Biomedical Engineering: Frontier Research and Converging Technologies

Gene therapy has not been investigated as much as pharmacotherapy because of immunogenic issues when a virus was used as a gene delivery vector. Despite the challenges, gene therapy still has attractive aspects. It has less side effects and is more target-specific compared to pharmacotherapy, and it also has potential for generic disease treatment or personalized medicine. Therefore, it would be truly beneficial if safe and reliable vectors are used and targeted for area of interest. Interest in multifunctional nanomedicine for diagnostics and therapeutics has been increasing. For this reason, non-viral gene delivery has been studied, combined with molecular imaging to visualize targeting. In this review, complex nanoparticle systems designed for molecular imaging and gene delivery are discussed. There are design criteria which need to be considered for the nanoparticle complex systems. The criteria are as follows: i) the nanoparticle complex should be stable; ii) it should have efficient targeting capability; iii) controlled release of genes should be available; iv) molecular imaging should be possible; and lastly, v) there should be noticeable therapeutic efficacy. Examples on nanoparticle complex which meet these criteria are described in the review.

While clinical islet transplantation is being investigated as a useful method to cure diabetes mellitus (DM), the outcome of this therapy remains imperfect. This is mainly due to early graft rejection of transplanted islets by the instant blood-mediated inflammatory reaction (IBMIR) or islet ischemia. Therefore, it is important to develop imaging tools for transplanted islets, so that real-time treatment can be used to protect the islets from host immune reactions if required. Recently, synthetic nanoparticles are emerging in the area of biomedical imaging. Innovative nanoparticle developments have significantly enhanced the versatility of different imaging modalities. Nanoparticles represent potential probes to monitor transplanted islets through magnetic resonance imaging (MRI), positron emission tomography (PET), and optical imaging. Nanoparticles can be delivered to transplanted islets by conjugation onto the cell membrane, intracellular delivery, cellular membrane receptor or transporter targeting. Visualizing the survival, function, and biodistribution of transplanted islets may suggest an appropriate treatment, which will enhance islet graft survival. This chapter focuses on recent advances and applications of various nanoparticle-based imaging techniques used in molecular imaging to monitor transplanted islets.

Dendritic nanomaterials have attracted a great deal of scientific interest for use in various biomedical applications primarily due to their well-defined structure and capacity for multifunctionalization. In this chapter, we present a comprehensive overview of the recent advances in various dendrimers and their modified dendritic materials with a particular focus on their applications such as drug delivery, gene delivery, diagnostics and prognostics, and detoxification/prophylaxis. We also discuss the fundamentals of the biological interactions of dendritic nanomaterials in regard to non-specific cell interactions, multivalent binding, stimuli-responsive processes, and biodistribution. In addition, this chapter highlights the current drawbacks of dendrimers that have hindered their rapid clinical translation and introduce recent approaches to overcoming these challenges.

Various brain diseases including Alzheimer’s disease, stroke, and cancer are major causes of death worldwide. Due to the notion that early diagnosis significantly increases success in treatments, several non-invasive bioimaging modalities such as MRI, CT, and PET are increasingly used to locate pathologic sites in the brain. To further enhance the quality of diagnostic imaging, efforts are incrementally made to couple imaging contrasts of interests to macromolecules or nanoparticles designed to cross over the brain-blood barrier and to bind to pathologic tissue. This chapter will therefore review such important emerging technologies for diagnostic imaging of brain and some preclinical and clinical success, so we can ultimately assist efforts to take diagnosis quality to the next level.

