Organ Replacement Research Articles

Welcome Address

Welcome Address

3D Bioprinting: The Emergence of Programmable Biodesign.

Until recently, bioprinting was largely limited to highly interdisciplinary research teams, as the process requires significant input from specialists in the fields of materials science, engineering, and cell biology. With the advent of commercially available high-performance bioprinters, the field has become accessible to a wider range of research groups, who can now buy the hardware off the shelf instead of having to build it from scratch. As a result, bioprinting has rapidly expanded to address a wide array of research foci, which include organotypic in vitro models, complex engineered tissues, and even bioprinted microbial systems. Moreover, in the early days, the range of suitable bioinks was limited. Now, there is a plethora of viable options to suit many cell phenotypes. This rapidly evolving dynamic environment creates endless opportunities for scientists to design and construct highly complex biological systems. However, this scientific diversity presents its own set of challenges, such as defining standardized protocols for characterizing bioprinted structures, which is essential for eventual organ replacement. In this progress report, the current state-of-the-art in the field of bioprinting is discussed, with a special emphasis on recent hardware developments, bioprinting for regenerative medicine, and late-breaking nontraditional topics.

Utilization of Natural Detergent Potassium Laurate for Decellularization in Lung Bioengineering.

Recent advances in tissue engineering using decellularized organ scaffolds have expanded the possibilities for organ replacement therapy. However, detergent-based decellularization itself damages the extracellular matrix (ECM), which results in failure associated with the transplanted bioengineered organ. This study determined that potassium laurate (PL), a natural detergent, significantly reduces lung ECM damage during the decellularization process compared with protocols using sodium dodecyl sulfate. PL-decellularized lungs showed better microarchitecture preservation and low biological reactions after subcutaneous implantation. PL-decellularized scaffolds supported rat lung endothelial cell attachment/proliferation and the bioengineered lungs significantly reduced lung congestion after transplantation.

Molecular epidemiology of Colombian Histoplasma capsulatum isolates obtained from human and chicken manure samples

The thermally dimorphic fungus Histoplasma capsulatum is the causative agent of histoplasmosis, one of the most prevalent endemic mycosis in the Americas. In tropical regions, agro-ecosystems require organic matter replacement, therefore, the use of organic fertilizers has increased disregarding the fact that certain number of such fertilizers might be contaminated with the fungus, and with their handling resulting in human cases and even outbreaks of histoplasmosis. Additionally, in Colombia, chicken manure is the most common raw material used in the production of organic fertilizers. In this work, we reported the isolation of this fungus from chicken manure, and genetically compared with 42 clinical isolates. The genetically compared environmental isolates grouped together with the clinical ones. Our result suggests that chicken manure may be one of H. capsulatum infection sources. Also, the phylogenetic analyses done with other H. capsulatum isolates indicate that the Colombian isolates are widely distributed in the relational tree thus reveling towards the great genetic diversity among the H. capsulatum Colombian isolates.

Biocompatible and Antimicrobial Electrospun Membranes Based on Nanocomposites of Chitosan/Poly (Vinyl Alcohol)/Graphene Oxide.

Tissue engineering is gaining attention rapidly to replace and repair defective tissues in the human body after illnesses and accidents in different organs. Electrospun nanofiber scaffolds have emerged as a potential alternative for cell regeneration and organ replacement. In this paper, porous membranes, based on nanofibrous chitosan (CS), polyvinyl alcohol (PVA), and graphene oxide (GO), were obtained via electrospinning methodology. Three different formulations were obtained varying GO content, being characterized by Fourier Transform Infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). In vitro tests were carried out, consisting of hydrolytic degradation inside simulated biological fluid (SBF), and in vivo tests were carried out, where the material was implanted in Wistar rats’ subcutaneous tissue to determine its biocompatibility. The antibacterial activity was tested against Gram-positive bacteria Bacillus cereus and Staphylococcus aureus, and against Gram-negative Salmonella enterica and Escherichia coli, by contact of the electrospun nanofiber scaffolds above inoculum bacterial in Müeller Hinton agar with good inhibition only for scaffolds with the higher GO content (1.0%). The results confirmed good biocompatibility of the nanofibrous scaffolds after in vivo tests in Wistar rats, which evidences its high potential in applications of tissue regeneration.

