bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.08.20.608812

Effects of Release of TSG-6 from Heparin Hydrogels on Supraspinatus Muscle Regeneration

Pearson, J. J.·Mao, J.·Temenoff, J. S.
View original source ↗Export metadata ↓

Abstract

Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated (Hep) and fully desulfated (Hep-)) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of Tumor Necrosis Factor Stimulated Gene 6 (TSG-6) over 14+ days in vivo in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles in vivo, thus facilitating comparisons between delivery from heparin derivatives on level of tissue repair in two different areas of muscle (near the myotendious junction (MTJ) and in the muscle belly (MB)) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury through macrophage polarization, and that release from a fully sulfated heparin derivative (Hep) would potentiate this effect throughout the muscle. Inflammatory/immune cells, satellite cells, and fibroadipogenic progenitor cells, were analyzed by flow cytometery 3 and 7 days after injury and hydrogel injection, while metrics of muscle healing were examined via immunohistochemistry up to Day 14. Results showed controlled delivery of TSG-6 from Hep caused heightened macrophage response (Day 14 macrophages, 4.00 {+/-} 1.85% single cells, M2a, 3.27 {+/-} 1.95% single cells) and increased markers of early muscle regeneration (embryonic heavy chain staining) by Day 7, particularly in the MTJ region of the muscle, compared to release from desulfated heparin hydrogels. This work provides a novel strategy for localized, controlled delivery of TSG-6 to enhance muscle healing after rotator cuff tear. IMPACT STATEMENTRotator cuff tear is a significant problem that can cause muscle degeneration. In this study, a hydrogel particle system was developed for sustained release of an anti-inflammatory protein, Tumor Necrosis Factor Stimulated Gene 6 (TSG-6), to injured muscle. Release of the protein from a fully sulfated heparin hydrogel-based carrier demonstrated greater changes in amount inflammatory cells and more early regenerative effects than a less-sulfated carrier. Thus, this work provides a novel strategy for localized, controlled delivery of an anti-inflammatory protein to enhance muscle healing after rotator cuff tear.

Source connections

Explore related subjects

bioengineeringPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Pearson, J. J., Mao, J., Temenoff, J. S.. 2024-08-21. Effects of Release of TSG-6 from Heparin Hydrogels on Supraspinatus Muscle Regeneration. https://doi.org/10.1101/2024.08.20.608812

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

SpiraMed: A Stereotactic Helix-based Therapy Delivery system for the Human Brain

Stereotactic needle-based delivery remains the standard for local administration of Advanced Therapy Medicinal Products (ATMPs) to the human brain. ATMP administration typically involves multiple trajectories, presenting cumulative risks and prolonging surgery. Reflux-prone, patchy therapy coverage compromises clinical results. We demonstrate a novel approach, deploying a helical delivery catheter via a single access trajectory per target, referred to as SpiraMed. Helix retraction is synchronised with therapy delivery, enabling comprehensive target coverage in seconds. Helix pitch and diameter can be precisely tailored to patient-specific target volume and vascular anatomy, as part of the preoperative stereotactic surgical planning process. Testing in agarose phantoms, live sheep and cadaveric human brain confirms enhanced therapy delivery volume, delivery speed and target coverage, with reductions in reflux and predicted risk of bleeding complication. SpiraMed represents a new paradigm, promising to help deliver on the transformative potential of cell and gene therapies across the spectrum of human CNS disease.

bioengineering↗
bioRxiv2026

Normative Modeling of Molecular-Enriched Functional Connectivity for Detecting Deviations from Healthy Brain Aging

Inter-individual variability in adult brain aging can obscure early pathological alterations and is only partly represented by population-average or scalar brain-aging measures. We combined Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) with normative modeling (NM) to derive spatially resolved, molecularly informed deviation scores for dopamine transporter (DAT)-, norepinephrine transporter (NET)-, and serotonin transporter (SERT)-enriched resting-state functional connectivity (FC). We first evaluated whether these normative models could be transferred to independently processed external data through local calibration and then explored whether the resulting deviation profiles differed with cerebral amyloid burden in cognitively unimpaired older adults. Hierarchical Bayesian regression (HBR) models with a SHASHb likelihood were estimated separately for 204 cortical molecular-enriched FC features in 4,152 healthy adults (18.0--89.8 years) from seven publicly available neuroimaging datasets and evaluated in a held-out healthy test set. Pretrained models were locally adapted to three AMYPAD-PNHS acquisition batches using cognitively unimpaired, amyloid-negative participants (global Clinical Dementia Rating [CDR] = 0; Centiloid [CL] [lt] 10). The independent primary comparison contrasted participants with intermediate amyloid burden (10 [≤] CL [lt] 30; n = 111) and amyloid-positive participants (CL [≥] 30; n = 66); secondary analyses tested linear associations with continuous CL within participants with CL [≥] 10. Of 204 normative reference models, 199 (97.5%) met the predefined diagnostic criteria; median held-out explained variance (EXPV) was 0.174. Of 612 feature-by-batch transfers, 541 (88.4%) met the strict transfer-diagnostic criteria. In the primary false discovery rate (FDR)-controlled regional analysis, DAT-enriched right caudal middle frontal cortex showed lower locally standardized deviation scores in the intermediate-amyloid-burden group than in the amyloid-positive group (adjusted difference = -0.582, q = 0.016). DAT extreme-deviation burden was also greater in the intermediate-amyloid-burden group (difference = 0.032, q = 0.044). The right frontal effect was reproduced with model-native scores across the three acquisition batches (pooled standardized effect = -0.698, q = 0.010). No NET- or SERT-enriched regional difference between these two groups survived FDR correction, and no regional or subject-level linear association with continuous CL values survived FDR correction in the CL [≥] 10 group. Normative modeling can provide spatially resolved reference distributions of molecular-enriched FC that are deployable in independently processed external data when local adaptation, calibration, and feature-level transfer diagnostics are incorporated. The AMYPAD-PNHS application identified modest, spatially selective, and molecular-system-specific categorical differences during a cognitively unimpaired stage of amyloid accumulation, while continuous analyses within CL [≥] 10 did not support a linear association. These findings support a methodological basis for distributed application of molecular-enriched normative models and motivate independent and longitudinal evaluation of their biological relevance.

bioengineering↗
bioRxiv2026

AC-Diff: Anatomy-Contrast Disentangled Diffusion for Multi-Vendor Liver MRI Harmonization

Magnetic resonance imaging (MRI) exhibits substantial scanner and protocol dependent appearance variations, making harmonization challenging without distorting patient specific anatomy, particularly in abdominal imaging. We propose AC-Diff, an anatomy--contrast disentangled diffusion framework that formulates MRI harmonization as a factor-specific generative intervention. Using aligned multi-contrast supervision and cross-patient factor swapping, AC-Diff learns to separate anatomical structure from acquisition-dependent contrast. Unlike conventional image or latent diffusion, AC-Diff restricts stochastic generation to the contrast subspace while the source anatomy bypasses diffusion and is directly reused during reconstruction. Experiments on an in-house multi-vendor cohort and the external Duke Liver MRI dataset demonstrate improved target-domain alignment with strong structural preservation. In downstream liver segmentation, AC-Diff improves Dice from 0.942 for the original inputs to 0.954 for the harmonized images. These results support contrast-specific latent generation as a promising approach to anatomy-preserving MRI harmonization.

bioengineering↗