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Über dieses Buch

This book covers a broad area of engineering research in translational medicine. Leaders in academic institutions around the world contributed focused chapters on a broad array of topics such as: cell and tissue engineering (6 chapters), genetic and protein engineering (10 chapters), nanoengineering (10 chapters), biomedical instrumentation (4 chapters), and theranostics and other novel approaches (4 chapters). Each chapter is a stand-alone review that summarizes the state-of-the-art of the specific research area.

Engineering in Translational Medicine gives readers a comprehensive and in-depth overview of a broad array of related research areas, making this an excellent reference book for scientists and students both new to engineering/translational medicine and currently working in this area.

The ability for engineering approaches to change biomedical research are increasing and having significant impact. Development of basic assays and their numerous applications are allowing for many new discoveries and should eventually impact human health. This book brings together many diverse yet related topics to give the reader a solid overview of many important areas that are not found together elsewhere. Dr. Weibo Cai has taken great care to select key research leaders of many sub-disciplines who have put together very detailed chapters that are easy to read yet highly rich in content.

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This book brings together many diverse yet related topics to give the reader a solid overview of many important areas that are not found together elsewhere. Dr. Weibo Cai has taken great care to select key research leaders of many sub-disciplines who have put together very detailed chapters that are easy to read yet highly rich in content. It is very exciting to see such a great set of chapters all together to allow one to have a key understanding of many different areas including cell, gene, protein, and nano engineering as well as the emerging field of theranostics. I am sure the readers will find this collection of important chapters helpful in their own research and understanding of how engineering has and will continue to play a critical role in biomedical research and clinical translation.

Sanjiv Sam Gambhir M.D., Ph.D.
Stanford University, USA

Engineering in Translational Medicine is a landmark book bridging the fields of engineering and medicine with a focus on translational technologies and methods. In a single, well-coordinated volume, this book brings together contributions from a strong and international scientific cast, broadly covering the topics. The book captures the tremendous opportunities made possible by recent developments in bioengineering, and highlights the potential impact of these advances across a broad spectrum of pressing health care needs. The book can equally serve as a text for graduate level courses, a reference source, a book to be dipped into for pleasure by those working within the field, or a cover-to-cover read for those wanting a comprehensive, yet readable introduction to the current state of engineering advances and how they are impacting translational medicine.

Simon R. Cherry, Ph.D.
University of California, Davis, USA

Inhaltsverzeichnis

Frontmatter

Chapter 1. Engineering in Translational Medicine: An Introduction

Molecular and personalized medicine is the future for patient management. Translational medicine, a continuum of research that spans from basic science to clinical applications, is the key to twenty-first century personalized medicine. Engineering is an indispensable component of translational medicine. This book will cover a broad spectrum of engineering research in translational medicine, where leaders in each research topic provide a state-of-the-art summary in 34 chapters on various topics such as cell and tissue engineering (6 chapters), genetic and protein engineering (10 chapters), nanoengineering (10 chapters), biomedical instrumentation (4 chapters), and theranostics and other novel approaches (4 chapters). This book will give the readers a comprehensive and in-depth overview of a broad array of research areas, which can serve as an invaluable reference book for scientists/students/clinicians both new to engineering and currently working in this area.

Weibo Cai

Cell and Tissue Engineering

Chapter 2. Stem Cells: The Holy Grail of Regenerative Medicine

Recent advancement in understanding the complex characters and interdependent molecular pathways of biological diseases led to a new therapeutic approach of “Biological Solutions to Biological Diseases.” Stem cells that reside at the apex of cellular hierarchy are now considered as “Therapeutic wonders” due to their multilineage differentiation and self-renewal properties. These cells depending upon their differentiation potency and site of origin are being widely experimented for therapeutic purpose with emerging success in clinical application. The challenge posed by ethical problems and teratoma formation of embryonic stem (ES) cells; rare occurrence of tissue-specific adult stem cells has recently been overcome by the creation of dedifferentiated induced pluripotent stem cells (iPSCs) from mature differentiated cells. Research in stem cell therapy involves novel strategies for directed differentiation of ES cells, adult stem cells, and iPSCs in vitro; temporal and spatial monitoring of in vivo differentiation and functional output and final validation in human patients. In this chapter, we will review the detailed investigations currently undergoing in stem cell biology and their clinical applicability, which might bring revolutions in future patient outcome.

