Search

The aim of this study was to investigate whether body weight-supported treadmill training with voluntary-driven exoskeleton body weight-supported treadmill training (VDE-BWSTT) improves the quality of life (QOL) of persons with chronic spinal cord injury (SCI). Nineteen individuals with chronic SCI with walking limitation underwent a total of 20 sessions of VDE-BWSTT using the hybrid assistant limb. The QOL was measured using the Short Form-36v2 (SF-36v2) questionnaire at preintervention and postintervention. The Walking Index for SCI-II (WISCI-II), Functional Independence Measure (FIM) motor score, and Neuropathic Pain Symptom Inventory (NPSI) self-questionnaire were also administered/completed. In SF-36v2, the mean values of all subscales in our participants were lower than those in healthy individuals. None of the measures showed significant improvement, even in individuals with some residual walking ability (baseline WISCI-II score of 6 or higher). In the correlation analysis between the baselines WISCI-II, FIM, or NPSI values and the mean SF-36v2 subscale changes throughout the training, the baseline FIM motor score was positively correlated with the mean changes in Role Emotional and Mental Health. In addition, NPSI was negatively correlated with the mean change in Vitality and Mental Health. In our protocol, although VDE-BWSTT did not improve the QOL of persons with chronic SCI, those with higher functional independence or lower pain at preintervention likely improved. Further study with combination of task-specific training or pain-targeting treatment with more patients should be considered to more effectively improve their QOL.

Introduction Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI. Setting NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models. Methods The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 106 cells will be transplanted into the injured spinal cord parenchyma 14–28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000035074; Japan Registry of Clinical Trials [jRCT] number, jRCTa031190228). Discussion/conclusion We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned., Highlights • A first-in-human clinical study for spinal cord injury using iPSC-derived cells is about to begin. • The primary objective is to assess the safety of human iPSC-derived neural stem/progenitor cells. • Further clinical trials are expected to be conducted to statistically assess efficacy.

Background The effect of knee osteoarthritis, which causes knee pain, on higher-level functional competence (HLFC) is not clear. Objective To clarify the effect of knee pain on HLFC in older people. Design Community-based prospective cohort study. Setting Kurabuchi town, Gumma prefecture, Japan. Subjects Community-dwelling individuals aged 65 and older. Methods A total of 808 residents participated to the baseline examinations. The frequency of knee pain, degree of pain and functional impairment resulting from the pain were asked at baseline (2005–2006) via a self-administered questionnaire in Japanese based on an English version of the Western Ontario and McMaster Universities Osteoarthritis Index. Information on HLFC at baseline and during home visits were collected annually until 2014 with the Tokyo Metropolitan Institute of Gerontology Index of Competence. The association between baseline knee pain and HLFC decline was assessed with a Cox proportional hazards model. Results Two factors, persistent knee pain and severe functional impairment caused by the pain, were significantly associated with future declines in total HLFC, with adjusted hazard ratios (95% confidence intervals) of 1.51 (1.08–2.11) and 1.49 (1.10–2.00). In analysis by subcategory, persistent knee pain had a significant adverse effect on participants’ intellectual and social activities, and that severe physical functional impairment also had a significant impact on social activities. Conclusions The clear association of the frequency of knee pain and resultant functional impairment with future HLFC decline indicates that collecting information about these factors may be useful in identifying older people at high risk of future HLFC decline.

A non-randomized open-label single-arm clinical trial. To analyze the effect of body weight supported treadmill training (BWSTT) with the voluntary driven exoskeleton (VDE) in persons with differing levels and completeness of spinal cord injury (SCI) and differing walking abilities. Keio University Hospital, Tokyo, Japan. Twenty individuals with chronic SCI (age, 43 ± 17 years) classified as American Spinal Injury Association Impairment Scale grade A (n = 2), B (n = 4), C (n = 8), or D (n = 6) who had reached a plateau in recovery. Participants underwent twenty 60 min sessions of BWSTT with the hybrid assisted limb. The speed, distance, and duration walked in every 60 min training session were recorded. The Walking Index for SCI Scale II (WISCI-II), 10 meters walk test (10MWT), 2 min walk test, timed up and go (TUG) test, Berg Balance Scale (BBS), lower extremity motor score (LEMS), Barthel Index, and Functional Independence Measure were evaluated at pre and post intervention. There was a significant improvement in 10MWT, TUG, and BBS after the intervention. Walking ability significantly improved in participants with high walking ability at baseline (WISCI-II score 6–20; n = 12) but not in participants with low walking ability (WISCI-II score 0–3; n = 8). Significant improvement of BBS was also shown in participants with high walking ability at baseline. Patients with high walking ability at baseline responded better to the training than those with low walking ability.

