Natural Biomaterials as Instructive Engineered Microenvironments That Direct Cellular Function in Peripheral Nerve Tissue Engineering

Abstract

Nerve tissue function and regeneration depend on precise and well-synchronised spatial and temporal control of biological, physical, and chemotactic cues, which are provided by cellular components and the surrounding extracellular matrix. Therefore, natural biomaterials currently used in peripheral nerve tissue engineering are selected on the basis that they can act as instructive extracellular microenvironments. Despite emerging knowledge regarding cell-matrix interactions, the exact mechanisms through which these biomaterials alter the behaviour of the host and implanted cells, including neurons, Schwann cells and immune cells, remain largely unclear. Here, we review some of the physical processes by which natural biomaterials mimic the function of the extracellular matrix and regulate cellular behaviour. We also highlight some representative cases of controllable cell microenvironments developed by combining cell biology and tissue engineering principles.

Modified Hyaluronic Acid-Laminin-Hydrogel as Luminal Filler for Clinically Approved Hollow Nerve Guides in a Rat Critical Defect Size Model

“…Interestingly, a further modified formulation of the gel with increased concentration introduced into collagen-based nerve guides did well support axonal regeneration in a rabbit model of delayed repair of 25 mm tibial nerve defects [ 28 ]. This finding contributes to the view that complex structural support within nerve guidance conduits is a valuable condition for increasing functional outcome after nerve gap repair [ 26 ].…”

“…The percentile content of HA in our laminin-hyaluronic acid-based hydrogel luminal filler is influencing the viscosity or stiffness of the luminal content provided to invading cells and regenerating axons. From many studies, it can be concluded that optimally tuned nerve graft mechanical properties can give optimal support to repair Schwann cells as well as pro-regenerative macrophages as well as regenerating axons [ 9 , 26 ]. While the functional results presented here give already some indication of the quality of axonal outgrowth, and point towards more favorable properties of the higher concentrated 0.7% M-HAL, more details can be derived from our nerve morphometrical analyses.…”

“…In correlation to the functional motor recovery, this indicates that at least 15% to ≥20% of the myelinated fibers need to achieve a diameter >4 µm for supporting detectable motor recovery. Although we have to consider the overall recovery rates being lower for empty nerve guides and nerve guides filled with lower concentrated hydrogel than for conduits filled with higher concentrated M-HAL, this finding once again points towards the importance of tuning the hydrogel fillers towards the optimal mechanical properties for supporting axonal regeneration [ 9 , 26 ].…”

“…As Schwann cells represent the glia cells of the peripheral nervous system and are as such crucially involved in maintenance and regeneration processes [ 19 ], both, laminin and HA have been studied and demonstrated their potential as nanomedicals for supporting cellular regeneration [ 25 ]. How extracellular matrix components can work as instructive engineered microenvironments for peripheral nerve repair approaches has recently been reviewed in [ 26 ]. Here the authors also highlight the good potential for clinical use of these molecules due to their well standardized and reproducible synthesis [ 26 ].…”

“…How extracellular matrix components can work as instructive engineered microenvironments for peripheral nerve repair approaches has recently been reviewed in [ 26 ]. Here the authors also highlight the good potential for clinical use of these molecules due to their well standardized and reproducible synthesis [ 26 ].…”