Bone is an extremely important tissue with great versatility that provides support, movement, and protection for the organs of the body. Various bone related pathologies such as osteoporosis have the potential to create large defects that do not have the capability to heal with only basic clinical intervention. In these circumstances, the principles of tissue engineering are utilized in order to provide additional material to either replace or repair the damaged bone regions. Tissue engineering involves the utilization of various combinations of growth factors, cells, and biomaterials to recreate organs or lost tissue regions. Currently, the most prominent materials for this purpose are limited by issues such as availability for autografts, possible antigenicity for allografts, or insufficient of bioactivity as is the case with many synthetic materials. To address these concerns, research has shifted focus towards development of synthetic materials that faithfully mimic native bone’s natural structure and function. Bone formation and regeneration are dependent upon the dynamic interactions between bone cells and extracellular matrix components. Therefore, it is important that the native extracellular matrix components are recapitulated to the greatest extent possible. Specifically, this new paradigm shift requires the development of scaffolds that recreate both the structural and functional qualities of bone tissue. These materials are intended to enhance the interactions of bone forming cells and biomaterials. Adopting this strategy, many groups have developed self-assembling materials to serve as functionalized scaffolds for enhancing the dynamic interactions between the bone cells and the biomaterials for subsequent bone tissue regeneration. In this chapter, the underlying principles of bone tissue engineering, bone cell interactions, various bioactive, self-assembling biomaterial technologies, and the means by which they improve interactions with bone forming cells are discussed.

Because of their potential to regenerate tissues and organs, stem cells garner extensive interest worldwide for treating a wide range of degenerative diseases. In numerous efforts, a variety of stem cell formats have been considered for therapeutic purposes to combat such pathologies, one being vascular-related diseases. In particular, the prevalence of peripheral artery disease (PAD) has steadily increased with the growth of the aging population in many first-world countries. Considering this disturbing trend as well as the obesity epidemic and the ballooning population growth in third-world nations, the burden of PAD is expected to increase worldwide to alarming levels in the coming decades. The advent of stem cell treatments could stymie this burden by alleviating the complications and improving upon the less-than-satisfactory outcomes from current standard-of-care surgical/pharmacological interventions for PAD. This chapter reviews the relevant, cutting-edge clinical and animal model research efforts in the field and explores the remaining questions as they pertain to convergence technologies that may provide the potential for stem cells to reverse PAD-induced tissue damage. Harnessing and translating this potential to create more viable and efficacious PAD treatments should be of paramount global and public health concern.

The number of biomaterial scaffolds for tissue engineering applications continues to rise and holds promise for regenerative medicine. However, the complexity of the immune response poses a challenging environment for implanted biomaterial scaffolds for tissue repair. Specifically, the innate immune responses characterized by tissue infiltrating neutrophils and macrophages have been shown to govern either pro-inflammatory or tissue reparative microenvironments at the local site of tissue injury depending on their activation and phenotypic status. Thus, a selective strategy for developing immune-modulatory biomaterial scaffolds to improve the modulation of innate immune reactions may offer attractive features for tissue regeneration. The focus of this chapter is to discuss recent progress in the development of biomaterial scaffolds for modulating immune responses and their potential application for tissue repair. Specifically, important design variables for fabricating immuno-modulatory biomaterial scaffolds are highlighted.

Currently available vaccine adjuvants are ineffective against a wide range of infectious pathogens as well as cancers. Therefore, there is a critical demand for new vaccine strategies that can elicit potent cellular and humoral immune responses. Liposomes have been widely examined as vaccine delivery systems because of their safety, low toxicity, and ease of scale-up. However, successful clinical translation of liposomal vaccines has been hampered by their limited potency to induce strong T and B cell responses. In this chapter, we will present two classes of lipid-based nanoparticle systems designed to address limitations of liposomal vaccines and discuss their potential as vaccine delivery systems. The first class of lipid-based nanoparticles presented in this chapter is termed interbilayer-crosslinked multilamellar vesicles. These novel vaccine nanoparticles are stable vehicles that can effectively deliver antigens and adjuvant molecules to antigen-presenting cells in lymphoid tissues and induce robust T and B cell immune responses in vivo. The second class of vaccine nanoparticles is lipoproteins composed of endogenous proteins and lipids. Applications of lipoproteins for vaccine delivery have recently gained much attention due to their safety and multi-faceted functions as endogenous drug delivery vehicles. We provide an overview on the latest advances in this rapidly evolving interdisciplinary area of research, and we discuss biomaterial-based innovations enabled by nanotechnology for improving vaccine design and development.

