The Committee for Advanced Therapies of the European Medicines Agency recently classified autologous bone marrow‐derived mononuclear cells and CD133+ stem cells as tissue‐engineered products when ...intended for regeneration through stem cell‐induced angiogenesis in ischemic heart tissue. These scientific recommendations are reviewed in light of the scientific knowledge acquired over the last few years about the mechanisms of postnatal neovascularization. The negative impact that the consideration of these treatments as medicinal products, instead of cell transplants, will have on European public health services is also analyzed.
In November of 2011, the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) published two scientific recommendations regarding the classification of autologous bone marrow‐derived mononuclear cells (BM‐MNCs) and autologous bone marrow‐derived CD133+ cells as advanced therapy medicinal products (ATMPs), specifically tissue‐engineered products, when intended for regeneration in ischemic heart tissue on the basis that they are not used for the same essential function (hematological restoration) that they fulfill in the donor. In vitro and in vivo evidence demonstrates that bone marrow cells are physiologically involved in adult neovascularization and tissue repair, making their therapeutic use for these purposes a simple exploitation of their own essential functions. Therefore, from a scientific/legal point of view, nonsubstantially manipulated BM‐MNCs and CD133+ cells are not an ATMP, because they have a physiological role in the processes of postnatal neovascularization and, when used therapeutically for vascular restoration in ischemic tissues, they are carrying out one of their essential physiological functions (the legal definition recognizes that cells can have several essential functions). The consequences of classifying BM‐MNCs and CD133+ cells as medicinal products instead of cellular transplantation, like bone marrow transplantation, in terms of costs and time for these products to be introduced into clinical practice, make this an issue of crucial importance. Therefore, the recommendations of EMA/CAT could be reviewed in collaboration with scientific societies, in light of organizational and economic consequences as well as scientific knowledge recently acquired about the mechanisms of postnatal neovascularization and the function of bone marrow in the regeneration of remote tissues.
The Iniciativa Andaluza en Terapias Avanzadas (Andalusian Initiative for Advanced Therapies; IATA) is a publicly funded organization promoted by the Regional Government of Andalusia, Spain. Dr. ...Natividad Cuende, IATA's executive director, shares the organization's goals, accomplishments, and funding priorities.
A quality assurance programme for the tissue donation process was launched in Andalusia in 2020 to facilitate the integration of tissue donation into end-of-life care, and to respond to the growing ...need for human tissue for therapeutic purposes. The results of this programme are presented here.
After identifying the hospital departments in which to intensify the detection of tissue donors, expanding training activities and designing a specific data collection system for possible tissue donors who do not donate their tissues, the results of the donation activity were quantified and the causes of non-donation were analysed by applying the critical pathway for deceased tissue donation methodology.
After an initial drop in activity, which coincided with the coronavirus pandemic, the number of tissue donors increased by 48.4% in 2022 compared to 2019. From the eligible donors, 83% were actual tissue donors and 71% were utilised donors. The modifiable causes of tissue donation loss, in order of frequency, were family refusal, followed by organisational or logistical issues, failure to notify or failure to identify possible donors, and failure to complete donor evaluation.
As a result of the collaboration of the various professionals involved in the programme, tissue donation activity has increased remarkably, the potential and effectiveness of the donation process have been evaluated, and areas for improvement have been identified, which we hope will lead to continuous improvement of the process.
Sixteen years after regulating advanced therapy medicinal products (ATMPs) in the European Union, few ATMPs have gained marketing authorization. Additionally, market withdrawals for commercial ...reasons and a lack of reimbursement are de facto blocking patient access. Here, we pinpoint the major factors underlying this roadblock and how to circumvent it.
Corneal diseases are among the main causes of blindness, with approximately 4.6 and 23 million patients worldwide suffering from bilateral and unilateral corneal blindness, respectively. The standard ...treatment for severe corneal diseases is corneal transplantation. However, relevant disadvantages, particularly in high-risk conditions, have focused the attention on the search for alternatives.
We report interim findings of a phase I-II clinical study evaluating the safety and preliminary efficacy of a tissue-engineered corneal substitute composed of a nanostructured fibrin-agarose biocompatible scaffold combined with allogeneic corneal epithelial and stromal cells (NANOULCOR). 5 subjects (5 eyes) suffering from trophic corneal ulcers refractory to conventional treatments, who combined stromal degradation or fibrosis and limbal stem cell deficiency, were included and treated with this allogeneic anterior corneal substitute.
