# Interleukin‐8 Overexpressing Collagen Microgel‐Based Cellular Microtissue Accelerates the Healing of Diabetic Foot Ulcers

## TL;DR

A new cellular microtissue using collagen microgels and IL-8 overexpression speeds up healing of diabetic foot ulcers by boosting cell survival and tissue regeneration.

## Contribution

A novel cellular microtissue platform combining collagen microgels with IL-8 overexpression is developed to enhance diabetic wound healing.

## Key findings

- CCMs improve cell adhesion, survival, and IL-8 upregulation via FGFR-integrin-ERK signaling.
- IL-8 overexpression in CCMs enhances migration, proliferation, and angiogenesis in co-culture systems.
- In a rat model, CCMs with IL-8 overexpression accelerate wound closure and tissue regeneration.

## Abstract

Diabetic foot ulcers (DFUs) represent a major clinical challenge due to impaired healing and limited therapeutic options. Although stem cell therapy offers regenerative potential, its efficacy is restricted by poor survival and engraftment at the injury site. To address this, collagen microgels (CMGs) are developed to assemble with cells to form CMG‐based cellular microtissues (CCMs) with enhanced porosity, mass transfer, and viability. However, the diabetic microenvironment impairs healing by suppressing angiogenesis, keratinocyte migration, and fibroblast proliferation. Transcriptomic profiling identifies interleukin‐8 (IL‐8) as a key factor with multifaceted roles in promoting angiogenesis, migration, and proliferation. Compared with conventional aggregates, CCMs enhance adhesion, prevent anoikis, improve survival, and upregulate IL‐8 via FGFR‐integrin‐ERK signaling. Functional studies using shRNA knockdown and adenoviral overexpression validate the therapeutic role of IL‐8. In vitro co‐culture with keratinocytes, fibroblasts, and endothelial cells shows that CCMs promoted migration, proliferation, and angiogenesis–effects diminished by IL‐8 knockdown and amplified by overexpression. In a rat DFU model, CCMs accelerate wound closure by enhancing granulation tissue formation, collagen deposition, and expression of proliferative and angiogenic markers, all modulated by IL‐8. These findings establish CCMs as an effective therapeutic platform for DFUs and highlight IL‐8 overexpression as a strategy to further potentiate regeneration.

Collagen microgels (CMGs) incubated with cells self‐assemble into CMG‐based cellular microtissues (CCMs), enhancing cell adhesion and upregulating IL‐8 expression. A combinatorial strategy that integrates the CMG platform with IL‐8 overexpression promotes cell proliferation, migration, angiogenesis, and survival, thereby accelerating diabetic wound healing. Illustration is created using Biorender.com.