Ram K. Singh, Snehal M. Gaikwad, Subhoshree Chatterjee, Pritha Ray

Chapter 3. Engineering T Cells to Target Tumor Cells

The immune system can exert dual roles in cancer biology. Cellular elements serve both as an effector function to eradicate tumor cells and as a promoter to support tumor growth. The microenvironment of an established tumor is usually immune suppressive, protecting tumor cells from recognition and elimination by effector cells. Genetic engineering can be used to modify T cells ex vivo to improve their functionality in favor of tumor killing. Adoptive cell therapy with genetically modified T cells aims to (1) redirect specificity to tumor cell antigens, (2) increase the number and persistence of antigen-specific T cells, (3) improve T cell effector functions, (4) overcome suppression of T cells by disrupting inhibitory molecules, and (5) guide T cells to the tumor site through the interaction between chemokines and their receptors. T cells can be also equipped with suicide genes for their conditional elimination if they induce an unintended immune response or transform to a malignant phenotype. In this chapter, we describe the current status of adoptive therapy for cancer with genetically engineered T cells.

Hiroki Torikai, Judy S. Moyes, Laurence J. N. Cooper

Chapter 4. Engineering Biomaterials for Anchorage-Dependent and Non-anchorage-Dependent Therapeutic Cell Delivery in Translational Medicine

The delivery of functional and viable biological cells may potentially become a medical solution to replace the lost or abnormal cells, tissues, and organs. Cell delivery methods should deliver and localize viable and functional cells to the target site with high efficiency to repair the defect. Many research efforts have been focused on developing cell delivery vehicles, which are scaffold systems that carry cells. The biomaterials used in the scaffolds are crucial in determining the success of cell delivery—cells are able to interact with the environmental cues presented by biomaterials and modify their behavior accordingly. Cells can be categorized according to their dependence on anchorage to the extracellular matrix (ECM)—anchorage-dependent cells (ADCs) such as muscle cells and neurons require extensive cell adhesion to a substrate in order to survive and function properly, while non-anchorage-dependent cells (non-ADCs) such as chondrocytes and hepatocytes do not and often exhibit a rounded morphology in native environment. Here, the different cell delivery structures and their development in delivering both ADCs and non-ADCs are discussed.

Wenyan Leong, Dong-An Wang

Chapter 5. Tissue Engineering Applications for Peripheral Nerve Repair

Peripheral nerve injuries lead to variable levels of functional loss depending on the extent of the injury. Despite the modern treatment methods, peripheral nerve regeneration is still a time-consuming process mainly because of the limited regeneration capacity of the nervous system. Unfortunately, attempts to increase the regeneration potential of the peripheral nervous system yielded a limited improvement. However, Tissue engineering emerged as a more promising tool to ease the traditionally laborious process of peripheral nerve regeneration. A tissue-engineered nerve is a combination of a biodegradable scaffold, a neurogenic cell line, and growth factors. The main focus of current research is to improve the cell–scaffold and scaffold–tissue interactions. Engineering a fully biocompatible and natural nerve-like nerve segment should be possible in the future with the improved understanding of biological mechanisms of nerve healing. This chapter provides a detailed look into the components of tissue-engineered nerve grafts along with a review of clinically relevant studies.

Hakan Orbay, Weibo Cai

Chapter 6. Structure, Function, and Development of Blood Vessels: Lessons for Tissue Engineering

The establishment of blood vessel networks is a matter of life and death for tissues and organisms. Failure to form a functional vascular network causes early death of embryos, and also dysfunction of endothelial cells (ECs) contributes to many diseases, including stroke, thrombosis, and atherosclerosis. Furthermore, there is a considerable clinical need for alternatives to the autologous vein and artery tissues used for vascular reconstructive surgeries such as lower limb bypass, arteriovenous shunts, and repairs of congenital defects to the pulmonary outflow tract. So far, synthetic materials, particularly in small-diameter applications, have not matched the efficacy of native tissues.

Hamisha Ardalani, Amir H. Assadi, William L. Murphy

Chapter 7. Engineering Gene-Activated Matrices for the Repair of Articular Cartilage Defect

Cartilage tissue lacks the innate ability to repair itself effectively and is prone to significant dysfunction after damage. Damage to articular cartilage can easily lead to its more serious degeneration, which is one of the leading causes of disability in the elderly. Growth factors have been shown to promote cartilage repair. However, the structure of cartilage tissue has been shown to hinder the direct addition of protein growth factors into the traditional system because of the difficulty in controlling the amount of growth factor added and the short growth factor half-life. Developments in molecular biology and genetic engineering techniques have produced the gene-activated matrix (GAM) system for the repair of articular cartilage damage, in which a large quantity of growth factors is continuously secreted by transgenic target cells. Numerous studies have established GAM treatment as a new therapeutic approach for repairing cartilage damage.

