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Uzel, E.; Durgun, M.E.; Esentürk-Güzel, �.; Güngör, S.; Özsoy, Y. Nanofibers as an Ocular System. Encyclopedia. Available online: https://encyclopedia.pub/entry/43776 (accessed on 18 August 2024).
Uzel E, Durgun ME, Esentürk-Güzel �, Güngör S, Özsoy Y. Nanofibers as an Ocular System. Encyclopedia. Available at: https://encyclopedia.pub/entry/43776. Accessed August 18, 2024.
Uzel, Egemen, Meltem Ezgi Durgun, İmren Esentürk-Güzel, Sevgi Güngör, Yıldız Özsoy. "Nanofibers as an Ocular System" Encyclopedia, https://encyclopedia.pub/entry/43776 (accessed August 18, 2024).
Uzel, E., Durgun, M.E., Esentürk-Güzel, �., Güngör, S., & Özsoy, Y. (2023, May 04). Nanofibers as an Ocular System. In Encyclopedia. https://encyclopedia.pub/entry/43776
Uzel, Egemen, et al. "Nanofibers as an Ocular System." Encyclopedia. Web. 04 May, 2023.
Nanofibers as an Ocular System
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15041062

Nanofibers are frequently encountered in daily life as a modern material with a wide range of applications. The important advantages of production techniques, such as being easy, cost effective, and industrially applicable are important factors in the preference for nanofibers. Nanofibers, which have a broad scope of use in the field of health, are preferred both in drug delivery systems and tissue engineering. Due to the biocompatible materials used in their construction, they are also frequently preferred in ocular applications. The fact that they have a long drug release time as a drug delivery system and have been used in corneal tissue studies, which have been successfully developed in tissue engineering, stand out as important advantages of nanofibers. 

nanofiber ocular engineering

1. Anatomy and Physiological Barriers of the Eye

Anatomically, the eyes consist of two segments, anterior and posterior. The lens, which is a transparent structure responsible for refracting the light coming into the eye, is the border that separates these two parts [1]. The anterior segment includes the cornea, iris, ciliary body, conjunctiva, and anterior surface of the sclera. The choroid, retina, optic nerves, and the posterior surface of the sclera are located in the posterior segment. In both the anterior and posterior segments, the interstitial spaces are filled with aqueous humor and vitreous humor, respectively [2].
The anatomical structure of the eye can be classified independently of its segments, as well as according to the structural features of the layers that make it up. These layers are from outside to inside: Tunica fibrosa oculi (fibrous layer), tunica vasculosa oculi (vascular layer), and tunica interna oculi (neural layer). Tunica fibrosa oculi, the fibrous layer of the eye, consists of the cornea, conjunctiva, and sclera. This layer, which does not contain lymph and blood vessels, surrounds the eyeball from the outside [3]. The cornea is a thin and transparent tissue consisting of five layers (corneal epithelium, Bowman’s membrane, stroma, Descemet’s membrane, and the endothelial layer). The conjunctiva is a mucosal membrane [2]. The sclera is a fibrous tissue consisting of five layers (Tenon’s capsule, episclera, scleral spur, limbus, and posterior sclera) [4], just like the cornea. The tunica vasculosa oculi, located just below the tunica fibrosa oculi, is also known as the uvea. This layer consists of the choroid, ciliary body, and iris. Thanks to the vessels it contains, the blood circulation in the eye tissues and the production of aqueous humor are carried out by the tissues in this layer [2][3]. The tunica interna oculi is the inner layer where the light is transformed into a neural impulse and transmitted to the brain [5].
Since the eye is a vital organ in contact with the external environment, it must maintain its integrity. For this reason, it contains natural anatomical and physiological barriers. All ocular tissues, vessels, and fluids are the natural barriers of the eye. These barriers are the tear film, cornea, conjunctiva, sclera, blood–aqueous humor (iris–ciliary body), lens, and blood–retina barrier [6][7][8]. These barriers, whose main task is protecting the eye from foreign fluids and objects, also act as drug rate-limiting steps. They reduce the penetration of drugs into ocular tissues and their bioavailability. Since each of these barriers has different structures from the others, they also perform rate-restriction functions on drugs with different properties.
The tear film covers the surface of the cornea and conjunctiva. It is the primary protective structure against ocular problems of chemical, mechanical, bacterial, or viral origin. Likewise, it forms the largest barrier among drugs applied topically to the eye [4][9]. Topically applied drugs are usually applied to an area called the cul-de-sac with a volume of 7–10 µL [10]. However, the application dose of any drug is 20–50 µL on average [11]. Due to this sudden increase in the volume of the area, topical drugs such as drops and emulsions applied topically are removed from the eye by nasolacrimal drainage and added to the systemic circulation [7][12]. Around 80% of a topically applied conventional drug is eliminated due to the tear film and nasolacrimal drainage [13].
