1. Introduction

2. Methods of corneal decellularization

2.1. Biological techniques for the decellularization of cornea

2.1.1. Enzymatic agents

Enzyme-based treatments for decellularization disrupt the bonds and interactions between nucleic acids, as well as interacting cells in neighboring proteins and other cellular/tissue components [20]. These types of treatments are advantageous over other decellularization protocols in that they provide high specificity for removing cellular and detrimental ECM elements [10,35,36]. For example, trypsin, dispase, and phospholipase A2 (PLA2) are commonly used enzymatic treatments. Trypsin is a serine protease that targets the C-side bonds in arginine and lysine amino acids and is mostly used combined with ethylenediaminetetraacetic acid (EDTA), a chemical agent able to break cell-matrix interactions [10,36]. Notably, extended exposure to trypsin-EDTA treatment can dramatically alter the matrix’s structure, degrade laminin, and remove GAGs, reducing the tissue’s mechanically strength as it degrades collagen fibers [37,38]. As a result, it may not be well suited for corneal decellularization. Furthermore, epithelia and endothelia have been removed following treatment with Dispase II [39] before being fully decellularized using a subsequent method. It breaks down peptides linked to particular basement membranes proteins like collagen IV and fibronectin, but if administered over an extended length of time, it can also harm the basement membrane [40]. After delipidation of the dermis, a direct comparison of trypsin and dispase treatments showed superior decellularization by dispase accompanied by increased ECM disruption [41]. Likewise, PLA2 is an esterase that hydrolyses phospholipid components of cells but does not react with collagens or proteoglycans [42]. Hence, the application of PLA2 in decellularization helps maintain collagen and proteoglycans in the resulting scaffold [10,39]. It has also been demonstrated that PLA2, along with sodium deoxycholate [43], was influential in producing the acellular porcine corneal [42,44]. Other studies have also suggested that combining PLA2 with a bicarbonate salt, results in effective cellular removal and maintenance of collagen fibers [42,45].

Furthermore, with respect to combinative treatments, nucleases are mainly applied with other detergents to expedite the removal of DNAs and RNAs from scaffolds [46,47,48]. Nucleases such as RNase and DNase, are frequently used to cleave nucleic acids and aid in the removal of nucleotides after cell lysis in tissues [32]. For instance, porcine corneas treated with DNase and RNase resulted in the efficient decellularization, but the tissue became opaque due to severe distortion of the collagen structure [49]. However, other studies have identified, in many cases, as a general consequence of decellularization, and optical clearing agents like glycerol have been provided an ability to substantially reverse opacity [28,50,51,52], while providing antimicrobial benefits [53,54,55]. Compared with exonucleases, endonucleases such as benzonase [56] may be more effective because they cleave nucleotides mid-sequence and thereby more effectively remove DNA fragments [10]. Likewise, another category of enzymes, such as sera-derived enzymes, including fetal bovine serum, contain nucleases that can degrade both DNA and RNA [57]. They supports the removal of nucleic acids from tissues but fail to remove immunogenic elements [32]. The xenogeneic serum may also introduce immunogenic elements into the ECM which can cause adverse responses following recellularization or transplantation [32,58]. Moreover, the human serum has also been used as a standalone decellularizing agent to produce porcine decellularized cornea [3], after first mechanically removing the epithelium [58].

2.1.2. Non-enzymatic agents

Following the complete description of enzymatic agents used in decellularization, non-enzymatic treatments include the use of chelating agents and serine protease inhibitors. Chelating agents such as ethylenediamine tetra-acetic acid (EDTA) aid cell dissociation via the separation of metal ions [10,32,35]. However, these same mechanisms can lead to the disruption of protein-protein interactions [32]. Chelating agents alone are incapable of adequate cellular removal. Thus, they are often used in combination with enzymes and detergents [32]. EDTA has also been used with sodium dodecyl sulfate (SDS), a potent ionic detergent, to effectively decellularize corneal tissues [59].

In comparison, serine protease inhibitors, like aprotinin, phenylmethylsulfonyl fluoride, and leupeptin, can prevent some of the detrimental effects to the ECM caused by intracellular proteases released after cellular lysing process [10]. Specifically, protease inhibitors often accompany harsh detergents and decellularizing agents. One common agent used for corneal decellularization is aprotinin [10], an inhibitor of trypsin and related proteolytic enzymes. In studies that utilized these agents, authors have reported minimal damage to the ECM despite the use of harsh decellularizing agents [60,61]. A summary of enzymatic and non-enzymatic decellularization techniques is presented in Table 1 below.

