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PubMed2004

Genetically engineered Sertoli cells are able to survive allogeneic transplantation.

The immunoprotective nature of the testis has led to numerous investigations for its ability to protect cellular grafts. Sertoli cells (SCs) are at least partially responsible for this immunoprotective environment and survive allogeneic and xenogeneic transplantation. The ability of SCs to survive transplantation leads to the possibility that they could be engineered to deliver therapeutic proteins. As a model to test this hypothesis, we examined the ability of SCs that produce green fluorescent protein (GFP) to survive transplantation and continue expressing GFP. SCs were isolated from transgenic mice engineered to express GFP and transplanted as aggregates under the kidney capsule of severe combined immunodeficient (SCID) and Balb/c mice. Using this paradigm, it was possible to compare the survival of transgenic SCs directly in both immunodeficient and immunocompetent recipients. Fluorescence microscopy of the kidney capsule and immunohistochemistry of the grafts for GFP and GATA-4 revealed the presence of GFP-expressing SCs under the kidney capsule of SCID and Balb/c mice at both 30 and 60 days post-transplantation. In contrast, islets transplanted to Balb/c mice were rejected. Thus, SCs survive transplantation and continue to express GFP raising the possibility that SCs can be engineered using transgenic technology to produce proteins, such as insulin, factor VIII, or dopamine for the treatment of diabetes, hemophilia or Parkinson's disease, respectively.

Animals↗

PubMed2004

Microfabrication and microfluidics for tissue engineering: state of the art and future opportunities.

An introductory overview of the use of microfluidic devices for tissue engineering is presented. After a brief description of the background of tissue engineering, different application areas of microfluidic devices are examined. Among these are methods for patterning cells, topographical control over cells and tissues, and bioreactors. Examples where microfluidic devices have been employed are presented such as basal lamina, vascular tissue, liver, bone, cartilage and neurons. It is concluded that until today, microfluidic devices have not been used extensively in tissue engineering. Major contributions are expected in two areas. The first is growth of complex tissue, where microfluidic structures ensure a steady blood supply, thereby circumventing the well-known problem of providing larger tissue structures with a continuous flow of oxygen and nutrition, and withdrawal of waste products. The second, and probably more important function of microfluidics, combined with micro/nanotechnology, lies in the development of in vitro physiological systems for studying fundamental biological phenomena.

Animals↗

PubMed2003

Heart valve and arterial tissue engineering.

In the industrialized world, cardiovascular disease alone is responsible for almost half of all deaths. Many of the conditions can be treated successfully with surgery, often using transplantation techniques; however, autologous vessels or human-donated organs are in short supply. Tissue engineering aims to create specific, matching grafts by growing cells on appropriate matrices, but there are many steps between the research laboratory and the operating theatre. Neo-tissues must be effective, durable, non-thrombogenic and non-immunogenic. Scaffolds should be bio-compatible, porous (to allow cell/cell communication) and amenable to surgery. In the early days of cardiovascular tissue engineering, autologous or allogenic cells were grown on inert matrices, but patency and thrombogenicity of grafts were disappointing. The current ethos is toward appropriate cell types grown in (most often) a polymeric matrix that degrades at a rate compatible with the cells' production of their own extracellular matrical proteins, thus gradually replacing the graft with a living counterpart. The geometry is crucial. Computer models have been made of valves, and these are used as three-dimensional patterns for mass-production of implant scaffolds. Vessel walls have integral connective tissue architecture, and application of physiological level mechanical forces conditions bio-engineered components to align in precise orientation. This article reviews the concepts involved and successes achieved to date.

Arteries↗

PubMed2003

Ulcers caused by bullous morphea treated with tissue-engineered skin.