The cornea acts as an important barrier to conventional topical drugs in the anterior segment of the eye [14]. The epithelium, stroma, and endothelium, which are parts of the cornea, are tissue formations of different polarities. Depending on the arrangement of the cells in the epithelial layer, there is a high shunt resistance and is considered a tight tissue [6]. These tight junctions give the epithelium a lipophilic character. Stroma, conversely, has a highly hydrophilic character due to the collagen fibers in its structure. Therefore, while the epithelium prevents the passage of hydrophilic drugs, the stroma acts as a barrier to the passage of lipophilic drugs. In the endothelium, the innermost layer of the cornea, molecules of up to 70 kDa can pass through passive transport [7][8][14].
The conjunctiva acts as a barrier through the numerous capillaries and lymphatic structures in its structure. It dilutes applied drugs with the blood or lymphatic circulation. There are epithelial cells in the conjunctiva as well as in the cornea. These epithelial cells have a shunt resistance, although not as much as in the corneal epithelium. Points of this resistance are considered tight structures and act as barriers to drugs. The conjunctiva acts as the main barrier for drugs not administered via the corneal route. Compared to the cornea, the conjunctiva is a hydrophilic tissue and more suitable for passing large molecules. For this reason, the direct conjunctival application of ocular drugs is being studied by reducing corneal application to increase the absorption of larger bio-organic molecules such as proteins and peptides. However, considering that most of the drugs used in the clinic are lipophilic and small molecules, it is seen that corneal application will not lose its importance [4][6][14].
The sclera has a hydrophilic character due to the collagen fibers in its structure. For this reason, it acts as a barrier for lipophilic drugs. However, small-sized lipophilic drugs also show scleral permeability similar to hydrophilic drugs. In addition, the size of the molecules and the positive charge are other parameters that reduce the passage through the sclera [8][15].
The iris and ciliary body, the tissues of the tunica vasculosa bulbi form the blood–aqueous barrier (BAB). This barrier is also known as the anterior blood–eye barrier [8]. The ciliary body produces aqueous humor, which stabilizes intraocular pressure. On the other hand, the dense capillaries in this layer contain tight junctions. These tight junctions, the epithelial cells of the iris, and the barrier formed by aqueous humor are highly restrictive for hydrophilic drugs. Small molecules and lipophilic drugs can easily pass the BAB and enter the systemic circulation via the uvea. An inflammation that may occur in this barrier disrupts the integrity of the barrier. This causes the amount of drug passing to the anterior region of the eye to not be controlled [6][8][15][16][17].
The lens is the eye’s tissue, consisting of 65% water and the remainder predominantly proteins. It is distinctly different from other eye tissues with its protein content. The lens is a tissue in which active and passive transport, depending on Na+, are effective. It mainly affects the passage of drug molecules for this reason [6][15].
The blood–retinal barrier (BRB) is formed by the combination of several factors. Primarily, retinal pigment epithelial cells have Na+, K+-ATPase pumps that ensure the balance of Na+ and K+ ions in the eye. On the other hand, the capillaries in their structure have tight connection points. The passage of drug molecules through these tight junctions is the second rate-limiting step. At the same time, molecules that can pass through these capillaries quickly enter the systemic circulation, which reduces the number of drugs in the target area, thus reducing the bioavailability. Finally, the ganglion cells in the retina are nerve cells and form a barrier similar to the cerebrospinal barrier. The BRB acts as a barrier for the passage of proteinaceous and small hydrophilic molecules while allowing the passage of lipophilic molecules. However, these lipophilic molecules are also rapidly distributed and eliminated due to intense systemic circulation [4][6][8][15].
Increasing the ocular bioavailability of a drug to be applied to the eye can only be achieved by overcoming all of these barriers and delivering the drug to the target tissue. Two ways are followed for this purpose. One of them is the application of the drug to the eye in different routes. These routes of administration are classified as topical, periocular (subconjunctival, transscleral, and intravitreal), and systemic [4][8]. Although these different routes, which are actively used today, seem to have solved the problem of low ocular bioavailability, they contain risks as they can cause serious complications such as blindness. For this reason, the second way to increase ocular bioavailability is the development of drug delivery systems [1].

2. Drug Delivery System

Conventional dosage forms applied to the eye are solutions, suspensions, ointments, and gels [18][19]. Today, 90% of the drugs on the market fall into this group. These dosage forms usually target the anterior segment of the eye and may have little effect on a possible disease in the posterior segment [20]. On the other hand, they have very low bioavailability due to ocular barriers. Due to their low bioavailability, their dosing frequency during the day is high, which reduces patient compliance. In addition, the fact that gels and ointments cause blurred vision is another factor that reduces patient compliance [21]. To prevent all of these negativities, drug delivery systems targeting certain eye tissues are being developed.
Drug delivery systems are produced by using a suitable polymer/surfactant/lipid, have micro or nano size, and are developed to deliver the loaded drug to the target tissue [22]. Since they target the drug to the tissue where the effect is desired, they allow the use of active pharmaceutical ingredients (API) at lower doses. Thus, a decrease in the rate of side effects may occur. In addition, drug releases can be extended thanks to the polymer/surfactant/lipid used in their preparation. Thus, the dosing frequency can be reduced and patient compliance can be increased [23][24][25]. There are different delivery systems developed for ocular drug targeting. Micro and nanoparticles, micro and nanoemulsions, nanosuspensions, micelles, liposomes, solid lipid nanoparticles, dendrimers, cubosomes, discosomes, niosomes, spanlastics, bilosomes, hydrogels, implants, inserts, lenses, and nanofibers are among the carrier systems developed [1]. While some of these carrier systems have turned into commercial products, some have remained in experimental studies. The most well-known commercial products are Ocusert® (an ocular insert containing pilocarpine) [26], Xelpros® (a pilocarpine-containing micellar system) [27], Modusik-A Ofteno®, Papilock Mini®, and Cequa® (which are micellar systems containing cyclosporine A) [28][29].
