bims-biprem Biomed News
on Bioprinting for regenerative medicine
Issue of 2023–06–18
nineteen papers selected by
Seerat Maqsood, University of Teramo



  1. Int J Bioprint. 2023 ;9(4): 739
      Three-dimensional (3D) bioprinting is a computer-controlled technology that combines biological factors and bioinks to print an accurate 3D structure in a layer- by-layer fashion. 3D bioprinting is a new tissue engineering technology based on rapid prototyping and additive manufacturing technology, combined with various disciplines. In addition to the problems in in vitro culture process, the bioprinting procedure is also afflicted with a few issues: (1) difficulty in looking for the appropriate bioink to match the printing parameters to reduce cell damage and mortality; and (2) difficulty in improving the printing accuracy in the printing process. Data- driven machine learning algorithms with powerful predictive capabilities have natural advantages in behavior prediction and new model exploration. Combining machine learning algorithms with 3D bioprinting helps to find more efficient bioinks, determine printing parameters, and detect defects in the printing process. This paper introduces several machine learning algorithms in detail, summarizes the role of machine learning in additive manufacturing applications, and reviews the research progress of the combination of 3D bioprinting and machine learning in recent years, especially the improvement of bioink generation, the optimization of printing parameter, and the detection of printing defect.
    Keywords:  Additive manufacturing; Bioprinting; Ensemble learning; K-nearest neighbor; Long short-term memory
    DOI:  https://doi.org/10.18063/ijb.739
  2. Biomater Adv. 2023 Jun 05. pii: S2772-9508(23)00222-4. [Epub ahead of print]152 213499
      Three-dimensional (3D) bioprinting is a promising technology for fabricating complex tissue constructs with biomimetic biological functions and stable mechanical properties. In this review, the characteristics of different bioprinting technologies and materials are compared, and development in strategies for bioprinting normal and diseased hepatic tissue are summarized. In particular, features of bioprinting and other bio-fabrication strategies, such as organoids and spheroids are compared to demonstrate the strengths and weaknesses of 3D printing technology. Directions and suggestions, such as vascularization and primary human hepatocyte culture, are provided for the future development of 3D bioprinting.
    Keywords:  3D bioprinting; Disease modeling; Liver; Organoids; Spheroids
    DOI:  https://doi.org/10.1016/j.bioadv.2023.213499
  3. Transplantation. 2023 Jun 16.
      Although liver transplantation is the gold-standard therapy for end-stage liver disease, the shortage of suitable organs results in only 25% of waitlisted patients undergoing transplants. Three-dimensional (3D) bioprinting is an emerging technology and a potential solution for personalized medicine applications. This review highlights existing 3D bioprinting technologies of liver tissues, current anatomical and physiological limitations to 3D bioprinting of a whole liver, and recent progress bringing this innovation closer to clinical use. We reviewed updated literature across multiple facets in 3D bioprinting, comparing laser, inkjet, and extrusion-based printing modalities, scaffolded versus scaffold-free systems, development of an oxygenated bioreactor, and challenges in establishing long-term viability of hepatic parenchyma and incorporating structurally and functionally robust vasculature and biliary systems. Advancements in liver organoid models have also increased their complexity and utility for liver disease modeling, pharmacologic testing, and regenerative medicine. Recent developments in 3D bioprinting techniques have improved the speed, anatomical, and physiological accuracy, and viability of 3D-bioprinted liver tissues. Optimization focusing on 3D bioprinting of the vascular system and bile duct has improved both the structural and functional accuracy of these models, which will be critical in the successful expansion of 3D-bioprinted liver tissues toward transplantable organs. With further dedicated research, patients with end-stage liver disease may soon be recipients of customized 3D-bioprinted livers, reducing or eliminating the need for immunosuppressive regimens.
