Advancements in Biodegradable Scaffolds for Tissue Engineering: A Comprehensive Review

*Kamal Sharma, ¹Bharat Singh
*Research Scholar, ITM University, Gwalior
¹Research Scholar, ITM University, Gwalior

Article Details

Title: Advancements in Biodegradable Scaffolds for Tissue Engineering: A Comprehensive Review

Authors: Kamal Sharma, Bharat Singh

Published in: PEXACY International Journal of Pharmaceutical Science

Volume/Issue: 2(11)

Pages: 57-74

Publication Date: 30/11/2023

DOI: 10.5281/zenodo.10224130

ISSN: 2584-024X

Language: English

Publisher: PEXACY International Journal of Pharmaceutical Science

PDF Download: Access Full Paper

Abstract: The field of tissue engineering has witnessed significant advancements with the development of biodegradable scaffolds, offering promising solutions for regenerative medicine. This review article provides a comprehensive overview of biodegradable scaffolds, focusing on their application in tissue engineering. It begins with an introduction to tissue engineering and the pivotal role of scaffolds, emphasizing the importance of biodegradability. The methodology section outlines the processes involved in scaffold development, including material selection, fabrication techniques, and both in vitro and in vivo testing. The advantages and disadvantages of these scaffolds are critically analyzed, highlighting their biocompatibility and functionality versus challenges like mechanical stability and degradation rate variability. Ethical and regulatory considerations are discussed, underscoring the complexities of clinical applications and market introduction. The article concludes with a discussion on the current state, challenges, and future prospects of biodegradable scaffolds, emphasizing the need for continued research and interdisciplinary collaboration to overcome existing hurdles and fully realize their potential in clinical settings.

Keywords: Tissue Engineering, Biodegradable Scaffolds, Regenerative Medicine, Scaffold Fabrication, Biocompatibility, Clinical Applications, Ethical Considerations, Regulatory Framework

Article can be accessed online on: PEXACY International Journal of Pharmaceutical Science
DOI: 10.5281/zenodo.10224130
Corresponding Author- * Kamal Sharma
Update: Received on 18/11/2023; Accepted; 21/11/2023, Published on; 30/11/2023

INTRODUCTION

Tissue engineering has emerged as a transformative field in pharmaceutical sciences, offering groundbreaking approaches to regenerative medicine and drug delivery systems. At its core, tissue engineering aims to develop biological substitutes that restore, maintain, or improve tissue function or a whole organ. [1] This field integrates principles from various disciplines, including biology, chemistry, and materials science, to innovate solutions for tissue repair and replacement.

Central to tissue engineering is the concept of scaffolds. These scaffolds provide a three-dimensional structure that facilitates cell attachment, proliferation, and differentiation, essential for tissue regeneration. [2] They act as templates guiding the formation of new tissue, ensuring that the engineered tissue develops with the appropriate structural and functional properties. The design and composition of these scaffolds are crucial, as they directly influence the success of tissue regeneration.

The importance of biodegradability in scaffolds cannot be overstated. Biodegradable scaffolds are designed to degrade at a rate matching the formation of new tissue, thereby minimizing the risk of long-term complications, such as chronic inflammation or foreign body reactions. [3] This feature is particularly important in applications where scaffold removal through surgical intervention is impractical or risky. Biodegradable materials, such as polylactic acid, collagen, and gelatin, have been extensively studied for their compatibility with human tissues and their ability to degrade into non-toxic byproducts that are easily metabolized or excreted by the body. [4]

In summary, the integration of biodegradable scaffolds in tissue engineering represents a significant advancement in pharmaceutical sciences, offering new avenues for treating a wide range of medical conditions and improving patient outcomes.

