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At least 991 records · Page 55Linked to original sources
PubMed2001

In vitro construction of a potential skin substitute through direct human keratinocyte plating onto decellularized glycerol-preserved allodermis.

This work demonstrates that glycerol-preserved acellular allodermis can be used as support for the proliferation of human keratinocytes and that the characteristics of this bioengineered tissue suggest its possible use as a permanent skin substitute for therapeutic challenges such as extensive burns as well as its possible use as an in vitro model for pharmacological studies. The removal of all basal membrane components during preparation of the dermal support also provides an original in vitro situation that allows observation of the reorganization of the dermal-epidermal junction. The tissue composite obtained is constituted of dermis covered by a well attached, multistratified epithelium with morphological characteristics that resemble human epidermis as evidenced by light and transmission electron microscopy, including the neoformation, albeit incomplete, of the dermal-epidermal junction. Assessment of involucrin and cytokeratin 14 expression by immunohistochemical assays established differentiation patterns. Both immerse and air-liquid interface culture systems were tested.

Culture Techniques↗
PubMed2000

Emerging cell and molecular strategies for the study and treatment of painful peripheral neuropathies.

Pharmacologic treatment for the symptoms of painful neuropathy has been problematic, because there has been limited understanding of the underlying etiologies and systemic levels that an effective dose can have on multiple side effects. The use of molecular methods, such as gene deletion from knockout mice and cellular minipumps for delivery of biologic antinociceptive molecules, has led to a better understanding of the underlying mechanisms of the induction of intractable neuropathic pain. The initiation of an excitatory cascade after injury or disease leads to the induction of various second messenger systems, loss or down-regulation of the endogenous inhibitory spinal GABA system and central sensitization, causing such pain. The development and use of cellular minipumps, immortalized cell lines bioengineered to secrete various antinociceptive molecules for the reversal of neuropathic pain, makes cellular therapy a strategy for clinical use in the next few years. The development of molecular "disimmortalization" technologies will make the use of such engineered cell lines safe for human use. Direct somatic gene transfer for neuropathic pain will eventually overcome the problems associated with transplantation of non-autologous and xenogenic cells. These virus-mediated methods, although at the early stages of evolution and use, offer large-scale production of biologic agents that can be conveniently and confidently used for the long-term relief of chronic neuropathic pain in a clinical setting, without systemic effects or surgical interventions.

Animals↗
PubMed2003

The future of recombinant coagulation factors.

Hemophilias A and B are X chromosome-linked bleeding disorders, which are mainly treated by repeated infusions of factor (F)VIII or FIX, respectively. In the present review, we specify the limitations in expression of recombinant (r)FVIII and summarize the bioengineering strategies that are currently being explored for constructing novel rFVIII molecules characterized by high efficiency expression and improved functional properties. We present the strategy to prolong FVIII lifetime by disrupting FVIII interaction with its clearance receptors and demonstrate how construction of human-porcine FVIII hybrid molecules can reduce their reactivity towards inhibitory antibodies. While the progress in improving rFIX is impeded by low recovery rates, the authors are optimistic that the efforts of basic science may ultimately lead to higher efficiency of replacement therapy of both hemophilias A and B.

Factor IX↗
PubMed2004

Impact of functional genomics and proteomics on radionuclide imaging.

The assessment of gene function following the completion of human genome sequencing may be performed using radionuclide imaging procedures. These procedures are needed for the evaluation of genetically manipulated animals or newly designed biomolecules, which requires a thorough understanding of physiology, biochemistry, and pharmacology. The experimental approaches will involve many new technologies, including in vivo imaging with single photon emission computed tomography and positron emission tomography. Nuclear medicine procedures may be applied for the determination of gene function and regulation using established and new tracers, or using in vivo reporter genes, such as genes encoding enzymes, receptors, antigens, or transporters. Visualization of in vivo reporter gene expression can be performed using radiolabeled substrates, antibodies, or ligands. Combinations of specific promoters and in vivo reporter genes may deliver information about the regulation of the corresponding genes. Furthermore, protein-protein interactions and activation of signal transduction pathways may be visualized noninvasively. The role of radiolabeled antisense molecules for the analysis of messenger ribonucleic acid (RNA) content has to be investigated. However, possible applications are therapeutic intervention using triplex oligonucleotides with therapeutic isotopes, which can be brought near to specific deoxyribonucleic acid sequences to induce deoxyribonucleic acid strand breaks at selected loci. Imaging of labeled siRNA makes sense if these are used for therapeutic purposes to assess the delivery of these new drugs to their target tissue. Pharmacogenomics will identify new surrogate markers for therapy monitoring, which may represent potential new tracers for imaging. Drug distribution studies for new therapeutic biomolecules are needed at least during preclinical stages of drug development. New treatment modalities, such as gene therapy with suicide genes, will need procedures for therapy planning and monitoring. Finally, new biomolecules will be developed by bioengineering methods, which may be used for the isotope-based diagnosis and treatment of disease.

