Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento

Introducción y objetivo: La úlcera de pie diabético (UPD), es una complicación frecuente con alta carga de morbi-mortalidad en pacientes con Diabetes Mellitus (DM). La medicina regenerativa aparece como estrategia efectiva y segura en el tratamiento de la UPD. Nuestro objetivo fue evaluar el efecto...

Full description

Autores:
Celis Acevedo, Emmanuel José
Tipo de recurso:
Fecha de publicación:
2021
Institución:
Universidad Autónoma de Bucaramanga - UNAB
Repositorio:
Repositorio UNAB
Idioma:
spa
OAI Identifier:
oai:repository.unab.edu.co:20.500.12749/13931
Acceso en línea:
http://hdl.handle.net/20.500.12749/13931
Palabra clave:
Internal medicine
Medicine
Medical sciences
Health sciences
Diabetic foot ulcer
Clinical trial
Mother cells
Metabolism disorders
Endocrine gland diseases
Foot diseases
Medicina interna
Medicina
Ciencias médicas
Trastornos del metabolismo
Enfermedades de las glándulas endocrinas
Enfermedades delos pies
Ciencias de la salud
Úlcera de pie diabético
Ensayo clínico
Células madre
Rights
openAccess
License
http://creativecommons.org/licenses/by-nc-nd/2.5/co/
id UNAB2_8a173ee12e5ee695220ee570938fe64f
oai_identifier_str oai:repository.unab.edu.co:20.500.12749/13931
network_acronym_str UNAB2
network_name_str Repositorio UNAB
repository_id_str
dc.title.spa.fl_str_mv Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
dc.title.translated.spa.fl_str_mv Evaluation of the rate of closure of diabetic foot ulcers with the use of acellular derivatives of mesenchymal stem cells as treatment
title Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
spellingShingle Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
Internal medicine
Medicine
Medical sciences
Health sciences
Diabetic foot ulcer
Clinical trial
Mother cells
Metabolism disorders
Endocrine gland diseases
Foot diseases
Medicina interna
Medicina
Ciencias médicas
Trastornos del metabolismo
Enfermedades de las glándulas endocrinas
Enfermedades delos pies
Ciencias de la salud
Úlcera de pie diabético
Ensayo clínico
Células madre
title_short Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
title_full Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
title_fullStr Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
title_full_unstemmed Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
title_sort Evaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamiento
dc.creator.fl_str_mv Celis Acevedo, Emmanuel José
dc.contributor.advisor.none.fl_str_mv Arango Rodríguez, Martha Ligia
Wandurraga Sánchez, Edwin Antonio
Ochoa Vera, Miguel Enrique
dc.contributor.author.none.fl_str_mv Celis Acevedo, Emmanuel José
dc.contributor.cvlac.spa.fl_str_mv Wandurraga Sánchez, Edwin Antonio [0001475567]
Ochoa Vera, Miguel Enrique [0000898465]
dc.contributor.orcid.spa.fl_str_mv Ochoa Vera, Miguel Enrique [0000-0002-4552-3388]
dc.contributor.researchgate.spa.fl_str_mv Wandurraga Sánchez, Edwin Antonio [Edwin-Antonio-Wandurraga-Sanchez-2168480303]
Ochoa Vera, Miguel Enrique [Miguel-Enrique-Ochoa-2186675588]
dc.subject.keywords.spa.fl_str_mv Internal medicine
Medicine
Medical sciences
Health sciences
Diabetic foot ulcer
Clinical trial
Mother cells
Metabolism disorders
Endocrine gland diseases
Foot diseases
topic Internal medicine
Medicine
Medical sciences
Health sciences
Diabetic foot ulcer
Clinical trial
Mother cells
Metabolism disorders
Endocrine gland diseases
Foot diseases
Medicina interna
Medicina
Ciencias médicas
Trastornos del metabolismo
Enfermedades de las glándulas endocrinas
Enfermedades delos pies
Ciencias de la salud
Úlcera de pie diabético
Ensayo clínico
Células madre
dc.subject.lemb.spa.fl_str_mv Medicina interna
Medicina
Ciencias médicas
Trastornos del metabolismo
Enfermedades de las glándulas endocrinas
Enfermedades delos pies
dc.subject.proposal.spa.fl_str_mv Ciencias de la salud
Úlcera de pie diabético
Ensayo clínico
Células madre
description Introducción y objetivo: La úlcera de pie diabético (UPD), es una complicación frecuente con alta carga de morbi-mortalidad en pacientes con Diabetes Mellitus (DM). La medicina regenerativa aparece como estrategia efectiva y segura en el tratamiento de la UPD. Nuestro objetivo fue evaluar el efecto terapéutico de los derivados acelulares de células madre mesenquimales (dac-MSCs), en UPD tipo 1 y tipo 2. Materiales y métodos: Se realizó un análisis secundario de los datos obtenidos del ensayo clínico realizado en Foscal Internacional. El Análisis de datos para cinética y velocidad de la UPD se hizo realizando una comparación entro los grupos experimentales mediante la prueba de ANOVA y mediante un post-test de comparación múltiple de Bonferroni. Se calculó además la función de sobrevida de la úlcera hasta su cierre al 50% y 100% mediante el método de Kaplan-Meier. Finalmente se realizó un análisis de cociente de riesgo (HR, por sus siglas en ingles) al cierre de la úlcera al 50% y al 100%. Resultados: El 60.7% de los participantes fueron hombres, la media de edad fue de 61.5 ± 7.8 años y al inicio del tratamiento el 75% los participantes presentaron una HbA1c fuera de metas (HbA1c > 7%). Tanto los pacientes con UPD tipo 1 como tipo 2, lograron un velocidad y cinética de cierra mayor en comparación con el grupo de terapia convencional. El análisis de sobrevida de la úlcera hasta el cierre al 50 y 100% de la UPD mostró mayor eficacia tanto en el grupo de dac-MSCs y células madre mesenquimales de medula ósea (BM-MSCs) en comparación con el grupo convencional. El cociente de riesgo (HR, por sus siglas en ingles), de cierre de las UPD al 50 y 100%, fue significamente mayor en pacientes tratados con dac-MSCs y BM-MSCs en comparación con el grupo de tratamiento convencional. Conclusiones: La medicina regenerativa (BM-MSCs y dac-MSCS), surge como una estrategia terapéutica efectiva y segura para el tratamiento de pacientes con UPD.