This chapter introduces innovative organ-on-chip platforms for chemical assay and toxicity testing that measures the physiological properties of live, engineered muscular tissue samples. The advantages of using such engineered tissues for drug screening compared to more conventional cell-based assays are discussed. Specifically, this chapter will outline recent developments and applications of cardiac and skeletal muscle organ-on-chip systems. Recent advances in micro- and nanofabrication techniques, along with their biological applications with regard to organ-on-chips, are also reviewed in this chapter.

Developments in micro- and nanofluidic technologies have led to new kinds of cell culture and screening systems that are collectively termed organ-on-a-chip systems. Organ-on-a-chip systems are in vitro microfabricated devices that mimic dynamic interactions of in vivo microenvironments. In addition to existing two-dimensional and three-dimensional cell tissues, organ-on-a-chip systems can mimic the biomechanical and biochemical microenvironment of in vivo tissues as well as the interaction effect of the microenvironment on cell and tissue functions. Due to these features, organ-on-a-chip systems have become excellent platforms for drug screening and delivery test and tissue engineering. In this review, specific examples of various types of organ-on-a-chip devices and their applications in tissue engineering and drug delivery test are discussed. The ready feasibility and performance of current state-of-the-art organ-on-a-chip systems, including lung-on-a-chip, heart-on-a-chip, liver-on-a-chip, vessel-on-a-chip, and tumor-on-a-chip are also covered in this chapter. The limitations of conventional systems, basic fabrication process of organ-on-a-chip devices, and future prospective of organ-on-a-chip are discussed.

Calcific aortic valve disease (CAVD) is a significant cause of mortality among the aging population. Because disease mechanisms are still unclear, the only current treatment option for this disease is aortic valve replacement. In order to understand the disease and develop treatment targets, we must explore the hemodynamic and mechanical forces affecting the valve, as well as the biological pathways altered by those mechanics ultimately leading to tissue calcification. The unique structure of the valve allows it to adapt to the constantly changing mechanical environment and the wide array of forces exerted upon the tissue during the cardiac cycle. CAVD results in an impairment in the structure and function of the aortic valve, resulting in pathological systemic changes. A variety of mechanosensors at the valvular endothelial cell surface are responsible for transmission of mechanical signals to alter cell phenotype and ultimate tissue function. Recently, valvular microRNAs have been discovered to be mechanosensitive, possibly regulating key signaling in the pathology of CAVD. Our understanding of the aortic valve and CAVD is evolving rapidly, and future therapies rely on further exploration of this complex disease.

The aortic valve regulates the flow between the left ventricle and the aorta (Figure 1A) supplying oxygenated blood to the body. It opens during systole as the ventricle contracts, forwarding blood to the circulatory system, and closes as the ventricle relaxes—due to the beating of the heart known as the cardiac cycle. Calcific aortic valve disease encompasses a number of clinical conditions ranging from hardening and thickening of the aortic valve (aortic valve sclerosis) to severe reduction of the aortic valve area (aortic valve stenosis), resulting in obstruction of the blood flowing from the left ventricle [1]. This disease causes more than 28,000 deaths a year and 48,000 hospitalizations in the United States. CAVD is present in 25-29% of the population over 65 and is associated with a 50% increase in myocardial infarction and cardiovascular death [2-6]. By the time it is clinically recognized the only available treatment is valve replacement or repair surgery [7]. Traditionally, open-heart surgery was required for valve replacement; however, new technologies have allowed for less invasive methods, such as transcatheter aortic valve implantation (TAVI) [8, 9]. Of the 300,000 prosthetic valves implanted worldwide in 2010, a third (100,000) were in North America [10]; projections estimate that by 2050, 850,000 implants will occur per year [11].

