Review
Clinical application of cell, gene and tissue therapies in Spain
Aplicación clínica de las terapias con células, genes y tejidos en España
P. Gálvez-Martín
, A. Ruiz, B. Clares
Corresponding author
Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain
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Gálvez-Martín, A. Ruiz, B. Clares" "autores" => array:3 [ 0 => array:4 [ "nombre" => "P." "apellidos" => "Gálvez-Martín" "email" => array:1 [ 0 => "galmafarma@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Ruiz" ] 2 => array:2 [ "nombre" => "B." "apellidos" => "Clares" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Aplicación clínica de las terapias con células, genes y tejidos en España" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2452 "Ancho" => 3340 "Tamanyo" => 449754 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Stem cell classification according to its potentiality and origin. <span class="elsevierStyleItalic">Abbreviation</span>: IPS, induced pluripotent stem cell.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Advances in regenerative medicine have enabled the development of biological therapies, based on the application of cells, genes and tissues as therapeutic elements, therapies that have been called “advanced therapies”. These therapies constitute an emerging area in the treatment of numerous diseases such as malignancies,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> myocardial infarction,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> diabetes mellitus,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> osteochondral lesions<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and nervous system lesions.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Since 2007, regulatory agencies at the national (Spanish Agency for Medicines and Medical Devices [AEMPS]) and European (European Medicines Agency [EMA]) level have enacted legislation governing the classification and human use of biological elements included in the concept of advanced therapies.</p><p id="par0015" class="elsevierStylePara elsevierViewall">In this review, we describe the main aspects that define and classify the drugs based on cells, genes or tissues for human use in Spain, with the objective of facilitating their daily clinical application.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition and classification of advanced therapies</span><p id="par0020" class="elsevierStylePara elsevierViewall">The term “advanced therapies” includes cell therapy, gene therapy and tissue engineering, which are based on the use of cells, genes and tissues, respectively.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The development of these products entails a manufacturing process in which the safety and quality of the biological material must be rigorously controlled.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The first phase consists of obtaining a biological sample or biopsy, which can be of autologous, allogeneic or xenogeneic origin.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The active biological product is then isolated, manipulated and converted into the final product. Quality control is then performed, as well as characterization of the cells, genes or tissues for therapeutic goals. The product is then transported and, finally, administered to the patient (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Cell therapy</span><p id="par0030" class="elsevierStylePara elsevierViewall">The objective of cell therapy is to repair, replace or recover the biological function of a damaged tissue or organ, using specialized cells or stem cells.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Stem cells are nonspecialized cells that are capable of dividing (self-renewal) over indefinite periods during an individual's life. Under appropriate microenvironment conditions, these cells proliferate <span class="elsevierStyleItalic">ex vivo</span> and <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> through asymmetric divisions, differentiating into cells of distinct lineages with specialized characteristics and functions (e.g., erythrocytes, myocytes, neurons and hepatocytes).</p><p id="par0040" class="elsevierStylePara elsevierViewall">Depending on the type of tissue that originates the cells, stem cells are classified as totipotent, pluripotent, multipotent and unipotent.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Depending on their origin, the cells are classified as an embryonic stem cell (ESC), adult stem cell (ASC) or induced pluripotent stem cell (iPS)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Embryonic stem cells</span><p id="par0045" class="elsevierStylePara elsevierViewall">These are pluripotent stem cells from the embryo in the blastocyst phase, which has approximately 100–200 cells. ESCs are characterized by their capacity to remain in an undifferentiated proliferative state for an extended period.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> ESCs are the most polyvalent and have the capacity for originating all cell types of the 3 germ layers: endoderm, mesoderm and ectoderm.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The first ESCs were isolated from mice bone marrow by Evans and Kaufman in 1980.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In 1998, Thomson et al. isolated ESCs from human embryos, from <span class="elsevierStyleItalic">in vitro</span> fertilization clinics.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Experimentally, ESCs have been used successfully in various animal models for regenerating liver cells, hematopoietic stem cells, neuronal tissue and cardiac tissue.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The clinical application of ESCs in humans is still limited, however, due to ethical considerations regarding the use of embryos and the uncertainty in terms of their safety, the risk of formation of teratomas and immune transplant rejection.