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PubMedDate not supplied

Recent progress in biomolecular engineering.

During the next decade or so, there will be significant and impressive advances in biomolecular engineering, especially in our understanding of the biological roles of various biomolecules inside the cell. The advances in high throughput screening technology for discovery of target molecules and the accumulation of functional genomics and proteomics data at accelerating rates will enable us to design and discover novel biomolecules and proteins on a rational basis in diverse areas of pharmaceutical, agricultural, industrial, and environmental applications. As an applied molecular evolution technology, DNA shuffling will play a key role in biomolecular engineering. In contrast to the point mutation techniques, DNA shuffling exchanges large functional domains of sequences to search for the best candidate molecule, thus mimicking and accelerating the process of sexual recombination in the evolution of life. The phage-display system of combinatorial peptide libraries will be extensively exploited to design and create many novel proteins, as a result of the relative ease of screening and identifying desirable proteins. Even though this system has so far been employed mainly in screening the combinatorial antibody libraries, its application will be extended further into the science of protein-receptor or protein-ligand interactions. The bioinformatics for genome and proteome analyses will contribute substantially toward ever more accelerated advances in the pharmaceutical industry. Biomolecular engineering will no doubt become one of the most important scientific disciplines, because it will enable systematic and comprehensive analyses of gene expression patterns in both normal and diseased cells, as well as the discovery of many new high-value molecules. When the functional genomics database, EST and SAGE techniques, microarray technique, and proteome analysis by 2-dimensional gel electrophoresis or capillary electrophoresis in combination with mass spectrometer are all put to good use, biomolecular engineering research will yield new drug discoveries, improved therapies, and significantly improved or new bioprocess technology. With the advances in biomolecular engineering, the rate of finding new high-value peptides or proteins, including antibodies, vaccines, enzymes, and therapeutic peptides, will continue to accelerate. The targets for the rational design of biomolecules will be broad, diverse, and complex, but many application goals can be achieved through the expansion of knowledge based on biomolecules and their roles and functions in cells and tissues. Some engineered biomolecules, including humanized Mab's, have already entered the clinical trials for therapeutic uses. Early results of the trials and their efficacy are positive and encouraging. Among them, Herceptin, a humanized Mab for breast cancer treatment, became the first drug designed by a biomolecular engineering approach and was approved by the FDA. Soon, new therapeutic drugs and high-value biomolecules will be designed and produced by biomolecular engineering for the treatment or prevention of not-so-easily cured diseases such as cancers, genetic diseases, age-related diseases, and other metabolic diseases. Many more industrial enzymes, which will be engineered to confer desirable properties for the process improvement and manufacturing of high-value biomolecular products at a lower production cost, are also anticipated. New metabolites, including novel antibiotics that are active against resistant strains, will also be produced soon by recombinant organisms having de novo engineered biosynthetic pathway enzyme systems. The biomolecular engineering era is here, and many of benefits will be derived from this field of scientific research for years to come if we are willing to put it to good use.

Animals↗

PubMedDate not supplied

Tissue engineering of autologous cartilage grafts in three-dimensional in vitro macroaggregate culture system.

In the field of tissue engineering, techniques have been described to generate cartilage tissue with isolated chondrocytes and bioresorbable or nonbioresorbable biomaterials serving as three-dimensional cell carriers. In spite of successful cartilage engineering, problems of uneven degradation of biomaterial, and unforeseeable cell-biomaterial interactions remain. This study represents a novel technique to engineer cartilage by an in vitro macroaggregate culture system without the use of biomaterials. Human nasoseptal or auricular chondrocytes were enzymatically isolated and amplified in conventional monolayer culture before the cells were seeded into a cell culture insert with a track-etched membrane and cultured in vitro for 3 weeks. The new cartilage formed within the in vitro macroaggregates was analyzed by histology (toluidine blue, von Kossa-safranin O staining), and immunohistochemistry (collagen types I, II, V, VI, and X and elastin). The total glycosaminoglycan (GAG) content of native and engineered auricular as well as nasal cartilage was assayed colorimetrically in a safranin O assay. The biomechanical properties of engineered cartilage were determined by biphasic indentation assay. After 3 weeks of in vitro culture, nasoseptal and auricular chondrocytes synthesized new cartilage with the typical appearance of hyaline nasal cartilage and elastic auricular cartilage. Immunohistochemical staining of cartilage samples showed a characteristic pattern of staining for collagen antibodies that varied in location and intensity. In all samples, intense staining for cartilage-specific collagen types I, II, and X was observed. By the use of von Kossa-safranin O staining a few positive patches-a possible sign of beginning mineralization within the engineered cartilages-were detected. The unique pattern for nasoseptal cartilage is intense staining for type V collagen, whereas auricular cartilage is only weakly positive for collagen types V and VI. Engineered nasal and auricular macroaggregates were negative for anti-elastin antibody (interterritorially). The measurement of total GAG content demonstrated higher GAG content for reformed nasoseptal cartilage compared with elastic auricular cartilage. However, the total GAG content of engineered macroaggregates was lower than that of native cartilage. In spite of the mechanical stability of the auricular macroaggregates, there was no equilibrium of indentation. The histomorphological and immunohistochemical results demonstrate successful cartilage engineering without the use of biomaterials, and identify characteristics unique to hyaline as well as elastic cartilage. The GAG content of engineered cartilage was lower than in native cartilage and the biomechanical properties were not determinable by indentation assay. This study illustrates a novel in vitro macroaggregate culture system as a promising technique for tissue engineering of cartilage grafts. Further long-term in vitro and in vivo studies must be done before this method can be applied to reconstructive surgery of the nose or auricle.

