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In tissue engineering, a highly porous artificial extracellular matrix or scaffold is required to accommodate mammalian cells and guide their growth and tissue regeneration in three dimensions. However, existing three-dimensional scaffolds for tissue engineering proved less than ideal for actual applications, not only because they lack mechanical strength, but they also do not guarantee interconnected channels. In this paper, the authors analyze the factors necessary to enhance the design and manufacture of scaffolds for use in tissue engineering in terms of materials, structure, and mechanical properties and review the traditional scaffold fabrication methods. Advantages and limitations of these traditional methods are also discussed.
In this study, new nano-fluor-hydroxyapatite (nFHA)/polyurethane composite scaffolds were fabricated for potential use in bone tissue engineering. Polyester urethane samples were synthesized from polycaprolactone, hexamethylene diisocyanate, and 1,4-butanediol as chain extender. Nano fluor-hydroxyapatite (nFHA) was successfully synthesized by sol-gel method. The solid-liquid phase separation and solvent sublimation methods were used for preparation of the porous composites. Mechanical properties, chemical structure, and morphological characteristics of the samples were investigated by compressive test, Fourier transform infrared, and scanning electron microscopy (SEM) techniques, respectively. The effect of nFHA powder content on porosity and pore morphology was investigated. SEM images demonstrated that the scaffolds were constituted of interconnected and homogeneously distributed pores. The pore size of the scaffolds was in the range 50-250 μm. The result obtained in this research revealed that the porosity and pore average size decreased and compressive modulus increased with nFHA percentage. Considering morphological, physical, and mechanical properties, the scaffold with a higher ratio of nFHA has suitable potential use in tissue regeneration.
Biodegradable polymers form a unique class of materials that created an entirely new concept when originally proposed as biomaterials. That is, for the first time, a material performing a structural application was designed to be completely resorbed and to become weaker over time. This concept was first applied successfully with catgut sutures and later, with more arguable results, on bone fixation plates and pins. Current research on new and improved biodegradable polymers is focused on more sophisticated biomedical applications to solve patients' problems with higher efficacy and the least possible pain. One example is tissue engineering, in which a biodegradable scaffold seeded with an appropriate cell type provides a substitute for damaged human tissue while the natural process of regeneration is completed. An overview is given of the degradation properties and mechanisms of biodegradable polymers, their processability and biocompatibility, focusing on the aspects most relevant to biomedical applications. The main families of biodegradable polymeric systems are described and the systems that are commercially available or that are currently being studied and proposed for specific medical applications are reviewed.
Animal models play a central and pivotal role in tissue engineering. Although advances in areas such as 3D printing and bioreactor technologies now permit the in vitro development and testing of complex scaffold/cell composites, in vivo testing remains critical not only for refining methods being developed but also for the critical efficacy and safety testing required for regulatory approval. Yet, choosing the appropriate model for a particular application remains a challenge, as each model has its own strengths and weaknesses. In some cases, there are size issues to contend with as scale-up of a 3D structure brings with it considerable challenges with regard to diffusion, infiltration, and structural forces. In others, physiological differences between species make selection of the appropriate animal model that best represents the human disease or injury critical.
The field of tissue engineering is moving toward a new concept of "in vitro biomimetics of in vivo tissue development." In Part I of this series, we proposed a theoretical framework integrating the concepts of developmental biology with those of process design to provide the rules for the design of biomimetic processes. We named this methodology "developmental engineering" to emphasize that it is not the tissue but the process of in vitro tissue development that has to be engineered. To formulate the process design rules in a rigorous way that will allow a computational design, we should refer to mathematical methods to model the biological process taking place in vitro. Tissue functions cannot be attributed to individual molecules but rather to complex interactions between the numerous components of a cell and interactions between cells in a tissue that form a network. For tissue engineering to advance to the level of a technologically driven discipline amenable to well-established principles of process engineering, a scientifically rigorous formulation is needed of the general design rules so that the behavior of networks of genes, proteins, or cells that govern the unfolding of developmental processes could be related to the design parameters. Now that sufficient experimental data exist to construct plausible mathematical models of many biological control circuits, explicit hypotheses can be evaluated using computational approaches to facilitate process design. Recent progress in systems biology has shown that the empirical concepts of developmental biology that we used in Part I to extract the rules of biomimetic process design can be expressed in rigorous mathematical terms. This allows the accurate characterization of manufacturing processes in tissue engineering as well as the properties of the artificial tissues themselves. In addition, network science has recently shown that the behavior of biological networks strongly depends on their topology and has developed the necessary concepts and methods to describe it, allowing therefore a deeper understanding of the behavior of networks during biomimetic processes. These advances thus open the door to a transition for tissue engineering from a substantially empirical endeavor to a technology-based discipline comparable to other branches of engineering.