Purpose: Many people with chronic musculoskeletal pain (CMP) seek healthcare from conventional and complementary and alternative medicine. However, treatment/therapy is not always adequate, patients often change healthcare providers, and some patients are left untreated. This study clarified care-seeking behaviours and explored factors behind the behaviours in people with CMP. Methods: Using a Japanese cross-sectional online survey, participants aged ≥ 20 years with non-cancer/fracture CMP lasting for ≥ 6 months and presenting ≤1 month, interfering with daily living activities and/or work were enrolled. We summarized and analysed the characteristics and factors associated with choice of healthcare providers; information on socio-demographics, including employment; ability to use healthcare, including income; and need for healthcare, including pain intensity, using a logistic regression model. Results: Among the 9105 respondents, 24.5% consulted physicians, 18.3% complementary and alternative medicine practitioners, and 57.2% were untreated. More respondents who had moderate–severe pain visited physician, more regularly employed and with high income visited complementary and alternative medicine, and less respondents who had moderate–severe pain were untreated. These were found to be associated with the respective healthcare use versus untreated. Conclusions: People with severe conditions, higher income and regular employment, and less severe conditions have visited physicians, complementary and alternative medicine practitioners and none, respectively. By applying this result at each type of healthcare provider, it may be possible to treat patients more appropriately.

BackgroundThe progression of hyperkyphosis is a significant factor in declining general health. The purpose of this study was to investigate whether muscle strength and/or mobility is associated with the progression of hyperkyphosis in elderly people.MethodsAs part of a cohort study of community-dwelling elderly people, handgrip strength and mobility (evaluated with the Timed Up and Go Test: TUG) were assessed at baseline (2005–2006). Kyphosis was also evaluated at baseline and in follow-up examinations 4 years later, with the block method. To exclude the measurement error, the progression of kyphosis was defined as increase of 2 or more blocks. The association of kyphosis progression in each group with handgrip strength and/or mobility was assessed using Poisson regression analysis.ResultsResults on 403 participants were available for the final analysis, and kyphosis progression was observed in 53 (13.1%) of them. Multivariable analysis adjusted for sex, age, baseline block number, bone stiffness, TUG performance, or handgrip strength simultaneously revealed that low handgrip strength (13.5 seconds) at baseline were both independently associated with kyphosis progression (adjusted risk ratio [95% confidence interval]: 2.11 [1.06–4.20] and 2.48 [1.26–4.89], respectively).ConclusionsOur study showed that low handgrip strength and low mobility are clearly associated with the progression of kyphosis. Further study is needed on the applicability of these results to preventive measures.

Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic–severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270

There have been numerous attempts to develop stem cell transplantation approaches to promote the regeneration of spinal cord injury (SCI). Our multicenter team is currently planning to launch a first‐in‐human clinical study of an induced pluripotent stem cell (iPSC)‐based cell transplant intervention for subacute SCI. This trial was conducted as class I regenerative medicine protocol as provided for under Japan's Act on the Safety of Regenerative Medicine, using neural stem/progenitor cells derived from a clinical‐grade, integration‐free human “iPSC stock” generated by the Kyoto University Center for iPS Cell Research and Application. In the present article, we describe how we are preparing to initiate this clinical study, including addressing the issues of safety and tumorigenesis as well as practical problems that must be overcome to enable the development of therapeutic interventions for patients with chronic SCI. stem cells 2019;37:6–13, Ash1l can epigenetically promote the expression of essential osteogenic and chondrogenic transcription factors in C3H10T1/2 cells. It exerts this impact via modifications in the enrichment of H3K4me3 on their promoter regions. Ash1l hampered adipogenesis by enhancing H3K4me3 enrichment in promoter of Creb gene, which was reported to be a repressive gene of PPARγ.