Nanofibers have also been used in ocular drug targeting since the first years they were designed as drug delivery systems. Thanks to the materials used in their preparation, they increase the penetration and contact time of drugs with ocular tissues and show high biocompatibility. In addition, their extended-release profile also reduces the dosing frequency [30][31]. However, the features that make nanofibers distinctly superior to other drug delivery systems are that they have a large surface area, high porosity, easily adjustable diameters, and can be combined with other drug delivery systems [32]. Having a large surface area enables the nanofibers to be loaded with more drugs than other drug delivery systems. These features, coupled with extended drug release profiles, allow for further reductions in dosing frequencies. For this reason, nanofibers stand out as a promising approach to the medical treatment of chronic ocular diseases. The fact that porous structures can be produced to be similar to ocular tissues further increases their biocompatibility compared to other carrier systems [33][34][35]. One of the most important features of drug delivery systems is that they are micro or nanosized. The diameter size of nanofibers could be adjusted much more easily than other carrier systems. Thus, the permeation of the drug with ocular tissues can be increased. The studies found that the carrier systems should be smaller than 100 nm to overcome the corneal barriers [36], and the scleral pore openings were between 20–80 nm [2]. Nanofibers can be easily produced in the appropriate diameter according to the target tissue. It also provides an important advantage in that it can be used in combination with other drug delivery systems (nanoparticle, dendrimer, etc.). In recent years, studies in the hydrogel form of nanofibers, which are generally converted into insert or implant form, have also been carried out. Although the drug has been proven to increase penetration and permeation with ocular tissues, it can cause blurred vision, irritation, and watery discharge. Despite these problems, nanofibers may be a viable option for a variety of ocular drug delivery systems [37]. To avoid these side effects and maximize the benefits of using nanofibers for ocular drug delivery, nanofiber properties such as size, surface charge, and polymer type and composition can be optimized, which can significantly affect their interaction with ocular tissues. By optimizing these properties, researchers can minimize the negative effects of nanofiber-based drug delivery systems while maintaining their effectiveness. Thus, the irritation potential of formulations can be reduced by reducing interactions with ocular tissues. In addition, nanofibers can be combined with other delivery systems such as hydrogels or liposomes to increase their performance and reduce their adverse effects. For example, nanofibers prepared with hydrogelizing polymers can provide a protective barrier by minimizing irritation and other side effects. In Table 1, nanofibers developed as an ocular drug delivery system are summarized (in alphabetical order).
Table 1. Nanofiber-based ocular drug delivery systems.
Loaded Drug Polymer Comments References
Amphotericin B PLGA/Eu-L/Gellan Gum/ Pullulan,
Eu-L/Gellan Gum/Pulluln
  • Homogeneous nanofibers containing both nanoparticle and polyelectrolyte complexes separately.
  • A nanoparticle-based system that transforms into nanofiber in situ.
  • Good cellular tolerance in all formulations.
  • Higher antifungal effect of polyelectrolyte complex nanofiber compared to other formulations.
 [38]
Azithromycin PLGA/PL/PVP
  • Successfully produced azithromycin-loaded nanoparticle-in-nanofiber inserts.
  • Homogeneously dispersed nanoparticles in the nanofiber.
  • Inserts show sustained drug release over 10 days in in vitro drug release tests.Biodegradable and biocompatible inserts.
  • As a result of in vivo pharmacokinetic studies, inserts have a 14.8-fold higher AUCt compared to eye drops.
  • As a result of in vivo pharmacokinetic studies, inserts have a 1.6-fold higher Cmax compared to eye drops.
 [39]
Besifloxacin HP-β-CD/PLC/PEG
  • Drug loading efficiency is over 90% in all formulations.
  • Not high cytotoxicity in any of the formulations compared to the control product.
  • Burst drug release in the first 2 days followed by a slow-release profile.
  • In ex vivo drug permeability studies, the drug delivery of nanofibers was close to the commercial drug.
  • In in vivo studies, infected corneas were significantly treated.
 [40]
Bevacizumab PVA/PCL/Gelatin
  • Nanofibers with the appropriate release profile for all samples, based on the cumulative amount of drug released in 6 days.
  • The release rate of coaxial bevacizumab nanofibers is lower than that of PVA-only bevacizumab nanofibers.
  • In the CAM model experiment, all bevacizumab nanofibers showed antiangiogenic activity.
  • All formulations are nontoxic.
 [41]
Brimonidine tartrate PAMAM-mPEG/PEO
  • Successfully produced electrospun dendrimer-based nanofibers.
