Polymer- and Hybrid-Based Biomaterials for Interstitial, Connective, Vascular, Nerve, Visceral and Musculoskeletal Tissue Engineering.

In this review, materials based on polymers and hybrids possessing both organic and inorganic contents for repairing or facilitating cell growth in tissue engineering are discussed. Pure polymer based biomaterials are predominantly used to target soft tissues. Stipulated by possibilities of tuning the composition and concentration of their inorganic content, hybrid materials allow to mimic properties of various types of harder tissues. That leads to the concept of "one-matches-all" referring to materials possessing the same polymeric base, but different inorganic content to enable tissue growth and repair, proliferation of cells, and the formation of the ECM (extra cellular matrix). Furthermore, adding drug delivery carriers to coatings and scaffolds designed with such materials brings additional functionality by encapsulating active molecules, antibacterial agents, and growth factors. We discuss here materials and methods of their assembly from a general perspective together with their applications in various tissue engineering sub-areas: interstitial, connective, vascular, nervous, visceral and musculoskeletal tissues. The overall aims of this review are two-fold: (a) to describe the needs and opportunities in the field of bio-medicine, which should be useful for material scientists, and (b) to present capabilities and resources available in the area of materials, which should be of interest for biologists and medical doctors.


Introduction
Except for the gut epithelium [1], cornea [2], skin [3], and liver [4], regeneration of adult tissue after an injury or degeneration is is an inefficient process. This is addressed by designing and applying innovative biomaterials targeting regeneration of tissues. Although promising data have been obtained in laboratories, some hurdles limiting the clinical translation of implants still remain including cell survival, migration, and integration [5]. Polymer-based coatings perfectly fill the niche of soft-tissue repair, because of the similarity between their mechanical, physico-chemical, and physiological properties and those of tissue.
There are different methods of assembling polymers into coatings and scaffolds. These include, for example, hydrogels, layer-by-layer (LbL), Langmuir-Blodgett films, polymer brushes, etc. Hydrogels represent a broad research area with already existing practical applications; their biggest advantages include possibilities of incorporation of various particles, molecules, entities into the volume occupied by hydrogels. LbL assembly, where positively and negatively charged polyelectrolytes are sequentially applied, is often regarded as the substitute for Langmuir-Blodgett films, which are produced by drawing the substrate at a steady speed from a solution containing polymers. Flexibility of design of the coatings using LbL is one of their biggest advantages. Polymer brushes is another approach that Hydrogels are very useful but, at the same time, some of the softest bio-materials [86,87]. Functionalization of hydrogels with inorganic particles leads to enhancement of their mechanical properties through, for example, additional bio-mineralization [50] and incorporation of possibilities to release encapsulated materials or antibacterial properties [88].
Discussed by Decher, LbL films have seen two decades of rapid development [89][90][91][92][93][94], where both versatile planar layers and fully suspended polymeric capsules have been established. Typically, LbL films are quite thin, but a special design of the so-called exponentially grown films leads to micrometer thick gel-like films [95], which are applicable for tissue engineering. In this regard, the deposition time affects the uptake of polymers [96] and water [97]. The flexibility of the design of LbL coatings enables extensive opportunities including those in tissue engineering, where vascular patches [98] have been designed. Detachable cell sheets for tissue engineering have been reported [99].
Another desirable feature for tissue engineering is patterning, which was also reported for LbL structures [100]. Differentiation of stem cells has been obtained with LbL coatings [101]. Adhesion of cells can be promoted either by patterning [102], chemically patterning the LbL sources [103] or by adjusting mechanical properties [104]. Adjusting the mechanical properties, which can be done by addition of gold nanoparticles on the surface, allows not only for controlling cell adhesion, but also to controllably embed and pattern particle [105,106].
Composite LbL films containing inorganic nanoparticles allow one to control cells adhesion, while also giving the material the required properties (stiffness, antibacterial properties, etc.) [107]. Polymer brushes represent polymers attached or tethered to a surface [108]. To distinguish between, for example planar LbL layers, the density of polymers constituting polymer brushes is said to the higher than the gyration radius of polymers. Application in tissue engineering can be also thought with polymer brushes [109]. Control of rigidity, reversible physico-chemical properties and stimuli-responsiveness [109] are noted as some distinct properties of polymer brushes making them unique materials in tissue engineering.
In addition, 3D printing is a rapidly expanding area due to availability of new instruments and materials [110][111][112]. Several approaches to 3D printing are available including fused deposition modelling, selective laser sintering, stereolithography, near-field electrospinning, and bioprinting, where inkjet printing, laser-assisted 3D printing, extrusion [113,114].

Pure Polymeric Coatings Targeting Different Tissues
Numerous applications in tissue engineering are developed using the so-called hybrid materials, where polymers are supplemented by inorganic particles. But this is not always the case, and there are still applications where pure polymers are used for constructing scaffolds or other structures for tissue engineering.
One of the most important criteria for selecting pure polymers for various applications in different tissues and organs is their mechanical properties [115][116][117]. Indeed, human tissues have their own rigidity depending on the type of cells and their structural organization [118]. Peculiarly, mechanical properties of tissues range from kPa to GPa, based on data for arterial walls [119], brain [120], breast [121], bone [121], cartilage [122], cornea [123], heart [124], kidney [125], liver [125], prostate [126], vein [127], skin [127] and tendon [128]). A summary of these data is given in Figure 1. Analyzing these data, it can be seen that chest and liver have a very low modulus of elasticity of about 1 kPa, which is similar to that of polyacrylamide. Bones, on the other hand, have relatively speaking extremely high rigidity (of the order of 10 GPa), which can be matched by poly (methylactrylate) with rigidity in the range of 2 to 4 GPa [129]. It is these aspects that limit the use of pure polymers for tissue engineering prompting to use of hybrid materials, which are overall better suited for fine-tuning of relevant properties of implants [131], and can be also used for drug delivery through incorporated particles. In the following section, hybrid materials are discussed in regard with their applications in specific tissue engineering areas [25].

