Integrating Signaling Pathways in Design of Smart Hydrogels: Comparison
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Hydrogel biomaterials have been employed to facilitate the process of vascularization. These materials are designed to provide a supportive environment for the growth and development of blood vessels. By incorporating specific cues and factors, hydrogel biomaterials can effectively promote angiogenesis, allowing for the formation of a functional vascular network. The properties of hydrogels, such as their biocompatibility and tunable physical characteristics, make them suitable for creating a conducive microenvironment that supports vascular cell proliferation, migration, and organization. Through careful design and optimization, hydrogel biomaterials hold promise in advancing strategies for successful vascularization in various biomedical applications. Numerous hydrogel culture platforms are available, offering a variety of options for tissue growth. 

  • angiogenesis
  • biomaterials
  • hydrogel
  • molecular signaling
  • regenerative medicine
  • gene

1. Naturally Derived Hydrogels

Hydrogels made from natural polymers, such as collagen, gelatin, fibrin, and hyaluronic acid (HA), are commonly used in this context [1][2][3][4][5][6]. Natural polymer hydrogels possess innate and proper cell interaction activities achieved through receptor–ligand binding and can be biodegraded enzymatically, making them advantageous for supporting vascularization [2][4]. Consequently, they have been extensively employed in studying vascularization processes and facilitating the growth of blood vessels. Naturally derived hydrogels form through self-assembly physical crosslinking, a process which involves changes in intermolecular interactions. Gelation is achieved by modifying the temperature (increasing to 37 °C or decreasing to −20/−80 °C). Several parameters, including temperature, pH, and ionic strength, can be controlled to achieve the desired hydrogel structure, while chemical and physical crosslinking combinations are often applied. Table 1 reports principal gelation methods that are usually used.
Among natural polymers, hyaluronic acid (HA) is a versatile biomaterial widely used in tissue engineering and regenerative medicine. With its biocompatibility and ability to retain water, it forms a three-dimensional scaffold that mimics the native extracellular matrix [4]. Hyaluronic acid hydrogels promote cell adhesion, migration, and proliferation, making it suitable for applications in wound healing, drug delivery, and cartilage regeneration. Its tunable properties and bioactive modifications contribute to its therapeutic potential. HA is a prominent component of the natural ECM. It possesses high hydrophilicity and biodegradability [7][8][9][10][11]. The biological exploitation of HA mainly relies on the molecular weight: HA with a high molecular weight (approximately 106 Da) is nonimmunogenic and exhibits antiangiogenic properties, while low molecular weight HA (less than 3.5 × 104 Da) exerts pro-angiogenic activity but can also induce inflammation by activating APC also via chemokines [12][13]. Consequently, HA hydrogels designed to facilitate controlled vascularization are typically composed of high molecular weight HA and modified to enhance angiogenesis.
Collagen, which is the most abundant protein found in the ECM [14], is widely utilized as a natural polymer in biomaterials. Collagen gels offer cell adhesion, cell spreading, and enzymatic degradation properties, thus meeting the fundamental requirements for vascularization support, other than the necessary control of stiffness [15][16][17][18][18][19][20]. A hydrogel known as HA-KLT was developed by modifying hyaluronic acid (HA) with a VEGF mimetic peptide called KLT (KLTWQELYQLKYKGI). Characterization of the hydrogel revealed a porous, three-dimensional scaffold structure that offered a large specific surface area for cell adhesion and interaction. In comparison to the unmodified HA hydrogel, the HA-KLT hydrogel demonstrated enhanced capability in promoting the attachment, spreading, and proliferation of endothelial cells in vitro. Additionally, the pro-angiogenic potential of the hydrogels was assessed by implanting them into lesion cavities in injured rat brains. Results showed that the hydrogels were able to establish a permissive interface with the host tissues after four weeks of implantation [21].
Gelatin, derived from collagen through acid or base treatment, is another commonly used natural polymer in biomaterials due to its affordability, degradability by cell-secreted proteases, and stability under various conditions [4][22][23][24]. In addition, the physical and mechanical properties of gelatin hydrogels can be finely tuned via the crosslinking of type-A and type-B gelatin catalyzed by microbial transglutaminase via reactive methacryloyl groups; thus, gelatin can be transformed into gelatin methacrylate (GelMA) and subsequently crosslinked to form hydrogels that promote vascularization [25][26][27][28][29][30]. In addition, GelMA mechanical properties may be tuned by varying the degree of methacrylamide groups [31][32].