publishDate 2021
dc.date.accessioned.none.fl_str_mv 2021-08-19T22:45:56Z
dc.date.available.none.fl_str_mv 2021-08-19T22:45:56Z
dc.date.issued.none.fl_str_mv 2021
dc.type.driver.none.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.local.spa.fl_str_mv Tesis
dc.type.redcol.none.fl_str_mv http://purl.org/redcol/resource_type/TM
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/20.500.12749/13931
dc.identifier.instname.spa.fl_str_mv instname:Universidad Autónoma de Bucaramanga - UNAB
dc.identifier.reponame.spa.fl_str_mv reponame:Repositorio Institucional UNAB
dc.identifier.repourl.spa.fl_str_mv repourl:https://repository.unab.edu.co
url http://hdl.handle.net/20.500.12749/13931
identifier_str_mv instname:Universidad Autónoma de Bucaramanga - UNAB
reponame:Repositorio Institucional UNAB
repourl:https://repository.unab.edu.co
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv 1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019.
2. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98
3. A M. Diabetic Foot in Colombia. In: Dardik A (eds) Vascular Surgery Springer, Cham. 2017.
4. Snyder RJ, Hanft JR. Diabetic foot ulcers--effects on QOL, costs, and mortality and the role of standard wound care and advanced-care therapies. Ostomy Wound Manage. 2009;55(11):28-38.
5. Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, 3rd, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the beta-Cell-Centric Classification Schema. Diabetes Care. 2016;39(2):179-86.
6. Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes. 2017;66(2):241-55.
7. Vargas-Uricoechea H, Casas-Figueroa LA. An Epidemiologic Analysis of Diabetes in Colombia. Ann Glob Health. 2015;81(6):742-53.
8. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis (dagger). Ann Med. 2017;49(2):106-16
9. Armstrong DG, Lavery LA. Diabetic foot ulcers: prevention, diagnosis and classification. Am Fam Physician. 1998;57(6):1325-32, 37-8
10. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376(24):2367-75.
11. Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, Cid-Baez MA, Zamudio-Osuna MJ, Martinez-Blanco MDR, et al. Current Therapeutic Strategies in Diabetic Foot Ulcers. Medicina (Kaunas). 2019;55(11).
12. Schaper NC. Diabetic foot ulcer classification system for research purposes: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev. 2004;20 Suppl 1:S90-5
13. Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol. 2016;91(5):614-20
14. Ridiandries A, Tan JTM, Bursill CA. The Role of Chemokines in Wound Healing. Int J Mol Sci. 2018;19(10).
15. Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: Clinical review. J Tissue Viability. 2016;25(4):229-36.
16. Nour S, Baheiraei N, Imani R, Khodaei M, Alizadeh A, Rabiee N, et al. A review of accelerated wound healing approaches: biomaterial- assisted tissue remodeling. J Mater Sci Mater Med. 2019;30(10):120.
17. Matoori S, Veves A, Mooney DJ. Advanced bandages for diabetic wound healing. Sci Transl Med. 2021;13(585).
18. Mavrogenis AF, Megaloikonomos PD, Antoniadou T, Igoumenou VG, Panagopoulos GN, Dimopoulos L, et al. Current concepts for the evaluation and management of diabetic foot ulcers. EFORT Open Rev. 2018;3(9):513-25
19. Borys S, Ludwig-Slomczynska AH, Seweryn M, Hohendorff J, Koblik T, Machlowska J, et al. Negative pressure wound therapy in the treatment of diabetic foot ulcers may be mediated through differential gene expression. Acta Diabetol. 2019;56(1):115-20.
20. Petrofsky JS, Lawson D, Berk L, Suh H. Enhanced healing of diabetic foot ulcers using local heat and electrical stimulation for 30 min three times per week. J Diabetes. 2010;2(1):41-6.