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Adult stem cells</span><p id="par0055" class="elsevierStylePara elsevierViewall">These cells encompass a large variety of undifferentiated cells located in adult tissues, regardless of the individual's age. These cells have the capacity for single or multiple differentiation. ASCs are characterized by their high proliferative potential and their capacity for self-renewal and differentiation into at least one cell type.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">ASCs divide in a balanced manner, both asymmetrically and symmetrically. Their capacity to undergo asymmetric mitotic divisions produces two differentiated daughter cells for generating progenitors, which subsequently differentiate into mature cell types with specialized functions. Alternatively, ASCs undergo symmetrical divisions in a stochastic manner to produce new stem cells, maintaining their capacity for self-renewal.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The first type of isolated ASC was the hematopoietic stem cell, which is capable of self-renewal and differentiation into multipotent hematopoietic cells.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Subsequently in 1968, Friedenstein et al. described another stem cell population with similar characteristics, which they called “fibroblast colony-forming units”, currently known as mesenchymal stem cells (MSC).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> It is important to note that, to date, ASCs have been identified in practically all organs and tissues of the adult body (e.g., skin, liver, pancreas, blood, kidney, intestine, blood vessels, central nervous system, dental pulp, adipose tissue, skeletal muscle and heart).<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17,20</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">From the clinical standpoint, ASCs are the most widely used stem cells due to their safety, efficacy and the ease with which they are obtained.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21,22</span></a> Nevertheless, the use of ASCs has numerous limitations, such as the identification of the molecular signals that start their activation, the introduction of isolation protocols and simpler cultures, as well as <span class="elsevierStyleItalic">in vitro</span> differentiation that increases their plasticity, the increase in the end product's cellular viability and the cultures’ genetic stability.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Induced pluripotent stem cells</span><p id="par0075" class="elsevierStylePara elsevierViewall">These are pluripotent stem cells derived from nonpluripotent somatic stem cells, manipulated by inserting transcription factors.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The first trials on nuclear genetic material transfer to a somatic cell were conducted with oocytes, inducing their pluripotency by electrochemical stimuli.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In 2006, this technique was improved by Takahashi and Yamanaka, who showed that pluripotent stem cells can be generated from mouse fibroblasts.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,27</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In short, iPSs are reprogrammed cell elements that behave like ESCs. There are, however, functional differences between the two types of stem cells, such as gene expression, DNA methylation, the stability of the pluripotent phenotype and the cells’ epigenetic memory.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the differences between the three cell types: ESC, ASC and iPS.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Gene therapy</span><p id="par0085" class="elsevierStylePara elsevierViewall">This technique involves manipulating the gene expression of a specific cell, which confers new beneficial functions for the patient. The gene manipulation procedures can consist of the replacement of a mutated gene that causes the disease, the inactivation of the mutated gene or the introduction of a new gene.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The design of a gene therapy involves three fundamental elements: the target cells, the therapeutic transgene and the gene transfer vector. The target cell is that which we are attempting to modify genetically, which might coincide with the cell affected by the disease. The transgene or transduced gene is the genetic material (autologous or allogeneic) that is inserted into the target cell. The vector is the support that transports the genetic material and can be of viral origin. The vector must be safe and capable of expressing the desired gene during an extended period and in a sufficiently large cell population to cause a biological effect.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Nonviral vectors (e.g., liposomes, polycations, naked DNA) have greater biological safety but are less effective than viral vectors (adenovirus, retroviruses, lentivirus, adeno-associated virus).<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Tissue engineering</span><p id="par0095" class="elsevierStylePara elsevierViewall">Tissue engineering is an alternative to the use of natural, synthetic or semisynthetic tissues and organs and is defined as the application of engineering principles and methods to develop biological substitutes, using viable or nonviable cells combined with biomaterials and other factors to repair, improve or regenerate tissue function.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Currently, this technique combines the use of stem cells, specialized cells and their extracellular components, as well as factors that accelerate cell proliferation and differentiation, on a matrix or support, with the objective of reproducing a functional three-dimensional structure similar to the damaged tissue or organ.