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Umbilical cord blood transplantation (UCBT) has been performed in the clinic for over 30 years. The biological and immunological characteristics of umbilical cord blood (UCB) have been re‐recognized in recent years. UCB, previously considered medical waste, is rich in hematopoietic stem cells (HSCs), which are naïve and more energetic and more easily expanded than other stem cells. UCB has been identified as a reliable source of HSCs for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). UCBT has several advantages over other methods, including no harm to mothers and donors, an off‐the‐shelf product for urgent use, less stringent HLA match, lower incidence and severity of chronic graft‐vs‐host disease (GVHD), and probably a stronger graft‐vs‐leukemia effect, especially for minimal residual disease‐positive patients before transplant. Recent studies have shown that the outcome of UCBT has been improved and is comparable to other types of allo‐HSCT. Currently, UCBT is widely used in malignant, nonmalignant, hematological, congenital and metabolic diseases. The number of UCB banks and transplantation procedures increased exponentially before 2013. However, the number of UCBTs increased steadily in Asia and China but decreased in the United States and Europe year‐on‐year from 2013 to 2019. In this review, we focus on the development of UCBT over the past 30 years, the challenges it faces and the strategies for future improvement, including increasing UCB numbers, cord blood unit selection, conditioning regimens and GVHD prophylaxis for UCBT, and management of complications of UCBT. Advantages and disadvantages of UCBT and improving strategies.

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12–24, 36–48, and 60–72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

Hematopoietic stem cell transplantation (HSCT) is common practice today for life threatening malignant and non‐malignant diseases of the blood and immune systems. Umbilical cord blood (UCB) is rich in hematopoietic stem cells (HSCs) and is an attractive alternative to harvesting HSCs from bone marrow or when mobilized into peripheral blood. One of the most appealing attributes of UCB is that it can be banked for future use and hence provides an off‐the‐shelf solution for patients in urgent need of a transplantation. This has led to the establishment of publicly funded and private UCB banks, as seen by the rapid growth of the UCB industry in the early part of this century. However, from about 2010, the release of UCB units for treatment purposes plateaued and started to decrease year‐on‐year from 2013 to 2016. Our interest has been to investigate the factors contributing to these changes. Key drivers influencing the UCB industry include the emergence of haploidentical HSCT and the increasing use of UCB units for regenerative medicine purposes. Further influencing this dynamic is the high cost associated with UCB transplantation, the economic impact of sustaining public bank operations and an active private UCB banking sector. We foresee that these factors will continue in a tug‐of‐war fashion to shape and finally determine the fate of the UCB industry. Stem Cells Translational Medicine 2018 Stem Cells Translational Medicine 2018;7:643–650 Evolution and factors influencing the future growth of the umbilical cord (UCB) industry. Positive influencers will allow for a plateau or rise in UCB usage, while negative influencers will result in a further decline.

The use of two units of cord blood to reconstitute hematopoiesis in transplantation for relapsed hematologic cancers in patients 1 to 21 years of age proved to be no better and was in some ways worse than the standard one-unit transplant. Since 1993, unrelated-donor umbilical-cord blood has been used as the source of hematopoietic stem cells for transplantation in an estimated 30,000 patients with malignant and nonmalignant diseases. 1 As compared with stem-cell grafts from adult donors, cord blood has the advantages of more rapid availability, relative absence of donor attrition, and, after transplantation, a reduced risk of graft-versus-host disease (GVHD) despite donor–recipient HLA disparity. 2 , 3 In addition, less restriction on HLA matching permits greater use of cord blood for members of racial minorities, who are less likely to have a suitably HLA-matched volunteer adult donor. 4 However, the use of cord blood . . .