Junfeng Zhang, Zhen Huang

Genetic and Protein Engineering

Frontmatter

Chapter 8. Engineering Luciferases for Assays and Imaging

Luciferases have served a number of purposes in biomedical applications, including within reporter gene and split reporter complementation assays. These proteins, however, have not evolved for the purpose of biomedical research, and it is not surprising that the utility and robustness of these assays can be improved by protein engineering of the luciferase. In this chapter, we provide an overview of luciferases, protein engineering, and how protein engineering is applied to luciferases.

Andreas M. Loening, Zachary F. Walls

Chapter 9. Engineered Split Reporter Systems for Molecular Imaging of Protein–Protein Interactions in Living Subjects

In the last decade, there has been a veritable explosion in the field of reporter gene imaging, with the aim of determining the location(s), duration, and extent of gene expression within living subjects. An important application of this is in molecular imaging of interacting protein partners, an area that could pave the way to functional proteomics in living animals and provide a tool for whole-body evaluation of new pharmaceuticals targeted to modulate protein–protein interactions. We review the main methods currently available for imaging protein–protein interactions in living subjects using molecularly engineered and rationally designed split reporter gene and protein systems tailored to various protein complementation and reconstitution strategies.

Tarik F. Massoud, Ramasamy Paulmurugan

Chapter 10. Engineering Aspects of Bioluminescence Resonance Energy Transfer Systems

Development of optical probes for sensing biological functions in vivo is in high demand in modern biology. With several inherent advantages, the bioluminescence resonance energy transfer (BRET)-based sensors are rapidly expanding and showing great utilities in the study of protein–protein interactions (PPIs), protein dimerization, signal transduction, etc. Since its inception in the late nineties, BRET-related research has gained significant momentum in terms of adding versatility to the assay format and wider applicability where it has been suitably used. Beyond the scope of quantitative measurement of PPIs and protein dimerization, molecular imaging applications based on BRET assays have broadened its scope for screening pharmacologically important compounds by in vivo imaging and high-throughput screening (HTS) methods. Taking examples from literatures, this chapter will contribute to an in-depth knowledge on engineering requirements of BRET components such as donor, acceptor, substrate chemistry, and instrumentations. BRET applications having significant contributions toward making it an attractive single-format assay are also discussed.

Abhijit De, Rohit Arora, Akshi Jasani

Chapter 11. Antibody Engineering in Translational Medicine

Antibodies (Abs) are a major constituent of the human immune system and have become an important class of therapeutics in cancer and inflammatory diseases. Antibody engineering technologies aim at the development of new generations of antibody-based drugs with more favorable properties, including higher potency or improved safety profiles. This chapter provides an overview over current strategies to tailor Abs for medical applications. While some of the engineering technologies improve the inherent features of the antibody—like target specificity, effector functions, or pharmacokinetics—others empower the antibody with additional mechanisms of action. The latter category includes the development of antibody–drug conjugates (ADCs), radioimmunoconjugates, or bispecific Abs. These novel antibody-based therapeutics will likely have a big impact on the future treatment of many diseases, but especially in cancer therapy.

Eliane Fischer

Chapter 12. Engineered Affibodies in Translational Medicine

Affibody proteins are an emerging class of small protein (7 kDa) scaffold-based affinity reagents. Affibodies were first reported 10 years ago and have since been developed to bind to several important biomarkers. Affibody proteins were originally produced from staphylococcal protein A, and later, they are selected from phage display libraries based on a 58 amino acid and three alpha-helical Z-domain scaffolds. They can be reliable produced by both conventional peptide synthesis chemistry and recombinant expression in

Escherichia coli

. Protein engineering techniques have been used to make Affibody molecules bind to a target specifically and meet the requirement such as high affinity, high uptake, and high contrast imposed by intended application. General structures and engineering strategies to optimize Affibody molecules for diagnostic imaging and therapy applications are described in this book chapter. The current research on using Affibody molecules for molecular imaging and therapy is also discussed.

Xiang Hu, Hongguang Liu, Zhen Cheng

Chapter 13. Alternative Protein Scaffolds for Molecular Imaging and Therapy

Molecular targeting has tremendous potential to enhance the specificity and sensitivity of diagnostics and the safety and potency of therapeutics, as well as to induce unique and precise biological responses. Effective targeting requires specific binding of appropriate affinity, conjugation of effectors (

e.g.

, toxins, radioisotopes, or fusion proteins) as needed, stable maintenance of activity, and effective delivery physiologically. Ideally, solutions to these challenges will be efficiently implemented for a multitude of molecular targets unique to the relevant pathophysiology. Protein scaffolds, molecular frameworks amenable to local diversity to introduce specific binding while retaining favorable biophysical characteristics, offer an intriguing general solution. While antibodies and their derivatives offer viable options, a host of alternative topologies prove superior in stability, size, production, and/or conjugation. Validated scaffolds include the fibronectin domain, knottin, designed ankyrin repeat protein, anticalin, and affibody among others. These scaffolds have demonstrated efficacy in preclinical animal models and, in some cases, clinical trials in therapy or imaging. These translational developments will be reviewed here. The future is bright for both antibodies and their alternatives. Research should be undertaken to identify the most efficacious scaffold for each individual clinical indication and application.