    DOI:  https://doi.org/10.1097/TP.0000000000004668
  4. Biomater Adv. 2023 Jun 07. pii: S2772-9508(23)00217-0. [Epub ahead of print]152 213494
      Bioprinted tissues are currently being utilized for drug and cosmetic screening mostly, but the long-term goal is to achieve human scale functional tissues and organs for transplantation. Hence, recapitulating the multiscale architecture, 3D structures, and complexity of native tissues is the key to produce bioengineered tissues/organs. Decellularized extracellular matrix (dECM)-based biomaterials are widely being used as bioinks for 3D bioprinting for tissue engineering applications. Their potential to provide excellent biocompatibility for the cells drove researchers to use them extensively. However, the decellularization process involves many detergents and enzymes which may contribute to their loss of mechanical properties. Moreover, thermal gelation of dECM-based hydrogels is typically slow which affects the shape fidelity, printability, and physical properties while printing complex structures with 3D printing. But, thermally gelled dECM hydrogels provide excellent cell viability and functionality. To overcome this, a novel dual crosslinking of unmodified dECM has been proposed in this study to render shape fidelity and enhance cell viability and functionality. The dECM-based bioink can be initially polymerized superficially on exposure to light to achieve immediate stability and can attain further stability upon thermal gelation. This dual crosslinking mechanism can maintain the microenvironment of the structure, hence allowing the printing of stable flexible structures. Optimized concentrations of novel photo crosslinkers have been determined and printing of a few complex-shaped anatomical structures has been demonstrated. This approach of fabricating complex scaffolds employing dual crosslinking can be used for the bioprinting of different complex tissue structures with tissue-specific dECM based bioinks.
    Keywords:  3D printing; Complex structure printing; Decellularized extracellular matrix (dECM); Dual crosslinking; Shape fidelity
    DOI:  https://doi.org/10.1016/j.bioadv.2023.213494
  5. Front Bioeng Biotechnol. 2023 ;11 1169893
      Three-dimensional (3D) bioprinting is an advanced tissue engineering technique that has received a lot of interest in the past years. We aimed to highlight the characteristics of articles on 3D bioprinting, especially in terms of research hotspots and focus. Publications related to 3D bioprinting from 2007 to 2022 were acquired from the Web of Science Core Collection database. We have used VOSviewer, CiteSpace, and R-bibliometrix to perform various analyses on 3,327 published articles. The number of annual publications is increasing globally, a trend expected to continue. The United States and China were the most productive countries with the closest cooperation and the most research and development investment funds in this field. Harvard Medical School and Tsinghua University are the top-ranked institutions in the United States and China, respectively. Dr. Anthony Atala and Dr. Ali Khademhosseini, the most productive researchers in 3D bioprinting, may provide cooperation opportunities for interested researchers. Tissue Engineering Part A contributed the largest publication number, while Frontiers in Bioengineering and Biotechnology was the most attractive journal with the most potential. As for the keywords in 3D bioprinting, Bio-ink, Hydrogels (especially GelMA and Gelatin), Scaffold (especially decellularized extracellular matrix), extrusion-based bioprinting, tissue engineering, and in vitro models (organoids particularly) are research hotspots analyzed in the current study. Specifically, the research topics "new bio-ink investigation," "modification of extrusion-based bioprinting for cell viability and vascularization," "application of 3D bioprinting in organoids and in vitro model" and "research in personalized and regenerative medicine" were predicted to be hotspots for future research.
    Keywords:  3D bioprinting; bibliometrics; bio-ink; extrusion-based bioprinting; hydrogels; tissue engineering
    DOI:  https://doi.org/10.3389/fbioe.2023.1169893
  6. Front Bioeng Biotechnol. 2023 ;11 1210786
      Introduction: Growth plate injury is a significant challenge in clinical practice, as it could severely affect the limb development of children, leading to limb deformity. Tissue engineering and 3D bioprinting technology have great potential in the repair and regeneration of injured growth plate, but there are still challenges associated with achieving successful repair outcomes. Methods: In this study, GelMA hydrogel containing PLGA microspheres loaded with chondrogenic factor PTH(1-34) was combined with BMSCs and Polycaprolactone (PCL) to develop the PTH(1-34)@PLGA/BMSCs/GelMA-PCL scaffold using bio-3D printing technology. Results: The scaffold exhibited a three-dimensional interconnected porous network structure, good mechanical properties, biocompatibility, and was suitable for cellchondrogenic differentiation. And a rabbit model of growth plate injury was appliedto validate the effect of scaffold on the repair of injured growth plate. The resultsshowed that the scaffold was more effective than injectable hydrogel in promotingcartilage regeneration and reducing bone bridge formation. Moreover, the addition ofPCL to the scaffold provided good mechanical support, significantly reducing limbdeformities after growth plate injury compared with directly injected hydrogel. Discussion: Accordingly, our study demonstrates the feasibility of using 3D printed scaffolds for treating growth plate injuries and could offer a new strategy for the development of growth plate tissue engineering therapy.