Cartilage, Articular↗

PubMed2005

[Experimental study of tissue engineered bone with cryopreservation on healing of bone defects].

OBJECTIVE: To investigate the effect of tissue engineered bone with cryopreservation on healing of bone defects and to explore feasibility of cryopreservation for tissue engineered bone. METHODS: Tissue engineered bones were constructed with osteoblasts being seeded onto bio-derived materials made from fresh human bones,and they were preserved at 4 degrees C and - 196 degrees C for 3 months and 6 months respectively. They were applied to repair segmental bone defects of rabbit's radius while the tissue engineered bone without cryopreservation and bio-derived materials were brought into control groups. The experiment was divided into groups A3, A6, B3, B6, C and D (group A3: tissue engineered bones were preserved at 4 degrees C for 3 months; group A6: tissue engineered bones were preserved at 4 degrees C for 6 months; group B3:tissue engineered bones were preserved at --196 degrees C for 3 months; group B6:tissue engineered bones were preserved at - 196 degrees C for 6 months; group C: tissue engineered bones without cryopreservation; group D: bio-derived materials). Macroscopical and histological examination were done at the 2nd, 4th, 6th, 12th weeks, X-ray examination was done at the 6th, 12th weeks and biomechanics were determined at 12th weeks after operation respectively. RESULTS: Macroscopical observation showed no significant differences among group A3, A6, B3, B6 and C, but less new bone formation and more obvious boundary in group D were observed. Histological observation showed more collagen and new bone around the edge of implant of group A3, A6, B3, B6 and C than group D, and histological evaluation showed significant differences between group D and other groups (P <0.05). Radiographic observation showed no absorbability of the implant cortex and less new bone formation in group D, but the unity between implant and host bone, medullary cavity reopened, disappearance of fracture line and fine bone modelling were observed in other groups at 12 weeks after operation. Biomechanics between group D and other groups showed significant differences (P< 0. 05). CONCLUSION: Cryopreservation (4 degrees C and - 196 degrees C) were capable of preserving tissue engineered bone for long time, and tissue engineered bone with cryopreservation has significant effect on healing of bone defects. The methods fit clinical application.

Animals↗

PubMed2006

Engineering and public health at CDC.

Engineering is the application of scientific and technical knowledge to solve human problems. Using imagination, judgment, and reasoning to apply science, technology, mathematics, and practical experience, engineers develop the design, production, and operation of useful objects or processes. During the 1940s, engineers dominated the ranks of CDC scientists. In fact, the first CDC director, Assistant Surgeon General Mark Hollis, was an engineer. CDC engineers were involved in malaria control through the elimination of standing water. Eventually the CDC mission expanded to include prevention and control of dengue, typhus, and other communicable diseases. The development of chlorination, water filtration, and sewage treatment were crucial to preventing waterborne illness. Beginning in the 1950s, CDC engineers began their work to improve public health while developing the fields of environmental health, industrial hygiene, and control of air pollution. Engineering disciplines represented at CDC today include biomedical, civil, chemical, electrical, industrial, mechanical, mining, and safety engineering. Most CDC engineers are located in the National Institute for Occupational Safety and Health (NIOSH) and the Agency for Toxic Substances and Disease Registry (ATSDR). Engineering research at CDC has a broad stakeholder base. With the cooperation of industry, labor, trade associations, and other stakeholders and partners, current work includes studies of air contaminants, mining, safety, physical agents, ergonomics, and environmental hazards. Engineering solutions remain a cornerstone of the traditional "hierarchy of controls" approach to reducing public health hazards.

