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High-strength fully porous biomaterials built with additive manufacturing provide an exciting opportunity for load-bearing orthopedic applications. While factors controlling their ...mechanical and biological response have recently been the subject of intense research, the interplay between mechanical properties, bone ingrowth requirements, and manufacturing constraints, is still unclear. In this paper, we present two high-strength stretch-dominated topologies, the Tetrahedron and the Octet truss, as well as an intuitive visualization method to understand the relationship of cell topology, pore size, porosity with constraints imposed by bone ingrowth requirements and additive manufacturing. 40 samples of selected porosities are fabricated using Selective Laser Melting (SLM), and their morphological deviations resulting from SLM are assessed via micro-CT. Mechanical compression testing is used to obtain stiffness and strength properties, whereas bone ingrowth is assessed in a canine in vivo model at four and eight weeks. The results show that the maximum strength and stiffness ranged from 227.86±10.15 to 31.37±2.19MPa and 4.58±0.18 to 1.23±0.40GPa respectively, and the maximum 0.2% offset strength is almost 5 times stronger than that of tantalum foam. For Tetrahedron samples, bone ingrowth after four and eight weeks is 28.6%±11.6%, and 41.3%±4.3%, while for the Octet truss 35.5%±1.9% and 56.9%±4.0% respectively. This research is the first to demonstrate the occurrence of bone ingrowth into high-strength porous biomaterials which have higher structural efficiency than current porous biomaterials in the market.
We present two stretch-dominated cell topologies for porous biomaterials that can be used for load-bearing orthopaedic applications, and prove that they encourage bone ingrowth in a canine model. We also introduce an intuitive method to visualize and understand the relationship of cell topology, pore size, porosity with constraints imposed by bone ingrowth requirements and additive manufacturing. We show this strategy helps to gain insight into the interaction of exogenous implant factors and endogenous system factors that can affect the success of load-bearing orthopaedic devices.
Many emerging therapies rely on the delivery of biological cargo into the cytosol. Nanoparticle delivery systems hold great potential to deliver these therapeutics but are hindered by entrapment and ...subsequent degradation in acidic compartments of the endo/lysosomal pathway. Engineering polymeric delivery systems that are able to escape the endosome has significant potential to address this issue. However, the development of safe and effective delivery systems that can reliably deliver cargo to the cytosol is still a challenge. Greater understanding of the properties that govern endosomal escape and how it can be quantified is important for the development of more efficient nanoparticle delivery systems. This Topical Review highlights the current understanding of the mechanisms by which nanoparticles escape the endosome, and the emerging techniques to improve the quantification of endosomal escape.
Holometabolous insects undergo a radical anatomical re-organisation during metamorphosis. This poses a developmental challenge: the host must replace the larval gut but at the same time retain ...symbiotic gut microbes and avoid infection by opportunistic pathogens. By manipulating host immunity and bacterial competitive ability, we study how the host Galleria mellonella and the symbiotic bacterium Enterococcus mundtii interact to manage the composition of the microbiota during metamorphosis. Disenabling one or both symbiotic partners alters the composition of the gut microbiota, which incurs fitness costs: adult hosts with a gut microbiota dominated by pathogens such as Serratia and Staphylococcus die early. Our results reveal an interaction that guarantees the safe passage of the symbiont through metamorphosis and benefits the resulting adult host. Host-symbiont "conspiracies" as described here are almost certainly widespread in holometobolous insects including many disease vectors.
Stimuli‐responsive nanoparticles have the potential to improve the delivery of therapeutics to a specific cell or region within the body. There are many stimuli that have shown potential for specific ...release of cargo, including variation of pH, redox potential, or the presence of enzymes. pH variation has generated significant interest for the synthesis of stimuli‐responsive nanoparticles because nanoparticles are internalized into cells via vesicles that are acidified. Additionally, the tumor microenvironment is known to have a lower pH than the surrounding tissue. In this review, different strategies to design pH‐responsive nanoparticles are discussed, focusing on the use of charge‐shifting polymers, acid labile linkages, and crosslinking.
pH‐Responsive nanoparticles have significant potential for improving the efficiency of therapeutic delivery. This review discusses the three main strategies to design such materials, including the use of charge‐shifting polymers, acid labile side‐chains, and pH‐responsive crosslinking. Recent examples of pH‐responsive nanoparticles are also highlighted.
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Porous biomaterials can be additively manufactured with micro-architecture tailored to satisfy the stringent mechano-biological requirements imposed by bone replacement implants. In a ...previous investigation, we introduced structurally porous biomaterials, featuring strength five times stronger than commercially available porous materials, and confirmed their bone ingrowth capability in an in vivo canine model. While encouraging, the manufactured biomaterials showed geometric mismatches between their internal porous architecture and that of its as-designed counterpart, as well as discrepancies between predicted and tested mechanical properties, issues not fully elucidated. In this work, we propose a systematic approach integrating computed tomography, mechanical testing, and statistical analysis of geometric imperfections to generate statistical based numerical models of high-strength additively manufactured porous biomaterials. The method is used to develop morphology and mechanical maps that illustrate the role played by pore size, porosity, strut thickness, and topology on the relations governing their elastic modulus and compressive yield strength. Overall, there are mismatches between the mechanical properties of ideal-geometry models and as-manufactured porous biomaterials with average errors of 49% and 41% respectively for compressive elastic modulus and yield strength. The proposed methodology gives more accurate predictions for the compressive stiffness and the compressive strength properties with a reduction of the average error to 11% and 7.6%. The implications of the results and the methodology here introduced are discussed in the relevant biomechanical and clinical context, with insight that highlights promises and limitations of additively manufactured porous biomaterials for load-bearing bone replacement implants.
