# Scoping Review of the Biomedical Investigations of Cellulose Nanocrystal-Based Hydrogels: A Critical Analysis of Current Evidence, Research Gaps and Future Perspectives

## TL;DR

This review examines how cellulose nanocrystals improve hydrogels for biomedical uses, highlighting current research and areas needing standardization.

## Contribution

The paper uniquely focuses on biomedical models and assays for CNC-hydrogels, identifying methodological gaps and proposing standardization for translational success.

## Key findings

- CNC incorporation improved hydrogel mechanical properties by 20–40% and supported high cell viability for up to 21 days.
- In vivo studies showed benefits like preserved graft volume and reduced vascular hyperplasia, but lacked standardization and long-term data.
- Current research lacks human trials and consistent reporting, hindering reproducibility and translational progress.

## Abstract

Hydrogel-based products are used in many areas of biomedicine and healthcare. Recently, the incorporation of cellulose nanocrystals (CNC), a renewable and functional nanomaterial, into hydrogels has enhanced their functionality, particularly by imparting mechanical strength and structural integrity. This scoping review aims to appraise the types of biomedical models and assays that have been utilised to investigate the effects of CNC incorporation into hydrogels in tissue engineering, wound healing, medical implantation and drug delivery applications, and reports on the rationale for including these models and assays. A structured literature search was undertaken in major scientific databases (PubMed Central, PubMed, BioMed Central, ScienceDirect, Wiley and EBSCOhost), focusing on identifying primary research published between 2016 and 2024. From this process, fifteen studies providing biomedical analyses met the inclusion criteria. Most of these investigations employed in vitro cell-line models (n = 12), with a smaller number utilising in vivo experimental systems (n = 5). Across the included studies, CNC incorporation typically yielded measurable performance gains: reported compressive or storage modulus improvements of 20–40% over hydrogel-only controls, consistently high cell viability (>85%) across multiple human and murine cell types for up to 21 days, and sustained drug release profiles (days–weeks) in stent and antitumour contexts. Where quantified, functional outcomes in vivo included preserved graft volume (autologous fat grafts) and reduced intimal hyperplasia signals in vascular graft models. Critical gaps included heterogeneous CNC sources and surface chemistries, inconsistent reporting of CNC concentration and hydrogel formulation parameters, the limited duration and scope of biocompatibility testing, and minimal alignment with standard evaluation protocols, constraining reproducibility and cross-study comparability. To date, there are no human clinical trials of CNC-hydrogels. Translational readiness will require standardised ISO-compliant biocompatibility evaluations. Large-animal studies under relevant mechanical and physiological conditions, and rigorous long-term degradation and immunogenicity assessments to de-risk progression to human trials. We recommend standardised CNC sources and surface functionalisation reporting, concentration (wt%) ranges, hydrogel rheological characterisation (G′, G″, swelling), and consistent biological endpoints (viability, differentiation, inflammation panels) to enable robust meta-analyses and translational benchmarking. Distinct from prior nanocellulose reviews that emphasise material synthesis and properties, this analysis centres on the biomedical models and assays applied to CNC-incorporated hydrogels, identifying the methodological convergence and divergence that directly impact translational pathways.