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Jiawei Sun,1 Lei Jiang,2 Yi Lin,3 Ethan Michael Gerhard,4 Xuehua Jiang,1 Li Li,3 Jian Yang,4 Zhongwei Gu3 1West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 2Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu, 3National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA Abstract: Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity. Keywords: multistage tumor-targeting liposome, mitochondria, paclitaxel, anticancer, antiangiogenesis

Abstract Skin aging is driven by intrinsic and extrinsic factors impacting on skin functionality with progressive age. One factor of this multifaceted process is cellular senescence, as it has recently been identified to contribute to a declining tissue functionality in old age. In the skin, senescent cells have been found to markedly accumulate with age, and thus might impact directly on skin characteristics. Especially the switch from young, extracellular matrix-building fibroblasts to a senescence-associated secretory phenotype (SASP) could alter the microenvironment in the skin drastically and therefore promote skin aging. In order to study the influence of senescence in human skin, 3D organotypic cultures are a well-suited model system. However, only few “aged” skin- equivalent (SE) models are available, requiring complex and long-term experimental setups. Here, we adapted a previously published full-thickness SE model by seeding increasing ratios of stress-induced premature senescent versus normal fibroblasts into the collagen matrix, terming these SE “senoskin”. Immunohistochemistry stainings revealed a shift in the balance between proliferation (Ki67) and differentiation (Keratin 10 and Filaggrin) of keratinocytes within our senoskin equivalents, as well as partial impairment of skin barrier function and changed surface properties. Monitoring of cytokine levels of known SASP factors confirmedly showed an upregulation in 2D cultures of senescent cells and at the time of seeding into the skin equivalent. Surprisingly, we find a blunted response of cytokines in the senoskin equivalent over time during 3D differentiation.

It has been theorized that declines in g due to negative selection stemming from the inverse association between completed fertility and IQ, and the Flynn effect co-occur, with the effects of the latter being concentrated on less-heritable non-g sources of intelligence variance. Evidence for this comes from the observation that 19th Century populations were more intellectually productive, and also exhibited faster simple reaction times than modern ones, suggesting higher g. This co-occurrence model is tested via examination of historical changes in the utilization frequencies of words from the highly g-loaded WORDSUM test across 5.9 million texts spanning 1850 to 2005. Consistent with predictions, words with higher difficulties (δ parameters from Item Response Theory) and stronger negative correlations between pass-rates and completed fertility presented a steeper decline in use over time, than less difficult and less negatively selected words, which increased in use over time, suggestive of a Flynn effect. These findings persisted when explicitly controlled for word age, literacy rates and temporal autocorrelation. These trends constitute compelling evidence that both producers and consumers of text have experienced declines in g since the mid-19th Century.

The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T cell reactivity. Dkk3 is a secreted, mainly tissue derived protein with highest expression in organs considered as immune privileged such as the eye, embryo, placenta and brain. While T cell development and activation status in naïve Dkk3 deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T cell mediated rejection. Moreover, genetic deletion or antibody mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T cell polarization displayed by an increase of IFNγ producing T cells within in the CNS. In the wild type situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4+ and CD8+ T cell responses.

Although there is a wealth of evidence that physical activity has positive effects on psychological health, a large proportion of people are inactive. Data regarding counts, steps, and movement patterns are limited in their ability to explain why people remain inactive. We propose that multimodal ambulatory monitoring, which combines the assessment of physical activity with the assessment of psychological variables, helps to elucidate real world physical activity. Whereas physical activity can be monitored continuously, psychological variables can only be assessed at discrete intervals, such as every hour. Moreover, the assessment of psychological variables must be linked to the activity of interest. For example, if an inactive and overweight person is physically active once a week, psychological variables should be assessed during this episode. Linking the assessment of psychological variables to episodes of an activity of interest can be achieved with interactive monitoring. The primary aim of our interactive multimodal ambulatory monitoring approach was to intentionally increase the number of e-diary assessments during active episodes.We developed and tested an interactive monitoring algorithm that continuously monitors physical activity in everyday life. When predefined thresholds are surpassed, the algorithm triggers a signal for participants to answer questions in their electronic diary.Using data from 70 participants wearing an accelerative device for 24 hours each, we found that our algorithm quadrupled the frequency of e-diary assessments during the activity episodes of interest compared to random sampling. Multimodal interactive ambulatory monitoring appears to be a promising approach to enhancing our understanding of real world physical activity and movement.