    Keywords:  3D bioprinting scaffold; PTH(1–34); growth plate injury; mechanical support; tissue engineering
    DOI:  https://doi.org/10.3389/fbioe.2023.1210786
  7. Int J Bioprint. 2023 ;9(4): 723
      The use of three-dimensional (3D) bioprinting has remained at the forefront of tissue engineering and has recently been employed for generating bioprinted solid tumors to be used as cancer models to test therapeutics. In pediatrics, neural crest-derived tumors are the most common type of extracranial solid tumors. There are only a few tumor-specific therapies that directly target these tumors, and the lack of new therapies remains detrimental to improving the outcomes for these patients. The absence of more efficacious therapies for pediatric solid tumors, in general, may be due to the inability of the currently employed preclinical models to recapitulate the solid tumor phenotype. In this study, we utilized 3D bioprinting to generate neural crest-derived solid tumors. The bioprinted tumors consisted of cells from established cell lines and patient-derived xenograft tumors mixed with a 6% gelatin/1% sodium alginate bioink. The viability and morphology of the bioprints were analyzed via bioluminescence and immunohisto chemistry, respectively. We compared the bioprints to traditional twodimensional (2D) cell culture under conditions such as hypoxia and therapeutics. We successfully produced viable neural crest-derived tumors that retained the histology and immunostaining characteristics of the original parent tumors. The bioprinted tumors propagated in culture and grew in orthotopic murine models. Furthermore, compared to cells grown in traditional 2D culture, the bioprinted tumors were resistant to hypoxia and chemotherapeutics, suggesting that the bioprints exhibited a phenotype that is consistent with that seen clinically in solid tumors, thus potentially making this model superior to traditional 2D culture for preclinical investigations. Future applications of this technology entail the potential to rapidly print pediatric solid tumors for use in high-throughput drug studies, expediting the identification of novel, individualized therapies.
    Keywords:  3D bioprinting; Neuroblastoma; Neuroendocrine; Patient-derived xenografts; Pediatrics; Targeted therapy
    DOI:  https://doi.org/10.18063/ijb.723
  8. Int J Mol Sci. 2023 May 30. pii: 9464. [Epub ahead of print]24(11):
      Promising scaffolds for developing advanced tissue engineering architectures have emerged in recent years through the use of nanofibers and 3D printing technologies. Despite this, structural integrity and cell proliferation are highlighted as fundamental challenges for design scaffolds and future prospects. As a biomimetic scaffold, the nanofiber-reinforced hydrogels demonstrated a better compressive modulus and cell growth. Our review focuses on recent promising advances in the development of 3D-printed hydrogels containing polymeric nanofibers that can improve cell-material interaction in biomedical applications. Moreover, an effort has been made to induce studies with diverse types of scaffolds for various cells. Additionally, we discuss the challenges and future prospects of 3D-bioprinted reinforced hydrogels with nanofibers in the medical field, as well as high-performance bioinks.
    Keywords:  3D bioprinting; nanofibers; reinforce hydrogels; tissue engineering
    DOI:  https://doi.org/10.3390/ijms24119464
  9. Int J Bioprint. 2023 ;9(4): 724
      Articular osteochondral defects are quite common in clinical practice, and tissue engineering techniques can offer a promising therapeutic option to address this issue.The articular osteochondral unit comprises hyaline cartilage, calcified cartilage zone (CCZ), and subchondral bone.As the interface layer of articular cartilage and bone, the CCZ plays an essentialpart in stress transmission and microenvironmental regulation.Osteochondral scaffolds with the interface structure for defect repair are the future direction of tissue engineering. Three-dimensional (3D) printing has the advantages of speed, precision, and personalized customization, which can satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. This paper summarizes the anatomy, physiology, pathology, and restoration mechanisms of the articular osteochondral unit, and reviews the necessity for a boundary layer structure in osteochondral tissue engineering scaffolds and the strategy for constructing the scaffolds using 3D printing. In the future, we should not only strengthen the basic research on osteochondral structural units, but also actively explore the application of 3D printing technology in osteochondral tissue engineering. This will enable better functional and structural bionics of the scaffold, which ultimately improve the repair of osteochondral defects caused by various diseases.