Benjamin J. Hackel

Chapter 14. Engineering Multivalent and Multispecific Protein Therapeutics

In nature, there are a wide array of proteins that utilize the principles of multivalency and multispecificity to ensure optimal biological function. Their mechanisms of action have served as inspiration for the development of next-generation protein therapeutics with improved efficacy and safety profiles. Protein therapeutics leverage the inherent affinity and specificity of protein–protein interactions, offering an effective approach for targeting and modulating biochemical pathways. An increased molecular understanding of biological processes that underlie disease pathologies, as well as the advent of new protein engineering platforms, has elevated the sophistication of protein therapeutics entering the clinical pipeline. Here, we discuss the main advantages conferred by multivalency and multispecificity as they are related to protein therapeutics, namely increased targeting affinity through avidity effects, and selectivity for a diseased versus normal state. These aspects lead to greater therapeutic control over an intended biological response, with the potential for reduced side effects. In this chapter, we describe the basic biophysical principles underlying multivalency and multispecificity and discuss how they influence protein design parameters. Finally, we consider how one can utilize these concepts to develop protein therapeutics that address challenging biomedical problems.

Cassie J. Liu, Jennifer R. Cochran

Chapter 15. Engineering Aptamers for Biomedical Applications: Part I

Aptamers are single-stranded DNA or RNA oligonucleotides that are selected for specific binding to a wide range of targets by systematic evolution of ligands by exponential enrichment (SELEX) technology. Aptamers have high specificity and affinity toward target molecules and exhibit desired thermal stability. Additionally, the oligonucleotide nature makes aptamers easy to be chemically modified or incorporated with other DNA/RNA molecules. Owing to these outstanding properties, aptamers have attracted considerable attention within different branches of biomedicine. On the other hand, biosensors are miniaturized analytical devices that are playing an important role in biomedical applications, especially in clinical diagnoses. Recent advances in molecular engineering of aptamers with enhanced bioavailability signal generation and amplification abilities have greatly facilitated the development of aptamer-based biosensors and have pushed them closer to clinical applications. In this chapter, we will detail the recent development in engineering aptamers and highlight the work for sensor applications by using engineered aptamers.

Ya Cao, Genxi Li

Chapter 16. Engineering Aptamers for Biomedical Applications: Part II

The development of new targeting means for the specific and safe delivery of drugs to diseased cells or tissues has become a need with potential widespread applications in medicine. Because of their high specificity of targeting, aptamers offer an innovative highly promising option as delivery agents for nanoparticles, siRNA bioconjugates, chemotherapeutic cargos, and molecular imaging probes. Indeed, aptamers are short, single-stranded oligonucleotides (ODNs) that have been shown as high-affinity ligands and potential antagonists of disease-associated proteins. They discriminate between closely related targets and are characterized by high specificity, convenient synthesis and modification with high batch fidelity, rapid tissue penetration, and long-term stability. Further, nucleic acid aptamer-based drugs show low in vivo immunogenicity, a major obstacle in the development of protein-based therapeutics. As such, aptamers couple the advantages of the specific binding of monoclonal antibodies to the chemical nature of nucleic acids. Here, we will focus on the development of multifunctional aptamer-based bioconjugates for targeted delivery of therapeutics and imaging agents to diseased cells and tissues. The broad spectrum of ways for aptamer engineering will be discussed in light of the pros and cons for biomedical developments in terms of in vivo specificity, efficacy, stability, and toxicity.

Laura Cerchia, Luciano Cellai, Vittorio de Franciscis

Chapter 17. Engineering DNA Vaccines for Cancer Therapy

An anti-tumor DNA vaccine is a bacterial DNA plasmid that encodes the cDNA of a tumor antigen, which when injected into recipients can elicit humoral and/or cellular immunity against tumor cells expressing the encoded antigen. Dozens of DNA vaccines have entered clinical trials for a variety of malignancies, where they have demonstrated efficacy in eliciting immune responses and potential clinical responses. This is further demonstrated by the approval of a DNA vaccine for the treatment of canine melanoma, the first vaccine approved for the treatment of cancer. One of the primary advantages of DNA vaccines as opposed to some other methods of antigen delivery is that they can be easily constructed, purified, and delivered to recipients. Additionally, these vaccines can be easily modified to incorporate various elements that can enhance anti-tumor immune responses. In this review, we discuss engineering efforts to enhance the immune and anti-tumor efficacy of DNA vaccines, focusing on specific changes that can be made to the DNA backbone to enhance the expression, processing, and presentation of the encoded antigen, as well as improving the inherent immunogenicity of the vaccine itself.