Hybrid Biomaterials Applied for Tendon
The transfer of power between the musculoskeletal tissues is due to tendons and ligaments. The structure of the collagen fibrils that make up the tendons ensures their strength and elasticity. The main components of tendons are fibrillar, fibril-associated (I, III, IV, V), beaded filament-forming (VI), and network-forming collagen (IV), a large amount of elastin and decorin proteins are also present, expression of chondroitin and proteoglycans by cells provides for swelling in the aquatic environment. The orientation of cells inside the tendons occurs around collagen fibers-this positively affects also the mechanical properties [128,133]. The insertion of the tendon in the bone consists of three continuous regions, in which the soft tissue transforms in fibrocartilage and, then, in a bone. The fibro-cartilaginous region is further divided into calcified and noncalcified regions. These complex transitions are essential for the biological fixation of the tendon and exhibit a gradient of structural and mechanical properties (>310 kPa) to transmit complex loads between the tendon and the bone insertion site [134]. To mimic these structures, hybrid materials with engineered matrix inhomogeneities and structures are required. A wide variety of such synthetic and natural polymers as PCL, PGA, polyurethane, collagen, and silk fibroin, and a variety of scaffold production methods have been used to develop functional matrices for tendon and ligament tissue [66,135,136]. The base for tendon implants is made using polymers matrix, which can be obtained by electrospinning due to their architecture and good mechanical properties, but in connection with poor cell adhesion of the pure polymers and tendon construction often use collagen coating. Also, fibro-cartilaginous region formation stimulated by calcium-based nano and microparticles of hydroxyapatite [137] [68]. A striking example of a solution to this problem is the work of Savelyeva et al. They coated PCL nanofibers by CaCO3 particles loaded tannic acid. It was reported that particles improve cell adhesion on the surface of the PCL implant, and when connected to the bone, after a while passed into the form of hydroxyapatite, which significantly improved the integration of the implant on both sides [138] ( Figure 2). It is these aspects that limit the use of pure polymers for tissue engineering prompting to use of hybrid materials, which are overall better suited for fine-tuning of relevant properties of implants [131], and can be also used for drug delivery through incorporated particles. In the following section, hybrid materials are discussed in regard with their applications in specific tissue engineering areas [25].

Hybrid Biomaterials Applied for Tendon
The transfer of power between the musculoskeletal tissues is due to tendons and ligaments. The structure of the collagen fibrils that make up the tendons ensures their strength and elasticity. The main components of tendons are fibrillar, fibril-associated (I, III, IV, V), beaded filament-forming (VI), and network-forming collagen (IV), a large amount of elastin and decorin proteins are also present, expression of chondroitin and proteoglycans by cells provides for swelling in the aquatic environment. The orientation of cells inside the tendons occurs around collagen fibers-this positively affects also the mechanical properties [128,133]. The insertion of the tendon in the bone consists of three continuous regions, in which the soft tissue transforms in fibrocartilage and, then, in a bone. The fibro-cartilaginous region is further divided into calcified and noncalcified regions. These complex transitions are essential for the biological fixation of the tendon and exhibit a gradient of structural and mechanical properties (>310 kPa) to transmit complex loads between the tendon and the bone insertion site [134]. To mimic these structures, hybrid materials with engineered matrix inhomogeneities and structures are required. A wide variety of such synthetic and natural polymers as PCL, PGA, polyurethane, collagen, and silk fibroin, and a variety of scaffold production methods have been used to develop functional matrices for tendon and ligament tissue [66,135,136]. The base for tendon implants is made using polymers matrix, which can be obtained by electrospinning due to their architecture and good mechanical properties, but in connection with poor cell adhesion of the pure polymers and tendon construction often use collagen coating. Also, fibro-cartilaginous region formation stimulated by calcium-based nano and microparticles of hydroxyapatite [68,137]. A striking example of a solution to this problem is the work of Savelyeva et al. They coated PCL nanofibers by CaCO 3 particles loaded tannic acid. It was reported that particles improve cell adhesion on the surface of the PCL implant, and when connected to the bone, after a while passed into the form of hydroxyapatite, which significantly improved the integration of the implant on both sides [138] (Figure 2).