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> The artificial development of tissues and organs through tissue engineering also offers the possibility of performing <span class="elsevierStyleItalic">in vitro</span> studies on the development of a disease or tissue lesion and a drug's efficacy.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The main research lines are currently focused on the study of tissues, such as cartilage, bone, skin, blood vessels, muscles and nerve conduits.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Regulation of advanced therapies in Spain</span><p id="par0105" class="elsevierStylePara elsevierViewall">Medicinal products based on the use of cells, genes and tissues are classified according to their legal requirements as follows: (a) advanced therapy medicinal products (ATMPs), (b) advanced therapy medicinal products of nonindustrial manufacture, (c) platelet-rich plasma (PRP) and (d) medicinal products for special conditions.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Those cell products that are not considered medicinal products are included in cell and tissue transplantation.</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Advanced therapy medicinal products</span><p id="par0110" class="elsevierStylePara elsevierViewall">In 2007, the EMA regulated the use of ATMPs. The authorization of an ATMP is the responsibility of the EMA and allows the marketing of ATMPs in all European Union members, where each of the national agencies must define the cost and funding for each ATMP.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">ATMPs are classified into four types<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>: somatic cell therapy medicinal products (CTMPs), gene therapy medicinal products (GTMPs), tissue-engineered products (TEPs) and combined advanced therapy medicinal products (CPs).</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Somatic cell therapy medicinal products</span><p id="par0120" class="elsevierStylePara elsevierViewall">These products are compounds of live somatic cells or viable tissues whose biological characteristics have been altered for preventive, diagnostic or therapeutic purposes. It is important to note that not all cell products are considered CTMPs. To qualify as a CTMP, the product must meet at least one of the following conditions<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>: (a) the cells have been subjected to “substantial manipulation”, altering their relevant biological characteristics, functions or properties to achieve the therapeutic effect or (b) the manipulated cells lack the capacity to perform their initial biological function. “Substantial manipulation” is considered the slicing, trituration, molding, centrifugation, imbibition in antibiotic or antimicrobial solutions, sterilization, irradiation, separation, concentration, cell purification, filtration, lyophilization, freezing, cryopreservation or vitrification of the cells and/or tissues that make up the CTMP. The <span class="elsevierStyleItalic">in vitro</span> expansion of stem cells (e.g., MSCs) represents substantial manipulation; these types of manipulated cells are therefore considered a CTMP, while the simple isolation of mononuclear bone marrow cells for autologous use is not considered a medicinal product. In this case, the administration of mononuclear cells is considered a cell therapy and/or cell transplantation but not a CTMP. The regulation of these mononuclear cells is the legal responsibility of each member of the European Union.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Gene therapy medicinal products</span><p id="par0125" class="elsevierStylePara elsevierViewall">These products are obtained through a manufacturing process designed to transfer to human and animal cells (<span class="elsevierStyleItalic">in vivo</span> or <span class="elsevierStyleItalic">ex vivo</span>) a gene with preventive, diagnostic or therapeutic utility, for its subsequent <span class="elsevierStyleItalic">in vivo</span> expression.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> An <span class="elsevierStyleItalic">ex vivo</span> gene therapy medicinal product is based on the modification and correction of a genetic disorder, through the extraction of an individual's cells and their manipulation outside the body.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38,39</span></a> In the case of <span class="elsevierStyleItalic">in vivo</span> gene therapy, the genetic modifications are performed inside the patient's body. It is worth noting that vaccines against infectious diseases are not considered GTMPs.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Tissue-engineered products</span><p id="par0130" class="elsevierStylePara elsevierViewall">These products consist of cells or tissues of human, animal or mixed origin (viable or not) that are manipulated by engineering to regenerate, restore or replace a human tissue.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The products can incorporate other substances, such as cell products, growth factors and cytokines. Products consisting only of nonviable cells or tissues without pharmaceutical, immunologic or metabolic action are excluded from this definition.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Currently, the main TEPs are focused on the development of tissues such as cartilage, bone and skin, which incorporate a cell part (MSCs, chondrocytes, fibroblasts, keratinocytes or osteocytes), along with a two-dimensional or three-dimensional support that provides mechanical resistance to the designed tissues.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Combined advanced therapy medicinal products</span><p id="par0135" class="elsevierStylePara elsevierViewall">These products consist of a cell or tissue component (viable or not) combined with one or more medicinal products.