Brian M. Olson, Douglas G. McNeel

Nanoengineering

Frontmatter

Chapter 18. Multifunctional Nanoscale Delivery Systems for Nucleic Acids

Nanoscale systems have emerged in the past two decades as attractive platforms for delivering nucleic acids in vivo while performing other therapeutic or diagnostic functions, though their full potential for improving human health has yet to be realized in the clinic. Bioengineering techniques have been crucial for modifying and optimizing synthetic and viral delivery systems to include drugs, imaging agents and targeting moieties as well as reducing toxicity effects and increasing delivery efficiency and specificity. Directed delivery technologies can complement these nanoscale systems to localize therapy in vivo. The use of nucleic acid analogs can also enhance therapeutic efficacy under ideal circumstances. This chapter will review some of the recent developments in RNA and DNA delivery research with a focus on progress toward human therapies, the challenges that have been encountered, and the engineering approaches that have been employed. In addition to on-going work on the optimization of delivery systems, three challenging areas are identified: (1) the development of heterogeneous, three-dimensional microenvironments for testing delivery systems, (2) imaging approaches to understand the dynamic interactions of systems from administration through delivery in the human population, and (3) development and translation of directed technologies capable of enhancing delivery in a clinical setting and producing a sustained therapeutic effect.

Richard Conroy, Belinda Seto

Chapter 19. Engineering Nanomaterials for Biosensors and Therapeutics

Nanomaterials have attracted lots of recent research attention as they possess unique photophysical, magnetic, and thermal properties with the potential of being engineered for various biomedical theranostic applications. The objective of this book chapter is to provide a timely overview on the synthetic methodology, surface engineering, physiological itinerary, and theranostic applications for the nanophases and nanostructures consisting of inorganic and/or organic materials. This chapter starts with an introduction, followed by a brief review of the applications and preparative methods of the inorganic nanomaterials with surface plasmon resonance, photoluminescence, magnetic, and bioactive properties. The effects of surface modification with polymers and morphology on the physiological itinerary and toxicity of the nanomaterials are then discussed to help the design of vehicles for targeted tissue imaging and drug delivery. Finally, examples of several promising nanotechnologies and theranostic applications are given including biosensors, magnetic hyperthermia, and photodynamic therapy (PDT) for tumor treatment. This chapter ends with a conclusion and future perspective section. To make use of all the innovative ideas and demonstrative prove-of-principles of nanomaterials for practical biomedical applications, it is absolutely necessary to emphasize and expand efforts on their translational research and development, including clinical studies and large-scale manufacturing of these novel engineered nanomaterials.

Tse-Ying Liu, Chun-Liang Lo, Chih-Chia Huang, Syue-Liang Lin, C. Allen Chang

Chapter 20. Engineering Fluorescent Nanoparticles for Biomedical Applications

Fluorescent nanoparticles (NPs) have been widely studied in preclinical research, for cancer imaging and/or theranostics because of their attractive optical properties. Fluorescent NPs present several advantages compared to free fluorescent dyes, such as indocyanine green, for clinical application. Their design has to comprise not only parameters related to enhanced fluorescence but also provide efficient blood circulation half-life, tumor delivery, biocompatibility, and low toxicity. Safety is one of the most important criteria in NP design for clinical use, which explains, in part, why despite the high number NPs published, only very few have reached clinical trials. In this chapter, we focus on three major groups of fluorescent NPs: quantum dots (QDs), fluorescent dye-loaded inorganic and organic NPs, which include calcium phosphate, silica, lipid, and polymer based NPs. For each, we will briefly highlight their characteristics, advantages, limitations, and engineering strategies employed to enhance their in vivo use and describe preclinical studies. We will emphasize translational relevant work and when applicable describe examples of NPs that were translated to human studies. Finally, we would provide a perspective of the fluorescent NPs advances needed for future human application.

Oscar F. Silvestre, Xiaoyuan Chen

Chapter 21. Magnetic Nanoparticles for Biomedical Applications: From Diagnosis to Treatment to Regeneration

Magnetic nanoparticles are popular candidates for many biomedical applications because of their nontoxicity, biocompatibility, and unique magnetic properties. In the past decade, progresses in the synthesis and surface engineering of magnetic nanoparticles have further enhanced this image. This chapter aims to provide a general overview of their applications in biomedical fields such as bioseparation, gene delivery, diagnosis, antibacterial agent, disease therapy, tissue engineering, and regenerative medicine. Finally, remaining challenges and opportunities are discussed as well.

