Progress in Bioengineering: An Extensive Examination of State-of-the-Art Innovations in the Development of Artificial Corneas.

Neurological disorders impose a substantial global health burden, compounded by the limited regenerative capacity of neural tissues and the absence of curative therapies. 3D bioprinting offers a transformative tool to model, replace, and regenerate neural tissues through the precise spatial organization of cells and biomaterials. In this perspective article, recent advances are examined in: i) the development of in vitro neural platforms for disease modeling and drug screening; ii) bioprinted acellular scaffolds designed to guide endogenous neural repair; and iii) cell‐laden constructs that aim to replace or reconstruct damaged neural circuits. Key translational challenges are critically evaluated, including vascularization, immune integration, functional maturation, and replicating the complex cytoarchitectures of native neural tissues. Highlighting representative preclinical studies and emerging biofabrication technologies, we discuss how innovations in biomaterials, scaffold design, stem cell biology, and neuroengineering are converging to overcome existing limitations. Through tailored strategies and interdisciplinary collaboration, 3D bioprinting is poised to redefine therapeutic paradigms and drive the development of next‐generation, personalized regenerative therapies for neurological diseases and injuries.

Chapter 49 - Regenerative Medicine in the Cornea

Purpose: To examine the trend of tissue engineering and regenerative medicine (TERM) research progress. The study aims to fill the gap of literature dearth that systematically addresses the trend of TERM research and development in Malaysia. Methods: A scientometric study of published abstracts presented in International Conference on Biomaterials and Tissue Engineering 2004, National Tissue Engineering and Regenerative Medicine Scientific Meeting 2006 and Malaysian Tissue Engineering and Regenerative Medicine Scientific Meeting 2008-2014 was conducted. The study explored the publication productivity trends, authorship productivity, collaboration pattern, sources of funding and areas of interest. These data were examined in relation to the overall publications. Results: A total of 362 abstracts were published in 6 conferences from 2004 to 2014. Majority of publications were multi-authored involving public institutions of higher learning. The collaborations between local and international authors were noted. The active research areas and themes were identified. It can be appreciated that the conference participation expands with the coefficient of determination of R2 = 0.0775. Thus, Malaysian researchers seemed to be focusing on various cell sources, biomaterials, signaling factors and organ systems. A declining trend in these areas of interest is observed. Based on the study, certain prominent researchers and institutions are actively upholding the TERM research. Conclusion: The present study is hoped to shed some lights and serves as a reference towards the advancement of TERM research in Malaysia.

Stem cells can be defined as cells that have the capacity to self-renew and the ability to generate differentiated progeny or multiple cell lineages. True stem cells can turn into any type of cells, while progenitor cells are more or less committed to becoming cell types of a particular tissue. Human corneal epithelial stem cells (CESCs) represent a great example and model of adult stem or progenitor cells. Human CESCs have been identified to locate in the basal epithelial layer of the limbus, and thus also referred as to limbal stem cells. We would like to use the both terms, stem and progenitor cells in this chapter based on previous use in the literature for more than two decades. Although the CESCs have been identified to reside at the limbus and many stem cell markers have been proposed, there is no consensus to date regarding the definitive markers for CESCs, and identification and isolation of these cells are still challenging. Based on evaluation of a variety of proposed markers, we have characterized that the CESCs located in the basal layer of human limbal epithelium are small primitive cells expressing three patterns of molecular markers, which represent a unique phenotype of putative corneal epithelial stem or progenitor cells. Based on adult stem cell criteria and the putative limbal stem cell phenotype, our group has attempted to enrich for human CESCs through novel approaches including cell-sizing, adhering to extracellular matrix collagen type IV, and cell sorting for side population or for expression of ABCG2 or connexin 43 cell surface markers. The 5 clonogenic populations isolated from limbal epithelium and its cultures by different methods show the properties that are characteristics of adult stem/progenitor cells: 1) relatively undifferentiated, 2) high proliferative potential, 3) self-renewal. Expansion and cultivation of corneal epithelial progenitor cells have been achieved using different methods, such as limbal tissue explant culture, and limbal epithelial cell suspension co-culture with mouse 3T3 fibroblast feed layer. To avoid the use of xeno-components, two cell lines of commercial human fibroblasts have been identified that support human corneal epithelial regeneration, and have potential use in replacing mouse 3T3 cells for corneal tissue bioengineering. The concept of CESCs has formed the basis for identifying a class of blinding diseases that display features of corneal epithelial stem cell deficiency or limbal stem cell deficiency (LSCD), where the limbal epithelium is damaged. LSCD is characterized by persistent or recurrent epithelial defects, ulceration, corneal vascularization, chronic inflammation, scarring, and conjunctivalization (conjunctival epithelial ingrowth). Only transplantation of CESCs can restore vision. Due to an increasing shortage of corneal donors, corneal tissue engineering is becoming an important discipline that holds great promise for corneal reconstruction. CESCs and optical substrates are known to be the most important factors for corneal tissue bioengineering in regenerative medicine. Our team has recently explored the utilization of natural donor corneal stroma in corneal tissue engineering. In combination with fresh limbal epithelium containing stem cells, and the donor corneal stroma, a great source of natural optical substrate, we developed a native-like corneal equivalent construct with proliferative potential. This corneal construct provides a new clinical cell therapy for corneal reconstruction.

