L. Wise, Kai-Uwe Lewandrowski and Debra J. Trantolo self-reinforced bioabsorbable devices for osteofixation of craniofacial bones, Nureddin Ashammakhi, Timo Waris, Willy Serlo and Pertti Tormala osseous grafting materials for periodontal defects, David D. Hile, Stephen A. Doherty, Stephen T. Sonis, DonaldL. Wise, Kai-Uwe Lewandrowski and Debra J. Trantolo guided diaphysis regeneration, C. Olson, S.D. Wagner and Thomas D. McGee bioresorbable skeletal fixation systems in craniofacial surgery, Mutaz B. Habal. Nondegradable materials in orthopaedics:osseointegration principles in orthopedics - basic research and clinical applications, Lars Carlsson, Warren Macdonald, C. Magnus Jacobsson and Tomas Albrektsson recent developments in bone cements, Kemal Serbetci and Nesrin Hasirci three-dimensionallyengineered hydroxyapatite ceramics with interconnected pores as a bone substitute, Akira Myoui, Noriyuki Tamai, Masataka Nishikawa, Nobuhito Araki, Takanobu Nakase, Shosuke Akita and Hideki Yoshikawa the histological and immunhistochemical aspects of theinterfacial membranes of cemented total hip and knee arthroplastics, Najat Al-Saffar and Jochanan H. Boss ceramic spine prosthesis, Noboru Hosono, Hironobu Sakaura, Tetsuo Ohwada, Kazuo Yonenobu and Hideki Yoshikawa safety aspects of alumina andzirconia ceramics in hip surgery, Gunther Heimke plasma-sprayed hydroxyapatite-coated and plasma-sprayed titanium-coated implants in vivo and clinics, Y. Yang, Kazuhisa Bessho and Joo L. Ong calcium phosphate ceramics in Japan, Masataka Nishikawa andHajime Ohgushi aspects to consider in the clinical applications of NiTi and NiTiCu shape memory alloys, F. J. Gil and J.A. Planell.

Bioresorbable bone graft substitutes of different osteoconductivities: a histologic evaluation of osteointegration of poly(propylene glycol-co-fumaric acid)-based cement implants in rats.

Bioresorbable bone graft substitutes may significantly reduce the disadvantages associated with autografts, allografts and other synthetic materials currently used in bone graft procedures. We investigated the biocompatibility and osteointegration of a bioresorbable bone graft substitute made from the unsaturated polyester poly(propylene-glycol-co-fumaric acid), or simply poly(propylene fumarate), PPF, which is crosslinked in the presence of soluble and insoluble calcium filler salts. Four sets of animals each having three groups of 8 were evaluated by grouting bone graft substitutes of varying compositions into 3-mm holes that were made into the anteromedial tibial metaphysis of rats. Four different formulations varying as to the type of soluble salt filler employed were used: set 1--calcium acetate, set 2--calcium gluconate, set 3--calcium propionate, and set 4--control with hydroxapatite, HA, only. Animals of each of the three sets were sacrificed in groups of 8 at postoperative week 1, 3, and 7. Histologic analysis revealed that in vivo biocompatibility and osteointegration of bone graft substitutes was optimal when calcium acetate was employed as a soluble salt filler. Other formulations demonstrated implant surface erosion and disintegration which was ultimately accompanied by an inflammatory response. This study suggested that PPF-based bone graft substitutes can be designed to provide an osteoconductive pathway by which bone will grow in faster because of its capacity to develop controlled porosities in vivo. Immediate applicability of this bone graft substitute, the porosity of which can be tailored for the reconstruction of defects of varying size and quality of the recipient bed, is to defects caused by surgical debridement of infections, previous surgery, tumor removal, trauma, implant revisions and joint fusion. Clinical implications of the relation between developing porosity, resulting osteoconduction, and bone repair in vivo are discussed.

Effect of polymer foam morphology and density on kinetics of in vitro controlled release of isoniazid from compressed foam matrices.

The purpose of this study was to compare the effect of polymer foam morphology and density prior to compaction on the kinetics of isoniazid (INH) release from the final high-density extruded matrices. The feasibility of preparing low density foams of several biopolymers, including poly(L-lactide) (PLLA), poly(glycolide) (PGA), poly(DL-lactide-co-glycolide) (PLGA), poly(gamma-benzyl-L-glutamate) (PBLG), and poly(propylene fumarate) (PPF), via a lyophilization technique was investigated. Low-density foams of PLGA, PBLG, and a mixture of PLGA and PPF were successfully fabricated by lyophilization of the frozen polymer solutions either in glacial acetic acid or in benzene. The morphology of these foams depends on the polymer as well as the solvent used in the fabrication process. Thus, PLGA produces a capillary structure when lyophilized from benzene solution and a leaflet structure from glacial acetic acid, but PBLG yields a leaflet structure from benzene. Matrices were prepared by impregnating these foams with aqueous solutions of INH, removing the water by a second lyophilization, and then compressing the low-density INH containing foams by compaction and high-pressure extrusion. The resulting nonporous matrices had densities of approximately 1.30 g/cm3. In vitro kinetics were in accord with the Roseman-Higuchi diffusion model and demonstrate that release rates depend on the initial foam density, while foam structure has little influence on the release kinetics.

Lactic/glycolic acid polymers as narcotic antagonist delivery systems.

