3D Bioprinting of Cellular Therapeutic Systems in Ophthalmology: from Bioengineered Tissue to Personalized Drug Delivery

Abstract

Purpose of Review

In this article, we provide a brief overview of 3D bioprinting technologies and the types of cells employed in ophthalmic cell therapy. We then explore recent applications of 3D bioprinting in ophthalmic cell delivery systems.

Recent Findings

Cell therapy in ophthalmology is a promising treatment for various eye diseases, there exists some limitations of existing cell therapy strategies Such as cell loss, poor integration with Surrounding tissues, and the sustainability of long-term effects. In this regard, 3D bioprinting technology provides a beneficial method for developing highly biomimetic and reliable cell delivery systems for ophthalmic disease research. Recent advances have shown bioengineered tissues which replicate the microstructure of native tissues, personalized ophthalmic devices, and encapsulated cell-delivery systems. While still in the early stages of advancement, the development of cell delivery systems based on bioprinting technologies is indeed inspiring and has the potential to be applied to other ocular diseases.

Summary

Cell therapy based on 3D bioprinting technology in ophthalmology has great potential in ophthalmic disease treatment as well as ocular tissue engineering and regenerative medicine.

Introduction

Cell therapy in ophthalmology is a promising treatment for various eye diseases, from corneal damage to retinal degeneration [1, 2]. It has progressed towards personalized medicine that enables targeted cell-based delivery tailored to individual patient needs and has provided long-term drug delivery of proteins in degenerative eye disease. However, several challenges remain in the clinical and practical application of cell therapies, particularly concerning cell viability and function, caused by cell loss, poor integration with surrounding tissues, and the sustainability of long-term effects [3, 4]. Recently, hydrogels, encapsulation, and scaffolds, aimed at creating supportive environments for transplanted cells, have improved retention and therapeutic efficacy [5–7]. With tremendous advances, some cell delivery systems are clinically available for specific ocular diseases, and some cell-based therapeutic systems are under evaluation in large clinical trials for conditions like glaucoma [8]. Yet, significant hurdles, such as poor bioavailability and immune activation, continue to hold back progress. Therefore, there still exists the need for novel cell delivery systems that can effectively resolve such challenges and optimize the therapeutic effects of cell-based treatments.

3D bioprinting is a powerful technology in the medical field, wherein biomaterials—including cells—are deposited in a controlled, layer-by-layer manner. This capability enables fabrication of complex biological constructs customized to individual patient needs, addressing existing limitations in traditional cell delivery systems by improving cell retention and integration with host tissues [9]. Furthermore, various 3D bioprinting approaches have been developed to reduce immune rejection and inflammatory responses by providing a more natural and structured environment for both transplanted cells and those recruited from Surrounding tissues. This review will focus on cell-based therapies based on 3D bioprinting technology (Fig. 1). We will begin with a brief overview of 3D bioprinting technologies and the types of cells employed in ophthalmic cell therapy. Subsequently, we will explore recent applications of 3D bioprinting in ophthalmic cell delivery systems, particularly in the development of bioengineered tissues and therapeutic systems using encapsulated cell therapy (ECT).

Fig. 1.

Overview of 3D bioprinting in ophthalmic applications

3D Bioprinting Technologies

3D bioprinting has emerged as a transformative technology in regenerative medicine, enabling the construction of complex biological systems, including functional tissues such as vasculature, muscle, and bone, as well as personalized therapeutic systems capable of drug delivery [9]. Moreover, the versatility of bioprinting technology can also allow direct printing of actual living cells, which has introduced a new fabrication technique to the field of cell therapy and drug delivery. In ophthalmology, this technology is particularly promising due to its ability to create micro-precision, layered tissues, and patient-specific tissue grafts with minimum immune rejection [10–12]. These characteristics may facilitate advancements in implantable tissues, tissue models for drug testing, and cell-laden therapeutic systems.