21. Londahl M, Boulton AJM. Hyperbaric oxygen therapy in diabetic foot ulceration: Useless or useful? A battle. Diabetes Metab Res Rev. 2020;36 Suppl 1:e3233
22. Cao Y, Gang X, Sun C, Wang G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J Diabetes Res. 2017;2017:9328347.
23. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230-47
24. Friedenstein AJ. Stromal mechanisms of bone marrow: cloning in vitro and retransplantation in vivo. Haematol Blood Transfus. 1980;25:19-29
25. Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.
26. Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem Cell Investig. 2019;6:34.
27. de Mayo T, Conget P, Becerra-Bayona S, Sossa CL, Galvis V, Arango-Rodriguez ML. The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. PLoS One. 2017;12(6):e0177533.
28. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648-59.
29. Basiouny HS, Salama NM, Maadawi ZM, Farag EA. Effect of bone marrow derived mesenchymal stem cells on healing of induced full-thickness skin wounds in albino rat. Int J Stem Cells. 2013;6(1):12-25.
30. L PK, Kandoi S, Misra R, S V, K R, Verma RS. The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine Growth Factor Rev. 2019;46:1-9
31. Tocci A, Parolini I, Gabbianelli M, Testa U, Luchetti L, Samoggia P, et al. Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program. Blood. 1996;88(8):2878-88.
32. Nuschke A. Activity of mesenchymal stem cells in therapies for chronic skin wound healing. Organogenesis. 2014;10(1):29-37.
33. Obaid1 HAA, Eljedi2 A. Risk Factors for the Development of Diabetic Foot Ulcers in Gaza Strip: A Case-Control Study. International Journal of Diabetes Research 2019
34. Eleuteri S, Fierabracci A. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. Int J Mol Sci. 2019;20(18).
35. Cargnoni A, Piccinelli EC, Ressel L, Rossi D, Magatti M, Toschi I, et al. Conditioned medium from amniotic membrane-derived cells prevents lung fibrosis and 51 Protocolo V-01 – 26 de febrero 2020 preserves blood gas exchanges in bleomycin-injured mice-specificity of the effects and insights into possible mechanisms. Cytotherapy. 2014;16(1):17-32.
36. Guo ZY, Sun X, Xu XL, Zhao Q, Peng J, Wang Y. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res. 2015;10(4):651-8
37. Becerra-Bayona SM, Solarte-David VA, Sossa CL, Mateus LC, Villamil M, Pereira J, et al. Mesenchymal stem cells derivatives as a novel and potential therapeutic approach to treat diabetic foot ulcers. Endocrinol Diabetes Metab Case Rep. 2020;2020.
38. Bakker K, Apelqvist J, Lipsky BA, Van Netten JJ, International Working Group on the Diabetic F. The 2015 IWGDF guidance documents on prevention and management of foot problems in diabetes: development of an evidence-based global consensus. Diabetes Metab Res Rev. 2016;32 Suppl 1:2-6
39. Vargas-Uricoechea H, Casas-Figueroa LA. [Epidemiology of diabetes mellitus in South America: The experience of Colombia]. Clin Investig Arterioscler. 2016;28(5):245- 56
40. Carstens MH, Quintana FJ, Calderwood ST, Sevilla JP, Rios AB, Rivera CM, et al. Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year. Stem Cells Transl Med. 2021
41. Zhao L, Guo Z, Chen K, Yang W, Wan X, Zeng P, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing. Stem Cells Int. 2020;2020:8863649
42. Moon KC, Suh HS, Kim KB, Han SK, Young KW, Lee JW, et al. Potential of Allogeneic Adipose-Derived Stem Cell-Hydrogel Complex for Treating Diabetic Foot Ulcers. Diabetes. 2019;68(4):837-46.
43. Maksimova N, Krasheninnikov M, Zhang Y, Ponomarev E, Pomytkin I, Melnichenko G, et al. Early passage autologous mesenchymal stromal cells accelerate diabetic wound re-epithelialization: A clinical case study. Cytotherapy. 2017;19(12):1548-50
44. Qin HL, Zhu XH, Zhang B, Zhou L, Wang WY. Clinical Evaluation of Human Umbilical Cord Mesenchymal Stem Cell Transplantation After Angioplasty for Diabetic Foot. Exp Clin Endocrinol Diabetes. 2016;124(8):497-503
45. Jiang X, Zhang H, Teng M. Effectiveness of Autologous Stem Cell Therapy for the Treatment of Lower Extremity Ulcers: A Systematic Review and Meta-Analysis. Medicine (Baltimore). 2016;95(11):e271
46. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554-60.
47. Jain P, Perakath B, Jesudason MR, Nayak S. The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study. Ostomy Wound Manage. 2011;57(7):38-44
48. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009;12(5):359-66.
49. Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin 52 Protocolo V-01 – 26 de febrero 2020 spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299-312
50. Xu Y, Huang S, Ma K, Fu X, Han W, Sheng Z. Promising new potential for mesenchymal stem cells derived from human umbilical cord Wharton's jelly: sweat gland cell-like differentiative capacity. J Tissue Eng Regen Med. 2012;6(8):645-54
51. Santamaria N, Ogce F, Gorelik A. Healing rate calculation in the diabetic foot ulcer: comparing different methods. Wound Repair Regen. 2012;20(5):786-9.
