Kalpana Mandal

In this work, we used a label-free biosensor that provides optical readouts to perform continuous detection of human interleukin 8 (IL-8), which is especially overexpressed in certain cancers and, thus, could be an effective biomarker for cancer prognosis estimation and therapy evaluation. For this purpose, we engineered a compact, portable, and easy-to-assemble biosensing module device. It combines a fluidic chip for reagent flow, a biosensing chip for signal transduction, and an optical readout head based on fiber optics in a single module. The biosensing chip is based on independent arrays of resonant nanopillar transducer (RNP) networks. We integrated the biosensing chip with the RNPs facing down in a simple and rapidly fabricated polydimethyl siloxane (PDMS) microfluidic chip, with inlet and outlet channels for the sample flowing through the RNPs. The RNPs were vertically oriented from the backside through an optical fiber mounted on a holder head fabricated ad hoc on polytetrafluoroethylene (PTFE). The optical fiber was connected to a visible spectrometer for optical response analysis and consecutive biomolecule detection. We obtained a sensogram showing anti-IL-8 immobilization and the specific recognition of IL-8. This unique portable and easy-to-handle module can be used for biomolecule detection within minutes and is particularly suitable for in-line sensing of physiological and biomimetic organ-on-a-chip systems. Cancer biomarkers’ continuous monitoring arises as an efficient and non-invasive alternative to classical tools (imaging, immunohistology) for determining clinical prognostic factors and therapeutic responses to anticancer drugs. In addition, the multiplexed layout of the optical transducers and the simplicity of the monolithic sensing module yield potential high-throughput screening of a combination of different biomarkers, which, together with other medical exams (such as imaging and/or patient history), could become a cutting-edge technology for further and more accurate diagnosis and prediction of cancer and similar diseases.

Blood vessel embolization is a well-established treatment modality for liver cancer. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. However, embolization therapies are currently optimized in animal models, which often differ from humans at the cellular, tissue, and organ levels. We aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevant in vitro model that recapitulates human hepatocellular carcinoma capillary networks. A vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we evaluated the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. DESTH treatment induced tumor cell death, downregulated the expression of epithelial cell adhesion molecules in HepG2, increased levels of cytokines such as interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and vascular endothelial growth factor, and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. This vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response and can be applied for the development of innovative and effective embolization therapies for liver cancer.

Background: Embolization is a well-established treatment modality for liver cancer. However, traditional embolization agents are limited by inefficient delivery and aggregation in blood vessels. Novel shear-thinning hydrogels (STH) have been developed to address the need for safer and more effective local delivery of embolic agents and therapeutics. Objective: We aim to evaluate the efficacy of novel embolic agents such as STH using a human-relevant in vitro model that recapitulates human hepatocellular carcinoma capillary networks. Methods: A vascularized human liver-tumor-on-a-chip model was developed to assess embolic agent performance. The effects of drug-eluting STH (DESTH) on tumor cell viability, surface marker expression, vasculature morphology, and cytokine responses were evaluated. To study the effects of embolization on microvasculature morphology independent of the chemotherapy compound, we assessed the effect of different drug-free embolic agents on the vascular tumor microenvironment under flow conditions. Results: DESTH treatment induced tumor cell death, downregulated the expression of Epithelial Cell Adhesion Molecules (EpCAM) in HepG2, increased levels of cytokines such as Interleukin-4 (IL-4), Granulocyte-macrophage colony-stimulating factor (GM-CSF), and Vascular Endothelial Growth Factor (VEGF), and decreased albumin secretion. Furthermore, different embolic agents exert distinct effects on microvascular morphology, with STH causing complete regression of the microvascular networks. Conclusion: This vascularized liver tumor-on-a-chip model enables human-relevant, real-time assessment of embolic agent efficacy and vascular response, paving the way for the development of innovative and effective embolization therapies for liver cancer.

Smart biomaterials have significantly impacted human healthcare by advancing the development of medical devices designed to function within human tissue, mimicking the behavior of natural tissues. While the intelligence of biomaterials has evolved from inert to active over the past few decades, smart biomaterials take this a step further by making their surfaces or bulk respond based on interactions with surrounding tissues, imparting outcomes similar to natural tissue functions. This interaction with the surrounding tissue helps in creating stimuli-responsive biomaterials, which can be useful in tissue engineering, regenerative medicine, autonomous drug delivery, orthopedics, and much more. Traditionally, material engineering focused on refining the static properties of biomaterials to accommodate them within the body without evoking an immune response, which was a major obstacle to their unrestricted operation. This review highlights and explains various engineering approaches currently under research for developing stimuli-responsive biomaterials that tune their outcomes based on responses to bodily factors like temperature, pH, and ion concentration or external factors like magnetism, light, and conductivity. Applications in soft and hard tissue engineering, 4D printing, and scaffold design are also discussed. The advanced application of microfluidics, like organ-on-a-chip models, extensively benefits from the intrinsic smart properties of biomaterials, which are also discussed below. The review further elaborates on how smart biomaterial engineering could revolutionize biosensor applications, thereby improving patient care quality. We delineate the limitations and key challenges associated with biomaterials, providing insights into the path forward and outlining future directions for developing next-generation biomaterials that will facilitate clinical translation.

The structure and dynamics of the cell nucleus regulate nearly every facet of the cell. Changes in nuclear shape limit cell motility and gene expression. Although the nucleus is generally seen as the stiffest organelle in the cell, cells can nevertheless deform the nucleus to large strains by small mechanical stresses. Here, we show that the mechanical response of the cell nucleus exhibits active fluidization that is driven by the BRG 1 motor of the SWI/SNF/BAF chromatin-remodeling complex. Atomic force microscopy measurements show that the nucleus alters stiffness in response to the cell substrate stiffness, which is retained after the nucleus is isolated and that the work of nuclear compression is mostly dissipated rather than elastically stored. Inhibiting BRG 1 stiffens the nucleus and eliminates dissipation and nuclear remodeling both in isolated nuclei and in intact cells. These findings demonstrate a novel link between nuclear motor activity and global nuclear mechanics.

Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)‐mediated aneurysm progression. This study incorporates doxycycline (DOX), a well‐known sclerosant and MMPs inhibitor, into a shear‐thinning biomaterial (STB)‐based vascular embolizing hydrogel. The addition of DOX is expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results show that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX are injectable and have a twofold increase in storage modulus compared to those without DOX. STB‐DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels show sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells shows MMP inhibition (approximately an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occlude a patient‐derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB‐DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.