Animals↗
PubMed2001

Implant infections: a haven for opportunistic bacteria.

The insertion of implants and medical devices has emerged as a common and often life-saving procedure. A current estimate of the rate of total hip replacement in the world is approximately one million a year, and knee replacements more than 250000. More than 30% of hospitalized patients have one or more vascular catheters in place. More than 10% of hospitalized patients have an indwelling urinary catheter. Some patients require multiple joint replacements. In the United States, approximately 2 million nosocomial infections cost nearly $11 billion annually. Exposure to invasive medical devices is one of the most important risk factors.(1)Devices predispose to infection by damaging or invading epithelial or mucosal barriers and by supporting growth of micro-organisms, thus serving as reservoirs. Invasive medical devices impair host defence mechanisms and, when contaminated, can result in resistant chronic infection or tissue necrosis, the major objections to extended use of implant devices. Implant devices today account for approximately 45% of all nosocomial infections.(2)Implant infections are extremely resistant to antibiotics and host defences and frequently persist until the implant is removed, which is the standard therapy. Tissue damage caused by surgery and foreign body implantation further increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators; these are enhanced by bacterial activity and toxins.(3)The ability of bacteria such as Staphylococcus epidermidis, which are otherwise virtually avirulent, to escape from host defences and antibiotic therapy, has led to the development of alternative methods of control such as infection-resistant materials acting as antimicrobial drug-delivery systems. By these methods, there is a sustained delivery of antimicrobial drugs into the local micro-environment of implants, which avoids systemic side-effects and exceeds usual systemic concentrations by several orders of magnitude. Bioengineering of hybrid implant materials in order to achieve optimal performance and to prevent inflammatory reactions and interface cellular disorganization is a field undergoing rapid development. Hybrid materials that slowly deliver antimicrobial drugs may reduce implant infections in the future.

Anti-Bacterial Agents↗
PubMed2002

Engineering a composite neotrachea with surgical adhesives.

BACKGROUND/PURPOSE: Reconstructive surgery often is limited by the availability of normal tissue. Tissue engineering provides promise in the development of "artificial tissues." The purpose of this study was to test the efficacy and viability of the use of a biologic surgical adhesive TISSEEL in combining engineered bronchial epithelium with engineered cartilage. METHODS: Using isolated human cells, bronchial epithelium and mature cartilage were engineered. Using a contact adhesive technique, TISSEEL was used to biologically fuse the bronchial epithelium and the cartilage. The fused composite then was supported for 5 days in tissue culture. The mechanical properties of the adhesion were tested, and the construct was studied morphologically to assess viability of the cartilage and the bronchial epithelium. The bronchial epithelium showed a normal cell size (337.2 microm2) and epithelial thickness (46.47 microm). RESULTS: TISSEEL was effective in fusing the epithelium to the cartilage. The construct remained viable for 5 days in culture. There was no difference in the dimensions of the bronchial epithelium or the epithelial cells. Mechanical adhesion was achieved. CONCLUSIONS: Biologically compatible fibrin glue is an effective surgical adhesive that allows the tissue types to be fused while remaining viable and morphologically accurate. Surgical adhesives may show promise in the development of composite tissue development in the field of bioengineering.

Biodegradation, Environmental↗
PubMed2000

Vascular osteomuscular autograft prefabrication using coral, type I collagen and recombinant human bone morphogenetic protein-2.

