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At least 1,621 records · Page 90Linked to original sources
PubMed2006

Promotion of angiogenesis in tissue engineering: developing multicellular matrices with multiple capacities.

One of the aims of tissue engineering is to be able to develop multi-tissue organs in the future. This requires the optimization of conditions for the differentiation of multiple cell types and maintenance of the differentiated phenotype within complex engineered tissues. The goal of this study was to develop prototype tissue engineered matrices to support the simultaneous growth of different cell types with a particular focus on the angiogenic process. We examined two different matrix compositions for the promotion of blood vessel and tube formation. A fibrin-based matrix with the addition of a combination of growth factors supported vascular growth and the invasion of inflammatory cells. Using this fibrin matrix, in combination with a collagen-based hydrogel, a simple in vitro model of the cornea with adjacent sclera was developed that was complete with innervation and vascular structures. In addition, we showed that collagen-based matrices were effective in delivering mononuclear endothelial progenitor cells to ischemic tissue in vivo, and allowing these cells to incorporate into vascular structures. It is anticipated that with further development, these matrices have potential for use as delivery matrices for cell transplantation and for in vitro study purposes of multiple cell types.

Acrylamides↗
PubMed2000

Prospects for re-engineering salivary glands.

In the last decade, two areas of biomedical research--gene therapy and tissue engineering--have especially captured the imagination of the public. Both areas offer the potential for the treatment of clinical conditions that now are considered impossible or extremely difficult to manage by conventional therapeutic measures. Gene therapy has made remarkable scientific progress in the laboratory, but has yet to realize its enormous clinical promise. Tissue engineering studies have led to some tangible clinical breakthroughs, but the routine replacement of whole internal organs is still well into the future. This report will examine the applications of gene therapy and tissue engineering to salivary glands, with a focus on the repair of irreversible gland damage.

Artificial Organs↗
PubMed2001

Craniofacial tissue engineering.

There is substantial need for the replacement of tissues in the craniofacial complex due to congenital defects, disease, and injury. The field of tissue engineering, through the application of engineering and biological principles, has the potential to create functional replacements for damaged or pathologic tissues. Three main approaches to tissue engineering have been pursued: conduction, induction by bioactive factors, and cell transplantation. These approaches will be reviewed as they have been applied to key tissues in the craniofacial region. While many obstacles must still be overcome prior to the successful clinical restoration of tissues such as skeletal muscle and the salivary glands, significant progress has been achieved in the development of several tissue equivalents, including skin, bone, and cartilage. The combined technologies of gene therapy and drug delivery with cell transplantation will continue to increase treatment options for craniofacial cosmetic and functional restoration.

Adipose Tissue↗
PubMed2003

Tissue engineering--body parts from the Petri dish.

The development of methods to regenerate human tissues and organs by tissue engineering (TE), will have a dramatic influence on many medical specialities in the future. The essence of plastic surgery is to reconstruct disrupted and damaged tissues by the use of a plethora of techniques spanning from small local skin flaps to highly advanced microsurgery and free composite grafts. However, these methods only focus on moving tissue from one part of the patient to another without actual regeneration. To be able to take the next step in development of the speciality it is of necessity to address this issue. Hence it follows naturally that plastic surgeons lead and represent the driving force of the development within the research of tissue engineering. In this paper we would like to present active research and also give an overview of areas in tissue engineering that are of special interest to the plastic surgeon.

Artificial Organs↗
PubMed2006

Craniofacial tissue engineering by stem cells.

Craniofacial tissue engineering promises the regeneration or de novo formation of dental, oral, and craniofacial structures lost to congenital anomalies, trauma, and diseases. Virtually all craniofacial structures are derivatives of mesenchymal cells. Mesenchymal stem cells are the offspring of mesenchymal cells following asymmetrical division, and reside in various craniofacial structures in the adult. Cells with characteristics of adult stem cells have been isolated from the dental pulp, the deciduous tooth, and the periodontium. Several craniofacial structures--such as the mandibular condyle, calvarial bone, cranial suture, and subcutaneous adipose tissue--have been engineered from mesenchymal stem cells, growth factor, and/or gene therapy approaches. As a departure from the reliance of current clinical practice on durable materials such as amalgam, composites, and metallic alloys, biological therapies utilize mesenchymal stem cells, delivered or internally recruited, to generate craniofacial structures in temporary scaffolding biomaterials. Craniofacial tissue engineering is likely to be realized in the foreseeable future, and represents an opportunity that dentistry cannot afford to miss.

Absorbable Implants↗
PubMed2006

Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities.

Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell-mediated antitumor activity and has potential utility for anticancer therapy.

Animals↗
PubMed2006

Biosynthesis of plant-specific stilbene polyketides in metabolically engineered Escherichia coli.

