The ultimate goal of pancreatic tissue engineering is to create a long-lived substitute organ to treat diabetes. However, the lack of neovascularization and the occurrence of immune response limit the efficacy of tissue-engineered pancreas after in vivo transplantation. Platelet-rich plasma (PRP) is an autologous platelet concentrate containing a large number of growth factors and immunoregulatory factors. The aim of this study was to evaluate rat pancreatic decellularized scaffold (PDS) loaded with PRP for vascularization, host inflammatory response and macrophage polarization in an animal model. The study results indicated that compared to PDS, PRP-loading PDS exhibited the enhanced mechanical properties and released growth factors in a slow and sustained manner to supplement the loss of growth factors during decellularization. In vitro, human umbilical vein endothelial cells (HUVECs) were seeded in PDS and PRP-loading PDS, and cultured in the circular perfusion system. When compared with PDS, PRP-loading PDS significantly promoted the colonization, proliferation and pro-angiogenic genes expression of cells on scaffolds. In vivo, PDS loaded with PRP then re-endothelialized with HUVECs were implanted subcutaneously in rats, which enhanced the angiogenesis of scaffolds, inhibited the host inflammatory response, and induced the polarization dominated by pro-regenerative M2 macrophages that also facilitated tissue vascular regeneration. Thus, the re-endothelialized PRP-loading PDS may represent a promising bioengineered pancreas with sustained vascularization and excellent biocompatibility.
WouCUnwinNHuangY, et al.
Implications of the growing burden of diabetes for premature cardiovascular disease mortality and the attainment of the sustainable development goal target 3.4. Cardiovasc Diagn Ther2019;
9: 140–149.
2.
GohSKBerteraSOlsenP, et al.
Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering. Biomaterials2013;
34: 6760–6772.
3.
OrlandoGFarneyACIskandarSS, et al.
Production and implantation of renal extracellular matrix scaffolds from porcine kidneys as a platform for renal bioengineering investigations. Ann Surg2012;
256: 363–370.
4.
BadylakSFTaylorDUygunK.Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng2011;
13: 27–53.
5.
WuDWanJHuangY, et al.
3D culture of MIN-6 cells on decellularized pancreatic scaffold: in vitro and in vivo study. BioMed Res Int2015;
2015: 432645.
6.
FolkmanJHochbergM.Self-regulation of growth in three dimensions. J Exp Med1973;
138: 745–753.
7.
UllahIAbu-DawudRBuschJF, et al.
VEGF – supplemented extracellular matrix is sufficient to induce endothelial differentiation of human iPSC. Biomaterials2019;
216: 119283.
8.
CampagnoloPGormleyAJChowLW, et al.
Pericyte seeded dual peptide scaffold with improved endothelialization for vascular graft tissue engineering. Adv Healthc Mater2016;
5: 3046–3055.
9.
CarmelietP.Angiogenesis in health and disease. Nat Med2003;
9: 653–660.
10.
CaoRBråkenhielmEPawliukR, et al.
Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med2003;
9: 604–613.
11.
MaruiAKanematsuAYamaharaK, et al.
Simultaneous application of basic fibroblast growth factor and hepatocyte growth factor to enhance the blood vessels formation. J Vasc Surg2005;
41: 82–90.
12.
CarmelietP.VEGF gene therapy: stimulating angiogenesis or angioma-genesis?Nat Med2000;
6: 1102–1103.
13.
YuanTZhangCZengB.Treatment of chronic femoral osteomyelitis with platelet-rich plasma (PRP): a case report. Transfus Apher Sci2008;
38: 167–173.
14.
AnituaEAndíISanchezM, et al.
Autologous preparations rich in growth factors promote proliferation and induce VEGF and HGF production by human tendon cells in culture. J Orthop Res2005;
23: 281–286.
15.
SunWLinHXieH, et al.
Collagen membranes loaded with collagen-binding human PDGF-BB accelerate wound healing in a rabbit dermal ischemic ulcer model. Growth Factors2007;
25: 309–318.
16.
KimSJKimSYKwonCH, et al.
Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors2007;
25: 77–86.
17.
JanmeyPAWinerJPWeiselJW.Fibrin gels and their clinical and bioengineering applications. J R Soc Interface2009;
6: 1–10.
18.
ZhaoHMaLZhouJ, et al.
Fabrication and physical and biological properties of fibrin gel derived from human plasma. Biomed Mater2008;
3: 015001.
19.
MarxRE.Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg2004;
62: 489–496.
20.
ManDPloskerHWinland-BrownJE.The use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery. Plastic Reconst Surg2001;
107: 238–229; discussion 229–237.
21.
KeaneTJLondonoRTurnerNJ, et al.
Consequences of ineffective decellularization of biologic scaffolds on the host response. Biomaterials2012;
33: 1771–1781.
22.
SchererSSTobalemMVigatoE, et al.
Nonactivated versus thrombin-activated platelets on wound healing and fibroblast-to-myofibroblast differentiation in vivo and in vitro. Plastic Reconst Surg2012;
129: e46–e54.
23.
BazzoniGDejanaEMaschioD.A. Platelet-neutrophil interactions. Possible relevance in the pathogenesis of thrombosis and inflammation. Haematologica1991;
76: 491–499.
24.
OmarNNRashedRREl-HazekRM, et al.
Platelet-rich plasma-induced feedback inhibition of activin A/follistatin signaling: a mechanism for tumor-low risk skin rejuvenation in irradiated rats. J Photochem Photobiol B, Biol2018;
180: 17–24.
