Keeping an eye on sustainable regeneration

The shortage of viable organs for transplantation remains a significant problem in medical practice. Among the various causes of blindness, corneal blindness ranks among the top five, affecting approximately 36 million people worldwide [1]. Corneal blindness refers to conditions that cause the cornea, the transparent outer layer of the eye, to become opaque, leading to visual impairment and eventual blindness [2]. These conditions can be infectious, such as herpes simplex keratitis, bacterial keratitis and fungal keratitis, or noninfectious, including glaucoma, trachoma, uveitis, keratoconus, dry eye disease and trauma [1]. Factors such as contact lens usage and the use of steroid medications can also contribute to corneal damage. Certain regions of the world are more prone to specific corneal conditions due to poor public health infrastructure or genetic factors. When preventive strategies are unavailable or ineffective, corneal transplantation becomes the most effective treatment option for advanced corneal disease. Despite the fact that at least 4 million people worldwide suffer from corneal blindness, only 100,000 corneal transplants are performed each year due to limited access to suitable donor tissue [3].

Corneal transplantation (keratoplasty), a surgical procedure used to replace damaged or diseased corneal tissue, allows partial or complete corneal replacement depending on the severity of the injury. To meet the current and growing demand for transplantation, different sources such as cadaveric tissues, viable human tissues and xenografts are explored. Cadaveric tissues have been the primary source for corneal transplantation. They offer a large pool of donor corneas, well-established surgical techniques and a low risk of disease transmission. However, their availability is limited by organ donation rates. Moreover, given the complexities involved in surgical procedures and the recovery process, recipients frequently encounter issues such as graft rejection and failure. As a result, it becomes imperative to explore alternative options.

Tissue engineering and regenerative medicine techniques hold promise as alternatives to current autograft and allograft sources [4]. They can provide customized and readily available grafts, reduce the risk of immune rejection and address the shortage of viable tissues, like donor corneas. However, further research is needed to optimize these techniques and ensure long-term safety and efficacy. With approximately 100,000 corneal transplantation procedures performed annually worldwide [3], xenografts offer a promising solution to alleviate the scarcity of transplantable tissues. Xenotransplantation, the transplantation of corneas from nonhuman species, utilizes animals like porcine and ovine that share anatomical and physiological similarities with humans [5]. These livestock, which are commonly slaughtered for food, have a short gestation period and produce a large number of offspring. Repurposing byproducts, such as eyes, from slaughterhouse waste can generate personalized transplantable grafts, effectively increasing organ availability in sustainable and cost-effective manners [6].

Previous studies have underscored the complexities of devising viable corneal substitutes. As a result, waste generated from slaughterhouses provides a unique opportunity to reduce the scarcity of corneal tissues for transplantation. Such materials can create sustainable xenograft models and support circular economic practices [7,8]. This commentary highlights significant points, including slaughterhouse waste as a viable source for xenotransplantation, sustainable regeneration and technical approaches to generate functional xenografts.

Slaughterhouses, viable sources for xenotransplantation

Slaughterhouses produce approximately 150 million tonnes of organic waste annually that is rich in proteins consisting of collagen, keratin, fats and mineral products [9]. The live weight of the animals slaughtered for human consumption (bovine, ovine and porcine) is categorized as edible, inedible and discardable byproducts. A significant portion of the live weight of these byproducts, that is, 52% of ovine, 66% of bovine and 80% of porcine, live weights is considered discardable [8]. These discardable byproducts can be repurposed to produce bioartificial organs and tissues. Using slaughterhouse waste as a source for xenotransplantation offers several advantages over current sources like cadavers and laboratory-grown animals. These advantages include the vast supply of tissues and organs and platforms for high-throughput screening systems that can incorporate various artificial intelligence approaches [6,10–13], ensuring sustainability, cost–effectiveness and improved suitability for transplantation [14].

Repurposing slaughterhouse waste not only helps reduce the current problems related to transplantation but also helps ensure the principles of a circular economy. Only 20–30% of the discardable slaughterhouse byproducts are repurposed into valuable products like animal feed, biogas and fertilizers [9]. The remaining significant amount of this waste is disposed of directly or incinerated, both of which are environmentally unfriendly practices [8]. Hence, utilizing slaughterhouse byproducts for biomedical applications such as creating bioartificial corneas aligns with sustainability and resource efficiency principles. Slaughterhouses are viable sources of discarded corneas that can be developed into bioartificial corneas. Among the animal species slaughtered for human consumption, bovine, ovine and porcine are frequently used for xenotransplantation [14]. The corneas of these animals have advantages in this area due to their anatomical, biomechanical and chemical similarities of xenograft with human cornea [14]. Using xenografts from slaughterhouse waste addresses the scarcity of cornea for transplantation while aligning with the Declaration of Istanbul on Organ Trafficking and Tourism by providing an alternative source for transplantation.

Sustainable regeneration

There is tremendous slaughterhouse waste due to the rising demand for meat and agricultural goods. Due to such goods' chemical and physical characteristics, conversations about the volume of waste associated with biomaterials have attracted substantial interest in several biomedical replacement and regeneration applications. One of the most well-known fields demonstrating the use of waste-based biomaterials is tissue engineering, particularly in dentistry, dermatology, nephrology, cardiology and orthopedics. These biomaterials are primarily created from natural ceramics and polymers, including hydroxyapatite, collagen, alginate, chitosan and hyaluronic acids, to build various composites, hydrogels or scaffolds [8,15]. By combining biological cues with bioscaffold techniques, tissue engineering strives to heal, maintain or improve the form and function of damaged tissues or organs. Bioscaffold offers cells a range of biological and physicochemical signals by imitating the extracellular matrix's (ECM) composition, structure and properties. The ECM functions as a biomass network that combines flexibility, toughness and elasticity to give tissues and organs mechanical support and structural integrity. It comprises a polysaccharide matrix with many embedded proteins, including collagen, elastin and fibronectin. Through advanced tissue engineering techniques, tissues and organs sourced from slaughterhouse waste are repurposed to create biological grafts by maintaining the structural, biochemical and biomechanical properties of the ECM.