Bullous morphea is an uncommon form of localized scleroderma. The exact pathogenesis is unknown and treatment of the accompanying ulcers is problematic. We report a patient with bullous morphea with long-standing ulcers whom we successfully treated with the tissue-engineered skin Apligraf (Organogenesis Inc., Canton, MA). The patient experienced rapid improvement in granulation tissue and the ulcers healed 4 months after a single application. The rationale for the use of Apligraf is based on experience with patients with venous ulcers who have surrounding peri-ulcer fibrosis. This condition, termed lipodermatosclerosis, has been reported as a poor prognostic factor for healing, yet many ulcers associated with lipodermatosclerosis may respond to treatment with tissue-engineered skin. Taken in concert, these results suggest a role for tissue- engineered skin in the treatment of chronic wounds with surrounding fibrosis.

Collagen↗

PubMedDate not supplied

Tissue-engineered skin in the healing of wound stumps from limb amputations secondary to purpura fulminans.

Currently wound treatment options of amputation stumps due to purpura fulminans include healing by secondary intention from wound debridement, split-thickness skin grafting, tissue and muscle flaps, plantar skin free transfer, skin expansion, artificial skin, and hyperbaric oxygen therapy. We saw a 6-month-old girl with purpura fulminans as a complication of meningococcemia. She developed necrosis of the distal extremities resulting in bilateral amputation of the lower limbs. Shortly thereafter the leg stumps also became necrosed and she underwent unsuccessful split-thickness grafts of lower limb ulcers. The patient's difficult-to-heal wounds made her an excellent candidate for treatment with tissue-engineered skin. At 10 months of age, this was applied to her previously nonhealing wounds. The tissue-engineered skin induced rapid healing of the patient's chronic amputation stump ulcers and provided her with substantial pain relief. In conclusion, tissue-engineered skin appears to be a potential beneficial treatment for chronic wounds in children with nonhealing amputation stumps.

Amputation, Surgical↗

PubMed1998

Artificial cells with emphasis on cell encapsulation of genetically engineered cells.

Artificial cells are prepared in the laboratory for medical and biotechnological applications. Encapsulated cells are being studied for the treatment of diabetes, liver failure, and other conditions. More recently, there have been extensive studies into the use of encapsulated genetically engineered cells for gene therapy. We recently found that daily orally administered artificial cells, each containing a genetically engineered microorganism, can lower the elevated urea level in uremic rats to normal levels. This may solve the final obstacle of the lack of an effective oral urea removal system for the simple and inexpensive oral treatment of uremia. This is important because 85% of the world's uremic population cannot afford standard dialysis. Other areas of artificial cell application include use in hemoperfusion. Red blood cell substitutes based on modified hemoglobin are already in Phase 3 clinical trials in patients. Artificial cells containing enzymes are being developed for clinical trial in hereditary enzyme deficiency disease and other diseases. They are also being investigated for drug delivery and for use in other applications in biotechnology, chemical engineering, and medicine.

Administration, Oral↗

PubMed2003

[Tissue engineering: a tool to understand the physiological mechanisms].

Tissue engineering is a new domain, which allows some very unique studies of many human physiological mechanisms. This technology, based on cell capacity to reproduce a three-dimensional tissue with or without the help of biomaterials, is an interesting approach to study cells in an environment quite similar to the in vivo context. This article summarizes the LOEX's (laboratory of experimental organogenesis) scientific endeavor in tissue engineering in order to better understand some physiological or pathological mechanisms. Thus wound healing, stem cells, graft vascularization and cell interactions are domains where tissue engineering has already made a significant impact.

Cell Communication↗

PubMed2004

Potential tissue-engineering applications for neonatal surgery.

Tissue engineering attempts to build neotissue from its cellular building blocks. This neotissue can then be used for reconstructive surgical applications such as replacement of a congenitally abnormal heart valve or repair of a craniofacial abnormality. Since its inception in the late 1980s, tissue engineering has sparked the interests of physicians and scientists alike because of its great potential. Significant progress has been made in this burgeoning branch of science. This article reviews some of the ongoing preclinical and clinical tissue engineering research as it applies to neonatology.

Animals↗

PubMed2002

Interaction of chondrocytes, extracellular matrix and growth factors: relevance for articular cartilage tissue engineering.