Hybrid Biomaterials Applied for Skin
Knowledge of native tissue is one of the major factors in successful development of biomaterials for regenerative medicine [139]. Skin is the biggest organ of the human body, which has a lot of functions, some of them are protection, sensation, thermoregulation, control of evaporation etc. Skin includes two anatomically, functionally, and developmentally distinct tissues: the epidermis, which has a role of barrier to infection and regulator of transdermal water loss, and the dermis, which has mechano and thermoreceptors, hair follicles, different glands and vessels [140]. When developing biomaterials for skin regeneration, it is important to remember that the main components of a successful biomaterial are ECM, cells and bioactive molecules that help cell growth or differentiation [141,142] In the case of the development of skin implants, scientists can start using not only pure polymers, because the restoration of the skin occurs much faster if one uses various combinations of polymers with nano- [143] or micro- [67] particles and bioactive substances [144]. Hydrogels can be also used, because, although they are soft, skin represents also a soft tissue [145][146][147][148]. It should be added that the Young's modulus of skin is in the range from 4.5 till 8 kPa [134], that is why materials should match these values. Mechanically affected regions of skin are usually located near to the surface that may lead to a rejection of implants due to contamination and inflammation [149]. One solution to this potential problem is a modification of polymer hydrogels and fibers by microcontainers or microcapsules with, for example, tannic acid, which has antimicrobial properties. This would resist fibrosis and would improve angiogenesis of tissues [138,148,150,151]. It should be noted that signals generated by VEGF and TGF play an important role for proper regeneration of skin tissue and healing of wounds [144,147,152,153].

Hybrid Biomaterials for Vascular Tissue Reconstruction
Tissue engineering of vascular tissues is one of the major application areas of tissue engineering, because cardiovascular disease is linked to one of the highest number of death cases. Treatment for cardiovascular diseases can include a complete replacement of a destroyed vessel with an artificial one. Delivery of oxygen-rich blood from the heart to the different tissues is particularly important for blood vessels [154].
Arteries represent a muscular tube lined by smooth tissue. It has three layers: the intima, which presents a single layer of flat cells, the media, which present the thickest layer in arteries and rich in vascular smooth muscle, and the adventitia, which represent the thickest layer in veins and entirely made of connective tissue [155]. Such a vessel architecture allows you to experience high pressure from the heart (from 1600 till 8250 mmHg) [156].

Hybrid Biomaterials Applied for Skin
Knowledge of native tissue is one of the major factors in successful development of biomaterials for regenerative medicine [139]. Skin is the biggest organ of the human body, which has a lot of functions, some of them are protection, sensation, thermoregulation, control of evaporation etc. Skin includes two anatomically, functionally, and developmentally distinct tissues: the epidermis, which has a role of barrier to infection and regulator of transdermal water loss, and the dermis, which has mechano and thermoreceptors, hair follicles, different glands and vessels [140]. When developing biomaterials for skin regeneration, it is important to remember that the main components of a successful biomaterial are ECM, cells and bioactive molecules that help cell growth or differentiation [141,142].
In the case of the development of skin implants, scientists can start using not only pure polymers, because the restoration of the skin occurs much faster if one uses various combinations of polymers with nano- [143] or micro- [67] particles and bioactive substances [144]. Hydrogels can be also used, because, although they are soft, skin represents also a soft tissue [145][146][147][148]. It should be added that the Young's modulus of skin is in the range from 4.5 till 8 kPa [134], that is why materials should match these values. Mechanically affected regions of skin are usually located near to the surface that may lead to a rejection of implants due to contamination and inflammation [149]. One solution to this potential problem is a modification of polymer hydrogels and fibers by microcontainers or microcapsules with, for example, tannic acid, which has antimicrobial properties. This would resist fibrosis and would improve angiogenesis of tissues [138,148,150,151]. It should be noted that signals generated by VEGF and TGF play an important role for proper regeneration of skin tissue and healing of wounds [144,147,152,153].

Hybrid Biomaterials for Vascular Tissue Reconstruction
Tissue engineering of vascular tissues is one of the major application areas of tissue engineering, because cardiovascular disease is linked to one of the highest number of death cases. Treatment for cardiovascular diseases can include a complete replacement of a destroyed vessel with an artificial one. Delivery of oxygen-rich blood from the heart to the different tissues is particularly important for blood vessels [154].
Arteries represent a muscular tube lined by smooth tissue. It has three layers: the intima, which presents a single layer of flat cells, the media, which present the thickest layer in arteries and rich in vascular smooth muscle, and the adventitia, which represent the thickest layer in veins and entirely made of connective tissue [155]. Such a vessel architecture allows you to experience high pressure from the heart (from 1600 till 8250 mmHg) [156].
One of the useful polymers for vessels engineering of medium-large diameter blood vessels is expanded polytetrafluoroethylene (ePTFE), because of its high crystallinity and hydrophobicity. These two characteristics of ePTFE ensure the prevention of hydrolysis. But for small diameter vessels using ePTFE can be dangerous because of intimal hyperplasia, calcification, and thrombosis [157]. Therefore, a biodegradable implant is considered the best option, which will be replaced by vascular cells, preserving the architecture of the vessel, but without losing its mechanical properties [158].
In most cases, coatings of implants for vessels should contain bioactive molecules, which speed up vessel's integration. One of them is vascular endothelial growth factor (VEGF)-a family of signal proteins produced by cells for stimulating the formation of blood vessels. Interesting work in vessels implant area is done by the Gonzalez-garcía group. In that work, poly (ethyl acrylate) was shown to lead to the formation of fibronectin networks, where VEGF-presenting areas were generated, (Figure 3), which promote vascular cell response. Such a system allows to use extremely low doses of the growth factors, while at the same time improves vascularization. As such, it is robust and efficient approach to improve vascularization of the tissue and in can be implemented in 2D and 3D scaffolds [159].
Polymers 2020, 12, x FOR PEER REVIEW 8 of 28 One of the useful polymers for vessels engineering of medium-large diameter blood vessels is expanded polytetrafluoroethylene (ePTFE), because of its high crystallinity and hydrophobicity. These two characteristics of ePTFE ensure the prevention of hydrolysis. But for small diameter vessels using ePTFE can be dangerous because of intimal hyperplasia, calcification, and thrombosis [157]. Therefore, a biodegradable implant is considered the best option, which will be replaced by vascular cells, preserving the architecture of the vessel, but without losing its mechanical properties [158].
In most cases, coatings of implants for vessels should contain bioactive molecules, which speed up vessel's integration. One of them is vascular endothelial growth factor (VEGF) -a family of signal proteins produced by cells for stimulating the formation of blood vessels. Interesting work in vessels implant area is done by the Gonzalez-garcía group. In that work, poly (ethyl acrylate) was shown to lead to the formation of fibronectin networks, where VEGF-presenting areas were generated, ( Figure  3), which promote vascular cell response. Such a system allows to use extremely low doses of the growth factors, while at the same time improves vascularization. As such, it is robust and efficient approach to improve vascularization of the tissue and in can be implemented in 2D and 3D scaffolds [159].