Biodegradable Scaffolds: Materials and Properties

Types of Biodegradable Materials

Biodegradable scaffolds in tissue engineering are primarily composed of materials that can break down within the body without causing harm. Common materials include natural polymers like collagen and gelatin, and synthetic polymers such as polylactic acid (PLA) and polyglycolic acid (PGA). [5] These materials are favored for their biocompatibility and their ability to degrade into non-toxic byproducts. Natural polymers, in particular, are often preferred for their similarity to the extracellular matrix in human tissues, which supports cell adhesion and growth. [6]

Comparative Analysis of Properties

The properties of scaffold materials, such as mechanical strength, degradation rate, and biocompatibility, are critical for their performance. For instance, PLA offers high strength and slow degradation, making it suitable for applications where long-term support is needed. [7] Conversely, materials like collagen degrade more quickly and are used in situations where rapid tissue regeneration is desired. [8] The choice of material thus depends on the specific requirements of the tissue engineering application, including the type of tissue being regenerated and the desired lifespan of the scaffold.

Advancements in Scaffold Fabrication Techniques

Traditional Fabrication Techniques

Traditional methods for scaffold fabrication include solvent casting, gas foaming, and fiber bonding. These techniques have been fundamental in developing early scaffolds but often lack precision in controlling scaffold architecture. [9]

Emerging Fabrication Techniques

Recent advancements have seen the emergence of more sophisticated techniques like electrospinning and 3D printing. Electrospinning can produce fibrous scaffolds with high surface area-to-volume ratios, ideal for cell attachment and proliferation. [10] 3D printing, on the other hand, allows for precise control over scaffold architecture, enabling the fabrication of complex structures that closely mimic natural tissue morphology. [11] These advanced techniques represent a significant leap forward in scaffold design, offering enhanced control over physical properties and, consequently, better tissue integration and function.

Role in Tissue Regeneration

Case Studies of Biodegradable Scaffolds in Various Tissue Regeneration Applications

Biodegradable scaffolds have been successfully employed in the regeneration of a wide range of tissues. For instance, in bone tissue engineering, scaffolds made of materials like hydroxyapatite and tricalcium phosphate have shown promising results in supporting osteogenesis. [12] In skin tissue engineering, scaffolds composed of collagen and elastin have facilitated wound healing and skin regeneration. [13] Similarly, for vascular tissue engineering, scaffolds made from materials like polyglycolic acid have been used to support the formation of new blood vessels. [14] These case studies highlight the versatility and effectiveness of biodegradable scaffolds in various tissue regeneration contexts.

Integration of Scaffolds with Cells and Growth Factors

The integration of scaffolds with cells and bioactive molecules like growth factors is a critical aspect of tissue engineering. This approach enhances the scaffold’s ability to support tissue regeneration. For example, seeding scaffolds with stem cells or specific types of progenitor cells can significantly improve tissue formation and integration. [15] Additionally, incorporating growth factors such as bone morphogenetic proteins in bone tissue scaffolds can stimulate osteogenesis and accelerate healing. [16] This synergy between scaffolds, cells, and bioactive molecules represents a key strategy in the successful application of tissue engineering technologies.

Genetic Toxicology Perspective

Analysis of Genetic Toxicology Considerations in Scaffold Design

In the context of scaffold design, genetic toxicology plays a crucial role in ensuring the safety and efficacy of tissue engineering applications. It is essential to evaluate the mutagenicity and genotoxicity of scaffold materials, as well as their degradation products. [17] This evaluation helps in identifying potential risks to genetic material, which is paramount in maintaining the integrity of the regenerated tissue and preventing adverse effects such as tumorigenesis.

Impact of Scaffold Degradation Products on Genetic Material

The degradation products of scaffolds must be assessed for their potential genetic toxicity. Biodegradable materials are generally designed to break down into harmless byproducts; however, thorough testing is necessary to confirm their safety. Studies have shown that certain degradation products can have mutagenic or genotoxic effects, which could compromise the genetic stability of the host cells. [18] Therefore, understanding and mitigating these risks is a critical aspect of scaffold design in tissue engineering.

Pharmaceutical Applications

Use of Scaffolds in Drug Delivery Systems

Biodegradable scaffolds have found significant applications in the field of drug delivery. These scaffolds can be engineered to release therapeutic agents in a controlled manner, enhancing the efficacy and reducing the side effects of drugs. [19] For instance, scaffolds loaded with antibiotics have been used to prevent infections in tissue-engineered implants. [20] Similarly, scaffolds containing chemotherapeutic agents have been explored for localized cancer treatment, minimizing systemic toxicity. [21] This approach represents a significant advancement in personalized medicine, allowing for tailored drug release profiles based on individual patient needs.

