Novel Self-Forming Nanosized DDS Particles for BNCT: Utilizing A Hydrophobic Boron Cluster and Its Molecular Glue Effect

BNCT is a non-invasive cancer therapy that allows for cancer cell death without harming adjacent cells. However, the application is limited, owing to the challenges of working with clinically approved boron (B) compounds and drug delivery systems (DDS). To address the issues, we developed self-forming nanoparticles consisting of a biodegradable polymer, namely, "AB-type Lactosome (AB-Lac)" loaded with B compounds. Three carborane isomers (o-, m-, and p-carborane) and three related alkylated derivatives, i.e., 1,2-dimethy-o-carborane (diC1-Carb), 1,2-dihexyl-o-carborane (diC6-Carb), and 1,2-didodecyl-o-carborane (diC12-Carb), were separately loaded. diC6-Carb was highly loaded with AB-Lac particles, and their stability indicated the "molecular glue" effect. The efficiency of in vitro B uptake of diC6-Carb for BNCT was confirmed at non-cytotoxic concentration in several cancer cell lines. In vivo/ex vivo biodistribution studies indicated that the AB-Lac particles were remarkably accumulated within 72 h post-injection in the tumor lesions of mice bearing syngeneic breast cancer (4T1) cells, but the maximum accumulation was reached at 12 h. In ex vivo B biodistribution, the ratios of tumor/normal tissue (T/N) and tumor/blood (T/Bl) of the diC6-Carb-loaded particles remained stably high up to 72 h. Therefore, we propose the diC6-Carb-loaded AB-Lac particles as a promising candidate medicine for BNCT

Trabecular health of vertebrae based on anisotropy in trabecular architecture and collagen/apatite micro-arrangement after implantation of intervertebral fusion cages in the sheep spine

Healthy trabecular bone shows highly anisotropic trabecular architecture and the preferential orientation of collagen and apatite inside a trabecula, both of which are predominantly directed along the cephalocaudal axis. This makes trabecular bone stiff in the principally loaded direction (cephalocaudal axis). However, changes in these anisotropic trabecular characteristics after the insertion of implant devices remain unclear. We defined the trabecular architectural anisotropy and the preferential orientation of collagen and apatite as parameters of trabecular bone health. In the present study, we analyzed these parameters after the implantation of two types of intervertebral fusion cages, open and closed box-type cages, into sheep spines for 2 and 4 months. Alteration and evolution of trabecular health around and inside the cages depended on the cage type and implantation duration. At the boundary region, the values of trabecular architectural anisotropy and apatite orientation for the closed-type cages were similar to those for isotropic conditions. In contrast, significantly larger anisotropy was found for open-type cages, indicating that the open-type cage tended to maintain trabecular anisotropy. Inside the open-type cage, trabecular architectural anisotropy and apatite orientation significantly increased with time after implantation. Assessing trabecular anisotropy might be useful for the evaluation of trabecular health and the validation and refinement of implant designs.Ishimoto T., Yamada K., Takahashi H., et al. Trabecular health of vertebrae based on anisotropy in trabecular architecture and collagen/apatite micro-arrangement after implantation of intervertebral fusion cages in the sheep spine. Bone, 108, 25. https://doi.org/10.1016/j.bone.2017.12.012

Outstanding in vivo mechanical integrity of additively manufactured spinal cages with a novel “honeycomb tree structure” design via guiding bone matrix orientation

BACKGROUND CONTEXT: Therapeutic devices for spinal disorders, such as spinal fusion cages, must be able to facilitate the maintenance and rapid recovery of spinal function. Therefore, it would be advantageous that future spinal fusion cages facilitate rapid recovery of spinal function without secondary surgery to harvest autologous bone. PURPOSE: This study investigated a novel spinal cage configuration that achieves in vivo mechanical integrity as a devise/bone complex by inducing bone that mimicked the sound trabecular bone, hierarchically and anisotropically structured trabeculae strengthened with a preferentially oriented extracellular matrix. STUDY DESIGN/SETTINGS: In vivo animal study. METHODS: A cage possessing an anisotropic through-pore with a grooved substrate, that we termed “honeycomb tree structure,” was designed for guiding bone matrix orientation; it was manufactured using a laser beam powder bed fusion method through an additive manufacturing processes. The newly designed cages were implanted into sheep vertebral bodies for 8 and 16 weeks. An autologous bone was not installed in the newly designed cage. A pull-out test was performed to evaluate the mechanical integrity of the cage/bone interface. Additionally, the preferential orientation of bone matrix consisting of collagen and apatite was determined. RESULTS: The cage/host bone interface strength assessed by the maximum pull-out load for the novel cage without an autologous bone graft (3360±411 N) was significantly higher than that for the conventional cage using autologous bone (903±188 N) after only 8 weeks post-implantation. CONCLUSIONS: These results highlight the potential of this novel cage to achieve functional fusion between the cage and host bone. Our study provides insight into the design of highly functional spinal devices based on the anisotropic nature of bone. CLINICAL SIGNIFICANCE: The sheep spine is similar to the human spine in its stress condition and trabecular bone architecture and is widely recognized as a useful model for the human spine. The present design may be useful as a new spinal device for humans.Ishimoto T., Kobayashi Y., Takahata M., et al. Outstanding in vivo mechanical integrity of additively manufactured spinal cages with a novel “honeycomb tree structure” design via guiding bone matrix orientation. Spine Journal, 22, 10, 1742. https://doi.org/10.1016/j.spinee.2022.05.006

