Emerging role of stem cells and tissue engineering in oculoplastic surgery

Abstract

Advancements in stem-cell biology and tissue engineering (TE) are transforming the field of oculoplastic surgery by offering innovative solutions for eyelid, orbital, and periocular reconstruction. Stem cells, including mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and adipose-derived stem cells (ASCs), provide regenerative potential through their ability to differentiate into ocular adnexal tissues and modulate wound healing via paracrine effects. Tissue-engineered constructs, combining biocompatible scaffolds, cellular components, and growth factors, enable the development of functional replacements for eyelid skin, tarsus, conjunctiva, and lacrimal structures. These technologies enhance esthetic and functional outcomes, reduce donor-site morbidity, and may overcome limitations of traditional grafts and flaps. Current applications include periocular volume augmentation, eyelid reconstruction, and management of anophthalmic sockets, with ongoing research directed toward bioengineered lacrimal glands and dynamic eyelid substitutes. Although challenges remain, such as optimizing scaffold integration, vascularization, and long-term safety, stem-cell and TE approaches hold significant promise for personalized, restorative, and regenerative strategies in oculoplastic surgery.

Oculoplastic surgery encompasses a wide spectrum of procedures aimed at restoring the structural integrity and function of the eyelids, lacrimal system, orbit, and surrounding periocular tissues. Although conventional surgical techniques continue to achieve excellent outcomes, significant challenges remain, particularly in cases involving extensive tissue loss, post-traumatic deformities, congenital malformations, or cicatricial disorders. These conditions often necessitate the replacement or reconstruction of tissues that closely replicate the biomechanical, esthetic, and functional attributes of native ocular adnexal structures.

In recent years, the paradigm of oculoplastic reconstruction has progressively shifted toward more durable, biologically integrated, and patient-centric solutions.[1] This transition has been driven by remarkable advances in stem-cell science, tissue engineering (TE), and biomaterial development. Engineered scaffolds, advanced polymer composites, and bioactive materials have emerged as promising alternatives to traditional grafts and thereby offer advantages in biocompatibility, structural stability, reduced donor-site morbidity, and a possible avenue for personalized reconstruction.[2] The convergence of material science with regenerative medicine is now redefining boundaries in oculoplastics, enabling innovations that are unattainable through conventional surgical approaches alone.

These technological advances are poised to revolutionize the field of oculoplastic surgery by enabling personalized, biologically integrated, and functionally superior reconstructive solutions. Therefore, this review article encompasses the full spectrum of tissue-engineered autografts, biomaterial-based constructs, and diverse categories of harvested stem cells currently explored for regenerative applications in oculoplastic surgery. By synthesizing evidence across experimental, translational, and clinical domains, it aims to delineate the evolving realm of biologically driven reconstruction and highlight future directions that may ultimately redefine therapeutic paradigms in periocular and orbital regeneration.

Stem-Cell Biology

Multiple stem-cell populations, namely mesenchymal stem cells (MSCs), retinal progenitor cells, induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs), are under investigation for their potential to restore or replace dysfunctional ocular tissues.[3]

Types of Stem Cells

Embryonic stem cells

Although ESCs derived from the blastocyst have demonstrated robust pluripotency, their clinical use remains restricted by ethical considerations and the risk of teratoma formation.[4] Consequently, alternative stem-cell sources, particularly MSCs and iPSCs, have gained prominence as more feasible candidates for ocular regenerative applications.

Induced pluripotent stem cells

The development of iPSCs, as pioneered by Takahashi and colleagues,[5] marked a transformative milestone in regenerative medicine. Their identification of four key transcription factors, that is, OCT4, SOX2, KLF4, and c-MYC, enabled the reprogramming of adult somatic cells into pluripotent stem cells with properties comparable to ESCs. iPSCs exhibit self-renewal and multilineage differentiation potential across all three germ layers, facilitating the generation of patient-specific autologous cell lines.[5] This capacity offers an avenue for personalized regenerative therapy while mitigating concerns regarding immune rejection.

