Rehago - A Home-Based Training App Using Virtual Reality to Improve Functional Performance of Stroke Patients with Mirror Therapy and Gamification Concept: A Pilot Study.

Stroke is one of the prevalent diseases which leads to functional disabilities such as hemiparesis or hemiplegia. It is common practice to treat patients with proper rehabilitation as early as possible for better prognosis after the onset of stroke. One of the effective therapeutic techniques for treating stroke patients is mirror therapy, which can potentially facilitate patients' motor function recovery through repetitive practice. "Rehago" is a software as medical device that implements the concept of mirror therapy in combination with gamified exercises into virtual reality (VR) to provide a home-based rehabilitation environment for stroke patients. In this study, 48 stroke patients completed the full course of intervention with Rehago and their functional performance of pre- and post-intervention was investigated. The intervention with Rehago was predefined as 30 minutes training per day, 5 days per week over a course of 6 weeks. The patient's progress was evaluated by their therapists every 14 days, with a baseline assessment before the intervention began. The results showed an average improvement of 5.54 points in the Functional Independence Measurement score, and an improvement of 7.13 points in the assessed quality-of-life score (EQ5D-5L). An improvement of the FIM score and the quality-of-life score in EQ5D-5L was observed, indicating it is beneficial to the patients using Rehago as a home-based rehabilitation tool.

Influence of body visualization in VR during the execution of motoric tasks in different age groups.

Virtual reality (VR) has become a common tool and is often considered for sport-specific purposes. Despite the increased usage, the transfer of VR-adapted skills into the real-world (RW) has not yet been sufficiently studied, and it is still unknown how much of the own body must be visible to complete motoric tasks within VR. In addition, it should be clarified whether older adults also need to perceive their body within VR scenarios to the same extent as younger people extending the usability. Therefore, younger (18-30 years old) and elderly adults (55 years and older) were tested (n = 42) performing a balance-, grasping- and throwing task in VR (HMD based) accompanied with different body visualization types in VR and in the RW having the regular visual input of body's components. Comparing the performances between the age groups, the time for completion, the number of steps (balance task), the subjective estimation of difficulty, the number of errors, and a rating system revealing movements' quality were considered as examined parameters. A one-way ANOVA/Friedmann with repeated measurements with factor [body visualization] was conducted to test the influence of varying body visualizations during task completion. Comparisons between the conditions [RW, VR] were performed using the t-Tests/Wilcoxon tests, and to compare both age groups [young, old], t-Tests for independent samples/Mann-Whitney-U-Test were used. The analyses of the effect of body visualization on performances showed a significant loss in movement's quality when no body part was visualized (p < .05). This did not occur for the elderly adults, for which no influence of the body visualization on their performance could be proven. Comparing both age groups, the elderly adults performed significantly worse than the young age group in both conditions (p < .05). In VR, both groups showed longer times for completion, a higher rating of tasks' difficulty in the balance and throwing task, and less performance quality in the grasping task. Overall, the results suggest using VR for the elderly with caution to the task demands, and the visualization of the body seemed less crucial for generating task completion. In summary, the actual task demands in VR could be successfully performed by elderly adults, even once one has to reckon with losses within movement's quality. Although more different movements should be tested, basic elements are also realizable for elderly adults expanding possible areas of VR applications.

Effects of body visualization on performance in head-mounted display virtual reality.

Although there are many virtual reality (VR) applications in sports, only a handful of studies visualized the whole body. There is still a lack of understanding, how much of the own body must be visualized in the head-mounted display (HMD) based VR, to ensure fidelity and similar performance outcome as in the real-world. In the current study, 20 young and healthy participants completed three tasks in a real and virtual environment: balance task, grasping task, and throwing task with a ball. The aim was to find out the meaning of the visualization of different body parts for the quality of movement execution and to derive future guidelines for virtual body presentation. In addition, a comparison of human performance between reality and VR, with whole-body visualization was made. Focusing on the main goal of the current study, there were differences within the measured parameters due to the visualization of different body parts. In the balance task, the differences within the VR body visualization consisted mainly through no-body visualization (NB) compared to the other visualization types defined as whole-body (WB), WB except feet (NF), as well as WB except feet and legs (NLF). In the grasping task, the different body visualization seemed to have no impact on the participants' performances. In the throwing task, the whole-body visualization led to higher accuracy compared to the other visualization types. Regarding the comparison between the conditions, we found significant differences between reality and VR, which had a large effect on the parameters time for completion in the balance and grasping task, the number of foot strikes on the beam in the balance task, as well as the subjective estimation of the difficulty for all tasks. However, the number of errors and the quality of the performances did not differ significantly. The current study was the first study comparing sports-related tasks in VR and reality with further manipulations (occlusions of body parts) of the virtual body. For studies analyzing perception and sports performance or for VR sports interventions, we recommend the visualization of the whole body in real-time.

