Smart Hydrogels for the Augmentation of Bone Regeneration by Endogenous Mesenchymal Progenitor Cell Recruitment.

Philipp S Lienemann,Manuel Koch,Ulrich Blache,Stéphanie Metzger,Matthias P Lutolf,Queralt Vallmajo‐Martin,Olaia Naveiras,Panagiota Papageorgiou,Ana Sala,Wilfried Weber,Sylke Hoehnel,Martin Ehrbar,Aline Roch,Raphael Reuten,Franz E Weber,Anna‐Sofia Kiveliö,Vincent Milleret

doi:10.1002/advs.201903395

Abstract

The treatment of bone defects with recombinant bone morphogenetic protein‐2 (BMP‐2) requires high doses precluding broad clinical application. Here, a bioengineering approach is presented that strongly improves low‐dose BMP‐2‐based bone regeneration by mobilizing healing‐associated mesenchymal progenitor cells (MPCs). Smart synthetic hydrogels are used to trap and study endogenous MPCs trafficking to bone defects. Hydrogel‐trapped and prospectively isolated MPCs differentiate into multiple lineages in vitro and form bone in vivo. In vitro screenings reveal that platelet‐derived growth factor BB (PDGF‐BB) strongly recruits prospective MPCs making it a promising candidate for the engineering of hydrogels that enrich endogenous MPCs in vivo. However, PDGF‐BB inhibits BMP‐2‐mediated osteogenesis both in vitro and in vivo. In contrast, smart two‐way dynamic release hydrogels with fast‐release of PDGF‐BB and sustained delivery of BMP‐2 beneficially promote the healing of bone defects. Collectively, it is shown that modulating the dynamics of endogenous progenitor cells in vivo by smart synthetic hydrogels significantly improves bone healing and holds great potential for other advanced applications in regenerative medicine.

Highlights

Bone defects resulting from trauma or disease are currently treated by transplantation of autologous bone.[1]
In order to have a highly controlled and modular system to recruit and grow mesenchymal progenitor cells (MPCs), the previously described TG-poly(ethylene glycol) (PEG) hydrogels were used.[10a,b] These synthetic TG-PEG hydrogels are formed by the transglutaminase (TG) enzyme factor XIII (FXIII) that cross-links equimolar blends of eight-arm PEG precursors functionalized with either a peptide sequence containing a glutamine (n-PEG-Gln) or a lysine (n-PEG-MMPsensitive-Lys or n-PEG-MMPnondegradable-Lys) under physiological conditions
As shown in earlier studies, the design of these TG-PEG hydrogels allows their modular tailoring with respect to presentation of cell adhesion sites, proteolytic degradability, or mechanical properties (Figure 1B).[10c,11e,13] When formed at low initial polymer concentration (1.7–2.3% w/v), TG-PEG hydrogels were stable and did not swell in a physiological buffer (Figure 1C)

Summary

Introduction

Bone defects resulting from trauma or disease are currently treated by transplantation of autologous bone.[1] due to limited supply and transplantationassociated donor site morbidity, great efforts were put into development of offthe-shelf materials including recombinant osteogenic factors such as bone morphogenetic protein (BMP).[2] BMP has shown promising results in preclinical evaluations, its application in clinical settings requires high doses that bear the risk of severe side effects.[3] a significant effort has been directed toward the improved delivery of low-dose BMP.[4] A main reason for the low BMP-2 efficacy can be attributed to the limited availability of endogenous mesenchymal progenitor cells (MPCs) at the site of large bone defects.[5] it has been postulated

Results

Discussion

Conclusion