52. Pedras S, Carvalho R, Pereira Mda G. Sociodemographic and clinical characteristics of patients with diabetic foot ulcer. Rev Assoc Med Bras (1992). 2016;62(2):171-8
54. Abolfotouh MA, Alfaifi SA, Al-Gannas AS. Risk factors of diabetic foot in central Saudi Arabia. Saudi Med J. 2011;32(7):708-13.
55. MD MHJ. Disorders of the Foot and Ankle: Medical and Surgical Management,.3- Volume Set 2nd Edición
56. Brand PW. Diabetic foot - what can we learn from leprosy? Diabetes/Metabolism Research and Reviews 2012(6).
57. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26-36
58. Wu Q, Lei X, Chen L, Zheng Y, Huang H, Qian C, et al. Autologous platelet-rich gel combined with in vitro amplification of bone marrow mesenchymal stem cell transplantation to treat the diabetic foot ulcer: a case report. Ann Transl Med. 2018;6(15):307
59. Arno AI, Amini-Nik S, Blit PH, Al-Shehab M, Belo C, Herer E, et al. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling. Stem Cell Res Ther. 2014;5(1):28
60. Vieira Paladino F, de Moraes Rodrigues J, da Silva A, Goldberg AC. The Immunomodulatory Potential of Wharton's Jelly Mesenchymal Stem/Stromal Cells. Stem Cells Int. 2019;2019:3548917
61. Stefanska K, Ozegowska K, Hutchings G, Popis M, Moncrieff L, Dompe C, et al. Human Wharton's Jelly-Cellular Specificity, Stemness Potency, Animal Models, and Current Application in Human Clinical Trials. J Clin Med. 2020;9(4)
62. da Silva Meirelles L, Bolontrade MF, Markoski MM, Dallagiovanna B, Alaniz L. Improving the Therapeutic Ability of Mesenchymal Stem/Stromal Cells for the Treatment of Conditions Influenced by Immune Cells. Stem Cells Int. 2019;2019:6820395
63. Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150-6
64. Li M, Soder R, Abhyankar S, Abdelhakim H, Braun MW, Trinidad CV, et al. WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1. J Extracell Vesicles. 2021;10(4):e12067
65. Maacha S, Sidahmed H, Jacob S, Gentilcore G, Calzone R, Grivel JC, et al. Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis. Stem Cells Int. 2020;2020:4356359
66. Valle-Prieto A, Conget PA. Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev. 2010;19(12):1885-93
67. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol. 2014;34:132-43
68. Chen D, Hao H, Fu X, Han W. Insight into Reepithelialization: How Do Mesenchymal Stem Cells Perform? Stem Cells Int. 2016;2016:6120173.
dc.rights.uri.*.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/2.5/co/
dc.rights.local.spa.fl_str_mv Abierto (Texto Completo)
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
http://purl.org/coar/access_right/c_abf2
dc.rights.creativecommons.*.fl_str_mv Atribución-NoComercial-SinDerivadas 2.5 Colombia
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/2.5/co/
Abierto (Texto Completo)
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-SinDerivadas 2.5 Colombia
eu_rights_str_mv openAccess
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.coverage.spatial.spa.fl_str_mv Colombia
dc.publisher.grantor.spa.fl_str_mv Universidad Autónoma de Bucaramanga UNAB
dc.publisher.faculty.spa.fl_str_mv Facultad Ciencias de la Salud
dc.publisher.program.spa.fl_str_mv Especialización en Medicina Interna
institution Universidad Autónoma de Bucaramanga - UNAB
bitstream.url.fl_str_mv https://repository.unab.edu.co/bitstream/20.500.12749/13931/1/2021_Tesis_Enmanuel_Jose_Celis.pdf
https://repository.unab.edu.co/bitstream/20.500.12749/13931/2/2021_Licencia_Enmanuel_Jose_Celis.pdf
https://repository.unab.edu.co/bitstream/20.500.12749/13931/3/license.txt
https://repository.unab.edu.co/bitstream/20.500.12749/13931/4/2021_Tesis_Enmanuel_Jose_Celis.pdf.jpg
https://repository.unab.edu.co/bitstream/20.500.12749/13931/5/2021_Licencia_Enmanuel_Jose_Celis.pdf.jpg
bitstream.checksum.fl_str_mv 1b30b8d3be8c901af291669da899034d
7fb879a88ddfe19bc27d4be7b410799e
8a4605be74aa9ea9d79846c1fba20a33
5582080440b3aca1f23178392b82b5ab
997d1ffb32d17f4c3b25483c10aea55f
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional | Universidad Autónoma de Bucaramanga - UNAB
repository.mail.fl_str_mv repositorio@unab.edu.co
_version_ 1814277623941955584
spelling Arango Rodríguez, Martha LigiaWandurraga Sánchez, Edwin AntonioOchoa Vera, Miguel EnriqueCelis Acevedo, Emmanuel JoséWandurraga Sánchez, Edwin Antonio [0001475567]Ochoa Vera, Miguel Enrique [0000898465]Ochoa Vera, Miguel Enrique [0000-0002-4552-3388]Wandurraga Sánchez, Edwin Antonio [Edwin-Antonio-Wandurraga-Sanchez-2168480303]Ochoa Vera, Miguel Enrique [Miguel-Enrique-Ochoa-2186675588]Colombia2021-08-19T22:45:56Z2021-08-19T22:45:56Z2021http://hdl.handle.net/20.500.12749/13931instname:Universidad Autónoma de Bucaramanga - UNABreponame:Repositorio Institucional UNABrepourl:https://repository.unab.edu.coIntroducción y objetivo: La úlcera de pie diabético (UPD), es una complicación frecuente con alta carga de morbi-mortalidad en pacientes con Diabetes Mellitus (DM). La medicina regenerativa aparece como estrategia efectiva y segura en el tratamiento de la UPD. Nuestro objetivo fue evaluar el efecto terapéutico de los derivados acelulares de células madre mesenquimales (dac-MSCs), en UPD