Fundamentals of tissue engineering: tissues and applications.
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Biocompatible Materials↗
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Tissue engineering as a subdivision of bioprocess engineering: reparative tissue engineering as a subspecialty of tissue engineering.
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Animals↗
Bone and cartilage tissue engineering.
Tissue engineering of musculoskeletal tissues, particularly bone and cartilage, is a rapidly advancing field. In bone, technology has centered on bone graft substitute materials and the development of biodegradable scaffolds. Recently, tissue engineering strategies have included cell and gene therapy. The availability of growth factors and the expanding knowledge base concerning the genetics and regulation of bone formation have generated new materials for tissue-engineering applications. This information base also has benefited cartilage tissue engineering. The problems are more complex, however, and the solutions appear more elusive. Advances in scaffold design and cell culture have improved the prognosis for success.
Animals↗
Commercial considerations in tissue engineering.
Tissue engineering is a field with immense promise. Using the example of an early tissue-engineered skin implant, Dermagraft, factors involved in the successful commercial development of devices of this type are explored. Tissue engineering has to strike a balance between tissue culture, which is a resource-intensive activity, and business considerations that are concerned with minimizing cost and maximizing customer convenience. Bioreactor design takes place in a highly regulated environment, so factors to be incorporated into the concept include not only tissue culture considerations but also matters related to asepsis, scaleup, automation and ease of use by the final customer. Dermagraft is an allogeneic tissue. Stasis preservation, in this case cryopreservation, is essential in allogeneic tissue engineering, allowing sterility testing, inventory control and, in the case of Dermagraft, a cellular stress that may be important for hormesis following implantation. Although the use of allogeneic cells provides advantages in manufacturing under suitable conditions, it raises the spectre of immunological rejection. Such rejection has not been experienced with Dermagraft. Possible reasons for this and the vision of further application of allogeneic tissues are important considerations in future tissue-engineered cellular devices. This review illustrates approaches that indicate some of the criteria that may provide a basis for further developments. Marketing is a further requirement for success, which entails understanding of the mechanism of action of the procedure, and is illustrated for Dermagraft. The success of a tissue-engineered product is dependent on many interacting operations, some discussed here, each of which must be performed simultaneously and well.
Bioreactors↗
In vitro systems for tissue engineering.
Tissue engineering, by necessity, encompasses a wide array of experimental directions and scientific disciplines. In vitro tissue engineering involves the manipulation of cells in vitro, prior to implantation into the in vivo environment. In contrast, in vivo tissue engineering relies on the body's natural ability to regenerate over non-cell-seeded biomaterials. Cells, biomaterials, and controlled incubation conditions all play important roles in the construction and use of modern in vitro systems for tissue engineering. Gene delivery is also an important factor for controlling or supporting the function of engineered cells both in vitro and post implantation, where appropriate. In this review, systems involved in the context of in vitro tissue engineering are addressed, including bioreactors, cell-seeded constructs, cell encapsulation, and gene delivery. Emphasis is placed upon investigations that are more directly linked to the treatment of clinical conditions.
Animals↗
Biophysical regulation during cardiac development and application to tissue engineering.
Tissue engineering combines the principles of biology, engineering and medicine to create biological substitutes of native tissues, with an overall objective to restore normal tissue function. It is thought that the factors regulating tissue development in vivo (genetic, molecular and physical) can also direct cell fate and tissue assembly in vitro. In light of this paradigm, tissue engineering can be viewed as an effort of "imitating nature". We first discuss biophysical regulation during cardiac development and the factors of interest for application in tissue engineering of the myocardium. Then we focus on the biomimetic approach to cardiac tissue engineering which involves the use of culture systems designed to recapitulate some aspects of the actual in vivo environment. To mimic cell signaling in native myocardium, subpopulations of neonatal rat heart cells were cultured at a physiologically high cell density in three-dimensional polymer scaffolds. To mimic the capillary network, highly porous elastomer scaffolds with arrays of parallel channels were perfused with culture medium. To mimic oxygen supply by hemoglobin, culture medium was supplemented with an oxygen carrier. To enhance electromechanical coupling, tissue constructs were induced to contract by applying electrical signals mimicking those in native heart. Over only eight days of cultivation, the biomimetic approach resulted in tissue constructs which contained electromechanically coupled cells expressing cardiac differentiation markers and cardiac-like ultrastructure and contracting synchronously in response to electrical stimulation. Ongoing studies are aimed at extending this approach to tissue engineering of functional cardiac grafts based on human cells.
Animals↗
Prospects of micromass culture technology in tissue engineering.
Tissue engineering of bone and cartilage tissue for subsequent implantation is of growing interest in cranio- and maxillofacial surgery. Commonly it is performed by using cells coaxed with scaffolds. Recently, there is a controversy concerning the use of artificial scaffolds compared to the use of a natural matrix. Therefore, new approaches called micromass technology have been invented to overcome these problems by avoiding the need for scaffolds. Technically, cells are dissociated and the dispersed cells are then reaggregated into cellular spheres. The micromass technology approach enables investigators to follow tissue formation from single cell sources to organised spheres in a controlled environment. Thus, the inherent fundamentals of tissue engineering are better revealed. Additionally, as the newly formed tissue is devoid of an artificial material, it resembles more closely the in vivo situation. The purpose of this review is to provide an insight into the fundamentals and the technique of micromass cell culture used to study bone tissue engineering.
