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Beyond a code of ethics for bioengineers: the role of ethics in an integrated compliance program.

Developing a code of ethics for biomedical engineering professionals is a very important first step in clarifying their professional obligations and in helping to establish and maintain their professional autonomy. However, it is only that--a first step. Unless ways can be found to bring the principles contained in this code to bear on the everyday decision making of these professionals, this code will have little practical influence. One effective way to bring a code of ethics to bear on decision making is to integrate it into organizational compliance programs. Such programs often have company-specific codes of ethics attached to them, and these company-specific codes can either include the principles contained in the professional code of ethics or reference the code by title. After defining what I take to be the challenge of compliance, I consider four (4) roles that codes of ethics and ethics generally can play in helping to create and sustain programs at the organizational level that integrate ethics and compliance and thereby aim to make a practical difference in the everyday decision making of bioengineering professionals. These four roles include: framing the program, grounding the standards, achieving critical distance, and creating and sustaining an ethical organizational culture.

Biomedical Engineering↗

What is life, and what is a machine? The ontology of bioengineering.

In his Keynote address to the First Conference at Clemson University on Ethical Issues in Biomedical Engineering, George Bugliarello suggested that a most important ethical issue for bioengineering "is the positioning of the bio-machine interface." "Where," he asked, "should the biological organism end and the machine begin?" Central to this question of the limits of life and engineering is the more fundamental question of how life differs and how it is similar to a machine. This paper argues that until very recently, science, by its very nature, has treated life as if it were a machine, or has treated the parts of living systems as if they were machines. The distinctive feature of a machine is that its behavior is linear and hence predictable. On the other hand, living organisms may not be linear, but rather nonlinear systems. Thus, the interface between organism and machine may be conceived as the interface between nonlinear and linear systems.

Biomedical Engineering↗

Bilayered bioengineered skin substitute (Apligraf): a review of its use in the treatment of venous leg ulcers and diabetic foot ulcers.

UNLABELLED: The bilayered bioengineered skin substitute (BBSS) [Apligraf] is used for the treatment of venous leg ulcers and diabetic foot ulcers. It has an epidermal layer formed from human keratinocytes and a dermal layer composed of human fibroblasts in a bovine type I collagen matrix. BBSS does not contain any antigen-presenting cells such as Langerhans cells, dermal dendritic cells, endothelial cells or leucocytes. In clinical trials, there was no evidence of clinical rejection and immunological tests indicated no humoral or cellular response to the keratinocytes or fibroblasts of BBSS. Further clinical trials are required to identify the exact mechanism of action of BBSS in chronic wounds. BBSS plus compression therapy was well tolerated and was superior in efficacy to compression therapy alone in a multicentre, randomised trial in patients with venous leg ulcers. At 6 months' follow-up, complete wound healing occurred in 63 versus 49% of patients and the median time to wound closure was 61 versus 181 days. In a subgroup of patients with hard-to-heal ulcers (>1 year's duration), wound healing was achieved in significantly more patients (47 vs 19%) and the median time to wound healing was significantly shorter (181 days vs not attained). In a multicentre, randomised trial, BBSS was well tolerated and effective in patients with full-thickness neuropathic diabetic foot ulcers. Ulcer healing occurred in significantly more patients (56 vs 38%) and the median time to wound healing was shorter (65 vs 90 days) with BBSS than with saline-moistened gauze at 12 weeks' follow-up. Patients in both groups also received standard diabetic foot care. The cost effectiveness of BBSS in patients with chronic ulcers has yet to be examined in well designed, prospective clinical trials. However, according to a modelled analysis incorporating data from a multicentre randomised trial, BBSS was cost effective in patients with hard-to-heal venous leg ulcers. The average annual medical cost of managing patients with ulcers of >1 year's duration was estimated to be 20,041 US dollars per patient treated with BBSS plus compression therapy and 27,493 US dollars per patient treated with compression therapy alone (1996 costs). CONCLUSIONS: Clinical trials have shown that BBSS in conjunction with standard compression therapy was effective and well tolerated in patients with venous leg ulcers, especially patients with ulcers of >6 months' duration or that extended to the subcutaneous tissue. In addition, BBSS in conjunction with standard diabetic foot care was effective and well tolerated in patients with full-thickness neuropathic diabetic foot ulcers. BBSS represents a useful adjuvant to standard ulcer therapy in patients with venous leg ulcers or full-thickness neuropathic diabetic foot ulcers that do not respond to conventional ulcer therapy.