    Keywords:  3D printing; Osteochondral defect; Scaffold
    DOI:  https://doi.org/10.18063/ijb.724
  10. Int J Bioprint. 2023 ;9(4): 717
      48With the growing number of biomaterials and printing technologies, bioprinting has brought about tremendous potential to fabricate biomimetic architectures or living tissue constructs. To make bioprinting and bioprinted constructs more powerful, machine learning (ML) is introduced to optimize the relevant processes, applied materials, and mechanical/biological performances. The objectives of this work were to collate, analyze, categorize, and summarize published articles and papers pertaining to ML applications in bioprinting and their impact on bioprinted constructs, as well as the directions of potential development. From the available references, both traditional ML and deep learning (DL) have been applied to optimize the printing process, structural parameters, material properties, and biological/mechanical performance of bioprinted constructs. The former uses features extracted from image or numerical data as inputs in prediction model building, and the latter uses the image directly for segmentation or classification model building. All of these studies present advanced bioprinting with a stable and reliable printing process, desirable fiber/droplet diameter, and precise layer stacking, and also enhance the bioprinted constructs with better design and cell performance. The current challenges and outlooks in developing process-material-performance models are highlighted, which may pave the way for revolutionizing bioprinting technologies and bioprinted construct design.
    Keywords:  Biomaterials; Bioprinted constructs; Bioprinting; Deep learning; Machine learning
    DOI:  https://doi.org/10.18063/ijb.717
  11. Int J Bioprint. 2023 ;9(4): 740
      The coronary artery bypass grafting is a main treatment for restoring the blood supply to the ischemic site by bypassing the narrow part, thereby improving the heart function of the patients. Autologous blood vessels are preferred in coronary artery bypass grafting, but their availability is often limited by due to the underlying disease. Thus, tissue-engineered vascular grafts that are devoid of thrombosis and have mechanical properties comparable to those of natural vessels are urgently required for clinical applications. Most of the commercially available artificial implants are made from polymers, which are prone to thrombosis and restenosis. The biomimetic artificial blood vessel containing vascular tissue cells is the most ideal implant material. Due to its precision control ability, three-dimensional (3D) bioprinting is a promising method to prepare biomimetic system. In the 3D bioprinting process, the bioink is at the core state for building the topological structure and keeping the cell viable. Therefore, in this review, the basic properties and viable materials of the bioink are discussed, and the research of natural polymers in bioink, including decellularized extracellular matrix, hyaluronic acid, and collagen, is emphasized. Besides, the advantages of alginate and Pluronic F127, which are the mainstream sacrificial material during the preparation of artificial vascular graft, are also reviewed. Finally, an overview of the applications in the field of artificial blood vessel is also presented.