Fibrin, a protein formed from the breakdown of fibrinogen by thrombin during coagulation, serves not only as a hemostatic agent but also as a temporary matrix during the initial stages of wound healing [33][34][35]. It supports the invasion and adhesion of endothelial cells, facilitates the vascularization of wound sites, and acts as a reservoir for pro-angiogenic growth factors [36]. It was successfully used to promote anastomosis in vitro by the coculturing of endothelial cells (ECs) and fibroblasts in a fibrin 3D gel [37]. In vitro, a hydrogel material can be created by mixing fibrinogen with thrombin and calcium ions [38][39][40]. Fibrin-based hydrogels, renowned for their ability to promote vasculogenesis, are commonly employed in various models of vascularization due to their ease of fabrication [38][39][41][42][43][44]. Furthermore, fibrin can be recovered from blood for the creation of autologous hydrogel, which ensures that viable implants can be used therapeutic applications [45].
When aiming to create ECM-protein-based matrices for vascular tissue generation, it is beneficial to mimic the basement membrane of the native vascular environment. The basement membrane consists mainly of laminin, collagen, perlecan, nidogen, and smaller amounts of fibronectin [46][47][48]. Therefore, when designing pro-vasculogenic matrices, it is common to incorporate laminin along with other natural polymers, leading to improved angiogenic properties [49][50]. For instance, it has been shown that the incorporation of laminin within a collagen hydrogel enhances vessel formation when cells may make contact with it. This combination promotes cell adhesion, increases VEGFR expression, and facilitates the formation of endothelial networks [51]. Therefore, as a general rule, the combination of different natural polymers will provide a variety of signals which enhance vascularization [51][52][53][54][55][56]. Blending different natural polymers allows for optimal combinations of their advantageous properties (Figure 2). For example, combining collagen I with GelMA improves not only the mechanical properties of the hydrogel but also ensures improved vascularization due to the activation of additional molecular signaling pathways [53][54]. Other used combinations showed that the inclusion of fibrin, which contributes angiogenic signaling, within HA hydrogels improves scaffold longevity and supports vessel formation; mixing with chitosan also provides the same effects [57][58][59]. This has been reported to induce biodegradability, provide easy modification procedures, improve mechanical properties, and, in combination with gelatin, enhance ECM-related signaling [60][61].
The most accurate representation of the natural cellular environment is achieved with decellularized ECMs, a natural hydrogel material [62]. After decellularization, proteins and polysaccharides of the ECM still remain, offering a tissue-mimetic architecture experienced in vivo to the englobed cells [47]. Decellularized ECMs have been found to promote greater angiogenesis compared to collagen alone, as it also provides other ECM-related signaling [63][64]. It has been shown that the use of decellularized scaffolds mainly consisting of collagen and elastin, when seeded with ECs, are able support angiogenesis both in vitro and in vivo [64][65]. Similarly, retaining collagen and laminin in ECM-based scaffolds together with adipose-derived stem cells or microvascular fragments will enhance therapeutic approaches for the treatment of acute myocardial infarction [1][66][67][68].
As an advantage, this approach provides natural biocompatibility, the absence of toxicities, and the activation of several signaling pathways. However, several problems due to the simultaneous activation of different signals occur when aiming to study specific cell–ECM constituent interactions. Additionally, variations in the procedure of isolation from different provenances hinder the reproducibility because of large batch-to-batch variability [3].
Table 1. Naturally derived hydrogel preparation.
Gelation Method Biomaterials References
Crosslinkers HA [69]
Temperature increase Collagen [70]
2]. Among bioinert synthetic polymers, poly(ethylene glycol) (PEG) is the most widely used polymer in tissue engineering. PEG not only wards off protein adsorption due to its hydrophilicity and chain pliability, but also lacks hydrogen-bond-donating moieties, rendering it more impervious to protein adsorption in contrast to PHEMA and PVA [2]. While bio-inertness has been considered to be required for preventing undesired reactions including uncontrolled cell–protein interactions and foreign body responses, it also causes some limitations, such as in its impacts on interactions with cells and its influence on tissue support. Therefore, a tailored approach based on the integration of peptides and proteins is usually required to overcome such limitations.
This allows for the development of custom networks capable of executing specific functions like precise cell attachment, degradation rate control, and proper spatiotemporal presentation of angiogenic factors.
Artificial hydrogels have been extensively studied and display minimal batch-to-batch variability. They have found widespread use in promoting vascularization in both laboratory settings (in vitro) and in living organisms (in vivo). For example, gels formed from a blend of polymers based on polyvinyl alcohol (PVA) have been employed to investigate promoting vascularization [80][81][82]. However, hydrogels based on PEG are widely utilized and have consistently shown reliable support for vascularization when suitably modified [83][84][85].
Table 2. Common crosslinking methods and synthetic hydrogels in angiogenic applications.
Synthesis Hydrogel References
Free radical polymerization via