Animals↗
Cytokine delivery and tissue engineering.
Tissue engineering has been applied to various tissues, and particularly significant progress has been made in the areas of skin, cartilage, and bone regeneration. Inclusion of bioactive factors into the synthetic scaffolds has been suggested as one of the possible tissue engineering strategies. The growth factors are polypeptides that transmit signals to modulate cellular activities. They have short half-lives, for example, platelet-derived growth factor (PDGF), isolated from platelets, has a half life of less than 2 minutes when injected intravenously. Extended biological activity and the controlled release of growth factor are achieved by incorporating growth factor into the polymeric device. This review will focus on growth factor delivery for tissue engineering. Particular examples will be given whereby growth factors are delivered from a tissue-engineered device to facilitate wound healing and tissue repair.
Animals↗
State-of-the-art tissue engineering: from tissue engineering to organ building.
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Artificial Organs↗
Biodegradable polyester elastomers in tissue engineering.
Tissue engineering often makes use of biodegradable scaffolds to guide and promote controlled cellular growth and differentiation in order to generate new tissue. There has been significant research regarding the effects of scaffold surface chemistry and degradation rate on tissue formation and the importance of these parameters is widely recognised. Nevertheless, studies describing the role of mechanical stimuli during tissue development and function suggest that the mechanical properties of the scaffold will also be important. In particular, scaffold mechanics should be taken into account if mechanical stimulation, such as cyclic strain, will be incorporated into strategies to grow improved tissues or the target tissue to be replaced has elastomeric properties. Biodegradable polyesters, such as polyglycolide, polylactide and poly(lactide-co-glycolide), although commonly used in tissue engineering, undergo plastic deformation and failure when exposed to long-term cyclic strain, limiting their use in engineering elastomeric tissues. This review will cover the latest advances in the development of biodegradable polyester elastomers for use as scaffolds to engineer tissues, such as heart valves and blood vessels.
Animals↗
Breast tissue engineering.
Tissue engineering has the potential to redefine rehabilitation for the breast cancer patient by providing a translatable strategy that restores the postmastectomy breast mound while concomitantly obviating limitations realized with contemporary reconstructive surgery procedures. The engineering design goal is to provide a sufficient volume of viable fat tissue based on a patient's own cells such that deficits in breast volume can be abrogated. To be sure, adipose tissue engineering is in its infancy, but tremendous strides have been made. Numerous studies attest to the feasibility of adipose tissue engineering. The field is now poised to challenge barriers to clinical translation that are germane to most tissue engineering applications, namely scale-up, large animal model development, and vascularization. The innovative and rapid progress of adipose engineering to date, as well as opportunities for its future growth, is presented.
Adipocytes↗
Relevance and safety of telomerase for human tissue engineering.
Tissue engineering holds the promise of replacing damaged or diseased tissues and organs. The use of autologous donor cells is often not feasible because of the limited replicative lifespan of cells, particularly those derived from elderly patients. Proliferative arrest can be overcome by the ectopic expression of telomerase via human telomerase reverse transcriptase (hTERT) gene transfection. To study the efficacy and safety of this potentially valuable technology, we used differentiated vascular smooth muscle cells (SMC) and vascular tissue engineering as a model system. Although we previously demonstrated that vessels engineered with telomerase-expressing SMC had improved mechanics over those grown with control cells, it is critical to assess the phenotypic impact of telomerase expression in donor cells, because telomerase up-regulation is observed in >95% of human malignancies. To study the impact of telomerase in tissue engineering, expression of hTERT was retrovirally induced in SMC from eight elderly patients and one young donor. In hTERT SMC, significant lifespan extension beyond that of control was achieved without population doubling time acceleration. Karyotype changes were seen in both control and hTERT SMC but were not clonal nor representative of cancerous change. hTERT cells also failed to show evidence of neoplastic transformation in functional assays of tumorigenicity. In addition, the impact of donor age on cellular behavior, particularly the synthetic capability of SMC, was not affected by hTERT expression. Hence, this tissue engineering model system highlights the impact of donor age on cellular synthetic function that appears to be independent of lifespan extension by hTERT.
Blood Vessels↗
Perspectives of gene therapy in stem cell tissue engineering.
Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve tissue function. It is hoped that forming tissue de novo will overcome many problems in plastic surgery associated with such areas as wound healing and the immunogenicity of transplanted tissue that lead to dysfunctional repair. Gene therapy is the science of the transfer of genetic material into individuals for therapeutic purposes by altering cellular function or structure at the molecular level. Recently, tissue engineering has been used in conjunction with gene therapy as a hybrid approach. This combination of stem-cell-based tissue engineering with gene therapy has the potential to provide regenerative tissue cells within an environment of optimal regulatory protein expression and would have many benefits in various areas such as the transplantation of skin, cartilage or bone. The aim of this review is to outline tissue engineering and possible applications of gene therapy in the field of biomedical engineering as well as basic principles of gene therapy, vectors and gene delivery.
