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Biomedical subjects

D L Wise

Publications and source records attributed to D L Wise.

At least 37 records · Page 2Linked to original sources
PubMed1999

Improved osteoconduction of cortical bone grafts by biodegradable foam coating.

Alteration of the geometrical surface configuration of cortical bone allografts may improve incorporation into host bone. A porous biodegradable coating that would maintain immediate structural recovery and subsequently allow normal graft healing and remodeling by promoting bony ingrowth could provide an osteoconductive surface scaffold. We investigated the feasibility of augmenting cortical bone grafts with osteoconductive biodegradable polymeric scaffold coatings. Three types of bone grafts were prepared: Type I--cortical bone without coating (control), Type II--cortical bone coated with PLGA-foam, Type III--cortical bone coated with PPF-foam. The grafts were implanted into the rat tibial metaphysis (16 animals for each type of bone graft). Post-operatively the animals were sacrificed at 2 weeks and 4 weeks (8 animals for each type of bone graft at each time point). Histologic and histomorphometric analysis of grafts showed that the amount of new bone forming around the foam-coated grafts was significantly higher than in the control group (uncoated; p < 0.02). Although both foam formulations were initially equally osteoconductive, PLGA-based foam coatings appeared to have degraded at two weeks postoperatively, whereas PPF-based foam coatings were still present at 4 weeks postoperatively. While significant resorption was present in control allografts with little accompanying reactive new bone formation, PLGA-coated bone grafts showed evidence of bone resorption and subsequent bony ingrowth earlier than those coated with PPF-based foams suggesting that PPF-coated cortical bone grafts were longer protected against host reactions resulting in bone resorption.

Absorbable Implants↗
PubMed1999

Augmentation of osteoinduction with a biodegradable poly(propylene glycol-co-fumaric acid) bone graft extender. A histologic and histomorphometric study in rats.

We investigated the feasibility of enhancing the regeneration of skeletal tissues by augmenting bone grafts with a composite biodegradable bone graft extender material based on the polymer poly(propylene fumarate), PPF. The material was mixed with autograft and allograft and placed directly into a cylindrical metaphyseal defect made in the rat tibia. These formulations were compared to defects without any graft material, autografts, allografts and PPF alone. Nine animals were included in each group. Animals were sacrificed at 1 and 4 weeks postoperatively. Implantation sites were then evaluated using histologic and histomorphometric methods. Results of this study showed that defects did not heal in sham operated animals. In the experimental groups, there was early new woven bone formation in the autograft group with near complete healing of the defect at four weeks. When PPF was used alone, gradual ingrowth of new bone was seen. Mixing of the PPF bone graft extender with either allograft or autograft material resulted in enhancement of new bone formation with both allo- and autograft. However, significantly more new bone formation than in the autograft group was only seen when the PPF bone graft extender was mixed with fresh autograft. Histomorphometry corroborated these findings. Results of this study suggest that a PPF-based material may be used to increase the volume of smaller amounts of bone grafts supporting the concept of "bone graft extenders" by application of engineered biodegradable porous scaffolds.

Absorbable Implants↗
PubMed1997

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.

Antitubercular Agents↗
PubMed1996

Mechanisms of isoniazid release from poly(d,l-lactide-co-glycolide) matrices prepared by dry-mixing and low density polymeric foam methods.