UV-sensitive initiator		 PHEMA [86]
103
]

2.1. Exploiting Cell Adhesion

Adhesion of vascular cells to their substrate is crucial for their survival, as well as for spreading, migration, and cell–cell contacts. Within their native tissue environments, vascular cells directly attach to ECM proteins via integrin receptors. This attachment not only impacts their spreading and migration but also provides the sequestration of angiogenic factors and enhancement of protease expression, which, in turn, remodels the ECM. As a result, the interaction between cells and the surrounding matrix holds great significance in influencing cell behavior, including proliferation, differentiation, and the formation of blood vessels. Naturally derived hydrogels, like those composed of gelatin, collagen, fibrin, GelMA–collagen mixes, and collagen–laminin mixes, possess inherent cell-adhesive ligands that interact with receptors on endothelial and mural cells. These hydrogels promote cell adhesion, spreading, and even support the development of tubular structures when in contact with vascular cells.
Incorporating ECM constituents into synthetic hydrogels is usually associated to improved cell adhesion; however, the use of full length proteins may result in an undefined presentation of adhesive domains. To address this, a strategy is represented by the use of short peptides that can be bound to the matrix. These are designed to solely possess specific binding domains, offering greater control and stability across a broader range of conditions. These cell-adhesive peptides provide precise control over the presentation and density of adhesive sequences without introducing additional signals to the gel matrix.
Commonly used adhesive peptides, reported in Table 4, include fibronectin-derived RGD, which binds to integrins such as α5β3 and α5β1 found in various cell types including vascular cells [104][105]. Other peptides like REDV and KQAGDV, derived from fibronectin, facilitate the adhesion of vascular endothelial cells and vascular smooth muscle cells, respectively [106]. Laminin-derived peptides such as IKVAV and YIGSR bind to specific laminin receptors [107][108]. RGD, in particular, is widely utilized in hydrogel design for tissue engineering due to its presence in multiple ECM proteins and its ability to bind to integrin receptors expressed by various cell types, including fibroblasts, neural cells, and vascular cells [109][110]. Studies have shown that RGD-mediated vascular cell spreading promotes endothelialization, tubulogenesis, and vascular sprouting [111][112][113]. Similarly, IKVAV has demonstrated its supportive role in angiogenesis and wound healing [114].
Table 4. Common methods for improving cell adhesion.
Adhesive Peptides Hydrogel References
RGD PEG [111][112][113]
Crosslinkers
Gelatin [71][72]
Cation adding Fibrin [73]
Temperature decrease

