1. 2025;28;287-297Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence – A Scoping Review
   Scoping Review
   Suwannika Palee, MD, Atthakorn Jarusriwanna, MD, Danielle Lee, MD, Ugur Yener, MD, Alan D. Kaye, MD, PhD, Naum Shaparin, MD, and Sayed E. Wahezi, MD.

BACKGROUND: This scoping review systematically evaluates and synthesizes evidence on the presence of neoinnervation in chronic tendon pain. By analyzing the frequency and progression of neural biomarker upregulation, the present investigation seeks to illuminate existing knowledge gaps, contextualize shifts in research focus over time, and propose potential therapeutic approaches for the more precise and effective management of tendinopathy.

OBJECTIVES: To identify major neural biomarkers associated with nerve ingrowth, detailing historical development, current understanding, and implications in tendinopathy.

STUDY DESIGN: A scoping review.

SETTING: An academic medical center.

METHODS: Searches were conducted up to June 2024 using PubMed, Embase, Web of Science, and Scopus, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The selected studies included clinical human case-control studies and in vivo experimental animal models that examined neoinnervation in tendinopathy. Data extraction included study design, animal induction models, biomarker detection methods, neural biomarker upregulation, and supporting evidence to evaluate the involvement of neoinnervation and the role of the paratenon in tendinopathy. 

RESULTS: Of the 26 studies reviewed, 19 (73%) identified neoinnervation in chronic tendinopathy, and 20 (76.9%) highlighted the role of the paratenon, suggesting its potential as a key target for therapeutic interventions. Notably, 14 studies (53.8%) examined both neoinnervation and the paratenon’s role, indicating significant interplay. Analyses of neural biomarkers revealed possible upregulation of protein gene product 9.5 (PGP 9.5) in 15 studies (57.6%) and substance P in 13 studies (50%), emphasizing the crucial roles of those biomarkers in the neurobiological mechanisms of tendinopathy pain. Other biomarkers, including calcitonin gene-related peptide (CGRP), tyrosine hydroxylase, growth-associated protein-43 (GAP-43), NMDA receptor (NMDAR), glutamate, neurokinin 1 receptor (NK1R), neuropeptide Y, adrenoreceptor, nerve sprouting markers, specific chemokines, and various immune-related markers, were also identified as potentially upregulated. Our review of temporal trends indicates that recent research has expanded to encompass a broader range of biomarkers, thereby enhancing our understanding of the complexity and multisystem involvement in the pathology of tendinopathy. 

LIMITATIONS: This review is limited by the predominance of case-control and experimental studies, which inherently offer lower levels of evidence due to methodological constraints like lack of randomization and potential biases. Additionally, the present review may not fully address how biomarker expression or neoinnervation changes over disease stages or treatment, the comprehension of which is critical for understanding progression and management.

CONCLUSION: The present investigation highlights the critical role of neoinnervation and the paratenon in chronic tendinopathy, with a significant overlap suggesting interrelated roles in the condition. This finding emphasizes the need to incorporate neurobiological pathways into therapeutic strategies. The evolution of neural biomarker studies reveals a complex interplay in pain mechanisms, underscoring the potential for targeting specific nerve ingrowth pathways within the paratenon to enhance treatment efficacy. Future research should aim to elucidate the therapeutic potential of targeting specific paratenon nerve ingrowth pathways, which could improve the efficacy of treatments for chronic tendon pain substantially.

KEY WORDS: nerve tissue proteins, receptors, immunology, peritendinous tissue, paratenon, nerve sprouting, tendinopathy, tendon pain