The release mechanisms of a small molecular drug from biodegradable poly(d,l-lactide-co-glycolide) (PLGA) cylindrical matrices were investigated. Isoniazid (INH), one of the most effective drugs against tuberculosis (TB), was selected as the model drug. Controlled-release matrices consisting of the drug and polymer were fabricated by two methods. The first of these, the dry-mixing method, involved the extrusion of a mixture of micronized drug and polymer particles as rods. In the second technique, the low density polymeric foam method, drug particles were enclosed in the cells of porous polymeric foams prior to extrusion. In vitro, the dry-mixed matrices released INH more rapidly than the polymeric foam matrices. The Roseman-Higuchi diffusion model, which had previously been found to be effective in analyzing the release kinetics of INH from the dry-mixed matrices, also fit the kinetics of INH released from matrices prepared from polymeric foams. This indicated that the release was still diffusion-controlled rather than degradation-controlled. The release mechanisms were further investigated, and two diffusion mechanisms, pore diffusion and lattice diffusion, were proposed for the INH controlled-release matrices according to the way in which they were prepared. Matrices prepared by the dry-mixing method appear to segregate drug particles along polymer grain boundaries and thus have a pore diffusion mechanism, while matrices prepared by the foam method entrap drug within the porous structure of foams and thus display a lattice diffusion mechanism. Theoretically, these two diffusion mechanisms can be identified by their activation energies for diffusion. With varying in vitro temperature, the activation energies were calculated from plots of ln (DIT) vs T-1 and in D vs T-1, where D is the diffusivity and T is the in vitro temperature in K. According to the results, we concluded that the INH from the dry-mixed matrices diffused through the drug channels filled with the medium, while the INH from the foam matrices diffused through the polymer lattice.

Antitubercular Agents↗
PubMed1995

Analysis of a vinyl pyrrolidone/poly(propylene fumarate) resorbable bone cement.

A resorbable bone cement was formulated from N-vinyl-2-pyrrolidinone (VP), the unsaturated polyester poly(propylene fumarate) (PPF), and the inorganic filler tribasic calcium phosphate (hydroxy apatite). Cure, initiated by benzoyl peroxide and accelerated by N,N-dimethyl-p-toluidine, resulted in the formation of VP crosslinks between polyester chains. During cure the cement hardened from a viscous moldable putty to a rigid structure with a shore D hardness of 50-60. The purpose of this study was to determine the fractions of PPF and VP incorporated into the crosslinked structure. Dissolution of the cured cement in water followed by extraction of the residue in tetrahydrofuran indicated that over 90% of the PPF was crosslinked over the range of PPF/VP ratios explored, but that the fraction of VP used in formation of crosslinks depended linearly on the PPF/VP ratio. Kinetic analysis of these data suggests that k'pp/kpf (the reactivity ratio) was approximately 2.0 where k'pp is the rate constant for the addition of VP radical to VP monomer leading to formation of poly(vinyl pyrrolidone), and kpf is for the addition of VP radical to PPF unsaturation.

Biocompatible Materials↗
PubMed1995

Pulsatile release of FSH for superovulation in cattle.

The studies reported here were directed towards the development of an implantable microcapsule which "pulses" release of follicle stimulating hormone, FSH, for application to superovulating cows. Final dose forms were administered using membrane-coated cylinders. The "pulse" of the FSH is achieved by membrane encapsulation of an effervescent/swelling core containing citric acid, sodium bicarbonate, glucose and FSH. Entry of water results in sufficient pressure increase (by gas generation) to rupture ("burst") the membrane. Time to rupture is dependent upon several factors, such as membrane permeability and thickness, and core composition and loading. The final dose forms were implanted by means of a trochar. This system was tested in sheep to substantiate in vivo "burst" times and then tested in cows to determine efficacy. In vivo burst times in sheep varied from 8 to 96 hr, based upon maximal FSH values in blood serum, and generally paralled the planned times resulting from in vitro tests. Multiple capsules designed to release FSH as a pulse or steady state were tested on a limited number of cows plus a control (n = 10). Four of the combinations resulted in 11, 11, 14 and 16 ovulations, indicating that further development has promise of providing a one-injection system using FSH for superovulating cattle.

Journal Article↗
PubMed1994

Experimental chemotherapy of tuberculosis using single dose treatment with isoniazid in biodegradable polymers.

In previous studies we showed that a single implant of polylactic-co-glycolic acid (PLGA) polymer as a film containing isoniazid ensured sustained release of the drug for up to 4 weeks. These studies have been extended to PLGA polymer as a rod which is retrievable. Both types of implant gave therapeutically active levels of free isoniazid in liver and urine for prolonged periods. We assessed the in vivo chemotherapeutic efficacy of the rod implant against heavy infections of virulent Mycobacterium tuberculosis in C57Bl/6 mice. The chemotherapeutic data essentially confirmed the bioavailability data. In one chemotherapeutic study, one (7%) out of 15 mice which received the isoniazid polymer implant died within 30 days of bacterial challenge, while none of those receiving daily oral treatment died. In contrast, 14 (93%) of the 15 control mice died during the same period. In a second study similar results were obtained.

