Technological innovation has been integral to the development of tissue engineering over the past 25 years. Future advances will require the next generation of tissue engineers to embrace emerging technologies. In this study, we discuss four key areas of opportunity in which technology can play a role: biological manipulation, advanced characterization, process automation, and personalized medicine. This encompasses key developments in transdifferentiation, gene editing, spatially resolved -omics, and three-dimensional bioprinting. Taken together, we can imagine an idealized future in which computational predictions made by machine learning algorithms are used to program cells and materials to create personalized tissue constructs within automated culture systems.
Impact Statement
History has shown us how tissue engineering can be advanced by embracing technological innovation. In this perspective, we highlight some of the most promising emerging technologies and discuss how they can be integrated into existing tissue engineering protocols. The proposed technologies offer the opportunity to reshape how we currently design, engineer, and characterize tissue grafts for improved in vivo regeneration.
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References
1.
BellE., EhrlichH.P., ButtleD.J., and NakatsujiT.Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science, 211, 1052, 1981.
2.
FreedL.E., MarquisJ.C., NohriaA., EmmanualJ., MikosA.G., and LangerR.Neocartilage formation in vitro and in vivo using cells cultured on synthetic biodegradable polymers. J Biomed Mater Res, 27, 11, 1993.
3.
FreedL.E., Vunjak-NovakovicG., BironR.J., et al.Biodegradable polymer scaffolds for tissue engineering. Nat Biotechnol, 12, 689, 1994.
4.
ThomsonJ.A., Itskovitz-EldorJ., ShapiroS.S., et al.Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145, 1998.
5.
TakahashiK., and YamanakaS.Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663, 2006.
6.
MacNeilS.Progress and opportunities for tissue-engineered skin. Nature, 445, 874, 2007.
7.
BartlettW., SkinnerJ.A., GoodingC.R., et al.Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee. J Bone Joint Surg Br, 87, 640, 2005.
8.
DolginE.Next-generation stem cell therapy poised to enter EU market. Nat Biotechnol, 33, 224, 2015.
9.
SchmidtC.Gintuit cell therapy approval signals shift at US regulator. Nat Biotechnol, 30, 479, 2012.
10.
YuJ., VodyanikM.A., Smuga-OttoK., et al.Induced pluripotent stem cell lines derived from human somatic cells. Science, 318, 1917, 2007.
11.
WuS.M., and HochedlingerK.Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol, 13, 497, 2011.
12.
EfeJ.A., HilcoveS., KimJ., et al.Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol, 13, 215, 2011.
13.
KimJ., EfeJ.A., ZhuS., et al.Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A, 108, 7838, 2011.
14.
KurianL., Sancho-MartinezI., NivetE., et al.Conversion of human fibroblasts to angioblast-like progenitor cells. Nat Methods, 10, 77, 2013.
15.
ZhuS., RezvaniM., HarbellJ., et al.Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature, 508, 93, 2014.
16.
IedaM., FuJ.-D., Delgado-OlguinP., et al.Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell, 142, 375, 2010.
17.
VierbuchenT., OstermeierA., PangZ.P., KokubuY., SudhofT.C., and WernigM.Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463, 1035, 2010.
18.
SekiyaS., and SuzukiA.Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature, 475, 390, 2011.
19.
Ben-DavidU., and BenvenistyN.The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer, 11, 268, 2011.
20.
JinekM., ChylinskiK., FonfaraI., HauerM., DoudnaJ.A., and CharpentierE.A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 337, 816, 2012.
21.
CongL., RanF.A., CoxD., et al.Multiplex genome engineering using CRISPR/Cas systems. Science, 339, 819, 2013.
22.
MaliP., YangL., EsveltK.M., et al.RNA-Guided human genome engineering via Cas9. Science, 339, 823, 2013.
23.
RanF.A., HsuP.D., WrightJ., AgarwalaV., ScottD.A., and ZhangF.Genome engineering using the CRISPR-Cas9 system. Nat Protoc, 8, 2281, 2013.
24.
QiL.S., LarsonM.H., GilbertL.A., et al.Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell, 152, 1173, 2013.