Centers for Disease Control and Prevention, U.S.↗

PubMed1998

Videofetoscopically assisted fetal tissue engineering: skin replacement.

BACKGROUND/PURPOSE: Treatment of several congenital anomalies is frequently hindered by lack of enough tissue for surgical reconstruction in the neonatal period. The purposes of this study were (1) introduction of a novel concept in perinatal surgery, involving minimally invasive harvest of fetal tissue, which is then processed through tissue engineering techniques in vitro while pregnancy is allowed to continue, so that, at delivery, the newborn can benefit from having autologous, expanded tissue promptly available for surgical implantation at birth; (2) analysis of the progress of an engineered fetal skin graft with time, after implantation in the neonate; and (3) study of the effects of current tissue engineering techniques on fetal keratinocytes and fetal dermal fibroblasts. METHODS: Ten 90- to 95-day-gestation fetal lambs underwent surgical creation of two large paramedian excisional skin defects on the posterior body wall. Subsequently, fetal skin specimens no larger than 1.5 x 1.5 cm were videofetoscopically harvested. Fetal keratinocytes and dermal fibroblasts were then separately cultivated and expanded in vitro for 45 to 50 days, resulting in a total of approximately 250 to 300 million cells. Seven to 10 days before fetal delivery, all cells were seeded in two layers on a 16 to 20-cm2, 3-mm thick biodegradable polyglycolic acid polymer matrix. One to 4 days after delivery, the autologous engineered skin was implanted over one of two previously created skin defects. The second skin defect region received an absorbable polymer scaffold without cells as a control. If necessary, the original skin wounds were further amplified before implantation. Each animal provided at least one time-point for histological analysis of both types of repair through excisional biopsies performed at weekly intervals, up to 8 weeks postimplantation. Normal skin specimens were also used as controls. RESULTS: Fetal and neonatal survival rates were 100%. Based on previous postnatal skin engineering studies, fetal dermal fibroblasts multiplied significantly faster in vitro (approximately fivefold) than expected. Fetal keratinocytes multiplied at expected postnatal rates. The engineered grafts induced faster epithelization of the wound (partial at 1 week and complete between 2 and 3 weeks postoperatively) than did the acellular ones (partial at 3 weeks and complete between 3 and 4 weeks postoperatively). Analysis of skin architecture showed a higher level of epidermal organization and less dermal scarring in the wounds that received the engineered, cell-implanted polymer scaffold. CONCLUSIONS: (1) Videofetoscopically assisted fetal tissue engineering is a viable method for obtaining expanded autologous tissue for prompt surgical reconstruction at birth. (2) Fetal skin can be expanded and engineered in vitro at faster rates than expected postnatally, with current tissue engineering techniques. (3) Engineered autologous fetal skin induces a faster and more organized healing of neonatal skin defects than that observed with second intention. This concept may prove useful for the treatment of certain human neonatal conditions such as giant neoplasias, ectopia cordis, and other body wall defects.

Animals↗

PubMed1995

Re-engineering the hospital: a house without rooms.

Re-engineering of health care systems is defined, and the experience with re-engineering at a medical center is discussed. Re-engineering is a business concept that involves totally redesigning work processes to achieve much higher efficiencies and quality; it should not be confused with cost cutting, downsizing, and continuous improvement. Re-engineering seeks to combine multiple jobs into one, empower workers and make them more accountable, sequence the elements of work more naturally, create greater flexibility, and blur or remove organizational boundaries. Re-engineering at The Ohio State University Medical Center began with the formation of an operations improvement team consisting of department heads. Work processes were selected for re-engineering and prioritized, and teams were created to identify activities calling for radical change, such as activities that wasted time, could be done on an outpatient basis, or were duplicative. It was concluded that the redesign had to focus on the entire medical center, not the individual departments. A list of the characteristics of a better organization was prepared and distributed to the staff, along with other documents to help them understand the need for change. The operations improvement team specified expected outcomes of the re-engineering, and each re-engineering team developed measures of these outcomes. Many of the recommendations submitted have been implemented. One innovation has been the consolidation of the duties of utilization-review nurses, continuity-of-care nurses, social workers, and patient-education nurses into a single job category. When the medication-use re-engineering team meets, it will not be re-engineering the pharmacy department, it will be addressing the drug-use process. A medical center is re-engineering itself so that it will be able to continue to meet the health care needs of the community it serves.

