Promotion of cartilage extracellular matrix by anti-inflammatory peptides-loaded zirconium metal-organic frameworks encapsulated in hydrogels

Xiaoping QIN; Tao LI; Cheng CHEN; Liu YANG

doi:10.16016/j.2097-0927.202111169

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Promotion of cartilage extracellular matrix by anti-inflammatory peptides-loaded zirconium metal-organic frameworks encapsulated in hydrogels

Biomedical Engineering | 更新时间：2026-01-09

- Promotion of cartilage extracellular matrix by anti-inflammatory peptides-loaded zirconium metal-organic frameworks encapsulated in hydrogels
- Journal of Army Medical University Vol. 44, Issue 7, Pages: 673-683(2022)
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)第一附属医院关节外科
  2.400016 重庆，重庆医科大学医学信息学院
- 作者简介：
- 基金信息：
- DOI：10.16016/j.2097-0927.202111169
  CLC： R318.08;R322.72;R977.6
- Received：23 November 2021，
  
  Revised：2022-01-28，
  
  Published：15 April 2022
- 稿件说明：
移动端阅览
Xiaoping QIN, Tao LI, Cheng CHEN, et al. Promotion of cartilage extracellular matrix by anti-inflammatory peptides-loaded zirconium metal-organic frameworks encapsulated in hydrogels[J]. Journal of Army Medical University, 2022, 44(7): 673-683.
DOI：

Xiaoping QIN, Tao LI, Cheng CHEN, et al. Promotion of cartilage extracellular matrix by anti-inflammatory peptides-loaded zirconium metal-organic frameworks encapsulated in hydrogels[J]. Journal of Army Medical University, 2022, 44(7): 673-683. DOI： 10.16016/j.2097-0927.202111169.

摘要

目的

制备一种可用于修复伴有骨关节炎的软骨缺损的兼具软骨再生和炎性微环境调控的水凝胶支架。

方法

通过溶剂热法制备锆金属有机框架(Zr MOF)，并负载抗炎肽KAFAK，用紫外光交联法制备普鲁兰多糖/聚乙二醇复合水凝胶，将Zr MOF封装于水凝胶内部，通过扫描电镜、溶胀平衡、降解实验和流变力学表征水凝胶的理化性能。以兔骨髓间充质干细胞(bone mesenchymal stem cells，BMSCs)作为种子细胞，用活/死细胞染色验证水凝胶的生物活性，测定软骨细胞外基质糖胺聚糖的含量和成软骨标志基因COL2A1和ACAN及肥大化基因COL10A1的表达。

结果

成功将抗炎肽KAFAK负载到Zr MOF，水合粒径为352.5 nm，粒径分布(PDI)为0.29，Zeta电位为(18.27±0.55)mV。普鲁兰多糖/聚乙二醇复合水凝胶封装Zr MOF后，随着Zr MOF含量的增加，扫描电镜观察到孔壁上的小孔越多；溶胀时间缩短，降解速度增加，流变性能改善。抗炎肽KAFAK负载到Zr MOF后再用水凝胶封装，到第21天，有(84.1±5.0)%的释放，显示出对抗炎肽KAFAK较好的缓释作用。活细胞在Gel、Gel-100 Zr MOF和Gel-100 Zr MOF@KAFAK组的存活比率分别为(90.7±5.4)%、(93.5±4.3)%和(91.9±3.1)%，均显示出良好的生物相容性。以兔BMSCs为种子细胞，在成软骨诱导培养7 d和14 d后，Gel-100 Zr MOF@KAFAK组相较于Gel和Gel-100 Zr MOF组糖胺聚糖含量有显著提高(

＜0.05)，成软骨标志基因COL2A1、ACAN表达显著升高(

＜0.05)，而肥大化基因COL10A1表达显著降低(

＜0.05)。

结论

成功将负载抗炎肽的Zr MOF封装于水凝胶内部，通过对抗炎肽KAFAK的持续释放控制炎性微环境，产生更多的软骨细胞外基质，有利于维持成软骨表型。

Abstract

Objective

To prepare a hydrogel scaffold with cartilage regeneration and inflammatory microenvironment control capacity for chondrodefects treatment in osteoarthritis.

