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\"The body is the most complex machine in the world, and the only one for which you cannot get a replacement part from the manufacturer. For centuries, medicine has reached for what's available--sculpting noses from brass, borrowing skin from frogs and hearts from pigs, crafting eye parts from jet canopies and breasts from petroleum by-products. Today we're attempting to grow body parts from scratch using stem cells and 3D printers. How are we doing? Are we there yet? In Replaceable You, Mary Roach explores the remarkable advances and difficult questions prompted by the human body's failings. When and how does a person decide they'd be better off with a prosthetic than their existing limb? Can a donated heart be made to beat forever? Can an intestine provide a workable substitute for a vagina? Roach dives in with her characteristic verve and infectious wit. Her travels take her to the OR at a legendary burn unit in Boston, a \"superclean\" xeno-pigsty in China, and a stem cell \"hair nursery\" in the San Diego tech hub. She talks with researchers and surgeons, amputees and ostomates, printers of kidneys and designers of wearable organs. She spends time in a working iron lung from the 1950s, stays up all night with recovery techs as they disassemble and reassemble a tissue donor, and travels across Mongolia with the cataract surgeons of Orbis International. Irrepressible and accessible, Replaceable You immerses readers in the wondrous, improbable, and surreal quest to build a new you\"-- Dust jacket flap.

Background Tissue engineering techniques offer new strategies to understand complex processes in a controlled and reproducible system. In this study, we generated bilayered human tissue substitutes consisting of a cellular connective tissue with a suprajacent epithelium (full-thickness stromal-epithelial substitutes or SESS) and human tissue substitutes with an epithelial layer generated on top of an acellular biomaterial (epithelial substitutes or ESS). Both types of artificial tissues were studied at sequential time periods to analyze the maturation process of the extracellular matrix. Results Regarding epithelial layer, ESS cells showed active proliferation, positive expression of cytokeratin 5, and low expression of differentiation markers, whereas SESS epithelium showed higher differentiation levels, with a progressive positive expression of cytokeratin 10 and claudin. Stromal cells in SESS tended to accumulate and actively synthetize extracellular matrix components such as collagens and proteoglycans in the stromal area in direct contact with the epithelium (zone 1), whereas these components were very scarce in ESS. Regarding the basement membrane, ESS showed a partially differentiated structure containing fibronectin-1 and perlecan. However, SESS showed higher basement membrane differentiation, with positive expression of fibronectin 1, perlecan, nidogen 1, chondroitin-6-sulfate proteoglycans, agrin, and collagens types IV and VII, although this structure was negative for lumican. Finally, both ESS and SESS proved to be useful tools for studying metabolic pathway regulation, revealing differential activation and upregulation of the transforming growth factor-β pathway in ESS and SESS. Conclusions These results confirm the relevance of epithelial-stromal interaction for extracellular matrix development and differentiation, especially regarding basement membrane components, and suggest the usefulness of bilayered artificial tissue substitutes to reproduce ex vivo the extracellular matrix maturation and development process of human tissues. Graphical Abstract Highlights 1- Artificial bilayered substitutes developed by tissue engineering allow the spatiotemporal study of extracellular matrix maturation and development. 2- Epithelial tissue substitutes generated on the surface of acellular biomaterials display limited differentiation levels, with limited expression of relevant extracellular matrix components. 3- Full-thickness stromal-epithelial substitutes with a cellular stroma showed significantly higher levels of maturation and differentiation, with higher expression of epithelial (cytokeratin 10, claudin) and stromal markers (collagens, proteoglycans). 4- For the formation and development of the basement membrane, an interaction process between the epithelial and the stromal cells is necessary for the synthesis of most fibrillar and non-fibrillar components of this structure. 5- Our results confirm the intrinsic capability of epithelial cells to synthesize extracellular matrix components and the positive inductive effect of paracrine factors released by stromal cells.

