Special Issue on Tissue Engineering - ACS ... - ACS Publications

Click Chemistry and Material Selection for in Situ Fabrication of Hydrogels in Tissue Engineering Applications. ACS Biomaterials Science & Engineering...
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Special Issue on Tissue Engineering Within the past decade, the field of tissue engineering gave rise to an exciting new area termed “organ-on-a-chip engineering” that is focused on developing three-dimensional tissues for drug testing applications and modeling of human disease.25 Whereas the original tissue engineered paradigm focused on repairing, restoring, and replacing the function of damaged, impaired, and lost organs, this new approach aims to use labgrown 3D tissues to discover new drugs, test their safety and truly understand the mechanism of human disease, paving the way to new therapies. To use the 3D tissues for repair of organ function, one has to build tissues of relatively large size in the laboratory (e.g., centimeter-scale tissues and organs). Unfortunately, this problem has still not been fully solved and organ size is still limited by the issues of limited oxygen supply and lack of appropriate vascularization. In addition, to build transplantation-ready organs, millions and sometimes billions of cells would be needed, and thus cell expansion in GMP conditions becomes an issue. To use the 3D tissues as models of disease or for drug testing, scale is not as important, and structures on the order of hundreds of micrometers would suffice, built using several hundred thousand cells, compared to millions that are needed for transplantation. Despite the complexity and relative dissimilarity of various organs that tissue engineers have attempted to reproduce in the lab, several commonalities and guiding principles have emerged in the past decades. For example, it was recognized that the mechanical properties (e.g., Young’s modulus) of the substrate (e.g., a biomaterial scaffold) can be of critical importance in regulating cell phenotype and function. It was also recognized that it can be valuable to mimic the native cellular composition of the target tissue and that cell cocultures and often tricultures can perform much better both in vitro and in vivo in terms of survival, gene expression, and function due to enhanced cell− cell signaling. Thus, it is common, for example, to incorporate fibroblasts together with a main cell type of the tissue (e.g., cardiomyocytes) to grow tissues with improved matrix remodelling capabilities and an enhanced tissue function. Another important finding was that biophysical stimulation during tissue growth can result in enhanced cell differentiation and a cellular phenotype of a higher-fidelity to that of the native tissue. Lastly, for vascularized tissues, it was recognized that rapid induction of vascularization via, for example, the presence of endothelial cells or preformed blood vessels, helps with provision of oxygen and nutrients and survival of tissues posttransplantation. The best way to achieve this is still an active area of investigation. A number of additional unsolved challenges still remain for the field. For example, the issue of cell maturation when building 3D tissues from stem cells is still not fully solved. Stem cell biologists and tissue engineers must strive to achieve fully adult phenotypes in their 3D cell cultures. This is of critical

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issue engineering was defined in the late 1980s as an emerging and interdisciplinary field “that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function.”1 At the heart of the classical tissue engineering paradigm was the integrated use of cells, biomaterial scaffolds, bioactive factors, and/or bioreactors. The main idea was to start from biopsies of patient tissues, expand those primary cells in the laboratory, and seed them into precisely tailored biomaterial scaffolds to create 3D tissues during bioreactor cultivation, aided by various biochemical (e.g., growth factor stimulation) and biophysical factors (e.g., mechanical and electrical stimulation). In cases where primary cells were not abundantly available and expandable, such as cardiomyocytes, the field focused on using stem cell-derived progeny. Recent advances in pluripotent stem cell biology, development of directed differentiation protocols,2 and discovery of induced pluripotent stem cells3 truly pave the way to engineering of any tissue type of the human body when combined with biomaterials and/or bioreactors. As an alternative to laboratory-made biomaterial scaffolds, tissue engineers have realized that native organs contain extracellular matrix that may have the composition, organization, mechanical properties, and/or geometry capable of supporting the viability and phenotype of tissue-specific cells. Coupled with the fact that many native organs are not suitable for transplantation, there is active research investigating the potential of decellularized organs and scaffolds fabricated from these decellularized tissues to serve as instructive matrices for tissue engineering applications.4 Since the emergence of the field, engineered tissue constructs have been used in humans in various applications to replace skin,5 cartilage,6 bone,7 blood vessels,8 heart valve,9 nerve,10 bladder,11 trachea,12 urethra,13 and vaginal organs.14 They have also shown promise in the treatment of myocardial infarction,15 spinal cord injury,16 osteoarthritis,17 osteoporosis,18 diabetes,19 liver cirrhosis,20 and retinopathy.21 However, aside from the approved skin substitutes (e.g., Dermagraft, Apligraf), the past three decades have not resulted in the plethora of approved tissue engineered products as originally anticipated. After an overwhelming enthusiasm in the 1990s, two of the pioneering tissue engineering companies, Organogenesis (Canton, MA) and Advanced Tissue Sciences (ATS; La Jolla, CA), filed for bankruptcy protection in 2002.22 Whereas Organogenesis was able to bounce back, ATS did not, making the business community cautious when investing in tissue engineering companies. These early difficulties illustrate that both the science and business of tissue engineering are important when bringing a new tissue engineered product to the market. The next frontier that may result in approved products in the future are tissue engineered blood vessels8a,23 and cardiovascular grafts for congenital malformations24 based on the promising clinical trial results. © 2017 American Chemical Society

