Discusión

The diversity of collagen-based hydrogel systems varying the coupling agent has been widely exploited in BTERM strategies. The biocompatibility of collagen, inherent to its properties and functions of structural protein and signaling of the extracellular matrix, is the main reason to include it in these hydrogels systems. The coupling with natural polymers, synthetic polymers, inorganic phases and / or complex biological molecules has allowed adapting the properties of these hydrogels to improve their performance in BTERM applications. Mainly, the regularization of the degradation rate and the control of the mechanical properties of the 3D fibrillar network of collagen are achieved producing hybrid systems. These systems can be structurally as interpenetrated networks, presenting physical and / or chemical crosslinking that modify the entanglement of collagen fibers and their physicochemical properties.

These novel systems of hybrid hydrogels could be applied in diverse biotechnological strategies, not only in BTERM, due to the adaptation of their properties, which it has been studied in detail using diverse physicochemical techniques. This work visualizes successful performance of collagen-based hydrogels in the biotechnological field, being applied as: i) substrates for vegetable tissue, ii) hydrogels for encapsulation of microorganisms for environmental bioremediation, iii) matrices for heavy metal ion adsorption for remediation of water, iv) 3D matrices to regulate and study the growth of microorganisms with biotechnological interest, v) base substrates for the formulation of products in the food and/or cosmetological areas and vi) matrices for solid state and semisolid fermentation.

Collagen-based hydrogels for application as substrates for vegetal tissues could be developed using cellulose, alginate and / or dextran derivatives as coupling polymers. The degradation and swelling of these materials can be regulated controlling the concentration of the natural polymer. The diffusion of nutrients and moisture would be regulated modifying the composition of the hybrid hydrogel. The growth of vegetal tissue could be studied varying the structure of the hydrogels, and new substrates could be generated with potential application in the agroindustrial sector. Hydrogels with genes or encapsulated plasmids mimic the behavior of a virus, controlling the cellular metabolism.

Collagen as a protein, represents a source of C and N, for microorganisms that have potential application in the area of bioremediation of soils and waste water contaminated by heavy metals and/or environmentally dangerous chemical substances. These microorganisms could be encapsulated in hybrid matrices with controlled properties that ensure the bioavailability of the organism, potentizing its bioremediating effect. In this approach, synthetic

polymers are effective for the tailoring of the degradation of collagen, swelling and adapted mechanical properties, regulating the diffusion, absorption and release processes important for the optimization and effectiveness of environmental bioremediation processes.

The porosity and surface chemistry of hybrid collagen hydrogels could be used to promote the adsorption of heavy metal ions present in contaminated aqueous systems. These type of materials would represent a potential alternative for environmental strategies focused on the remediation of aqueous systems. The novel production of composite hydrogels that include inorganic phases to potentiate the effect of chemisorption, it could represent a promising area of research. The composite hydrogel with the ion of interest adsorbed could be treated with microorganisms to generate chemical species of these contaminants that can be reincorporated into the earth crust. In this way, the study of the application of this type of hydrogels for biotechnological purposes represents a current multidisciplinary challenge. The collagen source tissue and the residual composition of the ECM molecules present in the hydrolyzed collagen solution would directly affect the effectiveness of the biotechnological application, so it is essential to study the influence of the composition of the collagen matrix in the hydrogel state on the application of interest. For this, it would be convenient to continue developing collagen extraction and purification techniques that allow formulating hydrogels with high functionality. Various industrial processes involving tissues rich in collagen represent abundant sources of easily accessible of raw material for the production of these hydrogel systems.

The ease of manufacture of these hybrid systems, and the control in the sol-gel transition of the formulations, could be take advantage to encapsulate microorganisms, with which it would be possible to study the alteration of their phenotypes, induction of specific biochemical processes, related with the microorganism-matrix interactions and the stimulation of specific metabolic pathways, when a biological agent of complex functionality is coupled in the hydrogel. Therefore, the generation of metabolites of biotechnological interest could be implemented if the effects of the hybrid matrix on the growth of microorganisms are known. As it has been reviewed in this work, eukaryotic cells that constitute different tissues have regulated their metabolic processes interacting with the matrix in the hydrogel state, potentiating its applicability in the BTERM field. This approach would be interesting if the type of microorganism is modified, and the relationship of its metabolic activity is studied by the interaction with the matrix. Thus, the production of hydrogel matrices with adapted biotechnological functionality would be possible opening new research panoramas.

In another approach, several formulations of these hydrogels based on collagen that have shown promising results, they could be used as bases for the formulation of products of biotechnological interest, specifically in the food and cosmetological fields. Hydrogels can be dosed with additives to generate creams, gels, sprays, everyday products that improve the quality of life of people with dermatological problems, skin wounds, and burns, among others. In the food industry, hydrogels could be used as thickeners or fillers for food for daily consumption. In this sense,

researching and developing formulations based on collagen hydrogels with daily application represents another current challenge.

Collagen in combination with agro-industrial wastes is a good option for production of inert support and / or nutritional supplier in solid state fermentation (SSF) or semisolid fermentation, because it has been proved that matrices of collagen are biocompatible and biosafe with several types of cells. Also, the mechanical properties of collagen hydrogels can be adjusted for reached the optimal kinetics parameters of microorganisms or cells during SSF or semisolid fermentation, for production of several products of interest biotechnological such as enzymes, organic acids, flavors, colorants, and aromas. Besides, matrices based collagen can be utilized to immobilization of cells that not supporting high cutting effort for production of interleukins, interferons, hormones and other biopharmaceuticals whose cost of production are elevated. Some advantages of SSF and semisolid fermentation over submergible fermentation (SmF) are their higher products yield, environmental friendly (lower energy consumption, less wastewater generation) and the easer recovery product, so collagen and other type of hydrogels can be very useful in this field.

Finally, it is essential to inform the advances and the different approaches in the synthesis and application of collagen-based hydrogels, where the physicochemical aspect and the application in BTERM areas have been covered mainly; however, the panorama for the application of these novel materials in the biotechnological field is a promising area of research and development, which it should be started to study to know the potential of these innovative matrices in another fields.