  • Slower drug release from nanofibers compared to dendrimer and solution forms.
  • Compared to the solution form, the nanofibers have no difference in permeability.
  • Equivalent drug efficacy between nanofibers and solution form in terms of single dose IOP response in in vivo test results.
  • However, with continuous long-term (3 weeks) use of nanofibers, there is a significant decrease in the average intraocular pressure (IOP) values compared to the solution form.
  • Fast-dissolving, biodegradable, and biocompatible fibers.
 [42]
Brinzolamide β-CD/HPC/PCL
  • Possibility of more accurate dosing compared to control eye drops.
  • Near-linear drug migration through ex vivo sheep corneas over 6 h reaching therapeutic concentration in the receptor medium.
  • All formulations are biocompatible.
 [43]
Cyclosporine A (CsA) PLA
  • According to in vivo test results, CsA-loaded nanofibers significantly decreased the number of CD3-positive cells (T lymphocytes) and the production of proinflammatory cytokines in the corneas compared to eye drops and placebo.
  • Corneal inflammation and corneal neovascularization are effectively suppressed by CsA-loaded nanofibers.
  • Central corneal thickness returned to preinjury levels only in corneas treated with CsA-loaded nanofibers.
  • More sustained drug release than eye drops, despite lower drug concentration.
 [44]
Dexamethasone PLA/PVA
  • Drug release profiles of electrospun nanofiber inserts are more stable than solvent-cast polymeric inserts.
  • The cytotoxicity of electrospun nanofiber inserts is less than solvent-cast polymeric inserts.
  • The thickness of electrospun nanofiber inserts is less than solvent-cast polymeric inserts.
  • The electrospinning method is more suitable than the solvent casting method for preparing inserts with PLA/PVA polymers.
 [45]
Succinic anhydride
  • Nanofibrous hydrogel structure produced by the self-assembly method.
  • Sustained drug release is influenced by the initial pH of the hydrogel.
  • Biodegradable and biocompatible.
  • Higher precorneal retention compared to the solution form.
  • Higher ocular bioavailability compared to the solution form.
 [46]
Dexamethasone
gentamicin		 PVP/KP188
  • Nanofibers have a highly porous structure and a great surface-to-volume ratio.
  • Nanofibers dissolve rapidly in the tear fluid upon contact with the ocular surface.
  • Over 92% drug loading for both active ingredients.
  • Biocompatible formulation.
  • In the ex vivo microfluidic cornea model, the nanofiber insert has a much longer residence time compared to fluid eye drops.
  • Compared to eye drops, the AUC20–60min increased by 342.54%.
 [47]
Dexamethasone acetate PCL
  • Burst drug release of approximately 47% in the first 2 days.
  • Complete degradation and 100% drug release in 12 days.
  • Successful cellular biocompatibility on ARPE-19 and MIO-M1 cells in in vitro tests.
  • Excellent biocompatibility after vitreous implantation in mouse eye in in vivo tests.
  
Dorzolamide PLGA/PEG/PVA
  • Nanoparticles prepared by freeze-milling of electrospun nanofibers.
  • 2 times higher AUC compared to commercial eye drops in in vivo tests.
  • 2 times higher duration of IOP reduction compared to commercial eye drops in in vivo tests.
  • Enhanced preocular retention.
  • Safe and biocompatible formulation.
 [48]
Doxorubicin Glycopeptide
  • A nanoparticle-based system that transforms into nanofiber in situ.
  • Complete restoration of physiological angiogenesis and reduced pathological neovascularization in the mouse model of oxygen-induced retinopathy (OIR).
  • Having good histocompatibility.
  • Long-term accumulation within cells within 24 h, but significant reduction in the intracellular drug when incubation period exceeds 6 h.
 [49]
ε-polylysine
ferulic acid		 PVP/HA
  • Electrospun nanofiber inserts loaded with ferulic acid and cross-linked with ε-polylysine successfully produced.
  • Ferulic acid completely released from the inserts in 20 min.
  • ε-polylysine completely released from the inserts in 30 min.
  • Antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.
  • Biocompatible and nonirritant inserts as a result of Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) assay.
 [50]
Fluocinolone acetonide PCL
  • Drug loading efficiency is over 95%.
  • Sterile, nonirritating, and biocompatible nanofiber inserts.
  • Slow biodegradable nanofiber inserts.
  • Extended drug release and higher retention time compared to commercial eye drop drugs.
  • Higher t1/2 and AUC values, hence better bioavailability compared to commercial eye drop drugs in in vivo pharmacokinetic studies.
 [51]
Forskolin SA/PVA
  • Drug encapsulation of nanofibers is between 94.70 ± 0.26% and 96.90 ± 0.58%.
  • According to the Higuchi equation, nanofibers produce zero-order kinetic controlled drug release.
  • In in vivo intraocular pressure (IOP) reduction studies, nanofibers provided a significant and controlled reduction in IOP for up to 45 h.
 [52]
Itraconazole CA/PVA/PCL/PEG
  • Antifungal activity against candida albicans and Aspergillus fumigatus in all formulations.
  • Approximately 50–70% of the drug is released over 55 days (prolonged drug release).
