Regeneration of Biomechanically Functional Tendon Tissue Following Injection of Uncultured, Autologous, Adipose-Derived Regenerative Cells into Partial Achilles Tendon Defects in Rabbits
Abstract
1. Introduction
2. Results
2.1. Histology
2.2. Polarization Microscopy
2.3. Immunolabeling of Type I Procollagen
2.4. Immunolabeling of Type III Collagen
2.5. Immunolabeling of CD163
2.6. Immunolabeling of Aggrecan
2.7. Combination of Polarization Microscopy and Immunohistochemistry
2.8. Functional Histology and Functional Immunohistochemistry
2.9. Design-Based Stereologic Analysis
2.10. Non-Destructive Biomechanical Analysis
3. Discussion
4. Materials and Methods
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
sPTRCT | Symptomatic, partial-thickness rotator cuff tears |
UA-ADRCs | Uncultured, unmodified, autologous, adipose-derived regenerative cells |
RCT | Randomized clinical trial |
CCT | Common calcaneal tendon |
RLS | Ringer’s lactated solution |
ECM | Extracellular matrix |
PBS | Phosphate-buffered saline |
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Two-Way ANOVA (Source of Variation) | Variable: | Cells | Vessels | ECM | Artifacts |
---|---|---|---|---|---|
Interaction (Time × Treatment) | 0.021 | 0.019 | 0.112 | 0.705 | |
Time | 0.001 | 0.022 | 0.006 | 0.567 | |
Treatment | 0.228 | 0.001 | 0.385 | 0.324 | |
95% confidence interval of mean difference at W4 | −0.0755 to 0.170 | −0.0195 to 0.0520 | −0.136 to 0.0864 | −0.138 to 0.0603 | |
95% confidence interval of mean difference at W12 | −0.256 to −0.0105 | 0.0343 to 0.106 | −0.0309 to 0.192 | −0.117 to 0.0816 |
Peak Load | Equilibrium Load | Peak Stress | Equilibrium Stress | Percent Relaxation | Cross-Sectional Area | |
---|---|---|---|---|---|---|
Effect size | 0.29 | 0.27 | 0.4 | 0.3 | 0.54 | 0.45 |
OP [%] | 21.8 | 19.4 | 39.4 | 23.2 | 65.5 | 49.3 |
nTotal | 135 | 155 | 73 | 126 | 42 | 58 |
nGroup | 34 | 39 | 18 | 32 | 11 | 15 |
R | Y | Sp | T | I | P | S | AT | C | H | PM | IHC | B |
---|---|---|---|---|---|---|---|---|---|---|---|---|
[55] | 2011 | Rabbit | CCT | Incision | + | - | PRP | - | + | - | - | - |
[56] | 2012 | Rabbit | CCT | Transection | + | - | PRP | PRP alone | + | - | + | + |
[57] | 2013 | Horse | SDFT | Collagenase gel | - | - | PC | Sham | + | - | - | - |
[58] | 2014 | Horse | SDFT | Lesion created by a standardized surgical model | - | - | - | Sham | + | - | + | - |
[59] | 2014 | Rabbit | CCT | Resection of a 2 cm-long tendon fragment | - | + | - | Cell-free scaffold | + | -- | - | + |
[7] | 2014 | Rabbit | SST | Sharp release of the insertion of the SST at the greater tuberosity | + 1 | - | - | Sham | - | - | + | - |
[60] | 2016 | Horse | SDF | Lesion created by a standardized surgical model | - | - | - | Sham | + | - | + | - |
[61] | 2016 | Dog | FDPT | Transection | + | + | GF | Cell-free scaffold | - | - | - | + |
[62] | 2016 | Dog | FT | Transection | + | + | - | Cell-free scaffold | - | - | + | - |
[63] | 2017 | Horse | SDFT | Lesion created by a standardized surgical model | - | - | PRP | BM-MSCs | + | - | - | - |
[64] | 2017 | Horse | SDFT | Lesion created by a standardized surgical model | - | - | - | Sham | + | - | - | + |
[65] | 2017 | Dog | FDPT | Transection | + | + | GF | Cell-free scaffold | + | - | + | - |
[66] | 2018 | Horse | SDFT | Collagenase | - | - | - | Autologous serum | + | + | + | - |
[67] | 2019 | Rabbit | PT | Partial patellectomy | + | + | US | No cells, no US | + | + 3 | - | + |
[68] | 2019 | Rabbit | FDST | Transection | + | - | - | Sham | - | - | - | + |
[69] | 2019 | Sheep | AT | Collagenase | - | - | rESWT | PRP | + | - | + | - |
[70] | 2020 | Rat | SST | Sharp release of the insertion of the SST at the greater tuberosity | + 2 | + | - | Cell-free scaffold | + | - | + | + |
Cell Type | MSCs [%] | EP [%] | M2 [%] | CV [%] | |
---|---|---|---|---|---|
Surface Markers | CD45- CD31- CD34+ | CD45- CD31+ CD34+ | CD45+ CD206+ | ||
Reference | System/Method | ||||
[5] | A | 32.8 | 15.3 | 16.4 | 85.2 |