Biocompatible, Purified VEGF-A mRNA Improves Cardiac Function after Intracardiac Injection 1 Week Post-myocardial Infarction in Swine.

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, VEGF-A 165 mRNA improves systolic ventricular function and limits myocardial damage. Following a single administration a week post-infarction in mini pigs, left ventricular ejection fraction, inotropy, and ventricular compliance improved, border zone arteriolar and capillary density increased, and myocardial fibrosis decreased at 2 months post-treatment. Purified VEGF-A mRNA establishes the feasibility of improving cardiac function in the sub-acute therapeutic window and may represent a new class of therapies for ischemic injury.

Injection of Human Cord Blood Cells With Hyaluronan Improves Postinfarction Cardiac Repair in Pigs.

UNLABELLED: Recent clinical trials using autologous bone marrow or peripheral blood cells to treat myocardial infarction (MI) show controversial results, although the treatment has a good safety profile. These discrepancies are likely caused by factors such as aging, systemic inflammation, and cell processing procedures, all of which might impair the regenerative capability of the cells used. Here, we tested whether injection of human cord blood mononuclear cells (CB-MNCs) combined with hyaluronan (HA) hydrogel improves cell therapy efficacy in a pig MI model. A total of 34 minipigs were divided into 5 groups: sham operation (Sham), surgically induced-MI plus injection with normal saline (MI+NS), HA only (MI+HA), CB-MNC only (MI+CB-MNC), or CB-MNC combined with HA (MI+CB-MNC/HA). Two months after the surgery, injection of MI+CB-MNC/HA showed the highest left ventricle ejection fraction (51.32%±0.81%) compared with MI+NS (42.87%±0.97%, p<.001), MI+HA (44.2%±0.63%, p<.001), and MI+CB-MNC (46.17%±0.39%, p<.001) groups. The hemodynamics data showed that MI+CB-MNC/HA improved the systolic function (+dp/dt) and diastolic function (-dp/dt) as opposed to the other experimental groups, of which the CB-MNC alone group only modestly improved the systolic function (+dp/dt). In addition, CB-MNC alone or combined with HA injection significantly decreased the scar area and promoted angiogenesis in the infarcted region. Together, these results indicate that combined CB-MNC and HA treatment improves heart performance and may be a promising treatment for ischemic heart diseases. SIGNIFICANCE: This study using healthy human cord blood mononuclear cells (CB-MNCs) to treat myocardial infarction provides preclinical evidence that combined injection of hyaluronan and human CB-MNCs after myocardial infarction significantly increases cell retention in the peri-infarct area, improves cardiac performance, and prevents cardiac remodeling. Moreover, using healthy cells to replace dysfunctional autologous cells may constitute a better strategy to achieve heart repair and regeneration.

The time window for therapy with peptide nanofibers combined with autologous bone marrow cells in pigs after acute myocardial infarction.

BACKGROUND: We previously showed that injection of peptide nanofibers (NF) combined with autologous bone marrow mononuclear cells (MNC) immediately after coronary artery ligation improves cardiac performance in pigs. To evaluate the clinical feasibility, this study was performed to determine the therapeutic time window for NF/MNC therapy in acute myocardial infarction (MI). METHODS AND RESULTS: A total of 45 adult minipigs were randomly grouped into 7 groups: sham or MI plus treatment with NS (normal saline), or NF or MNC alone at 1 day (1D) post-MI, or NF/MNC at 1, 4, or 7 days post-MI (N≥6). Cardiac function was assessed by echocardiography and ventricular catheterization. Compared with the NS control, pigs treated with NF/MNC at 1 day post-MI (NF/MC-1D) had the greatest improvement in left ventricle ejection fraction (LVEF; 55.1±1.6%; P<0.01 vs. NS) 2 months after MI. In contrast, pigs treated with either NF/MNC-4D or NF/MNC-7D showed 48.9±0.8% (P<0.05 vs. NS) and 43.5±2.3% (n.s. vs. NS) improvements, respectively. The +dP/dt and -dP/dt, infarct size and interstitial collagen content were also improved in the NF/MNC-1D and -4D groups but not in the -7D group. Mechanistically, MNC quality and the states of systemic inflammation and damaged heart tissue influence the therapeutic efficiency of NF/MNC therapy, as revealed by another independent study using 16 pigs. CONCLUSIONS: Injection of NF/MNC at 1 or 4 days, but not at 7 days post-MI, improves cardiac performance and prevents ventricular remodeling, confirming the importance of early intervention when using this therapy for acute MI.

