Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo

Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin‐10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression. Lentivirus delivered from scaffolds in vivo achieved sustained transgene expression for 56 days. IL10 lentiviral expression, but not CXCL12 or CCL2, significantly decreased tumor cell recruitment to scaffolds in vivo. Delivery of CXCL12 enhanced CD45+ immune cell recruitment to scaffolds while delivery of IL10 reduced immune cell recruitment. CCL2 did not alter immune cell recruitment. Tumor cell phenotype was investigated using conditioned media from immunomodulated scaffolds, with CXCL12 microenvironments reducing proliferation, and IL10 microenvironments enhancing proliferation. Migration was enhanced with CCL2 and reduced with IL10‐driven microenvironments. Multiple linear regression identified populations of immune cells associated with tumor cell abundance. CD45+ immune and CD8+ T cells were associated with reduced tumor cell abundance, while CD11b+Gr1+ neutrophils and CD4+ T cells were associated with enhanced tumor cell abundance. Collectively, biomaterial scaffolds provide a tool to probe the formation and function of the premetastatic niche.Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin‐10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153114/1/bit27179.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153114/2/bit27179_am.pd

Hydrogel–Electrospun Fiber Mat Composite Coatings for Neural Prostheses

Achieving stable, long-term performance of implanted neural prosthetic devices has been challenging because of implantation related neuron loss and a foreign body response that results in encapsulating glial scar formation. To improve neuron–prosthesis integration and form chronic, stable interfaces, we investigated the potential of neurotrophin-eluting hydrogel–electrospun fiber mat (EFM) composite coatings. In particular, poly(ethylene glycol)-poly(ε-caprolactone) (PEGPCL) hydrogel–poly(ε-caprolactone) EFM composites were applied as coatings for multielectrode arrays. Coatings were stable and persisted on electrode surfaces for over 1 month under an agarose gel tissue phantom and over 9 months in a PBS immersion bath. To demonstrate drug release, a neurotrophin, nerve growth factor (NGF), was loaded in the PEGPCL hydrogel layer, and coating cytotoxicity and sustained NGF release were evaluated using a PC12 cell culture model. Quantitative MTT assays showed that these coatings had no significant toxicity toward PC12 cells, and neurite extension at day 7 and 14 confirmed sustained release of NGF at biologically significant concentrations for at least 2 weeks. Our results demonstrate that hydrogel–EFM composite materials can be applied to neural prostheses to improve neuron–electrode proximity and enhance long-term device performance and function

Biomaterial Scaffolds as Pre‐metastatic Niche Mimics Systemically Alter the Primary Tumor and Tumor Microenvironment

Primary tumor (PT) immune cells and pre‐metastatic niche (PMN) sites are critical to metastasis. Recently, synthetic biomaterial scaffolds used as PMN mimics are shown to capture both immune and metastatic tumor cells. Herein, studies are performed to investigate whether the scaffold‐mediated redirection of immune and tumor cells would alter the primary tumor microenvironment (TME). Transcriptomic analysis of PT cells from scaffold‐implanted and mock‐surgery mice identifies differentially regulated pathways relevant to invasion and metastasis progression. Transcriptomic differences are hypothesized to result from scaffold‐mediated modulations of immune cell trafficking and phenotype in the TME. Culturing tumor cells with conditioned media generated from PT immune cells of scaffold‐implanted mice decrease invasion in vitro more than two‐fold relative to mock surgery controls and reduce activity of invasion‐promoting transcription factors. Secretomic characterization of the conditioned media delineates interactions between immune cells in the TME and tumor cells, showing an increase in the pan‐metastasis inhibitor decorin and a concomitant decrease in invasion‐promoting chemokine (C‐C motif) ligand 2 (CCL2) in scaffold‐implanted mice. Flow cytometric and transcriptomic profiling of PT immune cells identify phenotypically distinct tumor‐associated macrophages (TAMs) in scaffold‐implanted mice, which may contribute to an invasion‐suppressive TME. Taken together, this study demonstrates biomaterial scaffolds systemically influence metastatic progression through manipulation of the TME.Biomaterial implants that mimic the pre‐metastatic niche are shown to redirect immune and tumor cell populations in vivo. However, the systemic effects of pre‐metastatic niche mimics on metastasis progression have yet to be characterized. In this work, synthetic biomaterial implants were shown to systemically alter the primary tumor and the tumor microenvironment to promote an invasion‐suppressive phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144244/1/adhm201700903-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144244/2/adhm201700903_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144244/3/adhm201700903.pd

Inherent Interfacial Mechanical Gradients in 3D Hydrogels Influence Tumor Cell Behaviors

Cells sense and respond to the rigidity of their microenvironment by altering their morphology and migration behavior. To examine this response, hydrogels with a range of moduli or mechanical gradients have been developed. Here, we show that edge effects inherent in hydrogels supported on rigid substrates also influence cell behavior. A Matrigel hydrogel was supported on a rigid glass substrate, an interface which computational techniques revealed to yield relative stiffening close to the rigid substrate support. To explore the influence of these gradients in 3D, hydrogels of varying Matrigel content were synthesized and the morphology, spreading, actin organization, and migration of glioblastoma multiforme (GBM) tumor cells were examined at the lowest (<50 µm) and highest (>500 µm) gel positions. GBMs adopted bipolar morphologies, displayed actin stress fiber formation, and evidenced fast, mesenchymal migration close to the substrate, whereas away from the interface, they adopted more rounded or ellipsoid morphologies, displayed poor actin architecture, and evidenced slow migration with some amoeboid characteristics. Mechanical gradients produced via edge effects could be observed with other hydrogels and substrates and permit observation of responses to multiple mechanical environments in a single hydrogel. Thus, hydrogel-support edge effects could be used to explore mechanosensitivity in a single 3D hydrogel system and should be considered in 3D hydrogel cell culture systems