Adult stem cells

Adult (somatic) stem cells represent a rare but functionally indispensable population of progenitor cells distributed across multiple human tissues.[6] Typically, they are maintained in a quiescent state; however, they can be mobilized in response to injury, disease, or physiologic demand to support tissue repair and homeostasis. Compared with pluripotent stem cells, adult stem cells are lineage-restricted, allowing greater predictability and control over their terminal phenotype.[7] Within the eye, several endogenous reservoirs of adult stem cells have been identified. The ocular immune-privileged environment, combined with the feasibility of localized and minimally invasive cell delivery techniques, renders ocular tissues amenable to stem-cell–based therapeutic interventions.[8]

Mesenchymal stem cell

In 2006, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy established explicit criteria for defining MSCs, thereby standardizing terminology across the field. According to these criteria, MSCs must adhere to plastic in standard culture conditions, express specific surface markers (CD73, CD90, CD105), lack hematopoietic and endothelial markers (CD45, CD34, CD14/CD11b, CD79α/CD19, HLA-DR), and have the capacity for trilineage mesodermal differentiation.[9,10] MSCs can be isolated from a broad array of tissues, including bone marrow, adipose tissue, neural tissue, amniotic fluid, placenta, and Wharton’s jelly of the umbilical cord.[11]

A notable feature of MSC biology is the secretion of a diverse array of bioactive molecules, collectively termed the MSC secretome. This secretome comprises soluble mediators such as cytokines, chemokines, immunomodulatory proteins, and growth factors, as well as membrane-bound vesicles, including microvesicles and exosomes.[12] Emerging evidence indicates that these paracrine factors significantly contribute to the therapeutic efficacy observed with MSC-based interventions, often exceeding the benefits attributable solely to direct differentiation.

Adipose-derived stem cells

Adipose tissue has gained much attention as a practical and biologically rich source of MSCs. Although adipocytes constitute only approximately 25% of the total cellular content, the stromal vascular fraction comprises the remaining 75% and contains adipose-derived stem cells (ASCs), endothelial cells, perivascular cells, macrophages, and lymphocytes.[13] Importantly, adipose tissue yields 100 to 500-fold more stem cells per unit volume than bone-marrow aspirate and contains an abundance of fibroblast colony-forming units.[14,15]

Mechanisms of Action

Stem cells exert their therapeutic potential through a multifaceted repertoire of biological mechanisms, Fig. 1. Central to their function is their intrinsic capacity for self-renewal and lineage-specific differentiation, which is tightly regulated by a complex interplay of signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, and transforming growth factor-β (TGF-β), as well as epigenetic regulatory networks that modulate chromatin accessibility, transcriptional activity, and post-transcriptional gene expression.[16,17,18,19] In addition to direct differentiation into epithelial, mesenchymal, or neuroectodermal lineages pertinent to periocular tissue repair, stem cells mediate significant paracrine effects through their secretome of growth factors, cytokines, chemokines, and extracellular vesicles.[20,21] These mediators promote angiogenesis and neovascularization, enhance fibroblast and keratinocyte migration, modulate extracellular matrix turnover, and attenuate pro-fibrotic pathways. These paracrine mechanisms are particularly crucial in restoring vascularity within ischemic or scar-prone periocular tissues, analogous to their established roles in cardiovascular and vascular regenerative therapies.[22,23,24] Moreover, stem cells can dampen aberrant immune activation and supporting a microenvironment conducive to wound healing.[25,26,27] Collectively, these mechanisms position stem cells as highly promising candidates for advancing reconstructive strategies in oculoplastic surgery.

Figure 1.

Summary of key biological functions of stem cells, including intrinsic self-renewal capacity, paracrine-mediated signal, promotion of angiogenesis, and modulation of inflammatory and immune responses

Bioengineering Principles in Oculoplastic Regeneration

Tissue-engineering triad

The concept of TE was first introduced during a workshop organized by the National Science Foundation at Granlibakken, California.[28] Broadly, TE strategies are categorized into three approaches:

Isolated cell implantation

This technique involves the direct transplantation of dissociated or cultured cells into the target tissue. Its success relies on the ability of the implanted cells to survive, integrate, and restore functional tissue architecture.[29]

Delivery of bioactive molecules

In this approach, growth factors, cytokines, or other signaling molecules are administered to stimulate the proliferation, migration, or differentiation of endogenous cells. By modulating the host microenvironment, these agents enhance intrinsic regenerative capacity.[29]