Yu Gao, Yi Liu, Chenjie Xu

Chapter 22. Engineering Upconversion Nanoparticles for Biomedical Imaging and Therapy

Upconversion nanoparticle (UCNP) has been attracting growing interests in the last few years owing to their unique upconversion luminescence features. Although the size and morphology control of UCNP have been well-documented, engineering of ultrasmall-sized UCNP with excellent optical properties is still in its early stage. With increasing interests in using UCNP as deeper tissue imaging probe, some new strategies have been developed for enhancing the emission efficiency of red and near-infrared bands. Also, doping suitable ions into UCNP crystal lattices has been accepted as one of the most unique and efficient techniques for integrating nearly all clinical relevant imaging modalities together in one single UCNP. Cancer multimodal imaging (or therapy) with these lanthanide ions-doped UCNPs has become a new hot topic in this field. Here, we summarized the very recent advances in engineering of UCNP for biological imaging and therapy.

Feng Chen, Wenbo Bu, Weibo Cai, Jianlin Shi

Chapter 23. Engineering of Mesoporous Silica Nanoparticles for In Vivo Cancer Imaging and Therapy

Mesoporous silica nanoparticles (MSNs) possess many attractive properties, such as good biocompatibility, large surface area, high pore volume, uniform and tunable pore size, and have been intensively investigated as novel drug delivery systems for more than 10 years. Although in vitro imaging and therapeutic applications by using MSNs have been reached a great success, transferring these to the in vivo level is still facing big challenges and is now under intensive investigations. In this chapter, we summarized the very recent progress and future directions of engineering MSNs for biological imaging and therapy in vivo.

Feng Chen, Weibo Cai, Hao Hong

Chapter 24. Engineering Carbon Nanomaterials for Stem Cell-Based Tissue Engineering

Recent advances in creating carbon nanomaterials and their derivatives have led to several opportunities in biomedical research and clinical applications. The current and most promising biomedical applications of carbon nanomaterials such as carbon nanotubes and graphene includes but are not limited to tissue engineering and regenerative medicine. Owing to their unique intrinsic physical and chemical properties, they have been engineered by different methods to develop suitable two-dimensional and three-dimensional scaffolds. Such biocompatible nanostructured scaffolds were found to sustain growth, proliferation, and adhesion of different stem cells. While some of these scaffolds were found to accelerate the osteogenic, neurogenic, and adipogenic differentiation of various stem cells in the presence of specific medium, some scaffolds have been reported to support spontaneous differentiation of the stem cells into specific adult tissues even in normal medium. Several underlying mechanisms such as nanotopography, preconcentration of growth factors, electrostatic and chemical interactions have been proposed for such behavior of stem cells growing on different carbon nanomaterial-based scaffolds. Above results indicate them as excellent nanoplatforms for tissue engineering and stem cell-based regenerative medicine. However, most of these literature reports consist only of in vitro studies with specific stem cells. Therefore, sufficient in vivo studies together with relevant toxicity and biocompatibility data are necessary for their future application as an implantable tissue engineering material.

Tapas R. Nayak, Weibo Cai

Chapter 25. Engineering Peptide-based Carriers for Drug and Gene Delivery

Recent research efforts have focused on the optimization of cell delivery systems with the aims of increasing cell specificity, incorporating organelle targeting and improving overall delivery efficiency. Peptides and proteins represent new and innovative strategies to meet these targets. The advantages of peptides are manyfold: they can condense DNA into compact particles for transport, disrupt the endosomal membrane, escape proteasomal degradation, traffic therapeutic molecules of various size, charge, and function to targeted intracellular compartments, and can have reduced cytotoxicity and immunogenicity. These properties can be part of a single peptide or the result from the conjugation of different peptides. Silk, a structural protein, is well known for its biodegradability and biocompatibility and can be tailored for specific design features via genetic engineering. With tunable structure, chemistry, and mechanical properties for silk proteins derived from spiders and insects, modified or recombinant silk proteins can be utilized in various biomedical applications such as for the design of gene delivery systems. This review summarizes the diversity and application of peptides and silk proteins to mediate intracellular delivery of genes and drugs.