There are three main types of 3D bioprinting technologies, each with its own set of strengths and weaknesses: extrusion, laser-assisted, and inkjet bioprinting (Table 1) [9]. Despite distinct differences, these technologies have all shown potential for personalized therapy on a small scale. The printing method would be selected depending on the desired structure. Once selected, various parameters including material viscosity, nozzle size, printing time, and printing pressure, can be adjusted to control not only external topography but also internal features such as shape, size, porosity, and interconnectivity [13]. These factors are critical to provide Sufficient oxygen and nutrients, necessary for tissue integration and functionality. Various manufacturing approaches have also been developed to address specific 3D bioprinting limitations. For example, bath printing offers structural support during printing, which allows fabrication of complex geometries. Further, the aqueous environment supports cell longevity while printing [14–16]. The fabricated structures support the transplanted or recruited cells’ attachment, growth, and maintenance of physiological functions.

Table 1.

Overview of various 3D Bioprinting technologies

Technology Type		Description	Resolution	Advantages	Disadvantages
Extrusion Bioprinting		Employs a syringe-based system to extrude bioinks, enabling the creation of macroscale structures or structures with high cell density.	Tens of −500 μm	- High cell density - Suitable for a variety of materials	- Lower resolution - Requires precise control
Laser-Assisted Bioprinting	Stereolithography (SLA) and Digital Light Processing (DLP)	Employ light source to cure photosensitive bioinks layer by layer using UV or digital light.	0.5–100 μm	- High resolution - Smooth surface finish - Fast printing speed (DLP)	- Limited material options - Requires post-processing
	laser-induced forward transfer (LIFT)	Utilizes laser energy to transfer bioinks onto a substrate, minimizing cell damage during the printing process.	50–100 μm	- High precision - Minimal cell damage	- Complex setup - Higher cost
Inkjet Bioprinting		Utilizes inkjet technology to deposit bioinks layer by layer, allowing for precise placement of cells and biomaterials.	20–100 μm (1–10 nL of droplet)	- High resolution - Low viscous materials	- Limited cell density - Slower printing speed

3D bioprinting applications of ophthalmic cell therapy include direct printing of hydrogel-type bioinks containing cells to replicate tissues like the cornea and retina (covered in "3D Bioprinted Ophthalmic Tissues" section), and the development of therapeutic cell delivery systems by printing biomaterials to create frameworks for cell injection (covered in "Encapsulated Cell Therapy and Applications for 3D Printing" section). These advancements enhance the study of disease progression, biological mechanisms of tissue, and drug action, contributing to personalized regenerative medicine.

Cells Used in Ophthalmic Cell Therapy and their Potential for Use with 3D Bioprinting

Effective 3D bioprinting for ophthalmic cell delivery relies significantly on cell sources that have strong therapeutic potential (Fig. 2 and Table 2). Stem cells are valuable due to their ability for self-renewal and differentiation into specific ocular cell types, including epithelial, photoreceptor, and endothelial cells [17–21]. Among these, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are pluripotent, offering potential for regenerative therapies, although ESCs face ethical issues [22]. Conversely, mesenchymal stem cells (MSCs) have the potential to differentiate into adult cell types, with their properties varying based on their tissue origin (e.g., dental pulp, bone marrow, and adipose tissue) [23–27]. Their strong immunosuppressive properties and lower risk of tumorigenicity compared to ESCs and iPSCs also make them advantageous for therapeutic use. Non-stem cells in regenerative medicines offer advantages by leveraging their intrinsic cellular function, avoiding ethical concerns, minimizing the risk of tumorigenesis, and reducing immunogenicity using autologous (patient-derived) cells. Oral mucosal epithelial cells (OMECs) [28]peripheral blood mononuclear cells (PBMCs) [28]limbal epithelial cells [29]corneal endothelial cells [30]photoreceptor precursor cells [18]and retinal pigment epithelium (RPE) [31] are the ideal cell types for use in autologous graft-based therapies. Allogeneic (donor) retinal pigment epithelium (ARPE19) is also well-suited for expressing therapeutic proteins, such as neuroprotective therapies or VEGF receptors, due to their low tumorigenicity and immunogenicity [32]. Additionally, genetically modified cells can be engineered to improve therapeutic outcomes by delivering local therapeutic molecules binding to correct genetic defects, improving functional integration, and reducing the risk of immune rejection post-transplantation [33–36]. Fouladi et al. employed a genetically engineered cornea graft (OXB-202) to express and deliver therapeutic proteins endostatin and angiostatin to suppress corneal neovascularization following transplantation [37].

