Healing of the tendon-bone interface (TBI) after rotator cuff injury is limited, often leading to scar-mediated repair. Decellularized tendon fibrocartilage–bone composite (dTFBC) and bone marrow mesenchymal stem cell sheets (BMSCS) improve repair in preclinical models, but full scaffold encapsulation with mechanical preconditioning remains unexplored.
Purpose:
To evaluate TBI regeneration using mechanically preconditioned, BMSCS-encapsulated dTFBC scaffolds in a rabbit model.
Study Design:
Controlled laboratory study.
Methods:
A total of 48 male New Zealand White rabbits were randomized into 4 groups (n = 12 each): (1) standard repair (control); (2) repair with dTFBC; (3) repair with dTFBC-BMSCS; and (4) repair with mechanically preconditioned dTFBC-BMSCS (mdTFBC-BMSCS). Healing at 12 weeks was assessed via gross observation, histomorphological and immunohistochemical analyses, and biomechanical testing.
Results:
The mdTFBC-BMSCS group demonstrated a higher ultimate failure load (mean, 203.9 ± 65.6 N) than both the control (118 ± 37.4 N; P = .003) and dTFBC groups (127 ± 44.1 N; P = .008), with no significant difference between the 2 BMSCS-treated groups. Histological analysis revealed enhanced fibrocartilage formation, improved collagen fiber organization, and reduced inflammation infiltration at the TBI in the mdTFBC-BMSCS group. Immunohistochemical analysis showed greater collagen type 2 alpha 1 chain-, interleukin 10-, and arginase 1-positive areas in the mdTFBC-BMSCS group than in the control and dTFBC groups.
Conclusion:
Mechanically preconditioned, fully BMSCS-encapsulated dTFBC scaffolds promoted TBI regeneration, with enhanced cellular integration, fibrocartilage formation, and favorable biomechanical performance.
Clinical Relevance:
This biomimetic scaffold strategy may enhance biological healing and reduce the risk of retear after rotator cuff repair.
AnderssonTEliassonPHammermanMSandbergOAspenbergP.Low-level mechanical stimulation is sufficient to improve tendon healing in rats. J Appl Physiol (1985). 2012;113(9):1398-1402.
2.
ChenCLiuFTangY, et al. Book-shaped acellular fibrocartilage scaffold with cell-loading capability and chondrogenic inducibility for tissue-engineered fibrocartilage and bone-tendon healing. ACS Appl Mater Interfaces. 2019;11(3):2891-2907.
3.
ChenJYuQWuB, et al. Autologous tenocyte therapy for experimental Achilles tendinopathy in a rabbit model. Tissue Eng Part A. 2011;17(15-16):2037-2048.
4.
Deymier-BlackACPasterisJDGeninGMThomopoulosS.Allometry of the tendon enthesis: mechanisms of load transfer between tendon and bone. J Biomech Eng. 2015;137(11):111005.
5.
HePRuanDHuangZ, et al. Comparison of tendon development versus tendon healing and regeneration. Front Cell Dev Biol. 2022;10:821667.
6.
JenkinsTLMeehanSPourdeyhimiBLittleD.* Meltblown polymer fabrics as candidate scaffolds for rotator cuff tendon tissue engineering. Tissue Eng Part A. 2017;23(17-18):958-967.
7.
KillianMLCavinattoLGalatzLMThomopoulosS.The role of mechanobiology in tendon healing. J Shoulder Elbow Surg. 2012;21(2):228-237.
8.
KishanAPRobbinsABMohiuddinSFJiangMMorenoMRCosgriff-HernandezEM.Fabrication of macromolecular gradients in aligned fiber scaffolds using a combination of in-line blending and air-gap electrospinning. Acta Biomater. 2017;56:118-128.
9.
KwonJKimYHRheeSM, et al. Effects of allogenic dermal fibroblasts on rotator cuff healing in a rabbit model of chronic tear. Am J Sports Med. 2018;46(8):1901-1908.
10.
LiYDengTAiliDChenYZhuWLiuQ.Cell sheet technology: an emerging approach for tendon and ligament tissue engineering. Ann Biomed Eng. 2024;52(2):141-152.
11.
LimWLLiauLLNgMHChowdhurySRLawJX. Current progress in tendon and ligament tissue engineering. Tissue Eng Regen Med. 2019;16(6):549-571.
12.
LinQLinX.Cyclic mechanical stretch pre-stimulated bone marrow mesenchymal stem cells promote the healing of infected bone defect in a mouse model. Biotechnol J. 2023;18(10):e2300070.
13.
LiuQHattaTQiJ, et al. Novel engineered tendon-fibrocartilage-bone composite with cyclic tension for rotator cuff repair. J Tissue Eng Regen Med. 2018;12(7):1690-1701.
14.
LiuQYuYReisdorfRL, et al. Engineered tendon-fibrocartilage-bone composite and bone marrow-derived mesenchymal stem cell sheet augmentation promotes rotator cuff healing in a non-weight-bearing canine model. Biomaterials. 2019;192:189-198.