Purpose of Review In this review, we focus on the multiple advancements in the field of cardiovascular regenerative medicine and the state-of-the art of building a heart. An organ is comprised of cells, but cells alone do not comprise an organ. We summarize the components needed, the hurdles, and likely translational steps defining the opportunities for discovery. Recent Findings The therapies being developed in regenerative medicine aim not only to repair, but also to regenerate or replace ailing tissues and organs. The first generation of cardiac regenerative medicine was gene therapy. The past decade has focused primarily on cell therapy, particularly for repair after ischemic injury with mixed results. Although cell therapy is promising, it will likely never reverse end-stage heart failure; and thus, the unmet need is, and will remain, for organs. Scientists have now tissue engineering and regenerative medicine concepts to invent alternative therapies for a wide spectrum of diseases encompassing cardiovascular, respiratory, gastrointestinal, hepatic, renal, musculoskeletal, ocular, and neurodegenerative disorders. Current studies focus on potential scaffolds and applying concepts and techniques learned with testbeds to building human sized organs. Special focus has been given to scaffold sources, cells types and sources, and cell integration with scaffolds. The complexity arises in combining them to yield an organ. Summary Regenerative medicine has emerged as one of the most promising fields of translational research and has the potential to minimize both the need for, and increase the availability of, donor organs. The field is characterized by its integration of biology, physical sciences, and engineering. The proper integration of these fields could lead to off-the-shelf bioartificial organs that are suitable for transplantation. Building a heart will necessarily require a scaffold that can provide cardiac function. We believe that the advent of decellularization methods provides complex, unique, and natural scaffold sources. Ultimately, cell biology and tissue engineering will need to synergize with scaffold biology, finding cell sources and reproducible ways to expand their numbers is an unmet need. But tissue engineering is moving toward whole organ synthesis at an unparalleled pace.

Purpose of Review Organoids are an emerging technology utilizing three-dimensional (3D), multi-cellular in vitro models to represent the function and physiological responses of tissues and organs. By using physiologically relevant models, more accurate tissue responses to viral infection can be observed, and effective treatments and preventive strategies can be identified. Animals and two-dimensional (2D) cell culture models occasionally result in inaccurate disease modeling outcomes. Organoids have been developed to better represent human organ and tissue systems, and accurately model tissue function and disease responses. By using organoids to study SARS-Cov-2 infection, researchers have now evaluated the viral effects on different organs and evaluate efficacy of potential treatments. The purpose of this review is to highlight organoid technologies and their ability to model SARS-Cov-2 infection and tissue responses. Recent Findings Lung, cardiac, kidney, and small intestine organoids have been examined as potential models of SARS-CoV-2 infection. Lung organoid research has highlighted that SARS-CoV-2 shows preferential infection of club cells and have shown value for the rapid screening and evaluations of multiple anti-viral drugs. Kidney organoid research suggests human recombinant soluble ACE2 as a preventative measure during early-stage infection. Using small intestine organoids, fecal to oral transmission has been evaluated as a transmission route for the virus. Lastly in cardiac organoids drug evaluation studies have found that drugs such as bromodomain, external family inhibitors, BETi, and apabetalone may be effective treatments for SARs-CoV-2 cardiac injury. Summary Organoids are an effective tool to study the effects of viral infections and for drug screening and evaluation studies. By using organoids, more accurate disease modeling can be performed, and physiological effects of infection and treatment can be better understood.

Purpose of Review Adult stem cells such as adipose tissue derived cells (ASCs) are often preferred for autologous cellular therapies. Nevertheless, their regenerative potential is vulnerable to donor conditions (age and disease status) as well as in vitro culture conditions (contamination, in vitro passaging). These donor- and culture-related variables compromise stem cell efficacy when used to treat and cure various diseases. Cryopreservation of stem cells may solve these problems by offering cryogenic preservation of healthy cells and tissues for future use. Recent Findings Establishment of stem cell banks to preserve tissues and stem cells is growing rapidly. Adipose tissue is a unique therapeutic option for patients in that it can be used not only as a “whole tissue” but also as a source of cells for regenerative medicine applications. Adipose tissue contains the highest number of mesenchymal stem cells (MSCs), called ASCs, per tissue weight. Adipose tissue has gained clinical interest for use in regenerative medicine because it is easily accessible and readily available, contains large numbers of stem cells, and is economical to utilize. However, optimal adipose tissue is not always available for autologous use when needed; therefore, cryopreservation could be an alternative approach to make it available for donors when needed. Stem cell banks have been developed to offer greater flexibility of use of adipose tissue and ASCs for biomedical research and future clinical applications. Summary Adipose tissue is routinely discarded during various surgical procedures and could be cryopreserved as “whole tissue” or as “cells” (i.e., ASCs). Stem cell banks may enhance the safety and efficacy of adipose tissue and ASC use for future cellular therapies. In addition, stem cell banks may make cell-based therapies more effective and economical for patients.