Fig. 2.

Cell sources for ophthalmic regeneration. The figure was created using BioRender software under an academic license

Table 2.

Cell sources for regenerative therapies in ophthalmology

Cell Sources			Advantages	Disadvantages
Stem cell	ESCs		- Pluripotent, potentially unlimited source of cells.	- Highest potential for tumor formation from undifferentiated human ESCs. - Can trigger immune rejection from transplantation. - Ethical concerns associated with culture from embryos.
	iPSCs		- Pluripotent by reactivation (easy accessibility and expandability). - Avoids ethical concerns of culture from embryos.	- Possible tumorigenesis or teratoma formation.
	MSCs		- Multipotent.	- Regulate tumor growth, invasion, metastasis.
	Ocular stem cells	LECs, LSCs, TMSCs, CjSCs	- Specialized for their target tissue. - Amenable to autologous transplantation. - Lower risk of tumorigenesis compared to ESCs/iPSCs.	- Obtaining a sufficient number of functional cells can be challenging.
Non-stem cell	OMECs, PBMCs, LECs, CECs, Photoreceptor precursor cells, RPE		- Leverage their instinct cellular function. - Easier accessibility, and potentially reduced ethical concerns. - Less likely to develop into tumors compared to stem cells. - Autologous cell minimizes the risk of immune rejection.	- Harvesting autologous cells causes donor site injury. - It may be difficult to harvest sufficient quantities for reconstruction.
Gene-modified cells			- Can be tailored to enhance therapeutic efficacy. - Can correct genetic deficits. - Can reduce the risk of immune rejection post-transplantation.	- Potentially off-targets effects for gene editing. - Safety concerns associated with gene delivery factors. - Complexity and cost of production and selection.

ESCs embryonic stem cells, iPSCs induced pluripotent stem cells, MSCs mesenchymal stem cells, LECs lens epithelial stem/progenitor cells, LSCs cornea limbal stem cells, TMSCs trabecular meshwork stem cells, CjSCs conjunctival epithelial stem cells, OMECs oral mucosal epithelial cells, PBMCs peripheral blood mononuclear cells, LECs limbal epithelial cells, CECs corneal endothelial cells, RPE retinal pigment epithelium

