The Martino group combines research in immunology, stem cells, and bioengineering in order to understand the mechanisms governing tissue repair and regeneration. Ultimately, we aim to engineer novel regenerative strategies using bioengineering approaches.

Research

To design successful regenerative therapies and make regenerative medicine a more widespread reality, we need to understand how the body is able to create an environment suitable for regeneration. For instance, tissue injury and the healing process is usually accompanied by the activation of the immune system and the mobilization of endogenous stem cells. The type of immune response, its duration, and the cells involved can considerably change the outcome of the healing process from tissue repair (i.e. scarring/fibrosis and loss of function) to true regeneration.

One of the main goals of the group is to reveal the key mechanisms that lead to tissue repair or regeneration. Our research tools include genetically modified and chimeric mice, as well as injury models in tissues such as bone, skin, and muscle. Finally, we seek to engineer effective strategies that aim at reactivating and stimulating endogenous regenerative pathways using various bioengineering approaches (e.g. biomaterials, protein engineering and immunoengineering).

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1. Dissecting how the immune system modulates tissue repair and regeneration

Tissue injury and the healing response is usually accompanied by the activation of the immune system. The type of immune response, its duration, and the cells involved can considerably change the outcome of the healing process from incomplete restoration (i.e. scarring/fibrosis and loss of function) to complete recovery (i.e. regeneration). [1]​

Our group aims to uncover key mechanisms by which our immune system modulates tissue repair and regeneration. For example, we found that inflammatory pathways involving the cytokine IL-1β inhibit the regenerative capacity of endogenous and transplanted stem cells. We could significantly improve stem cell-driven bone regeneration by engineering a stem cell delivery system that integrates an inhibitor of the IL-1β signalling pathway. [2]

In addition to the innate immune system, the adaptive immune system – in particular, T lymphocytes – is most likely a key factor in the tissue-healing process. [1] We aim to understand how the adaptive immune system modulates tissue repair and regeneration. Ultimately, we seek to use bioengineering approaches involving biomaterials, protein engineering and immunoengineering to design novel regenerative therapies.

 

 

 

 

2. Better delivery system for stem cells and pro-regenerative molecules

Stem cells and morphogens, such as growth factors, are obviously very promising for regenerative medicine. However, how can we actually create efficient and safe regenerative therapeutics based on stem cells or growth factors? While the first challenge is to find the right stem cell or the right morphogen for a particular application in regenerative medicine, the second challenge is to develop an appropriate and safe way to deliver these therapeutics. For example, stem cells need to survive and integrate into the host tissue after implantation, while morphogens need to signal in a controlled manner to stimulate endogenous regenerative pathways. [3-9] 

In addition, both stem cells and morphogens must display very limited side effects. To tackle these challenges, our group is developing delivery systems for stem cells and growth factors that are designed to maximize their therapeutic potential while limiting their side effects. For example, bone regeneration induced by mesenchymal stem cells has been significantly improved by limiting the inflammatory effect on stem cells. [2] Growth factor efficiency in promoting bone regeneration or chronic wound repair has been considerably enhanced by engineering growth factors to process a “built-in” delivery system which targets the endogenous extracellular matrix in our tissue. [7] 

Possible clinical applications:

  • Chronic wounds (diabetic and venous ulcers)
  • Scar prevention
  • Large musculoskeletal defects
  • Ischemia-reperfusion
  • Osteoarthrosis

References:

  1. Julier Z, Park AJ, Briquez PS, Martino MM, Promoting tissue regeneration by modulating the immune system. Acta Biomaterialia 53, 13-28 (2017).
  2. Martino MM, Maruyama K, Kuhn GA, Satoh T, Takeuchi O, Muller R, Akira S, Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nature communications 7, 11051 (2016).
  3. Briquez PS, Clegg LE, Martino MM, Gabhann FM, Hubbell JA, Design principles for therapeutic angiogenic materials. Nature Reviews Materials 1, 15006 (2016).
  4. Martino MM, Briquez PS, Maruyama K, Hubbell JA, Extracellular matrix-inspired growth factor delivery systems for bone regeneration. Advanced Drug Delivery Reviews 94, 41-52 (2015).
  5. Martino MM, Brkic S, Bovo E, Burger M, Schaefer DJ, Wolff T, Gurke L, Briquez PS, Larsson HM, Gianni-Barrera R, Hubbell JA, Banfi A, Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine. Frontiers in Bioengineering Biotechnology 3, 45 (2015).
  6. Briquez PS, Hubbell JA, Martino MM, Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing. Advances in Wound Care (New Rochelle) 4, 479-489 (2015).
  7. Martino MM, Briquez PS, Guc E, Tortelli F, Kilarski WW, Metzger S, Rice JJ, Kuhn GA, Muller R, Swartz MA, Hubbell JA, Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885-888 (2014).
  8. Martino MM, Briquez PS, Ranga A, Lutolf MP, Hubbell JA, Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proceedings of the National Academy of Sciences of the United States of America 110, 4563-4568 (2013).
  9. Martino MM, Tortelli F, Mochizuki M, Traub S, Ben-David D, Kuhn GA, Muller R, Livne E, Eming SA, Hubbell JA, Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Science translational medicine 3, 100ra189 (2011).
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K Maruyama, Y Takayama, T Kondo, K Ishibashi, BR Sahoo, H Kanemaru, Y Kumagai, MM Martino, H Tanaka, N Ohno, Y Iwakura, N Takemura, M Tominaga, S Akira.

Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis.

Cell reports 19 (13), 2730-2742, 2017.