Locomotive syndrome is a condition of reduced mobility, and patients have a high risk of requiring nursing care. In order to investigate the level of awareness of the term &ldquo, locomotive syndrome&rdquo, and the factors relating to awareness in a community, awareness of locomotive syndrome was included in a questionnaire survey on health and daily life conducted in Koumi Town (Japan), which was distributed to 3181 eligible residents aged 40 years or older. Information on age, sex, marital status, educational attainment, lifestyle, and social environment was also collected, and the association of awareness with various factors was analyzed with two multivariable Poisson regression models. As a result, awareness among respondents was 44.6%. Awareness was significantly higher among women, those who were 60&ndash, 79 years old, married, and had received higher education. Additionally, awareness was significantly associated with social factors, especially attendance at regional events within the last one year, in both women and men: the adjusted prevalence ratios (95% confidence intervals) were 1.26 (1.10&ndash, 1.43) and 1.48 (1.19&ndash, 1.83), respectively. In conclusion, in addition to strengthen awareness rising campaigns targeting men and for younger people, providing health education at social settings such as regional events may help improve future musculoskeletal health in the elderly.

Resolving the immunogenicity of cells derived from induced pluripotent stem cells (iPSCs) remains an important challenge for cell transplant strategies that use banked allogeneic cells. Thus, we evaluated the immunogenicity of mouse fetal neural stem/progenitor cells (fetus-NSPCs) and iPSC-derived neural stem/progenitor cells (iPSC-NSPCs) both in vitro and in vivo. Flow cytometry revealed the low expression of immunological surface antigens, and these cells survived in all mice when transplanted syngeneically into subcutaneous tissue and the spinal cord. In contrast, an allogeneic transplantation into subcutaneous tissue was rejected in all mice, and allogeneic cells transplanted into intact and injured spinal cords survived for 3 months in approximately 20% of mice. In addition, cell survival was increased after co-treatment with an immunosuppressive agent. Thus, the immunogenicity and post-transplantation immunological dynamics of iPSC-NSPCs resemble those of fetus-NSPCs.

The transcription factor STAT3 is known to control glial scar formation, but the underlying mechanism is unknown. Renault-Mihara et al. show that inhibition of the small GTPase RhoA by STAT3 coordinates reactive astrocyte dynamics during glial scar formation., Understanding how the transcription factor signal transducer and activator of transcription–3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. The inhibition of RhoA by STAT3 involves ezrin, the phosphorylation of which is reduced in STAT3-CKO astrocytes. Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/− mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.

Summary Human induced pluripotent stem cells (iPSCs) are promising in regenerative medicine. However, the risks of teratoma formation and the overgrowth of the transplanted cells continue to be major hurdles that must be overcome. Here, we examined the efficacy of the inducible caspase-9 (iCaspase9) gene as a fail-safe against undesired tumorigenic transformation of iPSC-derived somatic cells. We used a lentiviral vector to transduce iCaspase9 into two iPSC lines and assessed its efficacy in vitro and in vivo. In vitro, the iCaspase9 system induced apoptosis in approximately 95% of both iPSCs and iPSC-derived neural stem/progenitor cells (iPSC-NS/PCs). To determine in vivo function, we transplanted iPSC-NS/PCs into the injured spinal cord of NOD/SCID mice. All transplanted cells whose mass effect was hindering motor function recovery were ablated upon transduction of iCaspase9. Our results suggest that the iCaspase9 system may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies., Highlights • The iCaspase9 system induced apoptosis of iPSCs and all iPSC derivatives in vitro • Grafted iPSC-NS/PCs formed teratomas and non-teratomatous neural tumors • The iCaspase9 system prevented tumor progression and adverse effects with tumor • CID was demonstrated to be an effective inducer even in the CNS protected by the BBB, In this article, Okano, Nakamura and colleagues report that the iCaspase9 system abolished hiPSC-NS/PCs-derived tumors and controlled adverse events. The iCaspase system may serve as an important countermeasure against post-transplantation adverse events in stem cell transplant therapies.

