Anatomical Tissue Engineering of the Anterior Cruciate Ligament Entheses

Abstract

The firm integration of anterior cruciate ligament (ACL) grafts into bones remains the most demanding challenge in ACL reconstruction, since graft loosening means graft failure. For a functional-tissue-engineered ACL substitute to be realized in future, robust bone attachment sites (entheses) have to be re-established. The latter comprise four tissue compartments (ligament, non-calcified and calcified fibrocartilage, separated by the tidemark, bone) forming a histological and biomechanical gradient at the attachment interface between the ACL and bone. The ACL enthesis is surrounded by the synovium and exposed to the intra-articular micromilieu. This review will picture and explain the peculiarities of these synovioentheseal complexes at the femoral and tibial attachment sites based on published data. Using this, emerging tissue engineering (TE) strategies addressing them will be discussed. Several material composites (e.g., polycaprolactone and silk fibroin) and manufacturing techniques (e.g., three-dimensional-/bio-printing, electrospinning, braiding and embroidering) have been applied to create zonal cell carriers (bi- or triphasic scaffolds) mimicking the ACL enthesis tissue gradients with appropriate topological parameters for zones. Functionalized or bioactive materials (e.g., collagen, tricalcium phosphate, hydroxyapatite and bioactive glass (BG)) or growth factors (e.g., bone morphogenetic proteins [BMP]-2) have been integrated to achieve the zone-dependent differentiation of precursor cells. However, the ACL entheses comprise individual (loading history) asymmetric and polar histoarchitectures. They result from the unique biomechanical microenvironment of overlapping tensile, compressive and shear forces involved in enthesis formation, maturation and maintenance. This review should provide a road map of key parameters to be considered in future in ACL interface TE approaches.

Optimization of Polycaprolactone and Type I Collagen Scaffold for Tendon Tissue Regeneration

“…While achieving satisfactory live cell percentage and degradation rate, the study highlights the challenge of attaining mechanical strength equivalent to a native ACL [ 5 ]. Echoing biomechanical complexity, Gögele et al emphasize the challenge of translating regenerative medicine research into practical applications, with increasing complexity raising difficulties and costs in obtaining medical device approval [ 31 ].…”

Regenerative Anterior Cruciate Ligament Healing in Youth and Adolescent Athletes: The Emerging Age of Recovery Science

“…Regardless of which graft type is used, patient return to competitive sport outcomes are less than ideal [ 4 , 5 , 31 ]. Much remains to be learned about reconstructing a ruptured ACL in a manner that actually restores its complex three-dimensional anatomy, physiology, and regional structural heterogeneity [ 39 , 40 , 41 ]. In current practice, the likelihood of an ACL rupture progressing to knee osteoarthritis is similar regardless of whether it is treated non-surgically or with reparative or reconstructive surgery [ 42 ].…”

“…To improve ACL surgical repair or reconstruction efficacy, tissue engineers have been attempting to better replicate zones of differing ACL tissue heterogeneity. Despite these advances, one common acknowledgment in these reports is that we have a long way to go [ 39 , 40 , 41 ]. The native crimp pattern histological zones immediately adjacent to the entheses ( Figure 4 ) provide natural braking that dissipates acute loading forces through both the anteromedial and posterolateral ACL components ( Figure 5 ).…”

Could an Anterior Cruciate Ligament Be Tissue-Engineered from Silk?

“…These cells are the actors driving angiogenesis. The mature ACL is a poorly vascularized tissue, and the fibrocartilaginous zones of the mature enthesis parts are even void of blood vessels [141,142]; hence, angiogenesis appears, on the first look, subordinary for the ligamentization of ACL scaffolds. However, the graft ingrowth and integration steps into subligamental bones need vessel formation for graft supply.…”

“…Looking at a reconstructed ACL, the highest risk of failure after reconstruction is graft loosening. Therefore, a firm osseointegration is desired, mediated by enthesis zone formation [142]. Hence, silk scaffolds with enthesis zones were generated.…”