In this work, we perform mechanical characterization of load-bearing porous biomaterials for bone replacement over their entire design space. Results capture the shift in geometry and mechanical properties between as-designed and as-manufactured biomaterials induced by additive manufacturing. Characterization of this shift is crucial to ensure appropriate manufacturing of bone replacement implants that enable biological fixation through bone ingrowth as well as mechanical property harmonization with the native bone tissue. In addition, we propose a method to include manufacturing imperfections in the numerical models that can reduce the discrepancy between predicted and tested properties. The results give insight into the use of structurally porous biomaterials for the design and additive fabrication of load-bearing implants for bone replacement.
The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these ...responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
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•Optogenetic targeting reveals a pacemaker-like β cell subpopulation•These cells, termed hubs, are required for normal insulin release•Hubs are highly metabolic and transcriptionally immature•Hubs are targeted by a diabetic milieu to induce islet failure
Combining optogenetics and photopharmacology, Johnston et al. show that a few (1%–10%) β cells exert disproportionate control over islet responses to glucose. These specialized cells, called hubs, are transcriptionally immature and highly metabolic. Their failure during type 2 diabetes mellitus may lead to reduced insulin secretion and impaired glucose homeostasis.
Overcoming primary or secondary endocrine resistance in breast cancer remains critical to further enhancing the benefit of existing therapies such as tamoxifen or an aromatase inhibitor (AI). Much ...progress has been made in understanding the molecular biology associated with secondary endocrine resistance. Cotargeting the estrogen receptor, together with various key intracellular proliferation and cell survival signaling pathways, has been explored as a strategy either to treat endocrine resistance once it develops in the second-line setting or to enhance first-line endocrine responsiveness by preventing secondary resistance from developing via blockade of specific pathways from the outset. While attempts to improve endocrine therapy by adding growth factor inhibitors have been disappointing, success resulting in new drug approvals has been seen in secondary endocrine resistance by treating patients with the mTOR antagonist everolimus in combination with the AI exemestane and, more recently, in the first-line setting, by the addition of the CDK 4/6 inhibitor palbociclib to the AI letrozole. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on supportive preclinical evidence, including inhibitors of PI3K, Akt, HDAC, Src, IGFR-1, and FGFR. Appropriate clinical trial design and patient selection based on prior therapy exposure, together with predictive biomarkers derived through real-time molecular profiling, are needed to enrich future trials and maximize any additional benefit that cotargeting may bring to current endocrine therapies for estrogen receptor-positive breast cancer.
To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.
An Expert Panel conducted a systematic review to identify new, ...potentially practice-changing data.
Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations.
Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative,
-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect
mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with
mutations. There are insufficient data at present to recommend routine testing for
mutations to guide therapy for HR-positive, HER2-negative MBC. For
or
mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.Additional information can be found at www.asco.org/breast-cancer-guidelines.
Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our ...fundamental understanding of the bio-nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a 'minimum information standard' for experimental literature investigating bio-nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio-nano materials, and facilitate meta analyses and in silico modelling.
Over the last ten years, there has been considerable research interest in the development of polymeric carriers for biomedicine. Such delivery systems have the potential to significantly reduce side ...effects and increase the bioavailability of poorly soluble therapeutics. The design of carriers has relied on harnessing specific variations in biological conditions, such as pH or redox potential, and more recently, by incorporating specific peptide cleavage sites for enzymatic hydrolysis. Although much progress has been made in this field, the specificity of polymeric carriers is still limited when compared with their biological counterparts. To synthesize the next generation of carriers, it is important to consider the biological rationale for materials design. This requires a detailed understanding of the cellular microenvironments and how these can be harnessed for specific applications. In this review, several important physiological cues in the cellular microenvironments are outlined, with a focus on changes in pH, redox potential, and the types of enzymes present in specific regions. Furthermore, recent studies that use such biologically inspired triggers to design polymeric carriers are highlighted, focusing on applications in the field of therapeutic delivery.
Advances in the design of responsive therapeutic carriers for biomedical applications rely on a greater understanding of the biological microenvironments and how such environments can be harnessed to induce carrier responses. This review provides an overview on the relevant biological microenvironments within cells, focusing on pH, redox potential, and enzyme variations – conditions that can aid in the design of intelligent carrier systems. The review also covers recent literature on the design of smart polymeric carriers and future possibilities in advancing such carriers in the biomedical field.
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