Table 1. Methods for cornea decellularization and associated mechanisms, advantages, and disadvantages.

Table 1. Methods for cornea decellularization and associated mechanisms, advantages, and disadvantages.

Methods/Techniques	Mechanism of Action	Advantages	Disadvantages
Biological
Enzymatic Agents
Trypsin [35,39,62]	Hydrolyzes protein and disrupts protein-protein interactions	Breaks cell-matrix interactions	An extended exposure can disrupt the collagen structure
Dispase [56]	Cleaves peptides associated with basement membrane proteins	Can aid the decellularization process by initially removing epithelium and endothelium	May cause damage to the basement membrane
Phospholipases A2 (PLA2) [42]	Hydrolyzes phospholipid components of cells	Effective at the removal of DNA and residual cellular components that tend to adhere to ECM proteins Helps maintain collagen and proteoglycans in the corneal tissue
Nucleases (RNase and DNase) [63]	Cleaves nucleic acids and aid in their removal	Effective at the removal of DNA and residual cellular components that tend to adhere to the stroma’s ECM proteins	Incomplete removal of the enzymes may impede recellularization and successful transplantation
Sera [42]	Serum nucleases degrade DNA and RNA.	Effectively removes cells while maintaining tissue transparency	The use of non-human sera carries a risk of cross-species transmission of pathogens
Non-enzymatic Agents
EDTA [64]	Dissociates cells by separating metal ions	Can be used for effective when combined with other agents	Ineffective at cell removal when used unaccompanied
Chemical
Alcohols
Ethanol [10,65]	Dehydrates and lyses cells. Removes lipids from tissues.	More effective in removing lipids from tissues than lipase Antimicrobial, antifungal, and antiviral properties	Can cause damage to the ultrastructure of tissue
Glycerol [20,66]	Dehydrates and lyses cells Removes lipids from tissues	Can maintain or restore corneal transparency Cryoprotectant for long-term cornea storage	Can cause damage to the ultrastructure of tissue
Acids and Alkalis
Peracetic acid [62,65]	Solubilizes cytoplasmic components of cells Removes nucleic acids via hydrolytic degradation	Acts to simultaneously sterilize tissue	Ineffective decellularization that can also disrupt the ECM
Ammonium hydroxide [67,68]	Hydrolytic degradation of biomolecules	Results in complete DC with little effect on collagen architecture	Can eliminate GFs and reduce mechanical properties
Ionic Detergents
Sodium dodecyl sulfate(SDS) [60,65]	Solubilizes cell membranes and dissociates DNA from protein Disrupts protein-protein interactions	Complete removal of cells can be achieved	Can be highly detrimental to ECM structure including disorganization of collagen fibrils and loss of GAGs Loss of tissue transparency
Sodium deoxycholate [20,43,63]	Solubilizes cell membranes and dissociates DNA from protein Disrupts protein-protein interactions	Complete removal of cells can be achieved when used with other agents	Less effective at removal of cells
Non-ionic Detergents
Triton X-100 [63]	Breaks up lipid-lipid and lipid-protein interactions	Mild and non-denaturing	Less effective than ionic detergent treatments Can cause damage to the ECM
Zwitterionic Detergents
CHAPS [64,69]	Has properties of non-ionic and ionic detergents	Better cell removal than non-ionic detergents Improved preservation of the ECM ultrastructure than ionic detergents	Poor cellular removal Very disruptive to stromal architecture
Hypo- and Hypertonic Solutions
Sodium Chloride (NaCl) [10,64,70]	Detaches DNA from proteins	Can maintain optically clarity Ability to maintain the stromal architecture and retain GAG content	Does not remove cellular residues Mixed reports on the success of cell removal efficiency
Tris-HCl [10,64]	Lyses cells by osmotic shock	Reduces decellularization time	Mixed reports on cell removal
Physical
Freeze-thawing [20,32]	Ice crystal formation causes cell lysis	Effectively destroys tissue and organ cells	Expensive Needs subsequent treatment to remove cells Enhanced pore formation and disruptions to ECM
Hydrostatic Pressure [10,20,32,62]	Increase in pressure results in cell lysis	Effectively decellularizes whilst maintaining collagen fibril structure Kills bacteria and viruses	Expensive
Sonication and Mechanical Agitation [71]	Cell lysis and removal	Does not remove DNA remnants from the corneal tissue	Only effective with enzymatic treatments

