Negin Amanat

Optimal Timing of a Single Dose of Zoledronic Acid to Increase Strength in Rat Fracture Repair

We hypothesized that ZA treatment would bolster fracture repair. In a rat model for closed fracture healing, a single dose of ZA at 0, 1, or 2 wk after fracture significantly increased BMC and strength of the healed fracture. Delaying the dose (1 or 2 wk after fracture) displayed superior results compared with dosing at the time of fracture.

Manipulation of the Anabolic and Catabolic Responses With OP‐1 and Zoledronic Acid in a Rat Critical Defect Model

Bone repair involves both anabolic and catabolic responses. We hypothesized that anabolic treatment with OP‐1 (BMP‐7) and anti‐catabolic treatment with zoledronic acid could be synergistic. In a rat critical defect, this combination therapy produced significant increases in new bone volume and strength.

Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

INTRODUCTION It has been widely assumed that osteoclasts play a pivotal role during the entire process of fracture healing. Bisphosphonates (BPs) are anti-catabolic agents commonly used to treat metabolic bone diseases including osteoporosis, minimizing fracture incidence. Yet, fractures do occur in these patients and the potential for negative effects of BPs on healing has been suggested. We aimed to examine the effect of different dosing regimes of the potent BP zoledronic acid (ZA) on early endochondral fracture repair and later callus remodeling in a normal bone healing environment. METHODS Saline, a Bolus dose of 0.1 degrees mg/kg ZA or 5 weekly divided doses of 0.02 degrees mg/kg of ZA commenced 1 week post operatively in a rat closed fracture model. Samples at 1, 2, 4 and 6 weeks post fracture were used to analyze initial fracture union, and 12 and 26 weeks post fracture to investigate the progress of remodeling. RESULTS ZA did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the progressive reduction of cartilaginous soft callus between control and treatment groups over time. ZA treatment increased hard callus bone mineral content (BMC), volume and increased callus strength at 6 and 26 weeks post fracture. Hard callus remodeling commenced at 4 weeks post fracture with Bolus ZA treatment but was delayed until after 6 weeks in the Weekly ZA group. By 12 and 26 weeks, Bolus ZA had equivalent callus content of remodeled neo-cortical bone to the Saline controls, whereas Weekly ZA remained reduced compared to Saline controls at these times (P<0.01). Callus material properties such as peak stress were significantly reduced in both ZA groups at 6 weeks. At 26 weeks, Bolus ZA-treated calluses generated peak stress equivalent to control values, whereas Weekly ZA callus peak stress remained significantly reduced, indicating remodeling delay. CONCLUSIONS Osteoclast inhibition with ZA does not delay endochondral fracture repair in healthy rats. Bolus ZA treatment increased net callus size and strength at 6 weeks while allowing hard callus remodeling to proceed in the long term, albeit more slowly than control. Prolonged bisphosphonate dosing during repair does not delay endochondral ossification but can significantly affect remodeling long after the drug is ceased.

Welding methods for joining thermoplastic polymers for the hermetic enclosure of medical devices

New high performance polymers have been developed that challenge traditional encapsulation materials for permanent active medical implants. The gold standard for hermetic encapsulation for implants is a titanium enclosure which is sealed using laser welding. Polymers may be an alternative encapsulation material. Although many polymers are biocompatible, and permeability of polymers may be reduced to acceptable levels, the ability to create a hermetic join with an extended life remains the barrier to widespread acceptance of polymers for this application. This article provides an overview of the current techniques used for direct bonding of polymers, with a focus on thermoplastics. Thermal bonding methods are feasible, but some take too long and/or require two stage processing. Some methods are not suitable because of excessive heat load which may be delivered to sensitive components within the capsule. Laser welding is presented as the method of choice; however the establishment of suitable laser process parameters will require significant research.

Intermittent PTH((1-34)) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures.