In 20 male Sprague-Dawley rats, 10 pieces of L-shaped coral combined with type I collagen and recombinant human bone morphogenetic protein-2 (rhBMP-2) and 10 discs (diameter 5 mm) were wrapped in the gracilis muscle, and left pedicled on the femoral vessels. Untreated coral was buried in muscle at a distant control site in 4 animals. After 3 weeks, autografts were examined for the shape of new bone, vascular patency, and induction of bone. In all grafts in viable tissue, heterotopic bone was formed. The shape of the new bone was the same as that of the coral, and there was no significant inflammatory reaction. Part of the coral in the composite was absorbed. Bone was not formed in any of the control sites. Coral and type 1 collagen are effective as a carrier for BMP to prefabricate vascular osteomuscular autografts with designed shape. There is a potential clinical application for BMP to bioengineer microvascular free flaps with intrinsic skeletal muscle for maxillofacial reconstruction.

Animals↗
PubMed2003

The role of ultrasound in monitoring reconstruction of mandibular continuity defects using osteogenic protein-1 (rhOP-1).

Introducing bone bioengineering concepts in craniofacial surgery demands development of novel imaging strategies, which overcome the shortcomings of radiography such as exposure to ionizing radiation. This study is aimed to investigate the usefulness of ultrasonography (US) in monitoring reconstruction of continuity osteoperiosteal mandibular defects in sheep using rhOP-1. The study was conducted on six adult sheep in which a critical size defect was created at the body of the mandible and was reconstructed using rhOP-1 with type-I collagen as a carrier. Ultrasound images were used to assess onset of bone formation, contour, and surface topography. The results were then compared to corresponding plain radiographs and to post-mortem observations. US showed bone union in all the subjects that concurred with radiographic and post-mortem examinations. US was superior to plain radiography in monitoring early events of ossification. However, it was relatively less efficient in describing the contour of the newly formed bone. It was possible to describe the pattern of bone formation and the dynamic changes in contour and surface topography via US during the follow-up period. In experienced hands, ultrasonography can offer valuable information about bone healing comparable with those obtained by plain radiography. US may replace plain radiography in becoming a routinely used tool for monitoring bone healing in selected sites of the craniofacial skeleton.

Animals↗
PubMed2002

Signaling pathways that influence extracellular remodeling.

BACKGROUND: Remodeling of myocardial tissue requires a rearrangement of cells and extracellular matrix to form the new geometry through processes that are incompletely defined. Exploring new pathways beyond neurohormonal inhibition is essential for developing new therapies for the growing epidemic of heart failure. METHODS: One strategy relies on the discovery that progressive ventricular dilation requires matrix metalloproteinases, a family of enzymes that degrade components of matrix but may also participate in activation or release of signaling molecules. Here we will briefly review evidence that matrix metalloproteinase inhibition represents a potential strategy for preventing heart failure. CONCLUSION: Future applications for understanding cell-matrix interactions, including discovering new pathways with proteomics, will also be discussed. Finally, we propose that defining matrix-remodeling events at the level of the membrane and matrix receptors will be essential, and that new bioengineering tools will provide us with the necessary methods.

Extracellular Matrix↗
PubMed1999

The oxidative stress hypothesis of atherosclerosis: cause or product?

The oxidative stress hypothesis postulates that endogenous free radicals of unknown origin, possibly derived from mural cells, oxidize low density lipoproteins and that oxidation products are allegedly responsible for initiation and progression of atherosclerosis. The thesis fails to explain its topography, site specific severity and the iatrogenic and experimental hemodynamic induction of atherosclerosis under conditions complying with the logic of Koch's postulates. Free radicals are generated by biomechanical scission of macromolecules and polymers, the biophysical mechanism underlying bioengineering fatigue in atherogenesis with oxidative damage a secondary, contributory factor to mural pathology. The plentiful supply of antioxidants negates oxidative stress as the dominant factor in atherogenesis.

Antioxidants↗
PubMed2005

Reconstruction options for pediatric bone tumors about the knee.