Customization of Scaffolds for Targeted Therapy

The customization of scaffolds for targeted therapy is a burgeoning area of research. By modifying scaffold properties such as porosity, degradation rate, and surface chemistry, it is possible to control the spatial and temporal release of drugs. [22] This customization enables targeted therapy, where drugs are delivered precisely to the site of action, thereby increasing their therapeutic index. For example, scaffolds designed to target inflamed tissues in arthritis have shown promise in delivering anti-inflammatory drugs directly to the affected joints. [23] This targeted approach not only improves the effectiveness of the treatment but also significantly reduces the risk of side effects associated with systemic drug administration.

Challenges and Future Perspectives

Current Challenges in the Field

Despite the significant advancements, several challenges remain in the field of biodegradable scaffolds for tissue engineering. These include issues related to scalability, reproducibility, and regulatory aspects. [24] Scalability is a major concern, as producing scaffolds in large quantities while maintaining quality and consistency is challenging. Reproducibility is another critical issue, as slight variations in fabrication conditions can lead to significant differences in scaffold properties. Additionally, the regulatory landscape for tissue-engineered products is complex and varies across different regions, posing challenges for commercialization. [25]

Future Trends and Potential Research Areas

The future of biodegradable scaffolds in tissue engineering is promising, with several areas ripe for exploration. Advances in materials science could lead to the development of novel scaffold materials with enhanced properties. The integration of smart materials capable of responding to environmental stimuli is another exciting avenue. [26] Additionally, the convergence of tissue engineering with technologies like gene editing and stem cell therapy could open new frontiers in regenerative medicine. [27] The ongoing research in these areas is expected to address current challenges and pave the way for more effective and personalized tissue engineering solutions.

Methodology for Research and Development in Biodegradable Scaffolds

Material Selection and Characterization

The initial step in the development of biodegradable scaffolds is the selection and characterization of materials. This involves identifying suitable biodegradable polymers that meet specific criteria such as biocompatibility, mechanical strength, and degradation rate. [28] Material characterization techniques such as scanning electron microscopy (SEM) for morphology, tensile testing for mechanical properties, and in vitro degradation assays are commonly employed. [29] This phase ensures that the chosen materials are appropriate for the intended tissue engineering application.

Scaffold Fabrication Techniques

Once materials are selected, the next step is scaffold fabrication. This involves choosing an appropriate technique based on the desired scaffold properties and the application. Techniques like electrospinning, 3D printing, and solvent casting are commonly used. [30] The choice of technique is crucial as it determines the scaffold’s microarchitecture, which in turn influences cell behavior and tissue formation. [31]

In Vitro Testing

In vitro testing is conducted to assess the biocompatibility and functionality of the scaffolds. This includes cell culture experiments to evaluate cell attachment, proliferation, and differentiation on the scaffold. [32] Additionally, the release profile of any incorporated drugs or growth factors can be studied in vitro to optimize the scaffold for controlled release applications. [33]

In Vivo Testing

Following successful in vitro tests, in vivo studies are essential to evaluate the performance of the scaffold in a living organism. Animal models are typically used for this purpose. [34] These studies provide valuable information on the scaffold’s biocompatibility, biodegradation rate, and the effectiveness in supporting tissue regeneration in a physiological environment.

Clinical Trials

If in vivo studies are successful, the next step is clinical trials. These trials are crucial for assessing the safety and efficacy of the scaffold in humans. [35] Clinical trials involve several phases, from initial small-scale studies to assess safety to larger trials evaluating efficacy and comparing with standard treatments.