Animals↗
PubMed1994

Bioavailability and chemotherapeutic activity of clofazimine against Mycobacterium avium complex infections in beige mice following a single implant of a biodegradable polymer.

We have studied the bioavailability of clofazimine following administration of a single dose of the drug in the biodegradable polymer polylactic-co-glycolic acid (PLGA). We compared the levels of clofazimine achieved in the liver with single implants with those obtained with daily oral treatment. Even though the levels achieved with implants were much lower than those obtained after daily oral treatment, they were higher than the MIC of clofazimine for Mycobacterium leprae, Mycobacterium tuberculosis and Mycobacterium avium complex (MAC). Experimental studies in beige mice after infection with MAC strain 101 showed similar reductions in cfu counts, after both single dose polymer and daily oral treatment. Macroscopically, hyperpigmentation giving an orange-yellow colour to all visceral organs, was seen in animals after daily oral treatment but not in those animals that received polymer implants.

Animals↗
PubMed1993

Developmental toxicity of orally administered thiabendazole in Sprague-Dawley rats and New Zealand white rabbits.

The developmental toxicity of thiabendazole (TBZ) was assessed in studies in New Zealand white rabbits and Sprague-Dawley rats. The doses of TBZ for these studies were based on decreases in maternal weight gain in dose range-finding studies in pregnant females of each species. In rabbits, TBZ was administered orally at doses ranging from 24 to 600 mg/kg body weight/day in two separate studies. In rats, TBZ was administered at doses of 10, 40 or 80 mg/kg body weight/day. In all studies, TBZ was administered daily by gavage in aqueous suspension on gestation days 6 to 17. In the initial rabbit study, weight loss occurred in the 600 mg/kg/day group and weight gain decreased in the 120 mg/kg/day group. In addition, there were four complete litter resorptions and four abortions in the 120 and 600 mg/kg/day groups, respectively. To determine whether these changes (known to occur spontaneously in rabbits) were reproducible, the study was repeated. In this study, decreased maternal weight gain and decreased foetal weights were found at 600 mg TBZ/kg/day, but there was no evidence of selective developmental toxicity. Similarly, in rats TBZ produced decreased maternal weight gain (12 to 26%) associated with slight (5 to 7%) decreases in foetal weights at doses of 30 and 80 mg/kg/day. No changes were found at 10 mg TBZ/kg/day and no evidence of selective developmental toxicity or teratogenicity was found at any dose. On the basis of these results, it is concluded that TBZ is not teratogenic or selectivity foetotoxic in rats or rabbits.

Abnormalities, Drug-Induced↗
PubMed1991

Sustained release of isoniazid in vivo from a single implant of a biodegradable polymer.

In order to solve the problem of poor patient compliance, attempts were made to prolong the bioavailability of antimycobacterial drugs after a single administration. A single implant of polylactic-co-glycolic acid (PLGA) co-polymer containing isoniazid ensured its sustained release up to 6 weeks. The levels are comparable with those obtained from daily doses. Homogenates of liver and lungs from animals killed at 6 weeks after a single implant showed high antimycobacterial activity against Mycobacterium tuberculosis. Sera from the implant and daily dose group animals showed no significant difference in renal, hepatic and haematological parameters. The implant caused no local or systemic toxicity.

Biocompatible Materials↗
PubMed1983

Pharmacokinetic quantitation of naltrexone controlled release from a copolymer delivery system.

Naltrexone release rates from a controlled release delivery system have been quantitated over a time period greater than one month in the monkey. The method requires calibration of the pharmacokinetic parameters of each monkey utilizing an intravenous bolus dose and assay of unchanged naltrexone levels in plasma as a function of time after dosing. Also required are periodic plasma levels of unchanged naltrexone obtained subsequent to administration of the delivery system. Release rates are then calculated as well as the total amount released. Application of the methodology to a biodegradable copolymer naltrexone delivery system in three monkeys showed an initial release rate of 3-8% of the dose per day over the first 3-5 days followed by a slow, rather constant release rate of 1-3% per day from day 5 to the time of the last measurable plasma sample (36-43 days). Comparison of alternative calculation methods using both experimental and simulated plasma naltrexone data verified the accuracy of the release rate calculations. The sum of the calculated total amount of naltrexone released plus the assayed amount remaining in the delivery system after removal from the animal accounted for 91-94% of the administered dose in the two monkeys in which complete data were obtained.