2.3. Physical techniques for the decellularization of cornea

2.3.1. Freeze-thaw cycles

Physical technologies are also considered as an essential component in decellularization protocols. The application of freeze-thaw cycle have been shown to effectively degrade cells in tissue via the formation of intracellular crystals [32]. Freeze thaw cycles are generated by fluctuating between freezing temperature (−87 °C) and biological temperature (37 °C) [12,20]. such fluctuations help frozen water crystals occupy significant volumes inside cells, and thus cause their membranes to rupture. This process aids uniform degree of decellularization [36,80]. However, varied crystalline geometries may damage the scaffold, and alter the mechanical stability of the ECM [20,69]. Experiments by Xaio et al. utilized snap freezing followed by lyophilization to induce pore formation in DCs. The ice crystals formed during pre-freezing were sublimated under vacuum conditions leaving a network of interconnected pores that enabled infiltration by cells [10]. Pulver et al., 2014 [81], Xing et al., 2015 [82], and Rahman et al., 2018 [44] have also shown that multiple freeze-thaw cycle can be used for decellularization [12]. Freezing and incubating the tissue in nitrogen gas has been used to induce apoptosis, as freezing alone can be insufficient [10]. Furthermore, nitrogen freezing of tissues is a relatively mild, yet costly treatment when compared to enzymatic or detergent treatments [10].

2.3.2. High hydrostatic pressure

Compared with freeze-thaw cycle, high hydrostatic pressure (HHP) processes disrupt cellular membranes within the corneal tissue via the generation of isostatic pressures. Pulses of water are sprayed on tissues immersed in saline to generate acellular scaffolds [20,80]. The use of high hydrostatic pressure is non-cytotoxic and successfully removes cells whilst destroying bacteria and viruses [66]. Studies have demonstrated that this approach of decellularization can be more effective than detergents or enzymes while providing an ample platform for recellularization, despite the fact that the ice crystal formation may alter ECM ultrastructure [32,80]. However, in order to prevent non-ideal structural alterations in the ECM, the amount of force applied needs to be accurately managed [20]. High hydrostatic pressure has been reported to successfully decellularize porcine corneas whilst maintaining the collagen fibril matrix and GAG content [10] Nevertheless, this procedure is costly, as it requires specialized equipment to induce pressures of up to 1 GPa that are need to generate viable acellular corneal tissues [66].

2.3.3. Sonication and mechanical agitation

Unlike HHP and freeze-thaw cycles, which can be applied independently, sonication and mechanical agitation are used in combination with chemical and enzymatic treatments for decellularization [72]. For example, a porcine retinal specimen was completely decellularized using a hydrostatic pressure of 980 MPa for 10 minutes in a study by Hashimoto et al. [83]. The aorta of a pig sample was likewise the subject of a similar study. In both instances, a chemical agent was required to destroy and remove DNA remnants from the tissue because the physical approach by itself was unable to do so [80]. As a result, sonication, and mechanical agitation work better when used with chemical and enzymatic decellularization agents.

Figure 1. Methods for cornea decellularization.

Figure 1. Methods for cornea decellularization.

3. Characterization of decellularized cornea prostheses

3.3. Preservation of innate biological attributes post-decellularization

After the adequate removal of cellular materials and biocompatibility evaluations of decellularized scaffolds are properly conducted, the next step should be to perform characterizations that provide insight on how the decellularization protocol can preserve structural and functional characteristics of the native tissues. An overview of various characterization techniques used to evaluate decellularized corneal scaffolds are outlined in Table 2.

3.3.1. ECM architecture preservation

Although the preservation of the native tissue architecture and ECM composition during tissue decellularization is crucial for all tissues, it is of particular interest to corneas. This is because the cornea has the highly organized ECM, which is responsible for its primary function, light transmission [109]. Basic histological assays can be used to compare the architecture of DCs with the native cornea. Studies have shown that stains such as eosin and van Gieson’s have shown instant changes in collagen structure [60,78]. However, basic histological approaches do not always provide adequate specificity, and under these circumstances, immunohistochemistry is a helpful tool since it is possible to identify ECM proteins that are specific to the cornea [10]. Corneal-specific proteins commonly utilized include collagens I, II, III, IV, and V, keratin, fibronectin, and laminin, present in the basement membrane [60,67]. The presence and integrity of the Bowman’s layer and Descemet’s membrane must be determined if a fully intact acellular scaffold is the end goal. This can be done by identifying specific proteins rather than using a broad eosin stain, which will provide additional information. To identify other components of the scaffold, stains such as Alcian blue have been used as a way of assessing whether the GAG content within the corneal stroma has been retained [10,56].

