In Vivo Imaging of Fibroblast Activity Using a 68Ga-Labeled Fibroblast Activation Protein Alpha (FAP-α) Inhibitor: Study in a Mouse Rotator Cuff Repair Model. (19th May 2021)

• Record Type: Journal Article
• Authors: Zhang, Xueying; Chen, Daoyun; Babich, John W.; Green, Samuel J.E.; Deng, Xiang-Hua; Rodeo, Scott A.
• Is Part Of: Journal of bone and joint surgery. Volume 103:Number 10(2021)
• Publication Date: 2021-05-19
• Subjects: Bones -- Surgery -- Periodicals; Joints -- Surgery -- Periodicals; Orthopedics -- Periodicals; Orthopedics; General Surgery; Bone Diseases; Joint Diseases; Bones -- Surgery; Joints -- Surgery; Orthopedics; Bot (anatomie); Gewrichten; Chirurgie (geneeskunde); Periodicals; Electronic journals; Periodicals; 617.47005
• DOI: 10.2106/JBJS.20.00831
• Languages: English
• ISSNs: 0021-9355

Abstract

Abstract : Background: Rotator cuff repair site failure is a well-established clinical concern. Tendon-to-bone healing is initiated by inflammatory mediators followed by matrix synthesis by fibroblasts. The kinetics of fibroblast accumulation and activity are currently poorly understood. Methods: Ninety-six mice underwent supraspinatus tendon repair. Six were used for imaging using a novel 68 Gallium (Ga)-labeled fibroblast activation protein alpha (FAP-α) inhibitor and positron emission tomography-computed tomography (PET/CT) at days 0 (before surgery), 3, 7, 14, and 28. Sixty-eight animals were divided into 4 groups to be evaluated at 3, 7, 14, or 28 days. Twenty-two native shoulders from mice without surgery were used as the control group (intact tendon). Six animals from each group were used for histological analysis; 6 from each group were used for evaluation of fibroblastic response-related gene expression; and 10 mice each from the intact, 14-day, and 28-day groups were used for biomechanical testing. Results: There was minimal localization of 68 Ga-labeled FAP-α inhibitor in the shoulders at day 0 (before surgery). There was significantly increased uptake in the shoulders with surgery compared with the contralateral sides without surgery at 3, 7, and 14 days. 68 Ga-labeled FAP-α inhibitor uptake in the surgically treated shoulders increased gradually and peaked at 14 days followed by a decrease at 28 days. Gene expression for smooth muscle alpha (α)-2 (acta2), FAP-α, and fibronectin increased postsurgery followed by a drop at 28 days. Immunohistochemical analysis showed that FAP-α-positive cell density followed a similar temporal trend, peaking at 14 days. All trends matched closely with the PET/CT results. Biomechanical testing demonstrated a gradual increase in failure load during the healing process. Conclusions: 68 Ga-labeled FAP-α inhibitor PET/CT allows facile, high-contrast in vivo 3-dimensional imaging of fibroblastic activity in a mouse rotator cuff repair model. Clinical Relevance: Noninvasive imaging of activated fibroblasts using labeled radiotracers may be a valuable tool to follow the progression of healing at the bone-tendon interface.