Efficacy of Mechanically Processed Adipose-Derived Therapies and Nanofat in Peripheral Nerve Regeneration: A Systematic Review and Meta-Analysis of Preclinical In Vivo Models

Peripheral nerve injuries (PNIs)—arising from maxillofacial trauma, oncologic ablation, or iatrogenic insult—frequently result in severe functional deficits, aberrant reinnervation (e.g., facial synkinesis), and neuropathic sequelae. While tension-free epineurial neurorrhaphy and autologous nerve grafting remain the clinical benchmarks for transection and critical gap injuries, functional recovery is frequently incomplete due to chronic denervation, neurovascular compromise, and endoneurial scarring. Furthermore, in nerve crush/compression paradigms, secondary ischemic injury and neuroinflammatory cascades hinder spontaneous axonal elongation. Adipose tissue represents an accessible, autologous depot of regenerative cellular and acellular components. Traditional cell-based therapies reliant on enzymatically isolated and culture-expanded adipose-derived stem cells (ADSCs) entail significant translational hurdles, including protracted ex vivo expansion times, regulatory complexities, donor site cell senescence, and potential genomic instability. Mechanically processed, non-enzymatic fat grafts—principally Nanofat, micronized adipose matrices, and uncultured mechanical stromal vascular fraction (t-SVF)—have emerged as a potent translational alternative. Nanofat preserves the native extracellular matrix (ECM) architecture, mechanical microenvironment, and a rich secretome encompassing essential neurotrophic and angiogenic mediators (such as BDNF, GDNF, NGF, VEGF, and IGF-1) alongside perivascular cells and native stem cell niches, without requiring enzymatic digestion. Although a growing body of preclinical literature suggests that local nanofat or micronized adipose transfer facilitates axonal sprouting, remyelination, and neuromuscular junction reinnervation, empirical findings remain highly heterogeneous regarding delivery modality (e.g., direct perineurial injection, interpositional conduit filling, or external nerve wrapping), injury kinetics (crush vs. neurotmesis), and harvest/processing parameters (shear-force emulsification vs. filtration sizing). Therefore, this systematic review and preclinical meta-analysis aims to rigorously synthesize available in vivo mammalian evidence evaluating the therapeutic efficacy of mechanically processed adipose-derived therapies in peripheral nerve repair, delineating both functional, electrophysiological, and histomorphometrical endpoints, while systematically assessing the risk of bias across published translational studies.