    Keywords:  Artificial blood vessel; Bioink; Decellularized extracellular matrix; Three-dimensional bioprinting; Tissue-engineered vascular grafts
    DOI:  https://doi.org/10.18063/ijb.740
  12. Int J Bioprint. 2023 ;9(4): 719
      62Articular cartilage is a nonvascularized and poorly cellularized tissue with a low self-repair capacity. Therefore, damage to this tissue due to trauma or degenerative joint diseases such as osteoarthritis needs a high-end medical intervention. However, such interventions are costly, have limited healing capacity, and could impair patients' quality of life. In this regard, tissue engineering and three-dimensional (3D) bioprinting hold great potential. However, identifying suitable bioinks that are biocompatible, with the desired mechanical stiffness, and can be used under physiological conditions is still a challenge. In this study, we developed two tetrameric self-assembling ultrashort peptide bioinks that are chemically well-defined and can spontaneously form nanofibrous hydrogels under physiological conditions. The printability of the two ultrashort peptides was demonstrated; different shape constructs were printed with high shape fidelity and stability. Furthermore, the developed ultrashort peptide bioinks gave rise to constructs with different mechanical properties that could be used to guide stem cell differentiation toward specific lineages. Both ultrashort peptide bioinks demonstrated high biocompatibility and supported the chondrogenic differentiation of human mesenchymal stem cells. Additionally, the gene expression analysis of differentiated stem cells with the ultrashort peptide bioinks revealed articular cartilage extracellular matrix formation preference. Based on the different mechanical stiffness of the two ultrashort peptide bioinks, they can be used to fabricate cartilage tissue with different cartilaginous zones, including the articular and calcified cartilage zones, which are essential for engineered tissue integration.
    Keywords:  3D bioprinting; Chondrogenic differentiation; Peptide bioink; Ultrashort self-assembling peptide
    DOI:  https://doi.org/10.18063/ijb.719
  13. Methods Mol Biol. 2023 ;2683 185-192
      Available models to study neuropathological diseases include cell cultures and animal models. Brain pathologies, however, are often poorly recapitulated in animal models. 2D cell culture systems are well established and have been used since the early 1900s to grow cells on flat dishes. However, conventional 2D neural culture systems, which lack key features of the brain's 3D microenvironment, often inaccurately represent the diversity and maturation of multiple cell types and their interaction under physiological and pathological conditions.To improve CNS modeling, we have designed a 3D bioengineered neural tissue model generated from human iPSC-derived neural precursor cells (NPCs). This NPC-derived biomaterial scaffold, composed of silk fibroin with an intercalated hydrogel, matches the mechanical properties of native brain tissue and supports the long-term differentiation of neural cells in a donut-shaped sponge within an optically clear central window. This chapter describes integrating iPSC-derived NPCs in these silk-collagen scaffolds and differentiating them into neural cells over time.
    Keywords:  3D Bioengineered Model; Cell culture; Human Neural Tissue; Neural Precursor Cells
    DOI:  https://doi.org/10.1007/978-1-0716-3287-1_14
  14. Int J Bioprint. 2023 ;9(4): 737
      Three-dimensional printing (3DP) is a popular manufacturing technique with versatile potential for materials processing in tissue engineering and regenerative medicine. In particular, the repair and regeneration of significant bone defects remain as substantial clinical challenges that require biomaterial implants to maintain mechanical strength and porosity, which may be realized using 3DP. The rapid progress in 3DP development in the past decade warrants a bibliometric analysis to gain insights into its applications in bone tissue engineering (BTE). Here, we performed a comparative study using bibliometric methods for 3DP in bone repair and regeneration. A total of 2,025 articles were included, and the results showed an increase in the number of publications and relative research interest on 3DP annually worldwide. China was the leader in international cooperation in this field and also the largest contributor to the number of citations. The majority of articles in this field were published in the journal Biofabrication. Chen Y was the author who made the highest contribution to the included studies. The keywords included in the publications were mainly related to BTE and regenerative medicine (including "3DP techniques," "3DP materials," "bone regeneration strategies," and "bone disease therapeutics") for bone regeneration and repair. This bibliometric and visualized analysis provides significant insights into the historical development of 3DP in BTE from 2012 to 2022, which will be beneficial for scientists to conduct further investigations into this dynamic field.
    Keywords:  3D printing; Bibliometrics; Bone regeneration; Bone repair; Tissue engineering; Visualization research