Animals↗
PubMed1981

Development of drug delivery systems for use in treatment of narcotic addiction.

The long term goal of the NIDA narcotic antagonist program of developing an implantable, biodegradable, naltrexone/PLGA matrix system which will sustain the delivery of naltrexone to biological systems for one month has been achieved. The dosage forms which provide the desired delivery characteristics are 1.5 mm diameter beads composed of 70% by weight naltrexone base in 40,000 molecular weight, 90L/10G poly (L(+)-lactic-co-glycolic acid). Other dosage forms, including 1.5 mm diameter rods which provide 6 months' naltrexone release, finely divided injectable powders which provide up to 30 days' naltrexone release, and 1.5 mm diameter rods which provide 2 weeks' sustained delivery of morphine, have also been investigated. In vitro and in vivo release rates have been determined by measuring chemical concentrations in pH 7 buffer solution and urine, respectively. In vivo efficacy of naltrexone sustained delivery devices has been measured by direct challenge with morphine (Dewey-Harris mouse tail-flick test) and inhibition of morphine self-administration in monkeys. Good Manufacturing Practices documentation has been developed and used to produce a large batch of the 1.5 mm diameter naltrexone bead dosage forms at an FDA-registered pharmaceutical manufacturer. These beads, produced at the University of North Carolina School of Pharmacy, are awaiting use in human clinical trials.

Animals↗
PubMed1980

Long-term controlled delivery of levonorgestrel in rats by means of small biodegradable cylinders.

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.

Animals↗
PubMed1978

Sustained release of sulphadiazine.

An implantable system was developed which released sulphadiazine in mice over an extended period of time efficacious against infective challenges by Plasmodium berghei. The most successful preparation was a copolymer of L(+)-lactic acid + (+/-)-lactic acid (90 and 10% by weight, respectively) with a molecular weight of 150 000, with which sulphadiazine was mixed at 33.3% of the total weight, in a formulation as beads of 1.5 mm diameter. This preparation released sulphadiazine at a nearly constant rate over three months as measured by the appearance in urine of mice of radioactivity from [35S] sulphadiazine in transplanted material. When implanted in mice, the beads gave effective protection against repetitive (weekly) infective challenges with P. berghei by implanted beads at dosages equivalent to 57 mg kg(-1) sulphadiazine and greater over 21 weeks.

Animals↗
PubMed1977

Evaluation of wound-covering materials.

Physical and in vivo (burned rat model) evaluations as wound coverings were performed for 1) a freeze-dried collagen/poly (epsilon-caprolactone) (PCL) film laminate, 2) a freeze-dried PCL "foam"/PCL film laminate, and 3) a heat-dried collagen/PCL film laminate. Porcine skin and cadaver skin were also evaluated in vivo for the purpose of comparison. Water-vapor transmission rates and Young's moduli were measured. The degree of adherence of the coverings to the wound were measured. Grafts which became significantly adherent (greater than 150 dyne/cm2) to the wound within 1 day were most successful in promoting the formation of a viable tissue bed which appeared ready to accept further grafting. The force required to remove the PCL foam laminate from a full-thickness excision wound was found to increase from 170 dyne/cm2 on the first day postgraft to 1500 dyne/cm2 by the tenth day. The force required to remove freeze-dried collagen laminate remained constant at 200 dyne/cm2 over the 10 day test period. For the heat-dried collagen laminate, a force of only 50 dyne/cm2 was required on day 1, increasing to 200 dyne/cm2 on day 6. Insensible water-loss rates of animals grafted with the laminates were found to be similar to those from animals with human cadaver skin grafts and less than that from animals with porcine skin grafts. When moistened, the laminates prepared using the freeze-dried materials were flexible and somewhat transparent permitting observation of the wound.

Animals↗