A scoping review of trials for cell-based therapies in human spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is associated with significant and life-long disability. Yet, despite decades of research, no regenerative treatment has reached clinical practice. Cell-based therapies are one possible regenerative strategy beginning to transfer to human trials from a more extensive pre-clinical basis. METHODS: We therefore conducted a scoping review to synthesise all cell-based trials in SCI to consider the current state of the field and the cell transplant type or strategy with greatest promise. A search strategy of MEDLINE returned 1513 results. All clinical trials including adult human patients with acute or chronic, compete or incomplete SCI and a recorded ASIA score were sought. Exclusion criteria included non-traumatic SCI, paediatric patients and animal studies. A total of 43 studies, treating 1061 patients, were identified. Most trials evaluated cells from the bone marrow (22 papers, 660 patients) or the olfactory bulb (10 papers, 245 patients). RESULTS: Cell transplantation does appear to be safe, with no serious adverse effects being reported in the short-term. 86% of trials described efficacy as a primary outcome. However, varying degrees of outcome reporting prevented meta-analysis. No emerging cell type or technique was identified. The majority of trials, 53%, took place in developing countries, which may suggest more stringent regulatory requirements within Western countries. CONCLUSION: We believe cell-based transplantation translation remains in its infancy and that, although further robust clinical research is required, it is an important strategy to consider in the treatment of SCI.

Is cell transplantation a reliable therapeutic strategy for spinal cord injury in clinical practice? A systematic review and meta-analysis from 22 clinical controlled trials.

PURPOSE: It is an open question whether cell transplantation can provide safety and effective outcome to spinal cord injury (SCI) patient which has remained controversial for almost 40 years. This study aimed to evaluate the safety and efficacy of cell transplantation in SCI patients. METHOD: Studies of the cell transplantation for SCI were retrieved from PubMed, Embase, Medline, Cochrane Library and analyzed quantitative data by Review Manager 5.3. RESULTS: Twenty-one clinical controlled studies with 973 patients were included. The pooled results suggested that cell transplantation significantly improved ASIA score, ASIA motor score, ASIA sensory score, Barthel Index score, residual urine volume, rehabilitative time of automatic micturition. Furthermore, subgroup analysis indicated that the stem cells exhibited more potent than the non-stem cells in spinal cord repair. Cell transplantation at more than 14 days after injury showed more significant improvements than that within 14 days from injury. The dosage of cell transplantation between 1-5 × 107 and 10-20 × 107 was the potent quantity for the patient with SCI. Intrathecal injection and intravenous + intrathecal injection showed more superior to the other method. The top 5 adverse events were febrile reaction (11.5%), neurologic pain (11.3%), headache (2.6%), neurologic deterioration (2.4%), and rigidity or spasticity (1.6%). CONCLUSION: Cell transplantation appears to be a safe therapeutic strategy possessing substantial beneficial effects in the patients with SCI in clinic. Moreover, treating SCI with stem cell, the dosage of cells between 1-5 × 107 and 10-20 × 107, in intermediate or chronic phase, minimally invasive techniques, may bring more advantage to SCI patient. These slides can be retrieved under Electronic Supplementary Material.

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer.

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies.

[Xenotransplantation: recent developments and futur clinical applications]. / Xénotransplantation: nouveaux développements et applications cliniques à l'horizon.

The aim of xenotransplantation is to allow the transplantation of animal organs or cells to humans. This approach would immediately eliminate the human organ shortage that is responsible for a significant mortality of patients on the waiting list for transplantation of organs. The immune differences between pig and human induce an immediate rejection of porcine tissues by humans. This rejection has recently been partially controlled by genetic engineering of pigs, the use of new immunosuppressive drugs and encapsulation of isolated cells. However, due to the risk of transmission of animal infectious agents to humans, the WHO recommends that clinical application of xenotransplantation only takes place if adequate regulations are in place.

Transplantation of autologous cells and porous gelatin microcarriers to promote wound healing.