tipo 1 y tipo 2. Materiales y métodos: Se realizó un análisis secundario de los datos obtenidos del ensayo clínico realizado en Foscal Internacional. El Análisis de datos para cinética y velocidad de la UPD se hizo realizando una comparación entro los grupos experimentales mediante la prueba de ANOVA y mediante un post-test de comparación múltiple de Bonferroni. Se calculó además la función de sobrevida de la úlcera hasta su cierre al 50% y 100% mediante el método de Kaplan-Meier. Finalmente se realizó un análisis de cociente de riesgo (HR, por sus siglas en ingles) al cierre de la úlcera al 50% y al 100%. Resultados: El 60.7% de los participantes fueron hombres, la media de edad fue de 61.5 ± 7.8 años y al inicio del tratamiento el 75% los participantes presentaron una HbA1c fuera de metas (HbA1c > 7%). Tanto los pacientes con UPD tipo 1 como tipo 2, lograron un velocidad y cinética de cierra mayor en comparación con el grupo de terapia convencional. El análisis de sobrevida de la úlcera hasta el cierre al 50 y 100% de la UPD mostró mayor eficacia tanto en el grupo de dac-MSCs y células madre mesenquimales de medula ósea (BM-MSCs) en comparación con el grupo convencional. El cociente de riesgo (HR, por sus siglas en ingles), de cierre de las UPD al 50 y 100%, fue significamente mayor en pacientes tratados con dac-MSCs y BM-MSCs en comparación con el grupo de tratamiento convencional. Conclusiones: La medicina regenerativa (BM-MSCs y dac-MSCS), surge como una estrategia terapéutica efectiva y segura para el tratamiento de pacientes con UPD.1. PLANTEAMIENTO Y JUSTIFICACIÓN DEL PROBLEMA .......................... 10 2. MARCO TEÓRICO .......................................................................................... 11 2.1. Diabetes Mellitus tipo 2: fisiopatología ............................................................. 11 2.2. Diabetes Mellitus tipo 2: epidemiología ............................................................ 12 2.3. Úlcera de pie diabético: fisiopatología ............................................................... 13 2.4. Úlcera de pie diabético: clasificación ................................................................ 15 2.5. Proceso de cicatrización de heridas ................................................................... 16 2.6. Tratamientos actuales ........................................................................................ 18 2.7. Células madre mesenquimales .......................................................................... 19 2.8. Mecanismos terapéuticos de las MSCs en lesiones cutáneas .............................. 20 2.9. Derivados acelulares de células madre mesenquimales (dacMSCs) en lesiones cutáneas ........................................................................................................................22 3. ESTADO DEL ARTE .......................................................................................22 4. PREGUNTA DE INVESTIGACIÓN ................................................................ 27 5. OBJETIVOS ..................................................................................................... 27 5.1 Objetivo general ................................................................................................ 27 5.2 Objetivos específicos ......................................................................................... 28 6. METODOLOGÍA ............................................................................................. 28 6.1 Tipo de estudio .................................................................................................. 28 6.2 Población .......................................................................................................... 28 6.3 Criterios de inclusión y exclusión ...................................................................... 28 6.4 Muestra y recolección de datos .......................................................................... 29 6.5 Hipótesis ............................................................................................................ 29 6.6 Variables ............................................................................................................ 30 6.7 Plan de análisis de datos ..................................................................................... 33 6.8 Consideraciones éticas ........................................................................................ 33 7. RESULTADOS ..................................................................................................33 7.1 Características demográficas de los participantes ............................................... 33 7.2 Evaluación del cierre de la úlcera de pie diabético tipo 1 ................................... 35 7 Protocolo V-01 – 26 de febrero 2020 7.3 Evaluación del cierre de la úlcera de pie diabético tipo 2 ................................... 37 7.4 Analisis de sobrevida de la UPD hasta el cierre: comparación entre los grupos dac-MSCs vs terapia convencional ................................................................................ 