2. Synthetic Polymer Hydrogels and Modifications to Promote the Angiogenesis

While some naturally occurring polymer frameworks have shown potential in promoting vascularization, they do not provide a thoroughly regulated and precisely defined setting to investigate the impact of environmental signals on cell behavior. On the other hand, synthetic polymer hydrogels offer a highly customizable material, and they have been applied in different settings other than angiogenic ones [74][75][76]. However, they require significant modifications to mimic the natural environment of cells and interact effectively with them. Unlike naturally derived ones, the use of synthetic hydrogels may also account for the resulting cytotoxicity mainly due to the procedure of gelation or crosslinking. Common synthesis methods used for polymer hydrogel production are reported in Table 2. Biocompatibility is crucial for polymer gel components and gelation processes in tissue engineering applications. For instance, poly(acrylamide)-based gels have been employed in the past due to their tunable mechanical stiffness of the support [77][78][79]. Nonetheless, their utilization is restricted to 2D cell culture due to the toxic nature of acrylamide monomers before polymerization. Therefore, if cells are to be encapsulated in a 3D environment, biocompatible synthetic gels must be employed.
Apart from diminishing toxicity, synthetic gels should also aim to decrease inflammatory responses within a living organism. This objective can be accomplished by employing a bioinert chemical composition that discourages protein adsorption, a feature commonly found in numerous synthetic hydrogel-forming polymers like poly(2-hydroxyethyl methacrylate) (PHEMA) and poly(vinyl alcohol) (PVA) [
Freeze and thaw cycling PVA [87]
Free radical polymerization via