Cell-scaffold constructs

The most widely applied TE technique involves seeding viable cells onto or within biocompatible scaffolds, either synthetic or naturally derived. Natural materials like collagen, fibrin, and hyaluronic acid, and synthetic materials such as poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) are used.[30,31] These scaffolds serve as temporary extracellular matrix (ECM) analogues, providing structural support and biochemical cues that facilitate cellular adhesion, organization, and matrix deposition. Authors have also investigated the utilization of stem cells in conjunction with scaffolds for the purpose of ocular regeneration. Stem cells possess the capacity to undergo differentiation into distinct cell types that are present in the eye. This characteristic makes them a highly promising and viable option for the regeneration of impaired tissues.[32] By seeding stem cells onto scaffolds, researchers can create complex tissue structures that closely resemble native eye tissues.[33]

Hence, collectively, these strategies form the foundation of contemporary TE, enabling the development of biologically active constructs that replicate native tissue characteristics and support clinical reconstruction. By employing the patient’s own cells, ocular TE minimizes the likelihood of rejection and complications associated with the use of foreign materials.[34]

Regenerative Applications in Oculoplastic Surgery

Regenerative medicine is redefining the landscape of oculoplastic surgery by shifting the focus from conventional tissue replacement to biologically driven tissue restoration. Advances in stem-cell therapy, bioengineered scaffolds, and TE technologies now offer new pathways for reconstructing eyelid, conjunctival, and adnexal structures with greater functional and aesthetic outcomes, Fig. 2. As these innovations evolve, they hold the potential to minimize morbidity, enhance wound healing, and provide long-lasting solutions for complex oculoplastic defects.

Figure 2.

Comprehensive schematic depicting regenerative and tissue-engineering strategies applied to oculoplastic reconstruction

Table 1 summarizes the regenerative applications, highlighting regenerative strategies, stem cells used, current clinical status, and key limitations to provide a clinically oriented overview.

Table 1.

Regenerative applications in oculoplastic surgery

Oculoplastic subsite		Regenerative strategy		Stem cells/material		Clinical status		Availability		Key limitation
Eyelid skin		Cultured epithelial grafts		Autologous keratinocytes		Clinical		Limited to specialized tissue culture centers		High cost and long culture time
Posterior lamella		ADM, stem-cell scaffolds		MSC + PLGA/ECM		Clinical + preclinical		Tertiary centers and research hospitals		Expensive biomaterials and limited long-term outcome data
Lacrimal gland		iPSC differentiation		iPSCs, organoids		Experimental		Experimental laboratories only		Early research stage, complex cell culture
Orbital bone		BMP + scaffolds		MSC + β-TCP		Clinical trials		Selected research and clinical trial centers		Limited clinical evidence and regulatory approval
Socket		Fat graft + ASC		CAL technique		Clinical		Widely available in oculoplastic and plastic surgery centers		Variable graft survival and resorption
Lacrimal drainage		Nanocomposite conduits		POSS scaffolds		Preclinical		Experimental/laboratory settings		Not yet clinically validated

β-TCP=β-tricalcium phosphate, ADM=acellular dermal matrix, ASC=adipose-derived stem cells, CAL=cell-assisted lipotransfer, ECM=extracellular matrix, iPSCs=induced pluripotent stem cells, MSC=mesenchymal stem cell, PLGA=poly (lactic-co-glycolic acid)

Eyelid Reconstruction

Regenerative strategies have emerged as valuable adjuncts in eyelid reconstruction, particularly in settings of extensive tissue loss, chronic wounds, and burns. Among the earliest clinical applications is the use of cultured autologous keratinocytes, harvested from a small patient biopsy and expanded ex vivo for approximately 2 weeks. When applied to a debrided wound bed within a fibrin matrix, these cells promote re-epithelialization and support endogenous tissue repair[35] This approach reflects a shift toward facilitating biologic regeneration rather than mechanical replacement.

Several commercial epithelial substitutes have broadened the clinical utility of this strategy.