To Successfully integrate the aforementioned therapeutic cells into 3D bioprinting technology, several critical attributes must be considered: the ability to support the growth and survival of living cells (cell viability), the capacity to perform specialized functions required by the tissue (functionality), and the assurance of safe interaction with the body (biocompatibility). Cell viability is a critical factor in 3D bioprinting. Maintaining high cell viability is challenging, particularly for stem cells or primary cells, which are vulnerable to environmental stressors and can further influence cell signaling and protein expression [38, 39]. An improved strategy to reduce cell stress, for instance, in extrusion-based bioprinting is lowering extrusion pressure and using wider nozzles [40]. SLA and DLP use photocrosslinking materials with LED light sources instead of cytotoxic UV-activated crosslinkers. Additionally, employing nature-derived polymers (e.g., alginate, collagen, gelatin) or injectable decellularized extracellular matrix (dECM) can create a cell-friendly environment conducive to cell survival [41, 42]. To mimic target tissue-specific extracellular matrix (ECM), hydrogel-based scaffolds have been developed [43]. Agrawal et al. developed Kuragel, a photo-crosslinkable hydrogel and an ideal sacrificial matrix (a temporary structure used in 3D printing), which exhibits stromal cell survival by providing familiar ECM characteristics and promoting corneal regeneration [44]. Engineering hydrogels have also been utilized in growing microvessel networks in vivo as a valuable tool to mimic ECMs [45, 46]. Crosslinked collagen hydrogel has been found to generate endothelial cell-mediated vascular networks, an important design for cell-based delivery strategies [47]. Functionality of 3D-printed tissues is another critical challenge that requires further attention. Achieving functional 3D-printed tissues depends on the biological behavior of cells embedded within the construct. Tan et al. demonstrated that mechanical cues like cyclic stretching can guide cell growth and lineage-specific differentiation, as seen with corneal fibroblasts maintaining shape under stretch [48]. Incorporating bioactive molecules, such as growth factors like glia cell-derived neurotrophic factor (GDNF) into bioinks can further enhance tissue regeneration [49]. Controlling cellular organization, such as cellular spatial distribution and alignment, is also a key factor that affects cell behavior. Samandari et al. address this challenge via a microcompartmentalization system containing GelMA to help with cell growth and alginate to provide cell alignment during cell maturation [50]. These factors can essentially promote cellular activities, support tissue regeneration, and facilitate the establishment of a more physiologically relevant environment. Biocompatibility is an important factor in determining the viability of 3D printed biomaterials. Therefore, 3D bioprinted constructs need to be non-toxic, non-immunogenic, non-carcinogenic and preclude any adverse local or systemic effects. As previously noted, selecting non-toxic materials and implementing purification processes to eliminate toxic residues or solvents after printing are essential to avoid systemic toxicity. If the material is biodegradable, byproducts also need to behave likewise to prevent severe reactions [51]. In addition to toxicity, such reactions may also lead to inflammatory responses caused by foreign materials, structures, and cells. To mitigate this, the infusion of immunomodulating cells and immunosuppressive molecules has been investigated. MSCs can improve immune regulation during tissue regeneration through cell-to-cell interaction with various immune cell types, such as monocytes and neutrophils [26, 52]. MSCs and hESC-derived RPE cells can inhibit the proliferation of activated T cells in vitro, reduce the secretion of pro-inflammatory cytokines such as interferon-γ, and enhance T cell apoptosis [53, 54]. The incorporation of immunosuppressive molecules such as cyclosporine A or tacrolimus can further prevent acute cellular rejection by blocking T cell activation and inhibiting IL-2 transcription, especially in high-risk corneal grafts [55–58]. In addition to the combination treatment, such as hematopoietic stem cells and Tr1-cell therapy tested in phase I-II trials may can overcome individual limitations and leverage unique immune-tolerating properties [59]. Regulating the Surface properties of biomaterials after 3D printing can help reduce the risk of tumorigenesis by promoting the full differentiation of stem cells [60]. For example, surface modification, particularly with self-assembled monolayers (SAMs) bearing functional groups, has been found to enhance cell-biomaterial interactions and induce stem cell differentiation. For example, the amino group (–NH₃) promotes osteogenesis differentiation, and the methyl group (–CH₃) supports chondrogenesis in human MSCs [61, 62]. Those strategies might potentially be applied to advance 3D printing applications.

3D Bioprinting of Ophthalmic Tissues and Devices

As discussed in the previous section, various 3D bioprinting options are available for different materials and cells, so that they can be used to quickly fabricate a biological prototype and become customized according to the patient’s needs. Based on the advantages, 3D bioprinting is an ideal Choice to replicate the complex microstructure of tissues. Many researchers have developed 3D bioprinted functional tissues and related devices. As Such, this section explores the 3D bioprinting of ophthalmic tissues and ophthalmic devices.

