Three-dimensional bioprinting in tissue engineering and regenerative medicine

With the advances of stem cell research, development of intelligent biomaterials and three-dimensional biofabrication strategies, highly mimicked tissue or organs can be engineered. Among all the biofabrication approaches, bioprinting based on inkjet printing technology has the promises to deliver and create biomimicked tissue with high throughput, digital control, and the capacity of single cell manipulation. Therefore, this enabling technology has great potential in regenerative medicine and translational applications. The most current advances in organ and tissue bioprinting based on the thermal inkjet printing technology are described in this review, including vasculature, muscle, cartilage, and bone. In addition, the benign side effect of bioprinting to the printed mammalian cells can be utilized for gene or drug delivery, which can be achieved conveniently during precise cell placement for tissue construction. With layer-by-layer assembly, three-dimensional tissues with complex structures can be printed using converted medical images. Therefore, bioprinting based on thermal inkjet is so far the most optimal solution to engineer vascular system to the thick and complex tissues. Collectively, bioprinting has great potential and broad applications in tissue engineering and regenerative medicine. The future advances of bioprinting include the integration of different printing mechanisms to engineer biphasic or triphasic tissues with optimized scaffolds and further understanding of stem cell biology.     

Polymer‐based microparticles in tissue engineering and regenerative medicine

Different types of biomaterials, processed into different shapes, have been proposed as temporary support for cells in tissue engineering (TE) strategies. The manufacturing methods used in the production of particles in drug delivery strategies have been adapted for the development of microparticles in the fields of TE and regenerative medicine (RM). Microparticles have been applied as building blocks and matrices for the delivery of soluble factors, aiming for the construction of TE scaffolds, either by fusion giving rise to porous scaffolds or as injectable systems for in situ scaffold formation, avoiding complicated surgery procedures. More recently, organ printing strategies have been developed by the fusion of hydrogel particles with encapsulated cells, aiming the production of organs in in vitro conditions. Mesoscale self‐assembly of hydrogel microblocks and the use of leachable particles in three‐dimensional (3D) layer‐by‐layer (LbL) techniques have been suggested as well in recent works. Along with innovative applications, new perspectives are open for the use of these versatile structures, and different directions can still be followed to use all the potential that such systems can bring. This review focuses on polymeric microparticle processing techniques and overviews several examples and general concepts related to the use of these systems in TE and RE applications. The use of materials in the development of microparticles from research to clinical applications is also discussed. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011     

Bio-piezoelectricity: fundamentals and applications in tissue engineering and regenerative medicine

In recent years, smart materials have piqued the interest of scientists and physicians in the biomedical community owing to their ability to modify their properties in response to an external stimulation or changes in their surroundings. Biocompatible piezoelectric materials are an interesting group of smart materials due to their ability to produce electrical charges without an external power source. Electric signals produced by piezoelectric scaffolds can renew and regenerate tissues through special pathways like that found in the extracellular matrix. This review summarizes the piezoelectric phenomenon, piezoelectric effects generated within biological tissues, piezoelectric biomaterials, and their applications in tissue engineering and their use as biosensors.     

Adult mesenchymal stem cells for tissue engineering versus regenerative medicine

Adult mesenchymal stem cells (MSCs) can be isolated from bone marrow or marrow aspirates and because they are culture-dish adherent, they can be expanded in culture while maintaining their multipotency. The MSCs have been used in preclinical models for tissue engineering of bone, cartilage, muscle, marrow stroma, tendon, fat, and other connective tissues. These tissue-engineered materials show considerable promise for use in rebuilding damaged or diseased mesenchymal tissues. Unanticipated is the realization that the MSCs secrete a large spectrum of bioactive molecules. These molecules are immunosuppressive, especially for T-cells and, thus, allogeneic MSCs can be considered for therapeutic use. In this context, the secreted bioactive molecules provide a regenerative microenvironment for a variety of injured adult tissues to limit the area of damage and to mount a self-regulated regenerative response. This regenerative microenvironment is referred to as trophic activity and, therefore, MSCs appear to be valuable mediators for tissue repair and regeneration. The natural titers of MSCs that are drawn to sites of tissue injury can be augmented by allogeneic MSCs delivered via the bloodstream. Indeed, human clinical trials are now under way to use allogeneic MSCs for treatment of myocardial infarcts, graft-versus-host disease, Crohn's Disease, cartilage and meniscus repair, stroke, and spinal cord injury. This review summarizes the biological basis for the in vivo functioning of MSCs through development and aging.     