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The integrated cells or tissues must exert a clinical effect, acting as an adjuvant to the desired pharmaceutical action. This definition includes ATMPs that are administered along with biomechanical implants and bioprinting systems. These products must already be authorized medicinal products and have a European conformity marking.</p><p id="par0140" class="elsevierStylePara elsevierViewall">To date, the EMA has authorized the marketing of six ATMPs (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Advanced therapy medicinal products of nonindustrial manufacture</span><p id="par0145" class="elsevierStylePara elsevierViewall">In 2014, AEMPS published Royal Decree 477/2014, which governs the authorization of ATMPs of nonindustrial manufacture, to establish the standards for approving and using certain cell and tissue-based products not considered in the European legislation. These products represent a small number of medicinal products, such as autologous chondrocyte transplantation, keratinocyte implantation and limbocorneal stem cells.</p><p id="par0150" class="elsevierStylePara elsevierViewall">These medicinal products require a specific procedure for authorization in Spain, which demonstrates the quality, safety, efficacy, identification and information of the cell or tissue, as well as the consolidated use of the therapy. The administration of these nonindustrially produced medicinal products must be performed in hospital centers, which must request prior authorization from AEMPS for the use of the medicinal product under the responsibility of a licensed physician.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Platelet-rich plasma</span><p id="par0155" class="elsevierStylePara elsevierViewall">Autologous plasma and its fractions, components and derivatives (for nonreplacement therapeutic use and commonly known as PRP or growth factors) are considered medicinal products for human use, in which an industrial process is not involved in the product's preparation. PRP is defined as a volume of autologous plasma obtained from peripheral venous blood, with a concentration between 300,000 and 1,400,000 platelets/μL.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">AEMPS published a report (Report/V1/23052013) in 2013 where it defined the specific regulatory framework for the manufacture and administration of PRP. This report stated that PRP may be manufactured using an open (manual process) or closed technique and referred to commercial techniques. In both cases, the quality, safety and efficacy of the medicinal product must be ensured. PRP must be administered under a restricted prescription by a physician or dentist, in centers authorized by AEMPS and the respective autonomous community.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Medicinal products for special situations</span><p id="par0165" class="elsevierStylePara elsevierViewall">AEMPS has considered the use of unauthorized medicinal products (outside the authorized conditions) in special situations as described in Royal Decree 1015/2009. ATMPs are also included in these situations.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Cell and tissue transplantation</span><p id="par0170" class="elsevierStylePara elsevierViewall">Products with cells and tissues not considered in the definition of an ATMP are considered transplants and are regulated by Royal Decree 9/2014, which established the standards of quality and safety for donating, obtaining, assessing, processing, preserving, storing and distributing human cells and tissues. The decree also approved the standards for coordination and operation for the use of these products in humans. Tissues and cells for transplantation should be obtained in centers authorized by the competent healthcare institution (autonomous community). A specific authorization must be requested for each type of cell and tissue.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Currently, 6598 clinical trials with cells, genes and tissues have been authorized worldwide, 224 of which have been conducted in Spain.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Despite the considerable number of clinical trials currently underway, the required mechanism of action of cells, genes and tissues as pharmacologically active ingredients is still unclear. There are therefore numerous preclinical and basic research studies dedicated to determining this mechanism.</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1022766" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec980852" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1022767" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec980853" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Definition and classification of advanced therapies" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "sec0015" "titulo" => "Cell therapy" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Embryonic stem cells" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Adult stem cells" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Induced pluripotent stem cells" ] ] ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Gene therapy" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Tissue engineering" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Regulation of advanced therapies in Spain" "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0050" "titulo" => "Advanced therapy medicinal products" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Somatic cell therapy medicinal products" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Gene therapy medicinal products" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Tissue-engineered products" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Combined advanced therapy medicinal products" ] ] ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Advanced therapy medicinal products of nonindustrial manufacture" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Platelet-rich plasma" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Medicinal