Clinical Trials as Topic↗

Construction and physiological studies on a stable bioengineered strain of shengjimycin.

Shengjimycin is a group of 4"-acylated spiramycins with 4"-isovalerylspiramycin as the major component, produced by recombinant S. spiramyceticus F21 harboring a 4"-O-acyltransferase gene from S. mycarofaciens 1748. A stable bioengineered strain of Streptomyces spiramyceticus WSJ-1 was constructed by integrating the 4"-O-acyltransferase gene (ist) by homologous recombination into the chromosome of the spiramycin-producing strain S. spiramyceticus F21. In this construction, a Streptomyces/E. coli shuttle plasmid pKC1139 (AmR) was used as the vector with the tsr gene used as selection marker for homologous recombination. The constructed strain, S. spiramyceticus WSJ-1,was genetically stable in production titer and proportion of components of shengjimycin as well as in maintaining the tsr selective marker when grown without selection. Southern hybridization confirmed the integrated status of the ist gene in the host genome. The production and the proportion of major component of 4"-isovalerylspiramycin of S. spiramyceticus WSJ-1 was also improved comparing with the strain harboring an autonomous plasmid -S. spiramyceticus F21/pIJ680(311) as shown by HPLC analysis. Physiological studies indicated that increase of the VDH ( valine dehydrogenase ) and LDH ( leucine dehydrogenase ) activities of WSJ-1 may be involved in this improvement.

Amino Acid Oxidoreductases↗

Scaling, dry skin and gender. A bioengineering study of dry skin.

Dry skin and scaling was studied in a group of 72 healthy volunteers by using subjective self-assessment and by clinical assessment by a dermatologist, as well as application of noninvasive bioengineering techniques to measure scaling and epidermal hydration. The study revealed that 67% of the volunteers had subjective complaints, while only 5.6% had definite clinical signs of dry skin at the time of examination. Subjective complaints were more common in women than in men (p < 0.001), though neither clinical nor objective measurements showed any sex difference, which suggests that other factors may play a role in the way men and women perceive dry skin. Subjective and clinical scores were correlated (p < 0.02), though neither was significantly correlated to objective measurements. Grading of skin scaling on D-squame tapes correlated with densitometry of the tapes (p < 0.001), as did the electrical capacitance (p < 0.001). Both clinical and objective methods can identify dry skin. However, the study showed that in healthy persons a number of irrational factors play a role in the use of moisturizers, and while these factors cannot be measured, they must be taken into account. Healthy, but dry skin is a vaguely defined clinical entity, which may explain the generally poor correlation between the two methods. This underlines the need for several methods to be used simultaneously in order to elicit complementary information.

Adult↗

[Functional role' of hemodialysis equipment in the bioengineering system of artificial purification].

The paper deals with hemodialysis equipment as a constituent of the bioengineering system for artificial blood purification. This approach allows us to objectively evaluate its functional capacities and the usefulness of objective results of hemodialysis and to provide scientific evidence for the structure of hemodialysis equipment. The artificial purification of the biological organism is presented as a variety of interrelated controlling and diagnostic processes in the controlling and actuating elements of extracorporeal artificial organs.

Biomedical Engineering↗

Construction of a stable bioengineered strain of biotechmycin.

A stable bioengineered strain of Biotechmycin (Streptomyces spiramyceticus WSJ-1) was constructed by integrating the 4"-isovaleryltransferase gene (ist) through homologous recombination into the chromosome of spiramycin-producing strain S.spiramyceticus F21. In this construction, a Streptomyces/E.coli shuttle plasmid pKC1139 (AmR) was used as the vector and tsr gene was inserted as the marker for selection of homologous recombination. This constructed strain, S.spiramyceticus WSJ-1, was genetically very stable in production titer and in the production of biotechmycin as well as in carrying tsr selective marker when grown without pressure. The fermentation of S.spiramyceticus WSJ-1 was also improved compared with the original strain harboring unintegrated plasmid. Southern hybridization confirmed the integrated status of the ist gene in the host genome.

Acyltransferases↗

Interfacial bioengineering to enhance surface biocompatibility.

This article reviews recent developments in interfacial bioengineering to improve the biocompatibility of implanted materials. It includes a discussion of biomimetic approaches to bioinert and bioactive surface coatings to improve the in vivo performance of existing medical devices.

Biocompatible Materials↗

Mechanical stretch regimen enhances the formation of bioengineered autologous cardiac muscle grafts.