Part 1 Introduction to materials (living and non-living): Metals Ceramics Polymers Biocomposites Cells and tissues Inflammation and wound healing. Part 2 Clinical needs and concepts of repair: The skeletal system The cardiovascular system Biomedical polymers Biomedical hydrogels. Part 3 Applications: Repair of skeletal tissues Joint replacement Artificial organs Mass transport processes in artificial organs Artificial exchange systems Cardiovascular assist systems. Part 4 Tissue engineering: Introduction to tissue engineering Scaffolds for tissue engineering A guide to basic cell culture and applications in biomaterials and tissue engineering Immunochemical techniques in tissue engineering and biomaterial science Clinical applications of tissue engineering. Part 5 Societal, regulatory and ethical issues: Regulatory classification of biomaterials and medical devices Technology transfer Ethical issues.
Bone repair and regeneration is a dynamic process that involves a complex interplay between the (1) ground substance, (2) cells, and (3) milieu. While each constituent is integral to the final product, it is often helpful to consider each component individually. Therefore, we created a two-part review to examine scaffolds and cells' roles in bone tissue engineering. In Part I, we review the myriad of materials use for in vivo bone engineering. In Part II, we discuss the variety cell types (e.g., osteocytes, osteoblasts, osteoclasts, chondrocytes, mesenchymal stem cells, and vasculogenic cells) that are seeded upon or recruited to these scaffolds. In Part III, we discuss the optimization of the microenvironment. The biochemical processes and sequence of events that guide matrix production, cellular activation, and ossification are vital to developing successful bone tissue engineering strategies and are thus succinctly reviewed herein.
Almost 30 years have passed since a term 'tissue engineering' was created to represent a new concept that focuses on regeneration of neotissues from cells with the support of biomaterials and growth factors. This interdisciplinary engineering has attracted much attention as a new therapeutic means that may overcome the drawbacks involved in the current artificial organs and organ transplantation that have been also aiming at replacing lost or severely damaged tissues or organs. However, the tissues regenerated by this tissue engineering and widely applied to patients are still very limited, including skin, bone, cartilage, capillary and periodontal tissues. What are the reasons for such slow advances in clinical applications of tissue engineering? This article gives the brief overview on the current tissue engineering, covering the fundamentals and applications. The fundamentals of tissue engineering involve the cell sources, scaffolds for cell expansion and differentiation and carriers for growth factors. Animal and human trials are the major part of the applications. Based on these results, some critical problems to be resolved for the advances of tissue engineering are addressed from the engineering point of view, emphasizing the close collaboration between medical doctors and biomaterials scientists.
Mimicking natural tissue structure is crucial for engineered tissues with intended applications ranging from regenerative medicine to biorobotics. Native tissues are highly organized at the microscale, thus making these natural characteristics an integral part of creating effective biomimetic tissue structures. There exists a growing appreciation that the incorporation of similar highly organized microscale structures in tissue engineering may yield a remedy for problems ranging from vascularization to cell function control/determination. In this review, we highlight the recent progress in the field of microscale tissue engineering and discuss the use of various biomaterials for generating engineered tissue structures with microscale features. In particular, we will discuss the use of microscale approaches to engineer the architecture of scaffolds, generate artificial vasculature, and control cellular orientation and differentiation. In addition, the emergence of microfabricated tissue units and the modular assembly to emulate hierarchical tissues will be discussed.
Current strategies of regenerative medicine are focused on the restoration of pathologically altered tissue architectures by transplantation of cells in combination with supportive scaffolds and biomolecules. In recent years, considerable interest has been given to biologically active scaffolds which are based on similar analogs of the extracellular matrix that have induced synthesis of tissues and organs. To restore function or regenerate tissue, a scaffold is necessary that will act as a temporary matrix for cell proliferation and extracellular matrix deposition, with subsequent ingrowth until the tissues are totally restored or regenerated. Scaffolds have been used for tissue engineering such as bone, cartilage, ligament, skin, vascular tissues, neural tissues, and skeletal muscle and as vehicle for the controlled delivery of drugs, proteins, and DNA. Various technologies come together to construct porous scaffolds to regenerate the tissues/organs and also for controlled and targeted release of bioactive agents in tissue engineering applications. In this paper, an overview of the different types of scaffolds with their material properties is discussed. The fabrication technologies for tissue engineering scaffolds, including the basic and conventional techniques to the more recent ones, are tabulated.