Pros and Cons of Biodegradable Scaffolds in Tissue Engineering

Advantages of Biodegradable Scaffolds

1. Biocompatibility: Biodegradable scaffolds are typically made from materials that are biocompatible, minimizing the risk of immune rejection and inflammation. [36]
2. Degradation Aligned with Tissue Regeneration: These scaffolds are designed to degrade at a rate that matches the formation of new tissue, ensuring that the scaffold supports the tissue only as long as needed. [37]
3. Reduced Need for Surgical Removal: Unlike permanent implants, biodegradable scaffolds eliminate the need for a second surgery to remove the scaffold, reducing patient risk and healthcare costs. [38]
4. Customizability: They can be engineered to have specific properties such as mechanical strength, porosity, and degradation rate, tailored to the needs of different types of tissue regeneration. [39]
5. Drug Delivery Capability: Biodegradable scaffolds can be used as platforms for localized drug delivery, offering controlled release of therapeutics. [40]

Disadvantages of Biodegradable Scaffolds

1. Mechanical Stability Issues: Some biodegradable materials may not provide sufficient mechanical support for the duration needed, especially in load-bearing applications like bone tissue engineering. [41]
2. Inconsistency in Degradation Rates: Variability in degradation rates can occur due to differences in material properties, fabrication methods, and patient-specific factors, potentially impacting tissue regeneration. [42]
3. Risk of Acidic Byproducts: The degradation of certain polymers can lead to the release of acidic byproducts, which might cause inflammation or other adverse reactions in the surrounding tissues. [43]
4. Complexity in Fabrication: Fabricating scaffolds with precise architecture and properties can be technically challenging and expensive, particularly for more complex tissues. [44]
5. Regulatory and Standardization Challenges: The regulatory approval process for biodegradable scaffolds can be complex due to the variability in materials and applications, posing challenges in standardization and quality control. [45]

Ethical and Regulatory Considerations

The use of biodegradable scaffolds in tissue engineering raises several ethical considerations. These include concerns about the source of cells used in conjunction with scaffolds, particularly if stem cells are involved. [46] Issues related to patient consent, especially in the context of using personalized cells, and the potential for creating tissues or organs for transplantation, also need careful ethical scrutiny. [47] Furthermore, the possibility of creating tissues with enhanced functions raises questions about fairness and access in healthcare. [48]

Regulatory Landscape for Biodegradable Scaffolds

The regulatory framework for biodegradable scaffolds in tissue engineering is complex and varies across different countries. In general, these products are subject to rigorous scrutiny to ensure their safety and efficacy. [49] This includes evaluation of the scaffold material, the fabrication process, and the final product, especially if it includes cells or bioactive molecules. The regulatory process often involves multiple stages, including preclinical studies, clinical trials, and post-market surveillance. [50]

Standardization and Quality Control

Ensuring standardization and quality control is crucial in the development and manufacturing of biodegradable scaffolds. This involves establishing consistent protocols for scaffold fabrication, characterization, and performance evaluation. [51] Standardization is essential not only for regulatory approval but also for ensuring reproducibility and reliability in clinical applications. Quality control measures must be stringent, covering every aspect from raw material selection to final product testing. [52]

Commercialization and Market Potential

Market Trends in Biodegradable Scaffolds

The market for biodegradable scaffolds in tissue engineering is rapidly expanding, driven by the increasing prevalence of chronic diseases, the aging population, and technological advancements. [53] The demand for more effective and personalized healthcare solutions is fueling growth in this sector. Biodegradable scaffolds are gaining traction not only in regenerative medicine but also in drug delivery and wound healing applications. [54] The market is expected to continue growing as new materials and fabrication technologies emerge, offering improved scaffolds for a wider range of applications.

Challenges in Commercialization

Despite the promising market potential, several challenges impede the commercialization of biodegradable scaffolds. High manufacturing costs, stringent regulatory requirements, and the need for extensive clinical testing are significant barriers. [55] Additionally, ensuring consistent quality and performance of scaffolds on a commercial scale remains a challenge. Overcoming these hurdles requires coordinated efforts among researchers, manufacturers, and regulatory bodies.

Strategies for Successful Market Entry

For successful commercialization, companies must focus on developing scalable manufacturing processes and robust quality control systems. [56] Collaborations between academia and industry can accelerate the translation of research findings into marketable products. Furthermore, navigating the regulatory landscape effectively is crucial for market entry. Companies must engage with regulatory agencies early in the development process to ensure compliance with all requirements. [57]

Future Directions in Commercialization

Looking ahead, the commercialization of biodegradable scaffolds is likely to benefit from advancements in materials science, biofabrication technologies, and computational modeling. [58] The integration of smart materials that can respond to physiological stimuli and the use of AI for personalized scaffold design are promising areas for future development. [59] Additionally, exploring new business models and partnerships can provide pathways for bringing innovative scaffold technologies to the market more efficiently.