40 7.5 Analisis de sobrevida de la UPD hasta el cierre: comparación entre los grupos BM-MSCs vs terapia convencional ................................................................................ 41 7.6 Cociente de riesgo de cierre al 50% de las UPD y tasa de curación persona/día ................................................................................................................... 42 7.7 Cociente de riesgo de cierre al 100% de las UPD y tasa de curación persona/día ................................................................................................................... 43 8. DISCUSIÓN ...................................................................................................... 44 9. CONCLUSIONES ............................................................................................. 49 REFERENCIASEspecializaciónIntroduction and objective: Diabetic foot ulcer (DFU) is a frequent complication with a high morbidity and mortality burden in patients with Diabetes Mellitus (DM). Regenerative medicine appears as an effective and safe strategy in the treatment of UPD. Our aim was to evaluate the therapeutic effect of acellular derivatives of mesenchymal stem cells (dac-MSCs) in type 1 and type 2 UPD. Materials and methods: A secondary analysis of the data obtained from the clinical trial conducted at Foscal International was performed. Data analysis for UPD kinetics and velocity was performed by comparing the experimental groups by ANOVA test and by Bonferroni's multiple comparison post-test. The survival function of the ulcer to closure at 50% and 100% was also calculated using the Kaplan-Meier method. Finally, a hazard ratio (HR) analysis was performed at ulcer closure at 50% and 100%. Results: 60.7% of the participants were men, the mean age was 61.5 ± 7.8 years and at the start of treatment 75% of the participants had an HbA1c outside the target range (HbA1c > 7%). Both type 1 and type 2 UPD patients achieved higher velocity and kinetics of closure compared to the conventional therapy group. Analysis of ulcer survival to closure at 50 and 100% UPD showed greater efficacy in both the dac-MSCs and bone marrow mesenchymal stem cells (BM-MSCs) group compared to the conventional group. The hazard ratio (HR) of 50 and 100% UPD closure was significantly higher in patients treated with dac-MSCs and BM-MSCs compared to the conventional treatment group. Conclusions: Regenerative medicine (BM-MSCs and dac-MSCS), emerge as an effective and safe therapeutic strategy for the treatment of patients with UPD.application/pdfspahttp://creativecommons.org/licenses/by-nc-nd/2.5/co/Abierto (Texto Completo)info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-SinDerivadas 2.5 ColombiaEvaluación de la velocidad de cierre de las úlceras de pie diabético con el uso de derivados acelulares de células madre mesenquimales como tratamientoEvaluation of the rate of closure of diabetic foot ulcers with the use of acellular derivatives of mesenchymal stem cells as treatmentEspecialista en Medicina InternaUniversidad Autónoma de Bucaramanga UNABFacultad Ciencias de la SaludEspecialización en Medicina Internainfo:eu-repo/semantics/masterThesisTesishttp://purl.org/redcol/resource_type/TMInternal medicineMedicineMedical sciencesHealth sciencesDiabetic foot ulcerClinical trialMother cellsMetabolism disordersEndocrine gland diseasesFoot diseasesMedicina internaMedicinaCiencias médicasTrastornos del metabolismoEnfermedades de las glándulas endocrinasEnfermedades delos piesCiencias de la saludÚlcera de pie diabéticoEnsayo clínicoCélulas madre1. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019.2. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-983. A M. Diabetic Foot in Colombia. In: Dardik A (eds) Vascular Surgery Springer, Cham. 2017.4. Snyder RJ, Hanft JR. Diabetic foot ulcers--effects on QOL, costs, and mortality and the role of standard wound care and advanced-care therapies. Ostomy Wound Manage. 2009;55(11):28-38.5. Schwartz SS, Epstein S, Corkey BE, Grant SF, Gavin JR, 3rd, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the beta-Cell-Centric Classification Schema. Diabetes Care. 2016;39(2):179-86.6. Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis. Diabetes. 2017;66(2):241-55.7. Vargas-Uricoechea H, Casas-Figueroa LA. An Epidemiologic Analysis of Diabetes in Colombia. Ann Glob Health. 2015;81(6):742-53.8. Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis (dagger). Ann Med. 2017;49(2):106-169. Armstrong DG, Lavery LA. Diabetic foot ulcers: prevention, diagnosis and classification. Am Fam Physician. 1998;57(6):1325-32, 37-810. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017;376(24):2367-75.11. Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, Cid-Baez MA, Zamudio-Osuna MJ, Martinez-Blanco MDR, et al. Current Therapeutic Strategies in Diabetic Foot Ulcers. Medicina (Kaunas). 2019;55(11).12. Schaper NC. Diabetic foot ulcer classification system for research purposes: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev. 2004;20 Suppl 1:S90-513. Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing - A literature review. An Bras Dermatol. 