UNLABELLED: The abundant extracellular matrix of articular cartilage has to be maintained by a limited number of chondrocytes. Vice versa, the extracellular matrix has an important role in the regulation of chondrocyte function. OBJECTIVE: In this review we discuss the role of the extracellular matrix in the regulation of chondrocyte function and the relevance for cartilage tissue engineering. To reach this goal the international literature on this subject has been searched with a major focus on the last 5 years. RESULTS: Structural matrix macromolecules (e.g. collagen, hyaluronate), but also growth factors (e.g. IGF-I, TGF beta) entrapped in the matrix and released under specific conditions affect chondrocyte behavior. These factors communicate with the chondrocyte via specific membrane receptors. In this way there is a close interaction between the extracellular and intracellular milieu. Articular cartilage has a limited capacity of intrinsic repair, which has resulted in the development of tissue engineering approaches to repair damaged cartilage. Successful application of scaffolds has to take into account the important role of both soluble and insoluble matrix-derived factors in cartilage homeostasis. CONCLUSION: Functional tissue engineering will only be realized when the scaffolds used will provide cartilage cells with the correct extracellular signals.

Annexins↗

PubMed2003

Formation of a mandibular condyle in vitro by tissue engineering.

PURPOSE: Mandibular reconstructive procedures often produce significant donor site morbidity. Recently, the use of minimally invasive techniques has been reported for mandibular reconstruction with decreased morbidity at the primary operative site. To date, these techniques have not addressed the graft donor site. We hypothesize that tissue-engineering techniques may be used to fabricate bone and thereby eliminate donor site morbidity. METHODS: Porcine mesenchymal stem cells (pMSCs) were isolated from the bone marrow of 3 Yucatan minipigs and grown in standard culture flasks. When they became near-confluent, cells were detached and replated with the addition of osteogenic supplements. A model of a porcine mandibular condyle was made and used to fabricate porous polymer scaffolds from biodegradable poly DL-lactic-co-glycolic acid (PLGA). Differentiated osteoblasts were transferred to the PLGA scaffold and cultured for 6 weeks in a rotational oxygen-permeable bioreactor system. The cultured constructs, consisting of scaffold and cells, were evaluated by gross, radiologic, and histologic examinations. RESULTS: The engineered constructs were white and hard and had a shape that closely resembled that of the model condyle. Plain radiographs demonstrated that the radiodensity of the construct was between that of the normal condyle and that of control scaffolds. Histologically, bone was observed on the entire surface of the PLGA scaffolds with an average thickness of 0.03 mm. Bone was not observed in the control scaffolds. CONCLUSION: In this pilot study, autologous tissue-engineered bone constructs were successfully made by combining biodegradable polymers and pMSCs.

Alkaline Phosphatase↗

PubMed2002

Engineered fetal cartilage: structural and functional analysis in vitro.

BACKGROUND/PURPOSE: This study was aimed at characterizing the structure and function of engineered fetal cartilage in vitro. METHODS: Chondrocytes from ovine specimens of fetal elastic, fetal hyaline, and adult elastic cartilage were expanded in culture and their growth rates determined. Cells were seeded onto synthetic scaffolds, which were then maintained in a bioreactor. Matrix deposition was determined by specific staining and quantitative assays for glycosaminoglycans (GAG), type II collagen (CII), and elastin, as well as compared with native tissue. Statistical analysis was by analysis of variance (ANOVA) and Students' t test, with significance set at P less than.01. RESULTS: Fetal elastic chondrocytes grew significantly faster than all other cell types. All fetal constructs resembled hyaline cartilage, regardless of the cell source. There were significantly higher levels of GAG and CII in fetal versus adult constructs, but no significant difference between fetal constructs from different sources. Unlike their adult counterparts, fetal constructs had GAG and CII levels similar to native tissues. CONCLUSIONS: Fetal chondrocytes can be rapidly expanded in culture. Compared with adult constructs, matrix deposition is enhanced in engineered fetal cartilage, which closely resembles native tissue, regardless of the cell source. Engineered fetal cartilage may be a preferable option during surgical reconstruction of select congenital anomalies.

