PMID- 35896136
OWN - NLM
STAT- MEDLINE
DCOM- 20220908
LR  - 20221116
IS  - 1878-7568 (Electronic)
IS  - 1742-7061 (Linking)
VI  - 150
DP  - 2022 Sep 15
TI  - Microenvironmentally optimized 3D-printed TGFbeta-functionalized scaffolds 
      facilitate endogenous cartilage regeneration in sheep.
PG  - 181-198
LID - S1742-7061(22)00431-7 [pii]
LID - 10.1016/j.actbio.2022.07.029 [doi]
AB  - Clinically, microfracture is the most commonly applied surgical technique for 
      cartilage defects. However, an increasing number of studies have shown that the 
      clinical improvement remains questionable, and the reason remains unclear. 
      Notably, recent discoveries revealed that signals from regenerated niches play a 
      critical role in determining mesenchymal stem cell fate specification and 
      differentiation. We speculate that a microenvironmentally optimized scaffold that 
      directs mesenchymal stem cell fate will be a good therapeutic strategy for 
      cartilage repair. Therefore, we first explored the deficiency of microfractures 
      in cartilage repair. The microfracture not only induced inflammatory cell 
      aggregation in blood clots but also consisted of loose granulation tissue with 
      increased levels of proteins related to fibrogenesis. We then fabricated a 
      functional cartilage scaffold using two strong bioactive cues, transforming 
      growth factor-beta3 and decellularized cartilage extracellular matrix, to modulate 
      the cell fate of mesenchymal stem cells. Additionally, poly(epsilon-caprolactone) was 
      also coprinted with extracellular matrix-based bioinks to provide early 
      mechanical support. The in vitro studies showed that microenvironmentally 
      optimized scaffolds exert powerful effects on modulating the mesenchymal stem 
      cell fate, such as promoting cell migration, proliferation and chondrogenesis. 
      Importantly, this strategy achieved superior regeneration in sheep via scaffolds 
      with biomechanics (restored well-organized collagen orientation) and 
      antiapoptotic properties (cell death-related genes were also downregulated). In 
      summary, this study provides evidence that microenvironmentally optimized 
      scaffolds improve cartilage regeneration in situ by regulating the 
      microenvironment and support further translation in human cartilage repair. 
      STATEMENT OF SIGNIFICANCE: Although microfracture (MF)-based treatment for 
      chondral defects has been commonly used, critical gaps exist in understanding the 
      biochemistry of MF-induced repaired tissue. More importantly, the clinically 
      unsatisfactory effects of MF treatment have prompted researchers to focus on 
      tissue engineering scaffolds that may have sufficient therapeutic efficacy. In 
      this manuscript, a 3D printing ink containing cartilage tissue-specific 
      extracellular matrix (ECM), methacrylate gelatin (GelMA), and transforming growth 
      factor-beta3 (TGF-beta3)-embedded polylactic-coglycolic acid (PLGA) microspheres was 
      coprinted with poly(epsilon-caprolactone) (PCL) to fabricate tissue engineering 
      scaffolds for chondral defect repair. The sustained release of TGF-beta3 from 
      scaffolds successfully directed endogenous stem/progenitor cell migration and 
      differentiation. This microenvironmentally optimized scaffold produced improved 
      tissue repair outcomes in the sheep animal model, explicitly guiding more 
      organized neotissue formation and therefore recapitulating the anisotropic 
      structure of native articular cartilage. We hypothesized that the cell-free 
      scaffolds might improve the clinical applicability and become a new therapeutic 
      option for chondral defect repair.
CI  - Copyright (c) 2022. Published by Elsevier Ltd.
FAU - Yang, Zhen
AU  - Yang Z
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China; Arthritis Clinic & Research Center, Peking University People's 
      Hospital, Peking University, Beijing, 100044, China.
FAU - Cao, Fuyang
AU  - Cao F
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; Department of Orthopedics, the First Affiliated Hospital 
      of Zhengzhou University, 1 Jian East Road, Erqi District, Zhengzhou, 450052, 
      China.
FAU - Li, Hao
AU  - Li H
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - He, Songlin
AU  - He S
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - Zhao, Tianyuan
AU  - Zhao T
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - Deng, Haoyuan
AU  - Deng H
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - Li, Jianwei
AU  - Li J
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - Sun, Zhiqiang
AU  - Sun Z
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China.
FAU - Hao, Chunxiang
AU  - Hao C
AD  - Institute of Anesthesia, Chinese PLA General Hospital, 28 Fuxing Road, Haidian 
      District, Beijing, 100853, China.
FAU - Xu, Jianzhong
AU  - Xu J
AD  - Department of Orthopedics, the First Affiliated Hospital of Zhengzhou University, 
      1 Jian East Road, Erqi District, Zhengzhou, 450052, China. Electronic address: 
      xujianzhong@zzu.edu.cn.
FAU - Guo, Quanyi
AU  - Guo Q
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China. Electronic address: doctorguo_301@163.com.
FAU - Liu, Shuyun
AU  - Liu S
AD  - Institute of Orthopedics, the First Medical Center, Chinese PLA General Hospital, 
      Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of 
      Musculoskeletal Trauma & War Injuries PLA, 28 Fuxing Road, Haidian District, 
      Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, 
      China. Electronic address: clear_ann@163.com.
FAU - Guo, Weimin
AU  - Guo W
AD  - Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Department 
      of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 
      Guangzhou, 510080, China. Electronic address: guowm5@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220725
PL  - England
TA  - Acta Biomater
JT  - Acta biomaterialia
JID - 101233144
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta3)
RN  - 76057-06-2 (Transforming Growth Factors)
SB  - IM
MH  - Animals
MH  - *Cartilage, Articular
MH  - Chondrogenesis
MH  - *Fractures, Stress
MH  - Humans
MH  - Printing, Three-Dimensional
MH  - Regeneration
MH  - Sheep
MH  - Tissue Engineering/methods
MH  - Tissue Scaffolds/chemistry
MH  - Transforming Growth Factor beta/pharmacology
MH  - Transforming Growth Factor beta3/metabolism/pharmacology
MH  - Transforming Growth Factors/pharmacology
OTO - NOTNLM
OT  - Cartilage regeneration
OT  - Cell fate modulation
OT  - Mesenchymal stem cells
OT  - Microenvironment regulation
OT  - Microfracture
COIS- Declaration of Competing Interest All authors of this article have no conflicts 
      of interest regarding the publication of this paper to declare.
EDAT- 2022/07/28 06:00
MHDA- 2022/09/09 06:00
CRDT- 2022/07/27 19:13
PHST- 2022/03/27 00:00 [received]
PHST- 2022/06/22 00:00 [revised]
PHST- 2022/07/19 00:00 [accepted]
PHST- 2022/07/28 06:00 [pubmed]
PHST- 2022/09/09 06:00 [medline]
PHST- 2022/07/27 19:13 [entrez]
AID - S1742-7061(22)00431-7 [pii]
AID - 10.1016/j.actbio.2022.07.029 [doi]
PST - ppublish
SO  - Acta Biomater. 2022 Sep 15;150:181-198. doi: 10.1016/j.actbio.2022.07.029. Epub 
      2022 Jul 25.