2016;91(5):614-2014. Ridiandries A, Tan JTM, Bursill CA. The Role of Chemokines in Wound Healing. Int J Mol Sci. 2018;19(10).15. Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: Clinical review. J Tissue Viability. 2016;25(4):229-36.16. Nour S, Baheiraei N, Imani R, Khodaei M, Alizadeh A, Rabiee N, et al. A review of accelerated wound healing approaches: biomaterial- assisted tissue remodeling. J Mater Sci Mater Med. 2019;30(10):120.17. Matoori S, Veves A, Mooney DJ. Advanced bandages for diabetic wound healing. Sci Transl Med. 2021;13(585).18. Mavrogenis AF, Megaloikonomos PD, Antoniadou T, Igoumenou VG, Panagopoulos GN, Dimopoulos L, et al. Current concepts for the evaluation and management of diabetic foot ulcers. EFORT Open Rev. 2018;3(9):513-2519. Borys S, Ludwig-Slomczynska AH, Seweryn M, Hohendorff J, Koblik T, Machlowska J, et al. Negative pressure wound therapy in the treatment of diabetic foot ulcers may be mediated through differential gene expression. Acta Diabetol. 2019;56(1):115-20.20. Petrofsky JS, Lawson D, Berk L, Suh H. Enhanced healing of diabetic foot ulcers using local heat and electrical stimulation for 30 min three times per week. J Diabetes. 2010;2(1):41-6.21. Londahl M, Boulton AJM. Hyperbaric oxygen therapy in diabetic foot ulceration: Useless or useful? A battle. Diabetes Metab Res Rev. 2020;36 Suppl 1:e323322. Cao Y, Gang X, Sun C, Wang G. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer. J Diabetes Res. 2017;2017:9328347.23. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230-4724. Friedenstein AJ. Stromal mechanisms of bone marrow: cloning in vitro and retransplantation in vivo. Haematol Blood Transfus. 1980;25:19-2925. Hass R, Kasper C, Bohm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.26. Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem Cell Investig. 2019;6:34.27. de Mayo T, Conget P, Becerra-Bayona S, Sossa CL, Galvis V, Arango-Rodriguez ML. The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. PLoS One. 2017;12(6):e0177533.28. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648-59.29. Basiouny HS, Salama NM, Maadawi ZM, Farag EA. Effect of bone marrow derived mesenchymal stem cells on healing of induced full-thickness skin wounds in albino rat. Int J Stem Cells. 2013;6(1):12-25.30. L PK, Kandoi S, Misra R, S V, K R, Verma RS. The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine Growth Factor Rev. 2019;46:1-931. Tocci A, Parolini I, Gabbianelli M, Testa U, Luchetti L, Samoggia P, et al. Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program. Blood. 1996;88(8):2878-88.32. Nuschke A. Activity of mesenchymal stem cells in therapies for chronic skin wound healing. Organogenesis. 2014;10(1):29-37.33. Obaid1 HAA, Eljedi2 A. Risk Factors for the Development of Diabetic Foot Ulcers in Gaza Strip: A Case-Control Study. International Journal of Diabetes Research 201934. Eleuteri S, Fierabracci A. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. Int J Mol Sci. 2019;20(18).35. Cargnoni A, Piccinelli EC, Ressel L, Rossi D, Magatti M, Toschi I, et al. Conditioned medium from amniotic membrane-derived cells prevents lung fibrosis and 51 Protocolo V-01 – 26 de febrero 2020 preserves blood gas exchanges in bleomycin-injured mice-specificity of the effects and insights into possible mechanisms. Cytotherapy. 2014;16(1):17-32.36. Guo ZY, Sun X, Xu XL, Zhao Q, Peng J, Wang Y. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res. 2015;10(4):651-837. Becerra-Bayona SM, Solarte-David VA, Sossa CL, Mateus LC, Villamil M, Pereira J, et al. Mesenchymal stem cells derivatives as a novel and potential therapeutic approach to treat diabetic foot ulcers. Endocrinol Diabetes Metab Case Rep. 2020;2020.38. Bakker K, Apelqvist J, Lipsky BA, Van Netten JJ, International Working Group on the Diabetic F. The 2015 IWGDF guidance documents on prevention and management of foot problems in diabetes: development of an evidence-based global consensus. Diabetes Metab Res Rev. 2016;32 Suppl 1:2-639. Vargas-Uricoechea H, Casas-Figueroa LA. [Epidemiology of diabetes mellitus in South America: The experience of Colombia]. Clin Investig Arterioscler. 2016;28(5):245- 5640. Carstens MH, Quintana FJ, Calderwood ST, Sevilla JP, Rios AB, Rivera CM, et al. Treatment of chronic diabetic foot ulcers with adipose-derived stromal vascular fraction cell injections: Safety and evidence of efficacy at 1 year. Stem Cells Transl Med. 202141. Zhao L, Guo Z, Chen K, Yang W, Wan X, Zeng P, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Colony-Forming Cells Accelerates Refractory Diabetic Foot Ulcer Healing. Stem Cells Int. 2020;2020:886364942. Moon KC, Suh HS, Kim KB, Han SK, Young KW, Lee JW, et al. Potential of Allogeneic Adipose-Derived Stem Cell-Hydrogel Complex for Treating Diabetic Foot Ulcers. Diabetes. 2019;68(4):837-46.43. Maksimova N, Krasheninnikov M, Zhang Y, Ponomarev E, Pomytkin I, Melnichenko G, et al. Early passage autologous mesenchymal stromal cells accelerate diabetic wound re-epithelialization: A clinical case study. Cytotherapy. 