redox/thermalphotoinitiators		 PEG [88]
Chwalek et al. [89] developed an innovative approach to stimulate angiogenesis by incorporating heparin into PEG hydrogels, effectively sequestering VEGF, bFGF, and SDF1α. The inclusion of this component enables the regulated and prolonged release of growth factors over a period, facilitating the administration of a singular dose that proves to be effective at continuously delivering soluble growth factors throughout the culture or regeneration duration. As stated above, the reduction of adverse cell behaviors and inflammatory responses is usually achieved via the minimization of uncontrolled protein adsorption to synthetic biomaterials; however, this, in turn, may hinder cell adhesion to the hydrogel.
To achieve controlled vascularization, it is desirable to have spatiotemporal control over the presentation of pro-angiogenic factors, ensuring sustained local exposure. While soluble delivery of pro-angiogenic growth factors has shown some success in driving vascularization, a higher level of control can be achieved by permanently immobilizing these factors within the hydrogel matrix [90][91][92][93]. A widely adopted technique for attaching bioactive molecules involves covalent linking, establishing a lasting bond between the bioactive molecule and the polymer chains in the hydrogel matrix. This approach has been extensively utilized to modulate cell behavior, including directing cell phenotype and promoting stem cell differentiation [92][94]. Effective strategies supporting this approach include light-triggered, free-radical-mediated linking and click chemistry reactions (Table 3). Free-radical-mediated tethering encompasses joining biomolecules to a vinyl-modified polymer which creates crosslinks with the main polymer during network formation. In click reactions, the biomolecule is attached to a functional group that binds independently to the crosslinking pattern. The covalent attachment of angiogenic factors to hydrogels has demonstrated the activation of pro-angiogenic differentiation, both in laboratory settings and in living organisms [95][96][97].
For instance, upon covalent linking of VEGFs to a PEG gel through free radical crosslinking, notable enhancements in endothelial tubule formation in 2D culture and augmented migration of endothelial cells and cell–cell connections in 3D encapsulation are exhibited [92].
Similarly, PDGF-BB, responsible for vessel maturation, was tethered within PEG hydrogels, providing evidence for increased mature vessels either in 2D or 3D systems. The addition of covalently tethered bFGFs further increased endothelial cell migration [98]. In addition, it has been shown that gels containing both soluble and tethered PDGF-BB exhibited a significant increase in endogenous vessel ingrowth when compared to gels with only soluble PDGF-BB.
Click-chemistry-based tethering of VEGFs has also shown angiogenic behavior, with VEGFs immobilized in agarose and PEG gels leading to endothelial tubule formation in either in vitro or in vivo settings [89][99].
Although proteins like VEGF, bFGF, and PDGF have shown efficacy in enhancing vascularization, peptides present unique benefits, including their compact size, stability, and customizable manufacturing process. Peptides can be tailored to present essential regions of the protein to elicit desired cell responses while minimizing immunogenic reactions and preserving bioactivity when bound to hydrogels [100]. For example, the VEGF-mimetic peptide Qk, which consists of the 17–25 helix region of the VEGF protein, can bind the corresponding receptors on vascular ECs, stimulating their proliferation and angiogenesis [90]. Covalently linking Qk to various polymer hydrogels causes proliferation and outgrowth of ECs from spheroids, increased expression of phosphorylated VEGFR2, and enhanced vessel formation [101][102]. Immobilized Qk in combination with soluble VEGF has demonstrated the most robust angiogenic response, surpassing the performance of tethered VEGF alone [92]. This combination approach mimics the natural tissue environment and promotes the greatest vessel density and branching.
Table 3. Common methods for covalently tethering growth factors hydrogels.
Hydrogel Type/Tethering Angiogenic Factors References
PEG/free radical and click chemistry mediated VEGF [92]
PEG/free radical mediated PDGF [98]
IKVAV PEG [114] PEG/free radical mediated PDGF + bFGF [98]
PEG-gelatin/click chemistry mediated
PEG-IKVAV PEG [114] Qk [102][103]
PEG-YIGSR PEG [114] GelMA-nanoliposomes/encapsulation Qk [102]
PEG-RGD PEG [114][
PEG-RGD + YIGSR + IKVAV PEG [108]
The synergy between the hydrogel, proper cell adhesiveness peptides, the degradation sequences, and the presentation of angiogenic signals is instrumental in promoting vascular morphogenesis in both controlled laboratory settings and living organisms. Cell–matrix interactions in vivo involve encountering different extracellular matrix proteins and their specific domains simultaneously. Studies have investigated the effects of combining multiple peptides on vascularization. For instance, in peptide-functionalized, degradable, PEG-based hydrogels, incorporating both YIGSR and RGDS results in the highest tubulogenesis and ECM protein production by encapsulated cells, which are hallmarks for proper angiogenesis. In an in vivo corneal experiment, the combination of RGDS, IKVAV, and YIGSR in a PEG hydrogel resulted in increased vessel density, branching, and other tubulogenic measures compared to using the peptides alone. These provide evidence for synergetic use of various cell–protein domain adhesion [108].
In contrast to earlier approaches that necessitated surgical implantation, a novel technique utilizes microgels created from PEG engineered to present RGD and VEGF. An MMP-degradable protein sequence was used to crosslink them. This innovation allows for the direct injection of microgels into mice, effectively triggering vascularization and facilitating tissue regeneration as the material gradually degrades over time [115].
In summary, attaching short peptides to hydrogel matrices provides better control over cell adhesion, allowing precise modulation of adhesive sequence presentation and density. Peptides such as RGD, IKVAV, and YIGSR have demonstrated their effectiveness in promoting cell adhesion, tubulogenesis, and vascularization, both in vitro and in vivo, offering promising opportunities for tissue engineering applications.