CAVD is associated with subclinical inflammation, which leads to thickening of the valve and fibrosis and ends with calcium deposition within the valve [12]. The region of the valve that is preferentially calcified is the fibrosa, the side facing the aorta. This side of the valve experiences higher mechanical stimuli combined with lower magnitude oscillatory shear stress. Regions of the cardiovascular system exposed to these mechanical conditions are considered especially susceptible to inflammation leading to cardiovascular disease, including during atherosclerotic plaque development [13-15]. In fact, the role of shear stress in development of valvular dysfunction is clear when considering the individual valve leaflets and the flow experienced by each. The noncoronary cusp (NCC, Figure 1B) is subjected to a lower magnitude of shear stress than the other two leaflets due to the absence of diastolic coronary flow, and this leaflet is commonly the first to exhibit calcification [16].

Early inflammation in the aortic valve endothelium is believed to occur due to a wide range of events, usually as a consequence of valvular endothelial dysfunction due to pathological flow, chronic inflammatory disease, or other inflammatory conditions [17, 18]. The thickening of the aortic valve follows the inflammatory phase and is due to lipoprotein accumulation, cellular infiltration and extracellular matrix (ECM) formation [2]. As a result of extensive endothelial inflammation in early stages of aortic valve calcification, T lymphocytes and monocytes infiltrate the tissue and are activated, releasing cytokines such at TGF-β1 or IL-1β [19-21]. These cytokines contribute in later stages of the disease by promoting ECM formation and remodeling, and at the later stages local calcification is observed as calcium phosphate crystals are deposited in the ECM (Figure 1C) [22, 23]. Calcification of the aortic valve is the result of valvular interstitial cell (VIC) differentiation into osteoblasts, characterized by an upregulation of bone-related intermediates and transcription factors, including bone morphogenetic proteins, transforming growth factor β1, osteopontin, bone sialoprotein, osteocalcin, alkaline phosphatase and Runx2 [24].

In order to understand the mechanisms leading to CAVD, this chapter explores the mechanical and biological aspects of the valvular environment. First, a general overview of the valve structure, including the crucial extracellular components, gives a picture of the complex construction allowing for the tissue’s physiological function. The following discussion explores the biomechanical forces exerted on the valve, giving insight into new tissue engineering approaches useful for studying CAVD. Finally, a thorough examination of the biological pathways involved in initiation of the pathological disease, with a focus on the mechanosensory mechanisms within the endothelium, links the mechanical forces in the tissue environment to the resulting pathological inflammation and ultimate valve calcification.

The mechanical properties of the cell - cytoskeleton elasticity, membrane tension, and adhesion strength - play an important role in the regulation of stem cell differentiation. While the cellular mechanical properties are significantly altered during stem cell specification to a particular phenotype, the complexity of events associated with transformation of these precursor cells leaves many questions unanswered about morphological, structural, proteomic, and functional changes in differentiating stem cells. However, control of cell behaviors might be feasible through manipulation of the cellular mechanical properties using external physical stimuli and manipulation of mechanically sensitive signaling molecules. Biomechanical regulation of stem cell differentiation can minimize the number of chemicals and growth factors that would otherwise be required for tissue engineering. Coupled with a thorough understanding of stem cell behavior, both experimentally and computationally, development of more effective approaches is a feasible way to expand stem cells and to regulate their phenotypic commitment. We recently developed a high-content/high-throughput screening algorithm that offers significant improvements in 3D quantitative analysis at the single cell level. A consistent pattern observed in all types of stem cell differentiation indicates the cytoskeleton remodeled significantly before lineage-specific cellular changes occurred. This demonstrates that cellular mechanical transformations are a precursor to stem cell differentiation and to phenotypic functionality.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases accounting for approximately more than 40 million patients worldwide. Progress in the fundamental understanding and effective therapy of these diseases has been hindered by the failure of currently FDA-approved pharmacological agents and the lack of research models that properly recapitulate disease pathology. One promising approach for the treatment of these diseases is regenerative medicine and its associated technologies. The rise of stem cells technology, cellular replacement, gene therapy, and immunomodulation together present an opportunity for novel combination approaches for AD and PD treatment. Additionally, fundamental studies of human-derived cellular environments may enable truly personalized medicine. In this Chapter, we review these technologies for disease modeling and therapeutic intervention in AD and PD and discuss current challenges associated with their clinical translations.

