Implementation Of Stem Cell Therapy Research Articles

Development of a Smart Wireless Multisensor Platform for an Optogenetic Brain Implant.

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Potential Plausible Role of Stem Cell for Treating Depressive Disorder: a Retrospective Review.

Depression poses a significant threat to global physical and mental health, impacting around 3.8% of the population with a rising incidence. Current treatment options primarily involve medication and psychological support, yet their effectiveness remains limited, contributing to high relapse rates. There is an urgent need for innovative and more efficacious treatment modalities. Stem cell therapy, a promising avenue in regenerative medicine for a spectrum of neurodegenerative conditions, has recently garnered attention for its potential application in depression. While much of this work remains preclinical, it has demonstrated considerable promise. Identified mechanisms underlying the antidepressant effects of stem cell therapy encompass the stimulation of neurotrophic factors, immune function modulation, and augmented monoamine levels. Nonetheless, these pathways and other undiscovered mechanisms necessitate further investigation. Depression fundamentally manifests as a neurodegenerative disorder. Given stem cell therapy's success in addressing a range of neurodegenerative pathologies, it opens the door to explore its application in depression treatment. This exploration may include repairing damaged nerves directly or indirectly and inhibiting neurotoxicity. Nevertheless, significant challenges must be overcome before stem cell therapies can be applied clinically. Successful resolution of these issues will ultimately determine the feasibility of incorporating stem cell therapies into the clinical landscape. This narrative review provides insights into the progress of research, potential avenues for exploration, and the prevailing challenges in the implementation of stem cell therapy for treatment of depression.

Stem cell therapies for periodontal tissue regeneration: A meta-analysis of clinical trials

ObjectiveStem cell therapy in periodontal tissue regeneration has reported optimistic regenerative results; evidence supporting its superiority over conventional methods is still ambiguous. Therefore, this meta-analysis aims to evaluate the therapeutic effects of stem cells in human periodontal regeneration. DesignA literature search was conducted to retrieve relevant articles on periodontal regeneration in stem cell therapy. A meta-analysis of the studies was conducted using the Stata software. ResultsFifteen studies that examined the effect of stem cell therapies on periodontal tissue regeneration in 369 patients were selected from databases. Regardless of the various types of cells, both odontogenic (periodontal ligament, dental pulp, gingiva stem cell) and non-odontogenic (bone marrow, periosteum-derived, and umbilical cord stem cells), the cell therapies witnessed significant improvements in terms of clinical attachment level (SMD, −0.67; 95CI, −0.90 to −0.43), probing depth (SMD, −0.76; 95% CI, −1.21 to - 0.31), radiographic intrabony defect depth (SMD, −0.87; 95% CI, −1.52 to −0.23), and histomorphometric analysis of mineralized bone (SMD, 0.80; 95% CI, 0.42 to 1.19) when compared to traditional without-cell treatment in patients. However, evidence on gingival recession, alveolar thickness gain, bone mineral density of bone core, and bone volume fraction of bone core outcomes did not reach statistical significance. ConclusionsEvidence suggests that the implementation of stem cell therapies in reconstructing compromised gingiva and alveolar bone tissue produces positive outcomes compared with conventional approaches. However, further well-designed investigations are needed to comprehensively identify the most effective source of cells and biomaterials for each case.

Intranasal delivery of stem cells labeled by nanoparticles in neurodegenerative disorders: Challenges and opportunities.

Neurodegenerative disorders occur through progressive loss of function or structure of neurons, with loss of sensation and cognition values. The lack of successful therapeutic approaches to solve neurologic disorders causes physical disability and paralysis and has a significant socioeconomic impact on patients. In recent years, nanocarriers and stem cells have attracted tremendous attention as a reliable approach to treating neurodegenerative disorders. In this regard, nanoparticle-based labeling combined with imaging technologies has enabled researchers to survey transplanted stem cells and fully understand their fate by monitoring their survival, migration, and differentiation. For the practical implementation of stem cell therapies in the clinical setting, it is necessary to accurately label and follow stem cells after administration. Several approaches to labeling and tracking stem cells using nanotechnology have been proposed as potential treatment strategies for neurological diseases. Considering the limitations of intravenous or direct stem cell administration, intranasal delivery of nanoparticle-labeled stem cells in neurological disorders is a new method of delivering stem cells to the central nervous system (CNS). This review describes the challenges and limitations of stem cell-based nanotechnology methods for labeling/tracking, intranasal delivery of cells, and cell fate regulation as theragnostic labeling. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Therapeutic Use of Stem Cells in the Management of Coronary Artery Disease and Heart Failure; Current Trends, Progress, and Challenges