3D Bioprinted Ophthalmic Tissues

Cornea

The cornea consists of the epithelium, stroma, endothelium, Bowman layer, and Descemet membrane. Mimicking the native cornea structure is challenging for tissue printing due to the cornea’s transparency, curvature, and layered cellular composition [63]. Sorkio et al. developed a laser-assisted 3D bioprinting strategy to fabricate corneal tissue constructs using human stem cells and bioactive collagen-based hydrogels (Fig. 3a) [64]. In this study, collagen and two kinds of cells are used: human embryonic stem cell-derived limbal epithelial stem cells for printing epithelium-mimicking structures and human adipose tissue-derived stem cells for constructing layered stroma-mimicking structures. The printed tissues exhibit desirable mechanical properties, high cell viability, and transparency comparable to native tissues. Kim and colleagues leveraged the shear stress generated by extrusion upon 3D bioprinting, to induce the alignment of collagen fibers within a bioengineered corneal stromal construct (Fig. 3b) [65]. This shear-induced alignment mimics the anisotropic microstructure of the native stroma providing substantial improvements in transparency and mechanical strength. Furthermore, human corneal keratocyte precursors, which were encapsulated in cornea-derived decellularized extracellular matrix, responded favorably to the aligned matrix. This resulted in high cell viability and elongation in the fibril orientation, mimicking corneal tissue functionality. Recently, SPAAC (strain-promoted azide–alkyne cycloaddition)-based collagen bioinks have been developed for corneal reconstruction due to their rapid crosslinking under physiological conditions and excellent cytocompatibility [7, 15, 16]. These materials demonstrate high structural integrity and precise control over microscale porosity with embedded bath printing strategies, promoting elongation and spreading of encapsulated corneal mesenchymal stromal cells. This approach holds a great potential for replicating the mechanical and structural features of the native corneal stroma in 3D bioprinted constructs as well as for developing ophthalmic drug delivery systems.

Fig. 3.

3D bioprinted implants. (a) 3D bioprinted corneal tissue using human corneal keratocytes and bioactive collagen-based hydrogels. 3-day co-culture results showed a stratified, corneal progenitor marker p40 positive layer on the surface of the laser-printed structures compared to the natural cornea. Adapted from Sorkio et al. [64] (b) Bioengineered cornea constructed with alignment of collagen fibrils, whose shear stress is induced from the extrusion in 3D bioprinting. Adapted from Kim et al. [65] (c) Functional in vitro RPE model printed by hybrid membrane printing technology for disease investigation. Immunofluorescence images confirm the in-vitro function of the tissue in disease models. Adapted from Kim et al. [75] (d) 3D-printed ABCB5-positive stem cells for corneal regeneration on contact lens. Adapted from Lee et al. [80] (e) DLP 3D-printed punctal plugs and its cumulative drug release profile. Adapted from Xu et al. [81]

In addition to implantable tissues, in vitro platforms better mimic the operation of the real organ with the assistance of 3D tissue printing. This can be used for customized cell studies, disease modeling, and drug development [66]. For example, corneal curvature influences cell alignment. Curvature is difficult to fabricate or customize using traditional methods, but can be fabricated easily via 3D bioprinting [67]. With 3D printing, an affordable and customizable corneal perfusion chamber is developed to maintain ex vivo corneal tissues in physiologically relevant conditions, enabling precise control over intraocular pressure and nutrient delivery for corneal research [68]. Although specific disease models are limited in the study, the system is adaptable and holds strong potential for use in ophthalmic drug testing, disease modeling, and transplantation research.

4D printing, which means the 3D printed model changes with stimulation, is also applied. Cell-laden tissue constructs with controllable degradation are printed by tuning the mole ratio of sodium citrate to sodium alginate [69]. Human corneal epithelial cells (HCECs) encapsulated within these constructs exhibited increased proliferation rates and higher expression of cytokeratin 3 (CK3), indicating improved cellular activity with enhanced degradation. This approach assessed the impact of the 3D printed scaffold’s degradation properties on cellular behavior, aiming to optimize the bioink system for improved outcomes in tissue engineering applications.

Retina

The retina is a complex multi-layer tissue, responsible for collecting and processing optical signals, and then transmitting the signals to the brain for further processing. Retinal regeneration treatments are promising through use of mature photoreceptors, progenitor cells, retinal sheets and retinal pigment epithelium (RPE) cells. For regeneration, first, the photoreceptors/RPE layer organization, polarization, and alignment are critical to the functioning of the tissues. Second, cell viability must be ensured as the implantation will cause cell loss [70, 71]. 3D bioprinting has been shown to help both tissue structure and the cell viability after subretinal implantation [72, 73].

