David R. Pichora

Biodegradable Controlled Antibiotic Release Devices for Osteomyelitis: Optimization of Release Properties

Abstract— Controlled antibiotic release films, melt‐extruded cylinders, and suspension‐extruded/coated cylinders were manufactured from biodegradable poly(d, l‐lactide) (PDLLA) and poly(d, l‐lactide‐co‐∈‐caprolactone). These devices have potential application in the treatment of osteomyelitis. The in‐vitro release properties of the devices were examined with drug loadings varying from 16 to 50%. Gentamicin sulphate films and melt‐extruded gentamicin/PDLLA cylinders demonstrated a large initial burst and incomplete release. The films and melt‐extruded cylinders made from poly(d, l‐lactide‐co‐∈‐caprolactone), low mol. wt poly(d, l‐lactide), and a mixture of d, l‐lactic acid oligomer and high mol. wt poly(d, l‐lactide), did not remain intact during the entire release period. While this is undesirable, these materials do have the advantage of not requiring a processing temperature of greater than 110°C. Antibiotic release from high mol. wt PDLLA‐coated gentamicin/PDLLA cylinders, with 40 and 50% loading, was very rapid. The antibiotic could only diffuse out through the open ends of the cylinder. Coated gentamicin sulphate cylinders with 20 and 30% drug loading gave the most promising properties in terms of a small initial burst, and a gradual and sustained release. The release rate and duration from the coated cylinders could be adjusted by cutting the cylinder into different lengths; the time required for 90% of the entrapped gentamicin to be released into water from 30% loaded PDLLA‐coated cylinders 0·2, 0·4, 0·7 and 1 cm in length was 1000, 1700, 2300, and 2800 h, respectively. This offers a convenient method to adjust the release to meet the specific antibiotic requirement of different patients. Cephazolin and benzylpenicillin were found to be unsuitable for sustained release longer than 300 h due to the hydrolytic instability of the drugs in water.

An Investigation of Poly(lactic acid) Degradation

To elucidate the degradation mechanism of poly(lactic acid), the decrease in the intrinsic viscosity of poly(D,L-lactide) in a homogeneous water/ acetone solution was investigated. The hydrolysis of poly(D,L-lactic acid) in water/acetone solution can be catalyzed by protons. The molecular weight degradation of solid poly(D,L-lactic acid) in water was primarily affected by the degree of polymer purity. Polymerization conditions such as initiator concen tration, temperature and time did not have an obvious effect on the molecular weight degradation. In the case of polymer samples with low purity (i.e., directly polymerized or containing solvent or oligomer), degradation was ini tially very rapid. On the other hand, initial degradation of purified polymer was very slow before accelerating.

An investigation of the synthesis and thermal stability of poly(dl-lactide)

SummaryThe synthesis and thermal degradability of poly (DL-lactide) were investigated. Key factors affecting the polymer molecular weight were found to be monomer recrystallization, initiator concentration and the vacuum level during drying/sealing of the polymerization reaction ampoule. It was found that poly (DL-lactide) is thermally unstable above its melting temperature. Monomer recrystallization, polymer precipitation and a low initiator content of the polymer significantly inhibited the rate and extent of thermal degradation.

Glenoid cancellous bone strength and modulus

The objectives of this study were to determine the strength and modulus of glenoid cancellous bone, including regional variations. The motivations were: to select a suitable bone substitute for standardized testing of glenoid prosthesis loosening, to assist in shoulder prosthesis design and to provide input data for finite element analyses. Ten glenoids from eight cadavers (mean age, 81) were tested by in situ indentation. Mean strength ranged from 6.7 to 17 MPa for the ten glenoids, the overall mean being 10.3 MPa. Mean E moduli ranged from 67 to 171 MPa for the individual glenoids, the overall mean being 99 MPa. These values are likely at the lower end of what would be expected for normal bone since strength and modulus decrease with age and the available specimens were older. These values may be appropriate for prosthesis design, however, since mechanical properties are reduced in rheumatoid arthritic bone. Regional trends were very similar for modulus and strength. The strongest region was postero-superior. The central column, correlating with the keel position in many glenoid components, was weaker than both the anterior and posterior regions but deeper. A large drop in strength and modulus below the subchondral layer emphasizes the importance of maintaining this layer during prosthetic replacement.

Glenohumeral contact forces

Abstract Glenohumeral contact forces have only been calculated previously either for simple abduction or for athletic activities. The objective of this study was to determine the glenohumeral contact forces for tasks which are demanding of the shoulder but which would commonly be performed by older people. The functional tasks chosen were using the arms to stand up from and sit down into a chair, walking with a cane, lifting a 5 kg box to shoulder height with both hands, and lifting a 10 kg suitcase. The trunk angles, arm angles and hand loads of six healthy subjects, average age 55 years, were recorded. This information was input into a biomechanical computer model which optimized the muscle force distribution by minimizing the sum of squared muscle stresses subject to constraints on the maximum muscle forces and maintaining the direction of the resultant force within the glenoid fossa. Average contact forces ranged from 1.3 to 2.4 times body weight (930-1720 N), the highest force being for lifting a suitcase. This latter value would be even higher if lifting either a greater load or to a greater height. Thus, contact forces at the shoulder should not be underestimated. This study provides functionally relevant contact forces which can be used for mechanical testing or finite element modelling of shoulder prostheses.