25.
SpillerKLAnfangRRSpillerKJ, et al.
The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials2014;
35: 4477–4488.
26.
LinsleyCSWuBMTawilB.stem cell growth on and mechanical properties of fibrin-based biomimetic bone scaffolds. J Biomed Mater Res A2016;
104: 2945–2953.
27.
MoorenRECMHendriksEJvan den BeuckenJJJP, et al.
The effect of platelet-rich plasma in vitro on primary cells: rat osteoblast-like cells and human endothelial cells. Tissue Eng Part A2010;
16: 3159–3172.
28.
KakudoNMorimotoNOgawaT, et al.
Angiogenic effect of platelet-rich plasma combined with gelatin hydrogel granules injected into murine subcutis. J Tissue Eng Regen Med2017;
11: 1941–1948.
29.
ItoRMorimotoNPhamLH, et al.
Efficacy of the controlled release of concentrated platelet lysate from a collagen/gelatin scaffold for dermis-like tissue regeneration. Tissue Eng Part A2013;
19: 1398–1405.
30.
RoweSLStegemannJP.Interpenetrating collagen-fibrin composite matrices with varying protein contents and ratios. Biomacromolecules2006;
7: 2942–2948.
31.
CummingsCLGawlittaDNeremRM, et al.
Properties of engineered vascular constructs made from collagen, fibrin, and collagen-fibrin mixtures. Biomaterials2004;
25: 3699–3706.
32.
MosherDFSchadPE.Cross-linking of fibronectin to collagen by blood coagulation Factor XIIIa. J Clin Invest1979;
64: 781–787.
33.
DevineDVBishopPD.Platelet-associated factor XIII in platelet activation, adhesion, and clot stabilization. Semin Thromb Hemost1996;
22: 409–413.
34.
SkarjaGABrashJLBishopP, et al.
Protein and platelet interactions with thermally denatured fibrinogen and cross-linked fibrin coated surfaces. Biomaterials1998;
19: 2129–2138.
35.
GrasslEDOegemaTRTranquilloRT.Fibrin as an alternative biopolymer to type-I collagen for the fabrication of a media equivalent. J Biomed Mater Res2002;
60: 607–612.
36.
MartakosPKarwoskiT.Healing characteristics of hybrid and conventional polytetrafluoroethylene vascular grafts. ASAIO J1995;
41: M735–M741.
37.
RubensFDPerryDWHattonMW, et al.
Platelet accumulation on fibrin-coated polyethylene: role of platelet activation and factor XIII. Thromb Haemost1995;
73: 850–856.
38.
SugimoriEShintaniSIshikawaK, et al.
Effects of apatite foam combined with platelet-rich plasma on regeneration of bone defects. Dental Mater J2006;
25: 591–596.
39.
HarrisonSVavkenPKevyS, et al.
Platelet activation by collagen provides sustained release of anabolic cytokines. Am J Sports Med2011;
39: 729–734.
40.
TakamiyaMSaigusaKAokiY.Immunohistochemical study of basic fibroblast growth factor and vascular endothelial growth factor expression for age determination of cutaneous wounds. Am J Forensic Med Pathol2002;
23: 264–267.
41.
LiXTjwaMMoonsL, et al.
Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors. J Clin Invest2005;
115: 118–127.
42.
NakamuraYMorishitaRHigakiJ, et al.
Expression of local hepatocyte growth factor system in vascular tissues. Biochem Biophys Res Commun1995;
215: 483–488.
43.
BalajiSLeSaintMBhattacharyaSS, et al.
Adenoviral-mediated gene transfer of insulin-like growth factor 1 enhances wound healing and induces angiogenesis. J Surg Res2014;
190: 367–377.
44.
OrlovaVVLiuZGoumansMJ, et al.
Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways. Histol Histopathol2011;
26: 1219–1230.
45.
ChenWHLoWCHsuWC, et al.
Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy. Biomaterials2014;
35: 9599–9607.
46.
GobbiALadDKarnatzikosG.The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc2015;
23: 2170–2177.
47.
BendinelliPMatteucciEDogliottiG, et al.
Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-κB inhibition via HGF. J Cell Physiol2010;
225: 757–766.
48.
MontaseriABuschFMobasheriA, et al.
IGF-1 and PDGF-bb suppress IL-1β-induced cartilage degradation through down-regulation of NF-κB signaling: involvement of Src/PI-3K/AKT pathway. PloS One2011;
6: e28663.
49.
AnituaESánchezMNurdenAT, et al.
Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients. Rheumatology (Oxford, England)2007;
46: 1769–1772.
50.
AnituaESánchezMZalduendoMM, et al.
Fibroblastic response to treatment with different preparations rich in growth factors. Cell Proliferation2009;
42: 162–170.
51.
MorwoodSRNicholsonLB.Modulation of the immune response by extracellular matrix proteins. Arch Immunol Ther Exp (Warsz)2006;
54: 367–374.
52.
NeherMDWeckbachSFlierlMA, et al.
Molecular mechanisms of inflammation and tissue injury after major trauma – is complement the “bad guy”?J Biomed Sci2011;
18: 90.
53.
BrownBNRatnerBDGoodmanSB, et al.
Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials2012;
33: 3792–3802.
54.
GongDShiWYiSJ, et al.
TGFbeta signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol2012;
13: 31–06.
55.
GleissnerCAShakedILittleKM, et al.
CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol2010;
184: 4810–4818.
56.
VasinaEMCauwenberghsSFeijgeMA, et al.
Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis2011;
2: e211.