K Maruyama, N Takemura, MM Martino, T Kondo, S Akira.

Netrins as Prophylactic Targets in Skeletal Diseases: A Double-Edged Sword?

Pharmacological Research, 2017, 122, 46-52.

Y Pilehvar-Soltanahmadi, M Nouri, MM Martino, A Fattahi, E Alizadeh, M Darabi, M Rahmati-Yamchi, N Zarghami.

Cytoprotection, proliferation and epidermal differentiation of adipose tissue-derived stem cells on emu oil based electrospun nanofibrous mat.

Experimental Cell Research, 2017, 357(2), 192-201.

Z Julier, AJ Park, PS Briquez, MM Martino.

Promoting tissue regeneration by modulating the immune system.

Acta biomaterialia, 2017, 53, 13-28.

JA Hubbell, MM Martino, L De LaPorte, JJ Rice, F Tortelli.

Extracellular matrix heparin-binding domains.

US Patent 9,540,428 2017.

K Maruyama, T Kawasaki, M Hamaguchi, M Hashimoto, M Furu, H Ito, T Fujii, N Takemura, T Karuppuchamy, T Kondo, M Fukasaka, T Misawa, T Saitoh, Y Suzuki, MM Martino, Y Kumagai, S Akira.

Bone-protective Functions of Netrin 1 Protein.

Journal of Biological Chemistry, 2016, 291(46):23854-23868. doi: 10.1074/jbc.M116.738518.

Martino MM, Maruyama K, Kuhn AG, Satoh T, Takeuchi O, Müller R, Shizuo A.

Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration.

Nat Commun. 2016;7:11051. Epub: 2016 Mar 22. doi: 10.1038/ncomms11051. PMCID: PMC4804175.

Briquez PS, Clegg LE, Martino MM, Gabhann FM, Hubbell JA.

Design principles for therapeutic angiogenic materials.

Nat Rev Mats 2016;1:15006. doi: 10.1038/natrevmats.2015.6.

Briquez PS, Hubbell JA, Martino MM.

Extracellular matrix-inspired growth factor delivery systems for skin wound healing.

Adv Wound Care (New Rochelle). 2015 Aug 1;4(8):479-489. doi:10.1089/wound.2014.0603.

Martino MM, Briquez PS, Maruyama K, Hubbell JA.

Extracellular matrix-inspired growth factor delivery systems for bone regeneration.

Adv Drug Deliv Rev; 2015 Nov 1;94:41-52. doi: 10.1016/j.addr.2015.04.007.

Najjar M, Manzoli V, Martino MM, Molano RD, Pileggi A, Camillo R, Hubbell JA, Tomei AA.

Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice.

Biotechnol Bioeng; 2015 Sep;112(9):1916-26. doi: 10.1002/bit.25589.

Martino MM, Brkic S, Bovo E, Burger M, Schaefer DJ, Briquez PS, Gianni-Barrera R, Hubbell JA, Banfi A.

Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.

Front Bioeng Biotechnol; 2015 Apr 1;3:45. doi: 10.3389/fbioe.2015.00045.

Maruyama K, Fukasaka M, Uematsu S, Takeuchi O, Kondo T, Saitoh T, Martino MM, Akira S.

AZI2 regulates bone mass by fine-tuning osteoclast survival.

J Biol Chem; 2015 Apr 10;290(15):9377-86. doi: 10.1074/jbc.M114.631374.

Julier Z, Martino MM, de Titta A, Jeanbart J, Hubbell JA.

The immunological activity of the extra domain A of fibronectin (EDA) in agonizing TLR4 and inducing CD8+ T cell responses is cryptic and exposed by elastase 2.

Sci Rep; 2015 Feb 24;5:8569. doi: 10.1038/srep08569.

Vila OF, Martino MM, Nebuloni L, Kuhn G, Pérez-Amodio S, Müller R, Hubbell JA, Rubio N, Blanco J.

Bioluminescent and μCT tomography imaging of bone repair induced by fibrin-binding growth factors.

Acta Biomater; 2014 Oct;10(10):4377-89. doi: 10.1016/j.actbio.2014.05.028.

Sacchi V, Mittermayr M, Hartinger J, Martino MM, Wolbank S, Hofmann A, Largo R, Marshall J, Groppa E, Gianni-Barrera R, Ehrbar M, Hubbell JA, Redl H, Banfi A.

Sustained and highly tunable delivery of recombinant VEGF164 from optimized fibrin matrices ensures normal, stable and functional angiogenesis.

Proc Natl Acad Sci U S A; 2014 May 13;111(19):6952-7. doi: 10.1073/pnas.1404605111.

Martino MM, Briquez PS, Güç E, Tortelli F, Kilarski WW, Metzger S, Rice JJ, Kuhn GA, Müller R, Swartz MA, Hubbell JA.

Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing.

Science; 2014 Feb 21;343(6173):885-8. doi: 10.1126/science.1247663.

Mosiewicz KA, Kolb L, van der Vlies AJ, Martino MM, Lienemann P, Hubbell JA, Ehrbar M, Lutolf MP.

In situ cell fate manipulation by light-activated enzymatic hydrogel patterning.

Nat Mater; 2013 Nov;12(11):1072-8. doi: 10.1038/nmat3766.

Maruyama K, Uematsu S, Kondo T, Takeuchi O, Martino MM, Kawasaki T, Akira S.

Strawberry notch homologue 2 plays a key role in fine-tuning osteoclast fusion.

J Exp Med; 2013 Sep 23;210(10):1947-60. doi: 10.1084/jem.20130512.2