|Year : 2021 | Volume
| Issue : 5 | Page : 38-43
A review of current developments in three-dimensional scaffolds for medical applications
Ufkay Karabay1, Resit Bugra Husemoglu2, Mehtap Yuksel Egrilmez1, Hasan Havitcioglu2
1 Department of Molecular Medicine, Health Science Institute, Dokuz Eylul University, Izmir, Turkey
2 Department of Biomechanics, Institute of Health Sciences, Dokuz Eylül University, Izmir, Turkey
|Date of Submission||18-Jun-2020|
|Date of Decision||12-Jul-2020|
|Date of Acceptance||23-Aug-2020|
|Date of Web Publication||17-Mar-2021|
Mr. Ufkay Karabay
Department of Molecular Medicine, Health Science Institute, Dokuz Eylul University, Izmir
Source of Support: None, Conflict of Interest: None
Humans require treatment due to the loss of tissues after trauma and diseases. Tissue engineering is a growing field of engineering and medical science to restore, maintain, or improve function of damaged or diseased tissues. The use of three-dimension (3D) scaffolds in particular offers a potential option for patients with tissue deficiency. Polylactic acid (PLA), poly-caprolactone (PCL), polyether-ether-ketone (PEEK), and thermoplastic polyurethane (TPU) are biomaterials that are commonly used in tissue engineering. Their applications of pure material or composite and supportive materials are of great importance for clinical practices. This review provides information on biomaterials and major areas of application and discusses their advantages and disadvantages against each other. The literature search from the database PubMed was done for the key words 3D PLA, PCL, PEEK, and TPU separately and 2029 articles were identified. These articles were limited according to clinical, in vivo and observational studies published in English and 140 articles were evaluated for this review. We selected the main articles according to the current data of 3D scaffolds and identical articles were removed. Fifty articles were included in the review. Many studies have reported the advantages of 3D scaffolds with composite or supplement materials over pure materials in the medical treatment. The advances in the development of new 3D scaffolds hold great promise for the prospective applications in the medical treatment.
Keywords: Clinical, three-dimension scaffolds, tissue engineering
|How to cite this article:|
Karabay U, Husemoglu RB, Egrilmez MY, Havitcioglu H. A review of current developments in three-dimensional scaffolds for medical applications. Turk J Plast Surg 2021;29, Suppl S1:38-43
|How to cite this URL:|
Karabay U, Husemoglu RB, Egrilmez MY, Havitcioglu H. A review of current developments in three-dimensional scaffolds for medical applications. Turk J Plast Surg [serial online] 2021 [cited 2022 Jun 29];29, Suppl S1:38-43. Available from: http://www.turkjplastsurg.org/text.asp?2021/29/5/38/311435
| Introduction|| |
Tissue engineering has been in the extensive process to serve the needs of medical treatment of humans. Additive manufacturing (AM), also known as three-dimension (3D) printing, has been the focus of attention in recent years. AM includes several techniques such as stereolithography, fused deposition modeling (FDM), and selective laser sintering. FDM (also known as fused filament production) is mostly used to process the thermoplastic polymers. With 3D printing technology, tissue scaffolds can be produced rapidly by programming its pore size and shape. Particularly, the development of 3D tissue scaffolds and the use of different biomaterials have found applications in the medical treatment of the tissue that has been damaged through trauma or disease. A few examples of these scaffolds include implant devices and prosthetics.,
Biomaterials such as polylactic acid (PLA), poly-caprolactone (PCL), polyether-ether-ketone (PEEK), and thermoplastic polyurethane (TPU) are used to produce 3D tissue scaffolds. The literature search from the database PubMed was done for the key words 3D PLA, PCL, PEEK, and TPU separately and 2029 articles were identified. These articles were limited according to clinical, in vivo, and observational studies published in English and 140 articles were evaluated for this review. We selected the main articles according to the current data of 3D scaffolds and identical articles were removed. Fifty articles were included in this review [Figure 1].
|Figure 1: PubMed search for three-dimension Polylactic acid, poly-caprolactone, polyether-ether-ketone, thermoplastic polyurethane separately|
Click here to view
| Biomaterials for Tissue Engineering|| |
PLA was first discovered in the 1700s by the Swedish chemist, Scheele. The first use of PLA in medical applications was the treatment of mandibular fractures in dogs. PLA has high mechanical strength and a low thermal expansion coefficient. Its renewable, biodegradable, biocompatible, nonimmunogenic, and noninflammatory properties make it an ideal biomaterial for the medical applications. PCL is used in the drug delivery system applications with its high permeability to many drugs and slowly biodegradable and high biocompatibility properties. One study reported that 3D PCL was a candidate for the use in the intrauterine system drug delivery. PEEK is biocompatible, radiolucent, and durable. It has an elastic modulus close to that of natural bone and enables radiological examinations. However, due to its hydrophobic property, it might cause problems in bone apposition. It also has high costs and is not compatible with traditional manufacturing methods. However, it was stated that suitable results could be produced by adjusting the printing speed of the PEEK material. TPU is a versatile polymer class with their chemical properties controllability and high durability. Designing with a hydrophilic polymer such as poly (ethylene glycol) could increase its hydrogel properties.
In general, the biocompatible, nontoxic, biodegradable, and hydrophilic properties of PLA make it an ideal biomaterial for many bioengineering applications. It can also be used alone in the hard tissue bioengineering due to its rigid properties. However, PLA does not appear to be suitable in the heart-valve systems due to its low elasticity and flexibility. On the other hand, PCL is a more elastic material than PLA and has poor cell adhesion properties due to its hydrophobic properties. However, it exhibits low degradation rate (approximately 2 years). PEEK is a hydrophobic rigid material with high tensile strength. It is especially used in bone tissue engineering. Finally, TPU, which is an extremely elastic and hydrophobic material, is a material that can be used for soft-tissue mimicking. All four materials above are approved by the Food and Drug Administration (FDA). The properties, advantages, and disadvantages of four biomaterials are shown in [Table 1].
|Table 1: The properties, advantages and disadvantages of polylactic acid, poly-caprolactone, polyether-ether-ketone, and thermoplastic polyurethane biomaterials|
Click here to view
| Coating of Three-Dimension Scaffolds with Supplements|| |
3D scaffolds can be used in the biomedical applications by coating with various materials. 3D PLA scaffolds nanocomposites acquire antibacterial properties when they were filled with micro-filling metal/metal alloy materials such as copper, bronze, and silver. It was reported that 3D PLA scaffolds coated with lignin had an enhancing effect on wound healing. The osteogenesis and osteoconductive properties of 3D PLA scaffolds were enhanced with hydroxyapatite (HA) and 3D PLA/HA composite scaffolds were suggested to have great potential for repairing and regeneration of large bone defects. Natural extracellular matrix (ECM) from porcine septal cartilage was produced to develop decellularized ECM (DECM) and 3D PCL scaffolds were coated with this DECM. Then, human primary nasoceptal chondrocytes were seeded in 3D PCL/DECM scaffolds. The cartilage regenerative capacity of PCL was found to be enhanced by DECM and PCL/DECM composite scaffolds were suggested to be a new composite material. The high hydrophobicity of PCL makes it difficult for cells to attach to its surface. Therefore, gelatin methacryloyl, a hydrogel which mimicks natural ECM, was used to increase surface adhesion by covering PCL. PEEK coated with TiO2 was shown to be used in the dental applications and PEEK decorated with Ag Nanoparticles was used in bone treatments. Its bioactivity was increased by coating with these supplements. TPU loaded with levofloxacin was found to be more anti-infective than the currently used poly (propylene) vaginal meshes and was recommended for the use in vaginal surgery.
Plastic surgery and three-dimension scaffolds
3D scaffolds are gaining extended applications in the plastic surgery. The greatest use of these scaffolds has been reported in craniomaxillofacial surgery in the literature, such as maxillofacial surgery, nasal tip plasty, and cranioplasty. Patient-specific 3D PCL scaffolds were implanted for maxillofacial bone reconstruction into patients with complex maxillary defects after surgical removal of cancer and the patients were followed up to 2 years. 3D PCL scaffolds were shown to promote the regeneration of deficient tissue while remaining stable in the body for the follow-up period. Rhinoplasty is one of the most common surgical procedures in the plastic surgery. 3D PCL scaffolds were used in patients who underwent nasal tip plasty and the patients were followed up 2–4 year postoperatively. It was shown that the technique using 3D PCL scaffolds increased the length and volume of the nasal tip without affecting the blood circulation of skin. It also enabled the creation of a nasal tip of the desired shape, in a safe and simple manner. Autologous bone grafting remains an option of choice in cranioplasty techniques. However, the graft is often not available due to infection, radiation, or traumatic damage. Although implants made of materials such as titanium, acrylics, ceramics, and plastics are currently used in cranioplasty, they share the disadvantages of infection and fracture. 3D PEEK scaffolds were used in patients who underwent cranioplasty procedures and the patients were followed for a minimum of 24-month postoperative. The procedure utilizing 3D PEEK scaffolds showed anatomical accuracy, simplification of complex 3D defects, mirror image esthetics, and intra-operative time savings. Customized maxillary and mandibular models were produced with silicone rubber-coated 3D scaffolds (acrylonitrile butadiene styrene and PLA). Low cost and simple 3D production of these two biomaterials with FDM seemed to be a promising method for training the students in selected surgical procedures compared to the materials produced for the high cost and high-risk procedures available on the market. Custom-made 3D scaffolds made of different biocompatible materials offer several advantages for plastic surgery procedures and surgical simulation for students.
| Bone Tissue and Three-Dimension Scaffolds|| |
Bone tissue is a specialized connective tissue composed of intercellular calcified material, the bone matrix, and cells. Since it is constantly being remodeled throughout life, it is a great candidate for tissue engineering applications because of high regenerative capacities. Dewey et al. 3D PLA scaffolds were shown to improve the repair of craniomaxillofacial defects. 3D PLA scaffolds containing human gingiva mesenchymal stem cells (SCs)/extracellular vesicles were implanted into the rats with calvaria bone damage. The in vitro results showed the increased expression of osteogenic and angiogenic markers such as Runt-related transcription factor-2, vascular endothelial growth factor, osteopontin, and type I collagen (COL1). In another study, 3D PLA scaffolds were coated with polydopamine (PDA) and COL1 and bone marrow SCs were seeded. The osteoinductivity of 3D PLA scaffolds was increased by PDA and COL1 coatings and provided the best conditions for early-stage cell response. 3D PCL/β-tricalcium phosphate tissue scaffolds were shown to have potential use in oromandibular reconstruction in beagle dogs. Patient-specific 3D PEEK rib prosthesis was used to reconstruct the chest wall after tumor excision. 3D PEEK rib prosthesis was strongly fastened to the remaining rib and offered better stability and safety. Although titanium prostheses are the most common implants for chest wall reconstruction, 3D PEEK can be a preferred material for a rib prosthesis. Another study showed that the viability of bone marrow and adipose-derived SCs were maintained 3D PEEK scaffolds. The osteodifferentiation of the adipose-derived SCs was also induced, suggesting adipose-derived SCs as an ideal candidate for bone tissue engineering using PEEK scaffolding. Thus, PEEK might be a suitable candidate for orthopedic, maxillofacial, and cranial surgeries.
| Cartilage Engineering and Three-Dimension Scaffolds|| |
Cartilage defects in head-and-neck regions and orthopedic sites are frequently caused by trauma, cancer removal, or congenital diseases. The traditional surgical procedure for cartilage repair includes autologous grafts. However, this method has limitations such as the lack of donor tissue and donor-site morbidity and may not provide optimal size and function. Total auricular reconstruction is a surgeon dependent, multistage procedure which requires rib cartilages. Tissue engineering of chondrocytes with a 3D PCL-based auricle scaffold seemed to be a promising alternative for the clinical practice. Patient-specific PCL scaffolds with chondrocytes were also used for auricular and nose reconstruction. 3D PCL scaffolds coated with SCs and fibrin were evaluated in the tracheal defect model in the rabbits and were found to be reconstructed the shape and function of the trachea 8 weeks after the operation. Articular cartilage is a very flexible organized tissue that has a low regenerative capacity. Since blood vessels do not supply cartilage tissue, injuries to cartilage heal very slowly and may require orthopedic surgery due to the related problems. Recent developments in the tissue engineering seem to provide the challenges for the treatment of these problems. Especially, 3D tissue scaffolds and alginate (Alg) are commonly used materials in this field. Alg is a natural polymer isolated from brown algae which mimicks ECM properties. Human bone marrow SCs were seeded into Alg-coated 3D PCL scaffolds and showed high viability and proliferation capacity. The gene expression of type II collagen and aggrecan, two molecules showing chondrogenic potential, also increased in the cells seeded in Alg-coated 3D PCL scaffolds.
| Cardiovascular Applications and Biodegradable Stents|| |
The limitations of permanent stents in the cardiovascular applications were eliminated with the production of biodegradable stents (BRSs). BRSs can provide long enough support to heal arteries. Various biomaterials were studied such as PCL, PLLA, poly-L-lysine and fibronectin, poly-1,8-octanediol-co-citric acid, poly-lactic-co-glycolic-acid (PLGA) to develop an ideal BRS. 3T3 murine fibroblast cell proliferation was found to be higher in 3D PCL stents than 3D PLA stents. 3D PCL stents degrade more slowly and 3D PLA stents support the artery vessel. Thus, 3D PCL/PLA composite stents were found to improve each material's separate limitations and are a highly promising solution to the current problems of BRSs.
| Inflammation and Three-Dimension Scaffolds|| |
The success of a biomaterial in the target tissue is associated with the inflammatory process in which many cell types play roles. This inflammatory process can occur as both tissue rejection and effective tissue regeneration and repair after implantation. Macrophages are descent infiltrate cells that secrete many mediators that affect tissue remodeling, inflammatory response, and blood vessel formation after biomaterial implantation. Macrophages exhibit both pro-inflammatory and anti-inflammatory phenotypes by polarization. PLA and chitosan (Ch) are polymers with different chemical, physical, and biological properties that might affect the inflammatory response. The metabolic activities of differentiated macrophages seeded on 3D PLA, PLA/calcium phosphate glass (G5) and Ch scaffolds were found to be higher than the control group. They also exhibited different cell shapes. 3D Ch scaffolds induced the highest production of TNF-α, whereas 3D PLA and PLA/G5 scaffolds induced higher production of interleukin-6, 10, 12/23. These results show the importance of material properties and scaffold features to build the right 3D platforms to modulate the macrophage responses.
| Fibroblasts and Three-Dimension Scaffolds|| |
Dermal fibroblasts are mesenchymal cells, which play a role in the production and regulation of ECM in the skin. They are the main actors of wound healing. Our group examined the proliferation and adhesion levels of dermal fibroblasts seeded on 3D PLA scaffolds with two different pore sizes (35% and 40%). Dermal fibroblasts attached to the scaffolds, proliferated, and fulfilled the inter-fiber gaps. Our results showed that cell density as well as pore size are important for the proliferation and adhesion of the fibroblasts. Scaffolds act as templates for the reconstruction of damaged area by promoting cell adhesion, proliferation, and ECM production. It contributes to angiogenesis, osteogenesis, and wound healing. The scaffold design is made by considering the mechanical properties such as stiffness, elasticity, physicochemical properties such as porosity, biodegradation, surface chemistry, and biological properties such as cell attachment, biocompatibility, and nontoxicity. To increase the bioactivity of the scaffolds, their size (pore and diameter), strength, shape, and degradation rate should be controlled. It is important that the pore sizes are adjusted according to specific sizes such as with 200–400 μm for bone tissue formation, 50–200 μm for smooth muscle cell growth, between 10–44 and 44–75 μm for fibrous tissue. Dermal fibroblasts were seeded on PLA–poly (ethylene oxide)–PLA type co-polymer scaffolds to make a dermal equivalent and were found to produce ECM. Then, keratinocytes were seeded on that dermal equivalent and generated an epidermal barrier. This study showed that both human fibroblasts and keratinocytes can proliferate on co-polymer scaffolds and these biodegradable, synthetic, porous scaffold might a candidate material for skin reconstruction purposes.
| Discussion|| |
Humans require treatment due to the loss of tissues after trauma and diseases. Tissue engineering is a progressive field of engineering and medical science to repair the damaged or diseased tissues. The use of 3D scaffolds alone or as a composite or with supportive materials offers a potential option for patients with tissue deficiency. Great progress has been made in the production of 3D scaffolds in tissue engineering over the last decades. An ideal biomaterial in tissue engineering should be biodegradable, and the rate of degradation of the scaffold should be close to the healing rate of the target tissue.
Biomaterials preferred in the tissue engineering applications may not exhibit perfection when used alone. For instance, PLA is more brittle and fast-degradable compared to PCL. However, PLA has a lower elasticity and flexibility. In addition, due to its low surface energy, PCL can reduce the adhesion of cells to the surface. Thus, blending these two biomaterials can lead to the production of a new biomaterial with more effective properties. The addition of bioactive nanoparticles, such as HA, to these blended composites, might produce more biocompatible biomaterials. 3D PLLA/PCL composite scaffolds with HA nanoparticles increased the proliferation rate and differentiation of bone cells and this led to the new bone development in a short time. However, the stiffness and slow degradation rate of PCL could be a disadvantage for the medical applications. Having the highest thermal stability and lowest melting point among aliphatic polyesters, PCL is ideal for melt extrusion-based printing. Thermoplastics such as PLA, PCL, and PLGA are the most common materials used in bone tissue engineering. PLA and PCL were approved by the FDA as human biomedical materials due to their excellent biosafety, good biocompatibility, and low toxicity.
On the other hand, 3D scaffolds coated with a supportive material might have better effects in the medical treatment compared to their pure state. Meniscus injuries are one of the most common orthopedic cases and can affect people of all ages. It was reported that 3D PCL coated with sodium hydroxide could be used in meniscus constructions by increasing the hydrophilicity. In addition, the use of 3D scaffolds in the drug delivery systems creates customized treatment opportunities. TPUs could be used with high drug loads (up to 60%, w/w) for personalized drug dosages. TPU polymer has extended drug release time compared to 3D printed tablets. It is possible to adjust the matrix composition and the porosity of the tablet and to use it for personalized drug treatment.
| Conclusion|| |
3D bioprinting technology has been rapidly growing over the last decade. The production of fully biomimetic and customized 3D scaffolds is the major focus of several studies. Current advances hold promise for the future studies. 3D printed transplants will continue to develop toward translational applications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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