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Lower extremity arterial disease (LEAD) is a major vascular complication of diabetes. Vascular endothelial cells dysfunction can exacerbate local ischemia, leading to a significant increase in amputation, disability, and even mortality in patients with diabetes combined with LEAD. Therefore, it is of great clinical importance to explore proper and effective treatments. Conventional treatments of diabetic LEAD include lifestyle management, medication, open surgery, endovascular treatment, and amputation. As interdisciplinary research emerges, regenerative medicine strategies have provided new insights to treat chronic limb threatening ischemia (CLTI). Therapeutic angiogenesis strategies, such as delivering growth factors, stem cells, drugs to ischemic tissues, have also been proposed to treat LEAD by fundamentally stimulating multidimensional vascular regeneration. Recent years have seen the rapid growth of tissue engineering technology; tissue-engineered biomaterials have been used to study the treatment of LEAD, such as encapsulation of growth factors and drugs in hydrogel to facilitate the restoration of blood perfusion in ischemic tissues of animals. The primary purpose of this review is to introduce treatments and novel biomaterials development in LEAD. Firstly, the pathogenesis of LEAD is briefly described. Secondly, conventional therapies and therapeutic angiogenesis strategies of LEAD are discussed. Finally, recent research advances and future perspectives on biomaterials in LEAD are proposed.

As conventional treatments for diabetic wounds often fail to achieve rapid satisfactory healing, the development of effective strategies to accelerate diabetic wound repair is highly demanded. Herein, fibroblast growth factor 21 (FGF21) and metformin co-loaded multifunctional polyvinyl alcohol (PVA) hydrogel were fabricated for improved diabetic wound healing. The in vitro results proved that the hydrogel was adhesive and injectable, and that it could particularly scavenge reactive oxygen species (ROSs), while the in vivo data demonstrated that the hydrogel could promote angiogenesis by recruiting endothelial progenitor cells (EPCs) through upregulation of Ang-1. Both ROSs’ removal and EPCs’ recruitment finally resulted in enhanced diabetic wound healing. This work opens a strategy approach to diabetic wound management by combining biological macromolecules and small chemical molecules together using one promising environmental modulating drug delivery system.

Pressure ulcer (PU) is a worldwide problem that is hard to heal because of its prolonged inflammatory response and impaired ECM deposition caused by local hypoxia and repeated ischemia/reperfusion. Our previous study discovered that the non-fouling zwitterionic sulfated poly (sulfobetaine methacrylate) (SBMA) hydrogel can improve PU healing with rapid ECM rebuilding. However, the mechanism of the SBMA hydrogel in promoting ECM rebuilding is unclear. Therefore, in this work, the impact of the SBMA hydrogel on ECM reconstruction is comprehensively studied, and the underlying mechanism is intensively investigated in a rat PU model. The in vivo data demonstrate that compared to the PEG hydrogel, the SBMA hydrogel enhances the ECM remolding by the upregulation of fibronectin and laminin expression as well as the inhibition of MMP-2. Further investigation reveals that the decreased MMP-2 expression of zwitterionic SBMA hydrogel treatment is due to the activation of autophagy through the inhibited PI3K/Akt/mTOR signaling pathway and reduced inflammation. The association of autophagy with ECM remodeling may provide a way in guiding the design of biomaterial-based wound dressing for chronic wound repair.

A core problem in wound healing – with both fundamental and technological significance – concerns the rational design of bioactive and moist microenvironments. Here, we design a new class of zwitterionic betaine-incorporated collagen sponges (BET@COL) with integrated anti-oxidation and anti-inflammatory properties for promoting wound healing in a full-thickness wound model. The presence of zwitterionic betaine in a 3D network structure of collagen enables tightly bound and locked water molecules inside sponges via ionic solvation and confinement effect, while the integration of this amino acid also empowers the sponge with anti-oxidation and anti-inflammatory functions. In vitro results demonstrated that BET@COL collagen sponges strongly preserved water content up to 33.78 ± 0.78% at the 80th min at 37°C (only 0.44 ± 0.18% in control), and also exhibited high cell biocompatibility. Further, BET@COL collagen sponges with different betaine contents were applied to a full-thickness cutaneous wound model in mice, followed by a systematical evaluation and comparison of the effect of preserved water on wound healing efficiency in vivo. The optimal BET@COL collagen sponges were able to maintain high water content (e.g., moist microenvironment), suppress oxidative stress, improve anti-inflammation, all of which impose synergetic healing effects to promote wound closure, granulation formation, re-epithelization, collagen deposition and angiogenesis. This work demonstrates a new material as a promising candidate for wound dressing.

Spinal cord injury (SCI) induces the disruption of blood-spinal cord barrier (BSCB), which elicits neurological deficits by triggering secondary injuries. Hydrogen sulfide (H2S) is a gaseous mediator that has been reported to have neuroprotective effect in the central nervous system. However, the relationship between H2S and BSCB disruption during SCI remains unknown. Therefore, it is interesting to evaluate whether the administration of NaHS, a H2S donor, can protect BSCB integrity against SCI and investigate the potential mechanisms underlying it. In present study, we found that SCI markedly activated endoplasmic reticulum (ER) stress and autophagy in a rat model of complete crushing injury to the spinal cord at T9 level. NaHS treatment prevented the loss of tight junction (TJ) and adherens junction (AJ) proteins both in vivo and in vitro. However, the protective effect of NaHS on BSCB restoration was significantly reduced by an ER stress activator (tunicamycin, TM) and an autophagy activator (rapamycin, Rapa). Moreover, SCI-induced autophagy was remarkably blocked by the ER stress inhibitor (4-phenylbutyric acid, 4-PBA). But the autophagy inhibitor (3-Methyladenine, 3-MA) only inhibited autophagy without obvious effects on ER stress. Finally, we had revealed that NaHS significantly alleviated BSCB permeability and improved functional recovery after SCI, and these effects were markedly reversed by TM and Rapa. In conclusion, our present study has demonstrated that NaHS treatment is beneficial for SCI recovery, indicating that H2S treatment is a potential therapeutic strategy for promoting SCI recovery.