  • Cell viability > 70% at all drug concentrations.
  • Safe, non-irritant, and suitable nanofibers.
 [53]
Levofloxacin PLA
  • Nanofiber in the form of composite scaffolds.
  • Drug releasing 50% of the levofloxacin content with burst effect on the first day, and between 2–7 days sustained drug releasing approximately 90% of the total levofloxacin content.
  • Despite low levofloxacin content, excellent therapeutic effects in in vivo rabbit models by promoting structural and functional restoration of conjunctiva after transplant.
 [54]
PCL
  • Drug-loaded nanofiber sutures prepared by electrospinning method.
  • Nanofiber sutures conform to U.S.P. specifications in terms of size and strength.
  • 96% retained breaking strength over 31 days.
  • Drug release detected in rat eyes for at least 30 days.
  • Biodegradable and biocompatible sutures.
  • More effective ocular bacterial infection prevention for 1 week compared to drug solution in in vivo studies.
 [55]
Moxifloxacin hydrochloride
pirfenidone		 PVP/PLGA
  • The nanofibers showed an antimicrobial effect for 24 h in the zone of inhibition test.
  • The antimicrobial and anti-scarring properties of the two drug-loaded nanofibers were found to be substantially equivalent to the free solutions of the two drugs in the Western blot method.
  • The AUC0–24h of moxifloxacin HCl and pirfenidone in nanofibers is 1.77 times and 2.49 times higher than in solution form, respectively.
  • The t1/2 of moxifloxacin HCl and pirfenidone in nanofibers is 2.34 times and 1.43 times higher than in solution form, respectively.
 [56]
Ofloxacin CS/PVA/Eu-RL/GA
  • Four different nanofiber formulations: (1) single-layered nanofibers with PVA/CS polymers, (2) multilayered nanofibers with Eu-RL polymers as the outer layer and PVA/CS polymers as the inner layer, (3) GA cross-linked formulation of single-layered nanofiber, and (4) GA cross-linked formulation of multilayered nanofiber.
  • All formulations have a drug loading capacity above 95%.Crosslinking of nanofibers causes an increase in their fiber diameters.
  • In the inhibition zone test, single-layered nanofibers have a greater antimicrobial effect than multilayered nanofibers.
  • Crosslinking reduces burst drug release in nanofibers.
  • Enhanced prolonged drug release in multilayered nanofibers.
  • Higher AUC in all formulations compared to the solution form of the drug.
  • Cross-linked multilayered nanofiber has the highest mean residence time (MRT).
  • All formulations are nonirritant and biocompatible.
 [57]
Silver (Ag)
nanoparticles		 CNF/PLA
  • Nanofiber membranes coated with CNF containing silver nanoparticles homogeneously on the surface.
  • High ocular biocompatibility and cell proliferation in in vitro cell culture experiments.
  • Provides over 95% inhibition of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus).
  • Approximately 75% antifungal effect against Fusarium spp.
 [58]
Triamcinolone acetonide Zein/Eu-S
PVP/CS
PVA/CS
PVP/PVA/CS
  • The aim is to compare the properties of nanofibers produced from different polymers.
  • Best quality, smallest diameter (120 ± 30 nm), and homogeneous structure: PVP/CS electrospun nanofiber.
  • As a result of in vitro drug release tests, the same formulation (PVP/CS) is the only nanofiber that follows the zero-order kinetic profile.
  • All formulations show a prolonged drug release profile.
 [59]
Timolol maleate PVP/PNIPAM
  • Novel drug delivery systems are designed as contact lenses coated with nanofibers.
  • Drug release is based on quasi-Fickian or Fickian diffusion with the application of Higuchi and Korsmeyer–Peppas models.
  • Biological evaluation using freshly cut bovine cornea confirms the biocompatibility of the formulations.
  • Nanofibers containing permeation enhancers (borneol) release 18.47% more drugs than nanofibers without penetration enhancers (86.71% and 68.24% drug releases, respectively).
 [60]
PVA/PL
  • Successfully prepared in situ gelling nanofiber system.
  • Drug loading efficiency is over 98.8%.
  • 100% drug release with first-order kinetics in 15 min.Increased ex vivo permeability compared to the solution form.
  • Higher drug retention in the corneal tissue.
  • Sustained IOP lowering effect for up to 24 h compared to drug solution in in vivo tests.
 [61]
Ac-(RADA)4-CONH2 peptide
solution
Ac-(IEIK)3I-CONH2 peptide
solution
  • Nanofibrous hydrogel structures produced by the self-assembly method.
  • The aim is to compare the properties of hydrogel nanofibers produced from different peptide solutions.
  • Ac-(IEIK)3I-CONH2 hydrogel shows slower drug release.
  • Slower ex vivo penetration for Ac-(IEIK)3I-CONH2 hydrogel due to the drug release rate.
  • Biocompatibility and safety for both hydrogels as a result of histological tests.
  • Enhanced bioavailability and efficient reduced IOP results up to 24 h for Ac-(RADA)4-CONH2 hydrogel in in vivo pharmacodynamic and pharmacokinetic tests.