Extrusion-based 3D printing is used to spatially organize RPE cell spheroids within retinal constructs, mimicking the layered architecture of native retinal tissue. The printed spheroids maintained high viability, expressed characteristic RPE markers, and formed monolayer-like structures, which may serve as a promising retina model for further investigations. Masaeli et al. utilized inkjet-based bioprinting strategy to deposit matured and differentiated photoreceptors onto printed RPE layer with a thin layer of gelatin methacrylate working as Bruch’s membrane. The results showed that a functional RPE monolayer was formed with time and the microstructures are well established, which is promising to serve as an in vitro model for disease investigations [74].

Many in vitro retina platforms are also set for investigation. Extrusion-based 3D bioprinting of bioactive basement membrane-derived dECM is used to realize monolayer RPE printing [75]. 3% gelatin was optimized as a sacrificial material in the bioink to support monolayer RPE cell deposition and was finally removed after gelation, leaving a viable and well-attached RPE layer (Fig. 3c). A highly functional, biomimetic in vitro outer blood-retinal barrier model was established offering superior cell compatibility, barrier integrity, and physiological relevance compared to conventional models. This model was evaluated as smoke-induced retinal pigment epithelium degeneration. A similar printing method with Human Müller glia (MIO-M1) was applied to build the MIO-M1-based retinal protection models [76]. Song et al. printed temperature-sensitive, fibrin-based bioinks on a custom PLGA scaffold, imitating essential cellular architecture and interactions among RPE, endothelial cells, pericytes, and fibroblasts [77]. The proposed platform emulates both key features of healthy retinal tissue and disease models such as drusen formation and choroidal neovascularization in age-related macular degeneration.

Others

3D printing is also very important in fabricating other ophthalmic tissues, such as orbital implants [78] and intraocular lenses (IOL) [79]. The combination of advanced imaging, computer-aided design, and additive manufacturing facilitates personalized surgical solutions, and improves precision and adaptability of ophthalmic implants in both structural and optical aspects.

3D Bioprinted Ophthalmic Devices

3D bioprinting also provides more options in the field of cell-incorporated ophthalmic devices in addition to the aforementioned tissue engineering. For example, contact lenses, which directly contact tears, are considered as an excellent platform for disease diagnosis and treatment and can be customized by 3D printing. Lee et al. fabricated a micro-contoured contact lens that holds and transfers ABCB5-positive limbal stem cells onto the corneal Surface using 3D bioprinting technology (Fig. 3d) [80]. The customized design and fabrication of the printed lens ensures its close attachment to the cornea and improves effective delivery and engraftment of the stem cells. This work Suggests that 3D printed contact lenses are a promising alternative to traditional autologous stem cell transplantation techniques for corneal epithelium regeneration and vision restoration in limbal stem cell deficiency.

In addition, 3D printing offers advantages in drug delivery by increasing the complexity in terms of drug geometry to release profiles. It allows for personalized medicine preparation, including dose, drug combination, and drug-loaded implants. On-demand production by 3D printing reduces waste and facilitates targeted delivery, especially in tissues that are hard to reach. These capabilities make 3D printing a powerful method for next-generation drug formulations and individualized therapies. For example, Xu et al. 3D-printed punctal plugs for personalized ocular drug delivery (Fig. 3e) [81]. Researchers evaluated cytocompatibility of the printed plugs using Balb/3T3 fibroblast cells to ensure safety for ocular applications. The results indicated that material composition significantly influences cell viability.

Although the development of bioprinting technologies is still in the early stages, the success of replicating the microstructure and alignment of native tissues and developing personalized ophthalmic devices makes great progress in tissue recovery, which is inspiring and has the potential to be applied to other cell-based systems.

Encapsulated Cell Therapy and Applications for 3D Printing

In this section, we explore ophthalmic therapeutic system with ECT and applications of 3D bioprinting. ECT was proposed in the 1960 s [82]and has since been adapted for use throughout the body. ECT involves using cells to produce therapeutic factors which are released into their local environment. To prevent rejection of the cells, implanted cells are encapsulated within a semi-permeable barrier that allows nutrients and oxygen to reach the cells while shielding them from immune attack. These cells may be allogeneic cells Such as encapsulated pancreatic cells that respond to local glucose levels to provide insulin in type 1 diabetics [83]. They may also be transgenic cell lines which are used to produce specific protein therapeutics to treat disease.

