Extreme Tissue Engineering – Concepts and Strategies for Tissue Fabrication by Robert A. Brown, Wiley, 2012, 268 pages, ISBN 978-0-470-97447-6

Prof. Sujata K. Bhatia*, * Harvard University, School of Engineering and Applied Sciences, MA, USA

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In 1993, Langer and Vacanti published an influential review paper in Science [1], in which they defined tissue engineering as an interdisciplinary field that incorporates engineering and life sciences to create biological substitutes to restore, maintain, or improve tissue and organ function. Twenty years later, tissue engineer Robert A. Brown is concerned about the potential for stagnation in the field, and he contends that engineering concepts must be reintroduced to tissue engineers. He has written Extreme Tissue Engineering, a textbook which advocates for a new “extreme” approach to tissue engineering that includes serious consideration of both engineering and the life sciences, and enables the translation of technological innovations into clinical applications. The textbook aims to provide a unified introduction to the field of tissue engineering, as well as to allow newcomers to understand the underlying basic concepts and unsolved challenges of tissue engineering. The book argues convincingly for better integration of various fields within tissue engineering. The book is readable, accessible to a wide audience, and often humorous; the tone is reminiscent of a personal conversation with an experienced tissue engineer. Brown states emphatically in the preface, “In the face of false hopes. it is not enough only to point to long hours in the lab and a healthy grant income. Only extremely clear, joined-up thinking will do.”

Chapters 1 through 3 explain overarching themes and problems of tissue engineering. The first chapter of the book discusses the different approaches of engineers versus life scientists, as well as the unique technical demands of tissue engineering. Because tissues are living and dynamic systems, engineers cannot precisely control the removal and refitting processes of tissues. A tissue engineered material must integrate not only mechanically, but also biologically, with surrounding tissues. While engineers are comfortable with precision, life scientists are comfortable with uncertainty and complexity. Therefore, both engineers and life scientists must move outside their spheres of expertise and cooperate to design tissue engineered scaffolds. The second chapter expands this theme and outlines best practices for planning a tissue engineering project, namely the specification and quantitative definition of performance targets, also known as Key Functional Properties (KFPs). For instance, a left carotid artery can be described functionally as a visco-elastic tube containing a physiological non-Newtonian fluid, under pulsatile pressure, with minimal turbulence. Such function-based design will enable wider applications of tissue engineered implants. The third chapter of the book discusses the problematic, currently widely-used terminology of “2D” and “3D” cell culture systems. In reality, all culture systems are three-dimensional; it is more precise to specify culture systems as monolayers or embedded cultures, each of which simulates different in vivo conditions. Monolayers are appropriate for epithelial cells, while embedded cultures are appropriate for stromal cells.

Brown: “ is not enough only to point to long hours in the lab and a healthy grant income. Only extremely clear, joined-up thinking will do.”

Chapters 4 through 6 identify optimal strategies for conceptualizing, investigating, and fabricating tissue engineering scaffolds. The fourth chapter critiques the contemporary frequently-used approach in which materials scientists develop biomaterial scaffolds while biologists separately develop cells. This strategy of separation ultimately requires an additional step of cell seeding once the scaffold is complete. The book advocates for an integrated approach in which native scaffolds (derived of collagen, fibrin, or silk for example) are developed with cells already embedded inside. The fifth chapter continues in this vein, discussing the advantages of scaffolds based on natural materials over those based on synthetic materials; natural scaffolds can be actively modified by embedded cells, while synthetic scaffolds cannot. The discussion also contrasts top-down fabrication with bottom-up fabrication of scaffolds, favoring the latter approach. Bottom-up fabrication with self-assembly allows cells to be enmeshed interstitially at time zero, resulting in better three-dimensional biomimesis. The sixth chapter dives into deeper detail regarding fabrication of engineered tissues. A complex, native tissue can be viewed as a sequence of many layers and zones in different planes, each of which may be individually simple. Therefore, a complex tissue can be fabricated via the repetitive assembly of many compositionally simple layers; this is layer engineering. Layers can be utilized in all three planes, and layering techniques can be applied to manufacture planar stacks, radial/concentric structures, and non-parallel structures.

Chapters 7 through 9 discuss novel, cutting-edge research concepts for engineering tissues. The seventh chapter considers what can be learned from natural tissue growth and reconstructive surgery. During childhood and adolescence, long bone growth is the directional motor which drives soft connective tissue growth. In both children and adults, soft connective tissues grow when placed under a directional tensile load. Growth and remodeling maintain a tensional homeostasis; cells are mechano-responsive, and connective tissue cells adapt matrix stiffness by increasing or decreasing collagen deposition. Tissue engineers should consider how to alter the external loading on tissues, to entice resident cells into growing extracellular matrix. The eighth chapter focuses on tissue-generating bioreactors, and discusses the trade-offs between in vivo bioreactors that enable early implantation, and in vitro bioreactors that require late implantation. In vivo bioreactors for early implantation are simpler and less costly, but allow minimal control over the outcome. In vitro bioreactors for late implantation allow much more control of construct development, but are costly and complex. The ninth and final chapter discusses the need for “4D” tissue engineering, which takes into account time as the fourth dimension. The chapter advocates for real-time process monitoring of tissue engineering fabrication, with the ultimate goal of real-time tuning of fabrication to meet clinical needs. Such monitoring will also enable the development of useful mathematical models for tissue fabrication.

...Brown proposes “4D” tissue engineering, with time as the fourth dimension...

Overall, Extreme Tissue Engineering is an insightful textbook that enables scientists and engineers to understand and explain major barriers to progress in tissue engineering, and set priorities for surmounting these barriers. The book will additionally allow students to read the current tissue engineering literature with a critical eye. Finally, the book may be utilized as a troubleshooting manual, which can help tissue engineers to overcome roadblocks in scaffold development.

Prof. Sujata K. Bhatia, Harvard University, School of Engineering and Applied Sciences, MA, USA, E-mail:

About the book author

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Professor Robert A. Brown is Director of the Tissue Repair & Engineering Centre (TREC) of the University College London. He is also coordinator of the London Tissue Engineering Consortium (Tissue Bioreactor Science) and the British Tissue Engineering Network (BRITE Net). Prof. Brown's research is focused on the platform science and underpinning engineering problems for regeneration of human tissues. This includes research into novel micro-structured (cell support) biological materials and the mechanisms by which mechanical cues act through such materials to regulate 3D tissue growth.


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