Waste-derived materials have been converted into different bioceramic and natural polymer materials demonstrating outstanding biocompatibility and biodegradability in tissue engineering applications. Employing waste-derived products may reduce garbage disposal and hence have a significant impact on environmental sustainability. Utilizing waste materials increases source availability while lowering production costs, landfill waste generation and greenhouse gas emissions [11]. Therefore, green biomaterials, also known as sustainable biomaterials, have taken on the role of nonecological biomaterials, opening up new possibilities for their therapeutic uses in 3D bioprinting, tissue engineering, drug delivery and the creation of various scaffolds. The interaction and cohabitation of these natural biomaterials inside human bodies may be safe if they satisfy minimum requirements. In particular, they must be nontoxic, biodegradable and biocompatible for these green biomaterials that act as a foundation for cell growth [16].

Technical approaches to generate functional xenografts

As the scarcity of human donor corneas necessitates exploring alternative options, corneal transplantation from animals obtained from slaughterhouses shows promise as a solution [7,17]. Notable advancements in regenerative medicine and tissue engineering indicate promising prospects for the feasibility of corneal xenotransplantation as a viable clinical alternative. These approaches include genetic modification of native animal tissues and transplanting recellularized tissues. While these two technical approaches involve using nonhuman sources to generate functional tissues, they differ in their methods and underlying principles [11]. The genetic modification of native animal tissues utilizes several strategies to mitigate potential risks by implementing approaches such as gene editing or transgenic technology to suppress the expression of specific molecules that can trigger immune responses in humans due to molecular discrepancies between the donor and the host [1]. Previous research has found the lack of α-Gal antigen in humans can trigger hyper-acute rejection [18]. At the same time, innate immune response genes might cause an acute rejection leading to thrombosis in xenotransplantation [1]. Although transplantation involves meticulous surgical techniques to attain proper vascularization, immunosuppressive medications are administered to the recipient to minimize rejection [18]. Such drugs ensure immediate functionality and reduce waiting time for patients needing corneal transplantation. Clinical studies have shown promising results in corneal xenotransplantation from porcine to nonhuman primates, with transplanted corneas surviving for more than six months [19]. However, immunological barriers and the risk of xeno-zoonotic infections are significant biological challenges [1]. Moreover, public acceptance, influenced by cultural and religious beliefs, and ethical scrutiny play crucial roles in shaping the progress and implementation of xenotransplantation [2].

On the other hand, using a decellularized corneal scaffold is also a promising approach in tissue engineering once recellularization occurs. Recellularizing a decellularized corneal involves repopulating a corneal scaffold with viable cells to create functional corneal tissue. The process begins with removing cellular components from a donor cornea, leaving behind a 3D ECM scaffold. This scaffold is then seeded with corneal cells, such as keratocytes or corneal epithelial cells, which gradually adhere and proliferate, reconstructing a bioengineered cornea. Recellularization techniques aim to restore the biological and structural properties of the cornea by allowing patient-specific cornea, which reduces immune rejection and improves long-term outcomes [20]. Aside from reducing the risk of xenogeneic infections by removing animal cells from the scaffold, it addresses ethical concerns related to animal welfare and the moral status of animals. While the likelihood of rejection is lessened, there remains a risk of chronic rejection, which can be mediated by CD4⁺ T cells and macrophages [20]. This approach entails higher costs and requires more time to develop a compatible corneal graft. Another obstacle during recellularization is retaining the original characteristics of keratocytes to mimic native tissue architecture, biocompatibility and vascularization to effectively utilize grafts in clinical settings. However, keratocytes, specialized cells responsible for maintaining the clarity and integrity of the cornea, may face hindrances such as phenotypic changes, migration challenges, inflammatory response and lack of suitable growth factors, which can affect their behavior and functionality [18]. To this end, further research and clinical trials are necessary to optimize protocols, refine immunosuppressive strategies and assess long-term graft survival to advance corneal transplantation from animal donors. These advancements could address the shortage of corneal transplantations and enhance access to vision-restoring procedures.

Conclusion

Corneal blindness is a major global health problem. When prevention or primary treatment fails, corneal transplantation can provide curative therapy. Limitations regarding the availability of deceased human donor corneas necessitate exploring alternative approaches. In tissue engineering and regenerative medicine, advances offer a promising alternative using viable human tissue and xenotransplantation. Sustainable xenografts sourced from slaughterhouse waste provide a regenerative source to reduce the scarcity of corneal tissues for transplantation while simultaneously providing a synchronized opportunity to foster circular economic practices. Despite the potential of tissue engineering to create functional replacement tissues and organs that closely resemble natural structures, the practical implementation of this technology still must be improved. It is crucial to conduct additional research and clinical trials to bridge the gap between theory and application. These efforts should focus on optimizing protocols, improving immunosuppressive strategies and assessing the long-term viability of corneal transplants from slaughterhouse waste. By doing so, we can address the shortage of corneal grafts and make vision-restoring procedures more accessible.