Efficiency, Organizational↗

PubMed2006

Teaching cellular engineering.

Cellular engineering is one of the fastest growing subdisciplines in the field of Biomedical Engineering. It involves the application of engineering analysis to understand and control cellular behavior, with the ultimate objective of developing novel therapeutic or diagnostic approaches for the clinic or harnessing cellular function for commercial applications. Well-educated students in this area need strong foundational knowledge in engineering science, chemistry, and cell and molecular biology. In undergraduate curricula, the challenge is to include essential engineering skills plus appropriate levels of training in chemistry and biology while satisfying accreditation-mandated breadth in engineering training. At the graduate level, educators must accommodate students with diverse backgrounds and provide them with both a state-of-the-art understanding of the life sciences and the most advanced engineering skills. Engineering curricular content should include mechanics and materials, physical chemistry, transport phenomena, and control theory. Training from faculty with appointments and research programs in the life sciences is generally recommended, and additional life science content should also be integrated within the engineering curriculum. A capstone course in cellular engineering that includes opportunities for students to have hands-on experiences with state-of-the-art laboratory techniques is highly recommended.

Benchmarking↗

PubMed2005

Scaffold-based bone engineering by using genetically modified cells.

The first generation of clinically applied tissue engineering concepts in the area of skin, cartilage and bone marrow regeneration was based on the isolation, expansion and implantation of cells from the patient's own tissue. Although successful in selective treatments, tissue engineering needs to overcome major challenges to allow widespread clinical application with predictable outcomes. One challenge is to present the cells in a matrix to the implantation site to allow the cells to survive the wound healing contraction forces, tissue remodeling in certain tissues such as bone and biomechanical loading. Hence, several tissue engineering strategies focus on the development of load-bearing scaffold/cell constructs. From a cell source point of view, bone engineers face challenges to isolate and expand cells with the highest potential to form osseous tissue along with harvesting tissue without extensive donor site morbidity. A major hurdle to tissue engineering is de-differentiation and limited ability to control cell phenotype following in vitro expansion. Due to early successes with genetic engineering, bone tissue engineers have used different strategies to genetically alter various types of mesenchymal cells to enhance the mineralization capacity of tissue-engineered scaffold/cell constructs. Although the development of multi-component scaffold/osteogenic cell constructs requires a combination of interdisciplinary research strategies, the following review is limited to describe the general aspects of bone engineering and to present overall directions of technology platforms, which include a genetic engineering component. This paper reviews the most recent work in the field and discusses the concepts developed and executed by a collaborative effort of the multi-disciplinary teams of the two authors.

Animals↗

PubMed2003

Green engineering education through a U.S. EPA/academia collaboration.

The need to use resources efficiently and reduce environmental impacts of industrial products and processes is becoming increasingly important in engineering design; therefore, green engineering principles are gaining prominence within engineering education. This paper describes a general framework for incorporating green engineering design principles into engineering curricula, with specific examples for chemical engineering. The framework for teaching green engineering discussed in this paper mirrors the 12 Principles of Green Engineering proposed by Anastas and Zimmerman (Environ. Sci. Technol. 2003, 37, 94A-101A), especially in methods for estimating the hazardous nature of chemicals, strategies for pollution prevention, and approaches leading to efficient energy and material utilization. The key elements in green engineering education, which enlarge the "box" for engineering design, are environmental literacy, environmentally conscious design, and beyond-the-plant boundary considerations.

Education↗

PubMedDate not supplied

Measurement of DNA biomarkers for the safety of tissue-engineered medical products, using artificial skin as a model.

