Advances for the treatment of lower extremity arterial disease associated with diabetes mellitus

Abstract

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.

1 Introduction

Lower extremity arterial disease (LEAD) is a critical component of peripheral arterial disease (PAD), which defined as a vascular disease caused by occlusion of lower extremity arteries. It is widely recognized that LEAD is associated with type 2 diabetes mellitus (T2DM) (Fowkes et al., 2017). LEAD is an essential factor contributing to the increased mortality in T2DM patients (Nativel et al., 2018). Over the past century, preclinical and clinical research of LEAD have been intensively studied. Here, Figure 1 presented the time line of importance matter of LEAD. Since 1925, the risk factors associated with T2DM and LEAD have been gradually revealed, such as hyperlipidemia (Barker, 1939), hypertension (Adler et al., 2000) and oxidative stress (Belch et al., 1995). Meanwhile, different diagnosis methods (Naide, 1939; Campbell and Smith, 1950) and conventional treatments (Sethi et al., 1980; Jonason and Bergstrom, 1987) of LEAD have also emerged. For instance, there are several treatments commonly used in clinical practice, such as lifestyle management, medication, open surgery, and endovascular revascularization (Teraa et al., 2016). These treatments can increase blood perfusion and restore microcirculation in the ischemic limbs. Unfortunately, these may be ineffective in some patients.

FIGURE 1

In 1994, the concept of therapeutic angiogenesis was put forward (Takeshita et al., 1994), and since then, researchers have started to use growth factors (Rajagopalan et al., 2003) or stem cells (Amann et al., 2009) to treat LEAD. With the continuous progress of medicine, therapeutic angiogenesis arises at the historical moment with aims to promote revascularization by changing the pathological conditions around ischemic tissues (Xing et al., 2021a). At present, therapeutic angiogenesis mainly includes growth factor therapy, stem cell therapy and gene therapy (Veith et al., 2019). However, since most studies remain in the laboratory stage, further clinical tests are needed to verify the efficiency of therapeutic angiogenesis in people who suffer from LEAD.

Biomaterial-based gene therapy for vascular diseases was introduced in 1997 (Schwartz and Moawad, 1997); from then on, researchers have turned their attention to the field of biomaterials (Delcroix et al., 2010; Moon et al., 2011; Agudelo et al., 2012; Kim et al., 2014; Hong et al., 2020). Biomaterials become suitable carriers for encapsulating and delivering biologically active substances or drugs, which provide new therapeutic ideas for promoting angiogenesis in diabetes patients with LEAD. Among different kinds of biomaterials, hydrogel has been extensively studied. Researchers have used natural or synthetic materials to create various hydrogels with diverse biological properties, of which injectable hydrogel has proved to improve blood perfusion in animals with lower limb ischemia. Given many advantages, such as biocompatibility, biodegradability and non-toxicity, hydrogel and other biomaterials, for example, scaffold, nanoparticle and spheroid, are hopefully being used in clinical research to increase the therapeutic efficiency of diabetic LEAD.

2 Overview of diabetic LEAD

The 10th edition of the IDF Diabetes Atlas indicates that over 500 million people worldwide are affected by T2DM (Sun et al., 2022), and it is reported that the number of people who suffer from LEAD are over 200 million globally (Fowkes et al., 2013). Compared to non-diabetic people, patients with both T2DM and LEAD show a worse prognosis, for example, the increased risks of CLTI, major adverse limb events (MALEs) and major adverse cardiac events (MACEs).

Although the pathogenesis of diabetic LEAD is still not fully clarified, it is believed that the key factor contributing to LEAD is atherosclerosis. The hallmark of atherosclerosis is endothelial dysfunction, which is caused by multiple interrelated risk factors, such as the overproduction of advanced glycation end products (AGEs), excessive oxidative stress and inflammation (Soyoye et al., 2021). Besides, the migration of low-density lipoprotein cholesterol (LDL-C) to the intima is a precursor of atherosclerosis (Suzuki et al., 2001; Taniwaki et al., 2001; Yang et al., 2017). Endothelial dysfunction and hyperglycemia are associated with abnormal clotting. Thus, abnormal platelet activation and aggregation are important factors in the development of atherosclerosis (American Diabetes, 2003).

