Neural cell type-specific responses to glycomimetic functionalized collagen

Abstract

Despite their noted functional role, glycans have had limited therapeutic use due to difficulties in synthesis and quick degradation in vivo. The recent discovery of glycomimetics has provided new opportunities for their application. In this study, we have functionalized type I collagen with peptide mimics of two glycans: (1) polysialic acid (PSA) and (2) an epitope first discovered on human natural killer cells (HNK-1). These glycans and their glycomimetic counterparts have been shown to be important regulators of repair following injury through their unique and phenotypically specific effects on neural behavior. We show that these molecules retain their bioactivity following functionalization to the collagen backbone. Grafted HNK-1 encouraged motor neuron outgrowth, while grafted PSA encouraged sensory and motor neuron outgrowth and enhanced Schwann cell proliferation and process extension. These data support the potential of glycomimetic-functionalized collagen as a biomaterial strategy to increase the efficiency of synaptic reconnection following nervous system injury.

The effect of glycomimetic functionalized collagen on peripheral nerve repair

“…In its hydrogel form, collagen provides a highly controlled environment for nerve cells to grow by providing both mechanical and biological support for neuritogenesis [26]. In a previous study, we confirmed the in vitro bioactivity of type I collagen hydrogels that were functionalized with PSA and HNK-1 glycomimetics and showed that the molecules retain their modality specific responses towards neural cells after conjugation [27]. …”

“…This has been attributed to a number of reasons including the local inflammatory response, ingrowth of fibrous scar tissue, lack of mechanical support for emerging neurites, and more recently the malrouted regrowth of axons. We have previously shown that covalent conjugation of glycomimetic HNK-1 and PSA peptides to type I collagen results in neural cell type-specific responses in vitro [27]. Given these unique, modality-defined effects, we investigated the potential for glycomimetic functionalized collagen to promote axonal regeneration and targeting in a challenging, 5 mm gap size femoral nerve injury model.…”

“…During gait, the quadriceps muscle maintains knee extension in single support phases thereby allowing the contralateral leg to swing forward. Given this distinct biomechanical role, Irintchev et al [27] developed an approach to quantify the kinematic effects of this type of injury. We used two of Irintchev’s defined parameters to evaluate functional recovery: the foot base angle (FBA) and the protraction limb ratio (PLR).…”

Small-molecule based musculoskeletal regenerative engineering

“…This compound has been implicated in preferential motor reinnervation, as well as axon path finding in regenerating peripheral neurons (67). Glycans are complex to synthesize and have a short half-life in vivo , making them minimally useful for in vivo applications (68). Glycan mimetics, however, have a great potential for achieving the same effect without these complications (69).…”

Salicylic acid‐based poly(anhydride‐ester) nerve guidance conduits: Impact of localized drug release on nerve regeneration

“…Sterile PBS or type I collagen hydrogel was used as luminal fillers. Type I collagen hydrogels (2.0 mg/mL) were prepared as previously described . Both PE tubes and SA‐NGCs were incubated with type I collagen hydrogel fillers at 37°C to ensure hydrogel self‐assembly.…”