Definitive treatment to achieve wound healing in major burns frequently include skin transplantation, where split-thickness skin grafts is considered gold standard. This method is associated with several drawbacks. To overcome these hurdles, efforts have been made to develop tissue engineered skin substitutes, often comprised of a combination of cells and biomaterials. In the present study, we aimed to investigate transplantation of autologous keratinocytes and fibroblasts seeded on porous gelatin microcarriers using a porcine wound model. Pre-seeded microcarriers were transplanted to a total of 168 surgical full-thickness wounds (2cm diameter) on eight adult female pigs and covered with occlusive dressings. The experimental groups included wounds transplanted with microcarriers seeded with the combination of keratinocytes and fibroblasts, microcarriers seeded with each cell type individually, microcarriers without cells, each cell type in suspension, and NaCl control. Wounds were allowed to heal for one, two, four or eight weeks before being excised and fixated for subsequent histological and immunohistochemical analysis. In vitro, we confirmed that viable cells populate the surface and the pores of the microcarriers. In vivo, the microcarriers were to a large extent degraded after two weeks. After one week, all treatment groups, with the exception of microcarriers alone, displayed significantly thicker neo-epidermis compared to controls. After two weeks, wounds transplanted with microcarriers seeded with cells displayed significantly thicker neo-epidermis compared to controls. After four weeks there was no difference in the thickness of neo-epidermis. In conclusion, the experiments performed illustrate that autologous cells seeded on porous gelatin microcarriers stimulates the re-epithelialization of wounds. This method could be a promising candidate for skin transplantation. Future studies will focus on additional outcome parameters to evaluate long-term quality of healing following transplantation.

Detecting qualitative interaction: a Bayesian approach.

Differences in treatment effects between centers in a multi-center trial may be important. These differences represent treatment by subgroup interaction. Peto defines qualitative interaction (QI) to occur when the simple treatment effect in one subgroup has a different sign than in another subgroup: this interaction is important. Interaction where the treatment effects are of the same sign in all subgroups is called quantitative and is often not important because the treatment recommendation is identical in all cases. A hierarchical model is used here with exchangeable mean responses to each treatment between subgroups. The posterior probability of QI and the corresponding Bayes factor are proposed as a diagnostic and as a test statistic. The model is motivated by two multi-center trials with binary responses. The frequentist power and size of the test using the Bayes factor are examined and compared with two other commonly used tests. The impact of imbalance between the sample sizes in each subgroup on power is examined, and the test based on the Bayes factor typically has better power for unbalanced designs, especially for small sample sizes. An exact test based on the Bayes factor is also suggested assuming the hierarchical model. The Bayes factor provides a concise summary of the evidence for or against QI. It is shown by example that it is easily adapted to summarize the evidence for 'clinically meaningful QI,' defined as the simple effects being of opposite signs and larger in absolute value than a minimal clinically meaningful effect.

Stepping Into and Out of the Void: Funding Dynamics of Human Embryonic Stem Cell Research in California, Sweden, and South Korea.

Nonprofit organizations and philanthropists stepped into a funding void caused by controversies over public funding of human embryonic stem cell (hESC) research. Based on interviews of 83 representatives of 53 funders, we examine the motivations and accountability structures of public agencies, corporations, fundraising dependent nonprofit organizations and philanthropic organizations that funded hESC research in three jurisdictions: California, Sweden, and South Korea. While non-traditional forms of funding are essential in the early stages of research advancement, they are unreliable for the long timeframes necessary to advance cell therapies. Such funding sources may enter the field based on high expectations, but may exit just as rapidly based on disappointing rates of progress.

The survey on cellular and engineered tissue therapies in Europe in 2012.

Following the coordinated efforts of five established scientific organizations, this report describes activity in Europe for the year 2012 in the area of cellular and engineered tissue therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis. Three hundred thirteen teams from 33 countries responded to the cellular and engineered tissue therapy survey: 138 teams from 27 countries provided data on 2157 patients, while a further 175 teams reported no activity. Indications were musculoskeletal/rheumatological disorders (36%; 80% autologous), cardiovascular disorders (25%; 95% autologous), hematology/oncology, predominantly prevention or treatment of graft versus host disease and HSC graft enhancement (19%; 1% autologous), neurological disorders (3%; 99% autologous), gastrointestinal disorders (1%; 71% autologous), and other indications (16%; 79% autologous). Autologous cells were predominantly used for musculoskeletal/rheumatological (42%) and cardiovascular (34%) disorders, whereas allogeneic cells were mainly used for hematology/oncology (60%). The reported cell types were mesenchymal stem/stromal cells (49%), HSC (28%), chondrocytes (11%), dermal fibroblasts (4%), keratinocytes (1%), and others (7%). In 51% of the grafts, cells were delivered after ex vivo expansion, whereas cells were transduced or sorted in 10% and 16%, respectively, of the reported cases. Cells were delivered intra-organ (35%), intravenously (31%), on a membrane or gel (15%), or using 3D scaffolds (19%). The data are compared with those collected since 2008 to identify trends in the field and discussed in the light of recent publications and ongoing clinical studies.