BACKGROUND: Phenylpropanoids are the precursors to a range of important plant metabolites such as the cell wall constituent lignin and the secondary metabolites belonging to the flavonoid/stilbene class of compounds. The latter class of plant natural products has been shown to function in a wide range of biological activities. During the last few years an increasing number of health benefits have been associated with these compounds. In particular, they demonstrate potent antioxidant activity and the ability to selectively inhibit certain tyrosine kinases. Biosynthesis of many medicinally important plant secondary metabolites, including stilbenes, is frequently not very well understood and under tight spatial and temporal control, limiting their availability from plant sources. As an alternative, we sought to develop an approach for the biosynthesis of diverse stilbenes by engineered recombinant microbial cells. RESULTS: A pathway for stilbene biosynthesis was constructed in Escherichia coli with 4-coumaroyl CoA ligase 1 4CL1) from Arabidopsis thaliana and stilbene synthase (STS) cloned from Arachis hypogaea. E. coli cultures expressing these enzymes together converted the phenylpropionic acid precursor 4-coumaric acid, added to the growth medium, to the stilbene resveratrol (>100 mg/L). Caffeic acid, added in the same way, resulted in the production of the expected dihydroxylated stilbene, piceatannol (>10 mg/L). Ferulic acid, however, was not converted to the expected stilbene product, isorhapontigenin. Substitution of 4CL1 with a homologous enzyme, 4CL4, with a preference for ferulic acid over 4-coumaric acid, had no effect on the conversion of ferulic acid. Accumulation of tri- and tetraketide lactones from ferulic acid, regardless of the CoA-ligase expressed in E. coli, suggests that STS cannot properly accommodate and fold the tetraketide intermediate to the corresponding stilbene structure. CONCLUSION: Phenylpropionic acids, such as 4-coumaric acid and caffeic acid, can be efficiently converted to stilbene compounds by recombinant E. coli cells expressing plant biosynthetic genes. Optimization of precursor conversion and cyclization of the bulky ferulic acid precursor by host metabolic engineering and protein engineering may afford the synthesis of even more structurally diverse stilbene compounds.

Acyltransferases↗
PubMed2005

Tissue engineering: a challenge of today's medicine.

During the last years, tissue engineering-based therapies have been introduced in clinical practice in the head and face area. The regeneration of complex tissue structures for all sites of the body is envisioned for the future. In the present situation, specialists of the different fields publish excellent research papers in specialised journals. As a result, the scientific community, separated towards distinct sub-specialities, has difficulties in communication. To overcome this problem, the demanding, complex and interdisciplinary aspects of tissue engineering has to be approached from new ways. We have conceptualised Head & Face Medicine therefore as a thematically broad ranged journal, including all disciplines involved in the head and neck area. We hope this journal will attract basic researchers and clinicians who are involved in investigating and applying complex themes (examplified by tissue engineering) in the head and face region and will contribute to a gain in scientific information, communication, and collaboration in order to improve the outcome of patient treatments.

Biomedical Research↗
PubMed2007

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↗
PubMed2004

Myocardial tissue engineering: creating a muscle patch for a wounded heart.

Cardiac tissue engineering promises to revolutionize the treatment of patients with end-stage heart failure and provide new solutions to the serious problem of heart donor shortage. By its broad definition, tissue engineering involves the construction of tissue equivalents from donor cells seeded within three-dimensional polymeric scaffolds, then culturing and implanting of the cell-seeded scaffolds to induce and direct the growth of new, healthy tissue. Here, we present an up-to-date summary of research studies in cardiac tissue engineering, with an emphasis on the critical design principles.

Cardiomyopathies↗
PubMed2005

Genetic engineering of mice to test the oxidative damage theory of aging.

The laboratory mouse Mus musculus domesticus provides the best current mammalian models for the genetic analysis of aging. We give a brief overview of the use of transgenic manipulations to test the oxidative damage theory of aging. These manipulations are of two types: The first approach engineers mice that exhibit increased sensitivities to oxidative damage and thus produces mice that are likely to be short-lived. The second approach engineers mice to be more resistant to such injuries, and thus may produce mice that exhibit enhanced longevities, something that is much harder to engineer. The latter result is thus more meaningful, with the caveat that it may result from some special vulnerability of a particular lab strain or lab strains in general. The first approach, most elegantly carried out by Arlan Richardson's laboratory, provides evidence against the oxidative damage theory. My colleagues and I have been engaged in the second approach and have accumulated evidence supporting the theory. These conventional transgenic experiments, however, should be supplemented by alternative genetic approaches. One that is surprisingly neglected takes advantage of the pleuripotency of embryonic stem cells and the power of somatic cell genetics. A cautionary note is that interventions that minimize oxidative stress may be complicated by unwanted compromises of physiologically adaptive actions such as superoxide signaling and the possible protective effects of certain oxidatively modified proteins.

Aging↗
PubMed2006

Engineering improvements in endovascular devices: design and validation.

Advances in endovascular treatment of vascular disease have focused on basic and translational research of vascular disease and endovascular devices. Clinical trials serve to establish the safety and efficacy of engineering advances that incorporate this research. Recent position statements by the Food and Drug Administration (FDA) emphasize that research into conducting these trials in a timely and cost-effective manner (critical path research) is as important to patient care as the engineering advances themselves. This article reviews the recent FDA documents discussing critical path research, highlighting those topics that the FDA emphasizes. Several directions of translational research in which engineering advances may contribute to enhanced device design and improved patient care are reviewed.