Hybrid Biomaterials for Nervous Tissues Reconstruction
The causes of death of neurons, astrocytes, and oligodendrocytes may be apoptotic or necrotic. The causes of death and poor functionalization can also be axon damage, demyelination, ischemia, oxidative damage, and inflammation. The main problem of neural tissue regeneration is the complete lack of stimulating growth and migration factors, but there are factors responsible for inhibiting axon growth. In this regard, the damaged area quickly forms a healed scar, which is a chemical and physical barrier to regeneration [160]. Therapy of damaged areas is very difficult due to the architecture of the central nervous system. Cell transplantation is also difficult to achieve due to adverse conditions at the lesion sites. These factors make neural tissue engineering one of the most complex. Nowadays, the area of nanofibers consisting of natural and synthetic polymers receives substantial scientific interest.
One of the main approaches of tissue engineering of nerves is the creation of nerve conduits and the replacement of damaged ones. New conduits can be synthetic, biological or hybrid, which are biosynthetic. Synthetic polymers such as polyester, polyurethane, and polyols are widely used to create conduits. Also, biological polymers can be used to create them: polyesters, proteins, and polysaccharides [161]. Nerve conduits can be of three types: tubular, fibrous and matrix. A striking example is the creation of a hybrid fibrous nerve conduit, which consists of PCL and gelatin. Fibrous PCL has an excellent architecture for cell migration, and gelatin stabilizes the electrically pumped

Hybrid Biomaterials for Nervous Tissues Reconstruction
The causes of death of neurons, astrocytes, and oligodendrocytes may be apoptotic or necrotic. The causes of death and poor functionalization can also be axon damage, demyelination, ischemia, oxidative damage, and inflammation. The main problem of neural tissue regeneration is the complete lack of stimulating growth and migration factors, but there are factors responsible for inhibiting axon growth. In this regard, the damaged area quickly forms a healed scar, which is a chemical and physical barrier to regeneration [160]. Therapy of damaged areas is very difficult due to the architecture of the central nervous system. Cell transplantation is also difficult to achieve due to adverse conditions at the lesion sites. These factors make neural tissue engineering one of the most complex. Nowadays, the area of nanofibers consisting of natural and synthetic polymers receives substantial scientific interest.
One of the main approaches of tissue engineering of nerves is the creation of nerve conduits and the replacement of damaged ones. New conduits can be synthetic, biological or hybrid, which are biosynthetic. Synthetic polymers such as polyester, polyurethane, and polyols are widely used to create conduits. Also, biological polymers can be used to create them: polyesters, proteins, and polysaccharides [161]. Nerve conduits can be of three types: tubular, fibrous and matrix. A striking example is the creation of a hybrid fibrous nerve conduit, which consists of PCL and gelatin. Fibrous PCL has an excellent architecture for cell migration, and gelatin stabilizes the electrically pumped PCL Polymers 2020, 12, 620 9 of 30 fibers and provides good cell adhesion. The growth of neurons in the hybrid conduit showed a better differentiation and migration of neurons than that for a channel consisting of only one component [162].
Hydrogel implants consisting of agarose, hyaluronic and polyethylene glycol and containing a ciliary neurotrophic factor (CNTF), sonic hedgehog (SHH) [167], vascular endothelial growth factor-165 (VEGF165) [168], and EGF [169], as well as cell-adhesive arginylglycylaspartic acid (RGD peptides) [169] have been created. Martino et al. showed the incorporation of VEGF, PDGF, and bone morphogenetic protein-2 growth factor into the same binding site as integrin on fibrin fibers. This approach increased the biological activity of the growth factor [170].
Mechanical properties are some of the most important characteristics for nerve regeneration. A good flexibility of the implant helps to avoid axon destruction at the bending of the nerve [171,172]. An implant that is too rigid can compress the growing tissue [173]. But a substantially weak mechanical strength of the matrix can lead to breakage, rupture, and kinks of the nerve. Thus, an optimal polymer or copolymer ratio must be ascertained through experimental studies [172]. Using hydrogels as one of the components for creating hybrid implants, it is worth emphasizing the importance of swelling. As a result of swelling, axons are compressed, and their growth is disturbed. Swelling occurs due to the accumulation of conduit decomposition products, and it is controlled by changing the ratio of the polymers [174]. Optimal degradation should be uniform along the entire length of the implant, because, too fast degradation causes inflammation and swelling, and too slow degradation causes compression [172].