Purpose of Review Myocardial regeneration is a promising alternative to heart transplantation, but the ideal stem cell type remains unknown due to conflicting results in clinical trials. Trial discrepancies may be addressed by standardizing cell handling protocols, broadening clinical endpoints, and selecting patients likely to benefit from cell therapy. Machine learning can potentially assist with these tasks. Recent Findings We introduce machine learning and review literature with the most efficacious results translatable to regenerative cardiology, such as in quality control systems during cell culturing, automated segmentation, and myocardial tissue characterization. Investigators are then cautioned on potential pitfalls and offered solutions to minimize model biasing. Summary Standardizing imaging with automated segmentation can improve the quantification of left ventricular endpoints. Additionally, myocardial textural analysis has significant potential to uncover hidden biomarkers, which may address the need for novel clinical endpoints. Lastly, phenogrouping through radiomics signatures can assist in appropriating patients likely to respond to stem cell therapy.

The formation of artificial organs with tissue engineering techniques is necessary to address the growing disparity between the supply and need for donor organs. For use in tissue engineering regenerative applications, biomaterials should be biocompatible, porous (to allow cellular infiltration, nutrient transport and waste removal), mechanically tunable (to match and maintain the intrinsic mechanical properties of the tissue through the healing process), biodegradable (to allow the tissue to develop as the material degrades), reproducible, easily prepared, and cell/tissue compatible. This review will focus on various biomaterial design considerations and their effect on regenerative outcomes. By adjusting material designs, including pore size and degradation kinetics, in combination with functionalization with cell- and tissue-specific factors, intrinsic properties of tissue constructs can be controlled to enhance remodeling and functional outcomes.

Purpose of Review Cell and tissue products do not just reflect their present conditions; they are the culmination of all they have encountered over time. Currently, routine cell culture practices subject cell and tissue products to highly variable and non-physiologic conditions. This article defines five cytocentric principles that place the conditions for cells at the core of what we do for better reproducibility in Regenerative Medicine. Recent Findings There is a rising awareness of the cell environment as a neglected, but critical variable. Recent publications have called for controlling culture conditions for better, more reproducible cell products. Summary Every industry has basic quality principles for reproducibility. Cytocentric principles focus on the fundamental needs of cells: protection from contamination, physiologic simulation, and full-time conditions for cultures that are optimal, individualized, and dynamic. Here, we outline the physiologic needs, the technologies, the education, and the regulatory support for the cytocentric principles in regenerative medicine.

Purpose of Review Tissue engineered constructs (TECs)—commonly developed using natural or synthetic biomaterials—are crucially needed for addressing the shortage of organ donations, immune rejection of transplants, pre-clinical in vitro drug efficacy testing, evaluation of personalized therapy options, and development of cell-laden substitutes for regenerative therapies. Unfortunately, constructs thicker than 200 microns suffer from poor diffusion rates of oxygen and nutrients needed for the survival of embedded cells as well as compliance of nearby tissue. To circumvent this challenge, biomaterials that promote vascularization are of upmost significance in the field of regenerative medicine. This article serves to review the current biomaterials (natural and synthetic) commonly utilized in the past few years to initiate and promote vascularization of TECs. Recent Findings Natural biomaterials have greater bioactivity compared to synthetic biomaterials; however, they suffer from uncontrollable rates of biodegradation, lack of batch-to-batch reproducibility, and low mechanical strength. Synthetic biomaterials, although also biocompatible and non-immunogenic, offer superior tunable mechanical strength and slow biodegradation rates. In the past few years, researchers have focused on making composite materials (combining natural and synthetic biomaterials or combining biomaterials with chemical additives), performing chemical modifications to circumvent subpar material performance properties, or utilizing techniques like electrospinning to fabricate fibrous networks resembling native ECM to promote vascularization. Summary The works reviewed in this article illustrate a variety of chemically, structurally, or compositionally modified natural and/or synthetic biomaterials capable of promoting vascularization of TECs. We believe future efforts in this avenue should include (1) methacrylation of dECM components, (2) inclusion of pre-vascularized constructs using on-chip technologies, (3) immobilization/integration of soluble angiogenic factors, (4) exploration of more versatile chemically modifications, (5) utilization of more non-cytotoxic crosslinking agents, (6) electrospinning technologies to mimic ECM architecture, and (7) implementation of additional environmental/structure factors to promote vascularization.

Purpose of Review It is a great challenge to scale up current cell therapy processes developed in 2D systems, and bioreactor technology could play an essential role in the scale-up of cell therapeutic products. Recent Findings Cell quality is critical to the therapeutic efficacy and their critical quality attributes (CQAs) are tightly related to their manufacturing processes. Employment of appropriate bioreactors for cellular products would enhance the productivity, reduce the cost as well as ensure the product CQAs. Summary The article reviews current commercially available bioreactors and their applications for regenerative therapeutic products. Regulatory, quality, and manufacturing aspects of these bioreactors are discussed.