Page 305 - IJB-9-5

International Journal of Bioprinting Scaffold for engineering enthesis organ

skeletal system, in which bones articulate with each other Xie et al. [10] followed a similar approach to provide a
forming joints whose stability and function are supported volumetric 3D distribution of the graded tissue. After
by ligaments. Both tendons and ligaments (T/Ls) connect electrospun-aligned PCL nanofibers on a gap collector,
to bones through the osteotendinous junction, also called mats were relocated to a planar collector, and random
enthesis. This interface area is crucial for the structural PCL fibers were electrospun on top, obtaining a bilayer
integrity and functionality of the entire musculoskeletal construct. A different fabrication approach was used by
apparatus. The enthesis is a specialized region that facilitates Xiong et al. , fabricating a PCL-made gradient scaffold by
[11]
load transmission between dissimilar tissues with a large melt electrowriting (MEW) technology. It is composed of
mismatch in constitutive behavior, such as bone and T/Ls. a grid structure with decreasing porosity along the length
Depending on the anatomical location, entheses appear of the scaffold that mimics the morphological gradient that
either as fibrous or fibrocartilaginous, showing different occurs moving from the bone to the UFC and MFC regions.
structural and mechanical properties . In fibrous The scaffold ends with PCL-aligned fibers that mimic
[1]
insertions, T/Ls attach directly to bones with a 45 degrees the anisotropic orientation of collagen fibers. However,
angle of incidence [2,3] . Fibrocartilaginous entheses are these fabrication approaches are limited to processing
more complex and more relevant from the clinical point only one material with one technology. To fabricate more
of view. They comprise four adjacent tissues that create bioinspired enthesis-like scaffolds, a multitechnological
gradients in topology, mechanical, physiological behavior, and multimaterial approach is crucial. In this context,
and cellular type: (i) T/Ls, (ii) unmineralized fibrocartilage Criscenti et al. fabricated a multiscale and multimaterial
[12]
(UFC), (iii) mineralized fibrocartilage (MFC), and triphasic scaffold by exploiting the combination of
(iv) bone. The T/Ls structure is characterized by aligned fused deposition modeling (FDM) and electrospinning
collagen type I fibrils arranged to form fibers, fascicles, technologies. The scaffold consists of PCL processed by
and fibroblasts that synthesize the fibrous collagen-based FDM and poly(lactic-co-glycolic acid) (PLGA) processed
matrix. Moving into the UFC region, the alignment of the by electrospinning to replicate the characteristics of bone
fibers decreases until reaching the MFC region, mainly and T/Ls, respectively. The overlap of the two materials
composed of randomly oriented collagen fibrils (types I, II, mimics the gradient of the enthesis.
and III). Fibroblasts are replaced by fibrochondrocytes that Given the complex 3D structure of T/L and the necessity
synthesize the extracellular matrix of fibrocartilage, giving to scale these scaffolds up to clinically relevant, researchers
the enthesis the ability to withstand compressive loads . have investigated the fabrication of twisted, braided, or
[4]
The physiological line that separates UFC from MFC is knitted scaffolds . Barber et al. observed enhanced
[14]
[13]
named tidemark. The last zone is bone, where the structure mechanical properties as the braided bundles increased.
becomes highly hierarchical and populated by osteocytes . They fabricated a nanofibrous braided scaffold composed
[5]
Due to this complexity constrained in its micrometer of poly(L-lactic acid) (PLLA) electrospun mats. Sahoo
size , researchers consider this interface an organ . In et al. developed a biodegradable scaffold fabricated by
[7]
[6]
[15]
modern society, musculoskeletal diseases are the leading electrospinning PLGA nanofibers onto a knitted PLGA
cause of disability worldwide, and T/L injuries are the construct. Exploiting the same technique, Jayasree et al.
[16]
most common , where the injury or rupture of a tendon fabricated a braided multiscale fibrous Achilles tendon
[8]
or ligament often occurs at the enthesis. To date, surgical scaffold consisting of aligned PCL micro/collagen-bFGF
approaches are unable to completely repair a damaged nanofibers that showed tendon tissue regeneration in vivo
enthesis, registering an increasing number of failures after after 12 weeks of implantation. However, all these scaffolds
surgery. In light of this, tissue engineering (TE) provides an lack the proper connection between the T/L and the bone.
alternative to traditional medical approaches. The additive The other pivotal player in enthesis engineering is cells .
[10]
manufacturing technologies in TE allow complex three-
dimensional (3D) structures to be fabricated layer-by-layer Several types of cells have been integrated with the 3D
using biomaterials synthetized ad-hoc to replicate features scaffolds in TE. Recently, induced pluripotent stem cells
of the targeted tissues. In recent years, the study of interface (iPSCs) have been proposed . However, the use of iPSCs
[17]
tissues has become crucial in TE. Several works have been still faces several challenges, and mesenchymal stem cells
reported in the literature that gradient scaffolds were (MSCs) remain the main source of cells in musculoskeletal
successfully fabricated to mimic enthesis characteristics. TE and regenerative medicine . MSCs are stem/stromal
[18]
Nowlin et al. exploited the electrospinning technology cells with self-renewal and multilineage differentiation
[9]
using a collector made of two aluminum bars separated abilities . They are derived from different tissues.
[19]
by an air gap. Researchers were able to fabricate a gradient Among these, the adipose-derived (AD-MSCs) and bone
scaffold made of polycaprolactone (PCL) with aligned marrow-derived (BM-MSCs) MSCs have been mainly
fibers in the middle and randomly oriented ones externally. used in tendon regeneration. The challenge to recreate a
Volume 9 Issue 5 (2023) 297 https://doi.org/10.18063/ijb.763