Surgical implications of varus deformity of the knee with obliquity of joint surfaces

Some arthritic knees with varus deformity show excessive valgus angulation of the femoral joint surface with proximal tibia vara. This causes a downward and medial inclination of the articular surfaces in the coronal plane. The patients we studied had a medial shift of the standing load-bearing axis, and arthritic changes mainly in the medial compartment. Some also had lateral tibial subluxation with twisting of the distal femur and proximal tibia in opposite directions. We assessed the articular geometry by precise radiographic analysis, and compared the results with those in normal volunteers and a group of osteoarthritic patients. The prevalence of this type of deformity in our osteoarthritic patients was 11.5%; its recognition allows the use of specific operative correction that may include double osteotomy or the precise orientation of prosthetic components.

Biodegradable Polymers for Orthopedic Applications

Abstract Polymeric materials and their composites have been employed in a variety of medical and surgical applications, such as tissue replacement and support. In the case of biodegradable polymers, primary areas of application include sutures, macroscopic implants for fixation, and drug release systems [1-4].

Biomechanically constrained groupwise ultrasound to CT registration of the lumbar spine

We present a groupwise US to CT registration algorithm for guiding percutaneous spinal interventions. In addition, we introduce a comprehensive validation scheme that accounts for changes in the curvature of the spine between preoperative and intraoperative imaging. In our registration methodology, each vertebra in CT is treated as a sub-volume and transformed individually. A biomechanical model is used to constrain the displacement of the vertebrae relative to one another. The sub-volumes are then reconstructed into a single volume. During each iteration of registration, an US image is simulated from the reconstructed CT volume and an intensity-based similarity metric is calculated with the real US image. Validation studies are performed on CT and US images from a sheep cadaver, five patient-based phantoms designed to preserve realistic curvatures of the spine and a sixth patient-based phantom where the curvature of the spine is changed between preoperative and intraoperative imaging. For datasets where the spine curve between two imaging modalities was artificially perturbed, the proposed methodology was able to register initial misalignments of up to 20mm with a success rate of 95%. For the phantom with a physical change in the curvature of the spine introduced between the US and CT datasets, the registration success rate was 98.5%. Finally, the registration success rate for the sheep cadaver with soft-tissue information was 87%. The results demonstrate that our algorithm allows for robust registration of US and CT datasets, regardless of a change in the patients pose between preoperative and intraoperative image acquisitions.

Development of a Three-Dimensional Finite Element Model for Carpal Load Transmission in a Static Neutral Posture

AbstractA three-dimensional developmental finite element model has been created to analyze load transmission pathways in the constrained carpus during static compressive loading. The bone geometry was extracted from an in vivo computed tomography scan using a combination of commercial and proprietary software. The complete geometry, including bone, cartilage, and ligament tissues, was compiled using a commercial finite element program. This model extends the state of biomechanical modeling by being the first to incorporate all eight carpal bones of the wrist and the related soft tissues in three dimensions. The model results indicate that cartilage material modulus and unconstrained carpal rotation have substantial impacts on the articular contact patterns and pressures.

A mechanistic study of antibiotic release from biodegradable poly(d,1-lactide) cylinders

Abstract Biodegradable poly(d,1-lactide) (PDLLA) coated gentamicin/PDLLA and cefazolin/PDLLA and cefazolin/PDLLA cylinders were made for the controlled release of antibiotics. The antibiotic release properties as well as release mechanisms (i.e., diffusion through channel, osmotic pressure, and polymer degradation) were investigated. Water soluble antibiotics could only be released through channels formed by connected drug particles and through polymer mass loss. Osmotic pressure played a key role by turning isolated drug clusters into connected channels through fracturing of the polymer matrix. The osmotic process of turning isolated clusters into connected clusters required time. This in turn gave a more gradual and sustained release than pure diffusion-through-channel release (i.e., without osmotic pressure effect involved). The effect of polymer biodegradation on release was significant when polymer mass loss started and at the same time there was a substantial amount of drug remaining in the device. In this case drug was released along with polymer mass loss. The cylinder core degraded faster than the cylinder shell when the longer gentamicin device was incubated in salt eluent. Gentamicin sulface remained in the core and therefore catalysed the polymer degradation. For the release into water or low osmotic eluent, three critical factors affected the release properties, namely drug loading, drug particle size, and length of the coated cylinder. For antibiotic release from the coated cylinder with drug loading below the percolation threshold, as in the case of the 30 wt% loaded gentamicin cylinder, the mechanism was a combination of pure diffusion-through-channels and osmotic pressure-induced diffusion-through-channels. Above the threshold (e.g., 40 wt%-50 wt% loaded gentamicin cylinders), the release was purely diffusion-through-channels and was very fast. A large drug particle size resulted in a large degree of pure diffusion-through-channel at the same drug loading. The longer the cylinder, the longer and the slower the release. This gave a convenient method of being able to adjust the release properties.