DISCUSSION

Evaluating the Progress and Potential of Biodegradable Scaffolds

The development and application of biodegradable scaffolds in tissue engineering represent a significant advancement in regenerative medicine. These scaffolds have shown immense potential in facilitating the repair and regeneration of various tissues, from bone to vascular tissues. [60] The ability of these scaffolds to degrade in a controlled manner, thereby eliminating the need for surgical removal, is a notable advantage. [38] Furthermore, their compatibility with various cell types and their potential in drug delivery applications underscore their versatility. [40]

However, the journey from laboratory research to clinical application is fraught with challenges. One of the primary concerns is the mechanical stability of these scaffolds, especially in load-bearing applications. [41] The variability in degradation rates, which can be influenced by environmental conditions and patient-specific factors, adds another layer of complexity. [42] Moreover, the potential release of acidic byproducts during degradation, which could harm surrounding tissues, cannot be overlooked. [43]

Bridging the Gap Between Research and Clinical Application

To bridge the gap between research and clinical application, a multi-faceted approach is required. This includes the development of more robust and reliable materials that can withstand physiological conditions while providing the necessary support for tissue regeneration. [61] Additionally, there is a need for more sophisticated fabrication techniques that can produce scaffolds with precise architectures suitable for complex tissue structures. [44]

The regulatory landscape also plays a crucial role in the translation of these scaffolds from the bench to the bedside. Navigating this landscape requires a thorough understanding of the regulatory requirements and a proactive approach to compliance. [49] Furthermore, the ethical implications, particularly concerning the source of cells used in conjunction with scaffolds, must be carefully considered. [46]

The Future of Biodegradable Scaffolds

Looking forward, the future of biodegradable scaffolds in tissue engineering appears promising. Advances in materials science, coupled with innovative fabrication techniques such as 3D printing and electrospinning, are likely to overcome many of the current limitations. [62] The integration of smart materials that can respond to physiological stimuli presents an exciting avenue for creating more dynamic and functional scaffolds. [59]

Moreover, the application of computational modeling and artificial intelligence in scaffold design is an emerging trend that could revolutionize the field. These technologies can help in designing scaffolds that are not only structurally and functionally optimized but also personalized to individual patient needs. [63]

In conclusion, while biodegradable scaffolds in tissue engineering have made significant strides, there is still a long road ahead. Continued research and collaboration across disciplines, coupled with a keen understanding of regulatory and ethical considerations, are essential for realizing the full potential of these innovative technologies in improving patient care.

Conclusion

The exploration of biodegradable scaffolds in tissue engineering has opened new horizons in regenerative medicine, offering innovative solutions for tissue repair and regeneration. These scaffolds, with their ability to mimic the natural extracellular matrix, support cell growth and tissue formation while gradually degrading to leave behind newly formed tissue. [60] Their biocompatibility, customizability, and potential for drug delivery applications highlight their versatility and adaptability to various medical needs. [40]

However, the path from research to clinical application is not without its challenges. Issues such as mechanical stability, variability in degradation rates, and potential inflammatory responses due to degradation byproducts are critical areas that require further research and innovation. [41],[42],[43] The complexity of scaffold fabrication and the stringent regulatory landscape add additional layers of complexity to the translation of these technologies into clinical practice. [44],[49]

Despite these challenges, the future of biodegradable scaffolds in tissue engineering looks promising. Advances in materials science, biofabrication technologies, and computational modeling are expected to address current limitations and open up new possibilities for more effective and personalized tissue engineering solutions. [62],[63] The integration of smart materials and the application of artificial intelligence in scaffold design are particularly exciting developments that could revolutionize the field.

In summary, biodegradable scaffolds represent a significant step forward in the quest to regenerate damaged tissues and organs. While there are hurdles to overcome, the ongoing research and development in this field are paving the way for groundbreaking advancements that have the potential to transform healthcare and improve the quality of life for patients worldwide.