The reconstruction of skeletal muscle tissue either lost by traumatic injury or tumor ablation or functional damage due to myopathies is hampered by the lack of availability of functional substitution of this native tissue. Until now, only few alternatives exist to provide functional restoration of damaged muscle tissues. Loss of muscle mass and their function can surgically managed in part using a variety of muscle transplantation or transposition techniques. These techniques represent a limited degree of success in attempts to restore the normal functioning, however they are not perfect solutions. A new alternative approach to addressing difficult tissue reconstruction is to engineer new tissues. Although those tissue engineering techniques attempting regeneration of human tissues and organs have recently entered into clinical practice, the engineering of skeletal muscle tissue ist still a scientific challenge. This article reviews some of the recent findings resulting from tissue engineering science related to the attempt of creation and regeneration of functional skeletal muscle tissue.
A loss of function of an organ often represents a life-threatening situation. Transplantations are successful, but "replacement" availability, its compatibility with the host, and subsequent healing often pose serious questions. Tissue engineering, where a carefully prepared scaffold is populated, in vitro, by cells to form an artificial organ, addresses some of the problems mentioned above. Trauma associated with the implant introduction to the host often complicates the process. The novel concept of in vivo tissue engineering which is designed to mediate the healing and tissue regeneration process by providing an in vitro formed porous, microcellular scaffold is proposed. The scaffold (part or entire organ) is then populated by cells either spontaneously (the surrounding cells will spread and populate to inhabit the scaffold) or by cellular augmentation (encapsulated cells are delivered to this in statu nascendi scaffold). Minimally traumatic arthroscopic surgery combined with a unique polymer delivery system is envisioned for the introduction of this implant to a site to be repaired. Such an approach will require the formation of polymer in-situ, in a reasonable time. The scaffold-forming polymers will be, in principle, biodegradable. We propose to utilize biodegradable polyurethane systems for in vivo tissue engineering. Diversity of their structure/property relationships, relative "ease" of their preparation, and excellent biocompatibility predetermine polyurethanes to be the materials of choice. This paper describes the genesis of this concept and potentials for its realization. It is intended to initiate and stimulate discussion among the related scientific disciplines to form a basis for this field. The synthesis, application, and biodegradation of selected polyurethanes and variety of its medical utilization will be discussed in upcoming papers.
Bone morphogenetic proteins (BMPs) are cytokines with a strong effect on bone and cartilage growth and with important roles during embryonic patterning and early skeletal formation. BMPs have promising potential for clinical bone and cartilage repair, working as powerful bone-inducing components in diverse tissue-engineering products. Synthetic polymers, natural origin polymers, inorganic materials and composites may be used as carriers for the delivery of BMPs. Carriers range from nanoparticles to complex three-dimensional (3D) scaffolds, membranes for tissue-guided regeneration, biomimetic surfaces and smart thermosensitive hydrogels. Current clinical uses include spinal fusion, healing of long bone defects and craniofacial and periodontal applications, amongst others. BMP-2 and BMP-7 have recently received approval by the US Food and Drug Administration (FDA) for specific clinical cases, delivered in absorbable collagen sponges. Considering the expanding number of publications in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs.
The field of regenerative medicine has tremendous potential for improved treatment outcomes and has been stimulated by advances made in bioengineering over the last few decades. The strategies of engineering tissues and assembling functional constructs that are capable of restoring, retaining, and revitalizing lost tissues and organs have impacted the whole spectrum of medicine and health care. Techniques to combine biomimetic materials, cells, and bioactive molecules play a decisive role in promoting the regeneration of damaged tissues or as therapeutic systems. Hydrogels have been used as one of the most common tissue engineering scaffolds over the past two decades due to their ability to maintain a distinct 3D structure, to provide mechanical support for the cells in the engineered tissues, and to simulate the native extracellular matrix. The high water content of hydrogels can provide an ideal environment for cell survival, and structure which mimics the native tissues. Hydrogel systems have been serving as a supportive matrix for cell immobilization and growth factor delivery. This review outlines a brief description of the properties, structure, synthesis and fabrication methods, applications, and future perspectives of smart hydrogels in tissue engineering.
Bone tissue engineering has been continuously developing since the concept of "tissue engineering" has been proposed. Biomaterials that are used as the basic material for the fabrication of scaffolds play a vital role in bone tissue engineering. This paper first introduces a strategy for literature search. Then, it describes the structure, mechanical properties and materials of natural bone and the strategies of bone tissue engineering. Particularly, it focuses on the current knowledge about biomaterials used in the fabrication of bone tissue engineering scaffolds, which includes the history, types, properties and applications of biomaterials. The effects of additives such as signaling molecules, stem cells, and functional materials on the performance of the scaffolds are also discussed.
This third edition of the biomedical optics classic Tissue Optics covers the continued intensive growth in tissue optics-in particular, the field of tissue diagnostics and imaging-that has occurred since 2007. As in the first two editions, Part I describes fundamentals and basic research, and Part II presents instrumentation and medical applications. However, for the reader's convenience, this third edition has been reorganized into 14 chapters instead of 9. The chapters covering optical coherence tomography, digital holography and interferometry, controlling optical properties of tissues, nonlinear spectroscopy, and imaging have all been substantially updated. The book is intended for researchers, teachers, and graduate and undergraduate students specializing in the physics of living systems, biomedical optics and biophotonics, laser biophysics, and applications of lasers in biomedicine. It can also be used as a textbook for courses in medical physics, medical engineering, and medical biology.