No significant association between immunosuppression in solid organ transplantation and prostate cancer risk: a meta-analysis of cohort studies

Background: It is known that organ transplant recipients have a significantly higher risk for developing cancers, but the association between immunosuppression in organ transplantation and the risk for prostate cancer (PCa) remains unclear. We aimed to assess the evidence regarding the association of solid organ transplantation with PCa risk. Methods: A literature search of the PubMed, Embase, and Web of Science databases was performed up to March 2019. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using a fixed-effect or random-effect model. Results: In total, 26 articles including 33 independent population-based cohort studies with 556,812 recipients and 2,438 PCa cases were identified and included in this meta-analysis. PCa risk in the solid organ transplant recipients did not increase compared with the general population (RR=1.04; 95% CI: 0.90–1.18). Independent analysis of different kinds of organ replacements further indicated immune inhibition in the transplantation of kidney, liver, heart, and lung, and was not associated with elevated PCa risk (RR=0.89; 95% CI: 0.83–0.95; RR=0.61, 95% CI: 0.21–1.02; RR=1.70, 95% CI: 0.88–2.52; RR=0.87, 95% CI: 0.57–1.16, respectively). Conclusions: This study demonstrated that immunosuppression in solid organ transplant recipients was not associated with higher PCa risk.

Aged Acacia melanoxylon bark as an organic peat replacement in container media

The continuous search for peat substitution by local available organic materials, to reduce horticulture industry environmental foot-print, is growing worldwide. In Mediterranean region, Acacia melanoxylon bark is an abundant waste material from non-native tree species control actions, lacking suitable disposal. This study explores the potential use of A. melanoxylon bark as an alternative material for container media. Bark anatomy was characterized, the effect of different bark sieve sizes (4, 6, 8, and 10 mm) and the ageing treatment among successive periods of time (at 0, 4 and 8 weeks) were evaluated regarding substrate physical and chemical performance, as well as phytotoxic effect on tested seeds. Fresh bark was phytotoxic (cress root index < 22%) due to phenolic and extractives presence in bark material. Ageing bark during 8 weeks might eliminate those toxic elements which promoted cress roots growth equal to peat (root index > 99%). Ageing process may motivate Nitrogen immobilization which raises pH (up to 6.2) and dropped electrical conductivity (minimum of 14 mS m−1), however initial substrate amendment is required prior to potting, thus providing enough nutrients according to microbial-plant needs. Physical substrate performance was strongly correlated with particle size distribution: coarse bark (10 mm) increase air filled porosity, enhancing substrate aeration, while fine bark (4 mm) retain equal water content as commercial peat. Aged A. melanoxylon bark can be blended up to 50% with peat and produce plants as great as in commercial peat-based substrates.

Fibrosis in tissue engineering and regenerative medicine: treat or trigger?

Fibrosis is a life-threatening pathological condition resulting from a dysfunctional tissue repair process. There is no efficient treatment and organ transplantation is in many cases the only therapeutic option. Here we review tissue engineering and regenerative medicine (TERM) approaches to address fibrosis in the cardiovascular system, the kidney, the lung and the liver. These strategies have great potential to achieve repair or replacement of diseased organs by cell- and material-based therapies. However, paradoxically, they might also trigger fibrosis. Cases of TERM interventions with adverse outcome are also included in this review. Furthermore, we emphasize the fact that, although organ engineering is still in its infancy, the advances in the field are leading to biomedically relevant in vitro models with tremendous potential for disease recapitulation and development of therapies. These human tissue models might have increased predictive power for human drug responses thereby reducing the need for animal testing.

No significant association between immunosuppression in solid organ transplantation and prostate cancer risk: a meta-analysis of cohort studies.