REFRENCES

1. Langer, R., & Vacanti, J. P. (1993). Tissue engineering. Science, 260(5110), 920-926.
2. O’Brien, F. J. (2011). Biomaterials & scaffolds for tissue engineering. Materials Today, 14(3), 88-95.
3. Nair, L. S., & Laurencin, C. T. (2007). Biodegradable polymers as biomaterials. Progress in Polymer Science, 32(8-9), 762-798.
4. Place, E. S., Evans, N. D., & Stevens, M. M. (2009). Complexity in biomaterials for tissue engineering. Nature Materials, 8(6), 457-470.
5. Gunatillake, P. A., & Adhikari, R. (2003). Biodegradable synthetic polymers for tissue engineering. European Cells and Materials, 5, 1-16.
6. Lee, K. Y., & Mooney, D. J. (2001). Hydrogels for tissue engineering. Chemical Reviews, 101(7), 1869-1879.
7. Middleton, J. C., & Tipton, A. J. (2000). Synthetic biodegradable polymers as orthopedic devices. Biomaterials, 21(23), 2335-2346.
8. Friess, W. (1998). Collagen—biomaterial for drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 45(2), 113-136.
9. Sachlos, E., & Czernuszka, J. T. (2003). Making tissue engineering scaffolds work. Review on the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. European Cells and Materials, 5, 29-40.
10. Pham, Q. P., Sharma, U., & Mikos, A. G. (2006). Electrospinning of polymeric nanofibers for tissue engineering applications: A review. Tissue Engineering, 12(5), 1197-1211.
11. Melchels, F. P., Domingos, M. A., Klein, T. J., Malda, J., Bartolo, P. J., & Hutmacher, D. W. (2012). Additive manufacturing of tissues and organs. Progress in Polymer Science, 37(8), 1079-1104.
12. Rezwan, K., Chen, Q. Z., Blaker, J. J., & Boccaccini, A. R. (2006). Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials, 27(18), 3413-3431.
13. Shevchenko, R. V., James, S. L., & James, S. E. (2010). A review of tissue-engineered skin bioconstructs available for skin reconstruction. Journal of the Royal Society Interface, 7(43), 229-258.
14. Niklason, L. E., Gao, J., Abbott, W. M., Hirschi, K. K., Houser, S., Marini, R., & Langer, R. (1999). Functional arteries grown in vitro. Science, 284(5413), 489-493.
15. Lutolf, M. P., & Hubbell, J. A. (2005). Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nature Biotechnology, 23(1), 47-55.
16. Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., Hewick, R. M., & Wang, E. A. (1988). Novel regulators of bone formation: molecular clones and activities. Science, 242(4885), 1528-1534.
17. Singh, A. V., Ansari, M. H. D., Rosenkranz, D., Maharjan, R. S., Kriegel, F. L., Gandhi, K., Kanase, A., Singh, R., Laux, P., & Luch, A. (2020). Artificial intelligence and machine learning in computational nanotoxicology: Unlocking and empowering nanomedicine. Advanced Healthcare Materials, 9(17), 1901862.
18. Williams, D. F. (2008). On the mechanisms of biocompatibility. Biomaterials, 29(20), 2941-2953.
19. Hollister, S. J. (2005). Porous scaffold design for tissue engineering. Nature Materials, 4(7), 518-524.
20. Antoci, V., Jr., King, S. B., Jose, B., Parvizi, J., Zeiger, A. R., Wickstrom, E., & Freeman, T. A. (2007). Vancomycin-modified implant surface inhibits biofilm formation and supports bone-healing in an infected osteotomy model in sheep: A proof-of-concept study. Journal of Bone and Joint Surgery – American Volume, 89(8), 1746-1755.
21. Sahoo, S., Ang, L. T., Goh, J. C., & Toh, S. L. (2010). Bioactive nanofibers for fibroblastic differentiation of mesenchymal stem cells for ligament tissue engineering. Acta Biomaterialia, 6(2), 502-510.
22. Place, E. S., George, J. H., Williams, C. K., & Stevens, M. M. (2009). Synthetic polymer scaffolds for tissue engineering. Chemical Society Reviews, 38(4), 1139-1151.