In recent years, stem cell therapy has been considered a novel therapy for human subjects with coronary artery disease and heart failure. While stem cells of different types have been successfully isolated in laboratory settings and transplanted into animal models, doubts still exist on the successful outcome of stem cell therapy for cardiomyocyte regeneration in human subjects who develop coronary artery disease and heart failure. Given the limited progress on stem cell therapy for this indication in human subjects, we aim to understand normal cardiomyocyte embryogenesis and apply it as a guide in identifying an ideal stem choice, critical growth, and transcription factors for cardiomyocyte regeneration as well as in the implementation of stem cell therapy for in human subjects with coronary artery disease and heart failure. Ethical limitations, safety, and long-term complications are critical in identifying the ideal stem cell choice. The route of infusion of the ideal stem cell, dose, and timing of administration must also be standardized for a favorable clinical outcome. All stem cell sources evaluated for this clinical indication in animal and human studies were associated with some level of structural remodeling and improved cardiac performance following infusion. In the search for and identification of the ideal stem cell type, ethical choices with limited complications of restenosis, arrhythmias, ischemic vasculopathy, graft rejection, and malignant transformation would therefore rank high for the successful implementation of the therapeutic use of stem cells in the management of coronary artery disease and heart failure in human subjects. Original research and review articles from March 1995 – March 2022 were searched online. Search engines included Google Scholar, PubMed, Web of Science, and National Institute of Health. The keywords for the literature search included the use of stem cells for treatment, stem cell therapy, coronary artery disease, coronary heart disease, ischemic heart disease, and heart failure. Manual searches were also conducted for articles related to the pool generated from the online search. Statistical data were obtained from American Heart Association, Center for Disease Control (CDC), World Health Organization (WHO), and clinicaltrials.gov. From the articles generated, relevant sections were reviewed to understand the progress made with the therapeutic use of stem cells for managing coronary artery disease and heart failure in human subjects. The sources of stem cells, transcription factors, isolation methods, routes, and timing of infusion of different stem cell types evaluated for this clinical indication in preclinical and clinical studies were reviewed and outlined. The clinical outcomes of using different types of stem cells from both studies were also reviewed and compared, as well as ethical limitations, study limitations, and resultant adverse effects.

Estrogen Signaling Dictates Musculoskeletal Stem Cell Behavior: Sex Differences in Tissue Repair.

Sexual dimorphisms in humans and other species exist in visually evident features such as body size and less apparent characteristics, including disease prevalence. Current research is adding to a growing understanding of sex differences in stem cell function and response to external stimuli, including sex hormones such as estrogens. These differences are proving significant and directly impact both the understanding of stem cell processes in tissue repair and the clinical implementation of stem cell therapies. Adult stem cells of the musculoskeletal system, including those used for development and repair of muscle, bone, cartilage, fibrocartilage, ligaments, and tendons, are no exception. Both in vitro and in vivo studies have found differences in stem cell number, proliferative and differentiation capabilities, and response to estrogen treatment between males and females of many species. Maintaining the stemness and reducing senescence of adult stem cells is an important topic with implications in regenerative therapy and aging. As such, this review discusses the effect of estrogens on musculoskeletal system stem cell response in multiple species and highlights the research gaps that still need to be addressed. The following evidence from investigations of sex-related phenotypes in adult progenitor and stem cells are pieces to the big puzzle of sex-related effects on aging and disease and critical information for both fundamental tissue repair and regeneration studies and safe and effective clinical use of stem cells.Impact StatementThis review summarizes current knowledge of sex differences in and the effects of estrogen treatment on musculoskeletal stem cells in the context of tissue engineering. Specifically, it highlights the impact of sex on musculoskeletal stem cell function and ability to regenerate tissue. Furthermore, it discusses the varying effects of estrogen on stem cell properties, including proliferation and differentiation, important to tissue engineering. This review aims to highlight the potential impact of estrogens and the importance of performing sex comparative studies in the field of tissue engineering.

Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease

ImportanceAlthough progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist.ObjectivesTo summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them.Evidence ReviewInformation for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included.FindingsOne of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity.Conclusions and RelevanceDespite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.

Analysis of the Expectation of Stem Cell Therapy in Patients with Alzheimer's Disease.

Background and PurposeAlzheimer’s disease (AD) is the most common form of dementia which typically manifests as loss of memory and cognitive functions. Currently, available treatments for AD provide only symptomatic improvement and the benefit is minimal. Stem cell therapy (SCT) has been considered a promising treatment option for AD. We investigated the caregiver’s perception about implementation of SCT in their AD patients, and determined the factors related to SCT.MethodsA total of 100 caregivers, who cared for their AD patients, were interviewed at two hospitals. Structured open and closed questions about SCT for AD were asked by trained interviewers using the conventional in-person method. In addition, 60 dementia-related physicians were randomly interviewed via an e-mail questionnaire.ResultsOf the 100 subjects, 61 caregivers replied that they wanted their AD patients to receive SCT. Approximately 50% of the caregivers expected high improvement in cognitive function, behavioral and psychological symptoms, and activities of daily living, and physical improvements among their AD patients. However, physicians had much lower expectations of improvements in the above parameters. Multi-variate analysis revealed that female gender [odds ratio (OR): 3.747, 95% confidence interval (CI): 1.425–9.851] and familiarity with stem cells (OR: 3.873, 95% CI: 1.290–11.622) were independently associated with caregivers’ desire that their AD patients should undergo SCT. The major source of information on SCT was television (76.7%), and the most reliable source of information on SCT was physicians (83.6%).ConclusionsIn this study, many caregivers of AD patients fantasized and overestimated the need for SCT in comparison with physicians’ expectation. Therefore, it is necessary for physicians to develop strategies for educating caregivers about the appropriate risks and benefits of SCT.

Enhanced Homing Ability and Retention of Bone Marrow Stromal Cells to Diabetic Nephropathy by Microbubble-Mediated Diagnostic Ultrasound Irradiation

Bone marrow stromal cell (BMSC) transplantation can successfully treat diabetic nephropathy (DN), but the lack of a specific homing place for intravenously injected cells limits the effective implementation of stem cell therapies. The migration and survival of transplanted BMSCs are determined by inflammatory reactions in the local kidney micro-environment. We tested the hypothesis that microbubble-mediated diagnostic ultrasound irradiation could provide a suitable micro-environment for BMSC delivery and retention in DN therapy. In this study, red fluorescent protein–labeled BMSCs were administered combined with microbubbles to streptozotocin-induced DN rats 4 wk after diabetes onset. We observed enhanced BMSC homing and retention in microbubble-mediated diagnostic ultrasound-irradiated kidneys compared with the contralateral kidneys on days 1 and 3 post-treatment. The results from immunohistochemical analysis, Western blot and enzyme-linked immunosorbent assay indicated that the local and transient expression of various chemo-attractants (i.e., cytokines, integrins and trophic factors) found to promote BMSC homing was much higher than observed in non-treated kidneys. The local capillary endothelium rupture observed by transmission electron microscopy may account for local micro-environment changes. Histopathologic analysis revealed no signs of kidney damage. These results confirmed that renal micro-environment changes caused by appropriate microbubble-mediated diagnostic ultrasound irradiation may promote BMSC homing ability to the diabetic kidney without renal toxicity and cell damage. This non-invasive and effective technique may be a promising method for BMSC transplantation therapy.