Atmospheric pressure plasma (APP), composed of multiple active components, including charged particles, reactive oxygen species, and radicals, recently emerged as a promising tool in cancer therapy and wound treatment. Driven by the increasingly growing interests on plasma medicine, numerous in vivo tests and in vitro studies on the applicability of the APP for clinical treatments have been performed. In particular, the APP was shown to be effective in removing the targeted cells by causing apoptosis or necrosis. More importantly, in some studies, these effects were demonstrated to be specific to cancer cells, which was further confirmed in animal models where the APP effectively suppressed the tumor growth. In addition to the cancer therapy, the APP treatment targeting the chronic wound has shown that the plasma could improve the healing process by accelerating blood coagulation, bacteria sterilization, and re-epithelialization around the wounded area. Interestingly, the plasma therapy on cutaneous wound also presented promising outcomes in an animal study with reduced scar formations. In this chapter, we report a general overview of the recent trends and progresses in the effects of the APP treatment on cancer and wound, and discuss the potential applications of the APP as a therapeutic tool.

Monitoring tumor response following treatment is essential to tailor therapeutic strategy to achieve the most favorable clinical outcomes for cancer patients. Imaging is a non-invasive approach to assess tumor response quantitatively, and it has been clinically validated as a reliable tool. RECIST (Response Evaluation Criteria in Solid Tumors) is a published protocol to determine tumor response mainly based on change in tumor size as a response to therapy. The high-resolution anatomical information of a tumor can be obtained using computer tomography (CT), ultrasound imaging or magnetic resonance imaging (MRI). However, it is often insufficient to evaluate tumor viability and aggressiveness using only anatomical information, thus a new protocol named PERCIST (Positron Emission Tomography (PET) Response Criteria in Solid Tumors) has been recently proposed. PERCIST evaluates therapy based on the change of glycolic metabolism using ¹⁸F-FDG PET, and its effectiveness has been compared with RECIST. In addition, many other physiologic and molecular imaging modalities have been tested for more objective, rapid, and reproducible measurement of tumor response. In this chapter, both conventional and experimental non-invasive imaging modalities to evaluate therapy for cancer patients having solid tumors are reviewed.

Over the past decades, there has been significant evolution in coronary stents used in percutaneous coronary intervention. These coronary stents were developed to prevent the recoil and acute closure that limited the effectiveness of angioplasty. New problems of in-segment restenosis and stent thrombosis emerged despite the advantages of bare metal stents (BMS) for these issues. Antiplatelet therapy and better stent ballooning strategies decreased complications; however, restenosis remained a problem until the development of drug-eluting stents (DES). First generation sirolimus- and paclitaxel-eluting stents were very successful in lowering restenosis, but still other safety concerns emerged, in particular, higher rates of late stent thrombosis. This led to the continuous research and development of new types of DES, and the birth of fully biodegradable stent platforms, which is foreseen to truly overcome the obstacle of having a permanent polymer and metallic stent remaining in the vessel wall that may precipitate sustained inflammation, persistent vasomotor dysfunction, and in-stent neo-atherosclerosis. In this chapter, we will cover the wide spectrum of advancements in stent technologies, and the approaches that were undertaken to surmount the issues that arose with the use of the various devices in vivo, such as material, design, drugs etc., until the most recent ones, an overview of the biological background for the use of percutaneous coronary intervention, and the complications that appear through the use of the different generations of stents.