To test the hypothesis that the process of tissue engineering introduces genetic damage to tissue-engineered medical products, we employed the use of five state-of-the-art measurement technologies to measure a series of DNA biomarkers in commercially available tissue-engineered skin as a model. DNA was extracted from the skin and compared with DNA from cultured human neonatal control cells (dermal fibroblasts and epidermal keratinocytes) and adult human fibroblasts from a 55-year-old donor and a 96-year-old donor. To determine whether tissue engineering caused oxidative DNA damage, gas chromatography/isotope-dilution mass spectrometry and liquid chromatography/isotope-dilution mass spectrometry were used to measure six oxidatively modified DNA bases as biomarkers. Normal endogenous levels of the modified DNA biomarkers were not elevated in tissue-engineered skin when compared with control cells. Next, denaturing high-performance liquid chromatography and capillary electrophoresis-single strand conformation polymorphism were used to measure genetic mutations. Specifically, the TP53 tumor suppressor gene was screened for mutations, because it is the most commonly mutated gene in skin cancer. The tissue-engineered skin was found to be free of TP53 mutations at the level of sensitivity of these measurement technologies. Lastly, fluorescence in situ hybridization was employed to measure the loss of Y chromosome, which is associated with excessive cell passage and aging. Loss of Y chromosome was not detected in the tissue-engineered skin and cultured neonatal cells used as controls. In this study, we have demonstrated that tissue engineering (for TestSkin II) does not introduce genetic damage above the limits of detection of the state-of-the-art technologies used. This work explores the standard for measuring genetic damage that could be introduced during production of novel tissue-engineered products. More importantly, this exploratory work addresses technological considerations that need to be addressed in order to expedite accurate and useful international reference standards for the emerging tissue-engineering industry.

Biomarkers↗

PubMed2006

Repair of tendon defect with dermal fibroblast engineered tendon in a porcine model.

Harvesting autologous tenocytes for tendon engineering may cause secondary tendon defect at the donor site. Dermal fibroblasts are an easily accessible cell source and do not cause major donor site defect. This study aims to explore the possibility of tendon engineering using dermal fibroblasts. A total of 45 hybrid pigs were randomly divided into three groups: experimental group (n = 15)--repair of tendon defect with a dermal fibroblast engineered tendon; control group 1 (n = 15)--repair of defect with a tenocyte engineered tendon; and control group 2 (n = 15)-repair of defect with a scaffold alone. Both autologous dermal fibroblasts and tenocytes were seeded on polyglycolic acid (PGA) unwoven fibers to form a cell-scaffold construct and cultured in vitro for 7 days before in vivo implantation to repair a defect of flexor digital superficial tendon. Specimens were harvested at weeks 6, 14, and 26 for gross, histological, and mechanical analyses. Microscopy revealed good attachment of both dermal fibroblasts and tenocytes on PGA fibers and matrix production. In vivo results showed that fibroblast and tenocyte engineered tendons were similar to each other in their gross view, histology, and tensile strength. At 6 weeks, parallel collagen alignment was observed at both ends, but not in the middle in histology, with more cellular components than natural tendons. At weeks 14 and 26, both engineered tendons exhibited histology similar to that of natural tendon. Collagens became parallel throughout the tendon structure, and PGA fibers were completely degraded. Interestingly, dermal fibroblast and tenocyte engineered tendons did not express type III collagen at 26 weeks, which remained observable in normal pig skin and control group 2 tissue using polarized microscopy, suggesting a possible phenotype change of implanted dermal fibroblasts. Furthermore, both fibroblast and tenocyte engineered tendons shared similar tensile strength, about 75% of natural tendon strength. At 6 weeks in control group 2, neo-tissue was formed only at the peripheral area by host cells. A cord-like tissue was formed at weeks 14 and 26. However, the formed tissue was histologically disorganized and mechanically weaker than both cell-engineered tendons (p < 0.05). These results suggest that dermal fibroblasts may have the potential as seed cells for tendon engineering.

Absorbable Implants↗

PubMed2004

Tissue engineering: the current status of this futuristic modality in head neck reconstruction.

PURPOSE OF REVIEW: To define tissue engineering and describe the components that are involved in engineering tissue. To provide examples of the most recent developments in tissue engineering as they apply to the otolaryngologist. To provide a general overview of selected exciting advances outside the field of general otolaryngology but of general interest to the reconstructive community. RECENT FINDINGS: Tissue engineering is a rapidly evolving field that can be defined as the regeneration of new tissues through the use of biologic mediators and matricis. The three components required are scaffolds, signaling molecules, and cells. A significant amount of work has been done to generate bone, cartilage, cornea, and vascular grafts. Tissue engineered bone is the only tissue type that has been evaluated in Phase III clinical trials and is in routine clinical use. Engineered bone from BMP-2 and BMP-7 is used in orthopedics for lumbar fusions and long bone nonunions. Clinical application of bone tissue engineering in the head and neck is limited to case reports. There has been success in tissue engineering with cartilage for the nose and ear in immune incompetent animal models but there has been difficulty with generating scaffolds that do not incite an immune reaction in an immune competent model. The most advanced organ engineered is a bladder that has been successful in a canine model. SUMMARY: Tissue engineering holds the promise of "off the shelf" parts for reconstruction of tissues and organs. The widest clinical application is with bone in orthopedics. Applications in the head and neck are limited, at present, due to the immunogenicity of the scaffolds and the challenging wounds encountered in both cancer and cosmetic patients.