2017;19(12):1548-5044. Qin HL, Zhu XH, Zhang B, Zhou L, Wang WY. Clinical Evaluation of Human Umbilical Cord Mesenchymal Stem Cell Transplantation After Angioplasty for Diabetic Foot. Exp Clin Endocrinol Diabetes. 2016;124(8):497-50345. Jiang X, Zhang H, Teng M. Effectiveness of Autologous Stem Cell Therapy for the Treatment of Lower Extremity Ulcers: A Systematic Review and Meta-Analysis. Medicine (Baltimore). 2016;95(11):e27146. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D, Fried D, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554-60.47. Jain P, Perakath B, Jesudason MR, Nayak S. The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study. Ostomy Wound Manage. 2011;57(7):38-4448. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009;12(5):359-66.49. Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin 52 Protocolo V-01 – 26 de febrero 2020 spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299-31250. Xu Y, Huang S, Ma K, Fu X, Han W, Sheng Z. Promising new potential for mesenchymal stem cells derived from human umbilical cord Wharton's jelly: sweat gland cell-like differentiative capacity. J Tissue Eng Regen Med. 2012;6(8):645-5451. Santamaria N, Ogce F, Gorelik A. Healing rate calculation in the diabetic foot ulcer: comparing different methods. Wound Repair Regen. 2012;20(5):786-9.52. Pedras S, Carvalho R, Pereira Mda G. Sociodemographic and clinical characteristics of patients with diabetic foot ulcer. Rev Assoc Med Bras (1992). 2016;62(2):171-854. Abolfotouh MA, Alfaifi SA, Al-Gannas AS. Risk factors of diabetic foot in central Saudi Arabia. Saudi Med J. 2011;32(7):708-13.55. MD MHJ. Disorders of the Foot and Ankle: Medical and Surgical Management,.3- Volume Set 2nd Edición56. Brand PW. Diabetic foot - what can we learn from leprosy? Diabetes/Metabolism Research and Reviews 2012(6).57. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26-3658. Wu Q, Lei X, Chen L, Zheng Y, Huang H, Qian C, et al. Autologous platelet-rich gel combined with in vitro amplification of bone marrow mesenchymal stem cell transplantation to treat the diabetic foot ulcer: a case report. Ann Transl Med. 2018;6(15):30759. Arno AI, Amini-Nik S, Blit PH, Al-Shehab M, Belo C, Herer E, et al. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling. Stem Cell Res Ther. 2014;5(1):2860. Vieira Paladino F, de Moraes Rodrigues J, da Silva A, Goldberg AC. The Immunomodulatory Potential of Wharton's Jelly Mesenchymal Stem/Stromal Cells. Stem Cells Int. 2019;2019:354891761. Stefanska K, Ozegowska K, Hutchings G, Popis M, Moncrieff L, Dompe C, et al. Human Wharton's Jelly-Cellular Specificity, Stemness Potency, Animal Models, and Current Application in Human Clinical Trials. J Clin Med. 2020;9(4)62. da Silva Meirelles L, Bolontrade MF, Markoski MM, Dallagiovanna B, Alaniz L. Improving the Therapeutic Ability of Mesenchymal Stem/Stromal Cells for the Treatment of Conditions Influenced by Immune Cells. Stem Cells Int. 2019;2019:682039563. Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150-664. Li M, Soder R, Abhyankar S, Abdelhakim H, Braun MW, Trinidad CV, et al. WJMSC-derived small extracellular vesicle enhance T cell suppression through PD-L1. J Extracell Vesicles. 2021;10(4):e1206765. Maacha S, Sidahmed H, Jacob S, Gentilcore G, Calzone R, Grivel JC, et al. Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis. Stem Cells Int. 2020;2020:435635966. Valle-Prieto A, Conget PA. Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev. 2010;19(12):1885-9367. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol. 2014;34:132-4368. Chen D, Hao H, Fu X, Han W. Insight into Reepithelialization: How Do Mesenchymal Stem Cells Perform? Stem Cells Int. 2016;2016:6120173.ORIGINAL2021_Tesis_Enmanuel_Jose_Celis.pdf2021_Tesis_Enmanuel_Jose_Celis.pdfTesisapplication/pdf1116990https://repository.unab.edu.co/bitstream/20.500.12749/13931/1/2021_Tesis_Enmanuel_Jose_Celis.pdf1b30b8d3be8c901af291669da899034dMD51open access2021_Licencia_Enmanuel_Jose_Celis.pdf2021_Licencia_Enmanuel_Jose_Celis.pdfLicenciaapplication/pdf17660https://repository.unab.edu.co/bitstream/20.500.12749/13931/2/2021_Licencia_Enmanuel_Jose_Celis.pdf7fb879a88ddfe19bc27d4be7b410799eMD52metadata only accessLICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://repository.unab.edu.co/bitstream/20.500.12749/13931/3/license.txt8a4605be74aa9ea9d79846c1fba20a33MD53open accessTHUMBNAIL2021_Tesis_Enmanuel_Jose_Celis.pdf.jpg2021_Tesis_Enmanuel_Jose_Celis.pdf.jpgIM Thumbnailimage/jpeg6467https://repository.unab.edu.co/bitstream/20.500.12749/13931/4/2021_Tesis_Enmanuel_Jose_Celis.pdf.jpg5582080440b3aca1f23178392b82b5abMD54open access2021_Licencia_Enmanuel_Jose_Celis.pdf.jpg2021_Licencia_Enmanuel_Jose_Celis.pdf.jpgIM Thumbnailimage/jpeg8557https://repository.unab.edu.co/bitstream/20.500.12749/13931/5/2021_Licencia_Enmanuel_Jose_Celis.pdf.jpg997d1ffb32d17f4c3b25483c10aea55fMD55open access20.500.12749/13931oai:repository.unab.edu.co:20.500.12749/139312021-08-19 18:02:18.279open accessRepositorio Institucional | Universidad Autónoma de Bucaramanga - UNABrepositorio@unab.edu.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

Publicaciones similares