Special Issue: Tissue Engineering Received: August 21, 2017 Published: September 11, 2017 1880

DOI: 10.1021/acsbiomaterials.7b00604 ACS Biomater. Sci. Eng. 2017, 3, 1880−1883

ACS Biomaterials Science & Engineering

Editorial

importance when growing tissues for drug testing; however, for transplantation, the sufficient levels of cell maturation remain to be defined. Reproducing cellular fidelity of the native tissues is also not fully solved. Although co- and tricultures can come closer to the complexity of the native cellular heterogeneity, for highly complex organs such as kidney, this simplistic approach may not be the most effective way of reproducing the correct cellular composition. The field of developmental engineering and organoids, where differentiation of stem cells is guided during the formation and maturation of 3D cellular condensations, may help to solve the problem of cellular fidelity.26,27 The issue of functional integration upon transplantation of engineered tissues is another problem that has not been solved. This is of particular importance for electrically active tissues such as heart muscle and tissues that offer mechanical support like articular cartilage. The field of biomaterials holds the potential to solve many of the current issues limiting the progress of tissue engineering, by providing a tailored environments and precisely engineered niches for cell growth and differentiation, thus motivating the preparation of this Special Issue. We present reviews and original research papers in the areas of cardiac, vascular, intestine, liver, lung, bone and cartilage tissue engineering. Heart and liver are most often affected by postapproval drug toxicity, thus there are intensive efforts to improve drug safety testing and detect potentially cardiotoxic and hepatotoxic drugs early in development. We open the issue up with an expert review by Fine and colleagues focusing on the use of engineered tissues, specifically cardiac, in drug testing and the potential to reduce and perhaps replace animal testing using this emerging approach.28 This review is followed by an expert assessment of the latest developments in the intestinal and liver models for drug toxicity testing provided by Orbach and colleagues.29 Further focusing the special issue on cardiovascular tissue engineering, Shin’oka and Breuer, who were the first in the world to implant tissue engineered patches into the hearts of pediatric patients, present a paper with Best et al. that investigates components of the clinical seeding protocol that confer patency of tissue engineered vascular grafts.30 Melhem and colleagues present a 3D printed hydrogel patch with a channel array containing encapsulated mesenchymal stem cells for the treatment of myocardial infarction in mice.31 The channel array supported the transport of the cell-secreted factors into the tissue and minimized the number of cells needed to attenuate pathological remodelling. Wang and colleagues report on the injectable coacervate used to control release fibroblast growth factor-1 (FGF-1) for the treatment of myocardial infarction in mice. Echocardiography demonstrated that FGF1 coacervate inhibited ventricular dilation and preserved cardiac contractility compared to the controls (i.e., free FGF1 and saline).32 Alemdar and colleagues present an innovative approach to cardiac tissue engineering using hydrogels based on oxygen releasing gelatin methacryloyl.33 Through this approach the authors can, in principle, overcome oxygen diffusional limitations, as the main factor influencing viability of engineered tissues. In line with using 3D tissues for drug discovery and testing, Nunes and colleagues present a method to induce pathological hypertrophy using a chronic drug exposure in stem-cell based cardiac tissues, termed Biowires.34

Le and colleagues focus on lung tissue engineering, specifically re-endothelialization of whole lung organ scaffolds.35 In the second part of the issue, we focus on bone and cartilage tissue engineering. We open up with a research paper by Huynh and colleagues focusing on catalyst-free formation of photodegradable hydrogels, and subsequent delivery of RNA for induction of osteogenesis in human mesenchymal stem cells.36 We then present a paper by Harding and colleagues describing an approach to mineralize hydrogels with calcium phosphate that was inspired by natural mineralization processes.37 Luo and colleagues contribute a paper on a method to mimic the zonal nature of articular cartilage using decellularized cartilage explants seeded with human infrapatellar fat pad derived stem cells.38 Gupta and colleagues present an idea, for further optimization, to tissue engineer osteochondral grafts relying on microsphere based scaffolds with opposing gradients of decellularized cartilage and demineralized done matrix.39 Mitra and colleagues present a study on osteogenic differentiation of mesenchymal stem cells (MSCs) on hyperglycemia-mediated cross-linked collagen.40 Understanding the underlying pathology is important to fully address diabetic challenges such as impaired bone healing. Finally, Helling and colleagues’ contribution focuses on the activity of matrix metalloproteinase-1 and -8, implicated in wound healing and remodelling processes and the best way to optimize an assay for collagen, important for assessing the extracellular matrix composition in many tissues.41 These examples represent some of the latest cutting-edge developments in the area of biomaterials for tissue engineering applications. We are excited to present them with hopes that they will stimulate further research in the field, to overcome current limitations in both science and commercialization of tissue engineered products.

Milica Radisic, Associate Editor University of Toronto and Toronto General Research Institute

Eben Alsberg, Guest Editor



Case Western Reserve University

AUTHOR INFORMATION

ORCID

Milica Radisic: 0000-0003-1249-4135 Eben Alsberg: 0000-0002-3487-4625 Notes

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.



REFERENCES

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DOI: 10.1021/acsbiomaterials.7b00604 ACS Biomater. Sci. Eng. 2017, 3, 1880−1883

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DOI: 10.1021/acsbiomaterials.7b00604 ACS Biomater. Sci. Eng. 2017, 3, 1880−1883