23. Kim, K., Fisher, J. P., & Mikos, A. G. (2007). Enzymatically degradable poly(ethylene glycol) hydrogels for the release of therapeutic peptides. Biomacromolecules, 8(10), 3146-3150.
24. Hutmacher, D. W. (2000). Scaffolds in tissue engineering bone and cartilage. Biomaterials, 21(24), 2529-2543.
25. Hollister, S. J., Flanagan, C. L., Zopf, D. A., Morrison, R. J., Nasser, H., Patel, J. J., Ebramzadeh, E., Sangiorgio, S. N., Wheeler, M. B., & Green, G. E. (2015). Design control for clinical translation of 3D printed modular scaffolds. Annals of Biomedical Engineering, 43(3), 774-786.
26. Tibbitt, M. W., & Anseth, K. S. (2009). Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnology and Bioengineering, 103(4), 655-663.
27. Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773-785.
28. Ratner, B. D., Hoffman, A. S., Schoen, F. J., & Lemons, J. E. (Eds.). (2004). Biomaterials Science: An Introduction to Materials in Medicine. Elsevier Academic Press.
29. Ho, M. H., Kuo, P. Y., Hsieh, H. J., Hsien, T. Y., Hou, L. T., Lai, J. Y., & Wang, D. M. (2004). Preparation of porous scaffolds by using freeze-extraction and freeze-gelation methods. Biomaterials, 25(1), 129-138.
30. Zein, I., Hutmacher, D. W., Tan, K. C., & Teoh, S. H. (2002). Fused deposition modeling of novel scaffold architectures for tissue engineering applications. Biomaterials, 23(4), 1169-1185.
31. Sachlos, E., & Czernuszka, J. T. (2003). Making tissue engineering scaffolds work. Review on the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. European Cells and Materials, 5, 29-40.
32. Hollister, S. J. (2005). Porous scaffold design for tissue engineering. Nature Materials, 4(7), 518-524.
33. Richardson, T. P., Peters, M. C., Ennett, A. B., & Mooney, D. J. (2001). Polymeric system for dual growth factor delivery. Nature Biotechnology, 19(11), 1029-1034.
34. Hutmacher, D. W. (2000). Scaffolds in tissue engineering bone and cartilage. Biomaterials, 21(24), 2529-2543.
35. Griffith, L. G., & Naughton, G. (2002). Tissue engineering–current challenges and expanding opportunities. Science, 295(5557), 1009-1014.
36. Williams, D. F. (2008). On the mechanisms of biocompatibility. Biomaterials, 29(20), 2941-2953.
37. Nair, L. S., & Laurencin, C. T. (2007). Biodegradable polymers as biomaterials. Progress in Polymer Science, 32(8-9), 762-798.
38. Agrawal, C. M., & Ray, R. B. (2001). Biodegradable polymeric scaffolds for musculoskeletal tissue engineering. Journal of Biomedical Materials Research, 55(2), 141-150.
39. Hollister, S. J. (2005). Porous scaffold design for tissue engineering. Nature Materials, 4(7), 518-524.
40. Sahoo, S., Ang, L. T., Goh, J. C., & Toh, S. L. (2010). Bioactive nanofibers for fibroblastic differentiation of mesenchymal stem cells for ligament tissue engineering. Acta Biomaterialia, 6(2), 502-510.
41. Rezwan, K., Chen, Q. Z., Blaker, J. J., & Boccaccini, A. R. (2006). Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials, 27(18), 3413-3431.
42. Gunatillake, P. A., & Adhikari, R. (2003). Biodegradable synthetic polymers for tissue engineering. European Cells and Materials, 5, 1-16.
43. Middleton, J. C., & Tipton, A. J. (2000). Synthetic biodegradable polymers as orthopedic devices. Biomaterials, 21(23), 2335-2346.
44. Sachlos, E., & Czernuszka, J. T. (2003). Making tissue engineering scaffolds work. Review on the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. European Cells and Materials, 5, 29-40.
45. Hutmacher, D. W. (2000). Scaffolds in tissue engineering bone and cartilage. Biomaterials, 21(24), 2529-2543.