Intermittent Parathyroid Hormone (PTH)((1-34)) has an established place in osteoporosis treatment, but also shows promising results in models of bone repair. Previous studies have been dominated by closed fracture models, where union is certain. One of the major clinical needs for anabolic therapies is the treatment of open and high energy fractures at risk of non-union. In the present study we therefore compared PTH((1-34)) treatment in models of both open and closed fractures. 108 male Wistar rats were randomly assigned to undergo standardized closed fractures or open osteotomies with periosteal stripping. 27 rats in each group were treated s.c. with PTH((1-34)) at a dose of 50 mug/kg 5 days a week, the other 27 receiving saline. Specimens were harvested at 6 weeks for mechanical testing (n=17) or histological analysis (n=10). In closed fractures, union by any definition was 100% in both PTH((1-34)) and saline groups at 6 weeks. In open fractures, the union rate was significantly lower (p<0.05), regardless of treatment. In open fractures the mechanically defined union rate was 10/16 (63%) in saline and 11/17 (65%) in PTH((1-34)) treated fractures. By histology, the union rate was 3/9 (33%) with saline and 5/10 (50%) with PTH((1-34)). Radiological union was seen in 13/25 (52%) for saline and 15/26 (58%) with PTH((1-34)). Open fractures were associated with decreases in bone mineral content (BMC) and volumetric bone mineral density (vBMD) on quantitative computerized tomography (QCT) analysis compared to closed fractures. PTH((1-34)) treatment in both models led to significant increases in callus BMC and volume as well as trabecular bone volume/total volume (BV/TV), as assessed histologically (p<0.01). In closed fractures, PTH((1-34)) had a robust effect on callus size and strength, with a 60% increase in peak torque (p<0.05). In the open fractures that united and could be tested, PTH((1-34)) treatment also increased peak torque by 49% compared to saline (p<0.05). In conclusion, intermittent PTH((1-34)) produced significant increases in callus size and strength in closed fractures, but failed to increase the rate of union in an open fracture model. In the open fractures that did unite, a muted response to PTH was seen compared to closed fractures. Further research is required to determine if PTH((1-34)) is an appropriate anabolic treatment for open fractures.

An Interlocking Ligamentous Spinal Disk Arthroplasty with Neural Network Infrastructure

An elastomeric spinal disk prosthesis design (BioFI™) with vertebral interlocking anchors has been modified using an embedded TiNi wire array. Bioinert styrenic block copolymer (Kraton®) and polycarbonate urethane (Bionate®) thermoplastic elastomer (TPE) matrices were utilized. Fatigue resistant NiTi wire was pretreated to induce superelastic martensitic microstructure. Stent-like helical structures were produced for incorporation within homogenous TPE matrix. Composite prototypes were fabricated in a vacuum hot press using transfer moulding techniques. Implant prototypes were subject to axial compression using a BOSE ® ELF3400. The NiTi reinforced implants exhibited reduction in axial strain, compliance, and creep compared to TPE controls. The axial properties of the NiTi reinforced Bionate® BioFI™ implant best approximated those of a spinal disk followed by Kraton®-NiTi, Bionate® and Kraton® prototypes. An ovine lumbar segment biomechanical model was used to characterize the disk prosthesis prototypes. Specimens were subject to 7.5Nm pure moments in axial rotation, flexion-extension and lateral bending with a custom jig mounted on an Instron® 8874. The motion preserving ligamentous nature of this arthroplasty prototype was not inhibited by NiTi reinforcement. Joint stiffness for all prototypes was significantly less than the intact and discectomy controls. This was due to lack of vertebral anchor rigidity rather than BioFI™ motion segment matrix type or reinforcement. Implant stress profiles for axial compression and axial torsion conditions were obtained using finite element methods. The biomechanical testing and finite element modelling both support existing BioFI™ design specifications for higher modulus vertebral anchors, endplates and motion segment periphery with gradation to a low modulus core within the motion segment. This closer approximation of the native spinal disk form translates to improvements in prosthesis biomechanical fidelity and longevity. Axial compressive strain induced within a TiNi reinforced Kraton® BioFI™ was found to be linearly proportional to the NiTi helical coil electrical resistance. This neural network capability delivers opportunities to monitor and telemeterize in situ multiaxis joint structural performance and in vivo spine biomechanics.

Optimal process parameters for thermoplastic polyetheretherketone joints fabricated using transmission laser welding and Lumogen® IR absorptive pigment

This study investigates the effects of the process parameters (laser power and irradiation time) on the bond quality of transmission laser welded polyetheretherketone. Commercially available Lumogen® IR pigment was added to the bulk of the polymer for laser absorption. Quasisimultaneous beam configuration was used to weld injection molded samples of 0.7 mm thickness in a lap joint configuration. Combinations of laser power (40–80 W) and irradiation times (10–50 s) were investigated. The laser power was found to have the most effect on weld strength, while irradiation time did not have a marked effect on weld strength. At optimal process conditions, the weld strength ranged from 20 to 45 MPa. High variability in weld strength was seen within groups with identical process parameters and was attributed to the variability in material morphology as a result of injection molding. X-ray tomography was utilized to view intact weld interfaces. A significant finding was the presence of voids (up to 0.5 mm diameter)...