[4] | A | 20.0 | -- | -- | -- |
[99] | B | 16.1 | 9.4 | 5.6 | 82.0 |
[100] | C | 10.7 | -- | -- | 84.0 |
[100] | D | 9.1 | -- | -- | 82.0 |
[100] | B | 8.9 | -- | -- | 69.3 |
[98] | E | 7.2 | -- | -- | 50.3 |
Group | n | Treatment | Type | Time Post-Treatment |
---|---|---|---|---|
1 | 4 | UA-ADRCs | H/I | W4 |
2 | 4 | UA-ADRCs | H/I | W12 |
3 | 4 | RLS | H/I | W4 |
4 | 4 | RLS | H/I | W12 |
5 | 8 | UA-ADRCs | B/I | W12 |
6 | 8 | RLS | B/I | W12 |
Antibody | Characteristic | Specification |
---|---|---|
Procollagen 1 | ||
Immunoglobuline isotype/clone status | IgG1/mouse, monoclonal | |
Catalog no./provider | SP1.D8/DSHB a | |
Demasking of antigen | Not applicable | |
Blocking | Vector Bloxall SP-6000 b, LOT ZG1216 from 4 April 2021, and normal horse serum blocking solution 2.5% (S-2012-50) b | |
Dilution and incubation parameters | 1:10, 4 °C, over night | |
Secondary antibody used | Horse-anti-mouse IgG BA-2000 b, 1:200 | |
Type III collagen | ||
Immunoglobuline isotype/clone status | IgG1/mouse, monoclonal | |
Catalog no./provider | C7805 (Clone FH-7A)/Sigma-Aldrich (St. Louis, MO, USA) | |
Demasking of antigen | Protease XIV | |
Blocking | Vector Bloxall SP-6000 b, LOT ZG1216 from 4 April 2021, and normal horse serum blocking solution 2.5% (S-2012-50) b | |
Dilution and incubation parameters | 1:150, 4 °C, over night | |
Secondary antibody used | Horse-anti-mouse IgG BA-2000 b, 1:200 | |
CD163 | ||
Immunoglobuline isotype/clone status | IgG1/mouse, monoclonal | |
Catalog no./provider | 5C6 FAT BMA Biomedicals (Augst, Switzerland) | |
Demasking of antigen | Not applicable | |
Blocking | 3% H2O2 in Methanol | |
Dilution and incubation parameters | 1:400, 4 °C, over night | |
Secondary antibody used | Horse-anti-mouse IgG BA-2000 b, 1:200 | |
Aggrecan | ||
Immunoglobuline isotype/clone status | IgG1/mouse, monoclonal | |
Catalog no./provider | 12/21/1-C-6/DSHB a | |
Demasking of antigen | 3% H2O2 in Methanol/Chondroitinase AC c | |
Blocking | Normal horse serum blocking solution 2.5% (S-2012-50) b | |
Dilution and incubation parameters | 1:5, 4 °C, over night | |
Secondary antibody used | Horse-anti-mouse IgG BA 2000 b, 1:200 |
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Schmitz, C.; Alt, C.; Wuerfel, T.; Milz, S.; Dinzey, J.; Hill, A.; Sikes, K.J.; Burton, L.H.; Easley, J.; Stewart, H.L.; et al. Regeneration of Biomechanically Functional Tendon Tissue Following Injection of Uncultured, Autologous, Adipose-Derived Regenerative Cells into Partial Achilles Tendon Defects in Rabbits. Int. J. Mol. Sci. 2025, 26, 6800. https://doi.org/10.3390/ijms26146800
Schmitz C, Alt C, Wuerfel T, Milz S, Dinzey J, Hill A, Sikes KJ, Burton LH, Easley J, Stewart HL, et al. Regeneration of Biomechanically Functional Tendon Tissue Following Injection of Uncultured, Autologous, Adipose-Derived Regenerative Cells into Partial Achilles Tendon Defects in Rabbits. International Journal of Molecular Sciences. 2025; 26(14):6800. https://doi.org/10.3390/ijms26146800
Chicago/Turabian StyleSchmitz, Christoph, Christopher Alt, Tobias Wuerfel, Stefan Milz, Jacqueline Dinzey, Ashley Hill, Katie J. Sikes, Lindsey H. Burton, Jeremiah Easley, Holly L. Stewart, and et al. 2025. "Regeneration of Biomechanically Functional Tendon Tissue Following Injection of Uncultured, Autologous, Adipose-Derived Regenerative Cells into Partial Achilles Tendon Defects in Rabbits" International Journal of Molecular Sciences 26, no. 14: 6800. https://doi.org/10.3390/ijms26146800
APA StyleSchmitz, C., Alt, C., Wuerfel, T., Milz, S., Dinzey, J., Hill, A., Sikes, K. J., Burton, L. H., Easley, J., Stewart, H. L., Puttlitz, C. M., Gadomski, B. C., Labus, K. M., Pearce, D. A., Maffulli, N., & Alt, E. U. (2025). Regeneration of Biomechanically Functional Tendon Tissue Following Injection of Uncultured, Autologous, Adipose-Derived Regenerative Cells into Partial Achilles Tendon Defects in Rabbits. International Journal of Molecular Sciences, 26(14), 6800. https://doi.org/10.3390/ijms26146800