Hybrid Biomaterials Applied for Lungs
To create hybrid materials for tissue engineering of the lungs, one must have a good understanding of the anatomy and physiology of this organ [175]. Anatomically, the lungs are divided into two sections-the proximal and distal airways. The proximal respiratory (>2 mm internal diameter) consists of the pseudostratified epithelium. The pseudostratified epithelium is multilayered: the basal layer (discontinuous layer of the basal cells) and the luminal layer (ciliated cells, Clara-like cells (secretory club cells), human goblet cells, and neuroendocrine cells that aggregate to form neuroendocrine bodies). The distal airway (small bronchi and bronchioles) consists of a single layered epithelium containing Clara cells, ciliated cells, neuroendocrine cells, and p631Krt51 basal cells [176].
Alveoli are located in the most distal part of the lung and consist of two types of epithelial cells: alveolar type I cells (AEC I) and cuboidal alveolar type II cells (AEC II). Alveolar type I cell provide a gas exchange surface. Cuboidal alveolar cells containing secretory vesicles filled with surfactant [176]. Park et al. have hypothesized that a biodegradable implant that "disappears" over time will have a good effect on the regeneration of tracheal tissue and facilitate the approximation of native tissue ( Figure 4A) [8]. The authors used a hybrid implant consisting of L-lactide and ε-caprolactone, which was synthesized by ring-opening polymerization (P [LA/CL]). Such a hybrid matrix decomposes in 2-3 months in vivo by hydrolysis. A special advantage is the high porosity of such a matrix-80%. Pores have a size of approximately 20 to 100 µm, which allows cells to migrate into the implant. It was also possible to strengthen the matrix due to the gelatin coating, which also improved cell adhesion on the surface [69,177]. This is not the only example of the successful use of hybrid matrices. Also, the gelatin matrix coated with PLCL/TGF-B1 with cultured chondrocytes on the surface showed good results in vivo experiments ( Figure 4B). Within 8 weeks after implantation, the matrix retained its mechanical properties, despite the gradual replacement by native tracheal tissues ( Figure 4B) [8].
micro/nanoscale architecture of the alveolar environment. They used this system to study the effect of the structural properties of the ECM on damaged epithelial cells during the reopening of the airway ( Figure 3C). Gelatin coated PCL nanofibres are used to adjust Young's modulus. As a result, it was found that the stiffness of hybrid matrices significantly affects the barrier function of the epithelium/endothelium. An increase in the rigidity or density of the matrix led to a change in the structure of the cytoskeleton and a change in cell permeability [178].

Hybrid Biomaterials Applied for Kidneys
Kidneys perform the following essential functions: excretion and filtration of metabolites, regulation of the electrolytes, fluids, the balance of acids and bases, and maintenance of the production of red blood cells (RBC). The renin-angiotensin-aldosterone system of the kidneys is also responsible for regulating blood pressure [179].
An important factor in tissue regeneration in the kidneys is the cellular microenvironment, which can be adjusted by the proper engineering of hybrid materials. One example of success using hybrid material is hyaluronic acid/collagen crosslinked with PEGDA and loaded stromal cell-derived factor-1 (SDF-1). This hybrid material was also used as an endothelial progenitor for cell delivery system. There, hydrogel protects EPCs from cytotoxic insult. SDF-1 loaded into hydrogel stimulated proliferation and increased cell engraftment in kidneys [180,181]. It should be noted that such strategies for using hybrid polymer hydrogels as cell carriers for kidney reparation are used quite often [182][183][184][185].
Lih et al. developed a PLGA matrix coated with Mg(OH)2 and acellular ECM. Mg(OH)2 can affect the acidity of the cellular microenvironment, which changes during the decomposition of the PLGA. As a result of reducing the acidity of the microenvironment, the inflammatory effect is also reduced. The ECM also improves the normal biological function of cells on the matrix [186].
Growth factors are a promising component of polymer-based hybrid materials. Hybrid materials can also be used for kidney tissue, as it is closely related to kidney regeneration in renal failure [186]. The acellular ECM could promote the normal biological function of kidney cells.
Classical methods for coating polymers with growth factors are adsorption and chemical bonding [159,187]. The healing process needs the replacement of damaged tubular cells to restore the connection of the renal epithelium. This process includes some growth factors that are provided in renal tissues. The growth factors include epidermal growth factor (EGF), a potent proximal tubule cell mitogen [188]; transforming growth factor-α (TGF-α), a participant in the reconstruction of the injured proximal tubule via the EGF receptor [188]; insulin-like growth factor 1 (IGF-1); fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) [189]. Higuita-Castro et al. have been successful in developing a platform that mimics the micro/nanoscale architecture of the alveolar environment. They used this system to study the effect of the structural properties of the ECM on damaged epithelial cells during the reopening of the airway ( Figure 3C). Gelatin coated PCL nanofibres are used to adjust Young's modulus. As a result, it was found that the stiffness of hybrid matrices significantly affects the barrier function of the epithelium/endothelium. An increase in the rigidity or density of the matrix led to a change in the structure of the cytoskeleton and a change in cell permeability [178].

