Abstract
Jellyfish collagen, which can be defined as “collagen type 0” due to its homogeneity to the mammalian types I, II, III, V, and IX and its batch-to-batch consistent producibility, is of special interest for different medical applications related to (bone) tissue regeneration as an alternative to mammalian collagen-based biomaterials. However, no in vivo studies regarding the induction of M1- and M2-macrophages and their time-dependent ration as well as the analysis of the bone regeneration capacity of jellyfish collagen scaffolds have been conducted until now. Thus, the goal of this study was to determine the nature of the immune response to jellyfish collagen scaffolds and their bone healing capacities. Two in vivo studies using established implantation models, i.e., the subcutaneous and the calvarian implantation model in Wistar rats, were conducted. Furthermore, specialized histological, histopathological, and histomorphometrical methods have been used. As a control biomaterial, a collagen scaffold, originating from porcine pericardium, which has already been stated as biocompatible, was used for the subcutaneous study. The results of the present study show that jellyfish collagen scaffolds are nearly completely resorbed until day 60 post implantation by stepwise integration within the subcutaneous connective tissue mediated mainly by macrophages and single multinucleated giant cells. Interestingly, the degradation process ended in a vessel rich connective tissue that is understood to be an optimal basis for tissue regeneration. The study results showed an overall weaker immune response to jellyfish collagen than to porcine pericardium matrices by the induction of significantly lower numbers of macrophages together with a more balanced occurrence of M1- and M2-macrophages. However, both collagen-based biomaterials induced balanced numbers of both macrophage subtypes, which supports their good biocompatibility. Moreover, the histomorphometrical results for the calvarial implantation of the jellyfish scaffolds revealed an average of 46.20% de novo bone formation at day 60, which was significantly higher compared to the control group. Thereby, the jellyfish collagen scaffolds induced also significantly higher numbers of anti-inflammatory macrophages within the bony implantation beds. Altogether, the results show that the jellyfish collagen scaffolds allowed for a directed integration behavior, which is assumed to be in accordance with the concept of Guided Bone Regeneration (GBR). Furthermore, the jellyfish collagen scaffolds induced a long-term anti-inflammatory macrophage response and an optimal vascularization pattern within their implant beds, thus showing excellent biocompatibility and (bone) tissue healing properties.
Highlights
Biomaterials such as bone substitute materials (BSM) should support the regeneration process without adversely affecting the living organism and its components
The results of the histological analysis showed that the jellyfish collagen scaffolds (Jellagen®-3D scaffolds from Jellagen® Ltd., Cardiff, UK) were detectable within the subcutaneous connective tissue at day 10 post implantationem surrounded by a thin wall of interacting cells (Figure 1A)
A more detailed analysis revealed that mainly macrophages and some single multinucleated giant cells beside single fibroblasts and low numbers of granulocytes were observable at the outer scaffold surfaces (Figure 1B)
Summary
Biomaterials such as bone substitute materials (BSM) should support the regeneration process without adversely affecting the living organism and its components. They should allow for an adapted integration behavior needed for tissue regeneration. Different materials are able to support the bone regeneration process such as extracellular matrix proteins for use alone or in combination with CaM [5,6]. Collagen makes up a major protein component of the extra cellular matrix, which is secreted by cell types such as fibroblasts or osteoblasts [7,8]. Vascularization is one of the great challenges facing tissue engineering, as a vascular network capable of distributing oxygen and other nutrients is required to support cell survival [15,16]
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