Intervertebral disc (IVD) degeneration is one of the major neurodegenerative diseases throughout the world. Development of new and advanced treatment methods are highly warranted due to the limitations of conventional protocols. Very recently, regenerative medicine techniques based on biomaterials, stem cell and bioactive molecules have been demonstrated as the most powerful concept to regenerate IVD. In this chapter, we will review the recent progress in (1) biomaterial scaffolds for annulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous end plates (CEP), (2) stem cells as cell sources, and finally introduce (3) our recent research studies focusing on the fabrication of natural/synthetic hybrid scaffolds for various purposes during the last 5 years.

The mammalian heart beats spontaneously without conscious input from the brain. Each heartbeat starts from a minuscule region, called the sinoatrial node (SA node or SAN). The SA node is a small highly-specialized structure containing just a few thousand genuine pacemaker cells. In contrast, the vast majority of the myocardium is populated by the ~5 billion working cardiomyocytes which remain quiescent until the electrical signal propagated from the SAN stimulates them. When the SAN fails, it could lead to circulatory collapse, requiring implantation of electronic pacemaker devices. These electronic devices generally work quite well. However, problems such as lead failure/repositioning, pediatric patients outgrowing the device, finite battery life, and infection call for biologics that are free from all hardware. Toward this goal, we and others have tested the concept of biological pacing. This article focuses on recent breakthroughs in the engineering of biological pacemakers. Combined with efforts to create clinically-relevant, large animal models of biological pacing, the field is moving beyond a conceptual novelty toward a future with clinical reality.

Minimally invasive surgery and interventional procedures have seen rapid advancement as one of leading trend in medical technology innovation for its distinguished clinical benefit for patient. Robotic systems and technologies have made remarkable contribution to the innovation enabling various innovative devices and procedures including robotic laparoscopic surgery assist system. While robotic systems to assist general surgery seem to become mature technology, robotic systems for interventional procedures and neurological surgery are newly emerging. The minimally invasive procedures have inherent limitations and constraints that make human operation difficult or less optimal. Various medical imaging modalities are utilized as visual sensor for the procedures and each has limitations such as radiation exposure, resolution and sensitivity, real-time imaging capability, electromagnetic interference and etc. Tiny and complex tissue structure through which devices for the minimally invasive procedures perform diagnostic or therapeutic operation is another major limiting condition in terms of dexterity or precision. Robotic systems that converge various electro-mechanical engineering and computer science technologies facilitate human physician overcoming these limitations and achieving better clinical outcome for patient. Computed tomography (CT) or ultrasound guided biopsy is one of long researched applications for robotic system utilization. Several robotic systems for cardiac intervention and neurological surgery are already available for clinical use. The clinical efficacy of the robotic technologies needs further study including large scale randomized clinical study and safety issue with the use of robotic system either in assist or automation manner also need more research. It seems increasingly clear that robotic system technologies will continuously provide answers to many of unmet clinical needs in minimally invasive diagnosis and therapy.

Since the first industrial robot was introduced in the 1960s, robotic technologies have contributed to enhance the physical limits of human workers in terms of repeatability, safety, durability, and accuracy in many industrial factories including those of the automobile, consumer electronics and shipbuilding industries. In the 21^st century, robots are expected to be further applied in healthcare, which requires procedures that are objective, repetitive, robust and safe for users. Fueled by the rapid improvements of medical imaging and mechatronics technologies, healthcare robots have been rapidly adopted in almost every stage of the medical procedure by surgeons and physical therapists. In this chapter, we describe applications and the state of the art of healthcare robotics developed in the last decade. We focus on research and clinical activities that have followed successful demonstrations of early pioneering robots such as daVinci telesurgical robots and LOKOMAT training robots. First, we categorize major areas of healthcare robotics. Second, we discuss robotics for surgical operating rooms. Third, we review rehabilitation and assistive technologies. Finally, we summarize challenges and limitations of biomedical robotics as assistive tools for medical personnel.