The growth of tissue engineering.

This report draws upon data from a variety of sources to estimate the size, scope, and growth rate of the contemporary tissue engineering enterprise. At the beginning of 2001, tissue engineering research and development was being pursued by 3,300 scientists and support staff in more than 70 startup companies or business units with a combined annual expenditure of over $600 million. Spending by tissue engineering firms has been growing at a compound annual rate of 16%, and the aggregate investment since 1990 now exceeds $3.5 billion. At the beginning of 2001, the net capital value of the 16 publicly traded tissue engineering startups had reached $2.6 billion. Firms focusing on structural applications (skin, cartilage, bone, cardiac prosthesis, and the like) comprise the fastest growing segment. In contrast, efforts in biohybrid organs and other metabolic applications have contracted over the past few years. The number of companies involved in stem cells and regenerative medicine is rapidly increasing, and this area represents the most likely nidus of future growth for tissue engineering. A notable recent trend has been the emergence of a strong commercial activity in tissue engineering outside the United States, with at least 16 European or Australian companies (22% of total) now active.

Clinical and experimental transplantation of isolated organ or tissue cells indications problems from the Polish perspective.

Clinical cell transplantation remains as a clinical experiment. Morphologically intact and functional cells transplanted into their tissue of origin undergo rapid disintegration by attacking granulocytes and macrophages, leading to the so-called early graft dysfunction. When transplanted to sites remote from their origin, the process of elimination is even faster. Among millions of transplanted cells, only a few survive in an autologous or syngeneic recipient, not to mention an allogeneic combination. What is the mechanism of elimination of the majority of transplanted cells? Which cells survive and what is their genotype and phenotype? There are several problems that should be investigated: (1) the mechanism of anoikis, namely, detachment-induced apoptosis, (2) the reaction of the innate immune system to transplanted cells, (3) the microchimerism created by the transplanted cells, and (4) the "niche" for transplanted cells within the local cell chemical environment and signalling. Our experience with transplantation of hepatocytes illustrates current problems in isolated cell grafting. Proposals to increase the in vivo survival rate of transplanted syngeneic hepatocytes are essential to the vision of the future of cell transplantation.

Is the length of time in acute burn surgery associated with poorer outcomes?

BACKGROUND: Acute wound closure surgery improves outcomes, after burn particularly mortality, but also imposes physiological stress on the patient. The duration of surgery is associated with adverse outcomes in other populations. This study aimed to examine if extended acute burn surgery duration was associated with poorer in-hospital outcomes. METHODS: This retrospective cohort study included adult burn patients who required a single wound closure surgery at Royal Perth Hospital between 2004 and 2011. Multivariable regression analyses were used to assess the influence of patient and injury factors on surgery duration and length of stay (LOS). RESULTS: Surgery duration independently increased LOS (incidence rate ratio [IRR]=1.004, p<0.001). This translates to a predicted 13% increase in LOS for a 30min increase in surgery 'knife to skin' time. Total body surface area (TBSA) was identified as a significant predictor of surgery duration (IRR=1.047, p<0.001), estimating that a 10% TBSA increase results in a 59% increase in surgery duration. CONCLUSION: The results show that surgery duration is associated with LOS after adjusting for size of burn and other factors. The study justifies the need to explore strategies to reduce acute burn surgery duration.

The survey on cellular and engineered tissue therapies in Europe in 2010.