15.
Lo SiccoCReverberiDBalbiC, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6(3):1018-1028.
16.
LongZNakagawaKWangZ, et al. Engineered tendon-fibrocartilage-bone composite with mechanical stimulation for augmentation of rotator cuff repair: a study using an in vivo canine model with a 6-month follow-up. Am J Sports Med. 2024;52(13):3376-3387.
17.
MatsuuraKUtohRNagaseKOkanoT.Cell sheet approach for tissue engineering and regenerative medicine. J Control Release. 2014;190:228-239.
18.
MiyaharaYNagayaNKataokaM, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med. 2006;12(4):459-465.
19.
NingLJZhangYChenXH, et al. Preparation and characterization of decellularized tendon slices for tendon tissue engineering. J Biomed Mater Res A. 2012;100(6):1448-1456.
20.
OrrSBChainaniAHippensteelKJ, et al. Aligned multilayered electrospun scaffolds for rotator cuff tendon tissue engineering. Acta Biomater. 2015;24:117-126.
21.
PedowitzRAYamaguchiKAhmadCS, et al. Optimizing the management of rotator cuff problems. J Am Acad Orthop Surg. 2011;19(6):368-379.
22.
PetersonBERolfeRAKunselmanAMurphyPSzczesnySE.Mechanical stimulation via muscle activity is necessary for the maturation of tendon multiscale mechanics during embryonic development. Front Cell Dev Biol. 2021;9:725563.
23.
PhilippDSuhrLWahlersTChoiYHPaunel-GörgülüA.Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization. Stem Cell Res Ther. 2018;9(1):286.
24.
PulatkanAAnwarWAyıkO, et al. Tear completion versus in situ repair for 50% partial-thickness bursal-side rotator cuff tears: a biomechanical and histological study in an animal model. Am J Sports Med. 2020;48(8):1818-1825.
25.
QinTWSunYLThoresonAR, et al. Effect of mechanical stimulation on bone marrow stromal cell-seeded tendon slice constructs: a potential engineered tendon patch for rotator cuff repair. Biomaterials. 2015;51:43-50.
26.
RijalGLiW.Native-mimicking in vitro microenvironment: an elusive and seductive future for tumor modeling and tissue engineering. J Biol Eng. 2018;12:20.
27.
SaadatFDeymierACBirmanVThomopoulosSGeninGM.The concentration of stress at the rotator cuff tendon-to-bone attachment site is conserved across species. J Mech Behav Biomed Mater. 2016;62:24-32.
28.
SekineHShimizuTDobashiI, et al. Cardiac cell sheet transplantation improves damaged heart function via superior cell survival in comparison with dissociated cell injection. Tissue Eng Part A. 2011;17(23-24):2973-2980.
29.
SongWZhangDWuD, et al. Cryopreserved adipose-derived stem cell sheets: an off-the-shelf scaffold for augmenting tendon-to-bone healing in a rabbit model of chronic rotator cuff tear. Am J Sports Med. 2023;51(8):2005-2017.
30.
SunYKwakJMQiC, et al. Remnant tendon preservation enhances rotator cuff healing: remnant preserving versus removal in a rabbit model. Arthroscopy. 2020;36(7):1834-1842.
31.
TangYChenCLiuF, et al. Structure and ingredient-based biomimetic scaffolds combining with autologous bone marrow-derived mesenchymal stem cell sheets for bone-tendon healing. Biomaterials. 2020;241:119837.
32.
WeeksKDDinesJSRodeoSABediA.The basic science behind biologic augmentation of tendon-bone healing: a scientific review. Instr Course Lect. 2014;63:443-450.
33.
WuXLBriggsLMurrellGAC. Intraoperative determinants of rotator cuff repair integrity: an analysis of 500 consecutive repairs. Am J Sports Med. 2012;40(12):2771-2776.
34.
YangJYuanJWenYQWuLLiaoJJQiHB.Bone marrow mesenchymal stem cells promote uterine healing by activating the PI3K/AKT pathway and modulating inflammation in rat models. World J Stem Cells. 2025;17(1):98349.
35.
ZhangCWuJLiXWangZLuWWWongTM.Current biological strategies to enhance surgical treatment for rotator cuff repair. Front Bioeng Biotechnol. 2021;9:657584.
36.
ZhangWZhangFShiH, et al. Comparisons of rabbit bone marrow mesenchymal stem cell isolation and culture methods in vitro. PLoS One. 2014;9(2):e88794.
37.
ZhaoJPanJZengLFWuMYangWLiuJ.Risk factors for full-thickness rotator cuff tears: a systematic review and meta-analysis. EFORT Open Rev. 2021;6(11):1087-1096.
38.
ZhongSLanYLiuJ, et al. Advances focusing on the application of decellularization methods in tendon-bone healing. J Adv Res. 2025;67:361-372.
ZouJYangWCuiW, et al. Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon-bone healing. J Nanobiotechnology. 2023;21(1):14.