Abstract Lactic/glycolic acid polymers of several compositions were evaluated as the vehicle material for long term, controlled delivery of narcotic antagonists. L(+)-lactic, and glycolic acids-designated L(+), and G, respectively-were converted to polymers with weight ratios of 75 L(+)/25 G, 90 L(+)/10 G, and 100 L(+). Naltrexone base and naltrexone pamoate were incorporated into these polymers as a physical blend at several drug/polymer mass ratios. The mixtures were formed into small cylinders and spheres which were suitable for subcutaneous implantation by means of a trochar. In vitro screening was carried out followed by in vivo testing in mice. Radioactive assay and direct challenge with morphine using the tail-flick test were used to evaluate the drug release. The release rates approximated zero-order kinetics for most of the release period and the narcotic antagonist response to a challenge dose of morphine was maintained from one month to over six months depending on the formulation tested. Factors affecting narcotic antagonist delivery system design were polymer composition, narcotic antagonist solubility, drug loading level of the dosage form, use of a pure polymer coating around the drug/polymer matrix, and the surface area/unit volume of the dosage form.

Influence of glial growth factor and Schwann cells in a bioresorbable guidance channel on peripheral nerve regeneration.

Using an established rat peripheral nerve regeneration model, we investigated the role of glial growth factor (GGF) in nerve regeneration in combination with a novel bioresorbable poly(lactic-co-glycolic) acid (PLGA) guide in vivo. Schwann cells, established from a 1-cm segment of excised rat sciatic nerve, were isolated and seeded onto nerve guides with or without GGF (n = 24/group). Living nerve guides were re-established in these animals, and nerve regeneration was assessed over a period of 12 weeks. Histological studies revealed a reduction in the total axon count and the number of myelinated axons in the presence of exogenously added Schwann cells compared to saline controls. In contrast, the addition of GGF alone enhanced the total number of axons and significantly increased the number of blood vessels. Although combining GGF with Schwann cells negated the enhanced numbers of axons and blood vessels seen with GGF alone, this combination resulted in the highest myelination index and the fastest conduction velocities recorded. The PLGA guide material did not trigger any histologically detectable host response and was permissive for nerve regeneration in this animal model. The results from this study demonstrate the potential utility of this guide in vivo and establish a promotional role for GGF in nerve regeneration.

Controlled release of biologically active agents for purposes of agricultural crop management

Abstract Increasing attention is being directed to reducing the amount of pesticides, herbicides, and other biologically active agents used in modern agricultural crop management. One method for reducing the amount of such agents, while still maintaining effectiveness, is to encapsulate or otherwise incorporate the active agent into some from of plastic. Such ‘filled’ plastics, usually prepared by certain techniques for standard broadcast methods used in agriculture, may be sprayed, dusted, or spread as needed. By being incorporated into the plastic, the active agent diffuses slowly, but continuously, from the plastic matrix. It has been found in numerous instances that this use of controlled release delivery systems results in using less amount of the active agent. Further, with increasing attention being directed toward biologicals, rather than organic chemicals, for use in crop management, this incorporation of the biologicals into plastic serves the role of protection of the biological, as well as providing for slow release. One method of preparing an encapsulated polymeric controlled release system will be reviewed in depth, as well as field results.

Expression of liver-specific functions by rat hepatocytes seeded in treated poly(lactic-co-glycolic) acid biodegradable foams.

Techniques of liver replacement would benefit patients awaiting donor livers and may be a substitute for transplantation in patients whose livers can regenerate. Poly(lactic-co-glycolic acid) (PLGA) copolymers are biodegradable and have been shown to be useful as scaffolds for seeding and culturing various types of cells. In this study, foam disks were prepared from PLGA (lactic-to-glycolic mole ratio of 85:15) by lyophilization of benzene (5% w/v) solutions. These disks were then used as scaffolds for rat hepatocyte culture. Foams were coated with either a type I collagen gel (0.1% w/v), coated with gelatin (5% w/v), or treated with oxygen plasma (25 W, 90 s) to modify their surface chemistry and wettability. The disks were then seeded with rat hepatocytes (10(6)/mL) and cultured for a period of 2 weeks. All surface treatments resulted in increased hydrophilicity, the greatest being obtained by collagen treatment (contact angle < 10 degrees ), and a minimal decrease in void fraction (5%). DNA content after a 2-week culture period increased proportionally with the wettability of the treated foam surface. Urea synthesis in untreated foams averaged 15.3 +/- 2.3 microg/h/microg DNA, which was significantly higher than that for controls, whereas gelatin and collagen treated foams exhibited urea synthetic rates below the control levels at all times. The DNA content decreased significantly by about 50% between days 1 and 12. PLGA foams, treated and untreated, represent a promising scaffold for scaling up hepatocyte cultures.

Tissue engineering and novel delivery systems

Biocompatibility and the Biomaterial-Tissue Interface. Tissue Engineering Equivalents. Delivery Systems. Emerging Concepts in Biomaterials. Index.

Enhanced peripheral nerve regeneration through a poled bioresorbable poly(lactic-co-glycolic acid) guidance channel

In this study we investigated the effects of materials prepared with electrical poling on neurite outgrowth in vitro and nerve regeneration in vivo. Neuro-2a cells were seeded on poled and unpoled poly(lactic-co-glycolic) (PLGA) films and observed at time periods 24, 48 and 72 h post-seeding. The percentage of cells with neurites and the neurites per cell were quantified using light microscopy. At 48 and 72 h post-seeding, both the number of cells with neurites and the neurites per cell were significantly increased on the poled films compared to those on unpoled films. An established rat sciatic nerve model was used for in vivo studies to assess the effects of PLGA guides, poled for two different periods, on peripheral nerve regeneration. Guides were inserted in rats to bridge a 1.0 cm gap created in the right sciatic nerve. After four weeks, nerves regenerated through poled guides displayed a significant increase in conduction velocity and significantly increased numbers of axons across the guides, as compared to nerves regenerating through an unpoled guidance channel. Electrical poling was shown to promote neurite growth, axon regeneration and the conduction rate of the repaired nerve. We concluded that guides prepared with electrical poling enhance peripheral nerve regeneration.