The implant completely covered the corneal surface, and ocular surface inflammation decreased following surgery. Only four adverse reactions were registered, and none of them were severe. No detachment, ulcer relapse nor surgical re-interventions were registered after 2 years of follow-up. No signs of graft rejection, local infection or corneal neovascularization were observed either. Efficacy was measured as a significant postoperative improvement in terms of the eye complication grading scales. Anterior segment optical coherence tomography images revealed a more homogeneous and stable ocular surface, with complete scaffold degradation occurring within 3–12 weeks after surgery.
Our findings suggest that the surgical application of this allogeneic anterior human corneal substitute is feasible and safe, showing partial efficacy in the restoration of the corneal surface.
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•NANOULCOR human bioartificial corneas can be surgically implanted in human patients.•Bioartificial human corneas are highly biocompatible and free from side effects.•Preliminary signs of efficacy were found in the first cases grafted with NANOULCOR.
Abstract
A previously developed fibrin‐agarose skin model—UGRSKIN—showed promising clinical results in severely burnt patients. To determine the histological parameters associated to the ...biocompatibility and therapeutic effects of this model, we carried out a comprehensive structural and ultrastructural study of UGRSKIN grafted in severely burnt patients after 3 months of follow‐up. The grafted epidermis was analogue to native human skin from day 30th onward, revealing well‐structured strata with well‐differentiated keratinocytes expressing CK5, CK8, CK10, claudin, plakoglobin, filaggrin, and involucrin in a similar way to controls, suggesting that the epidermis was able to mature and differentiate very early. Melanocytes and Langerhans cells were found from day 30th onward, together with a basement membrane, abundant hemidesmosomes and lack of rete ridges. At the dermal layer, we found an interface between the grafted skin and the host tissue at day 30th, which tended to disappear with time. The grafted superficial dermis showed a progressive increase in properly‐oriented collagen fibers, elastic fibers and proteoglycans, including decorin, similarly to control dermis at day 60‐90th of in vivo follow‐up. Blood vessels determined by CD31 and SMA expression were more abundant in grafted skin than controls, whereas lymphatic vessels were more abundant at day 90th. These results contribute to shed light on the histological parameters associated to biocompatibility and therapeutic effect of the UGRSKIN model grafted in patients and demonstrate that the bioengineered skin grafted in patients is able to mature and differentiate very early at the epithelial level and after 60–90 days at the dermal level.
Stem cell scientists trying to reach patients often lack the multidisciplinary skills needed to overcome complex regulatory barriers and may feel deterred from pursuing clinical implementation. In ...order to help bridge this gap, we offer a European perspective based on our hands-on experience at the Andalusian Initiative for Advanced Therapies.
Cellular therapies have been increasingly applied to diverse human diseases. Intracoronary infusion of bone marrow-derived mononuclear cells (BMMNC) has demonstrated to improve ventricular function ...after acute myocardial infarction. However, less information is available about the role of BMMNC therapy for the treatment of dilated myocardiopathies (DCs) of non-ischemic origin. This article presents the methodological description of a study aimed at investigating the efficacy of intracoronary injection of autologous BMMNCs in the improvement of the ventricular function of patients with DC.
This randomised, placebo-controlled, double-blinded phase IIb clinical trial compares the improvement on ventricular function (measured by the changes on the ejection fraction) of patients receiving the conventional treatment for DC in combination with a single dose of an intracoronary infusion of BMMNCs, with the functional recovery of patients receiving placebo plus conventional treatment. Patients assigned to both treatment groups are monitored for 24 months. This clinical trial is powered enough to detect a change in Left Ventricular Ejection Fraction (LVEF) equal to or greater than 9%, although an interim analysis is planned to re-calculate sample size.
The study protocol was approved by the Andalusian Coordinating Ethics Committee for Biomedical Research (Comité Coordinador de Ética en Investigación Biomédica de Andalucia), the Spanish Medicines and Medical Devices Agency (Agencia Española de Medicamentos y Productos Sanitarios), and is registered at the EU Clinical Trials Register (EudraCT: 2013-002015-98). The publication of the trial results in scientific journals will be performed in accordance with the applicable regulations and guidelines to clinical trials.
ClinicalTrials.gov Identifier NCT02033278 (First Posted January 10, 2014): https://clinicaltrials.gov/ct2/show/NCT02033278 ; EudraCT number: 2013-002015-98, EU CT Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002015-98 . Trial results will also be published according to the CONSORT statement at conferences and reported peer-reviewed journals.
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