Animals↗

PubMed2004

Genetically engineered animals in drug discovery and development: a maturing resource for toxicologic research.

Genetically engineered mice that either over-express a foreign gene (transgenic) or in which the activity of a specific gene has been removed ("knock-out") or replaced ("knock-in") will be used increasingly to investigate molecular mechanisms of disease, to evaluate innovative therapeutic targets, and to screen novel agents for efficacy and/or toxicity. Recent innovations of relevance to toxicologic researchers include the construction of genetically engineered mice with (1) multiple engineered genes, (2) mutations that can be induced at specific sites and times throughout life, and (3) the substitution of human genes for their mouse counterparts ("humanized" mice) to allow in vivo investigation of xenobiotic toxicity. Contemporary applications of genetically engineered mice in toxicology include basic mechanistic research exploiting newly engineered mouse lines as well as applied screening for genotoxicity and carcinogenicity using commercially available animals. Many caveats must be considered when interpreting genetically engineered mice-derived toxicity data, the chief of which will be the extent to which the model's phenotype has been fully characterized, the type and incidence of background lesions for the given mouse strain and engineered gene, and the possibility of misinterpreting the presence or absence of a phenotype due to compensatory physiologic processes that mask the outcome produced by the engineering event. Toxicity data acquired using genetically engineered mice currently supplements and in time likely will supplant those gathered using the present "gold standard" bioassays, as genetically engineered mice typically develop more lesions after a shorter latency period than do age- and strain-matched, wild-type mice.

Animals↗

PubMed2006

Cardiovascular tissue engineering I. Perfusion bioreactors: a review.

Tissue engineering is a fast-evolving field of biomedical science and technology with future promise to manufacture living tissues and organs for replacement, repair, and regeneration of diseased organs. Owing to the specific role of hemodynamics in the development, maintenance, and functioning of the cardiovascular system, bioreactors are a fundamental of cardiovascular tissue engineering. The development of perfusion bioreactor technology for cardiovascular tissue engineering is a direct sequence of previous historic successes in extracorporeal circulation techniques. Bioreactors provide a fluidic environment for tissue engineered tissue and organs, and guarantee their viability, maturation, biomonitoring, testing, storage, and transportation. There are different types of bioreactors and they vary greatly in their size, complexity, and functional capabilities. Although progress in design and functional properties of perfusion bioreactors for tissue engineered blood vessels, heart valves, and myocardial patches is obvious, there are some challenges and insufficiently addressed issues, and room for bioreactor design improvement and performance optimization. These challenges include creating a triple perfusion bioreactor for vascularized tubular tissue engineered cardiac construct; designing and manufacturing fluidics-based perfused minibioreactors; incorporation of systematic mathematical modeling and computer simulation based on computational fluid dynamics into the bioreactor designing process; and development of automatic systems of hydrodynamic regime control. Designing and engineering of built-in noninvasive biomonitoring systems is another important challenge. The optimal and most efficient perfusion and conditioning regime, which accelerates tissue maturation of tissue-engineered constructs also remains to be determined. This is a first article in a series of reviews on critical elements of cardiovascular tissue engineering technology describing the current status, unsolved problems, and challenges of bioreactor technology in cardiovascular tissue engineering and outlining future trends and developments.

Bioreactors↗

PubMed2001

Engineered antibodies take center stage.