Summary This cohort study conducted in Japan showed that severe age-related kyphosis was visually detected. The visual assessment of kyphosis was associated with declines in ADL, suggesting that we can easily identify people at high risk to develop future ADL reduction in the community setting. Purpose Age-related kyphosis is related with declines in activities of daily living (ADL). Its conventional diagnosis has been made by orthopedic surgeons and trained examiners using specialized equipment such as X-rays. We investigated whether visual classification of kyphosis by laypersons accurately predicted future ADL decline. Methods This study was part of the Kurabuchi Study, a cohort study of community-dwelling elderly Japanese. Between 2009 and 2010, three layperson raters used reference illustrations to classify 532 participants without ADL decline at study baseline into four categories. Other examiners used conventional methods to assess kyphosis in the same participants: curve ruler, Spinal Mouse, and the block method. ADL decline was defined as the development of dependence according to the Katz Index, admission to a nursing home, or certification of long-term care need. Results Thirty-five of the participants (6.6%) were classified with the most severe degree of kyphosis at baseline by visual assessment. Interrater agreement was high (Kappa = 0.73) for the most severe group. During 4.5 years of follow-up, 106 participants (19.9%) showed ADL decline. On the basis of visual assessment, the adjusted risk ratio for ADL decline among the participants with the most severe kyphosis was 2.6 (95% CI: 1.4–4.6). Assessments of kyphosis made with the Spinal Mouse also accurately predicted ADL decline. Conclusions Visual assessment of kyphosis predicted future declines in ADL in this study. Since our method requires no special tools or training, it may be useful for identifying those at high risk of ADL decline. Electronic supplementary material The online version of this article (10.1007/s11657-018-0551-4) contains supplementary material, which is available to authorized users.

Neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) are expected to be a valuable cell source for cell therapies that target central nervous system disorders. For clinical applications, NS/PCs should be induced and maintained under clinical grade conditions, which are challenging to achieve. In the present study, we established a procedure to obtain xeno-free long-term self-renewing neuroepithelial-like stem cells (xf-lt-NES cells) from feeder-free hiPSCs using a newly developed xeno-free medium, StemFit(®)AS200. xf-lt-NES cells were cultured for long periods in StemFit(®)AS200 while retaining normal karyotypes, NS/PC marker expression and differentiation capacity for neuronal and glial differentiation in vitro and in vivo. Furthermore, the cells were cryopreserved using a defined serum-free freezing reagent, which demonstrated the feasibility of this xeno-free culture system for large-scale lt-NES cell production and cell banking. Taken together, our system represents a promising approach for the manufacture of clinically relevant products for cell therapy using NS/PCs.

Objectives To examine the association between knee pain and function and depressive symptoms in older Japanese adults. Design Community‐based prospective cohort study. Setting Kurabuchi Town, Gumma Prefecture, Japan. Participants Individuals aged 65 and older (N = 573; n = 260 men, n = 313 women) without depressive symptoms participated in baseline examinations in 2005 and 2006; 95.6% participated in follow‐up interviews (2007–08). Measurements Degree of knee pain and functional impairment was assessed at baseline using a self‐administered questionnaire in Japanese based on an English version of the Western Ontario and McMaster Universities Osteoarthritis Index. The Geriatric Depression Scale was used to identify depressive symptoms in face‐to‐face home‐visit interviews conducted 2 years later, and the association between knee pain and functional impairment and depressive symptoms was assessed using logistic regression. Results During the 2‐year follow‐up, 11.9% of participants developed depressive symptoms, and pain and functional impairment were found to be associated with development of these symptoms. Pain at night while in bed (adjusted odds ratio (aOR) = 2.6, 95% confidence interval (CI) = 1.4–4.9) and difficulty putting on socks (aOR = 3.7, 95% CI: 1.8–7.5), getting into and out of a car (aOR = 3.4, 95% CI = 1.8–6.5), and taking off socks (aOR = 3.1, 95% CI = 1.5–6.5) were found to be most strongly associated with development of depressive symptoms. Conclusion Examining elderly people's responses to questions about pain at night and difficulties performing daily activities may be an efficient way of identifying those at high risk of developing depressive symptoms.

Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.

