Umbilical Cord Blood Platelet Rich Plasma Derivatives for Therapeutic Applications and Development of Clinical Trials for Treatment of Skin and Ocular Ulcers

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Umbilical Cord Blood Platelet Rich Plasma Derivatives for Therapeutic Applications and Development of Clinical Trials for Treatment of Skin and Ocular Ulcers ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en PhD THESIS Title: Umbilical Cord Blood Platelet Rich Plasma derivatives for therapeutic applications and development of clinical trials for treatment of skin and ocular ulcers PhD Student: Dinara Samarkanova Directors: Dr. Sergio Luis Querol Giner Dr. Ricardo Pedro Casaroli-Marano Tutor: Dr. Susan Webb Youdale Department: PhD in Medicine, Department of Medicine, Universitat Autònoma de Barcelona Barcelona, 2020 The future belongs to those who believes in the beauty of their dreams. Eleanor Roosevelt 2 Acknowledgements: First of all, I would like to acknowledge Dr Sergio Querol. Thank you for showing me how to stand my ground and have a career that I can be proud of. I can count myself lucky for having had you as my mentor. Accept my heartfelt gratitude for your time, patience, support, and trust. Thank to Dr Ricardo Casaroli for support and to be a part of this work. I really appreciate your advice and support. Also for kind tutorship of Dr. Susan Webb. I thank cord blood donors and health care professionals in all hospitals participating in the Programa Concordia BST for making the public cord blood program possible. I thank the Banc de Sang i Teixits staff, including central and territorial centers, for all support and kind help during the projects, and all colleagues in the Cell Therapy service for their incredible support, especially to Dr Luciano Rodriguez for his support and improving the quality of projects, as well as for facilitating me the attendance of patients. My gratitude to Professor Paolo Rebulla for mentorship, his support, scientific consultations during the progression of the projects, and critical revision of manuscripts. I would like thank all Hospital staff who took a part in the projects development and took care of each patient treated with our products. Additionally, I acknowledge to Anthony Nolan Research Institute staff, especially Professor Alejandro Madrigal, Dr. Diana Hernandez and Dr. Steven Cox. I also would like thank Dr. Margarita Codinach, Dr. Emma Enrich and Dr. Anna Belen Alvarez for their critical revision of the Thesis. The biggest acknowledgment is for my loving mother – Samarkanova Sholpan, very positive person, she always insisted on investing in education and never give up. During the PhD I also built a family and had my best project – my son – Dani – the fruit of globalization. Thanks to my husband – Leonardo Colussi for his love and support. Special mention to all those who have accompanied me on this interesting path to pursue the development of this PhD thesis. 3 Abbreviations: BST – Banc de Sang i Teixits CT – clinical trial CB – cord blood CBB – cord blood bank CBED – cord blood eye drops CBPG – cord blood platelet gel GVHD – graft versus host disease PB – peripheral blood PBMC – peripheral blood mononuclear cells PC – platelet concentrates PG – platelet gel PL – platelet lysate PPP – platelet poor plasma PR – platelet releasate PRP – platelet rich plasma 4 Index: Abstract ................................................................................................................................................. 7 Resumen ................................................................................................................................................ 8 I. Introduction: .................................................................................................................................. 9 1. Cord blood for therapy: state-of-the art ................................................................................. 10 1.1. Cord blood for transplantation ........................................................................................ 10 1.2. Cord blood Banks ............................................................................................................ 10 1.3. Cord blood collection and processing ............................................................................. 11 1.4. Cord blood beyond transplantation ................................................................................ 12 2. Cord blood derived medicinal products ............................................................................... 13 2.1. Cord blood as starting material for advanced therapies................................................. 15 2.2. Multicomponent cord blood bank. ................................................................................. 16 3. Plasma, platelets and other bioactive components in cord blood ............................................ 17 4. The wound healing .................................................................................................................. 22 5. Cord blood platelet rich plasma derivatives in wound healing ............................................... 22 5.1. Mechanism of action ....................................................................................................... 22 5.2. Clinical uses ..................................................................................................................... 24 5.2.1. PRP derived product for skin lesions ........................................................................... 24 5.2.2. Blood derived eye drops for ophthalmic application .................................................. 27 5.3. Other application of cord blood PRP derivatives ............................................................ 32 II. Hypothesis ................................................................................................................................... 34 III. Objectives ................................................................................................................................ 36 IV. Materials & Methods .............................................................................................................. 38 Paper 1. Cord blood derived platelet concentrates as starting material for new therapeutic blood- components prepared in a public cord blood bank: from product development to clinical application....................................................................................................................................... 40 Paper 2. Cord Blood Platelet Rich Plasma Derivatives for Clinical Applications in Non-transfusion Medicine .......................................................................................................................................... 53 Paper 3. Clinical evaluation of allogeneic eye drops from cord blood platelet lysate ..................... 69 V. Results summary ......................................................................................................................... 97 VI. Discussion .............................................................................................................................. 101 VII. Conclusions ................................................................................................................................. 108 VIII. Future investigations ................................................................................................................. 110 IX. References .................................................................................................................................... 112 X. Annex............................................................................................................................................. 129 5 Annex I. Paper 4. Rapid review: next generation of cord blood banks; transplantation and beyond. ....................................................................................................................................................... 130 Annex II. Ethical considerations .................................................................................................... 134 Annex III. Thesis projects development ........................................................................................ 135 1. Public cord blood banks for large scale production of PRP derivatives ............................ 135 2. Concordia Program ............................................................................................................ 135 3. The Research BioBank at Banc de Sang i Teixits ............................................................... 136 4. Spanish regulations for allogeneic PRP and their derivatives ........................................... 137 5. CB-PRP projects development .......................................................................................... 137 6 Abstract Background: There are many advantages to using cord blood (CB) as a source of therapeutic platelet and plasma derivatives for regenerative medicine. These include availability, universal use, young donor source, and virally safe biological material, rich in tissue regenerative factors. CB platelet rich plasma (CB-PRP) derivatives have been investigated as potential therapeutic agents for the treatment
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