durability of bonded restorations (Li et al., 2024).Another contribution reported by Rangel et al. focuses on the pivotal role of cellinstructive biomaterials in tissue engineering and regenerative medicine (Rangel et al., 2024). Over the past three decades, significant strides have been made in regenerating diseased or damaged tissues by integrating innovations in biomaterials, signaling molecules, and cell therapies. Despite these advancements, challenges such as material property limitations, the need for advanced manufacturing technologies, and clinical translation hurdles persist. The article highlights breakthroughs in selfhealing and modular biomaterials, 3D bioprinting, and emerging research technologies like multi-omics and spatial biology. The perspective offered underscores the critical contributions of clinician-scientists in driving innovation, clinical validation, and adoption of next-generation biomaterials, emphasizing their transformative potential in tissue and organ engineering (Rangel et al., 2024).Additionally, a study on pneumatic, fabric-reinforced inflatable soft actuators made of Dragon Skin 30 silicone provides insights into material endurance and variability (Bui et al., 2023). The research elucidates how material properties affect actuator performance over time by examining repeatability, durability, and failure pressure.These findings contribute to a deeper understanding of the real-world behavior of soft actuators and their material constraints, enabling improved design and control in practical applications (Bui et al., 2023).The overarching aim of this Research Topic was to provide a platform for early career scientists to share their innovative contributions while fostering an understanding of their work within the larger scientific community. The articles included here reflect the broad applicability and interdisciplinary nature of biomaterials and bio-inspired materials, emphasizing their importance in creating sustainable and functional solutions. The collective findings illustrate significant progress in the synthesis, design, and application of these materials, demonstrating their potential to address pressing global needs in healthcare, environmental sustainability, and beyond.The compilation of studies in this Research Topic exemplifies innovative approaches to biomaterial development, such as the pH-responsive dentin adhesives and cellinstructive biomaterials, which address both performance enhancement and sustainability in practical applications. Early career scientists are uniquely positioned to lead this charge, leveraging their creativity and openness to novel approaches. The insights shared in this Research Topic highlight their essential role in shaping the field's future and provide a glimpse into the directions that biomaterials research is likely to take. However, the insights shared also illuminate persistent challenges, such as the scalability of self-healing biomaterials, the durability and stability of soft actuators, and the clinical translation of tissue engineering technologies. Addressing these challenges requires precise understanding of the structure and function of biological systems to translate them into bioinspired materials effectively as well as interdisciplinary collaborations and advancements in manufacturing techniques, such as 3D bioprinting and high-throughput material characterization methods.For early career scientists, there are vast opportunities in exploring areas such as bioinspired 3D printing, the development of multifunctional biomaterials, and the application of machine learning in material design. Collaborations across disciplines and with industry partners can accelerate the translation of these materials into realworld applications. By focusing on underexplored niches like low-cost sustainable biomaterials or modular designs for regenerative medicine, early career researchers can carve impactful pathways for future advancements.The editorial team extends its gratitude to the authors, reviewers, and collaborators who contributed to this Research Topic. Their collective efforts have ensured that the work presented here reflects the highest standards of scientific rigor and relevance. This Research Topic stands as a testament to the ingenuity and dedication of early career researchers, serving as both a snapshot of current advancements and a catalyst for future innovations in biomaterials and bio-inspired materials research.As editors, we believe that the findings presented here underscore the transformative potential of biomaterials and bio-inspired materials in addressing global challenges.The pioneering work of early career scientists featured in this Research Topic serves as a beacon for future research. The integration of innovative material properties, sustainable practices, and interdisciplinary approaches is not just a necessity but a pathway to breakthroughs that can redefine the field. We hope this compilation inspires