Regenerative Medicine, Stem Cells, and Low-Level Laser Therapy: Future Directives

The idea of being able to replace, restore, or regenerate damaged or diseased tissues and organs in order to establish normal function in the human body has never been so prominent and possible than with the development of the field of regenerative medicine. Using material from the body or activating the body’s own repair mechanisms to prepare and grow or heal irreparable tissues or organs is now a real possibility, as demonstrated by research and clinical studies published over the last 10 years. Born from the collaboration of several biomedical disciplines and clinical approaches, regenerative medicine promises the real possibility of not only replacing pharmaceutical solutions to disease but also paves the road to a more autologous and holistic approach in clinical treatment of disease and disease control. Historically, the foundation of regenerative medicine was cemented with the successful transplantation of corneas, soft tissue, and bone in the early twentieth century. The first kidney transplantation in 1954 was followed by pancreas, liver, and heart transplants in the 1960s and success continued in the 1980s with heart– lung and living donor liver and lung transplants. Progressively, an increase in demand for tissues and organs and subsequent decrease in organ availability has left a need for new technology to meet the demand for suitable organs and organ donors as well as leading to an increase in the disgraceful enterprise of black market organs. Currently, tissueengineered skin used for burn survivors and diabetic ulcers, products derived from tissue engineering to induce bone growth and regeneration, as well as the autologous reintroduction of ex-vivo engineered bladder are a reality, once again establishing a firm foothold for the development of further and more advanced applications for regenerative medicine. The discovery of stem cells by the Russian histologist Alexander Maksimov in 1908, as part of his theory of hematopoiesis followed by Joseph Altman and Gopal Das in the 1960s presenting evidence of constant stem cell activity in the brain and the demonstration of self-renewing cells found in the bone marrow of mice by James E. Till and Ernest A. McCulloch in 1963, established stem cell research and the development of stem cell therapy as a new and very promising and exciting discipline for regenerative medicine. Embryonic and adult stem cells are available from a variety of sources and hold variable differentiation potential, not to mention the myriad potential therapeutic applications, albeit associated with some ethical and political concerns. Mammalian stem cells can be sourced from either the embryo or the adult organism. Embryonic stem cells originate from the inner cell mass of blastocysts, whereas adult stem and progenitor cells can be found in various tissues repairing or replenishing adult tissue. Of specific interest and application in regenerative medicine are autologous adult stem cells accessible from bone marrow, adipose tissue, or blood. Contemporary stem cell therapy includes bone marrow transplants for the treatment of leukemia, whereas extensive current research is undertaken for the implementation of stem cell therapy for the treatment of cancer, spinal cord injuries, and Parkinson’s disease, as well as multiple sclerosis and muscle conditions including heart disease. The use of vascular grafts for heart bypass surgery and cardiovascular disease treatment have been researched extensively and are at the pre-clinical trial stage. Advances in therapeutic applications do not come without much debate and controversy surrounding risks associated with it. The risk that transplanted stem cells could form tumors and metastasize uncontrollably is but one of the concerns of stem cell therapy. Inducing forced expression of specific genes in order to derive pluripotent stem cells from non-pluripotent cells generate the so-called induced pluripotent stem cell (iPSC). However, significant risk is associated with reprogramming of adult cells to obtain iPSCs. Potentially, this risk could limit their use in patients. The use of viruses to genomically alter the cells may lead to the expression of cancer-causing oncogenes. Low-level laser therapy (LLLT) has been scientifically proven as a beneficial therapeutic modality for numerous diseases and diseased conditions. Using very specific laser and light-emitting diode irradiation parameters, specific cellular activities can be induced, namely, cellular proliferation and viability while stimulating mitochondrial activity, thereby increasing adenosine triphosphate (ATP) production, synthesis of DNA and RNA, and activating cellsignaling cascades including the production of reactive oxygen species (ROS), nitric oxide (NO) release, activating cytochrome c oxidase, and modifying intracellular organelle membrane activity, calcium flux, and expression of stress proteins. The molecular mechanism underlying these cellular activities is less well understood, and several research groups are conducting intensive research studies in an effort to elucidate the relation between these biological