Both macroencapsulation and microencapsulation have been evaluated in ECT. Macroencapsulation involves construction of an engineered device, with an internal cell supportive scaffold that is enclosed with an immunoprotective membrane. Cells suspended in culture medium or buffer are loaded into the device, which is then sealed [84]. Suture clips may be used to fasten the device during implantation. This provides a structural advantage for implantation and the engineered implant materials can offer longevity of over a decade [85]. Macroencapsulated ARPE-19 cells have delivered soluble vascular endothelial growth factor receptor [86]ciliary neurotrophic factor (CNTF) [87–91] and brain-derived neurotrophic factor (BDNF) [92]. The first ECT was approved by the FDA in March 2025 and is a macroencapsulated device for treatment of macular telangiectasia type-2.

Microencapsulation consists of immobilizing groups of cells within a polymeric semi-permeable membrane. This leads to an increased surface area to volume compared with macroencapsulation, which may be beneficial for cellular transport. ARPE-19 cells microencapsulated in sodium alginate have delivered a complement receptor-2 fragment linked to the inhibitory domain of factor H (CR2-fH) [93]. Murine myoblasts microencapsulated in alginate-poly-l-lysine-alginate have delivered vascular endothelial growth factor soluble receptor-2 [94]. HEK293 cells microencapsulated in a composite collagen-alginate scaffold have delivered glial cell line-derived neurotrophic factor (GDNF) [95]. Further, soluble vascular endothelial growth factor receptor secreting ARPE-19 cells were encapsulated in hydrogel, which may be directly injected or used as the matrix for a macroencapsulated device [96].

3D printing has been used to assist manufacturing for this regenerative medicine-based drug delivery device. Traditional macroencapsulation fabrication has involved assembly of thin fibers for the supportive cell scaffold, with an outer semipermeable membrane and sealed capsule. Advances in additive manufacturing may be used to increase flexibility and reduce fabrication time for ECT.

Kojima et al. developed a 3D printed macroencapsulated device for delivery of BDNF. The device is meant to be placed adjacent to the sclera, in the subconjunctival, subtenon, retrobulbar, or peribulbar space and allow for trans-scleral drug delivery. This device consists of a cylindrical reservoir with a glued-on cap and is filled with ARPE-19 cells cultured on collagen coated polystyrene sheets. A semipermeable membrane that allows nutrients to reach the cells and allows diffusion of BDNF is located on the side of the reservoir facing the sclera. Polyethylene glycol dimethylacrylate (PEGDM) was chosen for the semipermeable membrane as it was shown to significantly reduce IGG permeability while allowing smaller molecules of 40 kDa and less to more freely diffuse. The cap and walls of the device were fabricated using triethylene glycol dimethacrylate (TEGDM) and bonded together using PEGDM. For 3D printing, resins were fabricated from PEGDM and TEGFM using photoinitiator and photosensitizers. The resins were printed using a QiDi Tech Shadow 5.5 s with 50-µm thickness layers. To allow a multi-material print, the TEGDM resin was used to print the first layer, followed by washing the build plate and printing of the semi porous PEGDM layer. Once this was complete, the build plate was washed again and the TEGDM resin was used to complete the reservoir [92]. Using 3D printing shortened fabrication time by 4–5 times and has the potential to build complex ECT devices that are not buildable using traditional techniques.

ECT shows promise for regenerative drug delivery to the eye. Not only is the eye the first location where ECT has been approved in the body, but there are many other ocular diseases which may be treated using cell-based therapeutic delivery. The eye is especially amenable to ECT given it is an immune privileged site, there is a large precedence of safely implanting medical devices into the eye, and the clinician’s ability to directly monitor the implanted device. ECT has the potential to provide long-term drug delivery for periods of time much longer than bioerodible or reservoir-based, extended drug delivery systems. Unlike current gene therapy systems, ECT is reversible by surgical removal of the device [85]. Further, ECT may not have the inflammatory limitations that have been seen by current gene therapies [97]. However, ECT devices require surgical implantation, with the risks of the surgery and post-operative complications of an implanted device [98]. Further, the cells need to be able to deliver a therapeutic amount of pharmaceutical over time [99]. 3D printing has shown promise for the fabrication of future ECT due to flexibility in manufacturing complex structures, the ability to incorporate multiple materials into a device, and increased throughput of 3D printing.