2.2. Exploiting Hydrogel-Controlled Breakdown and Cell Migration for Improved Vascularization

Cell migration and the formation of new vascular networks are essential processes in tissue engineering. Macroporous hydrogels, such as cryogels, have been employed to support vascularization by providing large pores that allow cell spreading and migration, enabling vessel ingrowth [116][117][118][119]. However, in nanoporous hydrogels, cell migration through the gel network requires the degradation of the hydrogel material. Degradation allows cells to remodel their hydrogel environment and change the original materials with the ECM [120][121].
Efforts were made in the design of synthetic hydrogels, which can be remodeled as cells differentiate. Generally, synthetic gel biodegradation is obtained via hydrolysis and incorporation of proteolytic peptide sequences derived from ECM proteins [120][122]. Hydrolysis occurs when polymers linked by certain chemical groups undergo cleavage in aqueous environments. This process can be controlled by environmental factors and the hydrophilicity and permeability of the gel. Polymers prone to hydrolysis, like poly(lactic acid) and poly(glycolic acid), can be mixed with non-degradable polymers such as PEG to impart hydrolytic degradation to hydrogels [123][124]. However, hydrolysis is not directly responsive to cell behavior, limiting its control over tissue development.
To achieve cell-mediated and spatially controlled gel degradation, enzyme-degradable peptides derived from ECM proteins are often conjugated with synthetic polymers. Matrix metalloproteinases (MMPs) released by local cells during ECM remodeling are known to cleave in these sequences [125][126]. MMPs play a crucial role in tissue vascularization and are upregulated in various diseases. Different peptides have different susceptibilities to MMPs, and their inclusion in hydrogel designs allows for degradation rates controlled by cell behavior. Changing the number and sequence type also affects the degradation profile [120][127]. MMP-sensitive, collagen-derived peptide sequences were initially used for enzymatically degradable hydrogels, but modified versions have been developed to enhance degradation rates. Peptides can vary in their degradation rates and sensitivities to different MMPs, offering design flexibility for gels supporting vascularization. MMP-degradable peptide sequences, particularly those sensitive to MMP2 and MMP9 secreted by vascular cells, are commonly employed in vascularization support [128][129]. Studies have shown that optimizing the degradation rate of hydrogels influences vascular sprout formation and architecture. An intermediate degradation rate promotes multicellular migration, resulting in more complete sprout formation, while very fast or slow degradation rates hinder sprout connectivity and cell invasion [113][130].
In summary, the incorporation of degradable peptides into synthetic hydrogel matrices allows for cell-mediated gel degradation and controlled tissue remodeling. By responding to cell behavior and MMP activity, these hydrogels facilitate cell migration, ECM remodeling, and the formation of functional vascular networks.