Background: Previous epidemiological surveys conducted in Japan highlighted problems with conventional approaches to treating chronic musculoskeletal pain. On the basis of prior studies, we initiated the “longitudinal investigation of chronic musculoskeletal pain” in 2010. In our first two reports, we revealed a high prevalence of chronic musculoskeletal pain, low satisfaction with treatment, and reduced quality of life. Those with severe and consistent low back pain had the highest risk of the persisting pain. The risk factors for developing chronic pain also included working in a professional, managerial, or clerical/specialist occupation, being female, having a body mass index ≥25, currently using alcohol or cigarettes, and having completed an educational level of vocational school or higher. As the final step of the epidemiological survey, the present study examined the effect of chronic musculoskeletal pain on a future decline in activities of daily living (ADL). Methods: A questionnaire was sent to individuals who participated in the research project in 2010. Follow-up research examining loss of basic or instrumental ADL, or certification of long-term care requirements, was conducted in 2013 ( n = 4989 subjects). Results: The 3-year follow-up data revealed that chronic musculoskeletal pain was associated with a decline in ADL, even after adjusting for covariables such as age, sex, and smoking (adjusted odds ratio, 1.56; 95% confidential interval, 1.16–2.10). Conclusions: Chronic musculoskeletal pain is associated with future declines in ADL; therefore, relief of the chronic musculoskeletal pain may be important to maintain an active elderly population.

SUMMARY The implantable cardioverter-defibrillator (ICD) is an effective therapeutic device for preventing mortality in patients with cardiac diseases caused by life-threatening arrhythmias. The authors previously proposed an algorithm for the detection of life-threatening arrhythmias using a multiple regression model. To enhance the classification accuracy, we have now incorporated a moving average filter and a multiple detection process into the original detection algorithm. The experimental results showed that the proposed method could attain sufficiently high accuracy for all ventricular fibrillation rhythms to be detected precisely. In addition, the cases of false detection of sinus rhythm or supraventricular tachyarrhythmias, which could cause ICD malfunction, have been reduced. © 2013 Wiley Periodicals, Inc. Electron Comm Jpn, 96(12): 1–8, 2013; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.11585

The maximum ventricular elastance is a reliable index for assessing the cardiac function from changes in its pressure-volume relationship. The advantage of this index is that it can represent the contractility of either unassisted hearts or native hearts assisted with rotary blood pumps. However, there are situations in which changes in the ventricular load required for the conventional estimation method might be risky. For example, in a bridge-to-recovery the cardiac function should also be continuously observed after the implantation of a rotary blood pump. In this article, we present the results of the estimation of the maximum elastance with in vivo data using the parameter optimization method, which is a single-beat estimation method. The estimated values for the normal cardiac function (6.8 +/- 0.6, 4.5 +/- 0.9, 4.2 +/- 1.8 mm Hg/mL) were significantly different from those for the low cardiac function (3.2 +/- 1.5, 1.9 +/- 1.0, 1.9 +/- 1.2 mm Hg/mL) from the data of the three animals that were analyzed. Besides, the maximum elastance values were independent of the pump rotational speed. These results indicate that this index might be useful for the detection of the myocardial recovery.

Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.

Fontan procedure is one of the common surgical treatment of congenital heart diseases. Patients with Fontan circulation have single ventricle in the systemic circulation with the total cavopulmonary connection. Pulmonary blood flow in the Fontan circulation is lower than in healthy subjects, and the central venous pressure may elevate. In this study, we developed a mechanical circulatory assist device for the extracardiac conduit for Fontan circulation and examined its driving method in the mock pediatric pulmonary circulatory system. We used shape memory alloy (SMA) fiber as an actuator of the device. The SMA actuator wrapped the extracardiac conduit between inferior vena cava and pulmonary artery. We designed two different types of the circulatory assist devices. We drove these devices in two different modes by the synchronized and sequential motions. The flow volume was 10mL/min against a load of 10mmHg, and the maximum contractile force indicated 60mmHg in the mock test. These results suggested the effective mechanical assistance for Fontan pulmonary circulation.