Future Direction

Recent advances of cell therapy and 3D bioprinting technology in ophthalmology have shown great potential in tissue engineering and regenerative medicine. However, there exist several regulatory and technical hurdles. The FDA has established guidelines for 3D-printed medical devices since 2017 [100], however, comprehensive regulations for 3D-printed therapeutic systems remain underdeveloped. To bridge the current research from innovative to clinical and practical applications, it is important to establish robust quality standards and evaluation protocols for 3D-printed therapeutic systems. Once regulatory issues are addressed, the field of cell therapy, 3D bioprinting technology, and their combinations will likely increase applicability in clinical settings, particularly for personalized treatment approaches. To do so, cellular functionality will be enhanced, Such as the development of cells capable of detecting physiological Changes and modulating the secretion of therapeutic molecules. To apply these responsive cells, cellular reservoir-containing implants need to be designed not to impede cellular function. Furthermore, from a systems perspective, upgrading bioprinting technologies to incorporate biomaterials with diagnostic and therapeutic capabilities would be necessary. Therefore, a thorough and interdisciplinary effort is needed to explore innovative manufacturing techniques alongside advancements in cell engineering. By pursuing these parallel research avenues, we can pave the way for the development of sophisticated 3D bioprinted cellular therapeutic systems tailored for ophthalmic applications.

Key References

• Brunel, L. G. et al. Embedded 3D bioprinting of collagen inks into microgel baths to control hydrogel microstructure and cell spreading. Advanced healthcare materials 13, 2303325 (2024).

  • This study presented that embedded 3D bioprinting with microgel support baths enables precise control over collagen hydrogel microstructure and cell spreading. By incorporating SPAAC crosslinking, the printed constructs achieve both mechanical stability and cellular functionality, showing strong potential for corneal tissue reconstruction.
• Xiao, Y., McGhee, C. N. & Zhang, J. Adult stem cells in the eye: Identification, characterisations, and therapeutic application in ocular regeneration–A review. Clinical & Experimental Ophthalmology 52, 148-166 (2024).

  • This review highlights the use of various stem cells in ocular regeneration, emphasizing adult stem cells and their therapeutic potential, while addressing key challenges like integration, immune compatibility, and long-term stability.
• Hoseinzadeh, A. et al. Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights. Stem Cell Research & Therapy 16, 33 (2025).

  • This study highlights a promising approach of co-incorporating mesenchymal stem cells (MSCs) to address challenges in therapeutic cell delivery. It shifts from direct engraftment to immune modulation via apoptotic body uptake as mechanism behind MSCs’ therapeutic effects in bioprinted constructs.
• Chew, E. Y. et al. Cell-based ciliary neurotrophic factor therapy for macular telangiectasia type 2. NEJM evidence 4, EVIDoa2400481 (2025).

  • This is the most recent paper from the only FDA approved encapsulated cell therapy device. The paper presents the results from the two phase 3 clinical trials and discusses longevity of encapsulated cell therapy of at least 14.5 years.
• Bhise, M. G., Patel, L. & Patel, K. 3D Printed Medical Devices: Regulatory Standards and Technological Advancements in the USA, Canada and Singapore-A Cross-National Study. International Journal of Pharmaceutical Investigation 14 (2024).

  • This study presents a concise overview of 3D printed medical devices and the related regulatory. It highlights high demands of bioprinting-related regulatory to expand creating and implementing patient-specific solutions.

Author Contributions

H.K. developed the outline for the manuscript. H.K., G.N., W.H., and C.D. wrote the main manuscript. W.H. and G.N. prepared figures. V.M. helped with the concept of the manuscript. All authors reviewed and helped with revisions of the manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interests

The authors declare no competing interests.