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double‐blind, placebo‐controlled, crossover study of a single intravenous infusion of 1–5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post‐treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty‐three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure‐66 (GMFM‐66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post‐ACB treatment, those who received doses ≥2 × 107/kg demonstrated significantly greater increases in GMFM‐66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales‐2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071–2078 Change in brain connectivity 1 year after autologous cord blood treatment by cell dose. The nodes and edges included are those that demonstrated significantly increased improvement in children receiving high doses compared with those receiving low doses, as indicated by the color chart, with insignificant nodes shown in gray. High dose ≥2 × 107/kg, low dose <2 × 107/kg.

Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Patients with Kellgren‐Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell‐based medicinal product (a composite of culture‐expanded allogeneic hUCB‐MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7‐year extended follow‐up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12‐week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow‐up. The histological findings at 1 year showed hyaline‐like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment‐emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell‐based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees. Stem Cells Translational Medicine 2017;6:613–621

Stroke is a major cause of death and long‐term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open‐label trial to assess the safety and feasibility of a single IV infusion of non‐human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3–9 days post‐stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well‐tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post‐treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non‐HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo‐controlled phase 2 study. Stem Cells Translational Medicine 2018;7:521–529 We conducted a phase I open‐label trial to assess the safety and feasibility of a single IV infusion of non‐human leukocyte antigen matched, ABO matched, unrelated allogeneic umbilical cord blood (UCB) into adult patients who had recently experienced an acute ischemic stroke. UCB was administered between 3 and 10 days post‐stroke.

Cord blood (CB) has been an alternative stem cell source for patients with a wide variety of hematological diseases. Cord blood confers the advantages of rapid availability and higher tolerance to two HLA antigen mismatches compared with unrelated donors, and this has increased opportunities for patients who do not have suitable donors or require urgent transplantation. Although the higher rate of engraftment failure remains a serious concern after cord blood transplantation (CBT), the mechanisms underlying this risk have gradually been clarified, which has helped to improve engraftment. Recent studies of CBT and other alternatives have reported comparable outcomes. Moreover, CBT shows promise even when patients are in a non-remission status, which may reflect the potent graft-versus-leukemia effect of CB. Here we compare the most recent outcomes of CBT with those of other stem cell sources and discuss the potential of CB and several outstanding issues that require resolution.

Purpose Interest gaps between public and private umbilical cord blood banks have led to the introduction of hybrid banking options. Hybrid models combine features of private and public banks as well as interests of parents, children and of patients, in order to find an optimized solution. While several different models of hybrid banks exist, there is a lack of literature about this novel model of cord blood stem cell banking. Therefore, the aim of this literature review is to assess different options of umbilical cord blood banking and whether hybrid banking could be a valuable alternative to the existing public and private cord blood banking models. Methods We performed a systematic literature search, using five main databases. Five hybrid models regarding their advantages as well as their challenges are discussed in this review. Results We found that a wealth of literature exists about public cord blood banking, while private and hybrid banking are understudied. Different modalities of hybrid cord blood banking are being described in several publications, providing the basis to assess different advantages and disadvantages as well as practicability. Conclusion Hybrid banks, especially the sequential model, seem to have potential as an alternative to the existing banking models worldwide. A previously conducted survey among pregnant women showed a preference for hybrid banking, if such an option was available. Nevertheless, opinions among stakeholders differ and more research is needed to evaluate, if hybrid banking provides the expected benefits.

Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT ( n =51) versus peripheral blood MUD transplant ( n =57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT ( P =0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT ( P =0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients ( P <0.0001). Late infections and late hospitalized days were reduced in CB patients ( P =0.1 and <0.001, respectively). Three-year CI of transplant-related mortality (TRM) and relapse as well as 3-year overall survival (OS) were similar following CB and MUD transplantation. We demonstrate a significantly lower incidence of cGVHD, immunosuppression burden and late complication rate following UCB versus peripheral blood MUD transplant without decreased OS, increased relapse or early TRM. Combined with the rapid availability of UCB, these findings have led our center to move primarily to UCB over peripheral blood MUD when a MRD is not available.