Hybrid Biomaterials Applied for Kidneys
Kidneys perform the following essential functions: excretion and filtration of metabolites, regulation of the electrolytes, fluids, the balance of acids and bases, and maintenance of the production of red blood cells (RBC). The renin-angiotensin-aldosterone system of the kidneys is also responsible for regulating blood pressure [179].
An important factor in tissue regeneration in the kidneys is the cellular microenvironment, which can be adjusted by the proper engineering of hybrid materials. One example of success using hybrid material is hyaluronic acid/collagen crosslinked with PEGDA and loaded stromal cell-derived factor-1 (SDF-1). This hybrid material was also used as an endothelial progenitor for cell delivery system. There, hydrogel protects EPCs from cytotoxic insult. SDF-1 loaded into hydrogel stimulated proliferation and increased cell engraftment in kidneys [180,181]. It should be noted that such strategies for using hybrid polymer hydrogels as cell carriers for kidney reparation are used quite often [182][183][184][185].
Lih et al. developed a PLGA matrix coated with Mg(OH) 2 and acellular ECM. Mg(OH) 2 can affect the acidity of the cellular microenvironment, which changes during the decomposition of the PLGA. As a result of reducing the acidity of the microenvironment, the inflammatory effect is also reduced. The ECM also improves the normal biological function of cells on the matrix [186].
Growth factors are a promising component of polymer-based hybrid materials. Hybrid materials can also be used for kidney tissue, as it is closely related to kidney regeneration in renal failure [186]. The acellular ECM could promote the normal biological function of kidney cells.
Classical methods for coating polymers with growth factors are adsorption and chemical bonding [159,187]. The healing process needs the replacement of damaged tubular cells to restore the connection of the renal epithelium. This process includes some growth factors that are provided in renal tissues. The growth factors include epidermal growth factor (EGF), a potent proximal tubule cell mitogen [188]; transforming growth factor-α (TGF-α), a participant in the reconstruction of the injured proximal tubule via the EGF receptor [188]; insulin-like growth factor 1 (IGF-1); fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) [189].

Hybrid Biomaterials Applied for Liver
The largest internal organ in a body is the liver, which performs hundreds of different functions that help the normal body homeostasis [190]. Damage to tissues or cells that entail hepatic pathology provokes a change in physiology and metabolic activity. Although the liver has a high regenerative ability and can completely restore its mass and function, some disorders affect the physiology so much that therapy is required to restore its functions. Typically, these effects cause hepatitis, cancer and various toxins, such as drugs and alcohol [191].
Hybrid polymeric materials are actively used for tissue engineering of the liver too. Due to them, there is the possibility of current adjustment of cell adhesion and migration. Earlier, natural (cellulose, chitosan, gelatin, alginate, collagen, fibrin, heparin, hyaluronic acid) and synthetic (PVA, PLA, poly-(N-isopropylacrylamide), poly (lactide-co-glycolic acid) and PCL) polymers have been applied for tissue engineering of the liver. Besides, growth factors and specific enzymes have been be used as one of the components of the hybrid matrix [192][193][194].
Currently, hybrid polymeric materials are already actively used in tissue engineering of the liver [195]. The adhesion peptides RGD or YIGSR significantly improved the adhesion of hepatocytes on the surface of PCL and PLA, compared with pure polymers [196]. Lee et al. showed a polymer poly (ethylene glycol) diacrylate (PEGDA)/hyaluronic acid-coated with a synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS). This semi-permeable gel supported the differentiation of hepatocytes for 16 days [197]. The 3D sandwich culture of hepatocytes between the top and bottom layers maintained their functional state over a period of 14 days. Such cultures were even faster than collagen sandwich cultures in the rate of tissue formation [198]. Qui et al. modified PCL scaffold with galactosylated chitosan and showed an improved hepatic functionality over a period of 7 days as compared to a 2D monolayer or PCL 3D scaffold [199].

Hybrid Biomaterials for Musculoskeletal Tissue Reconstruction
The replacement of bones, cartilage and skeletal muscle are the most essential goals of musculoskeletal tissue engineering. Although the cell type and even their source as well as materials themselves influence the tissue growth, new developments, recent progress in this area allows for effective cell cultivation and growth. The following polymers with their particular advantages have been used in musculoskeletal tissue engineering: collagen (cell differentiation), Matrigel (proliferation), Sylgard (matrix formation), fibrin gels (cell survival), PGA (vascularization), alginate (adhesion), PCL (adhesion), hyaluronic acid (immunogenicity) [200]. Just like in other application areas, patterning of gels [201,202] is essential as well as application of natural and synthetic polymers [203] is essential for musculoskeletal tissue engineering. Overall, the designed scaffolds should withstand forces of external environment and match or mimic the properties of cells surrounding them.