Methods

The zirconium metal-organic framework (Zr MOF) was prepared by solvothermal synthesis and then loaded with anti-inflammatory peptide KAFAK. The pullulan/polyethylene glycol composite hydrogel was prepared by UV crosslinking. Then the obtained Zr MOF was encapsulated in the hydrogel. Then the physicochemical properties of the hydrogel were characterized by scanning electron microscopy (SEM)

swelling equilibrium

degradation experiments and rheological and mechanical studies. Rabbit bone mesenchymal stem cells (BMSCs) were used as seed cells. The bioactivity of the hydrogel and the content of glycosaminoglycans in the extracellular matrix were tested by live/dead staining. The expression of chondrogenic genes COL2A1 and ACAN

and hypertrophic gene COL10A1 was measured with RT-PCR.

Results

After being loaded with anti-inflammatory peptide KAFAK to Zr MOF

the hydrated particle exhibits a size of 352.5 nm

a particle size distribution (PDI) of 0.29

and a zeta potential of 18.27±0.55 mV. After the encapsulation of Zr MOF

when the content of Zr MOF was increased

there were more small holes in the scaffold observed by SEM

the swelling time was shortened

the degradation rate was increased and the rheological property was improved. In 21 d after KAFAK was loaded onto the Zr MOF and then encapsulated with hydrogel

the release of the peptide was (84.1±5.0)%

indicating a good sustained release. In Gel

Gel-100 Zr MOF

and Gel-100 Zr MOF@KAFAK groups

the cell survival rates was (90.7±5.4)%

(93.5±4.3)% and (91.9±3.1)%

respectively. With rabbit BMSCs as seed cells

after 7 and 14 d of chondrogenic induction

the glycosaminoglycan in Gel-100 Zr MOF @KAFAK group was significantly higher than that in Gel and Gel-100 Zr MOF group (

0.05). The results of RT-PCR indicated that the expression levels of COL2A1 and ACAN were increased

whereas that of COL10A1 was decreased (

0.05).

Conclusion

KAFAK-loaded Zr MOF is successfully encapsulated in hydrogels. The hydrogels control the inflammatory microenvironment through the sustained release of KAFAK

and result in more cartilage extracellular matrix and better maintenance of chondrogenic phenotype.

关键词

Keywords

references

KATZ J N, ARANT K R, LOESER R F. Diagnosis and treatment of hip and knee osteoarthritis: areview[J]. JAMA, 2021, 325(6): 568-578. DOI:10.1001/jama.2020.22171.

MARTEL-PELLETIER J, BARR A J, CICUTTINI F M, et al . Osteoarthritis[J ] . Nat Rev Dis Primers, 2016, 2: 16072. DOI: 10.1038/nrdp.2016.72.

KWON H, BROWN W E, LEE C A, et al . Surgical and tissue engineering strategies for articular cartilage and meniscus repair[J ] . Nat Rev Rheumatol, 2019, 15(9): 550-570. DOI:10.1038/s41584-019-0255-1.

ARMIENTO A R, ALINI M, STODDART M J. Articular fibrocartilage: why does hyaline cartilage fail to repair?[J]. Adv Drug Deliv Rev, 2019, 146: 289-305. DOI:10.1016/j.addr.2018.12.015.

MAKRIS E A, GOMOLL A H, MALIZOS K N, et al . Repair and tissue engineering techniques for articular cartilage[J ] . Nat Rev Rheumatol, 2015, 11(1): 21-34. DOI:10.1038/nrrheum.2014.157.

BALAKRISHNAN B, BANERJEE R. Biopolymer-based hydrogels for cartilage tissue engineering[J]. Chem Rev, 2011, 111(8): 4453-4474. DOI:10.1021/cr100123h.

HUA Y J, XIA H T, JIA L T, et al . Ultrafast, tough, and adhesive hydrogel based on hybrid photocrosslinking for articular cartilage repair in water-filled arthroscopy[J ] . Sci Adv, 2021, 7(35): eabg0628. DOI:10.1126/sciadv.abg0628.

XIE Y L, ZINKLE A, CHEN L, et al . Fibroblast growth factor signalling in osteoarthritis and cartilage repair[J ] . Nat Rev Rheumatol, 2020, 16(10): 547-564. DOI:10.1038/s41584-020-0469-2.

