AJSM - 2026-07-07 - Journal Article
Nerve Growth Factor Gene Delivery via Nanosphere-Hydrogel Composites and Tendon-Bone Interface Healing in a Rat Rotator Cuff Tear Model.
Yuan Y, Zhao Y, Cheng J, Lu J, Feng H, Zhang F, Zhu X, Hu Y, Zhou Y, Sun Y
Topics
Key Takeaway
pNGF-loaded nanosphere-hydrogel composites increased tendon-bone interface maximum load to 32.7 N versus 21.6 N in repair-alone controls at 8 weeks in a rat rotator cuff model.
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Summary
This controlled laboratory study evaluated whether local delivery of NGF-encoding plasmid via pH-responsive nanosphere-hydrogel composites improves tendon-bone interface healing after rotator cuff repair in a rat acute tear model. Sprague-Dawley rats were randomized to repair alone, repair plus empty-plasmid NP-GEL, or repair plus pNGF@NP/GEL, with biomechanical, histologic, micro-CT, and functional outcomes assessed at 4 and 8 weeks. The pNGF group demonstrated superior maximum load (32.7 vs 21.6 N, P<.001), higher Modified Histomorphometric Scoring (31.3 vs 22.67, P=.003), improved bone mineral density, and better collagen I/III ratio versus controls, with mild NT-3 upregulation and increased but non-critical heterotopic ossification.
Key Limitation
The 8-week rat model does not capture the full remodeling timeline relevant to human rotator cuff healing, and the observed heterotopic ossification signal—even if not in load-bearing regions—has unknown long-term consequences that cannot be assessed in this short follow-up window.
Original Abstract
BACKGROUND
Rotator cuff repair (RCR) often fails because of poor tendon-bone interface (TBI) healing. Nerve growth factor (NGF) has been shown to regulate tenocyte function and promote regeneration, but it lacks sufficient systematic research, limiting its clinical translation.
PURPOSE
To evaluate the therapeutic efficacy of NGF-encoding plasmid (pNGF) for TBI healing in a rat acute rotator cuff tear (RCT) model, delivered via nanosphere-hydrogel (NP-GEL) composites.
STUDY DESIGN
Controlled laboratory study.
METHODS
We performed physicochemical characterization of pNGF-loaded NP-GEL (morphology, particle size/zeta potential, and in vitro pNGF release) and assessed rat tenocyte responses (proliferation, migration, and protein expression) in vitro. For in vivo studies, 42 Sprague-Dawley rats were randomized into 3 groups after bilateral acute RCT model establishment: RCR alone (control group), RCR combined with local empty plasmid-loaded NP-GEL composites (pEmpty@NP/GEL group), and RCR combined with local pNGF-loaded NP-GEL composites (pNGF@NP/GEL group). Rats were euthanized at 4 and 8 weeks postoperatively (n = 7 rats per time point, 14 shoulders/group). At 4 weeks, 8 shoulders/group were allocated to biomechanical testing, and 6 shoulders/group to histologic analysis. At 8 weeks, 8 shoulders/group underwent pain threshold and gait analysis before biomechanical testing, while 6 shoulders/group underwent micro-computed tomography imaging before histologic analysis.
RESULTS
In vitro, pNGF@NP/GEL exhibited pH-responsive sustained release (88% at pH 5, 76% at pH 7 over 28 days), and pNGF maximized primary tenocyte proliferation/migration (peak effect at 2.5 μg pNGF). In vivo, the pNGF@NP/GEL group showed superior TBI healing: higher biomechanical strength (maximum load: 32.7 ± 4.9 N vs 25.5 ± 5.2 N in pEmpty@NP/GEL; P = .026 vs 21.6 ± 5.1 N in control; P < .001 at 8 weeks), improved bone microarchitecture (higher bone mineral density at 8 weeks; P < .001), better histologic repair (Modified Histomorphometric Scoring System: 31.3 ± 2.1 vs 25 ± 1 in pEmpty@NP/GEL; P = .015 vs 22.67 ± 2.31 in control; P = .003 at 8 weeks), optimized collagen I/III ratio, and enhanced functional recovery, with only mild neurotrophin-3 upregulation and increased heterotopic ossification (HO) although not in clinically concerning regions.
CONCLUSION
NGF gene delivery effectively enhances TBI healing in a rat model of acute RCT histologically, structurally, and functionally via NP-GEL composites, accompanied by mild upregulation of NT-3 and increased HO, although not in clinically concerning regions. Thus, this strategy holds translational potential to improve the clinical outcomes of RCTs.
CLINICAL RELEVANCE
The NGF has translational potential to improve clinical outcomes in RCTs.