products for special situations" ] 4 => array:2 [ "identificador" => "sec0090" "titulo" => "Cell and tissue transplantation" ] ] ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-06-28" "fechaAceptado" => "2017-08-13" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec980852" "palabras" => array:6 [ 0 => "Stem cells" 1 => "Cell therapy" 2 => "Gene therapy" 3 => "Tissue engineering" 4 => "Advanced therapies" 5 => "Regenerative medicine" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec980853" "palabras" => array:6 [ 0 => "Célula madre" 1 => "Terapia celular" 2 => "Terapia génica" 3 => "Ingeniería tisular" 4 => "Terapias avanzadas" 5 => "Medicina regenerativa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Scientific and technical advances in the areas of biomedicine and regenerative medicine have enabled the development of new treatments known as “advanced therapies”, which encompass cell therapy, genetics and tissue engineering. The biologic products that can be manufactured from these elements are classified from the standpoint of the Spanish Agency of Medication and Health Products in advanced drug therapies, blood products and transplants. This review seeks to provide scientific and administrative information for clinicians on the use of these biologic resources.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los avances científicos y técnicos en el área biomédica y la medicina regenerativa han permitido el desarrollo de nuevos tratamientos, denominados «terapias avanzadas», que engloban la terapia celular, la génica y la ingeniería tisular. Los productos biológicos que pueden fabricarse a partir de estos elementos se clasifican desde el punto de vista de la Agencia Española del Medicamento y Productos Sanitarios en medicamentos de terapias avanzadas, productos derivados de la sangre y trasplantes. Esta revisión pretende aportar información científica y administrativa, de utilidad para el clínico, sobre el uso de estos recursos biológicos.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Gálvez-Martín P, Ruiz A, Clares B. Aplicación clínica de las terapias con células, genes y tejidos en España. Rev Clin Esp. 2018;218:199–206.</p>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2107 "Ancho" => 2333 "Tamanyo" => 201227 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Phases of development of advanced therapies.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2452 "Ancho" => 3340 "Tamanyo" => 449754 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Stem cell classification according to its potentiality and origin. <span class="elsevierStyleItalic">Abbreviation</span>: IPS, induced pluripotent stem cell.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Embryonic stem cells \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adult stem cells \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Induced stem cells \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Properties \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pluripotent<br>Genetically compatible with the patient<br>High capacity for expansion and culture \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Multipotent-unipotent<br>Genetically compatible with the patient<br>Low tumorigenic risk<br>Demonstrated clinical application \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pluripotent<br>Genetically compatible with the patient \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Limitations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Limited number of available cell lines<br>Immune rejection<br>Risk of creating teratomas<br>Restricted clinical use \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Limited cell types<br>Difficult to identify<br>Limited capacity for expansion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Risk of mutagenesis due to the use of viral vectors<br>Risk of cancer and senescence<br>Risk of creating teratomas<br>Restricted clinical use \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ethical problems \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Destruction of human blast cells<br>Informed consent required for the donation of ovules and blast cells<br>Improper use of the reproductive cloning \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Without major ethical considerations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Without major ethical considerations \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1738115.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Properties, limitations and ethical problems of the various types of stem cells in cell therapy.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>: ATMP, advanced therapy medicinal product; CTMP, cell therapy medicinal product; PAP-GMCSF, prostatic acid phosphatase-granulocyte-macrophage colony-stimulating factor; GTMP, gene therapy medicinal product; TEP, tissue engineering product.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of ATMP \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Brand name \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Company (date of authorization) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cell, gene or tissue \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pharmaceutical form \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose and posology \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic indication \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CTMP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Provenge®<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dendreon UK Limited, United Kingdom<br>(2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autologous peripheral blood mononuclear cells activated with PAP-GMCSF (Sipuleucel-T) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dispersion for infusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 doses (approx. every 2 weeks): 