Aneurysm↗
PubMed2003

Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

PURPOSE: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer. PATIENTS AND METHODS: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106 cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease. CONCLUSION: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

Adenoviridae↗
PubMed1980

Mechanical engineering in hospitals.

The design of a modern hospital owes more to engineering than the layman may realize. In this context, many engineers are in the position of laymen, being unfamiliar with the multitude of services that lies behind the impressive facade of a modern hospital. In recent years medicine and surgery themselves have taken on many of the characteristics of a technology. This has required a matching development of the services both mechanical and electrical that are required in modern health care buildings. In medical terms, if the architectural features provide the 'skin' of the hospital, the mechanical and electrical engineering services provide the nerves and sinews. If we take as an example the recently completed Freeman Hospital, Newcastle upon Tyne, (Fig. 1), which cost 10 million pounds at current cost, the service network was responsible for about half the total cost. About 400 miles (643 km) of electrical wiring and more than 40 mile (64.5 km) of copper and steel piping were used to service 3000 separate rooms. This compares with percentages of between 18 and 25 per cent for other large buildings such as office blocks, hotels and sports complexes.

Equipment and Supplies, Hospital↗
PubMed2002

In vitro engineering of human autogenous cartilage.

A challenge in tissue engineering is the in vitro generation of human cartilage. To meet standards for in vitro-engineered cartilage, such as prevention of immune response and structural as well as functional integration to surrounding tissue, we established a three-dimensional cell culture system without adding exogenous growth factors or scaffolds. Human chondrocytes were cultured as spheroids. Tissue morphology and protein expression was analyzed using histological and immunohistochemical investigations on spheroid cryosections. A cartilage-like tissue similar to naturally occurring cartilage was generated when spheroids were cultured in medium supplemented only with human serum. This in vitro tissue was characterized by the synthesis of the hyaline-specific proteins collagen type II and S-100, as well as the synthesis of hyaline-specific mucopolysaccharides that increased with prolonged culture time. After 3 months, cell number in the interior of in vitro tissues was diminished and was only twice as much as in native cartilage. Additionally, spheroids quickly adhered to and migrated on glass slides and on human condyle cartilage. The addition of antibiotics to autologous spheroid cultures inhibited the synthesis of matrix proteins. Remarkably, replacing human serum by fetal calf serum resulted in the destruction of the inner part of the spheroids and only a viable rim of cells remained on the surface. These results show that the spheroid culture allows for the first time the autogenous in vitro engineering of human cartilage-like tissue where medium supplements were restricted to human serum.

Cartilage, Articular↗
PubMed2004

Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases.

Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs). The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group), some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i) bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii) the minimal PKS controls polyketide chain length by counting the number of atoms incorporated into the backbone rather than the number of elongation cycles; and (iii) in contrast, auxiliary PKS enzymes such as ketoreductases, aromatases, and cyclases recognize specific functional groups in the backbone rather than overall chain length. Among the anthracyclines engineered in this study were compounds with (i) more superior activity than R1128 against the breast cancer cell line MCF-7 and (ii) inhibitory activity against glucose-6-phosphate translocase, an attractive target for the treatment of Type II diabetes.

Anthraquinones↗
PubMed2005

Engineering a dimeric caspase-9: a re-evaluation of the induced proximity model for caspase activation.

Caspases are responsible for the execution of programmed cell death (apoptosis) and must undergo proteolytic activation, in response to apoptotic stimuli, to function. The mechanism of initiator caspase activation has been generalized by the induced proximity model, which is thought to drive dimerization-mediated activation of caspases. The initiator caspase, caspase-9, exists predominantly as a monomer in solution. To examine the induced proximity model, we engineered a constitutively dimeric caspase-9 by relieving steric hindrance at the dimer interface. Crystal structure of the engineered caspase-9 closely resembles that of the wild-type (WT) caspase-9, including all relevant structural details and the asymmetric nature of two monomers. Compared to the WT caspase-9, this engineered dimer exhibits a higher level of catalytic activity in vitro and induces more efficient cell death when expressed. However, the catalytic activity of the dimeric caspase-9 is only a small fraction of that for the Apaf-1-activated caspase-9. Furthermore, in contrast to the WT caspase-9, the activity of the dimeric caspase-9 can no longer be significantly enhanced in an Apaf-1-dependent manner. These findings suggest that dimerization of caspase-9 may be qualitatively different from its activation by Apaf-1, and in conjunction with other evidence, posit an induced conformation model for the activation of initiator caspases.

Caspase 9↗
PubMed2005

Genetically engineered myeloma cell vaccine.

Tumor cells engineered to express immunogenes have been used for cancer vaccines to induce antitumor immunity and to study the antitumor immune mechanisms derived from immunogene expression. In this chapter, we describe the design and methods for cloning a cDNA gene coding for the mouse CD40L molecule and for construction of the expression vector pcDNA-CD40L, as well as the methods for generation of engineered myeloma cells J558/CD40L expressing CD40 ligand. We also demonstrate that the engineered J558/CD40L tumor cells lose their tumorigenicity in syngeneic mice, and that the inoculation of J558/CD40L tumor cells further leads to protective immunity against wild-type J558 tumors.

Animals↗