The start of the post-genomic era provides a useful juncture for reflection on the state of antibody engineering, which will be a critical technology for relating function and pathology to genomic sequence in biology and medicine. The phenomenal progress in deciphering the human genome has given significant impetus to the application of engineered antibodies in proteomics. Thus, advances in phage display antibody libraries can now help to define novel gene function and the measurement of abnormal protein expression in pathological states. Furthermore, intrabody and antibody engineering provide vehicles for the development of molecular medicines of the future. In addition to these new directions, antibody engineering has begun to show concrete success in its long-term efforts to develop targeted immunotherapies for cancer and other diseases. The cornerstones of clinical development are the detailed academic clinical trials that continue to push the boundaries of engineered antibodies into the real world. The field displays a healthy impatience for practical results, as research accelerates with concerted efforts to transfer preclinical insights into clinical trials. Growing private and governmental expenditures will lead to the rapid expansion of life-saving immunotherapeutic agents. The present review developed from our effort to report on the 11th Annual International Conference on Antibody Engineering (3-6 December 2000). This annual meeting is a forum for discussions on the latest advances in antibody engineering groups from around the world, and now includes the broader agenda of engineering in molecular immunology. In bringing scientists together to exchange ideas at this open forum, new collaborations and the threads of new discoveries are woven. For example, Professors Gerhard Wagner (Harvard Medical School), Dennis Burton (Scripps Research Institute), and Peter Hudson (CSIRO, Melbourne, Australia) gave exciting insights on structural immunobiology that had implications across many disciplines. The growth in antibody engineering was highlighted by the attendance of some 600 participants at the meeting, doubling that of the 1999 meeting. Dramatic clinical acceptance of monoclonal antibodies during the past two years has fostered this growth, with sales in 2000 of 1.8 billion dollars and projections for 2001 of 3 billion dollars. However, economic measures cannot begin to convey the medical revolution that is being effected by these first humanized and chimerized monoclonal antibodies. At this juncture, the 10 monoclonal antibody therapeutics in clinical use are of murine origin, of which 3 are entirely murine (OKT3, Mylotarg, 90Y-labeled Bexxar), 4 have been chimerized (human constant domains replacing murine) (ReoPro, Rituxan and its 131I-labeled analogue (Zevalin), Simulect, Remicade) and 3 were chimerized and humanized (human residues being substituted for at least some mouse-specific framework residues in VH and VL) (Zenapax, Herceptin, Synagis). Fully humanized anti-CD52 (CAMPATH-1H) has also been approved by the FDA for the treatment of B-cell chronic lymphocytic leukemia and should become available in late 2001. Humanization was initially developed by Dr. Greg Winter at the MRC Laboratory of Molecular Biology (Cambridge, UK), who presented the meeting's keynote address, "Antibodies as a Paradigm for Molecular Evolution". His pioneering work in antibody phage display libraries has been reformulated into a daring approach to develop truly novel proteins with genetically paired structural elements. He described studies in combinatorial protein engineering with enormous implications for both industrial and therapeutic applications of macromolecules.

Animals↗

PubMed2003

[Clinical application of tissue engineered bone repair of human craniomaxillofacial bone defects].

OBJECTIVE: To explore the feasibility of tissue engineered bone formation in human being using human bone marrow stromal cells (hBMSCs) and the possibility of clinical repair of craniomaxillofacial bone defects with tissue engineered bone. METHODS: Total 11 patients of cranial defects and aperture piriformis bone depression were included in this study. The hBMSCs were isolated by Percoll gradient centrifugation from patient's bone marrow aspirated from iliac crest. The hBMSCs were cultured in vitro and induced to become osteogenic cells in the DMEM medium containing 10% self-serum, beta-glycerophosphate (10 nmol/L) dexamethasone (10(-8) mol/L), L-2-ascorbic acid (50 micro mol/L), and 1, 25 (OH)(2)VD(3)(10 nmol/L). Induced hBMSCs of passage 3 were harvested and seeded onto partly demineralized allogenic bone matrix (pDBM) to form a cell-scaffold construct and in vitro co-culture for 1 week. The defects were repaired with the cell-scaffold construct. In 3 cases of aperture piriformis bone depression, one side was repaired with hBMSC/pDBM, while the other side was repaired by pDBM alone. All cases were followed up for 1, 3, 6 months post-operation as short-term evaluation and 1 to 2.5 years post-operation as long-term evaluation by three-dimensional computerized tomography (3D-CT) and clinical examination. In 2 cases who received secondary surgery, extra engineered bone tissue and control pDBM were harvested at the implantation sites for histological examination and immunohistochemistry. RESULTS: 3D-CT demonstrated that engineered bone was formed in 3 to 6 months post-operation. Additionally, formed bone maintained stable up to 1 - 2 years without absorption. Histologically, engineered bones revealed their structures similar to that of normal bone in HE staining. Interestingly, endochondral ossification was also observed in engineered bone. Immunohistochemistry shows positive staining of osteonectin and osteocalcin in engineered and normal bones. In contrast, implanted pDBM was completely degraded in 3 - 6 months as revealed by 3D-CT. Histologically, degraded pDBM and fibrous tissue were observed in the sites where pDBM alone was implanted. CONCLUSIONS: Tissue engineered bone can be formed in human being. Engineered bone can be used to repair clinical bone defect with satisfactory result. Furthermore, the result of this study proves that tissue engineered bone is possible for clinical application.

Adolescent↗

PubMed1989

Carcinogenic potential of gasoline and diesel engine oils.