 [62]
Timolol maleate
Brimonidine tartrate		 Ac-(RADA)4-CONH2 peptide solution
  • Two separate APIs encapsulated nanofiber hydrogel structures produced by the self-assembly method.
  • Burst drug release of approximately 60% in the first 1 h for both APIs.
  • Drug release over 8 h in total.
  • Enhanced ex vivo permeability for both drugs compared to solution forms.
  • No significant change in the structural integrity of the corneas.
 [63]
Vitamin C
Zinc (Zn)		 LDH/ PUU
  • The drug release of nanofibers (LDH/PUU) is prolonged from 5 h to 5 days compared to nanoparticles (LDH).
  • Biocompatible nanofibers.
  • All scaffolds have homogeneous nanofiber morphology.
 [64]
β-CD: β-cyclodextrin, HP-β-CD: BH-hydroxypropyl-beta-cyclodextrin, CA: cellulose acetate, CNF: cellulose nanofibrils, CS: chitosan, Eu-L: Eudragit L, EU-RL: Eudragit RL-100, EU-S: Eudragit S100, GA: glutaraldehyde, HA: hyaluronic acid, HPC: hydroxypropyl cellulose, KP188: Kolliphor P188, LDH: Zn−Al-layered double hydroxide, mPEG: methoxy polyethylene glycol, PAMAM: polyamidoamine, PEG: polyethylene glycol, PCL: polycaprolactone, PEO: polyethylene oxide, PL: Pluronic F-127 (Poloxamer 407), PLA: poly(lactic acid), PLGA: poly(lactic-co-glycolic acid), PNIPAM: poly (N-isopropylacrylamide), PUU: poly(urethane-urea), PVA: polyvinyl alcohol, PVP: polyvinylpyrrolidone, and SA: sodium alginate.

3. Tissue Engineering

Many tissues in the living body cannot regenerate after injury. Even with surgical intervention on these damaged tissues, the tissue cannot regain its former form and return to the former quality of life of the individual [65]. One of the methods developed to solve this problem is tissue engineering. Tissue engineering, also known as regenerative medicine, is the science that deals with the development or production of therapeutic stem cells, tissues, and artificial organs [66]. Tissue engineering is widely used in bone and nerve regeneration, cartilage repair, and cardiovascular and ocular tissue development. Although it may seem simple and feasible, it is a multidisciplinary field of study and contains various difficulties in each step of obtaining tissue from stem cells [67].
The extracellular matrix (ECM) is a heterogeneous, binding network of fibrous glycoproteins with micro- and nanosized pores [68]. It provides the physical scaffold and mechanical stability required for tissue morphogenesis and homeostasis. It is aimed at developing scaffolds similar to ECMs in tissue engineering [33][34][35]. Electrospinning is the widely used method in producing scaffolds produced using biodegradable materials to obtain micro or nanosized fibrous tissue.
The eye has a unique structure and is rich in epithelial cells and neural networks. However, the structural integrity of this organ, which is in contact with the outer surface, may be impaired due to chemical, radiation and burn injuries, and infections caused by contact lenses. Unfortunately, these structural problems can be permanent. For example, the cornea, the outermost transparent layer of the eye, has two main functions. The first is to protect the structures inside the eye, and the second is to refract the light coming from outside and focus it clearly on the retina [69]. Good vision largely depends on corneal epithelial regeneration by limbal epithelial cells [70]. However, structural problems due to environmental factors may lead to limbal stem cell deficiency, and in this case, the act of seeing may not be performed. Therefore, the development of ocular tissues is an important field of study for tissue engineering. It is a great advantage that many biodegradable polymers used in the production of scaffolds are also biocompatible with ocular tissues. Table 2 summarizes the ocular tissue engineering studies with nanofibers.
When the studies are examined, it is generally emphasized that nanofibers produced with different methods and different materials in ocular tissue engineering studies are highly biocompatible with eye tissue and suitable for adhesion and proliferation for different types of cells [71][72]. In addition, successful results have been obtained from anti-inflammatory gene expression studies [73][74]. In other studies, it has been concluded that the prepared nanofibers have better mechanical properties than the amniotic membrane [75]. In some in vivo studies, it has also been observed that cell-cultured nanofibers provide re-epithelialization in the eye [76][77].
Table 2. Nanofiber-based ocular tissue engineering studies.
Tissue Polymer Comments References
Limbal stem cell PHBV
  • Electrospun nanofiber scaffold has favorable mechanical, physical, and chemical properties.
  • Biocompatible nanofiber scaffolds.
  • Similar transparency compared to the amniotic membrane (AM) in wet scaffolds.
  • Nanofiber scaffold suitable for cell adhesion.
  • The successful proliferation of limbal stem cells (LSCs) on nanofiber scaffolds in in vitro studies.
 [71]
Limbal stem cell PCL
  • Biocompatible nanofiber scaffolds.
  • Limbal epithelial cells (LECs) can be easily attached to the nanofiber scaffold.
  • LECs are active and proliferate on the nanofiber scaffold.
  • Immunofluorescence (IF) staining and reverse transcriptase polymerase chain reaction (RT–PCR) results show the same expression profile of LECs on the scaffold and AM.
