Search Results (11)

This study investigated the long-term patency of regenerative Biotube grafts and discusses their feasibility as an alternative to autologous vein grafts for peripheral artery disease. Six Biotubes with a diameter of 4 mm were autologously fabricated in recipients using in vivo tissue engineering (in-body tissue architecture) technology and implanted as carotid artery bypass grafts in a goat model. All six grafts remained patent at 6 months despite exceeding 10 cm in length, demonstrating their biocompatibility and durability. Histological analysis revealed neointima formation, endothelialization, and minimal inflammation. However, in one goat, a graft developed stenosis, while another showed dilatation. These findings demonstrate the use of Biotubes as a viable option for peripheral vascular reconstruction as tissue-engineered vascular grafts. However, further optimization is needed to address emerging issues with their use, such as stenosis and aneurysm formation, to improve long-term patency. Full article

Urinary tract diseases are common in cats, and often require surgical reconstruction. Here, to explore the possibility of urinary tract reconstruction in cats using in-body tissue architecture (iBTA), biosheets fabricated using iBTA technology were implanted into the feline bladder and the regeneration process was histologically evaluated. The biosheets were prepared by embedding molds into the dorsal subcutaneous pouches of six cats for 2 months. A section of the bladder wall was removed, and the biosheets were sutured to the excision site. After 1 and 3 months of implantation, the biosheets were harvested and evaluated histologically. Implantable biosheets were formed with a success rate of 67%. There were no major complications following implantation, including tissue rejection, severe inflammation, or infection. Urinary incontinence was also not observed. Histological evaluation revealed the bladder lumen was almost entirely covered by urothelium after 1 month, with myofibroblast infiltration into the biosheets. After 3 months, the urothelium became multilayered, and mature myocytes and nerve fibers were observed at the implantation site. In conclusion, this study showed that tissue reconstruction using iBTA can be applied to cats, and that biosheets have the potential to be useful in both the structural and functional regeneration of the feline urinary tract. Full article

Autologous-engineered artificial tissues constitute an ideal alternative for radical surgery in terms of natural anticoagulation, self-repair, tissue regeneration, and the possibility of growth. Previously, we focused on the development and practical application of artificial tissues using “in-body tissue architecture (iBTA)”, a technique that uses living bodies as bioreactors. This study aimed to further develop iBTA by fabricating tissues with diverse shapes and evaluating their physical properties. Although the breaking strength increased with tissue thickness, the nominal breaking stress increased with thinner tissues. By carving narrow grooves on the outer periphery of an inner core with narrow grooves, we fabricated approximately 2.2 m long cord-shaped tissues and net-shaped tissues with various designs. By assembling the two inner cores inside the branched stainless-steel pipes, a large graft with branching was successfully fabricated, and its aortic arch replacement was conducted in a donor goat without causing damage. In conclusion, by applying iBTA technology, we have made it possible, for the first time, to create tissues of various shapes and designs that are difficult using existing tissue-engineering techniques. Thicker iBTA-induced tissues exhibited higher rupture strength; however, rupture stress was inversely proportional to thickness. These findings broaden the range of iBTA-induced tissue applications. Full article

Securing high-quality cell sources is important in regenerative medicine. In this study, we developed a device that can accumulate autologous stem cells in the body. When small wire-assembled molds were embedded in the dorsal subcutaneous pouches of beagles for several weeks, collagen-based tissues with minimal inflammation formed inside the molds. At 3 weeks of embedding, the outer areas of the tissues were composed of immature type III collagen with large amounts of cells expressing SSEA3 or SSEA4 markers, in addition to growth factors such as HGF or VEGF. When separated from the tissues by collagenase treatment, approximately four million cells with a proportion of 70% CD90-positive and 20% SSEA3- or SSEA4-positive cells were recovered from the single mold. The cells could differentiate into bone or cartilage cells. The obtained cell-containing tissues are expected to have potential as therapeutic materials or cell sources in regenerative medicine. Full article