Epicel, a cultured epidermal autograft, is used primarily for severe burns and chronic ulcers, offering reliable epithelial coverage despite high costs and potential immunologic reactions.[36]

Recell employs a similar concept by generating a suspension of autologous keratinocytes, melanocytes, and stem cells from a small skin biopsy. This suspension accelerates wound closure and reduces donor-site requirements.[37,38]

Epidex, a differentiated keratinocyte-based autologous substitute, has demonstrated healing outcomes comparable to split-thickness grafts.[39]

Synthetic substitutes like Biobrane, a semisynthetic dressing, facilitate epithelialization in partial-thickness burns and serve as a temporary wound cover. DuoDERM, a hydrocolloid dressing, has been explored as a temporary measure to protect the ocular surface, including as a noninvasive alternative to tarsorrhaphy.[40]

Posterior Lamellar Reconstruction

Posterior lamellar TE can be broadly categorized into acellular and cellular approaches.[41]

Acellular approaches

Acellular biomaterials, including decellularized ECMs, natural polymers, and synthetic polymers, are widely used to replace the tarsal plate.[41] Acellular dermal matrices (ADMs) derived from human (AlloDerm^®, BellaDerm^®),[42] porcine (Endurage^®),[43] or bovine (SurgiMen^®)[44] dermis offer consistent biocompatibility and low immunogenicity. Composed of cross-linked collagen with distinct dermal and basement membrane surfaces, ADMs provide structural stability, support fibroblast infiltration, and facilitate epithelial migration.[45] Clinically, ADMs serve as posterior lamellar spacers to restore eyelid position following the release of lower eyelid retractors.[46] In cases of conjunctival deficiency, orienting the basement membrane surface toward the ocular surface permits complete epithelialization within 3–6 weeks.[47] Graft contraction and resorption, particularly in human-derived matrices, remain key limitations and influence long-term outcomes.

Cellular approaches

Cellular engineering aims to recreate both the mechanical integrity and physiologic functions of the posterior lamella. Dai et al.[48] introduced a composite graft consisting of a PLGA scaffold, bone-marrow–derived mesenchymal stem cells (BMSCs), TGF-β1 plasmid DNA, and fibrin gel. Implanted into rabbit tarsal defects, this construct demonstrated restoration of structure and partial meibomian gland-like acinar formation within eight weeks, suggesting potential recovery of lipid-secreting function. To improve scaffold integration, Chen et al.[49] developed 3D-bioprinted polycaprolactone (PCL) scaffolds coated with decellularized adipose-derived MSC matrix to enhance hydrophilicity and cellular adhesion, offering a more biomimetic tarsal replacement.

More recently, a biphasic scaffold composed of a rigid PPF–HEMA layer and a compliant collagen/chitosan layer was designed to replicate the dual structure of the native posterior lamella. In vivo studies in rabbits demonstrated that the rigid layer maintained eyelid contour while the softer layer promoted conjunctival regeneration, supporting its potential role in tarso-conjunctival repair.[50]

These technologies are paving the way toward functional, bi-layered constructs capable of addressing longstanding challenges in tarso-conjunctival deficit reconstruction surgery.

Lacrimal Gland Regeneration

The lacrimal gland possesses a population of resident tissue stem cells that contribute to its endogenous repair capacity. These progenitor cells, characterized by the expression of markers such as nestin and Ki67, have been shown to mediate regeneration in murine lacrimal glands following interleukin-1–induced inflammatory injury.[51] Their activity is thought to support both restoration after cellular loss and the maintenance of tissue homeostasis throughout aging.

Translating these insights to oculoplastic regenerative strategies opens promising avenues for patients with lacrimal gland dysfunction, including severe dry eye disease. Somatic cells obtained from affected individuals could potentially be reprogrammed into iPSCs, which may then be directed to differentiate into lacrimal gland stem cells or lineage-specific secretory epithelial cells. Following correction or enhancement of their functional properties, these cells could be transplanted back into the diseased lacrimal gland to restore tears and glandular function.[52] In lacrimal gland regeneration, microfluidic gland-on-chip systems are emerging as promising tools to replicate the natural process of lacrimal gland development. These systems recreate the interaction between epithelial and mesenchymal cells, which is essential for normal gland formation and function. In this model, epithelial cells are cultured in the central region, while mesenchymal cells are placed around them within a microfluidic environment to mimic organogenesis. Studies have shown that under dynamic culture conditions, the cells remain viable and organized for up to 14 days. This approach may enable the development of lacrimal gland organoids derived either from adult lacrimal gland stem cells or from iPSCs, providing a potential platform for future regenerative therapies.[53]

