In Situ Tissue Engineering: Seducing the Body to Regenerate

Novel tissue engineering (TE) strategies are increasingly focusing on the endogenous regeneration of damaged tissue directly in its functional site. This approach of in situ TE revolves around the use of bioresorbable scaffolds specifically designed to recruit and accommodate endogenous cells upon implantation and to stimulate neotissue formation and remodeling. By departing from the classical in vitro TE paradigm of growing tissues in the laboratory, in situ TE approaches can offer readily available grafts at reduced costs and regulatory complexity, especially when using synthetic scaffolds. This special collection features a selection of compelling recent articles that convey the state-of-the-art in in situ TE using synthetic-based scaffolds for load-bearing tissues, such as cardiovascular and orthopedic applications, and the current challenges toward clinical translation.

Scaffold-driven endogenous repair encompasses two important and highly interrelated aspects, namely (1) cell recruitment and (2) immunomodulation. A comprehensive review by Im provides an overview of the various recruitment factors involved in the recruitment of stem and progenitor cells, and the use of scaffolds to deliver such factors locally to induce endogenous cartilage regeneration. ¹ The scaffold's microstructural and topological design are effective tools in controlling the local migration of cells, as illustrated by Yoon et al. ² Instead of directly targeting downstream progenitor cells and/or tissue cells, Talacua et al. showed a remarkable increase in CD34⁺ (progenitor) cells and enhanced arterial regeneration after 3 months in rats as the downstream result of a significant increase in immediate leukocyte (neutrophils and monocyte-derived macrophages) infiltration within the first days of implantation, stimulated through local release of monocyte chemoattractant protein-1. ³ Such a phased healing cascade is in correspondence with previous findings (Roh et al., PNAS, 2010) and emphasizes the importance of the initial host response to the implanted scaffold.

In situ TE is built on the notion that the host response to an implanted scaffold is not necessarily detrimental, but that it can be modulated to induce regeneration. Apart from the type of material (e.g., biological or synthetic, as reviewed by Wiles et al. ⁴ ), the scaffold's mechanical properties, microstructure, surface chemistry, topology, and degradation kinetics are instrumental in immunomodulation, as well as the incorporation of biological factors such as extracellular matrix components, stem cells, or signaling factors. Interesting studies by Wise et al. and Rothuizen et al. highlight the importance of material chemistry and structure on the host response after subcutaneous implantation.^5,6 Correspondingly, a thorough study by Kim et al. nicely demonstrates the importance of the material composition on the regeneration of new cartilage in situ. ⁷ Notably, all the aforementioned studies report superior regenerative performance of synthetic–biological hybrid scaffolds in comparison with purely synthetic scaffolds. Interestingly, Pontailler et al. report on a successful method to avoid the use of a biological ingredient by functionalizing their vascular scaffolds with an Arg-Gly-Asp (RGD)-peptide. ⁸ Taking such a fully synthetic approach would provide a great logistical advantage.

With proof-of-principle of in situ TE and the concept of immunomodulation given in numerous studies, the main challenges now lie in the step toward safe and robust clinical translation. Being inherently dependent on the host, the efficiency of in situ TE therapies is likely to be highly variable between recipients of such a graft. Both Khosravi et al. and Kim et al. report on remarkably large variations in regenerative outcome within the same experimental groups, even between healthy laboratory animals.^7,9 Furthermore, large interspecies differences exist regarding the immune system and regenerative mechanisms. In this respect, Quijano et al. give a fascinating insight into the fundamental principles of epimorphic regeneration in various species and show how this knowledge translates to the potential “engineering of regeneration” in humans. ¹⁰ In addition to interspecies variability, the existence of comorbidities (e.g., diabetes) adds to the variability between patients in the clinical setting, as demonstrated in an excellent study by Krawiec et al. ¹¹ Sophisticated human in vitro models, combined with in silico analysis such as the method described by Wolf et al., represent invaluable tools to predict the human- and potentially even patient-specific response to an implanted scaffold. ¹² Taken together, increased mechanistic understanding of the fundamentals underlying in situ TE and identification of the key cellular and environmental players are essential for clinical translation and stratification of this exciting new field.