Bioengineered models to study tumor dormancy

Abstract The onset of cancer metastasis is the defining event in cancer progression when the disease is considered lethal. The ability of metastatic cancer cells to stay dormant for extended time periods and reawaken at later stages leading to disease recurrence makes treatment of metastatic disease extremely challenging. The tumor microenvironment plays a critical role in deciding the ultimate fate of tumor cells, yet the mechanisms by which this occurs, including dormancy, is not well understood. This mini-review discusses bioengineered models inspired from tissue engineering strategies that mimic key aspects of the tumor microenvironment to study tumor dormancy. These models include biomaterial based three dimensional models, microfluidic based models, as well as bioreactor based models that incorporate relevant microenvironmental components such as extracellular matrix molecules, niche cells, or their combination to study microenvironmental regulation of tumor dormancy. Such biomimetic models provide suitable platforms to investigate the dormant niche, including cues that drive the dormant to proliferative transition in cancer cells. In addition, the potential of such model systems to advance research in the field of tumor dormancy is discussed

AI Trainer: Autoencoder Based Approach for Squat Analysis and Correction

Artificial intelligence and computer vision have widespread applications in workout analysis. It has been extensively used in sports and the athlete industry to identify errors and improve performance. Furthermore, these methods prevent injuries caused by a lack of instructors or costly infrastructure. One such exercise is the squat, which is a movement in which a standing person descends to a posture with their torso vertical and their knees firmly bent, then returns to their original upright position. Each person&#x2019;s squat is distinct, with varying limb lengths causing their form to change when observed. It has been observed that the mobility of various joints and muscular strength have a role in this. A squat improves the user by increasing overall leg strength, strengthening knee and hip joints, and lowering the risk of heart disease due to cardiovascular development. This paper presents a method for classifying squat types and recommending the right squat version. This study uses MediaPipe and a deep learning-based technique to decide if squatting is good or bad. A stacked Bidirectional Gated Recurrent Unit (Bi-GRU) model with an attention layer is proposed to consistently and fairly assess each user, categorizing squats into seven classes. This stacked Bi-GRU model with an attention unit is then compared to other cutting-edge models, both with and without the attention layer. The model outperforms other models by attaining an accuracy of 94&#x0025; and is demonstrated to work the best and most consistently for our dataset. Furthermore, the individual executing the incorrect squat is corrected to the best of their ability, depending on their performance and body proportions, by providing the correct form

Microporous scaffolds loaded with immunomodulatory lentivirus to study the contribution of immune cell populations to tumor cell recruitment in vivo

Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin‐10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression. Lentivirus delivered from scaffolds in vivo achieved sustained transgene expression for 56 days. IL10 lentiviral expression, but not CXCL12 or CCL2, significantly decreased tumor cell recruitment to scaffolds in vivo. Delivery of CXCL12 enhanced CD45+ immune cell recruitment to scaffolds while delivery of IL10 reduced immune cell recruitment. CCL2 did not alter immune cell recruitment. Tumor cell phenotype was investigated using conditioned media from immunomodulated scaffolds, with CXCL12 microenvironments reducing proliferation, and IL10 microenvironments enhancing proliferation. Migration was enhanced with CCL2 and reduced with IL10‐driven microenvironments. Multiple linear regression identified populations of immune cells associated with tumor cell abundance. CD45+ immune and CD8+ T cells were associated with reduced tumor cell abundance, while CD11b+Gr1+ neutrophils and CD4+ T cells were associated with enhanced tumor cell abundance. Collectively, biomaterial scaffolds provide a tool to probe the formation and function of the premetastatic niche.Metastases are preceded by stochastic formation of a hospitable microenvironment known as the premetastatic niche, which has been difficult to study. Herein, we employ implantable polycaprolactone scaffolds as an engineered premetastatic niche to independently investigate the role of interleukin‐10 (IL10), CXCL12, and CCL2 in recruiting immune and tumor cells and impacting breast cancer cell phenotype via lentiviral overexpression.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153114/1/bit27179.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153114/2/bit27179_am.pd

Spectral and defect analysis of Cu-doped combustion synthesized new SrAl4O7 phosphor

A simple solution combustion synthesis route for preparation of Cu-doped SrAl4O7 has been described. Average particle size of 33 nm and platelet-like morphology has been observed. ESR studies confirm the presence of Cu in polycrystalline SrAl4O7. Bright-green luminescence under near-UV irradiation arising due to transition between Cu+ levels with microsecond level decay time makes it suitable for application in phosphor converted light emitting diode (LED). TL measurements show broad glow peaks which when deconvoluted indicate activation energies in the range of 0.6–1.1 eV and elucidate the trapping dynamics