BACKGROUND: Surgical repair of congenital and acquired cardiac defects may be enhanced by the use of autologous bioengineered muscle grafts. These tissue-engineered constructs are not optimal in their formation and function. We hypothesized that a mechanical stretch regimen applied to human heart cells that were seeded on a three-dimensional gelatin scaffold (Gelfoam) would improve tissue formation and enhance graft strength. METHODS AND RESULTS: Heart cells from children undergoing repair of Tetralogy of Fallot were isolated and cultured. Heart cells were seeded on gelatin-matrix scaffolds (Gelfoam) and subjected to cyclical mechanical stress (n=7) using the Bio-Stretch Apparatus (80 cycles/minute for 14 days). Control scaffolds (n=7) were maintained under identical conditions but without cyclical stretch. Cell counting, histology, and computerized image analysis determined cell proliferation and their spatial distribution within the tissue-engineered grafts. Collagen matrix formation and organization was determined with polarized light and laser confocal microscopy. Uniaxial tensile testing assessed tissue-engineered graft function. Human heart cells proliferated within the gelatin scaffold. Remarkably, grafts that were subjected to cyclical stretch demonstrated increased cell proliferation and a marked improvement of cell distribution. Collagen matrix formation and organization was enhanced by mechanical stretch. Both maximal tensile strength and resistance to stretch were improved by cyclical mechanical stretch. CONCLUSION: The cyclical mechanical stretch regimen enhanced the formation of a three-dimensional tissue-engineered cardiac graft by improving the proliferation and distribution of seeded human heart cells and by stimulating organized matrix formation resulting in an order of magnitude increase in the mechanical strength of the graft.

Absorbable Implants↗

Comparison of wide-field/deconvolution and confocal microscopy in bioengineering. Interest of multi-photon microscopy in the study of articular cartilage.

The increase in lateral and spatial resolutions is one of the major targets of research and development in the field of optical microscopies applied to living tissue. The optical geometry of Confocal Laser Scanning Microscopy (CLSM) demonstrates its undeniable advantage on conventional fluorescence microscopy by segregating the planes outside the focussing plane. The methodological and technological advances of the last five years have been fast evolving, especially with regard to the optimisation of CLSM and deconvolution process. The limited analysis in thick tissue have given rise to the development of other techniques, multi-photon excitation microscopy in particular. In this paper, we have applied these techniques on major biological applications in bioengineering (endothelial cell, chondrocyte in 3D-culture, human cartilage) and discussed the technical limitations and perspectives.

Actins↗

A bioengineering analysis of force actions at the knee in normal and pathological gait.

The paper describes a simplified bioengineering analysis for the determination of force actions at the knee joint for normal and pathological gaits. The stance phase of the gait cycle only is considered, and gravitational and inertia forces are excluded from the analysis. The anatomical and functional assumptions required for analysis are discussed. Force actions transmitted at the knee joint by the bearing surfaces, muscles and ligaments for normal individuals are presented with reference to magnitude and phasic relationship for the activity of level walking. Bearing loads transmitted at the knee joints of pathological limbs are also discussed.

Biomechanical Phenomena↗

Characterization of contact dermatitis and atopy using bioengineering techniques. A survey.

Bioengineering techniques useful in the characterization of contact dermatitis and atopy are surveyed, including non-invasive techniques for the measurement of skin colour, blood flow, skin surface temperature, skin surface contour, water barrier, and skin surface hydration. Ultrasound measurement of skin thickness and edema formation, and ultrasound cross-sectional imaging are also included. Structural and pathophysiological findings in the different types of dermatitis are outlined. Weal or hive formation is covered additionally.

Chronic Disease↗

[The preparation of human anti-HBs Fab fragment by bioengineering technique].

AIM: To prepare human anti-HBs Fab by bioengineering technique. METHODS: The specific human anti-HBs Fab gene screened from combinatorial library was cloned into plasmid pBAD/g IIIA, then positive clone was transformed into E.coli Top10. After the fermentation and expression processes, the soluble Fab fragment in the periplasm were purified by Ni-NTA-agarose affinity chromatography,and the inclusion bodies were in turn denatured, solubilized, purified and renatured. The specificity of Fab protein was confirmed by Western blot, and binding activity to HBsAg was verified by Dot blot. RESULTS: The quantity of soluble Fab protein purified from periplasm with Ni-NTA-Agarose which possessed good specificity as well as excellent binding activity to antigens was up to 80 mg per liter, but the biologically active protein acquired after renaturation of the inclusion bodies was quite small. CONCLUSION: Using pBAD/g IIIA-Top10 expression system, the soluble Fab protein with biological activity could be produced from periplasm of the E.coli Top10, and the strategy is available to prepare human anti-HBsAg Fab fragments in large quantity by gene engineering technique.