SWEET M B, THONAR E J, IMMELMAN A R, et al . Biochemical changes in progressive osteoarthrosis[J ] . Ann Rheum Dis, 1977, 36(5): 387-398. DOI:10.1136/ard.36.5.387.

YANG K G, SARIS D B, VERBOUT A J, et al . The effect of synovial fluid from injured knee joints on in vitro chondrogenesis[J ] . Tissue Eng, 2006, 12(10): 2957-2964. DOI:10.1089/ten.2006.12.2957..

LI X, LU Y, WANG Y X, et al . Thermo-responsive injectable naringin-loaded hydrogel polymerised sodium alginate/bioglass delivery for articular cartil age[J ] . Drug Deliv, 2021, 28(1): 1290-1300. DOI:10.1080/10717544.2021.1938752.

BRUGNANO J L, CHAN B K, SEAL B L, et al . Cell-penetrating peptides can confer biological function: regulation of inflammatory cytokines in human monocytes by MK2 inhibitor peptides[J ] . J Control Release, 2011, 155(2): 128-133. DOI:10.1016/j.jconrel.2011.05.007.

POH S, LIN J B, PANITCH A. Release of anti-inflammatory peptides from thermosensitive nanoparticles with degradable cross-links suppresses pro-inflammatory cytokine production[J]. Biomacromolecules, 2015, 16(4): 1191-1200. DOI:10.1021/bm501849p.

BARTLETT R L, PANITCH A. Thermosensitive nanopar-ticles with pH-triggereddegradation and release of anti- inflammatory cell-penetrating peptides[J]. Biomacromolecules, 2012, 13(8): 2578-2584. DOI:10.1021/bm300826v.

BARTLETT R L 2nd, SHARMA S, PANITCH A. Cell-penetrating peptides released from thermosensitive nanoparticles suppress pro-inflammatory cytokine response by specifically targeting inflamed cartilage explants[J]. Nanomedicine, 2013, 9(3): 419-427. DOI:10.1016/j.nano.2012.09.003.

MCMASTERS J, POH S, LIN J B, et al . Delivery of anti-inflammatory peptides from hollow PEGylated poly(NIPAM) nanoparticles reduces inflammation in an ex vivo osteoarthritis model[J ] . J Control Release, 2017, 258: 161-170. DOI:10.1016/j.jconrel.2017.05.008..

LIN J B, POH S, PANITCH A. Controlled release of anti-inflammatory peptides from reducible thermosensitive nanoparticles suppresses cartilage inflammation[J]. Nanomedicine, 2016, 12(7): 2095-2100. DOI:10.1016/j.nano.2016.05.010.

LI T, YANG J J, WENG C M, et al . Intra-articular injection of anti-inflammatory peptide-loaded glycol chitosan/fucoidan nanogels to inhibit inflammation and attenuate osteoarthritis progression[J ] . Int J Biol Macromol, 2021, 170: 469-478. DOI:10.1016/j.ijbiomac.2020.12.158.

DOONAN C, RICCÒ R, LIANG K, et al . Metal-organic frameworks at the biointerface: synthetic strategies and applications[J ] . Acc Chem Res, 2017, 50(6): 1423-1432. DOI:10.1021/acs.accounts.7b00090.

ZHOU Z X, VÁZQUEZ-GONZÁLEZ M, WILLNER I. Stimuli-responsive metal-organic framework nanoparticles for controlled drug delivery and medical applications[J]. Chem Soc Rev, 2021, 50(7): 4541-4563. DOI:10.1039/d0cs01030h.

DELLA ROCCA J, LIU D M, LIN W B. Nanoscale metal-organic frameworks for biomedical imaging and drug delivery[J]. Acc Chem Res, 2011, 44(10): 957-968. DOI:10.1021/ar200028a.

XUE S, ZHOU X J, SANG W L, et al . Cartilage-targeting peptide-modified dual-drug delivery nanoplatform with NIR laser response for osteoarthritis therapy[J ] . Bioact Mater, 2021, 6(8): 2372-2389. DOI:10.1016/j.bioactmat.2021.01.017.