In parallel, advances in biomaterial engineering have facilitated the development of scaffolds tailored for lacrimal gland tissue reconstruction. Polyester-based membranes and polyether sulfone (PES) scaffolds are frequently employed due to their favorable mechanical strength, structural stability, and compatibility with lacrimal epithelial cell growth.

Orbital Bone Regeneration

Bioactive molecules and cell-based therapies have emerged as promising strategies for orbital bone reconstruction, offering potential substitutes capable of stimulating bone healing and promoting physiologic bone growth. Among these, recombinant bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have garnered significant interest due to their potent osteoinductive capacity and facilitate differentiation of MSCs into osteoblasts, thereby driving new bone formation and supporting their application in orbital floor repair and other craniofacial defects.[54]

To enhance the regenerative efficacy of BMPs, various biomaterial-based delivery systems have been developed. Biomaterials such as demineralized bone matrix and bioresorbable synthetic polymers have been successfully combined with BMPs and auxiliary growth factors, including TGF-β, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), to optimize cell adhesion, biocompatibility, and controlled release profiles. A notable example is the work by Asamura et al.,[55] who utilized a gelatine-based hydrogel for sustained BMP-2 delivery and near-complete defect healing within 5 weeks.

Beyond BMPs, platelet-derived growth factors, particularly PDGF and TGF-β1/β2, have also demonstrated a substantial role in modulating osteogenesis and enhancing the bone healing microenvironment.[56]. The combination of BMSCs with osteoconductive scaffolds has shown the ability to generate a favorable milieu for bone regeneration, accelerating tissue integration and defect closure.[57]

Periocular and Orbital Fat Grafting

Stem cells and stem-cell–derived products have gained significant attention in periocular rejuvenation, improving the quality of radiotherapy-damaged skin and reconstructive surgery due to their regenerative, pro-angiogenic, and wound healing properties. One of the simplest clinical approaches involves the topical application of stem-cell–derived formulations such as creams, gels, or serums to the periocular skin. These preparations typically contain stem-cell extracts, conditioned media, or bioactive secretomes, which may stimulate dermal regeneration, enhance elasticity, and contribute to improved skin texture and overall rejuvenation.[58] Beyond topical therapies, MSCs may also be administered directly into periocular tissues through targeted injections, including microinjection techniques.[59]

Regenerative strategies are valuable in patients with periocular or ocular malignancies, where healthy periocular skin is essential for proper prosthesis wear and postoperative function. Further, eyelid malposition repair may be effectively combined with autologous fat grafting by providing a regenerative “boost” to compromised tissues.[60] Clinical observations have also suggested that micro fat grafting to the upper eyelid can improve levator palpebrae superioris function in selected cases of mild ptosis.

ASCs further expand these therapeutic options. Application of ASC sheets directly onto wound beds has demonstrated accelerated healing in human studies, with 18 of 23 patients exhibiting marked improvement.[61] Additional investigations have shown increased survival and improved viability of ischemic skin flaps treated with ASCs.[62] However, fat grafting is limited by postoperative volume reduction, internal calcification, and the risk of partial graft necrosis over time. Therefore, recent refinements in adipose tissue harvesting and injection techniques have substantially improved graft viability. Low-pressure aspiration, meticulous handling to minimize mechanical trauma, and the use of multi-layered microinjections of small volume fat parcels collectively enhance adipocyte survival, promote neovascular integration, and reduce long-term resorption. Nevertheless, variable retention rates persist due to partial adipocyte necrosis and resorption.[63] To address these limitations, the technique of cell-assisted lipotransfer (CAL) was developed. In CAL, ASCs are isolated from lipoaspirate through collagenase digestion, followed by filtration and centrifugation to obtain the stromal vascular fraction (SVF), believed to be the principal reservoir of ASCs.[64] Enriching fat grafts with ASCs aims to reduce complications associated with traditional fat transfer, thereby enhancing long-term graft viability and tissue regeneration.[65] In parallel, cell-free regenerative therapies, particularly MSC-derived exosomes and extracellular vesicles, are emerging as safer and more scalable alternatives to live-cell transplantation, providing immunomodulatory and regenerative benefits while minimizing the risk of tumorigenicity.[66]