Great progress has been made on the corneal tissue engineering in the past two decades. Much knowledge has been gained on the seed cells, carrier material, and strategies of corneal tissue reconstruction. However, there are still great challenges regarding the basic research of corneal tissue engineering, such as selection of appropriate carrier and cells, optimization and standardization of the construction method, and evaluation of the clinic outcome. Future studies may address these questions and bring tissue engineered cornea into clinic application.

Tissue engineering is a multi-disciplinary area of research bringing together the fields of engineering and life sciences with the aim of fabricating tissue constructs aiding in the regeneration of damaged tissues and organs. Scaffolds play a key role in tissue engineering, acting as the templates for tissue regeneration and guiding the growth of new tissue. The use of stem cells in tissue engineering and regenerative medicine becomes indispensable, especially for applications involving successful long-term restoration of continuously self-renewing tissues, such as skin. The differentiation of stem cells is controlled by a number of cues, of which the nature of the substrate and its innate stiffness plays a vital role in stem cell fate determination. By tuning the substrate stiffness, the differentiation of stem cells can be directed to the desired lineage. Many studies on the effect of substrate stiffness on stem cell differentiation has been reported, but most of those studies are conducted with two-dimensional (2D) substrates. However, the native in vivo tissue microenvironment is three-dimensional (3D) and life science researchers are moving towards 3D cell cultures. Porous 3D scaffolds are widely used by the researchers for 3D cell culture and the properties of such scaffolds affects the cell attachment, proliferation, and differentiation. To this end, the design of porous scaffolds directly influences the stem cell fate determination. There exists a need to have 3D scaffolds with tunable stiffness for directing the differentiation of stem cells into the desired lineage. Given the limited number of biomaterials with all the desired properties, the design of the scaffolds themselves could be used to tune the matrix stiffness. This paper is an in silico study, investigating the effect of various scaffold parameter, namely fiber width, porosity, number of unit cells per layer, number of layers, and material selection, on the matrix stiffness, thereby offering a guideline for design of porous tissue engineering scaffolds with tunable matrix stiffness for directing stem cell lineage specification.

Engineering topography: Effects on corneal cell behavior and integration into corneal tissue engineering

Corneal diseases are among the most common causes of blindness worldwide. Regardless of the etiology, corneal opacity- or globe integrity-threatening conditions may necessitate corneal replacement procedures. Several procedure types are currently available to address these issues, based on the complexity and extent of injury. Corneal allograft or keratoplasty is considered to be first-line treatment in many cases. However, a significant proportion of the world’s population are reported to have no access to this option due to limitations in donor preparation. Thus, providing an appropriate, safe, and efficient synthetic implant (e.g., artificial cornea) may revolutionize this field. Nanotechnology, with its potential applications, has garnered a lot of recent attention in this area, however, there is seemingly a long way to go. This narrative review provides a brief overview of the therapeutic interventions for corneal pathologies, followed by a summary of current biomaterials used in corneal regeneration and a discussion of the nanotechnologies that can aid in the production of superior implants.