2.3. Exploiting the Angiogenic Factors-Controlled Release for Improved Vascularization

Angiogenesis is a tightly regulated and time-sensitive process that requires prolonged exposure to factors. While the soluble release of pro-angiogenic factors is important for recruiting vascular cells, delivering them in a single bolus is insufficient to sustain all the process due to rapid clearance and unintended side effects. Therefore, several strategies are used to allow either the retention or the controlled release of angiogenic growth factors. They include: the integration of protease degradable linkers, the heparin and aptamer binding to signaling molecules, and the entrapment in emulsion of angiogenic factors in micelles.
  • The use of degradable linkers: Besides aiding in the migration of encapsulated cells and promoting endogenous tissue growth, matrix degradation can be employed as a mechanism to regulate the release of angiogenic growth factors into the proper sites. [131][132]. When growth factors are released through the degradation of the gel, they are released over an extended period, which has been shown to enhance angiogenesis. In this scenario, studies have indicated that VEGFs were encapsulated within RGD-functionalized PEG microgels and crosslinked using either a degradable peptide, GCRDVPMSMRGGDRCG (VPM), that can be broken down by MMP-1 and MMP-2 enzymes, or a non-degradable linker, DTT. The speed of gel degradation was modified by varying the proportion between the enzymatically breakable VPM linkers and the enzymatically unaffected DTT crosslinkers. As expected, the regulated release of VEGFs resulted in a significantly increased number of blood vessels [115].
    Using a different strategy, the angiogenic peptides SPARC113 and SPARC118 were integrated into the gel structure, surrounded by MMP-cleavable regions. In vivo experiments demonstrated that gel degradation and the subsequent release of these peptides substantially boosted endogenous angiogenesis. These results suggest that by incorporating various cleavable regions, the matrix’s degradation rate can be controlled, allowing for the regulated release of VEGFs, which, in turn, is able to control vessel formation [133].
  • The use of heparin binding: Another method for achieving prolonged release and presentation of angiogenic factors to cells is through heparin binding, which temporarily immobilizes biomolecules. This approach is due to the ability of heparin to bind GFs through electrostatic interactions [134][135]. This sequestration results in improved stability and gradual release of angiogenic factors such as VEGF and bFGF, which maintain their functions [81][136]. Heparin binding facilitates biomolecule presentation by mixing heparin with proteins in vitro. Covalently linked heparin-biomolecule complexes exhibit extended sustained growth factor release compared to non-covalent bonds in the polymer matrix. Studies with heparin-containing gels show reduced initial burst release and prolonged sustained release of pro-angiogenic factors in vitro for up to 21 days [137][138]. The extended duration of interaction has been discovered to amplify the angiogenic reaction of vascular cells in PVA-heparin gels, resulting in enhanced HUVEC migration when exposed to bFGF and VEGF separately, as well as with the simultaneous binding of both bFGFs and VEGFs [81]. Moreover, the in vivo implantation of hydrogel with heparin-bound GFs has demonstrated successful vascularization. Heparin-bound VEGFs have promoted the ingrowth of endogenous blood vessels either into degradable PE or gelatin-based hydrogels [27][139]. Similarly, poly(lactic-co-glycolic acid)-heparin microspheres loaded with bFGF have enhanced vascularization when implanted. Poly(lactic-co-glycolic acid)-heparin microspheres, when coupled with bFGFs, effectively increased the density of local capillaries in a subcutaneous model. Similarly, VEGF-bound hyaluronan-heparin gels stimulated angiogenesis in a subcutaneous context and supported the sustained formation of blood vessels for 28 days [136][137].
  • The use of aptamers: Aptamers are short oligonucleotide strands exhibiting high specificity in binding proteins [21][136][137]. They can also be conjugated to hydrogel constituents. These molecules offer an advantage in biomaterial functionalization as they specifically bind to targets without inducing an immunogenic response [140][141]. The conjugation of aptamers, which are specific to pro-vascular factors, with polymer hydrogels has yielded angiogenic responses. As an example, the use of anti-VEGF aptamer binding VEGFs showed greater HUVEC growth in the presence of the anti-VEGF aptamer than the soluble VEGF [142]. Additionally, fibronectin gel possessing anti-VEGF and anti-PDGF aptamers exhibit a significant increase in ECs in vitro and boosted vessel numbers showing hallmarks of mature vascularization units in vivo [143]. Similarly, an aptamer-based programmable VEGF delivery platform was implemented in GelMA hydrogels and was used to tune the microvasculature formation within engineered tissues [141]. Thus, both heparin and aptamers can serve as effective means of binding multiple pro-angiogenic factors to enable prolonged exposure to cells, thereby enhancing the angiogenic response.
  • The use of entrapment in emulsion of angiogenic factors: It represents an alternative strategy which enables the control of the release from gels of entrapped angiogenic factors, allowing for spatiotemporal regulation. Recently, a biomaterial was designed with ultrasound technology which enabled the synthesis of hydrogel-loaded, acoustically sensitive emulsions [144]. When subjected to ultrasound exposure, the emulsion underwent evaporation, leading to the release of bFGFs and inducing a controlled, time-dependent enhancement in endothelial cell tubule sprouting.

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