Cardiovascular surgery for realization of regenerative medicine

Regenerative medicine is emerging as a new approach to the treatment of severe cardiovascular diseases that are resistant to conventional therapies. Although the type of cell transplanted (e.g., pluripotent stem cells, bone marrow-derived stem cells, skeletal myoblasts, or cardiac stem cells) influences the outcome of stem cell transplantation, the method of transplantation is also important, as the efficiency of engraftment after simple needle injection is poor. Scaffold-free cell sheet transplantation technology is one of the most promising methods in this regard. Although the results of clinical trials of stem cell therapy have been marginal to date, further elucidation of the actual mechanisms of cardiac repair following cell therapy would enhance the potential for full-scale implementation of stem cell therapy. In addition to stem cell therapy, the field of cardiovascular regenerative medicine includes interspecific chimera technology, drug delivery systems using biodegradable materials, and gene therapy. Integration of these new modalities with conventional therapies will be important to realize the goal of cardiovascular regenerative medicine tailored to the condition of each individual patient. Cardiovascular surgery would be an excellent means of carrying out this strategy and could potentially resolve the health problems of the increasing number of advanced cardiovascular patients. Herein, we review the recent basic and clinical research associated with the realization of regenerative medicine in the field of cardiovascular surgery.

Stem Cell Therapies in Clinical Trials: Workshop on Best Practices and the Need for Harmonization

A workshop addressing regulation of clinical implementation of stem cell therapies preceded the ISSCR 8th Annual Meeting, cosponsored by the International Society for Stem Cell Research, the California Institute for Regenerative Medicine and the International Society for Cellular Therapy.

Potentials of Stem Cell Research and the Implications of Legislation

Potentials of Stem Cell Research and the Implications of Legislation

Time course and outcome of recovery from stroke: Relevance to stem cell treatment

Stroke is the third leading cause of death in the United States after heart disease and cancer; it has an incidence of approximately 750,000 cases per year, and it is a leading cause of disability in adults. The factors predicting a poor outcome from stroke include severe initial neurological dysfunction, hypertension, cardiac arrhythmias, myocardial infarction, hypercholesterolemia, and diabetes mellitus. The armamentarium available for improvement of neurological function after stroke is currently limited to placement in specialized stroke units, optimal therapy for medical complications, and intense physical, occupational and speech rehabilitation. Despite many trials, no pharmacological intervention has been shown convincingly to improve neurological outcome. This review was undertaken to determine the appropriate time for new approaches to the therapy of stroke such as the infusion of stem cells into the central nervous system. The literature shows in large case series that functional recovery from stroke reaches a maximum level by 3-6 months after onset, and no further recovery occurs beyond this time. Nevertheless, about 80% of these patients reach their maximum function for activities of daily living within 6 weeks from onset. Initiation of a clinical trial of stem cell therapy would require demonstration of optimal clinical improvement by neurological evaluations, with no change over at least 4 weeks of observation. Accordingly, in subjects with first-ever ischemic stroke who remained neurologically unchanged from the second until the third month after the acute event, implementation of stem cell therapy would be appropriate at approximately 3 months after the stroke.

Stem cell therapies in reparative medicine.

The future implementation of stem cell therapies to treat conditions thus far considered incurable has been envisioned as logical consequence of the fast-paced progress in stem cell research over the last few years. Still, many practical obstacles stand in the way to the routine application of these novel technologies in medicine. The conference "Stem Cell Therapies in Reparative Medicine," held aboard the cruise vessel Majesty of the Seas (Miami, USA-Nassau, Bahamas, April 19-22, 2002), focused on the analysis of these problems from different perspectives, including developmental biology (cell proliferation, fate determination, and enrichment), immunology (allorejection and prevention of autoimmunity recurrence), and clinical therapy, emphasizing the impact of stem cell technologies on the emerging field of tissue engineering and the treatment of alpha-1 antitrypsin deficiency.