25.
GilbertL.A., LarsonM.H., MorsutL., et al.CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell, 154, 442, 2013.
26.
HiltonI.B., D'IppolitoA.M., VockleyC.M., et al.Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol, 33, 510, 2015.
27.
ChakrabortyS., JiH., KabadiA.M., GersbachC.A., ChristoforouN., and LeongK.W.A CRISPR/Cas9-based system for reprogramming cell lineage specification. Stem Cell Reports, 3, 940, 2014.
28.
BlackJ.B., AdlerA.F., WangH.-G., et al.Targeted epigenetic remodeling of endogenous loci by CRISPR/Cas9-based transcriptional activators directly converts fibroblasts to neuronal cells. Cell Stem Cell, 19, 406, 2016.
29.
ArmstrongJ.P.K., and PerrimanA.W.Strategies for cell membrane functionalization. Exp Biol Med, 241, 1098, 2016.
30.
DickinsonS.C., SuttonC.A., BradyK., et al.The Wnt5a receptor, receptor tyrosine kinase-like orphan receptor 2, is a predictive cell surface marker of human mesenchymal stem cells with an enhanced capacity for chondrogenic differentiation. Stem Cells, 35, 2280, 2017.
31.
LundR.J., NärväE., and LahesmaaR.Genetic and epigenetic stability of human pluripotent stem cells. Nat Rev Genet, 13, 732, 2012.
32.
LockhartD.J., and WinzelerE.A.Genomics, gene expression and DNA arrays. Nature, 405, 827, 2000.
33.
BeckS., OlekA., and WalterJ.From genomics to epigenomics: a loftier view of life. Nat Biotechnol, 17, 1144, 1999.
34.
WangZ., GersteinM., and SnyderM.RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet, 10, 57, 2009.
35.
AebersoldR., and MannM.Mass spectrometry-based proteomics. Nature, 422, 198, 2003.
36.
WenkM.R.The emerging field of lipidomics. Nat Rev Drug Discov, 4, 594, 2005.
37.
BakerM.Metabolomics: from small molecules to big ideas. Nat Methods, 8, 117, 2011.
38.
CranfordS.W., BoerJ.D., BlitterswijkC.V., and BuehlerM.J.Materiomics: an—omics approach to biomaterials research. Adv Mater, 25, 802, 2013.
39.
WangD., and BodovitzS.Single cell analysis: the new frontier in “omics.” Trends Biotechnol, 28, 281, 2010.
40.
StahlP.L., SalmenF., VickovicS., et al.Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science, 353, 78, 2016.
41.
MarxV.Mapping proteins with spatial proteomics. Nat Methods, 12, 815, 2015.
42.
ReznikovN., BiltonM., LariL., StevensM.M., KrögerR.Fractal-like hierarchical organization of bone begins at the nanoscale. Science, 360, eaao2189, 2018.
43.
BertazzoS., GentlemanE., CloydK.L., ChesterA.H., YacoubM.H., and StevensM.M.Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat Mater, 12, 576, 2013.
44.
HuangB., BabcockH., and ZhuangX.Breaking the diffraction barrier: super-resolution imaging of cells. Cell, 143, 1047, 2010.
45.
BergholtM.S., St-PierreJ.P., OffedduG.S., et al.Raman spectroscopy reveals new insights into the zonal organization of native and tissue-engineered articular cartilage. ACS Cent Sci, 2, 885, 2016.
46.
BergholtM.S., SerioA., McKenzieJ.S., et al.Correlated heterospectral lipidomics for biomolecular profiling of remyelination in multiple sclerosis. ACS Cent Sci, 4, 39, 2018.
47.
ChughtaiK., and HeerenR.M.A.Mass spectrometric imaging for biomedical tissue analysis. Chem Rev, 110, 3237, 2010.
48.
BergholtM.S., AlbroM.B., and StevensM.M.Online quantitative monitoring of live cell engineered cartilage growth using diffuse fiber-optic Raman spectroscopy. Biomaterials, 140, 128, 2017.
49.