Stem cell- and scaffold-based tissue engineering approaches to osteochondral regenerative medicine

In osteochondral tissue engineering, cell recruitment, proliferation, differentiation, and patterning are critical for forming biologically and structurally viable constructs for repair of damaged or diseased tissue. However, since constructs prepared ex vivo lack the multitude of cues present in the in vivo microenvironment, cells often need to be supplied with external biological and physical stimuli to coax them toward targeted tissue functions. To determine which stimuli to present to cells, bioengineering strategies can benefit significantly from endogenous examples of skeletogenesis. As an example of developmental skeletogenesis, the developing limb bud serves as an excellent model system in which to study how osteochondral structures form from undifferentiated precursor cells. Alongside skeletal formation during embryogenesis, bone also possesses innate regenerative capacity, displaying remarkable ability to heal after damage. Bone fracture healing shares many features with bone development, driving the hypothesis that the regenerative process generally recapitulates development. Similarities and differences between the two modes of bone formation may offer insight into the special requirements for healing damaged or diseased bone. Thus, endogenous fracture healing, as an example of regenerative skeletogenesis, may also inform bioengineering strategies. In this review, we summarize the key cellular events involving stem and progenitor cells in developmental and regenerative skeletogenesis, and discuss in parallel the corresponding cell- and scaffold-based strategies that tissue engineers employ to recapitulate these events in vitro.     

Hair follicular cell/organ culture in tissue engineering and regenerative medicine

Hair follicles are complex organs composed of the dermal papilla (DP), dermal sheath (DS), outer root sheath (ORS), inner root sheath (IRS) and hair shaft. Development of hair follicles begins towards the end of the first trimester of pregnancy and is controlled by epidermal–mesenchymal interaction (EMI), which is a signaling cascade between epidermal and mesenchymal cell populations. Hair grows in cycles of various phases. Specifically, anagen is the growth phase, catagen is the involuting or regressing phase and telogen is the resting or quiescent phase. Alopecia is not life threatening, but alopecia often causes severe mental stress. In addition, the number of individuals afflicted by alopecia patients has been increasing steadily. Currently there are two methods employed to treat alopecia, drug or natural substance therapy and human hair transplantation. Although drug or natural substance therapy may retard the progress of alopecia or prevent future hair loss, it may also accelerate hair loss when the medication is stopped after prolonged use. Conversely, the transplantation of human hair involves taking plugs of natural hair from areas in which occipital hair is growing and transplanting them to bald areas. However, the number of hairs that can be transplanted is limited in that only three such operations can generally be performed. To overcome such problems, many researchers have attempted to revive hair follicles by culturing hair follicle cells or mesenchymal cells in vitro and then implanting them in the treatment area.     

Intervertebral disc biology, degeneration and novel tissue engineering and regenerative medicine therapies

Degeneration of the intervertebral disc (IVD) is a major cause of low back pain affecting a large percentage of the population at some point in their lives. Consequently IVD degeneration and its associated low back pain has a huge socio-economic impact and places a burden on health services world-wide. Current treatments remove the symptoms without treating the underlying problem and can result in reoccurrence in the same or adjacent discs. Tissue engineering offers hope that new therapies can be developed which can regenerate the IVD. Combined with this, development of novel biomaterials and an increased understanding of mesenchymal stem cell and IVD cell biology mean that tissue engineering of the IVD may soon become a reality. However for any regenerative medicine approach to be successful there must first be an understanding of the biology of the tissue and the pathophysiology of the disease process. This review covers these key areas and gives an overview of the recent developments in the fields of biomaterials, cell biology and tissue engineering of the IVD.     

Tissue specific microenvironments: a key tool for tissue engineering and regenerative medicine

The accumulated evidence points to the microenvironment as the primary mediator of cellular fate determination. Comprised of parenchymal cells, stromal cells, structural extracellular matrix proteins, and signaling molecules, the microenvironment is a complex and synergistic edifice that varies tissue to tissue. Furthermore, it has become increasingly clear that the microenvironment plays crucial roles in the establishment and progression of diseases such as cardiovascular disease, neurodegeneration, cancer, and ageing. Here we review the historical perspectives on the microenvironment, and how it has directed current explorations in tissue engineering. By thoroughly understanding the role of the microenvironment, we can begin to correctly manipulate it to prevent and cure diseases through regenerative medicine techniques.     

Two-photon laser polymerization: from fundamentals to biomedical application in tissue engineering and regenerative medicine

Three-dimensional material microstructuring by femtosecond laser-induced two-photon polymerization is emerging as an important tool in biomedicine. During two-photon polymerization, a tightly focused femtosecond laser pulse induces a crosslinking photoreaction in the polymer confined within the focal volume. As a rapid-prototyping technique, two-photon polymerization enables the fabrication of truly arbitrary three-dimensional micro- and nano-structures directly from computer models, with a spatial resolution down to 100 nm. In this review, we discuss the fundamentals, experimental methods, and materials used for two-photon polymerization; in addition, we present some applications of this technology related to microfluidics and to biomaterial scaffolds for tissue engineering and regenerative medicine.     

