Evaluation of Fibrin-Agarose Tissue-Like Hydrogels Biocompatibility for Tissue Engineering Applications

Abstract

Generation of biocompatible and biomimetic tissue-like biomaterials is crucial to ensure the success of engineered substitutes in tissue repair. Natural biomaterials able to mimic the structure and composition of native extracellular matrices typically show better results than synthetic biomaterials. The aim of this study was to perform an in vivo time-course biocompatibility analysis of fibrin-agarose tissue-like hydrogels at the histological, imagenological, hematological, and biochemical levels. Tissue-like hydrogels were produced by a controlled biofabrication process allowing the generation of biomechanically and structurally stable hydrogels. The hydrogels were implanted subcutaneously in 25 male Wistar rats and evaluated after 1, 5, 9, and 12 weeks of in vivo follow-up. At each period of time, animals were analyzed using magnetic resonance imaging (MRI), hematological analyses, and histology of the local area in which the biomaterials were implanted, along with major vital organs (liver, kidney, spleen, and regional lymph nodes). MRI results showed no local or distal alterations during the whole study period. Hematology and biochemistry showed some fluctuation in blood cells values and in some biochemical markers over the time. However, these parameters were progressively normalized in the framework of the homeostasis process. Histological, histochemical, and ultrastructural analyses showed that implantation of fibrin-agarose scaffolds was followed by a progressive process of cell invasion, synthesis of components of the extracellular matrix (mainly, collagen) and neovascularization. Implanted biomaterials were successfully biodegraded and biointegrated at 12 weeks without any associated histopathological alteration in the implanted zone or distal vital organs. In summary, our in vivo study suggests that fibrin-agarose tissue-like hydrogels could have potential clinical usefulness in engineering applications in terms of biosafety and biocompatibility. ; Spanish Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I+D+i) from the Spanish Ministerio de Ciencia, Innovacion y Universidades (Instituto de Salud Carlos III) (ERDF-FEDER, European Union) FIS PI17/0391 PI17/0393 PI18/332 ; ISCIII thorough AES 2017 AC17/00013 ; EuroNanoMed framework AC17/00013 ; Hispanagar, SA, Burgos, Spain, through CDTI, Ministry of Economy and Competitiveness, Spain IDI-20180052 ; Junta de Andalucia CS PI-0257-2017 PE-0395-2019 ; Ministerio de Economia, Industria y Competitividad, MINECO FIS2017-85954-R ; Agencia Estatal de Investigacion, AEI, Spain FIS2017-85954-R ; European Union (EU) FIS2017-85954-R ; National Cordoba University, Argentina Secyt 266 HCS 659/2018 ; Programa Operativo Pluriregional de Crecimiento Inteligente (CRIN) IDI-20180052 ; ERDF-FEDER funds, EU IDI-20180052