Embedded printing has emerged as a valuable tool for fabricating complex structures and microfluidic devices. Currently, an ample of amount of research is going on to develop new materials to advance its capabilities and increase its potential applications. Here, we demonstrate a novel, transparent, printable, photocrosslinkable, and tuneable silicone composite that can be utilized as a support bath or an extrudable ink for embedded printing. Its properties can be tuned to achieve ideal rheological properties, such as optimal self-recovery and yield stress, for use in 3D printing. When used as a support bath, it facilitated the generation microfluidic devices with circular channels of diameter up to 30 μm. To demonstrate its utility, flow focusing microfluidic devices were fabricated for generation of Janus microrods, which can be easily modified for multitude of applications. When used as an extrudable ink, 3D printing of complex-shaped constructs were achieved with integrated electronics, which greatly extends its potential applications towards soft robotics. Further, its biocompatibility was tested with multiple cell types to validate its applicability for tissue engineering. Altogether, this material offers a myriad of potential applications (i.e., soft robotics, microfluidics, bioprinting) by providing a facile approach to develop complicated 3D structures and interconnected channels., Competing Interests: Competing interests ITO has an equity stake in Biolife4D and is a member of the scientific advisory board for Biolife4D and Healshape. Other authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Embedded printing has emerged as a valuable tool for fabricating complex structures and microfluidic devices. Currently, an ample of amount of research is going on to develop new materials to advance its capabilities and increase its potential applications. Here, we demonstrate a novel, transparent, 3D printable, photocrosslinkable, and tuneable silicone composite that can be utilized as a support bath or an extrudable ink for embedded printing. The proposed silicone composite can be tuned to achieve ideal rheological properties, such as optimal self-recovery and yield stress, for use in 3D printing. When used as a support bath, it facilitated the generation microfluidic devices with circular channels of diameter up to 30 µm. To demonstrate its utility, flow focusing microfluidic devices were fabricated for generation of Janus microrods, which can be easily modified for multitude of applications. When used as an extrudable ink, 3D printing of complex-shaped micro- and macro-constructs were achieved with integrated electronics, which greatly extends its potential applications towards developing complex flexible parts for soft robotics and prosthetics. Further, its biocompatibility was tested with multiple cell types to validate its applicability for medical and tissue engineering use. Altogether, this material offers a myriad of potential applications in material and medical fields by providing a facile approach to develop complicated 3D structures and interconnected channels that can further advance microfluidics and soft-robotics research.

The high demand for rapid wound healing has spurred the development of multifunctional and smart bioadhesives with strong bioadhesion, antibacterial effect, real-time sensing, wireless communication, and on-demand treatment capabilities. Bioadhesives with bio-inspired structures and chemicals have shown unprecedented adhesion strengths, as well as tunable optical, electrical, and bio-dissolvable properties. Accelerated wound healing has been achieved via directly released antibacterial and growth factors, material or drug-induced host immune responses, and delivery of curative cells. Most recently, the integration of biosensing and treatment modules with wireless units in a closed-loop system yielded smart bioadhesives, allowing real-time sensing of the physiological conditions (e.g., pH, temperature, uric acid, glucose, and cytokine) with iterative feedback for drastically enhanced, stage-specific wound healing by triggering drug delivery and treatment to avoid infection or prolonged inflammation. Despite rapid advances in the burgeoning field, challenges still exist in the design and fabrication of integrated systems, particularly for chronic wounds, presenting significant opportunities for the future development of next-generation smart materials and systems., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

The field of tissue engineering and regenerative medicine relies heavily on materials capable of implantation without significant foreign body reactions and with the ability to promote tissue differentiation and regeneration. The field of bone tissue engineering in particular requires materials capable of providing enhanced mechanical properties and promoting osteogenic cell lineage commitment. While bone repair has long relied almost exclusively on inorganic, calcium phosphate ceramics such as hydroxyapatite and their composites or on non-degradable metals, the organically derived shell and pearl nacre generated by mollusks has emerged as a promising alternative. Nacre is a naturally occurring composite material composed of inorganic, calcium carbonate plates connected by a framework of organic molecules. Similar to mammalian bone, the highly organized microstructure of nacre endows the composite with superior mechanical properties while the organic phase contributes to significant bioactivity. Studies, both in vitro and in vivo, have demonstrated nacre's biocompatibility, biodegradability, and osteogenic potential, which are superior to pure inorganic minerals such as hydroxyapatite or non-degradable metals. Nacre can be used directly as a bulk implant or as part of a composite material when combined with polymers or other ceramics. While nacre has demonstrated its effectiveness in multiple cell culture and animal models, it remains a relatively underexplored biomaterial. This review introduces the formation, structure, and characteristics of nacre, and discusses the present and future uses of this biologically-derived material as a novel biomaterial for orthopedic and other tissue engineering applications., Statement of Significance: Mussel derived nacre, a biological composite composed of mineralized calcium carbonate platelets and interplatelet protein components, has recently gained interest as a potential alternative ceramic material in orthopedic biomaterials, combining the integration and mechanical capabilities of calcium phosphates with increased bioactivity derived from proteins and biomolecules; however, there is limited awareness of this material's potential. Herein, we present, to our knowledge, the first comprehensive review of nacre as a biomaterial. Nacre is a highly promising yet overlooked biomaterial for orthopedic tissue engineering with great potential in a wide variety of material systems. It is our hope that publication of this article will lead to increased community awareness of the potential of nacre as a versatile, bioactive ceramic capable of improving bone tissue regeneration and will elicit increased research effort and innovation utilizing nacre., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)