Innovative design of bone quality-targeted intervertebral spacer: accelerated functional fusion guiding oriented collagen and apatite microstructure without autologous bone graft

BACKGROUND CONTEXT: Although autologous bone grafting is widely considered as an ideal source for interbody fusion, it still carries a risk of nonunion. The influence of the intervertebral device should not be overlooked. Requirements for artificial spinal devices are to join the vertebrae together and recover the original function of the spine rapidly. Ordered mineralization of apatite crystals on collagen accelerates bone functionalization during the healing process. Particularly, the stable spinal function requires the ingrowth of an ordered collagen and apatite matrix which mimics the intact intervertebral microstructure. This collagen and apatite ordering is imperative for functional bone regeneration, which has not been achieved using classical autologous grafting. PURPOSE: We developed an intervertebral body device to achieve high stability between the host bone and synthesized bone by controlling the ordered collagen and apatite microstructure. STUDY DESIGN: This was an in vivo animal study. METHODS: Intervertebral spacers with a through-pore grooved surface structure, referred to as a honeycomb tree structure, were produced using metal 3D printing. These spacers were implanted into normal sheep at the L2–L3 or L4–L5 disc levels. As a control group, grafting autologous bone was embedded. The mechanical integrity of the spacer/bone interface was evaluated through push-out tests. RESULTS: The spacer with honeycomb tree structure induced anisotropic trabecular bone growth with textured collagen and apatite orientation in the through-pore and groove directions. The push-out load of the spacer was significantly higher than that of the conventional autologous graft spacer. Moreover, the load was significantly correlated with the anisotropic texture of the newly formed bone matrix. CONCLUSIONS: The developed intervertebral spacer guided the regenerated bone matrix orientation of collagen and apatite, resulting in greater strength at the spacer/host bone interface than that obtained using a conventional gold-standard autologous bone graft. CLINICAL SIGNIFICANCE: Our results provide a foundation for designing future spacers for interbody fusion in human.Matsugaki A., Ito M., Kobayashi Y., et al. Innovative design of bone quality-targeted intervertebral spacer: accelerated functional fusion guiding oriented collagen and apatite microstructure without autologous bone graft. Spine Journal 23, 609 (2023); https://doi.org/10.1016/j.spinee.2022.12.011

Short Notes A Variation of the Collapsing Method to Delineate Structures Inside a

Abstract We describe a modification to the collapsing method, a technique that aims to find the simplest structures in a cloud of microearthquakes by utilizing the statistical uncertainties in the data. In the modified collapsing method, the movements of the locations are dependent on the shape of the distribution of the locations within the confidence ellipsoid, and not just the position of the center of gravity, as is the case in the original method. Additionally, whereas the original collapsing method implicitly assumes that all locations belong to point structures, in this modified version three types of structure are considered: point, line, and plane. Principal component analysis of the locations is used to evaluate to which type of structure each location most probably belongs. The modified technique has been applied to microseismic events associated with hydraulic stimulation at the Fenton Hill HDR Field, New Mexico, and known small-scale structures were imaged

Effects of autogenous bone graft on mass and quality of trabecular bone in Ti-6Al-4V spinal cage fabricated with electron beam melting

A spinal cage is one of the primary spinal devices used for the treatment of spinal diseases such as lumbar spondylolisthesis. Since it is set in the intervertebral space that causes instability to promote the fusion of the adjacent vertebral bodies, it requires the early induction of healthy bones. For this reason, in most cases, an autogenous bone extracted from the patient’s ilium is implanted in the interior of the cage to stimulate bone formation. However, collecting autogenous bone involves secondary surgery and several clinical problems such as pain in the part from which it is collected. Additionally, the effect of the autogenous bone graft itself has not been sufficiently studied yet. Moreover, the mechanical functions of trabecular bones in a vertebral body are governed by the anisotropic structure of the trabeculae and the preferential orientation of the apatite/collagen in a trabecula with respect to the principal stress. Despite this fact, after the implantation of the cage, the mass of the bones is evaluated with soft X-ray photography, which does not guarantee an accurate measurement of bone functions. In this study, the effect of the autogenous bone graft on the spinal cage was verified based on structural anisotropy of trabecular bones and the preferential orientation of apatite/collagen in a trabecula using sheep. The autogenous bone graft demonstrated a significant effect on the increase of bone mass and anisotropy of the trabecular structure. However, compared to the trabecular anisotropy of normal parts, the anisotropy of the trabecular structure and apatite c-axis orientation of the parts with autogenous bone graft were considerably lower, indicating a minimal effect of the autogenous bone graft. Therefore, it was suggested that early stabilization of the spinal cage requires another strategy that rapidly forms the unique hierarchical anisotropic structure of trabecular bones.Takahashi H., Ishimoto T., Inoue T., et al. Effects of autogenous bone graft on mass and quality of trabecular bone in Ti-6Al-4V spinal cage fabricated with electron beam melting. Materials Transactions 60, 144 (2019); https://doi.org/10.2320/matertrans.M2018329