  • Cells infiltrate the nanofibers and form a viable three-dimensional (3D) corneal epithelium.
 [72]
Retinal pigment and corneal epithelial cells PCL
  • Two different nanofiber scaffolds with two different diameters were formed using the electrospinning method (527 ± 184 nm and 1309 ± 116 nm, respectively).
  • Retinal pigment epithelial cells (ARPE-19) and corneal epithelial cells (HCE-T) cultured on the nanofiber scaffold are both metabolically active on the two nanofiber scaffolds. However, ARPE-19 shows better adhesion and metabolic activity in scaffolds with a larger diameter.
  • HCE-T cells cultured on ~500 nm nanofiber show higher proliferation, differentiation, and lower apoptotic markers. However, HCE-T cells on ~1300 nm nanofiber show higher stem cell expression.
  • ARPE-19 cells cultured on ~500 nm nanofiber have a higher level of secretion of VEGF-A (Vascular endothelial growth factor A) compared to larger diameter nanofiber.
 [78]
Conjunctival
epithelial cells		 SF/PLCL
  • Hydrophilic, smooth, homogeneous electrospun nanofiber scaffolds.
  • Biocompatible nanofiber scaffolds.
  • In in vitro studies, rabbit conjunctival epithelial cells (rCjECs) and goblet cells successfully adhere and proliferate on the nanofiber scaffold.
  • Successful Cjec gene expression from the nanofiber scaffold, on one hand, decreases the expression of inflammatory mediators.
  • In vivo studies show that CjECs become more stratified, while the nanofiber scaffold structure degrades.
 [79]
Retinal ganglion cells PPy-G/PLGA
  • Biocompatible electrospun nanofiber.
  • In in vitro studies, retinal ganglion cells (RGCs) are significantly active and neurite outgrowths occur on the nanofiber.
  • Electrical stimulation to nanofibers provides an anti-aging effect on RGCs, improving cell length with 137% elongation.
 [80]
Ciliary pigment
epithelial cells		 RADA-16-I peptide
  • Nanofiber scaffolds produced by the self-assembly method.
  • Ciliary pigment epithelial stem cells (CPE-NS) were successfully encapsulated in a nanofiber scaffold.
  • Encapsulated CPE-NS have similar activity and proliferation compared to normal cell culture.
  • Encapsulated cells express neural progenitor markers through ambient (medium) conditions.
  • Encapsulated cells differentiate into the retinal neuronal direction.
 [81]
Limbal stem cell dAM/PCL
  • PCL nanofiber prepared by the electrospinning method.
  • The composite membrane is prepared by conjugation of PCL nanofiber and dAM.
  • Compared to dAM, the composite membrane has improved integrity and mechanical properties.
  • In in vivo studies, the composite membrane is as immunomodulatory as dAM.
  • The composite membrane is more suitable to support LSC survival, retention, transport, and proliferation compared to dAM alone.
  • In in vivo studies, the composite membrane promotes eye re-epithelialization and reduces inflammation and neovascularization.
 [76]
Limbal stem cell PCL
  • Biocompatible electrospun nanofiber.
  • Nanofiber scaffold suitable for cell adhesion.
  • The successful proliferation of LSCs on nanofiber scaffolds in in vitro studies.
  • Nanofibers take the form of viable 3D corneal epithelium from which cells can infiltrate.
  • No significant difference in the expression profile of LECs grown on nanofibrous scaffold compared to those cultured in human AM.
 [82]
Limbal stem cell PLA
  • Mesenchymal stromal/stem cells (BM–MSCs) from bone marrow, mesenchymal stromal/stem cells (Ad–MSCs) from adipose tissue, and LSCs successfully grow and proliferate on the nanofiber.
  • Cells on the nanofiber scaffold adequately migrate to the ocular surface.
  • In in vivo studies, cell-cultured nanofiber scaffolds show improvement in re-epithelialization, neovascularization, and corneal thickness properties in injured rabbit eyes.
 [77]
Limbal stem cell Carbodiimide cross-linked AM
  • As a result of crosslinking of AMs with carbodiimide, a triple helix molecular AM collagen structure is formed and a nanofiber scaffold is obtained.
  • The helical structure becomes a more random globular state as the crosslinking time of AMs increases.
  • As the crosslinking time of AMs increases, the nanofiber diameter becomes larger.
  • Compared to AM, cross-linked AMs show increased water content, light transmittance, and resistance to enzymatic degradation.
  • LECs show growth and gene expression on cross-linked AM nanofiber scaffold in in vitro studies.
 [83]
Limbal stem cell PCL/PLA/PLGA/dAM
  • Individually PCL, PLA, and PLGA electrospun nanofibers conjugate with dAM to form composite membranes.
  • Compared to dAM, the composite membranes have improved integrity and mechanical properties.
  • Composite membranes show bioactivity similar to dAM in terms of LSC adhesion, growth, and proliferation.
  • Anti-inflammatory gene expression was similar to dAM from composite membranes.
 [73]
Llimbal stem cell PCL
  • Surface-modified nanofiber scaffold formation by applying helium–oxygen discharge to electrospun PCL nanofibers.