BackgroundIt is known that organ transplant recipients have a significantly higher risk for developing cancers, but the association between immunosuppression in organ transplantation and the risk for prostate cancer (PCa) remains unclear. We aimed to assess the evidence regarding the association of solid organ transplantation with PCa risk.MethodsA literature search of the PubMed, Embase, and Web of Science databases was performed up to March 2019. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using a fixed-effect or random-effect model.ResultsIn total, 26 articles including 33 independent population-based cohort studies with 556,812 recipients and 2,438 PCa cases were identified and included in this meta-analysis. PCa risk in the solid organ transplant recipients did not increase compared with the general population (RR=1.04; 95% CI: 0.90–1.18). Independent analysis of different kinds of organ replacements further indicated immune inhibition in the transplantation of kidney, liver, heart, and lung, and was not associated with elevated PCa risk (RR=0.89; 95% CI: 0.83–0.95; RR=0.61, 95% CI: 0.21–1.02; RR=1.70, 95% CI: 0.88–2.52; RR=0.87, 95% CI: 0.57–1.16, respectively).ConclusionsThis study demonstrated that immunosuppression in solid organ transplant recipients was not associated with higher PCa risk.

Association Between the Publication of the Initiating Dialysis Early and Late Trial and the Timing of Dialysis Initiation in Canada

Published in 2010, the Initiating Dialysis Early and Late (IDEAL) randomized clinical trial, which randomized patients with an estimated glomerular filtration rate (GFR) between 10 and 15 mL/min/1.73 m2 to planned initiation of dialysis with an estimated GFR between 10 and 14 mL/min/1.73 m2 (early start) or an estimated GFR between 5 and 7 mL/min/1.73 m2 (late start), concluded that early initiation was not associated with improved survival or clinical outcomes. To assess the association between the IDEAL trial results and the proportion of early dialysis starts over time. This interrupted time series analysis used data from the Canadian Organ Replacement Register to study adult (≥18 years of age) patients with incident chronic dialysis between January 1, 2006, and December 31, 2015, in Canada, which has a universal health care system. Patients from the province of Quebec were excluded because its privacy laws preclude submission of deidentified data without first-person consent. The patients included in the study (n = 28 468) had at least 90 days of nephrologist care before starting dialysis and a recorded estimated GFR at dialysis initiation. Data analyses were performed from November 2016 to January 2019. The primary outcome was the proportion of early dialysis starts (estimated GFR >10.5 mL/min/1.73 m2), and the secondary outcomes included the proportions of acute inpatient dialysis starts, patients who started dialysis using a home modality, and patients receiving hemodialysis who started with an arteriovenous access. Measures included the trend prior to the IDEAL trial publication, the change in this trend after publication, and the immediate consequence of publication. The final cohort comprised 28 468 patients, of whom 17 342 (60.9%) were male and the mean (SD) age was 64.8 (14.6) years. Before the IDEAL trial, a statistically significant increasing trend was observed in the monthly proportion of early dialysis starts (adjusted rate ratio, 1.002; 95% CI, 1.001-1.004; P = .004). After the IDEAL trial, an immediate decrease was observed in the proportion of early dialysis starts (rate ratio, 0.874; 95% CI, 0.818-0.933; P < .001), along with a statistically significant change in trend between the pretrial and posttrial periods (rate ratio, 0.994; 95% CI, 0.992-0.996; P < .001). No statistically significant differences were found in acute inpatient dialysis initiations, the proportion of patients receiving home dialysis as the initial modality, or the proportion of arteriovenous access creation at hemodialysis initiation after the IDEAL trial publication. The publication of the IDEAL trial appeared to be associated with an immediate and meaningful change in the timing of dialysis initiation in Canada.

Use of Nanoparticles in Tissue Engineering and Regenerative Medicine.