Introduction: Chronic wounds caused by diabetes or lower-extremity artery disease are intractable because the wound healing mechanism becomes ineffective due to the poor environment of the wound bed. Biosheets obtained using in-body tissue architecture (iBTA) are collagen-based membranous tissue created within the body and which autologously contain various growth factors and somatic stem cells including SSEA4-posituve cells. When applied to a wound, granulation formation can be promoted and epithelialization may even be achieved. Herein, we report our clinical treatment experience with seven cases of intractable diabetic foot ulcers. Cases: Seven patients, from 46 to 93 years old, had large foot ulcers including in the heel area, which were failing to heal with standard wound treatment. Methods: Two or four Biosheet-forming molds were embedded subcutaneously in the chest or abdomen, and after 3 to 6 weeks, the molds were removed. Biosheets that formed inside the mold were obtained and applied directly to the wound surface. Results: In all cases, there were no problems with the mold’s embedding and removal procedures, and Biosheets were formed without any infection or inflammation during the embedding period. The Biosheets were simply applied to the wounds, and in all cases they adhered within one week, did not fall off, and became integrated with the wound surface. Complete wound closure was achieved within 8 weeks in two cases and within 5 months in two cases. One patient was lost due to infective endocarditis from septic colitis. One case required lower leg amputation due to wound recurrence, and one case achieved wound reduction and wound healing in approximately 9 months. Conclusions: Biosheets obtained via iBTA promoted wound healing and were extremely useful for intractable diabetic foot ulcers involving the heel area. Full article

The administration of mesenchymal stem cells (MSCs) has a positive effect on wound healing; however, the lack of adequate MSC engraftment at the wound site is a major limiting factor in current MSC-based therapies. In this study, a biosheet prepared using in-body tissue architecture (iBTA) was used as a material to address these problems. This study aimed to assess and evaluate whether biosheets containing somatic stem cells would affect the wound healing process in dogs. Biosheets were prepared by subcutaneously embedding molds in beagles. These were then evaluated grossly and histologically, and the mRNA expression of inflammatory cytokines, interleukins, and Nanog was examined in some biosheets. Skin defects were created on the skin of the beagles to which the biosheets were applied. The wound healing processes of the biosheet and control (no biosheet application) groups were compared for 8 weeks. Nanog mRNA was expressed in the biosheets, and SSEA4/CD105 positive cells were observed histologically. Although the wound contraction rates differed significantly in the first week, the biosheet group tended to heal faster than the control group. This study revealed that biosheets containing somatic stem cells may have a positive effect on wound healing. Full article

This study investigated six-month outcomes of first models of ascending aortic replacement. The molds used to produce the Biotube were implanted subcutaneously in goats. After 2–3 months, the molds were explanted to obtain the Biotubes (inner diameter, 12 mm; wall thickness, 1.5 mm). Next, we performed ascending aortic replacement using the Biotube in five allogenic goats. At 6 months, the animals underwent computed tomography (CT) and histologic evaluation. As a comparison, we performed similar surgeries using glutaraldehyde-fixed autologous pericardial rolls or pig-derived heterogenous Biotubes. At 6 months, CT revealed no aneurysmalization of the Biotube or pseudoaneurysm formation. The histologic evaluation showed development of endothelial cells, smooth muscle cells, and elastic fibers along the Biotube. In the autologous pericardium group, there was no evidence of new cell development, but there was calcification. The histologic changes observed in the heterologous Biotube group were similar to those in the allogenic Biotube group. However, there was inflammatory cell infiltration in some heterologous Biotubes. Based on the above, we could successfully create the world’s first Biotube-based ascending aortic replacement models. The present results indicate that the Biotube may serve as a scaffold for aortic tissue regeneration. Full article