3D bioprinting stands at the intersection of biology, engineering, and material science, enabling the precise fabrication of tissue constructs that mimic the architecture and function of native human tissues. This paper examines the evolution, techniques, materials, and multifaceted applications of 3D bioprinting in tissue engineering and regenerative medicine. From its foundational principles rooted in additive manufacturing to the development of smart bioinks and complex vascularized constructs, 3D bioprinting offers novel pathways for addressing the shortage of donor organs, personalized medicine, pharmacological testing, and even the development of food alternatives. Despite its promise, the technology faces significant challenges such as limited cell viability, bioink optimization, and unresolved regulatory frameworks. The future of bioprinting depends on interdisciplinary collaboration, innovation in biomaterials, and proactive regulatory engagement to translate laboratory successes into clinical and commercial reality. Keywords: 3D Bioprinting, Tissue Engineering, Regenerative Medicine, Bioink, Scaffold, Smart Biomaterials, Organ Fabrication.

Corneal stromal defects represent a significant global cause of blindness, necessitating innovative therapeutic strategies to address the limitations of conventional treatments, such as corneal transplantation. Tissue engineering, a cornerstone of regenerative medicine, offers a transformative approach by leveraging biomaterial-based solutions to restore damaged tissues. Among these, three-dimensional (3D) scaffolds fabricated using advanced techniques like 3D printing have emerged as a promising platform for corneal regeneration. These scaffolds replicate the native extracellular matrix (ECM) architecture, providing a biomimetic microenvironment that supports cell proliferation, differentiation, and tissue integration. This review highlights recent advances in the design and fabrication of 3D scaffolds for corneal stroma engineering (CSE), emphasizing the critical interplay between scaffold architecture, mechanical properties, and bioactive signaling in directing cellular behavior and tissue regeneration. Likewise, we emphasize the diverse range of biomaterials utilized in scaffold fabrication, highlighting their influence on cellular interactions and tissue reconstruction. By elucidating the complex relationship between scaffold design and biologics, this review aims to illuminate the evolution of next-generation strategies for engineering functional corneal tissue. Eventually, this review will provide a comprehensive synthesis of the current state-of-the-art in 3D scaffold-based corneal tissue engineering (CTE), offering insights that could advance progress toward effective vision restoration therapies.

Tissue engineering

Advancements in Vertebral Augmentation: Innovations in Biomaterials and Cement Compositions.

Nanotechnology is transforming the area of corneal tissue engineering by improving scaffold design and enabling sophisticated therapeutic strategies. Nanomaterials are being used to improve the corneal scaffolds' mechanical strength, permeability, and transparency, as well as to enable the therapeutic agents' targeted delivery by nanocarriers. These improvements deal with important problems in corneal repair, like inflammation, infections, and neovascularization. While corneal transplantation remains a standard treatment, the risk of rejection and availability of donor tissue are the main limitations. Recent improvements in electrospinning have made it possible to make nanofibers that look like the natural extracellular matrix (ECM). These fibers have a large surface area and high porosity, which help cells grow, stick to each other, and change into different types of cells. Both synthetic and natural polymers have been successfully employed to fabricate biocompatible and biodegradable nanofibers, indicating their potential for the treatment of various corneal disorders. Electrospun nanofibers are very useful for corneal tissue engineering because they are easy to use, can be used in surgery, and are structurally similar to the cornea. Adding nanofibers and nanoparticles to corneal tissue engineering improves the scaffold and allows for targeted therapies, which means that there are more advanced ways to reconstruct and rehabilitate the cornea. This study investigates the application of naturally derived and synthetic nanoparticles in drug delivery systems and the development of composite nanoparticles, highlighting their potential to improve corneal tissue engineering techniques.

The Human Cornea as a Model Tissue for Additive Biomanufacturing: A Review