Advances in nanoparticle (NP) production and demand for control over nanoscale systems have had significant impact on tissue engineering and regenerative medicine (TERM). NPs with low toxicity, contrasting agent properties, tailorable characteristics, targeted/stimuli-response delivery potential, and precise control over behavior (via external stimuli such as magnetic fields) have made it possible their use for improving engineered tissues and overcoming obstacles in TERM. Functional tissue and organ replacements require a high degree of spatial and temporal control over the biological events and also their real-time monitoring. Presentation and local delivery of bioactive (growth factors, chemokines, inhibitors, cytokines, genes etc.) and contrast agents in a controlled manner are important implements to exert control over and monitor the engineered tissues. This need resulted in utilization of NP based systems in tissue engineering scaffolds for delivery of multiple growth factors, for providing contrast for imaging and also for controlling properties of the scaffolds. Depending on the application, materials, as polymers, metals, ceramics and their different composites can be utilized for production of NPs. In this review, we will cover the use of NP systems in TERM and also provide an outlook for future potential use of such systems.

Smart Drug Release from Medical Devices.

Medical devices are becoming key players on health monitoring and treatment. Advances in materials science and electronics have paved the way to the design of advanced wearable, insertable, and implantable medical devices suitable for the prevention and cure of diseases and the physical or functional replacement of damaged tissues or organs. However, intimate and prolonged contact of the medical devices with the human body increases the risks of adverse foreign-body reactions and biofilm formation. Drugs can be included in/on the medical device not only to minimize the risks but also to improve the therapeutic outcomes. Drug-eluting medical devices can deliver the drug in the place where it is needed using lower doses and avoiding systemic effects. Drug-device combination products that release the drug following preestablished rates have already demonstrated their clinical relevance. The aim of this mini-review is to bring attention to medical devices that can actively regulate drug release as a function of tiny changes in their environment, caused by the pathology itself, microorganisms adhesion or some external events. Thus, endowing medical devices with stimuli-responsiveness should allow for precise, on-demand, regulated release of the ancillary drugs to expand the therapeutic performance of the medical device and also should serve as a first step to offer personalized solutions to each patient. Main sections deal with smart drug-eluting medical devices that are sensitive to infection-related stimuli, natural healing processes, mechanical forces, electric fields, ultrasound, near-infrared radiation, or chemicals such as vitamin C.

Three-Dimensional Bioprinting of Cell-Laden Constructs Using Polysaccharide-Based Self-Healing Hydrogels.

Development of biomaterial-based bioinks is critical for replacement and/or regeneration of tissues and organs by three-dimensional (3D) printing techniques. However, the number of 3D-printable biomaterials in practical use remains limited despite the rapid development of 3D printing techniques. Controlling the flow properties of bioinks and mechanical properties of the resultant printed objects is key considerations in the design of biomaterial-based bioinks for practical applications. In this study, a printable hydrogel comprising biocompatible polysaccharides that has potential for cartilage regeneration via tissue engineering approaches was designed. Self-healing hydrogels were prepared from partially oxidized hyaluronate (OHA) and glycol chitosan (GC) in the presence of adipic acid dihydrazide (ADH). The self-healing ability of OHA/GC/ADH hydrogels was attributed to the combination of two dynamic bonds in the gels, including imine bonds obtained via a Schiff base reaction between OHA and GC, as well as acylhydrazone bonds formed by the reaction between OHA and ADH. The OHA/GC/ADH hydrogels did not require any postgelation or additional cross-linking processes for use in the fabrication of 3D constructs using an extrusion-based 3D printer. The concentrations and molecular weights of the constituent polymers were found to be critical parameters affecting the flow and mechanical properties of the self-healing hydrogels, which showed great potential as bioinks for fabricating cell-laden structures using a 3D printer. The expression of chondrogenic marker genes such as SOX-9 and collagen type II of ATDC5 cells encapsulated in the OHA/GC/ADH hydrogel was not significantly affected by the printing process. This self-healing hydrogel system may have the potential in tissue engineering applications, including cartilage regeneration.

