Natural hydrogels R&D process: technical and regulatory aspects for industrial implementation.

Since hydrogel therapies have been introduced into clinic treatment procedures, the biomedical industry has to face the technology transfer and the scale-up of the processes. This will be key in the roadmap of the new technology implementation. Transfer technology and scale-up are already known for some applications but other applications, such as 3D printing, are still challenging. Decellularized tissues offer a lot of advantages when compared to other natural gels, for example they display enhanced biological properties, due to their ability to preserve natural molecules. For this reason, even though their use as a source for bioinks represents a challenge for the scale-up process, it is very important to consider the advantages that originate with overcoming this challenge. Therefore, many aspects that influence the scaling of the industrial process should be considered, like the addition of drugs or cells to the hydrogel, also, the gelling process is important to determine the chemical and physical parameters that must be controlled in order to guarantee a successful process. Legal aspects are also crucial when carrying out the scale-up of the process since they determine the industrial implementation success from the regulatory point of view. In this context, the new law Regulation (EU) 2017/745 on biomedical devices will be considered. This review summarizes the different aspects, including the legal ones, that should be considered when scaling up hydrogels of natural origin, in order to balance these different aspects and to optimize the costs in terms of raw materials and engine.

Overview of natural hydrogels for regenerative medicine applications.

Hydrogels from different materials can be used in biomedical field as an innovative approach in regenerative medicine. Depending on the origin source, hydrogels can be synthetized through chemical and physical methods. Hydrogel can be characterized through several physical parameters, such as size, elastic modulus, swelling and degradation rate. Lately, research is focused on hydrogels derived from biologic materials. These hydrogels can be derived from protein polymers, such as collage, elastin, and polysaccharide polymers like glycosaminoglycans or alginate among others. Introduction of decellularized tissues into hydrogels synthesis displays several advantages compared to natural or synthetic based hydrogels. Preservation of natural molecules such as growth factors, glycans, bioactive cryptic peptides and natural proteins can promote cell growth, function, differentiation, angiogenesis, anti-angiogenesis, antimicrobial effects, and chemotactic effects. Versatility of hydrogels make possible multiple applications and combinations with several molecules on order to obtain the adequate characteristic for each scope. In this context, a lot of molecules such as cross link agents, drugs, grow factors or cells can be used. This review focuses on the recent progress of hydrogels synthesis and applications in order to classify the most recent and relevant matters in biomedical field.

Angiogenic Potential in Biological Hydrogels.

Hydrogels are three-dimensional (3D) materials able to absorb and retain water in large amounts while maintaining their structural stability. Due to their considerable biocompatibility and similarity with the body's tissues, hydrogels are one of the most promising groups of biomaterials. The main application of these hydrogels is in regenerative medicine, in which they allow the formation of an environment suitable for cell differentiation and growth. Deriving from these hydrogels, it is, therefore, possible to obtain bioactive materials that can regenerate tissues. Because vessels guarantee the right amount of oxygen and nutrients but also assure the elimination of waste products, angiogenesis is one of the processes at the base of the regeneration of a tissue. On the other hand, it is a very complex mechanism and the parameters to consider are several. Indeed, the factors and the cells involved in this process are numerous and, for this reason, it has been a challenge to recreate a biomaterial able to adequately sustain the angiogenic process. However, in this review the focal point is the application of natural hydrogels in angiogenesis enhancing and their potential to guide this process.