Human placenta-derived adherent cells improve cardiac performance in mice with chronic heart failure.

Human placenta-derived adherent cells (PDACs) are a culture-expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory, anti-inflammatory, angiogenic, and neuroprotective properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. We tested the therapeutic effects of PDA-001 in mice with chronic heart failure (CHF). Three weeks after transaortic constriction surgery to induce CHF, the mice underwent direct intramyocardial (IM) or i.v. injection of PDA-001 at a high (0.5 × 10(6) cells per mouse), medium (0.5 × 10(5) cells per mouse), or low (0.5 × 10(4) cells per mouse) dose. The mice were sacrificed 4 weeks after treatment. Echocardiography and ventricular catheterization showed that IM injection of PDA-001 significantly improved left ventricular systolic and diastolic function compared with injection of vehicle or i.v. injection of PDA-001. IM injection of PDA-001 also decreased cardiac fibrosis, shown by trichrome staining in the vicinity of the injection sites. Low-dose treatment showed the best improvement in cardiac performance compared with the medium- and high-dose groups. In another independent study to determine the mechanism of action with bromodeoxyuridine labeling, the proliferation rates of endothelial cells and cardiomyocytes were significantly increased by low or medium IM dose PDA-001. However, no surviving PDA-001 cells were detected in the heart 1 month after injection. In vivo real-time imaging consistently revealed that the PDA-001 cells were detectable only within 2 days after IM injection of luciferase-expressing PDA-001. Together, these results have demonstrated the cardiac therapeutic potential of PDA-001, likely through a paracrine effect.

Injection of autologous bone marrow cells in hyaluronan hydrogel improves cardiac performance after infarction in pigs.

Intramyocardial injection of bone marrow mononuclear cells (MNCs) with hyaluronan (HA) hydrogel is beneficial to the ischemic heart in a rat model of myocardial infarction (MI). However, the therapeutic efficacy and safety must be addressed in large animals before moving onto a clinical trial. Therefore, the effect of combined treatment on MI was investigated in pigs. Coronary artery ligation was performed in minipigs to induce MI followed by an intramyocardial injection of normal saline (n = 7), HA (n = 7), normal saline with 1 × 10(8) freshly isolated MNCs (n = 8), or HA with 1 × 10(8) MNCs (HA-MNC; n = 7), with a sham-operated group serving as a control (n = 7). The response of each experimental group was estimated by echocardiography, ventricular catheterization, and histological analysis. Although injection of HA or MNCs slightly elevated left ventricular ejection fraction, the combined HA-MNC injection showed a significant increase in left ventricular ejection fraction, contractility, infarct size, and neovascularization. Importantly, injection of MNCs with HA also promoted MNC retention and MNC differentiation into vascular lineage cells in pigs. Therefore, this study not only provides evidence but also raises the possibility of using a combined HA-MNC injection as a promising therapy for heart repair.

Hyaluronan enhances bone marrow cell therapy for myocardial repair after infarction.

Hyaluronan (HA) has been shown to play an important role during early heart development and promote angiogenesis under various physiological and pathological conditions. In recent years, stem cell therapy, which may reduce cardiomyocyte apoptosis, increase neovascularization, and prevent cardiac fibrosis, has emerged as a promising approach to treat myocardial infarction (MI). However, effective delivery of stem cells for cardiac therapy remains a major challenge. In this study, we tested whether transplanting a combination of HA and allogeneic bone marrow mononuclear cells (MNCs) promotes cell therapy efficacy and thus improves cardiac performance after MI in rats. We showed that HA provided a favorable microenvironment for cell adhesion, proliferation, and vascular differentiation in MNC culture. Following MI in rats, compared with the injection of HA alone or MNC alone, injection of both HA and MNCs significantly reduced inflammatory cell infiltration, cardiomyocyte apoptosis, and infarct size and also improved cell retention, angiogenesis, and arteriogenesis, and thus the overall cardiac performance. Ultimately, HA/MNC treatment improved vasculature engraftment of transplanted cells in the infarcted region. Together, our results indicate that combining the biocompatible material HA with bone marrow stem cells exerts a therapeutic effect on heart repair and may further provide potential treatment for ischemic diseases.