Late Quaternary sediments on the carbonate platform off western India: Analogues of ancient platform carbonates

The Late Quaternary carbonate sediments and sedimentary rocks from the platform off western India were reviewed for their genesis and relationship with their ancient counter parts. Sub-marine cemented and vadose diagenetic limestones were recovered at different locations on the platform and, neomorphic limestones and caliche pisolites were recovered on the continental shelf south of the platform. Dolomites on the platform were primary and formed by microbial processes under hypersaline, sulphate-reducing conditions during the lowered sea levels. Aragonite ooids were formed from the mineralization of microbial filaments that enveloped their cortex portions. Phosphorites were found in organic-rich, aragonite muds on the continental slope adjacent to the platform and formed from the microbial mineralization of organic matter and replacement of carbonate by apatite during early diagenesis. Microbial processes thus played an important role in the formation of dolomites, ooids and phosphorites reported here and those in ancient deposits. Halimeda bioherms on the platform were grown luxuriantly from the nutrients brought by upwelling currents during the Late Pleistocene–Early Holocene sea level transgression and are similar to the Holocene–Recent deposits in the Indo-Pacific region. Lime muds were bio-detrital and formed primarily from the disintegration of Halimeda bioherms and carbonate skeletal on the platform and then exported to the slope. They resemble fine-grained limestones abundantly reported in ancient platforms. Thus, the different carbonate components on the platform are genetically related to their ancient ones and serve as Late Quaternary analogues for the ancient platform carbonates.

Functional ectodermal organ regeneration as the next generation of organ replacement therapy.

In this decade, substantial progress in the fields of developmental biology and stem cell biology has ushered in a new era for three-dimensional organ regenerative therapy. The emergence of novel three-dimensional cell manipulation technologies enables the effective mimicking of embryonic organ germ formation using the fate-determined organ-inductive potential of epithelial and mesenchymal stem cells. This advance shows great potential for the regeneration of functional organs with substitution of complete original function in situ. Organoids generated from multipotent stem cells or tissue stem cells via establishment of an organ-forming field can only partially recover original organ function owing to the size limitation; they are considered ‘mini-organs’. Nevertheless, they hold great promise to realize regenerative medicine. In particular, regeneration of a functional salivary gland and an integumentary organ system by orthotopic and heterotopic implantation of organoids clearly points to the future direction of organ regeneration research. In this review, we describe multiple strategies and recent progress in regenerating functional three-dimensional organs, focusing on ectodermal organs, and discuss their potential and future directions to achieve organ replacement therapy as a next-generation regenerative medicine.

Artificial Organs 2018: A Year in Review.

In this Editor's Review,articles published in 2018 are organized by category and summarized. We provide a briefreflection of the research and progress in artificial organs intended to advance and better human life while providing insight for continued application of these technologies and methods. Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery,and Regeneration from all over the world. Peer-reviewed special issues this year included contributions from the 13thInternational Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Perfusion edited by Dr. Akif Undar, and the 25th Congress of the International Society for Mechanical Circulatory Support edited by Dr. Marvin Slepian. Additionally, many editorials highlighted the worldwide survival differences in hemodialysis and perspectives on mechanical circulatory support and stem cell therapies for cardiac support. We take this time also to express our gratitudeto our authors foroffering their work to this journal. Weoffer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons for their expert attention and support in the production andmarketing of Artificial Organs. We look forward to reporting further advances in the coming years.

Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

The pressure towards innovation and creation of new model systems in regenerative medicine and cancer research has fostered the development of novel potential therapeutic applications. Kidney injuries provoke a high request of organ transplants making it the most demanding system in the field of regenerative medicine. Furthermore, renal cancer frequently threaten patients’ life and aggressive forms still remain difficult to treat. Ethical issues related to the use of embryonic stem cells, has fueled research on adult, patient-specific pluripotent stem cells as a model for discovery and therapeutic development, but to date, normal and cancerous renal experimental models are lacking. Several research groups are focusing on the development of organoid cultures. Since organoids mimic the original tissue architecture in vitro, they represent an excellent model for tissue engineering studies and cancer therapy testing. We established normal and tumor renal cell carcinoma organoids previously maintained in a heterogeneous multi-clone stem cell-like enriching medium. Starting from adult normal kidney specimens, we were able to isolate and propagate organoid 3D-structures composed of both differentiated and undifferentiated cells while expressing nephron specific markers. Furthermore, we were capable to establish organoids derived from cancer tissues although with a success rate inferior to that of their normal counterpart. Cancer cultures displayed epithelial and mesenchymal phenotype while retaining tumor specific markers. Of note, tumor organoids recapitulated neoplastic masses when orthotopically injected into immunocompromised mice. Our data suggest an innovative approach of long-term establishment of normal- and cancer-derived renal organoids obtained from cultures of fleshly dissociated adult tissues. Our results pave the way to organ replacement pioneering strategies as well as to new models for studying drug-induced nephrotoxicity and renal diseases. Along similar lines, deriving organoids from renal cancer patients opens unprecedented opportunities for generation of preclinical models aimed at improving therapeutic treatments.