Tissue engineering is a new and exciting technique which has the potential to create tissues and organs de novo. It involves the in vitro seeding and attachment of human cells onto a scaffold. These cells then proliferate, migrate and differentiate into the specific tissue while secreting the extracellular matrix components required to create the tissue. It is evident, therefore, that the choice of scaffold is crucial to enable the cells to behave in the required manner to produce tissues and organs of the desired shape and size. Current scaffolds, made by conventional scaffold fabrication techniques, are generally foams of synthetic polymers. The cells do not necessarily recognise such surfaces, and most importantly cells cannot migrate more than 500 microm from the surface. The lack of oxygen and nutrient supply governs this depth. Solid freeform fabrication (SFF) uses layer-manufacturing strategies to create physical objects directly from computer-generated models. It can improve current scaffold design by controlling scaffold parameters such as pore size, porosity and pore distribution, as well as incorporating an artificial vascular system, thereby increasing the mass transport of oxygen and nutrients into the interior of the scaffold and supporting cellular growth in that region. Several SFF systems have produced tissue engineering scaffolds with this concept in mind which will be the main focus of this review. We are developing scaffolds from collagen and with an internal vascular architecture using SFF. Collagen has major advantages as it provides a favourable surface for cellular attachment. The vascular system allows for the supply of nutrients and oxygen throughout the scaffold. The future of tissue engineering scaffolds is intertwined with SFF technologies.
Tissue engineering has become a promising strategy for repairing damaged cartilage and bone tissue. Among the scaffolds for tissue-engineering applications, injectable hydrogels have demonstrated great potential for use as three-dimensional cell culture scaffolds in cartilage and bone tissue engineering, owing to their high water content, similarity to the natural extracellular matrix (ECM), porous framework for cell transplantation and proliferation, minimal invasive properties, and ability to match irregular defects. In this review, we describe the selection of appropriate biomaterials and fabrication methods to prepare novel injectable hydrogels for cartilage and bone tissue engineering. In addition, the biology of cartilage and the bony ECM is also summarized. Finally, future perspectives for injectable hydrogels in cartilage and bone tissue engineering are discussed.
Cardiac tissue engineering is an emerging field. The suitability of engineered heart tissue (EHT) for both in vitro and in vivo applications will depend on the degree of syncytoid tissue formation and cardiac myocyte differentiation in vitro, contractile function, and electrophysiological properties. Here, we demonstrate that cardiac myocytes from neonatal rats, when mixed with collagen I and matrix factors, cast in circular molds, and subjected to phasic mechanical stretch, reconstitute ring-shaped EHTs that display important hallmarks of differentiated myocardium. Comparative histological analysis of EHTs with native heart tissue from newborn, 6-day-old, and adult rats revealed that cardiac cells in EHTs reconstitute intensively interconnected, longitudinally oriented, cardiac muscle bundles with morphological features resembling adult rather than immature native tissue. Confocal and electron microscopy demonstrated characteristic features of native differentiated myocardium; some of these features are absent in myocytes from newborn rats: (1) highly organized sarcomeres in registry; (2) adherens junctions, gap junctions, and desmosomes; (3) a well-developed T-tubular system and dyad formation with the sarcoplasmic reticulum; and (4) a basement membrane surrounding cardiac myocytes. Accordingly, EHTs displayed contractile characteristics of native myocardium with a high ratio of twitch (0.4 to 0.8 mN) to resting tension (0.1 to 0.3 mN) and a strong beta-adrenergic inotropic response. Action potential recordings demonstrated stable resting membrane potentials of -66 to -78 mV, fast upstroke kinetics, and a prominent plateau phase. The data indicate that EHTs represent highly differentiated cardiac tissue constructs, making EHTs a promising material for in vitro studies of cardiac function and tissue replacement therapy.
The potential of growth factors to stimulate tissue healing through the enhancement of cell proliferation, migration, and differentiation is undeniable. However, critical parameters on the design of adequate carriers, such as uncontrolled spatiotemporal presence of bioactive factors, inadequate release profiles, and supraphysiological dosages of growth factors, have impaired the translation of these systems onto clinical practice. This review describes the healing cascades for bone, cartilage, and osteochondral interface, highlighting the role of specific growth factors for triggering the reactions leading to tissue regeneration. Critical criteria on the design of carriers for controlled release of bioactive factors are also reported, focusing on the need to provide a spatiotemporal control over the delivery and presentation of these molecules.