Following the coordinated efforts of five established scientific organizations, this report describes the novel cellular therapy activity in Europe for the year 2010. One hundred six teams from 27 countries responded to the cellular therapy survey, 69 teams from 21 countries provided data on 1010 patients using a dedicated survey; 37 teams reported no activity. These data were combined with an additional 260 records reported by 37 teams in 15 countries to the standard European group for Blood and Marrow Transplantation (EBMT) database. Indications were graft-vs.-host-disease (GvHD; 26%; 11% autologous), musculoskeletal disorders (25%; 93% autologous), cardiovascular disorders (20%; 100% autologous), epithelial disorders (16%; 44% autologous), autoimmune diseases (11%; 55% autologous), and neurological disorders (2%; 62% autologous). Autologous cells were predominantly used for musculoskeletal (39%) and cardiovascular (32%) disorders, whereas allogeneic cells were mainly used for GvHD (58%) and epithelial disorders (23%). The reported cell types were mesenchymal stem/stromal cells (MSC; 49%), hematopoietic stem cells (28%), chondrocytes (10%), dermal fibroblasts (4%), keratinocytes (1%), and others (8%). In 63% of the grafts, cells were delivered following ex vivo expansion, whereas cells were transduced or sorted respectively in 10% or 28% of the reported cases. Cells were delivered intraorgan (45%), intravenously (31%), on a membrane or gel (20%) or using 3D scaffolds (4%). Compared with last year, the number of teams adopting the dedicated survey was 1.25-fold higher and, with few exceptions, the collected data confirmed the captured trends. This year's edition specifically discusses scientific, clinical, regulatory, and commercial aspects related to the use of cell therapy for the repair of cartilage defects.

When do tissues and cells become products? Regulatory oversight of emerging biological therapies.

Although therapeutics derived from biological sources have been subjected to regulatory oversight for some time, the products used in transplantation procedures have historically been exempt from this oversight. These products have been viewed as being part of medical practice rather than as the result of mainstream pharmaceutical manufacture. Furthermore, their unique source makes them difficult to assess in traditional regulatory systems based on the tenets of pharmaceutical quality control. With the increasing use of transplantation therapies to both replace dysfunctional organs and to influence genetic and metabolic processes, public health concerns on these therapies have increased. In addition, it is recognized that therapeutic claims for some of these interventions need to be properly assessed. These considerations have led the established regulatory agencies of the developed world to develop new regulatory paradigms for the products of transplantation practice. While a number of concerns have driven these developments, the minimization of infectious disease risk remains the paramount driver for introducing these regulatory systems. More than the regulation of medicines and medical devices manufactured in traditional pharmaceutical modes, the regulation of cell and tissue products is intimately linked to areas of public health policy and funding. This places regulators in a challenging position as they attempt to reconcile their roles as independent assessors with the needs of the overall public health framework. This is particularly difficult when considering measures which may affect access to life saving therapies. Regulators have recognized the need to assess these therapies through systems which incorporate consideration of risk-benefit ratios and include mechanisms for transparent and accountable release of products when full compliance to traditional concepts of manufacturing practice is not possible.

Cell therapy for neuropathic pain in spinal cord injuries.

Cell therapy to treat neuropathic pain after spinal cord injury (SCI) is in its infancy. However, the development of cellular strategies that would replace or be used as an adjunct to existing pharmacological treatments for neuropathic pain have progressed tremendously over the past 20 years. The earliest cell therapy studies for pain relief tested adrenal chromaffin cells from rat or bovine sources, placed in the subarachnoid space, near the spinal cord pain- processing pathways. These grafts functioned as cellular minipumps, secreting a cocktail of antinociceptive agents around the spinal cord for peripheral nerve injury, inflammatory or arthritic pain. These initial animal, and later clinical, studies suggested that the spinal intrathecal space was a safe and accessible location for the placement of cell grafts. However, one major problem was the lack of a homogeneous, expandable cell source to supply the antinociceptive agents. Cell lines that can be reversibly immortalised are the next phase for the development of a practical, homogenous cell source. These technologies have been modelled with a variety of murine cell lines, derived from embryonic adrenal medulla or CNS brainstem, in which cells are transplanted, which downregulate their proliferative, oncogenic phenotype either before or after transplant. An alternative approach for existing human cell lines is the use of neural or adrenal precursors, in which the antinociceptive properties are induced by in vitro treatment with molecules that move the cells to an irreversible neural or chromaffin, and non-oncogenic, phenotype. Although such human cell lines are at an early stage of investigation, their clinical antinociceptive potential is significant given the daunting problem of difficult-to-treat neuropathic SCI pain.