XIONG F, QIN Z N, CHEN H M, et al . pH-responsive and hyaluronic acid-functionalized metal-organic frameworks for therapy of osteoarthritis[J ] . J Nanobiotechnol, 2020, 18(1): 139. DOI:10.1186/s12951-020-00694-3.

LI Z, PENG Y, XIA X Y, et al . Sr/PTA metal organic framework as a drug delivery system for osteoarthritis treatment[J ] . Sci Rep, 2019, 9(1): 17570. DOI:10.1038/s41598-019-54147-5.

LI Z, PENG Y, PANG X C, et al . Potential therapeutic effects of Mg/HCOOH metal organic framework on relieving osteoarthritis[J ] . Chem Med Chem, 2020, 15(1): 13-16. DOI:10.1002/cmdc.201900546.

LI Z, ZHAO S J, WANG H Z, et al . Functional groups influence and mechanism research of UiO-66-type metal-organic frameworks for ketoprofen delivery[J ] . Colloids Surf B Biointerfaces, 2019, 178: 1-7. DOI:10.1016/j.colsurfb.2019.02.027.

SHYNGYS M, REN J, LIANG X Q, et al . Metal-organic framework (MOF)-based biomaterials for tissue engineering and regenerative medicine[J ] . Front Bioeng Biotechnol, 2021, 9: 603608. DOI:10.3389/fbioe.2021.603608.

TOPRAK Ö, TOPUZ B, MONSEF Y A, et al . BMP-6 carrying metal organic framework-embedded in bioresorbable electrospun fibers for enhanced bone regeneration[J ] . Mater Sci Eng C Mater Biol Appl, 2021, 120: 111738. DOI:10.1016/j.msec.2020.111738.

XUE Y Y, ZHUZ, ZHANG X, et al . Accelerated bone regeneration by MOF modified multifunctional membranes through enhancement of osteogenic and angiogenic performance[J ] . Adv Healthc Mater, 2021, 10(6): e2001369. DOI:10.1002/adhm.202001369.

ZHONG L N, CHEN J Y, MA Z Y, et al . 3D printing of metal-organic framework incorporated porous scaffolds to promote osteogenic differentiation and bone regeneration[J ] . Nanoscale, 2020, 12(48): 24437-24449. DOI:10.1039/d0nr06297a.

TELGERD M D, SADEGHINIA M, BIRHANU G, et al . Enhanced osteogenic differentiation of mesenchymal stem cells on metal-organic framework based on copper, zinc, and imidazole coated poly-l-lactic acid nanofiber scaffolds[J ] . J Biomed Mater Res A, 2019, 107(8): 1841-1848. DOI:10.1002/jbm.a.36707.

QIN X P, HE R, CHEN H, et al . Methacrylated pullulan/polyethylene (glycol) diacrylate composite hydrogel for cartilage tissue engineering[J ] . J Biomater Sci Polym Ed, 2021, 32(8): 1057-1071. DOI:10.1080/09205063.2021.1899888.

ZHANG Y, WANG F M, LIU C Q, et al . Nanozyme decorated metal-organic frameworks for enhanced photodynamic therapy[J ] . ACS Nano, 2018, 12(1): 651-661. DOI:10.1021/acsnano.7b07746.

HALEEM A M, CHU C R. Advances in tissue engineering techniques for articular cartilage repair[J]. Oper Tech Orthop, 2010, 20(2): 76-89. DOI:10.1053/j.oto.2009.10.004.

LOESER R F, GOLDRING S R, SCANZELLO C R, et al . Osteoarthritis: a disease of the joint as an organ[J ] . Arthritis Rheum, 2012, 64(6): 1697-1707. DOI:10.1002/art.34453.

STEINERT A F, GHIVIZZANI S C, RETHWILM A, et al . Major biological obstacles for persistent cell-based regeneration of articular cartilage[J ] . Arthritis Res Ther, 2007, 9(3): 213. DOI:10.1186/ar2195.

LIU Y Z, PENG L Q, LI L L, et al . 3D-bioprinted BMSC-laden biomimetic Multiphasic scaffolds for efficient repair of osteochondral defects in an osteoarthritic rat model[J ] . Biomaterials, 2021, 279: 121216. DOI:10.1016/j.biomaterials.2021.121216.

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