Surface functionalization of nanobiomaterials for application in stem cell culture,tissue engineering,and regenerative medicine

Stem cell‐based approaches offer great application potential in tissue engineering and regenerative medicine owing to their ability of sensing the microenvironment and respond accordingly (dynamic behavior). Recently, the combination of nanobiomaterials with stem cells has paved a great way for further exploration. Nanobiomaterials with engineered surfaces could mimic the native microenvironment to which the seeded stem cells could adhere and migrate. Surface functionalized nanobiomaterial‐based scaffolds could then be used to regulate or control the cellular functions to culture stem cells and regenerate damaged tissues or organs. Therefore, controlling the interactions between nanobiomaterials and stem cells is a critical factor. However, surface functionalization or modification techniques has provided an alternative approach for tailoring the nanobiomaterials surface in accordance to the physiological surrounding of a living cells; thereby, enhancing the structural and functional properties of the engineered tissues and organs. Currently, there are a variety of methods and technologies available to modify the surface of biomaterials according to the specific cell or tissue properties to be regenerated. This review highlights the trends in surface modification techniques for nanobiomaterials and the biological relevance in stem cell‐based tissue engineering and regenerative medicine. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:554–567, 2016     

Biomaterials in regenerative medicine: engineering to recapitulate the natural

The functional significance of the extracellular matrix (ECM) has generally been defined in terms of the provision of a structural support for cell adhesion and the establishment of tissue physical integrity. Recent evidence has, however, led to a paradigm shift according to which the ECM is increasingly recognised to exert a profound influence on cell behaviour, including gene expression, migration and the maintenance of functional homeostasis. The objective of this focussed review is to highlight selected observations underpinning this conclusion. Finally, we discuss the implications of these findings for regenerative medicine in the specific context of developing the 'next generation' of advanced wound care devices for the clinical management of recalcitrant chronic wounds.     

Stem cell-based composite tissue constructs for regenerative medicine

A major task of contemporary medicine and dentistry is restoration of human tissues and organs lost to diseases and trauma. A decade-long intense effort in tissue engineering has provided the proof of concept for cell-based replacement of a number of individual tissues such as the skin, cartilage, and bone. Recent work in stem cell-based in vivo restoration of multiple tissue phenotypes by composite tissue constructs such as osteochondral and fibro-osseous grafts has demonstrated probable clues for bioengineered replacement of complex anatomical structures consisting of multiple cell lineages such as the synovial joint condyle, tendon-bone complex, bone-ligament junction, and the periodontium. Of greater significance is a tangible contribution by current attempts to restore the structure and function of multitissue structures using cell-based composite tissue constructs to the understanding of ultimate biological restoration of complex organs such as the kidney or liver. The present review focuses on recent advances in stem cell-based composite tissue constructs and attempts to outline challenges for the manipulation of stem cells in tailored biomaterials in alignment with approaches potentially utilizable in regenerative medicine of human tissues and organs.     

Mesenchymal stem cells in regenerative medicine: Opportunities and challenges for articular cartilage and intervertebral disc tissue engineering

Defects of load‐bearing connective tissues such as articular cartilage and intervertebral disc (IVD) can result from trauma, degenerative, endocrine, or age‐related disease. Current surgical and pharmacological options for the treatment of arthritic rheumatic conditions in the joints and spine are ineffective. Cell‐based surgical therapies such as autologous chondrocyte transplantation (ACT) have been in clinical use for cartilage repair for over a decade but this approach has shown mixed results. This review focuses on the potential of mesenchymal stem cells (MSCs) as an alternative to cells derived from patient tissues in autologous transplantation and tissue engineering. Here we discuss the prospects of using MSCs in regenerative medicine and summarize the advantages and disadvantages of these cells in articular cartilage and IVD tissue engineering. We discuss the conceptual and practical difficulties associated with differentiating and pre‐conditioning MSCs for subsequent survival in a physiologically harsh extracellular matrix, an environment that will be highly hypoxic, acidic, and nutrient deprived. Implanted MSCs will be exposed to traumatic physical loads and high levels of locally produced inflammatory mediators and catabolic cytokines. We also explore the potential of culture models of MSCs, fully differentiated cells and co‐cultures as “proof of principle” ethically acceptable “3Rs” models for engineering articular cartilage and IVD in vitro for the purpose of replacing the use of animals in arthritis research. J. Cell. Physiol. 222:23–32, 2010. © 2009 Wiley‐Liss, Inc.     

Tissue engineering and regenerative medicine as applied to the gastrointestinal tract

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Telocytes in regenerative medicine

Telocytes (TCs) are a distinct type of interstitial cells characterized by a small cell body and extremely long and thin telopodes (Tps). The presence of TCs has been documented in many tissues and organs (go to http://www.telocytes.com ). Functionally, TCs form a three‐dimensional (3D) interstitial network by homocellular and heterocellular communication and are involved in the maintenance of tissue homeostasis. As important interstitial cells to guide or nurse putative stem and progenitor cells in stem cell niches in a spectrum of tissues and organs, TCs contribute to tissue repair and regeneration. This review focuses on the latest progresses regarding TCs in the repair and regeneration of different tissues and organs, including heart, lung, skeletal muscle, skin, meninges and choroid plexus, eye, liver, uterus and urinary system. By targeting TCs alone or in tandem with stem cells, we might promote regeneration and prevent the evolution to irreversible tissue damage. Exploring pharmacological or non‐pharmacological methods to enhance the growth of TCs would be a novel therapeutic strategy besides exogenous transplantation for many diseased disorders.