Jo-Ann Chuah, David L. Kaplan, Keiji Numata

Chapter 26. Activation Approaches on Delivery of Imaging and Therapeutic Agents

Successful treatment for a disease relies upon the effective delivery of a therapeutic agent to the target site. An approach to enhance the therapeutic efficacy and to minimize unwanted side effects is to formulate a drug carrier for active and passive targeting. Alternatively, activatable agents have been designed to release active pharmaceutical moieties in response to internal (pH and enzyme) or external (heat, light, and magnetic field) stimuli. Often, the drug releases from these agents are self-regulatory or are remotely controlled in a spatial and/or temporal manner. A site-specific drug release can also improve the therapeutic efficacy, decrease the side effect, and reduce dosage regimen. Complementary to nanotechnology, activatable agents with various built-in sophisticated mechanisms have recently been engineered. Some of them have been used for the development of contrast agents to reduce the imaging background. This chapter provides an update review of activatable agents, with specific examples being highlighted to illustrate their mechanisms and potential applications for imaging and the treatment for diseases, such as cancer.

Mitulkumar A. Patel, Benedict Law

Chapter 27. Opportunities for New Photodynamic Molecular Beacon Designs

The ability to provide biomolecular recognition with a fluorescence readout has made molecular beacons useful in various medical and biological applications. Combined with photodynamic therapy photosensitizers, photodynamic molecular beacons hold potential as new tools for not only disease diagnosis, but therapy as well. In this chapter, we focus on classic and emerging nucleic acid-based molecular beacon design considerations. Designs based on the original stem-and-loop structure have been expanded, and these concepts have direct applicability for conversion into photodynamic molecular beacons.

Kun Lou, Jonathan F. Lovell

Biomedical Instrumentation

Frontmatter

Chapter 28. Engineering the Next-Generation PET Detectors

Positron emission tomography (PET) is a functional imaging modality where image contrast is generated by exploiting the biochemical activity of the lesion of interest. The technique is widely used in the clinic, mainly for staging of cancerous lesions and monitoring their response to therapy. This chapter discusses recent research and engineering efforts aimed at improving images obtained with clinical PET cameras. We want to provide the reader with an overview of novel techniques that potentially will make it into clinical PET systems. After introducing PET and the current state-of-the-art commercially available clinical systems, we will discuss characteristics of current and novel scintillating materials and introduce improvements in spatial resolution through depth-of-interaction measurements and novel optical photon extraction methods. Next will be a discussion of various photodetectors: we present photomultiplier tubes, the current clinical workhorse in PET, as well as silicon-based solid-state photodetectors: avalanche photodiodes (APDs) and silicon photomultipliers (Si-PMs). We also briefly discuss semiconductor detectors that do not require photodetectors. Improved time resolution and its consequences for time-of-flight (TOF) imaging is the next topic of focus. Accurate TOF information significantly improves image SNR. Furthermore, we present the challenges involved in combining PET with MR systems and improvements in image reconstruction speed using GPUs.

Arne Vandenbroucke, Craig S. Levin

Chapter 29. Photoacoustic Imaging: Development of Imaging Systems and Molecular Agents

Photoacoustic imaging is a relatively new imaging modality with great promise to overcome most of the limitation of conventional optical imaging. By leveraging the conversion of short light pulses into ultrasound waves, it is possible to generate three-dimensional maps of a tissue with high spatial resolution and at a high tissue depth of penetration. Since the basic mechanism that gives rise to a photoacoustic signal is light absorption, several endogenous contrasts can be used for photoacoustic imaging of tissues, including hemoglobin and melanin. To allow photoacoustic imaging to reach its full potential, exogenous contrast agents that can target biomolecules in living tissues were developed, enabling molecular imaging studies. This chapter will review the physical basis of photoacoustic imaging, starting with the photoacoustic effect and the conditions needed to generate detectable ultrasonic waves from light excitation of an absorber. The different photoacoustic scanner implementations will then be discussed, including photoacoustic tomography (PAT) and microscopy systems and the biomedical applications to which they are best suited. Finally, the various exogenous contrast agents for photoacoustic imaging will be discussed and a general approach for contrast agent validation will be described.

Adam de la Zerda

Chapter 30. Engineering Miniature Imaging Instruments

Miniature instruments are being developed with millimeter dimensions for in vivo imaging with performance approaching that of conventional laboratory microscopes used in basic science. This reduction in size allows for in vivo imaging to visualize pathology in hollow organs to guide biopsy, identify surgical margins, and localize disease. Recently, significant advances have been made in endomicroscopy technology, including in optical designs, light sources, optical fibers, and miniature scanners, allowing for improved resolution, greater tissue penetration, and multi-spectral imaging. Key performance goals that challenge our engineering capabilities include the need for large displacements, high scan speeds, linear motions, and mechanical stability in a scaled-down instrument package. Tiny scanning and actuation mechanisms must be reduced in size for in vivo imaging and performed with high speeds to ultimately achieve fast two- and three-dimensional beam scanning, representing a significant challenge for this field. Here, we present several representative miniature imaging technologies that are currently under development. We have included novel methods for cross-sectional imaging with deep tissue penetration, wide area surveillance, and high-resolution microscopy. These emerging technologies represent only a small fraction of the exciting new developments that promise to generate new knowledge about human biology and diseases in the near future.