Rotary blood pumps which have contact-less suspension are small, durable and widely used for left ventricular assist devices (LVADs). In order to design a total artificial heart (TAH) with rotary blood pumps, two pumps one for each ventricle, are controlled independently. Some of the challenges for the development of a TAH includes the requirement of a small size and the anatomical fitting of inlets and outlets which should be arranged closely on the circumference in the same direction. And they should be combined into a unit. In this paper, a helical flow total artificial heart (HFTAH) combing two centrifugal pumps with helical inlet in face is proposed in order to achieve a smaller TAH. To examine the pump performance, a preliminary test model for left ventricle was built, the size of the pump was 69.0mm in diameter and 45.0mm height. The size of the impeller was 44.0mm in diameter and 23.0mm height including a 15.0mm-height hydrodynamic bearing. The pump was externally driven by a direct current motor. 5.0L/min flow rate against 100mmHg pressure difference was obtained, where the total power consumption was 5.0W, the system efficiency was 23% with a rotational speed of 2070rpm. In this system, maximum pressure head, flow rate and efficiency were 420mmHg, 15.0L/min and 26%, respectively. In acute animal experiments with three healthy adult goats, the total biventricular bypass assist system using the pumps was able to maintain the maximum aortic flow at approximately 5.0L/min, and the pulmonary arterial flow at approximately 4.6L/min, the mean aorta pressure was 105mmHg, and the mean pulmonary artery pressure was 51mmHg. The development of the control method is undergoing, and a driving system and the pump aiming at the chronic animal experiments will be developed.

The present paper has proposed two methods for obtaining the linear correlation of the baroreflex system without measurement of blood pressure. One is based on the pulse wave transit time which needs both the electrocardiogram and the photoplethysmogram. The other is based on the photoplethysmogram only. The results from the experiments showed that the effect of habitual exercise and the Valsalva maneuver can be verified quantitatively. The proposed methods are possible to be used for a test of the autonomic nervous function at home.

Total cavopulmonary connection (TCPC) is commonly applied for the surgical treatment of congenital heart disease such as single ventricle in pediatric patients. Patients with no ventricle in pulmonary circulation are treated along with Fontan algorithm, in which the systemic venous return is diverted directly to the pulmonary artery without passing through subpulmonary ventricle. In order to promote the pulmonary circulation after Fontan procedure, we developed a newly designed pulmonary circulatory assist device by using shape memory alloy fibers. We developed a pulmonary circulatory assist device as a non-blood contacting mechanical support system in pediatric patients with TCPC. The device has been designed to be installed like a cuff around the ePTFE TCPC conduit, which can contract from outside. We employed a covalent type functional anisotropic shape memory alloy fiber (Biometal, Toki Corporation, Tokyo Japan) as a servo actuator of the pulmonary circulatory assist device. The diameter of this fiber was 100 microns, and its contractile frequency was 2-3 Hz. Heat generation with electric current contracts these fibers and the conduit. The maximum contraction ratio of this fiber is about 7% in length. In order to extend its contractile ratio, we fabricated and installed mechanical structural units to control the length of fibers. In this study, we examined basic contractile functions of the device in the mock system. As a result, the internal pressure of the conduit increased to 63 mmHg by the mechanical contraction under the condition of 400 msec-current supply in the mock examination with the overflow tank of 10 mmHg loading.

The purpose of this study was to examine the hemodynamic characteristics of expanded polytetrafluoroethylene (ePTFE) pulmonary valves with bulging sinuses quantitatively in a pediatric pulmonary mechanical circulatory system designed by us, in order to propose the optimal design for clinical applications. In this study, we developed a pediatric pulmonary mock circulation system, which consisted of a pneumatic right ventricular model, a pulmonary heart valve chamber, and a pulmonary elastic compliance tubing with resistive units. The hemodynamic characteristics of four different types of ePTFE valves and a monoleaflet mechanical heart valve were examined. Relationships between the leaflet movements and fluid characteristics were evaluated based on engineering analyses using echocardiography and a high-speed video camera under the pediatric circulatory conditions of the mock system. We successfully performed hemodynamic simulations in our pediatric pulmonary circulatory system that could be useful for quantitatively evaluating the pediatric heart valves. In the simulation study, the ePTFE valve with bulging sinuses exhibited a large eddy in the vicinity of the leaflets, whereas the straight tubing exhibited turbulent flow. The Reynolds number obtained in the valve with bulging sinuses was calculated to be 1667, which was smaller than that in the straight tubing (R (e) = 2454).The hemodynamic characteristics of ePTFE pediatric pulmonary heart valves were examined in our mock circulatory system. The presence of the bulging sinuses in the pulmonary heart valve decreased the hydrodynamic energy loss and increased the systolic opening area. Based on an in vitro experiment, we were able to propose an optimal selection of pulmonary valve design parameters that could yield a more sophisticated pediatric ePTFE valve shape.