Analysis of Variance↗

PubMed2005

Tissue engineering for meniscus repair.

Meniscus injury is common in today's active society. Despite the frequent presentation of meniscus injury, the decision to repair or resect a torn meniscus is not always straightforward. Current repair techniques are effective in the peripheral vascularized meniscus, but their success is not dependable in the avascularized zone. Tissue engineering, a discipline that combines the technologies of cell culture and biodegradable scaffolds to deliver a cellular repair, may be one future answer to this problem. The concept of using cell-based repair for torn menisci could improve healing of lesions in the avascular zone and broadly expand the indication for repair rather than removal, obviating the need for meniscectomy. This article reviews current advances in the relatively new field of tissue engineering toward the development of a tissue-engineered meniscal repair technique.

Chondrocytes↗

PubMedDate not supplied

[Meniscus replacement: current aspects in the field of tissue engineering].

Tissue engineering offers new opportunities for meniscus repair and replacement. In this field different approaches are being studied to genererate a meniscus subsitute by a combination of a matrix scaffold, cells and specific stimuli. MENISCUS REPLACEMENT BY ACELLUAR MATRICES: For meniscus replacement the matrix material has to meet high biomechanical demands. Besides implant geometry, the material properties and a secure intraarticular attachment are important preconditions for implant function. A collagen scaffold has already been applied clinically for partial meniscus replacement. Scaffolds made of synthetic, bioabsorbable polymers and small intestine submucosa have been employed in animal studies. Following implantation, matrices are invaded by cells and undergo a process of remodeling. Formation of fibrocartilage repair tissue has been observerd. The biomechanical quality of implants and their effect on cartilage preservation have to be studied further. CELLULAR SEEDING OF MATRICES FOR MENSICUS REPLACEMENT: Advanced biological and biomechanical implant quality might be achieved by seeding matrices with cells in vitro. However, the ideal type of cell for this purpose has not yet been identified. Autologous mensicus cells, articular chondrocytes and mesenchymal stem cells represent possible cellular sources. Additional stimuli, such as cytokines and mechanical forces, and techniques of genetic engineering might further contribute to enhance the quality of engineered tissue.

Biocompatible Materials↗

PubMed2002

In vitro engineering of heart muscle: artificial myocardial tissue.

INTRODUCTION: Myocardial infarction followed by heart failure represents one of the major causes of morbidity and mortality, particularly in industrialized countries. Engineering and subsequent transplantation of contractile artificial myocardial tissue and, consequently, the replacement of ischemic and infarcted areas of the heart provides a potential therapeutic alternative to whole organ transplantation. METHODS: Artificial myocardial tissue samples were engineered by seeding neonatal rat cardiomyocytes with a commercially available 3-dimensional collagen matrix. The cellular engraftment within the artificial myocardial tissues was examined microscopically. Force development was analyzed in spontaneously beating artificial myocardial tissues, after stretching, and after pharmacologic stimulation. Moreover, electrocardiograms were recorded. RESULTS: Artificial myocardial tissues showed continuous, rhythmic, and synchronized contractions for up to 13 weeks. Embedded cardiomyocytes were distributed equally within the 3-dimensional matrix. Application of Ca(2+) and epinephrine, as well as electrical stimulation or stretching, resulted in enhanced force development. Electrocardiographic recording was possible on spontaneously beating artificial myocardial tissue samples and revealed physiologic patterns. CONCLUSIONS: Using a clinically well-established collagen matrix, contractile myocardial tissue can be engineered in vitro successfully. Mechanical and biologic properties of artificial myocardial tissue resemble native cardiac tissue. Use of artificial myocardial tissues might be a promising approach to reconstitute degenerated or failing cardiac tissue in many disease states and therefore provide a reasonable alternative to whole organ transplantation.

Animals↗

PubMed2004

Programmable cells: interfacing natural and engineered gene networks.