Tooth bioengineering from single cell suspensions

Recent advances in bioengineering and biomaterials, along with knowledge deriving from the fields of developmental biology and stem cell research, have rendered feasible functional replacement of full organs. Here, we describe the methodology for bioengineering a tooth, starting from embryonic epithelial and mesenchymal single cell suspensions. In addition, we describe the subsequent steps of processing this minute structure for use in applications such as histological examination, immunofluorescence and in situ hybridisation. This methodology can be used for any minute structure that needs to be used in paraffin blocks.•Detailed methodology for reproducible and reliable results•Extra step to ensure single cell populations•Subsequent minute structure processing for histological analysis

Tissue Engineering in Orthodontics-Clarion Call or Siren Song

Tissue engineering is a novel and exciting field that aims to re-create functional, healthy tissues and organs in order to replace diseased, dying, or dead tissues. The field has developed due to the inadequate supply of organs and tissues for patients requiring organ and tissue replacement. The fields of tissue engineering and orthodontics share a common general objective of applying scientific principles in conjunction with advanced technologies to achieve or restore tissue function and esthetics. For craniofacial anomalies, Stem cells have been applied to regenerate hard tissue (such as treatment of alveolar cleft) and soft tissue (such as treatment of hemifacial macrosomia). However, the predictable reconstruction of the innate organisation and function of whole teeth as well as their periodontal structures remains challenging.

Cell Versus Chemokine Therapy Effects on Cell Mobilization to Chronically Dysfunctional Urinary Sphincters of Nonhuman Primates.

PurposeA major question remaining in approaches to tissue engineering and organ replacement is the role of native mobilized native cells in the regeneration process of damaged tissues and organs. The goal of this study was to compare the cell mobilizing effects of the chemokine CXCL12 and cell therapy on the urinary sphincter of nonhuman primates (NHP) with chronic intrinsic urinary sphincter dysfunction.MethodsEither autologous lenti-M-cherry labeled skeletal muscle precursor cells (skMPCs) or CXCL12 were injected directly into the sphincter complex of female NHPs with or without surgery-induced chronic urinary sphincter dysfunction (n=4/treatment condition). All monkeys had partial bone marrow transplantation with autologous lenti-green fluorescent protein (GFP) bone marrow cells prior to treatment. Labeled cells were identified, characterized and quantified using computer-assisted immunohistochemistry 6 months posttreatment.ResultsGFP-labeled bone marrow cells (BMCs) were identified in the bone marrow and both BMCs and skMPCs were found in the urinary sphincter at 6-month postinjection. BMCs and skMPCs were present in the striated muscle, smooth muscle, and lamina propria/urothelium of the sphincter tissue. Sphincter injury increased the sphincter content of BMCs when analyzed 6-month postinjection. CXCL12 treatment, but not skMPCs, increased the number of BMCs in all layers of the sphincter complex (P<0.05). CXCL12 only modestly (P=0.15) increased the number of skMPCs in the sphincter complex.ConclusionsThis dual labeling methodology now provides us with the tools to measure the relative number of locally injected cells versus bone marrow transplanted cells. The results of this study suggest that CXCL12 promotes mobilization of cells to the sphincter, which may contribute more to sphincter regeneration than injected cells.