When recovery of the cardiac function is detected in assisted hearts, the ventricular assist device can be removed. Due to the invasiveness of the surgical procedure, an accurate assessment of cardiac function is fundamental for the treatment success. The main challenge for the detection of cardiac function during assistance is to know whether the cardiac function index represents the cardiac function after pump removal independently of the pump assist rate. Therefore in this paper we present an evaluation of the influence of the pump over the slope of the preload recruitable stroke work, a cardiac function index. Analyzing data from four acute animal experiments, we found that the pump affects the stroke work, which could be corrected by the end diastolic volume. However, the data set examined was limited and further investigation is necessary.

In the present study, “Electronic Doctor's Bag” which is a tele-healthcare tool for home-visit medical service using the mobile communications environment has been proposed and evaluated by preliminary experiments. It was shown that its basic function was sufficiently evaluated by a few doctors and nurses but further improvement in portability and operability is required on the basis of much more opinions of medical and nursing professionals.

Myocardial infarction (MI) may cause left ventricular aneurysms (LVAs) as the long-term and obsolete complications. Following MI, the scar will replace the necrotic lesion within a few weeks. As a result, a portion of the left ventricular free wall protrudes, which leads to appearance of LVAs. The three dimensional echocardiography, the computed tomography and the magnetic resonance imaging (MRI) are the most effective tools to diagnose the left ventricular volumetric function and its wall motion. And the primary choice to treat LVAs is surgical therapy, which is called the left ventricular reconstructive surgery (LVRS). The LVRS such as Dor procedure is performed to resume the left ventricular shape and its original myocardial fibre orientation as much as possible. Furthermore, we also have to consider the location of the couple of papillary muscle in order to maintain the mitral valvular functions. When the ventricle dilates due to the obsolete MI, the papillary muscles might be displaced away from the mitral valvular annulus, leading to decreased coaptaion of the mitral leaflets and mitral regurgitation. As the clinical status, the surgeons establish the surgical planning of LVRS according to their design, evidence and experience base on the diagnostic imaging, which is difficult to estimate the postoperative cardiac function and structure quantitatively. The purpose of this study was to support surgeons to examine more quantitative surgical strategies by dint of engineering approach as fabrication of diseased ventricular tangible elastic model and numerical analyses in each patient prior to the treatment. Then we developed a prototyping method of fabrication for elastic ventricular models by the normal sequence of MRI data, which could show the identical and quantitative representation of diagnostic imaging. It is anticipated that these methods could realise the quantitative images and expressions as well as the intercommunity to the strategy of surgical therapy to reduce the patients’ risk. As the results

Although implantable cardioverter-defibrillators have improved significantly in the past decades, the algorithms used in the identification of life-threatening arrhythmias are still not accurate enough. Conventional methods commonly misclassify tachycardias, sometimes initiating an unnecessary and uncomfortable treatment. In this paper, we proposed a new method for the identification of ventricular tachycardias and fibrillations based on the comparison of simultaneous electro-grams. Our method could successfully separate supraventricular tachycardias and normal sinus rhythm, which do not require any treatment, from ventricular tachycardias and fibrillation, which are life-threatening arrhythmias and must be terminated, with a sensitivity of 93.0% and a specificity of 92.7% from the comparison of ventricular electrograms. In future studies, the classification using electrograms from the right heart must be improved.

