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Biopolymer microgels are emerging as a versatile tool for aiding in the regeneration of damaged tissues due to their biocompatible nature, tunable microporous structure, ability to encapsulate bioactive factors, and tailorable properties such as stiffness and composition. These properties of microgels, along with their injectability, have allowed for their utilization in a multitude of different tissue engineering applications. Controlled release of growth factors, antibodies, and other bioactive factors from microgels have demonstrated their capabilities as transporters for essential bioactive molecules necessary for guiding tissue reconstruction. Additionally, recent in vitro studies of cellular interaction and proliferation within microgel structures have laid the initial groundwork for regenerative tissue engineering using these materials. Microgels have even been crosslinked together in various ways or 3D printed to form three-dimensional scaffolds to support cell growth. Additionally, in vivo studies of microgels have pioneered the clinical relevance of these novel and innovative materials for regenerative tissue engineering. This review will cover recent developments and research of microgels as they pertain to bioactive factor release, cellular interaction and proliferation in vitro, and tissue regeneration in vivo.

The physis is a cartilaginous tissue in children's long bones that is responsible for bone elongation. Physeal injuries can heal with bony repair tissue known as a “bony bar,” and this can cause growth deformities. Current treatments involve surgical resection of the bony bar and insertion of inert materials in hopes of preventing bony bar re‐formation and preserving bone elongation. However, these materials frequently fail and the bony bar commonly returns. This study investigated alginate–chitosan hydrogels as interpositional materials to block bony bar formation in a rat model of physeal injury. Further, biomaterial properties such as substrate stiffness, permeability, and degradation rate were studied. Different ratio alginate:chitosan hydrogels with or without calcium cross‐linking were tested for their inhibition of bony bar formation and restoration of the injured physis. Alginate:chitosan were mixed (a) 90:10 with calcium (90:10 + Ca); (b) 50:50 with calcium (50:50 + Ca); (c) 50:50 without calcium (50:50 − Ca); and (d) 50:50 made with irradiated alginate (IA) and without calcium. We found that repair tissue was determined primarily by the in vivo degradation rate of alginate–chitosan hydrogels. 90:10 + Ca had a slow degradation rate, prevented cellular infiltration, and produced the most bony bar tissue while having softer, more permeable material properties. IA had the fastest degradation, showed high cellular infiltration, and produced the most cartilage‐like tissue while having stiffer, less permeable material properties. Our results suggest that the in vivo biomaterial degradation rate is a dynamic property that can be optimized to influence cell fate and tissue repair in physeal injuries.

Physeal injuries can result in the formation of a “bony bar” which can lead to bone growth arrest and deformities in children. Vascular endothelial growth factor (VEGF) has been shown to play a role in bony bar formation, making it a potential target to inhibit bony repair tissue after physeal injury. The goal of this study was to investigate whether the local delivery of anti‐VEGF antibody (α‐VEGF; 7.5 μg) from alginate:chitosan hydrogels to the tibial physeal injury site in rats prevents bony bar formation. We tested the effects of quick or delayed delivery of α‐VEGF using both 90:10 and 50:50 ratio alginate:chitosan hydrogels, respectively. Male and female 6‐week‐old Sprague‐Dawley rats received a tibial physeal injury and the injured site injected with alginate‐chitosan hydrogels: (1) 90:10 (Quick Release); (2) 90:10 + α‐VEGF (Quick Release + α‐VEGF); (3) 50:50 (Slow Release); (4) 50:50 +  α‐VEGF (Slow Release +  α‐VEGF); or (5) Untreated. At 2, 4, and 24 weeks postinjury, animals were euthanized and tibiae assessed for bony bar and vessel formation, repair tissue type, and limb lengthening. Our results indicate that Quick Release + α‐VEGF reduced bony bar and vessel formation, while also increasing cartilage repair tissue. Further, the quick release of α‐VEGF neither affected limb lengthening nor caused deleterious side‐effects in the adjacent, uninjured physis. This α‐VEGF treatment, which inhibits bony bar formation without interfering with normal bone elongation, could have positive implications for children suffering from physeal injuries.

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