Cholla cactus frames as lightweight and torsionally tough biological materials.

Biological materials tested in compression, tension, and impact inspire designs for strong and tough materials, but torsion is a relatively neglected loading mode. The wood skeletons of cholla cacti, subject to spartan desert conditions and hurricane force winds, provide a new template for torsionally resilient biological materials. Novel mesostructural characterization methods of laser-scanning and photogrammetry are used alongside traditional optical microscopy, scanning electron microscopy, and micro-computed tomography to identify mechanisms responsible for torsional resistance. These methods, in combination with finite element analysis reveal how cholla meso and macro-porosity and fibril orientation contribute to highly density-efficient mechanical behavior. Selective lignification and macroscopic tubercle pore geometry contribute to density-efficient shear stiffness, while mesoscopic wood fiber straightening, delamination, pore collapse, and fiber pullout provide extrinsic toughening mechanisms. These energy absorbing mechanisms are enabled by the hydrated material level properties. Together, these hierarchical behaviors allow the cholla to far exceed bamboo and trabecular bone in its ability to combine specific torsional stiffness, strength, and toughness. STATEMENT OF SIGNIFICANCE: The Cholla cactus experiences, due to the high velocity desert winds, high torsional loads. Our study has revealed the amazingly ingenious strategy by which the tubular structure containing arrays of voids intermeshed with wood fibers resists these high loads. Deformation is governed by compressive and tensile stresses which are greatest at 45 degrees to the cross section. It proceeds by stretching, sliding, and bending of the wood fibers which are coupled with the pore collapse, resulting in delayed failure and a high torsional toughness.

Combinatorial targeting of cancer bone metastasis using mRNA engineered stem cells.

BACKGROUND: Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells ("the seed"), and their surrounding niche ("the soil"), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. METHODS: We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. FINDINGS: We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). INTERPRETATION: Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. FUND: National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer.