Biomedical Applications: Fiber or Tube Reinforced Scaffolds for Soft Tissue

Cartilage Tissue

Cartilage, composed of chondrocytes, fibers and matrix, is a slightly resilient tough tissue with the functions of support and protection in the body. As a typical cartilage tissue, articular cartilage is smooth and elastic and has the function of maximizing absorption and buffer stress. Articular cartilage often gets hurt in daily life. Injured articular cartilage will reduce the absorption of the force, resulting in joint damage and degeneration [34-36]. Due to the lack of blood supply, chondrocytes are not capable of providing adequate metabolism and proliferation, so the repair and regeneration capacity of cartilage after injury is very weak [1]. There is still a formidable task for successful long-term regeneration of cartilage tissues by using current surgical and nonsurgical treatment concepts. Although some new treatments and related products have entered clinical trials stage, and even commercialized, tissue engineering is the preferred target for most products to make up for the lack of traditional surgical treatment [37]. Scaffolds used to repair the cartilage can replace injured tissue with good time, cost efficiency and no donor site complications and lead to new tissue growth. The ideal scaffold should have stiffness and strength close to the surrounding cartilage, so as not to damage the mechanical environment of original tissues [38]. In addition, the improvement in mechanical properties can’t reduce the porosity and interconnectivity of scaffolds [39]. However, most of the scaffolds lack reasonable mechanical properties and physical structures that are detrimental to the long-term efficacy of cartilage repair [40].

There are two basic targets for artificial cartilage regeneration based on the scaffold. One is to obtain an interconnected structure with highly porous. The other is to offer the appropriate mechanical environment for cell growth and secretion of the matrix, which can lead to the regeneration of hyaline cartilage tissue. At present, popular materials for cartilage tissue engineering are mainly synthetic materials, such as PGA, PLA, PLGA, PCL, and PEG [41-43]. The stiffness of the scaffold can’t be too large nor too small, which may lead to high shear and opposing surface wear of the scaffold or high relative stress concentration in the other adjacent carti?lage. The main limitation of the engineering scaffolds is the relatively poor mechanical properties, for an implant without strong mechanical properties may be crushed inside the joint.

Multifarious synthetic scaffolds have been studied to provide adequate support for the cartilage regeneration. Among many efforts on improving or reinforcing mechanical properties of scaffolds for cartilage tissue engineering, fiber- or tube- reinforced scaffolds have made impressive results for the successful implantation. Slivka et al. [40] have prepared a porous, resorbable scaffold reinforced by fibers for the use of repairing articular cartilage. The scaffold was made of PGA fiber as the reinforcements with about 15 lm in diameter and about 2.5 mm in average length and a random copolymer of poly(D, L-lactide-co-glycolide) (PLGA 75:25) as the matrix. The method used to prepare scaffolds has been published and validated for several times [44, 45]. First, the PLGA was dissolved in the acetone solution, and the PGA was distributed into the ethanol. Both the PLGA and PGA were then mixed to form a matrix gel. Next, the matrix gel was blended for dispersing and preferring orientation of fibers. Finally, the composite was exposed under a high temperature vacuum, which could allow the gel to foam and remove residual acetone and ethanol. The mechanical properties of the composites was significantly improved by the addition of the PGA fibers. As the fiber content increased from 0 to 20%, the yield strength and the compressive modulus increased from 0.7 to 2.5 MPa and from 10 to 50 MPa, respectively. Based on the relationship between degradation and compression stiffness, PGA fiber reinforced PLGA in smaller amounts with proper porosity appeared to be an optimized articular cartilage repair scaffold. At the same time, PGA fibers with anisotropic optical properties appeared brighter in the orthogonally polarized light.

Agrawal et al. [46] also designed a new type of elastic fiber-reinforced hydrogel composites through 3D rapid prototyping technology. The fiber-reinforced gel formed a cartilage-like structure by impregnating elastic fibers, which had been arranged into crossed “log-piles”, with an epoxy-based hydrogel. Three different log-pile structures were shown in Fig. 8.1. This is a common problem in the traditional fiber-reinforced composite that the modulus and strength of the fibers are higher than that of the matrix, but a lower elongation at break, so the fiber’s fracture strain limits the maximum strain at the interface. Just like a hard glass fiber- reinforced gel has high strength and modulus but low the fracture strain. Therefore, it is not enough that a fiber-reinforced gel has a high strength, and it should have a high breaking strength. Elastic fiber-reinforced hydrogel scaffolds incorporated the mechanical properties of both elastic fibers and gels, which made them similar to the cartilage tissues. The results proved that the strength, modulus and toughness of the composites were improved, while the swell of the composite was limited. The effect of the addition of fibers on the strength was more complex, but the main effect of them was to increase the strain. The new gel composites had a much higher fracture strain, which could be compared with metal reinforced glass system. As for the elastic modulus of the composite, the fiber parallel to the stress axis in the half layer made about twice as much as the unreinforced gels. The new composite had significantly higher fracture toughness than that of natural cartilage, which made it pos-

(a) SEM image of polyurethane construct

Fig. 8.1 (a) SEM image of polyurethane construct (scale = 100 lm). (b) Cross-section image of the 200 x 200 construct (scale = 50 lm). (c) Cross-section image of reinforced composite gel; the pores correspond to the fiber and the smooth surface corresponds to the gel (scale = 50 lm). (d) Processing method sketch. (e) Fiber construct image of 1 in. x 1 in. dimensions. (f) Fiber reinforced hydrogel of 1 in. x 1 in. dimensions and about 0.25 in. thickness (Adapted with permission from Ref. [46]. Copyright 2013 Elsevier Ltd)

sible to be suitable for cartilage replacement and regeneration. Furthermore, the new type of elastic fiber-reinforced hydrogel composites with the modulus and strength in a MP range would have a potential to be applied in load bearing tissue engineering.

Visser et al. [47] combined the melt-electrospinning writing technology with 3D printing to create reinforced hydrogels with highly organized, high-porosity microfiber networks. Reinforced hydrogel scaffolds with different porosities were prepared from gelatin methacrylamide (GelMA) and PCL fibers. The high-porosity PCL fibers were fabricated by melt electrospinning in a direct writing mode, and then infused and crosslinked with GelMA [48]. By analyzing the stiffness and recovery of the composite in cyclic compression, the study found that the composite had a strong elasticity similar to native articular cartilage and was recovered after physiological axial strain. Compared with the hydrogel or microfiber scaffold alone, the stiffness of the composite was significantly increased by 54-fold, similar to the native articular cartilage. The reinforced GelMA hydrogel also had the stress-strain curve resembling that of native articular cartilage. Thus, the reinforced hydrogel was reinforced in a synergistic manner depending on the porosity of PCL fiber and the degree of crosslinking of the GelMA, and this cooperative effect can be adjusted by varying the porosity of the reinforcing scaffold. As for primary human chondrocytes encapsulated in the reinforced scaffold, they were keeping their circulation pattern and became more susceptible to physiological compressive loading in vitro

culture, which resulted in a significant change in vitro gene expression. These results provide the potential for building cell-culture platforms of tissue engineering to better simulate in vivo mechanical environment of natural cartilage. Thus, the new reinforced composite material provides an advantageous environment in the mechanical and biological aspects for cartilage repair or other tissue engineering. And the current method by using melt-electrospinning writing and 3D printing technology to fabricate microfiber reinforced hydrogels also provides the basis for the design and manufacture of new biomechanical organizational structures. In the other study, Boere and Visser et al. [49] also created a reinforced gelMA hydrogel scaffold with 3D-fabricated methacrylate groups of poly(hydroxymethylglycolide- co-e-caprolactone) (pHMGCL)/PCL as reinforcements to repair the focal articular cartilage defect. The fiber-reinforced composite composed of pMHMGCL/PCL covalently grafting to gelMA was fabricated by using a 3D fiber deposition technology. The reinforced composite constructs had a significantly improved mechanical, especially the resistance capacity to repeated axial and rotational loads. Both in vitro and in vivo, chondrocytes embedded in these fiber-reinforced scaffolds produced cartilage-specific matrix components. This means that the fiber-reinforced structure has the ability to guide matrix formation, so this study has the potential to be used to manufacture the substitute of patient-specific cartilage with improved mechanical properties.

Yodmuang et al. [50] reported a kind of silk-based fiber-reinforced hydrogel scaffolds, whose matrix and reinforcements were composed of the same material, silk from Bombyx mori, to imitate the collagen fiber and proteoglycan complex system structure of native cartilage. It was the first time that two forms of silk materials, microfiber and hydrogel, were jointly used for preparing an improved mechanical reinforced scaffold in cartilage tissue engineering. The silk hydrogels reinforced with silk microfibers provided a suited structural and mechanical microenvironment for chondrocyte attachment and growth, thus their mechanical constructs became more robust than those of silk hydrogels alone after 42 days in culture. Furthermore, the silk hydrogel with optimized diffusivity and mechanical properties had an excellent performance in supporting the cartilage matrix deposition. Through studying the role of silk microfibers as reinforcements in silk hydrogel, this work demonstrates that the composite hydrogel provides an excellent scaffold with properties close to native cartilage.

As for the other research of the reinforcing material for the cartilage regeneration, Seifzadeh and cooperators [51] studied the material parameters fiber-reinforced of biphasic poroviscoelastic (BPVE) for cartilage tissue engineering. The cartilage was modeled as a finite element (FE) model and assigned the material property of fiber-reinforced nonlinear biphasic elasticity. The constitutive parameters of articular cartilage materials were obtained from a series of stress relaxation indentation tests. A coupled finite element (FE) optimization scheme was a simulated annealing (SA) algorithm to optimize the fiber-reinforced biphasic poroviscoelastic material parameters. 15 material parameters were optimized and led to the consistency between the relaxation response and the measured stress. The study may provide not only a new fiber-reinforced composite material of scaffolds but also an effective research method for the cartilage tissue engineering.

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