Lacrimal Drainage Pathway Repair

Emerging TE approaches offer further potential to overcome the biological and mechanical challenges of lacrimal drainage reconstruction. Stem-cell-seeded scaffolds, bioactive polymers capable of delivering antifibrotic or pro-healing factors, and smart biomaterials designed to modulate local inflammation represent promising avenues for creating more physiologic and durable tear outflow pathways. In 2011, Chaloupka et al.[67] introduced a significant advancement toward overcoming the longstanding complications associated with rigid Lester Jones tubes, such as duct obstruction, extrusion, and poor tissue integration. By developing a lacrimal drainage conduit composed of polyhedral oligomeric silsesquioxane polycarbonate-urea urethane, they demonstrated marked improvements in biocompatibility, mechanical resilience, and functional performance compared with conventional materials. The nanocomposite’s favorable interaction with surrounding tissues and its enhanced structural stability position it as a promising next-generation alternative to existing bypass devices. Furthermore, nanocomposite conduits engineered with surface modifications to resist bacterial colonization and fibrosis could substantially reduce recurrent obstruction.

Limitations and Challenges

Stem-cell uses and TE approaches in oculoplastic surgery face several key limitations. Large-scale, reproducible manufacturing is difficult, as ensuring consistent cell quality, genomic stability, and batch-to-batch uniformity, particularly in iPSC-derived products, remains challenging. Both autologous and allogeneic stem cells may trigger immune reactions after transplantation, necessitating immune-evasive engineering. However, strategies such as Major histocompatibility complex (MHC) knockout or overexpression of anti-phagocytic molecules raise concerns about impaired immune surveillance and potential tumorigenicity.[68] Pluripotent stem cells also pose a risk of teratoma formation if residual undifferentiated cells persist in the final therapeutic product.[69] Ethical considerations in stem-cell–based therapies have traditionally centered on the use of human ESCs. More recently, concerns have shifted toward the broad differentiation potential of iPSCs, which raises theoretical risks such as misuse in human cloning or the creation of embryos and interspecies chimeras. In addition, safety issues, including unintended differentiation and possible malignant transformation, highlight the need for well-optimized differentiation protocols to ensure the purity of iPSC-derived cell populations before clinical application.[70] Similarly, although MSCs are widely explored for therapeutic use, their potential role in tumor promotion necessitates careful evaluation, continuous monitoring, and long-term follow-up in experimental and clinical studies.

Furthermore, the unique local microenvironment of eyelid and orbital tissues influences stem-cell behavior in ways not yet fully understood, complicating predictable regenerative outcomes.

In TE, achieving optimal scaffold biocompatibility, mechanical strength, vascular integration, and synchronized degradation is technically demanding, especially in the delicate and highly specialized periocular region. Finally, high production costs, stringent regulatory requirements, and difficulties in replicating complex functional anatomy continue to restrict widespread clinical translation.

Future Directions

Future advancements in oculoplastic regeneration are expected to be driven by innovations in stem-cell science, gene editing, and biomaterials engineering. Personalized regenerative constructs derived from patient-specific iPSCs hold the potential to create immunocompatible tissues for eyelid, orbital, and lacrimal reconstruction. Emerging CRISPR-based gene-editing strategies can enhance the safety, stability, and lineage-specific differentiation of therapeutic stem cells, thereby reducing oncogenic risk and improving clinical reliability.

Concurrently, AI-integrated bioprinting technologies are enabling the automated design and fabrication of anatomically precise periocular tissues.

Conclusion

Stem-cell therapies and bioengineering technologies represent a transformative frontier in oculoplastic surgery. By integrating cellular therapeutics, advanced biomaterials, and novel biofabrication techniques, regenerative approaches have the potential to restore complex periocular tissues with unprecedented precision.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.