Thromboembolic and haemorrhagic complications are the primary causes of mortality and morbidity in patients with artificial hearts, which are known to be induced by the interactions between blood flow and artificial material surfaces. The authors have been developing a new mechanical artificial myocardial assist device by using a sophisticated shape memory alloy fibre in order to achieve the mechanical cardiac support from outside of the heart without a direct blood contacting surface. The original material employed as the actuator of artificial myocardial assist devices was 100um fibred-shaped, which was composed of covalent and metallic bonding structure and designed to generate 4–7 % shortening by Joule heating induced by the electric current input. In this study, we focused on the synchronization of the actuator with native cardiac function, and the phase delay parameter was examined in animal experiments using Saanen goats. Total weight of the device including the actuator was around 150g, and the electric power was supplied transcutaneously. The device could be successfully installed into thoracic cavity, which was able to be girdling the left ventricle. The contraction of the device could be controlled by the originally designed microcomputer. The mechanical contraction signal input had been transmitted with the phase delay of 50–200 msec after the R-wave of ECG, and hemodynamic changes were investigated. Cardiac output and systolic left ventricular pressure were elevated with 20% delay of cardiac cycle by 27% and 7%, respectively, although there was smaller difference under the condition of the delay of over 30%. Therefore, it was suggested that the synchronization measures should be examined in order to achieve sophisticated ventricular passive/active support on physiological demand.

Recently, rotary blood pumps (RBPs) have been used as bridge to recovery. In such application the RBP might be weaned once the cardiac function has been recovered. In such cases, the detection of the cardiac function is fundamental for the treatment efficiency. However, most of the widely used cardiac function indices (CFIs) were proposed for unassisted hearts and have not been completely evaluated under assistance. In contrast, E Max , which is known as a reliable CFI, has already been validated under assistance with RBP. However, since the conventional method for the estimation of E max has some limitations for the clinical application, the objective of this study was to evaluate different single-beat estimation methods qualitatively and also quantitatively using in vivo data. The preliminary results showed that although single-beat estimation have more clinical applicability, not all those estimation methods are suitable for the RBP assistance.

Thromboembolic and haemorrhagic complications are the primary causes of mortality and morbidity in patients with artificial hearts, which are known to be induced by the interactions between blood flow and artificial material surfaces. The authors have been developing a new mechanical artificial myocardial assist device by using a sophisticated shape memory alloy fibre in order to achieve the mechanical cardiac support from outside of the heart without a direct blood contacting surface. The original material employed as the actuator of artificial myocardial assist devices was 100um fibred-shaped, which was composed of covalent and metallic bonding structure and designed to generate 4–7 % shortening by Joule heating induced by the electric current input. Prior to the experiment, the myocardial streamlines were investigated by using a MDCT, and the design of artificial myocardial assist devices were refined based on the concept of Torrent-Guasp’s myocardial band theory. As the hydrodynamic or hemodynamic examination exhibited the remarkable increase of cardiac systolic work by the assistance of the artificial myocardial contraction in the originally designed mock circulatory system as well as in the acute animal experiments, the chronic animal test has been started in a goat. Total weight of the device including the actuator was around 150g, and the electric power was supplied percutaneously. The device could be successfully installed into thoracic cavity, which was able to be girdling the left ventricle. In the chronic animal trial, the complication in respect to the diastolic dysfunction by the artificial myocardial compression was not observed.

The authors have been developing a sophisticated artificial myocardium for the treatment of heart failure, which is capable of supporting contractile function from the outside of the ventricle. The purpose of this study was to construct the control methodology of functional assistance by an artificial myocardium using small active mechanical elements composed of shape memory alloy fibres (Biometal). In order to achieve a sophisticated mechanical support by using shape memory alloy fibres, the diameter of which was 100 microns, the mechanical response of the myocardial assist device unit was examined by using PID (Proportional-Integral-Derivative) control method. Prior to the evaluation of dynamic characteristics, the relationship between strain and electric resistance of the shape memory alloy fibre and also the inditial response of each unit were obtained in the electrical bridge circuit. The component for the PID control was designed for the regulation of the myocardial contractile function. An originally-designed RISC microcomputer was employed and the input or output signals were controlled by pulse width modulation method in respect of displacement controls. Consequently, the optimal PID parameters were confirmed and the fibrous displacement was successfully regulated under the different heat transfer conditions simulating internal body temperature as well as bias tensile loading. Then it was indicated that this control methodology could be useful for more sophisticated ventricular passive or active restraint by using the artificial myocardium on physiological demand interactively.