Zhen Qiu, Thomas D. Wang

Chapter 31. Engineering Small Animal Conformal Radiotherapy Systems

Small animal conformal radiotherapy platforms are important tools for translational research in the field of radiation oncology. It is crucial that the effects of radiotherapy on small animals are studied under the same conditions under which clinical radiotherapy is delivered. In this chapter, the engineering aspects of small animal radiotherapy systems, including the sources of radiation, beam collimation, and imaging techniques are described. An overview of the principal existing systems is given, and their current and future applications are discussed.

Magdalena Bazalova, Edward E. Graves

Theranostics and Other Novel Approaches

Frontmatter

Chapter 32. Plasmonic Nanobubbles for Cancer Theranostics

Biomedical functions of plasmonic nanoparticles are usually determined by physical properties which are preset during their chemical synthesis. These properties are assumed to stay constant during continuous or pulsed optical excitation of plasmonic nanoparticles. We show that nonstationary excitation with short laser pulse creates entirely new transient photothermal and spectral properties of plasmonic nanoparticles that do not fit into the above stationary paradigm. Our novel nonstationary approach allowed, for example, to shift the spectral peak of standard gold colloids from visible to the near-infrared region, to narrow its width from hundreds to 1–2 nm, and to increase the photothermal efficacy. Replacing chemical engineering of sophisticated nanoparticles with the dynamic tuning of transient properties of standard and clinically proved nanoparticles opens principally new opportunities for nanomedicine including diagnosis, therapy, and theranostics. Furthermore, a nonstationary mechanism allowed to replace the photothermal therapy that cannot provide single cell selectivity and suffers from high optical and nanoparticle doses and their nonspecific uptake, by the cell-specific mechanical treatment that can rapidly and selectively destroy only pathological cells, deliver drugs and genetic cargo and unite diagnosis and treatment in one rapid theranostic procedure.

Ekaterina Y. Lukianova-Hleb, Dmitri O. Lapotko

Chapter 33. Cell-based Microfluidic Assays in Translational Medicine

Microfluidics is the study and use of fluid flow at small volumes (typically microliter and below). Microfluidic principles have great potential utility in many engineering and medical arenas, including point-of-care diagnostics tests. The home pregnancy test is an early example of a “microfluidic” diagnostic assay that utilized a colorimetric readout to detect human chorionic gonadotropin. More recently, microfluidics has been used to study and quantify cellular characteristics. Two areas where microfluidic cell-based assays have been used for clinical applications are chemotaxis (gradient-dependent cell migration) and the isolation and analysis of rare cells such as circulating tumor cells. This chapter will review current translational research studies, integrating microfluidics with chemotaxis and rare cell analysis, as well as future research directions in these emerging fields.

Eric K. Sackmann, Benjamin P. Casavant, S. Farshid Moussavi-Harami, David J. Beebe, Joshua M. Lang

Chapter 34. Engineering of Photomanipulatable Hydrogels for Translational Medicine

Photomanipulatable biomaterials are important for translational medicine because the spatial- and temporal-resoluted control on the property and function of biomaterials can be realized through light irradiation. As one of the most important types of biomaterials, hydrogels based on natural or synthetic polymers have been engineered to have photoreactive chemical moieties for the post-gelation photomanipulation. In this chapter, we summarized the chemistry involved in the engineering of photomanipulatable hydrogels, followed by some representative examples of photomanipulatable hydrogels including photopolymerizable hydrogels, photodegradable hydrogels, photopatternable hydrogels and smart supramolecular hydrogels with sensitive photoresponses. The applications of these photomanipulatable biomaterials in regenerative medicines and tissue engineering were demonstrated by recent examples.

Mingtao He, Yan Zhang

Chapter 35. Engineering AApeptides for Translational Medicine

Peptidomimetics, designed to mimic the structure and function of bioactive peptides, have found enormous application in the development of translational medicine. The emergence of novel peptidomimetics will continue to expand their biological applications. We recently have developed a new class of peptidomimetics termed “AApeptides” in order to advance the field of peptidomimetics. AApeptides have unnatural backbones and are resistant to protease degradation. In addition, they have limitless ability for derivatization. Their synthesis is also straightforward, augmenting their potential in biomedical applications. In this chapter, we try to summarize the chemical development of AApeptides and highlight examples of AApeptides as new unnatural peptidomimetics in the identification of potential therapeutics for translational medicine, such as antimicrobial agents and anticancer agents. At the end, a perspective is also discussed on the future development of AApeptides to fulfill their biological applications.

Haifan Wu, Jianfeng Cai
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