Hybrid Biomaterials Applied for Cardiac Muscle
One of the leading causes of death in developed countries is cardiovascular disease. The regenerative capabilities of the heart muscle are extremely limited; as a result, millions of cardiomyocytes die after myocardial infarction [204,205]. After a myocardial infarction, a scar forms within 4-6 weeks. This collagen scar, consisting of fibroblasts and endothelial cells, significantly reduces the contractile function of the heart. Such a change leads to heart failure. An appropriate combination of polymers, bioactive molecules and cells can help restore cardiac muscle function after such injuries [206].
A striking example of an application of a hybrid material is the use of an elastomeric framework of nanofibers treated with macromer-thick layers of acrylate poly (glycerolebacinate) (Acr-PGS) obtained by electrospinning. Gelatin was used as the polymer, which stimulated the adhesiveness of cells onto the scaffolds. The obtained scaffolds have different mechanical properties, depending on the ratio of the polymers used (tensile modulus from 60 kPa to 1 MPa) and degradation rate (weight loss from about 40 to 70% by the beginning of the 4th month). At different polymer ratios, a difference was also observed in the chemical response of the recipient to implantation [207]. A heart patch was constructed from poly (glycerol subacute) and was found to be sufficiently active even without gelatin for cell adhesion for more than three months [208].

Hybrid Biomaterials Applied for Skeletal Muscles
Skeletal muscles recover well in response to minor injuries, but serious damage can cause fatal consequences in muscle activity if therapy is not done on time. Hybrid biomaterials that provide chemical and physical signals can help improve muscle regeneration. The two main factors for restoring muscle work are the angionization and innervation of the implanted scaffold. An important factor in the survival of an implant after transplantation into muscle tissue is its vascularization. Often, to accelerate this process, implant pre-vascularization is carried out, for example, a matrix consisting of fibrin/poly (lactic-co-glycolic acid) is pre-seeded with a mix of fibroblasts and myoblasts. The matrix with cells is transplanted to the recipient. After a couple of weeks, angiogenesis and anastomosis of the vascular system of the recipient with implant begin. After that, this matrix is transferred to the damaged area, preserving the vasculature [209]. Also, polymers are coated with arginine and laminin before implantation, which improves the clustering of acetylcholine receptors [210,211]. This procedure improves subsequent tissue innervation [211]. When cultured with neurons, such myofibrils form acetylcholine receptors at the border of two cell types. When exposed to glutamic acid, one could observe shortening [212,213].

Hybrid Biomaterials Applied for Cartilage
Cartilage defects are some of the most common problems of orthopedics, while similar pathologies result from trauma, aging, etc. Cartilage has a very low ability to regenerate since it only consists of chondrocytes. Cartilage tissue lacks innervation and vascularization [214]. One of the most used form of polymers for the regeneration of cartilage tissue is a hydrogel. Hydrogel implantation procedures can be minimally invasive (injection or arthroscopy). The advantage of using polymer hydrogels is its properties: swelling and lubrication [215][216][217]. Mechanics can be also added to this list provided that the hardness can be tuned with an inorganic content in hybrid hydrogels. These properties are also inherent in native cartilage tissue, which allows the implanted material to successfully mimic the tissue. The morphology of the cells inside the hydrogel is mainly spherical, which is characteristic of chondrocytes [218]. One of the hybrid hydrogels used to regenerate cartilage is polyethylene glycol (PEG)-based hydrogel with methacrylate groups for photo-crosslinking [215]. When growth factors are added to such hydrogels, a significant acceleration of the cartilage formation of tissue by stem cells is observed [219].

Hybrid Biomaterials Applied for Bones
One type of tissue with an inherent regenerative capability is bone tissue [220]. However, if the disturbances or injuries are too extensive or the regeneration process has been interrupted by a new exposure, major healing problems may arise. There is also a big problem with bone regeneration for old people due to osteoporosis. In all these cases, an exterior intervention is required [221]. The bone mainly consists of connective tissue, which is continuously undergoing the destruction of old sites and the creation of new ones, by osteoclasts and osteoblasts, respectively. This occurs due to high physical stress on these tissues [222]. For material scientists, bone is a matrix composed of polymers (collagen) and ceramics (hydroxyapatite). Therefore, the use of hydrogel and ceramics can improve implant engraftment both at the cellular (good adhesion and fast differentiation) and at the organism level (mechanical properties required for bone tissue) [223].
An important parameter for creating hybrid materials for bone regeneration is the ability to promote primary biomineralization. For example, when using PCL fibrous matrices (fiber Ø 50 µm) coated with calcium phosphate, biomineralization occurs much faster than that on pure PCL. Such polymer coatings increase alkaline phosphatase activity and accelerate in vivo bone formation [224]. It was also demonstrated that implantation of only ceramics did not lead to an acceleration of osteogenesis [225]. This indicates the need for a stable surface. That is why hybrid materials are so in demand for bone therapy [226,227].
Grafting of enzymes can be also used for promoting the cell adhesion. In this regard, it was recently shown by Muderrisogly et al. that an enzyme (alkaline phosphatase, ALP) can be immobilized onto a titanium surface with a alginate hydrogel ( Figure 5) [228]. This was carried out in several steps: (1) the mineralization of a titanium substrate by CaCO 3 particles; (2) the adsorption of ALP enzymes; (3) the coating the substrate with the alginate hydrogel. Further, this structure is mineralized again, and ALP molecules are adsorbed on it. This design provides the implant with all the substances necessary for osteogenesis and improves the anti-corrosion properties of the matrix [229].
Polymers 2020, 12, x FOR PEER REVIEW 13 of 28 osteogenesis [225]. This indicates the need for a stable surface. That is why hybrid materials are so in demand for bone therapy [226,227]. Grafting of enzymes can be also used for promoting the cell adhesion. In this regard, it was recently shown by Muderrisogly et al. that an enzyme (alkaline phosphatase, ALP) can be immobilized onto a titanium surface with a alginate hydrogel ( Figure 5) [228]. This was carried out in several steps: (1) the mineralization of a titanium substrate by CaCO3 particles; (2) the adsorption of ALP enzymes; (3) the coating the substrate with the alginate hydrogel. Further, this structure is mineralized again, and ALP molecules are adsorbed on it. This design provides the implant with all the substances necessary for osteogenesis and improves the anti-corrosion properties of the matrix [229]. One can see from data discussed above that the invent of hybrid materials enable the so-called "all-in-one" concept. There, a polymer can be taken, modified by inorganic content, and tuned to match required properties of desired tissues or organs.
From discussion above, it is clear that pure polymer and hybrid materials have been used in various applications in general area of tissue engineering. These applications are often so distinct that they often are considered almost as stand-alone areas. Some selected applications are shown in Table  1 presenting tissue/organ type, coatings applied there, the type of polymers as well as targeted functionality. One can see from data discussed above that the invent of hybrid materials enable the so-called "all-in-one" concept. There, a polymer can be taken, modified by inorganic content, and tuned to match required properties of desired tissues or organs.
From discussion above, it is clear that pure polymer and hybrid materials have been used in various applications in general area of tissue engineering. These applications are often so distinct that they often are considered almost as stand-alone areas. Some selected applications are shown in Table 1 presenting tissue/organ type, coatings applied there, the type of polymers as well as targeted functionality. Collagen based Silk Improving cell adhesion [231][232][233] Maleic anhydride/cellulose nanocrystal based PLA Improving connection between two components and cells [136] Hap based PLLA Imitation of fibro-cartilaginous region [137] Skin (Section 3.2)

