Novel strategy to regulate foreign body response and enhance in situ periodontal regeneration

Release of cytokines and chemoattractant from stiff hydrogels makes a difference and appears as a new strategy to promote the self-regeneration of damaged periodontal tissues after “Periodontitis”, an illness affecting over 70% of the worldwide population [He et al., Acta Biomateralia (2019), doi.org/10.1016/j.actbio.2019.02.004].

Periodontitis, most commonly referred to as “Periodontal disease”, consists on a series of inflammatory events that affect the integrity of the tissues (ligament, bone and cementum) supporting the teeth. This ultimately results on loosening and potential lost of the teeth. Attempts to regenerate the tissue by combination of stem cells and high stiffness hydrogels have resulted in promising results in-vitro. However, when an implant material is introduced into the body a process called foreign body response is initiated. This process, in many cases, results on the encapsulation of the implant, hindering an adequate material-host interaction and fast tissue formation. Main players coordinating the foreign body recognition and response are the macrophages. Macrophages change their natural state (known as M0), to a pro-inflammatory (M1) or pro-healing (M2) state depending on the environmental conditions on a process known as polarization.

Now researchers from the Fourth Military Medical University in China have developed a hydrogel system that encapsulates cytokines capable of promoting the polarization of macrophages to the desired pro-healing (M2) state of macrophages, and a chemoattractant capable of recruiting stem cells from the patient`s tissue. 

The team used a stiff gelatin-based hydrogel cross-linked with transglutaminase to encapsulate a pro-healing cytokine (IL-4) and a chemokine protein capable of attracting stem cells (SDF-1α). Their test results in-vitro show that the co-presentation of both IL-4 and SDF-1α in TG-gels promotes the formation of an artificial pro-healing environment that modulates the macrophage activity towards a regenerative state, as shown by an upregulation of characteristic M2 markers such as arginase and CD260. They also showed that the presentation of SDF-1α attracts stem cells towards the material. Altogether, when both stem cells and macrophages are cultured together, these gels promote an enhanced osteogenic differentiation of stem cells that will potentially lead to the formation of a neo-periodontal tissue.

In view of these promising results, the researchers took the experiment one-step further and tested them in-vivo in a rat periodontal defect model. These experiments revealed the capability of the IL-4 and SDF-1α loaded stiff TG-gels to polarize macrophages to M2 within an in vivo milieu and to recruit resident stem cells toward the site of injury. Most importantly, their results show that these gels could accelerate the regeneration of the complex periodontal tissue apparatus including alveolar bone, periodontal and  the root cementum.