Animals↗
Biomaterials and scaffolds for ligament tissue engineering.
Tissue engineering has achieved much progress in an attempt to improve and recover impaired functions of tissues and organs. Although many studies have been done, progress for tissue-engineered anterior cruciate ligaments (ACLs) has been slow due to their complex structures and mechanical properties. In this review, the ACL anatomical structure, progresses achieved, material selection, structure design, and future direction have been discussed, while the challenges and requirements from materials and scaffolds are highlighted. There is a considerably huge amount work that needs to be carried out; as such, future direction in ligament tissue engineering is proposed in hope that this review will give information on future ligament tissue engineering.
Biocompatible Materials↗
Growth factors in cartilage tissue engineering.
Tissue engineering of cartilage consists of two steps. Firstly, the cells from a small biopsy of patient's own tissue have to be multiplied. During this multiplication process they lose their cartilage phenotype. In the second step, these cells have to be stimulated to re-express their cartilage phenotype and produce cartilage matrix. Growth factors can be used to improve cell multiplication, redifferentiation and production of matrix. The choice of growth factors should be made for each phase of the tissue engineering process separately, taking into account cell phenotype and the presence of extracellular matrix. This paper demonstrates some examples of the use of growth factors to increase the amount, the quality and the assembly of the matrix components produced for cartilage tissue engineering. In addition it shows that the "culture history" (e.g., addition of growth factors during cell multiplication or preculture period in a 3-dimensional environment) of the cells influences the effect of growth factor addition. The data demonstrate the potency as well as the limitations of the use of growth factors in cartilage tissue engineering.
Animals↗
The role of tissue engineering.
Tissue engineering is expected to have a great impact on wound repair. Tissue-engineering techniques bring a new element of rational design and development into therapeutic medicine. Increasing the understanding of the biology of wound repair will accelerate the improvement of patient care, and the knowledge of basic biologic processes will be applied to the development of new products. Tissue-engineered skin will be reviewed and directions for new products will be illustrated. In the future, tissue engineering is likely to continue to yield products that are rationally designed, robotically manufactured, and increasingly customized to fit patient needs.
Culture Techniques↗
Quantitative analysis of three-dimensional fluid flow in rotating bioreactors for tissue engineering.
Tissue engineering has emerged as a viable alternative to the problem of organ and tissue shortage. Our laboratory has developed matrices for bone tissue engineering based on sintered spherical particles and, using bioreactor technology, has demonstrated the ability to produce highly mineralized matrices in vitro. In this study, porous microcapsule scaffolds were developed for bone tissue engineering in the high aspect ratio vessel rotating bioreactor. The motion of individual microcapsules as well as scaffolds in the bioreactor were studied by numerical simulation and in situ imaging analysis. Results show that spherical microcapsules with density less than the surrounding fluid exhibited two motions: (1) a periodic circular orbit with tangential speed equal to the free fall speed of the particle, and (2) an inward radial migration of the circular orbit toward the center of the bioreactor vessel. Lighter-than-water scaffolds were fabricated by sintering poly(lactic-co-glycolic acid) hollow microcarriers with diameter from 500 to 860 microm into a fixed three-dimensional geometry with approximately 30% pore volume and 180 to 190 microm median pore size. Scaffolds were fabricated with aggregate densities ranging from 0.65 g/mL and 0.99 g/mL by appropriate combinations of hollow and solid microcarriers within the scaffold. Scaffold velocity in the bioreactor for the above range of densities was accurately predicted by numerical simulation and ranged from 100 mm/s to 3 mm/s. Maximum shear stress estimation due to media flow over the exterior of the scaffold ranged from 0.3 N/m(2) to 0.006 N/m(2). Internal perfusion velocity through scaffolds also was calculated and ranged from 13 mm/s to 0.2 mm/s. Estimates of maximum interior shear stress ranged from 0.03 to 0.0007 N/m(2). These analytical methods provide an excellent vehicle for the study of bone tissue synthesis in three-dimensional culture with fluid flow.
Bioreactors↗
Yarn design for functional tissue engineering.
Tissue engineering requires the ability to design scaffolds with mechanical properties similar to those of the native tissue. Here, B. mori silk yarns are used as a model system to demonstrate the potential benefits and drawbacks of several textile methods used to fabricate tissue engineering scaffolds. Fibers are plied, twisted, cabled, braided, and/or textured to form several geometries with a wide range of mechanical outcomes. Predictable changes in ultimate tensile strength and stiffness are demonstrated following processing and as a function of test environment. The mechanical effects of increasing turns per inch and combining groups of fibers into higher-order yarn structures are demonstrated. Braids, one of the most commonly used textile structures, are shown to be limited by a change in stiffness following the locking-angle and therefore, potentially not the ideal structure for tissue engineering. Cabled yarns appear to allow the most flexibility in mechanical outcomes with a highly organized geometry. Twisted yarns, while more economical than cabled yarns, result in a higher stiffness and lower percent elongation at break than cabled yarns.
Animals↗