The surgical decisions involved with high-grade sarcoma surgery about the knee in pediatric patients are complicated. The orthopedic oncologist must have experience as well as a great deal of insight into the intricacies of each procedure and the wishes and demands of patients--not only while they are young but in into their adult life. It is difficult to predict the interests and vocation young patients will choose as their lives progress. However, if the patient qualifies as a candidate for limb preservation, the functional and cosmetic results obtained by limb preservation seem to be preferred. Amputation and rotationplasty should be reserved for patients who are not candidates for limb preservation or who are in an otherwise salvage situation. The prognosis for quality of life and limb after treatment for bone sarcomas has increased dramatically during the past decade. Survival approaching the 70% to 90% range can be expected, with >90% of those patients having limb preservation surgery. With further advancements in the biologic control of tissue healing, bioengineering, and prosthetic design and implantation, the future of these patients continues to be optimistic.

Arthroplasty, Replacement, Knee↗
PubMed2003

[Permissive anemia].

Current data demonstrate a lack of support for allogeneic transfusion as a reliable means of delivering oxygen. For the ICU patient tolerance of anemia along with aggressive erythropoitin plus iron therapies can restore hemoglobin levels to normal earlier and with fewer morbidities and possibly enhanced survival than by allogeneic transfusion. Additional evidence on anemia treatment comes from case report studies where transfusions are prohibited and patients survived extremely low hemoglobin levels. While synthetic and bioengineered temporary oxygen carriers may soon be approved for clinical use, the current treatment of anemia remains permissive for the conscientious and informed physician. In the past, anemia meant an almost mandatory transfusion. Now, evidence provides the clinician with sufficient alternatives to treat anemic patients without the use of bank blood products at lower costs with excellent survival and with evidence accumulating to suggest better outcomes.

Anemia↗
PubMed2004

Prevention of experimentally induced irritant contact dermatitis by extracts of Isatis tinctoria compared to pure tryptanthrin and its impact on UVB-induced erythema.

Lipophilic extracts of Isatis tinctoria L. exhibit significant activity against several clinically relevant targets of inflammation. The alkaloid tryptanthrin was identified as one of the active principles in woad and characterised as a potent dual inhibitor of COX-2 and 5-LOX. Here, the anti-inflammatory efficacy of topical application of three different Isatis extracts and tryptanthrin was investigated in human volunteers. Two different models were used, namely the sodium lauryl sulphate (SLS)-induced irritant contact dermatitis (ICD) and UVB-induced erythema. Twenty healthy volunteers without any skin disease participated in the study. Cumulative irritant contact dermatitis was induced on test fields on the volunteers' backs by twice daily application of 0.5 % sodium lauryl sulphate over a period of four days. Half of the test fields were treated with the test substances during the eliciting phase, while the remaining test fields were treated over a period of 4 days after induction of dermatitis. In the second model, a UVB erythema on the volunteers' lower backs was induced using the double minimal erythema dose (MED). Twenty-four hours after irradiation the test fields were treated with the test substances over a period of 3 days. All reactions were assessed visually and by non-invasive bioengineering methods (evaporimetry and chromametry). Treatment with extracts during the ICD eliciting phase led to a significantly smaller increase of visual scores and transepidermal water loss compared to the untreated test field. For tryptanthrin this benefit was also observed, but the improvement was not statistically significant. When treatment was performed after completing the eliciting phase, accelerated resolution of the irritant reaction could not be observed. In the UVB erythema model anti-inflammatory effects of the test substances were not observed.

Adolescent↗
PubMed2004

Coagulation factors with improved properties for hemophilia gene therapy.