HagenmullerH., HitzM., MerkleH.P., MeinelL., and MullerR.Design and validation of a novel bioreactor principle to combine online micro-computed tomography monitoring and mechanical loading in bone tissue engineering. Rev Sci Instrum, 81, 014303, 2010.
50.
AhearneM., BagnaninchiP.O., YangY., and El HajA.J.Online monitoring of collagen fibre alignment in tissue-engineered tendon by PSOCT. J Tissue Eng Regen Med, 2, 521, 2008.
51.
GaoF.G., JeevarajanA.S., and AndersonM.M.Long-term continuous monitoring of dissolved oxygen in cell culture medium for perfused bioreactors using optical oxygen sensors. Biotechnol Bioeng, 86, 425, 2004.
52.
StarlyB., and ChoubeyA.Enabling sensor technologies for the quantitative evaluation of engineered tissue. Ann Biomed Eng, 36, 30, 2008.
53.
ArcherR., and WilliamsD.J.Why tissue engineering needs process engineering. Nat Biotechnol, 23, 1353, 2005.
54.
SiddappaR., LichtR., van BlitterswijkC., and BoerJ.D.Donor variation and loss of multipotency during in vitro expansion of human mesenchymal stem cells for bone tissue engineering. J Orthop Res, 25, 1029, 2007.
55.
van der ValkJ., BrunnerD., De SmetK., et al.Optimization of chemically defined cell culture media—replacing fetal bovine serum in mammalian in vitro methods. Toxicol Vitr, 24, 1053, 2010.
56.
ChenG., GulbransonD.R., HouZ., et al.Chemically defined conditions for human iPSC derivation and culture. Nat Methods, 8, 424, 2011.
57.
KatoR., IejimaD., AgataH., et al.A compact, automated cell culture system for clinical scale cell expansion from primary tissues. Tissue Eng Part C, 16, 947, 2010.
58.
LiuY., HourdP., ChandraA., and WilliamsD.J.Human cell culture process capability: a comparison of manual and automated production. J Tissue Eng Regen Med, 4, 45, 2010.
59.
DerbyB.Printing and prototyping of tissues and scaffolds. Science, 338, 921, 2012.
60.
ArmstrongJ.P.K., BurkeM., CarterB.M., DavisS.A., and PerrimanA.W.3D bioprinting using a templated porous bioink. Adv Healthc Mater, 5, 1724, 2016.
61.
GrahamA.D., OlofS.N., BurkeM.J., et al.High-resolution patterned cellular constructs by droplet-based 3D printing. Sci Rep, 7, 7004, 2017.
62.
KangH.-W., LeeS.J., KoI.K., KenglaC., YooJ.J., and AtalaA.A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechnol, 34, 312, 2016.
63.
MartinI., WendtD., and HebererM.The role of bioreactors in tissue engineering. Trends Biotechnol, 22, 80, 2004.
64.
RadisicM., MarsanoA., MaidhofR., WangY., and Vunjak-NovakovicG.Cardiac tissue engineering using perfusion bioreactor systems. Nat Protoc, 3, 719, 2008.
65.
GerisL., LambrechtsT., CarlierA., and PapantoniouI.The future is digital: in silico tissue engineering. Curr Opin Biomed Eng, 6, 92, 2018.
66.
BryantS.J., and VernereyF.J.Programmable hydrogels for cell encapsulation and neo-tissue growth to enable personalized tissue engineering. Adv Healthc Mater, 7, 1700605, 2018.
67.
SunW., DarlingA., StarlyB., and NamJ.Computer-aided tissue engineering: overview, scope and challenges. Biotechnol Appl Biochem, 39, 29, 2004.
68.
NevesL.S., RodriguesM.T., ReisR.L., and GomesM.E.Current approaches and future perspectives on strategies for the development of personalized tissue engineering therapies. Expert Rev Precis Med Drug Dev, 1, 93, 2016.
69.
De SolA., ThiesenH.J., ImitolaJ., SalasREC.Big-data-driven stem cell science and tissue engineering: vision and unique opportunities. Cell Stem Cell, 20, 157, 2017.