Novel cellular behaviors and characteristics can be obtained by coupling engineered gene networks to the cell's natural regulatory circuitry through appropriately designed input and output interfaces. Here, we demonstrate how an engineered genetic circuit can be used to construct cells that respond to biological signals in a predetermined and programmable fashion. We employ a modular design strategy to create Escherichia coli strains where a genetic toggle switch is interfaced with: (i) the SOS signaling pathway responding to DNA damage, and (ii) a transgenic quorum sensing signaling pathway from Vibrio fischeri. The genetic toggle switch endows these strains with binary response dynamics and an epigenetic inheritance that supports a persistent phenotypic alteration in response to transient signals. These features are exploited to engineer cells that form biofilms in response to DNA-damaging agents and cells that activate protein synthesis when the cell population reaches a critical density. Our work represents a step toward the development of "plug-and-play" genetic circuitry that can be used to create cells with programmable behaviors.

DNA Damage↗

PubMed2004

Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds.

The major challenge of tissue engineering is directing the cells to establish the physiological structure and function of the tissue being replaced across different hierarchical scales. To engineer myocardium, biophysical regulation of the cells needs to recapitulate multiple signals present in the native heart. We hypothesized that excitation-contraction coupling, critical for the development and function of a normal heart, determines the development and function of engineered myocardium. To induce synchronous contractions of cultured cardiac constructs, we applied electrical signals designed to mimic those in the native heart. Over only 8 days in vitro, electrical field stimulation induced cell alignment and coupling, increased the amplitude of synchronous construct contractions by a factor of 7, and resulted in a remarkable level of ultrastructural organization. Development of conductive and contractile properties of cardiac constructs was concurrent, with strong dependence on the initiation and duration of electrical stimulation.

Animals↗

PubMed2006

Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies.

The MHC class I-related receptor, neonatal Fc receptor (FcRn), plays a central role in regulating the transport and in vivo persistence of immunoglobulin G (IgG). IgG-FcRn interactions can be targeted for engineering to modulate the in vivo longevity and transport of an antibody, and this has implications for the successful application of therapeutic IgGs. Although mice are widely used to preclinically test antibodies, human and mouse FcRn have significant differences in binding specificity. Here we show that an engineered human IgG1 has disparate properties in murine and human systems. The mutant shows improved transport relative to wild-type human IgG1 in assays of human FcRn function but has short in vivo persistence and competitively inhibits FcRn activity in mice. These studies indicate potential limitations of using mice as preclinical models for the analysis of engineered antibodies. Alternative assays are proposed that serve as indicators of the properties of IgGs in humans.

Amino Acid Substitution↗

PubMed2003

The role of copper and protons in heme-copper oxidases: kinetic study of an engineered heme-copper center in myoglobin.

To probe the role of copper and protons in heme-copper oxidase (HCO), we have performed kinetic studies on an engineered heme-copper center in sperm whale myoglobin (Leu-29 --> HisPhe-43 --> His, called Cu(B)Mb) that closely mimics the heme-copper center in HCO. In the absence of metal ions, the engineered Cu(B) center in Cu(B)Mb decreases the O(2) binding affinity of the heme. However, addition of Ag(I), a redox-inactive mimic of Cu(I), increases the O(2)-binding affinity. More importantly, copper ion in the Cu(B) center is essential for O(2) reduction, as no O(2) reduction can be observed in copper-free, Zn(II), or Ag(I) derivatives of Cu(B)Mb. Instead of producing a ferryl-heme as in HCO, the Cu(B)Mb generates verdoheme because the engineered Cu(B)Mb may lack a hydrogen bonding network that delivers protons to promote the heterolytic OO cleavage necessary for the formation of ferryl-heme. Reaction of oxidized Cu(B)Mb with H(2)O(2), a species equivalent in oxidation state to 2e(-), reduced O(2) but, possessing the extra protons, resulted in ferryl-heme formation, as in HCO. The results showed that the Cu(B) center plays a critical role in O(2) binding and reduction, and that proton delivery during the O(2) reduction is important to avoid heme degradation and to promote the HCO reaction.

Amino Acid Sequence↗