Diabetic foot ulcers (DFUs) are one of the most prevalent complications associated with diabetes mellitus. DFUs are chronic injuries that often lead to non-traumatic lower extremity amputations, due to persistent infection and other ulcer-related side effects. Moreover, these complications represent a significant economic burden for the healthcare system, as expensive medical interventions are required. In addition to this, the clinical treatments that are currently available have only proven moderately effective, evidencing a great need to develop novel strategies for the improved treatment of DFUs. Hydrogels are three-dimensional systems that can be fabricated from natural and/or synthetic polymers. Due to their unique versatility, tunability, and hydrophilic properties, these materials have been extensively studied for different types of biomedical applications, including drug delivery and tissue engineering applications. Therefore, this review paper addresses the most recent advances in hydrogel wound dressings for effective DFU treatment, providing an overview of current perspectives and challenges in this research field.

Collagen I interactions with integrins α₁ and α₂ are known to support human mesenchymal stem cell (hMSC) osteogenesis. Nonetheless, elucidating the relative impact of specific integrin interactions has proven challenging, in part due to the complexity of native collagen. In the present work, we employed two collagen‐mimetic proteins—Scl2‐2 and Scl2‐3— to compare the osteogenic effects of integrin α₁ versus α₂ signaling. Scl2‐2 and Scl2‐3 were both derived from Scl2‐1, a triple helical protein lacking known cell adhesion, cytokine binding, and matrix metalloproteinase sites. However, Scl2‐2 and Scl2‐3 were each engineered to display distinct collagen‐based cell adhesion motifs: GFPGER (binding integrins α₁ and α₂) or GFPGEN (binding only integrin α₁), respectively. hMSCs were cultured within poly(ethylene glycol) (PEG) hydrogels containing either Scl2‐2 or Scl2‐3 for 2 weeks. PEG‐Scl2‐2 gels were associated with increased hMSC osterix expression, osteopontin production, and calcium deposition relative to PEG‐Scl2‐3 gels. These data indicate that integrin α₂ signaling may have an increased osteogenic effect relative to integrin α₁. Since p38 is activated by integrin α₂ but not by integrin α₁, hMSCs were further cultured in PEG‐Scl2‐2 hydrogels in the presence of a p38 inhibitor. Results suggest that p38 activity may play a key role in collagen‐supported hMSC osteogenesis. This knowledge can be used toward the rational design of scaffolds which intrinsically promote hMSC osteogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2594–2604, 2018.

The highly tunable biological, chemical, and physical properties of bioactive hydrogels enable their use in an array of tissue engineering and drug delivery applications. Systematic modulation of these properties can be used to elucidate key cell-material interactions to improve therapeutic effects. For example, the rate and extent of endothelialization are critical to the long-term success of many blood-contacting devices. To this end, we have developed a bioactive hydrogel that could be used as coating on cardiovascular devices to enhance endothelial cell (EC) adhesion and migration. The current work investigates the relative impact of hydrogel variables on key endothelialization processes. The bioactive hydrogel is based on poly(ethylene glycol) (PEG) and a streptococcal collagen-like (Scl2-2) protein that has been modified with integrin α1β1 and α2β1 binding sites. The use of PEG hydrogels allows for incorporation of specific bioactive cues and independent manipulation of scaffold properties. The selective integrin binding of Scl2-2 was compared to more traditional collagen-modified PEG hydrogels to determine the effect of integrin binding on cell behavior. Protein functionalization density, protein concentration, and substrate modulus were independently tuned with both Scl2-2 and collagen to determine the effect of each variable on EC adhesion, spreading, and migration. The findings here demonstrate that increasing substrate modulus, decreasing functionalization density, and increasing protein concentration can be utilized to increase EC adhesion and migration. Additionally, PEG-Scl2-2 hydrogels had higher migration speeds and proliferation over 1 week compared with PEG-collagen gels, demonstrating that selective integrin binding can be used to enhance cell-material interactions. Overall, these studies contribute to the understanding of the effects of matrix cues on EC interactions and demonstrate the strong potential of PEG-Scl2-2 hydrogels to promote endothelialization of blood-contacting devices.