3.3.2. Transparency

The corneal stroma is mainly composed of dense connective tissue [110]. The cornea protects the inner content of the eye and the refractive capability of the lens is based on the precise shape of the cornea [111]. The corneal layers include epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium. Optical transparency and clarity are two things needed for good vision. Assessing the transparent nature of corneal tissue is very challenging and techniques are extremely limited. Previously, the transparency was assessed subjectively by placing the cornea on top of a grid and evaluating how the lines were seen. Luckily, throughout the years, the quantitative measurement of cornea tissue has improved using various methods, and each technique has its advantage and disadvantage. Below is a discussion of various conventional and emerging microscopic techniques that can be used to measure and monitor the transparency of corneal scaffolds.

Light microscopy is a simple technique that uses visible light to detect small objects. It offers high-resolution magnitudes to the image [112]. A major drawback is that the specimen needs to be stained to visualize it, but this stain could interfere with the decellularization protocol and may cause the distortion of the specimen. The presence of light on the specimen will cause a reflection and scatter the light to cause the image to be concealed. While confocal microscopy offers a high-resolution optical imaging technique that can be used as a rapid non-invasive diagnostic tool to observe corneal nerves in vivo, assess cell organelle and provide a high-resolution image [16,113,114,115,116,117,118,119,120,121]. In a study, confocal microscopy was used to assess the structural architecture of a human cornea. The Bowman’s membrane, stroma, and endothelium were all visualized at a resolution of 1–2 μm. It was able to get a high resolution by limiting the field of view to a single spot and thus eliminating out-of-focus structure [113]. A drawback of this tool is that it can only precisely analyze a small part of the specimen and provide a limited field of view, so it will take a long time to analyze multiple scans. Overall confocal microscopy can reconstruct a full view by rapid scanning of the cornea but it is still not a feasible screening tool because it can’t assess the quality of the ECM or evaluate collagen organization after decellularization. In comparison, transmission electron microscopy uses a beam of electrons at the specimen to visualize ultrastructural details of the cornea and generate a high-resolution magnified image [34]. This form of microscopy was used to assess rabbit cornea stroma opacity. Researchers were able to achieve remarkable images of the regeneration of the epithelial basement membrane [122]. However, a drawback of technique is that it uses potent fixatives, which could distortion of the specimen and affect decellularization.

Alternatively, anterior segment, Fourier-domain optical coherence tomography [123] is a non-invasive tool that uses light waves to take cross-section images of the eye. It Is essential for diagnosing a broad spectrum of diseases that affect the eye, such as glaucoma, macular degeneration, and diabetic eye disease [124], as observed with other forms of comparable spectroscopic applications for easily accessible regions of the body [125]. It can provide microstructure information such as stromal thickness, stromal morphology with an axial resolution, and the Bowman layer, providing another tool to assess decellularization. In comparison, ultrasound biomicroscopy uses a probe that emits high-frequency sound waves (50 to 100 MHz) that reflect through the tissue and generate an image [126]. It Is useful for diagnosing a broad spectrum of diseases that affect the eye and giving an accurate, detailed image of the cornea. This form of microscopy provides advantages over the previously mentioned techniques as it does not require staining and can delineate the microarchitecture and measure variations in the corneal layer. Nevertheless, this approach is limited by its need for direct contact with the eye and low (4mm to 5mm) tissue depth penetration [127].

3.3.3. Biomechanical properties

Decellularization is a process that removes all the cellular and nuclear material from the tissue while trying to maintain the remaining and innate composition, biological and mechanical properties of the tissue [66]. Some decellularization protocols can damage the cornea by changing the 3D architecture of the tissue, altering the biomechanical properties, and reducing the transparency of the cornea [66]. Historically, quantitative measurements of cornea tissue biomechanical properties have improved. We are now able to measure the cornea intraocular pressure, load-bearing capacity, elasticity properties, central cornea thickness, stiffness, and many more properties. However further means are needed to assess the effect decellularization protocols could have on the viscoelastic properties of the cornea [66]. Below is a summary table of some of the mechanical techniques and their advantages and disadvantages in assessing the biomechanical properties of the cornea.

Table 2. A summary of characterization techniques used to evaluate decellularized corneal scaffolds.

Table 2. A summary of characterization techniques used to evaluate decellularized corneal scaffolds.