Biotubes are autologous tubular tissues developed within a patient’s body through in-body tissue architecture, and they demonstrate high potential for early clinical application as a vascular replacement. In this pilot study, we used large animals to perform implantation experiments in preparation for preclinical testing of Biotube. The biological response after Biotube implantation was histologically evaluated. The designed Biotubes (length: 50 cm, internal diameter: 4 mm, and wall thickness: 0.85 mm) were obtained by embedding molds on the backs of six goats for a predetermined period (1–5 months). The same goats underwent bypass surgery on the carotid arteries using Biotubes (average length: 12 cm). After implantation, echocardiography was used to periodically monitor patency and blood flow velocity. The maximum observation period was 6 months, and tissue analysis was conducted after graft removal, including the anastomosis. All molds generated Biotubes that exceeded the tensile strength of normal goat carotid arteries, and eight randomly selected Biotubes were implanted. Thrombotic occlusion occurred immediately postoperatively (1 tube) if anticoagulation was insufficient, and two tubes, with insufficient Biotube strength (<5 N), were ruptured within a week. Five tubes maintained patency for >2 months without aneurysm formation. The spots far from the anastomosis became stenosed within 3 months (3 tubes) when Biotubes had a wide intensity distribution, but the shape of the remaining two tubes remained unchanged for 6 months. The entire length of the bypass region was walled with an αSMA-positive cell layer, and an endothelial cell layer covered most of the lumen at 2 months. Complete endothelial laying of the luminal surface was obtained at 3 months after implantation, and a vascular wall structure similar to that of native blood vessels was formed, which was maintained even at 6 months. The stenosis was indicated to be caused by fibrin adhesion on the luminal surface, migration of repair macrophages, and granulation formation due to the overproliferation of αSMA-positive fibroblasts. We revealed the importance of Biotubes that are homogeneous, demonstrate a tensile strength > 5 N, and are implanted under appropriate antithrombotic conditions to achieve long-term patency of Biotube. Further, we clarified the Biotube regeneration process and the mechanism of stenosis. Finally, we obtained the necessary conditions for a confirmatory implant study planned shortly. Full article

The Internet of bio-nano things (IoBNT) is an emerging paradigm employing nanoscale (~1–100 nm) biological transceivers to collect in vivo signaling information from the human body and communicate it to healthcare providers over the Internet. Bio-nano-things (BNT) offer external actuation of in-body molecular communication (MC) for targeted drug delivery to otherwise inaccessible parts of the human tissue. BNTs are inter-connected using chemical diffusion channels, forming an in vivo bio-nano network, connected to an external ex vivo environment such as the Internet using bio-cyber interfaces. Bio-luminescent bio-cyber interfacing (BBI) has proven to be promising in realizing IoBNT systems due to their non-obtrusive and low-cost implementation. BBI security, however, is a key concern during practical implementation since Internet connectivity exposes the interfaces to external threat vectors, and accurate classification of anomalous BBI traffic patterns is required to offer mitigation. However, parameter complexity and underlying intricate correlations among BBI traffic characteristics limit the use of existing machine-learning (ML) based anomaly detection methods typically requiring hand-crafted feature designing. To this end, the present work investigates the employment of deep learning (DL) algorithms allowing dynamic and scalable feature engineering to discriminate between normal and anomalous BBI traffic. During extensive validation using singular and multi-dimensional models on the generated dataset, our hybrid convolutional and recurrent ensemble (CNN + LSTM) reported an accuracy of approximately ~93.51% over other deep and shallow structures. Furthermore, employing a hybrid DL network allowed automated extraction of normal as well as temporal features in BBI data, eliminating manual selection and crafting of input features for accurate prediction. Finally, we recommend deployment primitives of the extracted optimal classifier in conventional intrusion detection systems as well as evolving non-Von Neumann architectures for real-time anomaly detection. Full article

Blood access is a lifeline for dialysis patients. However, serious problems such as stenosis or obstruction of access blood vessels, which are life-threatening conditions in daily clinical practice, still remain. One of the most promising candidates for solving these problems may be Biotube blood vessels. More than 20 years have passed since the development of in-body tissue architecture (iBTA), a technology for preparing tissues for autologous implantation in patients. The tissues obtained by iBTA do not elicit immunological rejection, which is one of the ultimate goals of regenerative medical engineering; however, their practical applications were quite challenging. The seemingly unorthodox iBTA concepts that do not follow the current pre-established medical system may not be readily accepted in general medicine. In contrast, there are many diseases that cannot be adequately addressed even with the latest and most advanced medical technology. However, iBTA may be able to save patients with serious diseases. It is natural that the development of high-risk medical devices that do not fit the corporate logic would be avoided. In order to actively treat such largely unattached diseases, we started Biotube Co., Ltd. with an aim to contribute to society. Biotubes induced by iBTA are collagenous tubular tissues prepared in the patient’s body for autologous implantation. The application of Biotubes as tissues for vascular implantation has been studied for many years. Biotubes may have excellent potential as small-diameter artificial blood vessels, one of the most difficult to clinically achieve. Their possibility is currently being confirmed in preclinical tests. Biotubes may save hundreds of thousands of patients worldwide annually from amputation. In addition, we aim to eliminate the recuring access vascular problems in millions of dialysis patients. This study provides an update on the current development status and future possibilities of Biotubes and their preparation molds, Biotube Makers. Full article

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability. Full article