    DOI:  https://doi.org/10.18063/ijb.737
  15. J Biomed Mater Res A. 2023 Jun 15.
      Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent a valuable tool for in vitro modeling of the cardiac niche and possess great potential in tissue engineering applications. However, conventional polystyrene-based cell culture substrates have adverse effects on cardiomyocytes in vitro due to the stress applied by a stiff substrate on contractile cells. Ultra-high viscosity alginates offer a unique versatility as tunable substrates for cardiac cell cultures due to their biocompatibility, flexible biofunctionalization, and stability. In this work, we analyzed the effect of alginate substrates on hPSC-CM maturity and functionality. Alginate substrates in high-throughput compatible culture formats fostered a more mature gene expression and enabled the simultaneous assessment of chronotropic and inotropic effects upon beta-adrenergic stimulation. Furthermore, we produced 3D-printed alginate scaffolds with differing mechanical properties and plated hPSC-CMs on the surface of these to create Heart Patches for tissue engineering applications. These exhibited synchronous macro-contractions in concert with more mature gene expression patterns and extensive intracellular alignment of sarcomeric structures. In conclusion, the combination of biofunctionalized alginates and human cardiomyocytes represents a valuable tool for both in vitro modeling and regenerative medicine, due to its beneficial effects on cardiomyocyte physiology, the possibility to analyze cardiac contractility, and its applicability as Heart Patches.
    Keywords:  3D printing; alginate; cardiomyocytes; heart patch; human pluripotent stem cells; maturation
    DOI:  https://doi.org/10.1002/jbm.a.37558
  16. Int J Bioprint. 2023 ;9(4): 725
      Drug delivery devices which can control the release of drugs on demand allow for improved treatment to a patient. These smart drug delivery devices allow for the release of drugs to be turned on and off as needed, thereby increasing the control over the drug concentration within the patient. The addition of electronics to the smart drug delivery devices increases the functionality and applications of these devices. Through the use of 3D printing and 3D-printed electronics, the customizability and functions of such devices can also be greatly increased. With the development in such technologies, the applications of the devices will be improved. In this review paper, the application of 3D-printed electronics and 3D printing in smart drug delivery devices with electronics as well as the future trends of such applications are covered.
    Keywords:  3D printing; Printed electronics; Smart drug delivery device
    DOI:  https://doi.org/10.18063/ijb.725
  17. Int J Bioprint. 2023 ;9(4): 732
      Aging is inevitable, and how to age healthily is a key concern. Additive manufacturing offers many solutions to this problem. In this paper, we first briefly introduce various 3D printing technologies commonly used in the biomedical field, particularly in aging research and aging care. Next, we closely examine aging-related health conditions of nervous system, musculoskeletal system, cardiovascular system, and digestive system with a focus on the application of 3D printing in these fields, including the creation of in vitro models and implants, production of drugs and drug delivery systems, and fabrication of rehabilitation and assistive medical devices. Finally, the opportunities, challenges, and prospects of 3D printing in the field of aging are discussed.
    Keywords:  3D-printing; Aging; Biomaterials; Disease model; Regenerative medicine, Aging care
    DOI:  https://doi.org/10.18063/ijb.732
  18. Methods Mol Biol. 2023 ;2679 233-240
      Liquid biopsies are examination procedures for deciding the grouping of malignant growth cells tracked down in samples of blood and other body fluids. Liquid biopsies are likewise significantly less intrusive than tissue biopsies as they just require small amount of blood or body fluids from the patient. With the utilization of microfluidics, cancer cells can be isolated from the fluid biopsy and achieve early diagnosis. 3D printing is turning out to be progressively well known for microfluidic devices creation. 3D printing has shown multiple advantages compared to traditional microfluidic devices production, including effortless large-scale manufacturing of precise copies, the fuse of new materials, and execution of additional complicated or drawn-out plans that are hard to execute in conventional microfluidic devices. Combining 3D printing with microfluidics makes for a relatively inexpensive analysis of liquid biopsies with a chip that can be more advantageous to use over traditional microfluidic chips. In this chapter, a method for affinity-based separation of cancer cells in a liquid biopsy using a 3D microfluidic chip will be discussed, along with the rationale behind the method.
    Keywords:  3D printing; Bioanalysis; Cancer isolation; Liquid biopsies; Microfluidics
    DOI:  https://doi.org/10.1007/978-1-0716-3271-0_16
  19. Asian J Surg. 2023 Jun 07. pii: S1015-9584(23)00729-7. [Epub ahead of print]
      
    Keywords:  3D printing; Pilon fracture; Virtual surgery
    DOI:  https://doi.org/10.1016/j.asjsur.2023.05.059