Globus Lucidus: A porcine study of an intracranial implant designed to deliver closed, repetitive photodynamic and photochemical therapy in glioblastoma.

OBJECTIVE: Herein we describe initial results in a porcine model of a fully implantable device designed to allow closed, repetitive photodynamic treatment of glioblastoma (GBM). METHODS: This implant, Globus Lucidus, is a transparent quartz glass sphere with light-emitting diodes releasing wavelengths of 630 nm (19.5 mW/cm2), 405 nm (5.0 mW/cm2) or 275 nm (0.9 mW/cm2). 5-aminolevulinic acid was the photosensitizing prodrug chosen for use with Globus Lucidus, hence the implants illuminated at 630 nm or 405 nm. An additional 275 nm wavelength-emittance was included to explore the effects of photochemical therapy (PCT) by ultraviolet (UV) light. Twenty healthy domestic pigs underwent right-frontal craniotomies. The Globus Lucidus device was inserted into a surgically created right-frontal lobe cavity. After postoperative recovery, irradiation for up to 30 min daily for up to 14 d, or continuous irradiation for up to 14.6 h was conducted. RESULTS: Surgery, implants, and repeated irradiations using the different wavelengths were generally well tolerated. Social behavior, wound healing, body weight, and temperature remained unaffected. Histopathological analyses revealed consistent leukocyte infiltration around the intracerebral implant sites with no significant differences between experimental and control groups. CONCLUSION: This Globus Lucidus porcine study prepares the groundwork for adjuvant, long-term, repeated PDT of the GBM infiltration zone. This is the first report of a fully implantable PDT/PCT device for the potential treatment of GBM. A preclinical effectivity study of Globus Lucidus PDT/PCT is warranted and in advanced stages of planning.

Biomechanical testing of osteosynthetic locking plates for proximal humeral shaft fractures - a systematic literature review.

Proximal humeral shaft fractures can be treated with helically deformed bone plates to reduce the risk of iatrogenic nerve lesion. Controversially to this common surgical technique that was first established in 1999, no biomechanical investigation on humeral helical plating is recorded by other reviews, which focus on proximal fractures exclusively. Does an additional scope for shaft fractures reveal findings of helical testing? The present systematic literature review was performed based on guidelines by Kitchenham et al. to systematically search and synthesize literature regarding biomechanical testing of osteosynthetic systems for proximal humeral shaft fractures. Therefore, a systematic approach to search and screen literature was defined beforehand and applied on the findings of the database PubMed®. Synthesized information of the included literature was categorized, summarized and analyzed via descriptive statistics. Out of 192 findings, 22 publications were included for qualitative synthesis. A wide range of different test methods was identified, leading to a suboptimal comparability of specific results between studies. Overall, 54 biomechanical test scenarios were identified and compared. Physiological based boundary conditions (PB-BC) were referenced in 7 publications only. One study of testing straight and helical dynamic compression plates without PB-BCs was identified, showing significant differences under compressional loading. The absence of test standards of specific fields like humeral fractures lead to a high variance in biomechanical testing of osteosynthetic locking plates for proximal humeral shaft fractures. Physiological approaches offer realistic test scenarios but need to be uniformed for enhanced comparability between studies. The impact of helically deformed locking plates under PB-BC was not identified in literature.

Photodynamic Therapy Combined with Bcl-2/Bcl-xL Inhibition Increases the Noxa/Mcl-1 Ratio Independent of Usp9X and Synergistically Enhances Apoptosis in Glioblastoma.

The purpose of this study was to assess in vitro whether the biological effects of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy are enhanced by inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL in different glioblastoma models. Pre-clinical testing of a microcontroller-based device emitting light of 405 nm wavelength in combination with exposure to 5-ALA (PDT) and the Bcl-2/Bcl-xL inhibitor ABT-263 (navitoclax) was performed in human established and primary cultured glioblastoma cells as well as glioma stem-like cells. We applied cell count analyses to assess cellular proliferation and Annexin V/PI staining to examine pro-apoptotic effects. Western blot analyses and specific knockdown experiments using siRNA were used to examine molecular mechanisms of action. Bcl-2/Bcl-xL inhibition synergistically enhanced apoptosis in combination with PDT. This effect was caspase-dependent. On the molecular level, PDT caused an increased Noxa/Mcl-1 ratio, which was even more pronounced when combined with ABT-263 in a Usp9X-independent manner. Our data showed that Bcl-2/Bcl-xL inhibition increases the response of glioblastoma cells toward photodynamic therapy. This effect can be partly attributed to cytotoxicity and is likely related to a pro-apoptotic shift because of an increased Noxa/Mcl-1 ratio. The results of this study warrant further investigation.

Comparison of a standardized four-point bending test to an implant system test of an osteosynthetic system under static and dynamic load condition.

Current test standards of osteosynthetic implants examine the bone plate and screw separately leading to unrealistic load scenarios and unknown performance of the system as a whole, which prevents the identification of characteristic failures in clinical use. A standardized static and dynamic four-point bending test (ASTM F382) was performed on a bone plate. Based on that standard, an advanced implant system test (IST) was designed and performed to test a mechanical construct consisting of a bone plate, screws and an artificial bone substitute out of Polyoxymethylene (POM). The test object was an osteosynthetic system to treat fractured ulna bones. Both results of the conventional and advanced test method were analyzed and compared to one another. The static results show a similar yield point (YP) relative to the bending moment with just 9% difference. Dynamic results show a bi-phasic behavior of the displacement vs. cycle data for the IST. The secondary phase can be defined as a constantly increasing plastic deflection or ratcheting effect quantified by its slope in mm per one million cycles, leading to a 10 times higher slope for the IST than the conventional test. The IST has a high impact on the test results and the resultant interpretation of the mechanical behavior of the osteosynthetic system. A constantly increasing plastic deflection might lead to fatigue failures and to a loss of the mechanical durability. The development of new standardizations referring to the whole system within reasonable boundary conditions of individual biomechanical applications is crucial for high quality mechanical analysis.

Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen.

The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs-the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat-that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial.

Determination of Ankle and Metatarsophalangeal Stiffness During Walking and Jogging.

Forefoot stiffness has been shown to influence joint biomechanics. However, little or no data exist on metatarsophalangeal stiffness. Twenty-four healthy rearfoot strike runners were recruited from a staff and student population at the University of Central Lancashire. Five repetitions of shod, self-selected speed level walking, and jogging were performed. Kinetic and kinematic data were collected using retroreflective markers placed on the lower limb and foot to create a 3-segment foot model using the calibrated anatomical system technique. Ankle and metatarsophalangeal moments and angles were calculated. Stiffness values were calculated using a linear best fit line of moment versus of angle plots. Paired t tests were used to compare values between walking and jogging conditions. Significant differences were seen in ankle range of motion, but not in metatarsophalangeal range of motion. Maximum moments were significantly greater in the ankle during jogging, but these were not significantly different at the metatarsophalangeal joint. Average ankle joint stiffness exhibited significantly lower stiffness when walking compared with jogging. However, the metatarsophalangeal joint exhibited significantly greater stiffness when walking compared with jogging. A greater understanding of forefoot stiffness may inform the development of footwear, prosthetic feet, and orthotic devices, such as ankle foot orthoses for walking and sporting activities.

Bone plate-screw constructs for osteosynthesis - recommendations for standardized mechanical torsion and bending tests.

This paper follows up on a recent systematic review of test methods and parameters for biomechanical testing of bone plates and it is the first study that contains recommendations for standardized mechanical testing of bone plate-screw constructs for osteosynthesis. Following the testing philosophy of ASTM F382 and ISO 9585, we have developed standardized quasi-static and dynamic testing methods for straight linear and anatomically shaped plates, including locked type and conventional systems. The test specification comprises torsion and bending tests along the implant axis and therefore modifies and extends the methods proposed by ASTM F382. We present specific test setups in order to determine product-specific characteristics of the mechanical construct, consisting of the bone plate with corresponding screws (such as construct stiffness, yield strength, ultimate strength and fatigue properties) under the condition that it is rigidly fixed to "healthy bone". We also address specific testing requirements that are important for the purpose of standardization, such as the positioning of the construct for testing or the number of screws in the diaphysis and metaphysis. Finally, we define the outcome parameters and associated failure criteria related to quasi-static and dynamic testing for comparative purposes. This paper does not intend to replace biomechanical testing of those devices under physiological loading conditions.

Bone plates for osteosynthesis - a systematic review of test methods and parameters for biomechanical testing.

Bone plates for osteosynthesis are subject to biomechanical testing for safety and regulatory purposes. International standards applicable for those devices are designed for bone plates used in the surgical fixation of the skeletal system but not necessarily for all device variants available. We intend to summarize the test methods and parameters presented in the literature to evaluate bone plates in a clinical environment, especially for modern anatomically shaped implants. We conducted a systematic review on published biomechanical studies for lower and upper extremities (clavicle, humerus, ulna, radius, metacarpal, femur, tibia, fibula, metatarsal). The search process led to the identification of 159 relevant articles containing 330 individual tests, which were analyzed concerning various test criteria including test methods and parameters per bone segment for static and dynamic loading tests, as well as number of cycles, chosen bone model and outcome variables. The biomechanical literature for bone plates is diverse, inconsistent and heterogeneous. Test methods are not commonly applied per bone plate location and test parameters are not uniformly specified and displayed. They vary in particular for bending and torsion tests as well as for the number of loading cycles for dynamic testing. Outcome variables are not commonly applied nor defined. Consequently this paper is the first in a planned chronological series of three to identify the need (this publication), to develop a systematic procedural approach (2. publication) and to apply the process exemplary on a bone plate sample (3. publication).

Elastically suspending the screw holes of a locked osteosynthesis plate can dampen impact loads.

Impact damping by elastic fixation is a principal engineering strategy to increase the durability of load-bearing structures exposed to prolonged dynamic loading. This biomechanical study evaluated axial impact damping provided by a novel dynamic locking plate. In this design, locking screw holes are elastically suspended within a silicone envelope inside the locking plate. Axial impact damping was assessed for 3 distinct fixation constructs applied to bridge a 10-mm fracture gap of a femoral diaphysis surrogate: a standard locking plate, a dynamic locking plate, and an Ilizarov ring fixator. First, the 3 fixation constructs were characterized by determining their axial stiffness. Subsequently, constructs were subjected to a range of axial impact loads to quantify damping of force transmission. Compared with standard locked plating constructs, dynamic plating constructs were 58% less stiff (P < .01) and Ilizarov constructs were 88% less stiff (P < .01). Impact damping correlated inversely with construct stiffness. Compared with standard plating, dynamic plating constructs and Ilizarov constructs dampened the transmission of impact loads by up to 48% (P < .01) and 74% (P < .01), respectively. In conclusion, lower construct stiffness correlated with superior damping of axial impact loads. Dynamic locking plates provide significantly greater impact damping compared with standard locking plates.