  • No significant morphological difference between surface-modified and non-surface-modified nanofibers.
  • The surface-modified nanofiber scaffold has improved wettability and transparency.
  • Both nanofiber scaffolds (surface-modified and non-surface-modified) are biocompatible.
  • Cell adhesion and proliferation are better in surface-modified nanofiber.
  • Similar gene expression is seen in both nanofiber scaffolds.
 [84]
Limbal stem cell Silk
  • Silk nanofiber scaffold produced by electrospinning method.
  • Biocompatible nanofiber scaffolds.
  • LSCs grow and proliferate successfully on nanofiber.
  • LSCs infiltrate the nanofibers and form a viable three-dimensional (3D) corneal epithelium.
  • As a result of in vitro tests, the gene expression profile of LCSs on nanofiber is similar compared to AM.
 [85]
Retinal progenitor cells LPG/DPG/RPG
  • Nanofibrous hydrogel structures produced by the self-assembly method.
  • DPG and LPG hydrogels form in a helical structure while RPG does not have a helical form.
  • Nontoxic nanofiber hydrogels.
  • Compared to LPG nanofibers, DPG nanofibers promote better neuronal differentiation, migration, and synapse formation of retinal progenitor cells (RPCs).
 [86]
Limbal and mesenchymal stem cells Copolymer PA6/12
  • Biocompatible electrospun nanofiber scaffolds.
  • LSCs, MSCs, and corneal epithelial and endothelial cell lines show similar growth and proliferation on nanofiber scaffold compared to cell culture in plastic.
  • LSCs and MSCs successfully transfer from the nanofiber scaffold to the damaged ocular surface.
  • Anti-inflammatory gene expression from nanofiber scaffold.
 [74]
Scaffold-based corneal implant Keratin/PVA
  • 3D nanofiber structure prepared by applying the gas-foaming technique to electrospun nanofiber.
  • Successful cell viability, infiltration, growth, and proliferation on 3D nanofiber.
  • Compared to pristine nanofiber, 3D nanofiber shows improved transparency and mechanical properties.
  • In in vivo studies, the 3D nanofiber shows improved biocompatibility in the rabbit eye compared to the pristine nanofiber.
 [87]
Corneal wound dressing COL/HA/PEO/GA/CS
  • Three different nanofiber formulations: (1) COL/HA/PEO electrospun nanofiber, (2) glutaraldehyde (GA) cross-linked form of electrospun nanofiber, and (3) CS-coated form of electrospun nanofiber.
  • Compared to AM, CS-coated nanofiber has improved transparency and mechanical properties.
  • Successful cell viability, proliferation, and biocompatibility in all nanofiber formulations.
  • CS-coated nanofibers exhibit fibrosis-inhibiting properties similar to human AM.
  • In in vivo studies, CS-coated and GA cross-linked nanofibers show re-epithelialization ability.
 [75]
NIH3T3 fibroblast cell PCLPCL/GEL
  • Two separate PCL and PCL/GEL nanofiber structures prepared by the electrospinning method.
  • PCL/GEL nanofiber is more hydrophilic than PCL nanofiber.
  • Cells on random and aligned PCL/GEL nanofibers have a better growth rate than PCL nanofibers.
  • The orientation of the nanofiber matrix does not affect cell adhesion and proliferation, while the cells on the aligned nanofiber elongate parallel to the fibers.
  • Fibroblast cells on aligned nanofibers express genes associated with actin production, actin polymerization, and focal adhesion formation.
 [88]
The lipid phosphate phosphatase-related E-PA
  • Nanofiber structure produced by the self-assembly method.
  • Biocompatible nanofibers.
  • In vitro studies, LPPR–PA nanofibers inhibit VEGF-induced cellular migration and proliferation.
  • LPPR–PA nanofibers exhibit a comparable suppressive effect to bevacizumab in the in vitro angiogenesis assay.
  • In in vivo studies in rat eyes, LPPR–PA nanofibers reduce corneal neovascularization more effectively than bevacizumab.
 [89]
COL: collagen, CS: chitosan, dAM: decellularized amniotic membrane, DPG: D-phenylalanine gelators, E-PA: P Lauryl-VVAGE-Am, GA: glutaraldehyde, GEL: gelatin, HA: hyaluronate (HA), LPG: L-phenylalanine gelators, PA: peptide amphiphile, PA6/12: polyamide 6/12 (PA6/12), PCL: polycaprolactone, PEO: polyethylene oxide, PHBV: poly (3-hydroxybutyrate-co-3-hydroxyvalerate), PLA: poly(lactic acid), PLCL: poly(L-lactic acid-co-3-caprolactone), PLGA: poly(lactic-co-glycolic acid), PPy-G: polypyrrole functionalized graphene, PVA: polyvinyl alcohol RPG: a racemic mixture of LPG and DPG, and SF: silk fibroin.

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Subjects: Ophthalmology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Egemen Uzel
,
Meltem Ezgi Durgun
,
İmren Esentürk-Güzel
,
Sevgi Güngör
,
Yıldız Özsoy
View Times: 361
Revisions: 2 times (View History)
Update Date: 05 May 2023
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