46. Daley, G. Q., Hyun, I., Apperley, J. F., Barker, R. A., Benvenisty, N., Bredenoord, A. L., Breuer, C. K., Caulfield, T., Cedars, M. I., Frey-Vasconcells, J., Heslop, H. E., Jin, Y., Lee, R. T., McCabe, C., Munsie, M., Murry, C. E., Piantadosi, S., Rao, M., Rooke, H. M., Sipp, D., Studer, L., Sugarman, J., Takahashi, M., Zimmerman, M., & Kimmelman, J. (2016). Setting global standards for stem cell research and clinical translation: The 2016 ISSCR guidelines. Stem Cell Reports, 6(6), 787-797.
47. Skerrett, P. J. (2015). New guidelines for stem cell research. Harvard Health Blog. Retrieved from https://www.health.harvard.edu/blog/new-guidelines-for-stem-cell-research-201504157971
48. Brey, P. (2009). Ethical aspects of tissue engineering: A review. Tissue Engineering Part B: Reviews, 15(3), 241-248.
49. Hollister, S. J., Flanagan, C. L., Zopf, D. A., Morrison, R. J., Nasser, H., Patel, J. J., Ebramzadeh, E., Sangiorgio, S. N., Wheeler, M. B., & Green, G. E. (2015). Design control for clinical translation of 3D printed modular scaffolds. Annals of Biomedical Engineering, 43(3), 774-786.
50. U.S. Food and Drug Administration. (2020). Tissue Engineering and Regenerative Medicine. Retrieved from https://www.fda.gov/vaccines-blood-biologics/tissue-engineering-regenerative-medicine
51. Hutmacher, D. W., Schantz, J. T., Lam, C. X., Tan, K. C., & Lim, T. C. (2007). State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. Journal of Tissue Engineering and Regenerative Medicine, 1(4), 245-260.
52. Sachlos, E., & Czernuszka, J. T. (2003). Making tissue engineering scaffolds work. Review on the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. European Cells and Materials, 5, 29-40.
53. Grand View Research. (2020). Tissue Engineering Market Size, Share & Trends Analysis Report. Retrieved from https://www.grandviewresearch.com/industry-analysis/tissue-engineering-and-regeneration-market
54. MarketsandMarkets. (2019). Tissue Engineering Market – Global Forecast to 2024. Retrieved from https://www.marketsandmarkets.com/Market-Reports/tissue-engineering-regeneration-market-106748780.html
55. O’Brien, F. J. (2011). Biomaterials & scaffolds for tissue engineering. Materials Today, 14(3), 88-95.
56. Hollister, S. J., Flanagan, C. L., Zopf, D. A., Morrison, R. J., Nasser, H., Patel, J. J., Ebramzadeh, E., Sangiorgio, S. N., Wheeler, M. B., & Green, G. E. (2015). Design control for clinical translation of 3D printed modular scaffolds. Annals of Biomedical Engineering, 43(3), 774-786.
57. U.S. Food and Drug Administration. (2020). Tissue Engineering and Regenerative Medicine. Retrieved from https://www.fda.gov/vaccines-blood-biologics/tissue-engineering-regenerative-medicine
58. Murphy, S. V., & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773-785.
59. Tibbitt, M. W., & Anseth, K. S. (2009). Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnology and Bioengineering, 103(4), 655-663.
60. Langer, R., & Vacanti, J. P. (1993). Tissue engineering. Science, 260(5110), 920-926.
61. Mikos, A. G., & Temenoff, J. S. (2000). Formation of highly porous biodegradable scaffolds for tissue engineering. Electronic Journal of Biotechnology, 3(2), 23-24.
62. Zein, I., Hutmacher, D. W., Tan, K. C., & Teoh, S. H. (2002). Fused deposition modeling of novel scaffold architectures for tissue engineering applications. Biomaterials, 23(4), 1169-1185.
63. Sun, W., Starly, B., Nam, J., & Darling, A. (2005). Bio-CAD modeling and its applications in computer-aided tissue engineering. Computer-Aided Design, 37(11), 1097-1114.