Mechanical techniques	Application	Advantages	Disadvantages
Compression testing [128]	The tissue is placed under two plates and compressed The test is used to determine the mechanical behavior of the tissue under the crushing load	It can measure the mechanical behavior of the tissue and ductile fracture limits of the tissue It also gives you a detailed assessment of the tissue’s load-bearing capacity and elasticity properties	It flattens the tissue and damages the structural architecture Due to the corneal curvature shape, the test may not distribute the pressure equally
Holographic interferometry [129]	Is a tool that uses a laser to trace the changes in the tissue and perform interferometric measurements	It is a precise method that can detect residual stresses and cracks on the tissue without mechanical contact	There is no fixed distance so the location of the structure cannot be obtained
Bulge and inflation testing [128]	Is a tool that is used to biomechanical test corneal tissue by inflating the tissue and measuring the displacement	It is a reliable tool that demonstrates the intrinsic properties of the cornea layers and resembles Intraocular pressure	The inflation capacity is difficult to control and it could affect viscoelasticity
Corvis STL Tonometer/Pachymeter [130]	Corvis ST is a device that uses a high-speed Scheimpflug camera to record the cornea movement	Corvis ST device evaluates the central cornea thickness, corneal stiffness, and intraocular pressure	Very expensive
Ultrasound	It is a device that uses sound waves to get a very detailed image of structures	It is a non-invasive technique that shows detailed surface imaging of the cornea	It depends on the user’s skill
Ocular Response Analyzer [131]	Is a non-invasive device that uses rapid air pulse to make an indentation in the cornea	It measures the cornea biomechanical properties such as corneal hysteresis, intraocular pressure, and corneal resistance factor	Very expensive
Indentation testing [10]	Is a test that measures the indentation left behind in the cornea after it was compressed	Determine the hardness of the cornea with minimal destruction	Doesn’t assess tensile strength

4. Preclinical and clinical applications

Previous attempts outline the difficulty in developing artificial Kpros due to the formation of postoperative retroprosthetic membrane, corneal melt, limited implant retention, postoperative glaucoma, and overall poor postoperative visual acuity. On the other hand, CorNeat KPro is a synthetic alternative to bioartificial corneal implants. The undercut on the device’s posterior side allows it to easily snap into a trephined cornea and quickly seal the eye. The lens is surrounded by a nondegradable porous integrating skirt, which is fabricated through electrospinning and will be implanted subconjunctivally. The porous property of the skirt allows the conjunctiva to adhere to the sclera employing bio-stitching. The implanted skirt material stimulates cellular proliferation and colonization, contributing to full tissue integration. The CorNeat KPro is combined with a biocompatible, nondegradable biomimetic material that imitates the microstructure of the human ECM. It is a collagen mesh that provides structural and biochemical support to surrounding cells differing from scaffolding and collagen matrices used in tissue repair due to its nondegradable nature. Furthermore, this manufactured matrix was designed to provide human fibroblasts with a familiar environment that could support migration and colonization, which are crucial for wound healing and remodeling [14]. The in vivo studies have shown increased proliferation of fibroblasts and collagen fibrils within several weeks of implantation, indicating progressive tissue integration. A schematic of the novel design and implantation procedure are outlined in Figure 2.

Figure 2. Composition of CorNeat KPro and the implantation process.

Figure 2. Composition of CorNeat KPro and the implantation process.

5. Conclusion and perspectives

6. Hypothesis of proposed model for keratoprostheses

The Descemet membrane’s ink should be composed of hexagonal collagen VIII networks and associated collagens IV and XII [156,166], while the endothelial layer could be primarily composed of endothelial cells. Moreover, the stroma bioinks can be rich in collagen type I [167], GAGs, glycoproteins, proteoglycans, keratocytes, stem cells, and dendritic cells. The cells in bioinks can be cell-sheeted or printed into sheets. Following the complete preparation of bioinks, All the other components will be added into the extruder and printed layer by layer. The final printed product can be designed to possess mean central and peripheral thicknesses of 0.523 mm ± 0.039 and 0.660 mm ± 0.076, respectively, which correspond to the dimensions of the human cornea [168]. After that, the bioink of the sclera, which is made of electrospun nanofibers and decellularized ovine materials, can be printed separately onto a nanofiber skirt that will be sutured using biocompatible threads to the cornea. Figure 4 provides an outline of the proposed model.

Figure 3. (a) Native ovine cornea; (b) Decellularized ovine cornea; (c) Decellularized cornea regained transparency.

Figure 3. (a) Native ovine cornea; (b) Decellularized ovine cornea; (c) Decellularized cornea regained transparency.

Figure 4. Idea model for multilayered keratoprosthesis. EP = epithelial; BM = Bowman’s layer; DC = Descemet’s membrane; ED = endothelial.

Figure 4. Idea model for multilayered keratoprosthesis. EP = epithelial; BM = Bowman’s layer; DC = Descemet’s membrane; ED = endothelial.

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