50<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>106 CD54 cells<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>autologous activated with PAP-GMCSF, suspended in 250<span class="elsevierStyleHsp" style=""></span>mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Asymptomatic or minimally symptomatic (nonvisceral) castration-resistant metastatic prostate cancer in adult men for whom chemotherapy is still not clinically indicated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">GTMP</td><td class="td" title="table-entry " align="left" valign="top">Glybera® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UniQure Biopharma B.V., The Netherlands<br>(2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alipogene tiparvovec, a gene variant of the human lipoprotein lipase, LPLS447X, bound to a vector formed by a protein coating derived from the adeno-associated virus serotype 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Injectable solution of 3<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">12</span> genomic copies (cg)/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dosage:(patient weight in kg/3)<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>number of injection points and total number of syringes<br>Dose in each injection point: 1.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1012<span class="elsevierStyleHsp" style=""></span>cg (0.5<span class="elsevierStyleHsp" style=""></span>mL of injectable solution) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hereditary lipoprotein lipase deficiency that has presented severe or multiple attacks of pancreatitis despite maintaining a low-fat diet \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Imlygic® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Amgen Europe B.V., The Netherlands<br>(2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Talimogene laherparepvec, oncolytic virus derived from the herpes simplex virus type 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Injectable solution of 10<span class="elsevierStyleSup">6</span> and 10<span class="elsevierStyleSup">8</span> plaque-forming units (pfu)/mL of injectable solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Initial dose: up to 4<span class="elsevierStyleHsp" style=""></span>mL of 10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>pfu<br>Dose to the 3rd week: up to 4<span class="elsevierStyleHsp" style=""></span>mL of 10<span class="elsevierStyleSup">8</span><span class="elsevierStyleHsp" style=""></span>pfu<br>Dose to the 5rd week: up to 4<span class="elsevierStyleHsp" style=""></span>mL of 10<span class="elsevierStyleSup">8</span><span class="elsevierStyleHsp" style=""></span>pfu<br>**The volume of Imlygic to be injected depends on the size of the lesion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unresectable melanoma and regional or distant metastases (stages IIIB, IIIC and IVM1a) without bone, brain, lung or other visceral diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">TEP</td><td class="td" title="table-entry " align="left" valign="top">CondroCelet® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tigenix, Belgium<br>(2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autologous human chondrocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cell suspension of 4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> of autologous human chondrocytes in 0.4<span class="elsevierStyleHsp" style=""></span>mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.8–10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>cells/cm<span class="elsevierStyleSup">2</span>, equivalent to between 80 and 100<span class="elsevierStyleHsp" style=""></span>μL of the product by cm<span class="elsevierStyleSup">2</span> of lesion<br>Cover the lesion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cartilage defects in the femoral condyle of the knee measuring 1–5<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> (grade III or IV of the International Cartilage Repair Society) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MACI®<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Genzyme, Sanofi Biosurgery<br>(2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autologous human chondrocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Collagen membrane type I/III measuring 14.5<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span> to 1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span> cells/cm<span class="elsevierStyleSup">2</span> of matrix<br>Cover the lesion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Knee cartilage lesions measuring 3–20<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Holoclar® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chiesi Farmaceutici SPA, Italy<br>(2015) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Autologous human corneal epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Circular fibrin membrane measuring 2.2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79,000–316,000<span class="elsevierStyleHsp" style=""></span>cells/cm<span class="elsevierStyleSup">2</span> of matrix<br>1<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">2</span> of medication per cm<span class="elsevierStyleSup">2</span> of lesion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate or intense limbal stem cell deficiency in the cornea caused by physical or chemical burns \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1738116.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Marketing suspended due to business reasons.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Advanced therapy drugs authorized in Spain.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impact of human adipose tissue-derived stem cells on breast cancer cells: implications for cell-assisted lipotransfers in breast reconstruction" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. 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