Combinatorial Chemistry Techniques↗

Development of a vector system for the expression of bioengineered proteins.

The low natural abundance of many proteins is a major factor in preventing their development as therapeutic or diagnostic tools. To circumvent this barrier, we have used synthetic oligonucleotide technology to construct a gene based on the sequence of a cDNA for human interleukin 6 (IL-6). The synthetic gene encodes a cysteine-free, bioengineered rIL-6 protein, which is expressed at high concentrations in Escherichia coli as a tripartite fusion protein. Cleavage of the fusion protein with collagenase (EC 3.4.24.8) releases a 23-kDa rIL-6 protein that can be easily purified to homogeneity. This rIL-6 protein displays a range of biological activities similar to those of natural human IL-6, as demonstrated by its ability to (a) protect cells from viral infection and (b) stimulate the synthesis of fibrinogen in rat FAZA cells.

Amino Acid Sequence↗

Auditory processing of speech and its implications with respect to prosthetic rehabilitation. The bioengineering viewpoint.

A significant approach to medical problems from a bioengineering viewpoint generally implies the description of the biological system behaviour in terms of mathematical models. Some general considerations are reported about biological mathematical models and a short summary is given about the state of the art as far as the acoustical system is concerned. Finally, a general procedure is presented which makes use of mathematical models to conceive and analyse new prosthetic aids for the severely deaf.

Auditory Pathways↗

The role of bioengineering in orthopedics.

Orthopedic bioengineering is an example of professionals in distinct disciplines applying their skills to problems that require an interdisciplinary approach. Two current research projects, the development of replacement ligaments and tendons and of an absorbable fracture fixation device, illustrate this integrated approach.

Biocompatible Materials↗

Left ventriculometry: the Minnesota experience with a bioengineering approach.

Left ventriculography is used by cardiologists, surgeons, and pharmacologists. Cardiologists use it to assess ventricular function and to scan the results of longitudinal studies to follow the course of the patient. Surgeons employ the results to appreciate changes following surgery, as improvement postbypass, and to compare the effectiveness of alternative procedures or maneuvers. Pharmacologists examine the results to assess the consequences of drug administration. In patients with ischemic heart disease, left ventriculography is an indispensable adjunct to selective coronary arteriography, and it provides anatomic and functional information important for diagnosis and for predicting the outcome of the patient. Using the results from cine left ventriculography, it is possible to calculate the EDV, ESV, SV, and EF and thus to evaluate the pump function of the left ventricle objectively, quantitatively, and reproducibly. However, these measures indicate total left ventricular function. A more detailed analysis of the cine left ventriculogram can provide specific information about the impaired segments. Methods for measuring and calculating the volume changes of the entire left ventricle were described and illustrated with their clinical implementation. Five methods of determining regional myocardial wall motion were applied to a population of subjects with normal wall motion and to patients with abnormal wall motion. The method was chosen which agreed best with the visual assessment of the cine by experienced cardiovascular radiologists. Clinical applications of regional wall motion assessment were described. A computer-compatible data base was created for roentgen images of a normally and of an abnormally contracting left ventricle, and this data base was contributed to a national repository for computer-compatible data bases. An automatic pattern recognition method was used to determine whether regional wall motion was normal or abnormal, and it was able to distinguish between these two groups satisfactorily. Current trends in ventriculography were described. A bioengineering approach has been used to solve the problem of measuring and describing the wall motion of the left ventricle of the human heart. The approach has been applied to the analysis of the contraction of the whole ventricle, regional wall motion, and the temporal pattern of wall motion. The mathematical equations underlying the analysis have been given, explained, and illustrated with examples. The implementation of the analyses using computers was discussed. The assumptions and sources of error have received particular attention.

Angiocardiography↗

Bioengineering and the skin: from standard error to standard operating procedure.

Bioengineering techniques for examination of the skin, measuring principles and sources of error relative to technique, study design, measuring conditions and variability related to test subjects and preconditioning are reviewed. Principles of validation and standard operating procedures (SOP) are discussed, including guidelines for measurement of transepidermal water loss (TEWL) and laser Doppler cutaneous blood flow. Today typical errors are not related to a measuring device but to the way it is used.

Biomedical Engineering↗