Gelatin based
Chitosan Macrophage activation, high hemostatic effect and no antigenicity. [145] Collagen with immobilized epidermal growth factor (EGF) PCL and PCL/Gelatin Improving cells adhesion and stimulation of mitosis via regulation of Ca and pH inside cells [146,147] Micelles with tannic acid PCL/Collagen mix Improving of angiogenesis and antimicrobial properties [148] CaCO 3 with tannic acid/PCL PCL Improving of angiogenesis and antimicrobial properties [67] Platelet lysate PCL/PLCL Haemostatic plug stops bleeding [234] PLGA based VEGF and TGF-β3 Differentiation and angiogenesis of cells. [144] PCL based EGF + VEGF Differentiation and angiogenesis of cells. [152] Chitosan microparticles loaded with growth factors Dextran-based hydrogel Differentiation and angiogenesis of cells. [153] Vascular (Section 4)

Gelatin based PCL PGA
Adherence of NCI-H292 cells; tuning mechanical properties of materials [177,178,248] bFGF and AA2P based PGA/PLA Improving cells adhesion and stimulates cells proliferation and differentiation [249] Kidney (Section 6.2) Mg(OH) 2 and acellular ECM PLGA Neutralization of the effects induced by degradation of PLGA products, suppression of inflammatory reactions [186] l-DOPA and collagen IV PCL Improving cells adhesion and proliferation [250] Liver (Section 6.3) ECM-molecules PLA Microenvironment manipulation; changes of gene expression, protein contents, and cell adherence [251] PCL [252] HGF based Gelatin Controlled release for enhancement of the in vivo therapeutic effects RGD and YIGSR based PCL and PLA Improved hepatocyte adhesion [196]

Conclusions and Outlook
In summary, tissue engineering is an important interdisciplinary and multidisciplinary research area with an explosive growth potential. Two most important building blocks here are polymer-based and hybrid biomaterials. Innovations in the design of coatings, progress in their imaging and characterization as well as availability of new materials open opportunities for custom-tuned biomaterials suited for various tissue engineering sub-areas. Some of these materials are purely polymeric, yet they have been also shown to be directly applicable in tissues engineering. These polymeric materials are complementary to the so-called hybrids incorporating inorganic constituents together with organic (polymeric) matrix. These hybrids are increasingly used for matching the properties of various tissues and enabling thus the so-called "one-matches-all" concept. This refers to one or similar materials, which can be applied in various and most importantly different areas of tissue engineering. Besides inorganic particles or capsules in such hybrid coatings enable release of relevant bio-molecules. It can be alluded that although such tissues as tendon, skin, vascular and nerve tissue, lung, kidney, liver, cardiac and skeletal muscles, cartilage, bones) are very different, they can be all targeted with the same material base. An additional important functionality of hybrids is controlled release of encapsulated biomolecules.
Future directions of research are expected to experience further merger of biomaterials with bio-medical sciences, wherein scientists working in the former areas will be looking in more details to the needs in the bio-medicine. By the same token, doctors and biologists would benefit from new solutions and novel formulations offered by material scientists. Information on the properties of different tissues and state-of-art in their respective areas, overviewed here, will be helpful to design new materials and knowing already available ones. Further integration of biomaterials with tissue and organs will likely experience further interest to understanding their mechanical properties, surface functionalization, possibility of 3D and 4D printing technologies, physiological behavior. Additional in-vivo tests would play an increasing role in further integrating these two types of materials (organics and inorganics) and these two areas.