Used gasoline engine oils are carcinogenic in mouse skin and mutagenic in Salmonella. The toxicity of fresh gasoline engine oils and that of fresh and used diesel engine oils are less well defined. The present studies examined the dermal carcinogenic potential of a series of fresh and used oils from both gasoline and diesel engines. The used oils represented a variety of operating conditions. The objective of the study was to assess the potential carcinogenic hazards associated with exposure to these materials. The majority of the used gasoline engine oils tested were carcinogenic although one oil, collected after a relatively short drainage interval, was inactive in the dermal carcinogenesis bioassay. Additionally, polycyclic aromatic hydrocarbon (PAH) concentrations were elevated in the used oils in comparison to the fresh oils. The fresh gasoline engine oils and both the fresh and used diesel engine oil samples were noncarcinogenic, and there was little evidence of elevated PAH levels in the used diesel engine oils. The carcinogenic potency of used oils from gasoline engines was related to drainage interval, but other factors such as contribution of the fuel due to blowby and driving cycle may also have been important. The used diesel engine oils were not carcinogenic even after extended use.

Animals↗

PubMed1999

Biocommodity Engineering.

The application of biotechnology to the production of commodity products (fuels, chemicals, and materials) offering benefits in terms of sustainable resource supply and environmental quality is an emergent area of intellectual endeavor and industrial practice with great promise. Such "biocommodity engineering" is distinct from biotechnology motivated by health care at multiple levels, including economic driving forces, the importance of feedstocks and cost-motivated process engineering, and the scale of application. Plant biomass represents both the dominant foreseeable source of feedstocks for biotechnological processes as well as the only foreseeable sustainable source of organic fuels, chemicals, and materials. A variety of forms of biomass, notably many cellulosic feedstocks, are potentially available at a large scale and are cost-competitive with low-cost petroleum whether considered on a mass or energy basis, and in terms of price defined on a purchase or net basis for both current and projected mature technology, and on a transfer basis for mature technology. Thus the central, and we believe surmountable, impediment to more widespread application of biocommodity engineering is the general absence of low-cost processing technology. Technological and research challenges associated with converting plant biomass into commodity products are considered relative to overcoming the recalcitrance of cellulosic biomass (converting cellulosic biomass into reactive intermediates) and product diversification (converting reactive intermediates into useful products). Advances are needed in pretreatment technology to make cellulosic materials accessible to enzymatic hydrolysis, with increased attention to the fundamental chemistry operative in pretreatment processes likely to accelerate progress. Important biotechnological challenges related to the utilization of cellulosic biomass include developing cellulase enzymes and microorganisms to produce them, fermentation of xylose and other nonglucose sugars, and "consolidated bioprocessing" in which cellulase production, cellulose hydrolysis, and fermentation of soluble carbohydrates to desired products occur in a single process step. With respect to product diversification, a distinction is made between replacement of a fossil resource-derived chemical with a biomass-derived chemical of identical composition and substitution of a biomass-derived chemical with equivalent functional characteristics but distinct composition. The substitution strategy involves larger transition issues but is seen as more promising in the long term. Metabolic engineering pursuant to the production of biocommodity products requires host organisms with properties such as the ability to use low-cost substrates, high product yield, competitive fitness, and robustness in industrial environments. In many cases, it is likely to be more successful to engineer a desired pathway into an organism having useful industrial properties rather than trying to engineer such often multi-gene properties into host organisms that do not have them naturally. Identification of host organisms with useful industrial properties and development of genetic systems for these organisms is a research challenge distinctive to biocommodity engineering. Chemical catalysis and separations technologies have important roles to play in downstream processing of biocommodity products and involve a distinctive set of challenges relative to petrochemical processing. At its current nascent state of development, the definition and advancement of the biocommodity field can benefit from integration at multiple levels. These include technical issues associated with integrating unit operations with each other, integrating production of individual products into a multi-product biorefinery, and integrating biorefineries into the broader resource, economic, and environmental systems in which they function. We anticipate that coproduction of multiple products, for example, production of fuels, chemicals, power, and/or feed, is likely to be essential for economic viability. Lifecycle analysis is necessary to verify the sustainability and environmental quality benefits of a particular biocommodity product or process. We see biocommodity engineering as a legitimate focus for graduate study, which is responsive to an established personnel demand in an industry that is expected to grow in the future. Graduate study in biocommodity engineering is supported by a distinctive blend of intellectual elements, including biotechnology, process engineering, and resource and environmental systems.

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