Hemophilias A and B are X-linked bleeding disorders that result in a qualitative or quantitative deficiency in coagulation factors VIII (FVIII) and IX (FIX), respectively. Affected patients experience significant morbidity as a result of repeated joint hemorrhages and subsequent arthropathy, and there is increased mortality related to life-threatening bleeding events. The mainstay of therapy is episodic or prophylactic infusions of plasma-derived or recombinant FVIII or FIX. However, gene transfer holds the promise of maintaining plasma levels of FVIII or FIX high enough to prevent the development of joint disease and reduce the risk of life-threatening bleeds or possibly even achieving normal plasma levels. Human gene therapy trials thus far have fallen short of this goal. This review summarizes the inherent limitations in expression of recombinant FVIII and the bioengineering strategies that are currently being explored for constructing novel recombinant FVIII molecules that have improved function. Current strategies for FVIII include increasing mRNA levels, improving secretion efficiency, increasing the rate of thrombin activation, stabilization of the activated form of FVIII, and strategies to prolong FVIII half-life in plasma by disrupting FVIII interaction with its clearance receptors. Strategies to improve the function of FIX include increasing the mRNA levels, reducing interaction with collagen IV, and increasing the specific activity. These novel molecules partnered with advances in gene transfer vector design and delivery may ultimately achieve persistent expression of FVIII and FIX, leading to an effective long-term treatment strategy for the hemophilias.

Factor IX↗
PubMed1994

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.

BACKGROUND: Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS: We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS: One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS: In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

Adolescent↗
PubMed1998

Using electrical noise to enhance the ability of humans to detect subthreshold mechanical cutaneous stimuli.

Stochastic resonance (SR) is a phenomenon wherein the response of a nonlinear system to a weak input signal is optimized by the presence of a particular, nonzero level of noise. Our objective was to demonstrate cross-modality SR in human sensory perception. Specifically, we were interested in testing the hypothesis that the ability of an individual to detect a subthreshold mechanical cutaneous stimulus can be significantly enhanced by introducing a particular level of electrical noise. Psychophysical experiments were performed on 11 healthy subjects. The protocol consisted of the presentation of: (a) a subthreshold mechanical stimulus plus electrical noise, or (b) no mechanical stimulus plus electrical noise. The intensity of the electrical noise was varied between trials. Each subject's ability to identify correctly the presence of the mechanical stimulus was determined as a function of the noise intensity. In 9 of the 11 subjects, the introduction of a particular level of electrical noise significantly enhanced the subject's ability to detect the subthreshold mechanical cutaneous stimulus. In 2 of the 11 subjects, the introduction of electrical noise did not significantly change the subject's ability to detect the mechanical stimulus. These findings indicate that input electrical noise can serve as a negative masker for subthreshold mechanical tactile stimuli, i.e., electrical noise can increase the detectability of weak mechanical signals. Thus, for SR-type effects to be observed in human sensory perception, the noise and stimulus need not be of the same modality. From a bioengineering and clinical standpoint, this work suggests that an electrical noise-based technique could be used to improve tactile sensation in humans when the mechanical stimulus is around or below threshold. (c) 1998 American Institute of Physics.

Journal Article↗
PubMed1998

Enhancing aperiodic stochastic resonance through noise modulation.

We show that the conventional stochastic resonance (SR) effect for aperiodic signals in a model neuron can be enhanced by modulating the intensity of the input noise (which could be introduced artificially in bioengineering applications) with either the input signal or the unit's output rate signal. We analyze SR enhancement theoretically and numerically. We discuss how this work provides the theoretical foundation for the development of an optimal noise-based technique for enhancing sensory function. (c) 1998 American Institute of Physics.

Journal Article↗
PubMed2004

A first-principles density-functional calculation of the electronic and vibrational structure of the key melanin monomers.

We report first-principles density-functional calculations for hydroquinone (HQ), indolequinone (IQ), and semiquinone (SQ). These molecules are believed to be the basic building blocks of the eumelanins, a class of biomacromolecules with important biological functions (including photoprotection) and with the potential for certain bioengineering applications. We have used the difference of self-consistent fields method to study the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, Delta(HL). We show that Delta(HL) is similar in IQ and SQ, but approximately twice as large in HQ. This may have important implications for our understanding of the observed broadband optical absorption of the eumelanins. The possibility of using this difference in Delta(HL) to molecularly engineer the electronic properties of eumelanins is discussed. We calculate the infrared and Raman spectra of the three redox forms from first principles. Each of the molecules have significantly different infrared and Raman signatures, and so these spectra could be used in situ to nondestructively identify the monomeric content of macromolecules. It is hoped that this may be a helpful analytical tool in determining the structure of eumelanin macromolecules and hence in helping to determine the structure-property-function relationships that control the behavior of the eumelanins.

Benzoquinones↗