Based on the pathological factors identified so far, researchers have further explored advanced treatments for LEAD by establishing animal models of limb ischemia. Ligation or resection of superficial femoral artery and vein are one of the most commonly used surgical methods (Masaki et al., 2002; Tan et al., 2007; Wang et al., 2020a). However, as the ligation and resection result in a state of acute ischemia, this differs from the vascular pathology of the lower extremity in clinical diabetic patients, whose vascular disease developed after a long period of ischemia. Luckily, this animal model is suitable for studying new strategies to treat LEAD due to the severe degree of ischemia and long postoperative blood flow recovery time, which simulates the vascular state of CLTI patients.

3 Conventional treatments of diabetic LEAD

Conventional treatments of diabetic LEAD include: 1) medication; 2) open surgery or endovascular treatment; 3) amputation; and 4) lifestyle management. Firstly, a good lifestyle is a needed for all other treatments. Secondly, patients are advised to take their medication as prescribed by their doctor. In addition, open surgery and endovascular treatment are indicated in patients for whom medication has failed or been ineffective. Finally, people with CLTI may experience an amputation. Here, we will describe each of these four treatments.

3.1 Medication

The drug treatments are also commonly used in clinical practice to slow down the progression of LEAD, or prevent acute cardiovascular or limb events.

Firstly, glycemic control is a primary treatment for patients with diabetic LEAD. The research revealed that combining glucagon-like peptide-1receptor agonists (GLP-1RAs) (e.g., liraglutide) with standard treatment can decrease amputation in T2DM people who suffer from diabetic foot ulcers (DFU) (Dhatariya et al., 2018). However, the relationship between sodium-glucose co-transporter 2 inhibitors (SGLT2is) and lower limb amputation remains unclear; the Canagliflozin Cardiovascular Assessment Study (CANVAS) reported that canagliflozin increased amputation rates (Minami et al., 2021). A meta-analysis showed no increased risk for SGLT2is compared to placebo (Heyward et al., 2020). A synthesis of the current studies leads to the conclusion that SGLT2is does not increase the risk of amputation and that GLP-1RA reduces this risk.

Secondly, the incidence of LEAD in DM patients is greatly associated with blood pressure (Mohammedi et al., 2016). The ACC and AHA guidelines suggest using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor antagonists (ARBs) for patients with PAD (Gerhard-Herman et al., 2017).

Thirdly, high LDL-C is related to atherosclerosis, which leads to LEAD (Gebauer and Reinecke, 2018). There are large amounts of evidence prove the benefits of statins for LEAD (Gerhard-Herman et al., 2017). In addition, apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol (non-HDL-C) have been shown to predict CVD, even at low levels of LDL-C (McQueen et al., 2008). A recent study suggests that increased non-HDL and apoB are better predictors of arterial stiffness than LDL-C (Jia et al., 2022).

Finally, patients with ischemia symptoms should be treated with anti-platelet or anticoagulation therapy. The AHA/ACC guidelines suggest using aspirin or clopidogrel alone to reduce vascular risk and mortality (Gerhard-Herman et al., 2017). As an anticoagulant, rivaroxaban has proven benefit in PAD. In the VOYAGER PAD trial, rivaroxaban 2.5 mg twice daily plus low-dose aspirin significantly reduced acute limb, brain and cardiac ischemic events compared with aspirin alone (Bonaca et al., 2020).

3.2 Open surgery and endovascular treatment

Lower extremity open surgery and endovascular treatment (EVT) have been used to restore blood perfusion in patients with CLTI (Farber and Eberhardt, 2016). EVT has the advantage of a simpler and less time-consuming procedure, as well as a faster recovery and lower recurrence rate (Papavassiliou et al., 2003; Adam et al., 2005; Slovut and Lipsitz, 2012). However, neither open surgery nor EVT can prevent restenosis (Biscetti et al., 2021). LEAD patients often accompany with occlusion of the distal arteries in the calf and foot, there will be a lack of suitable arterial inflow as well as an adequate vascular bed, leading to the failure of surgical treatment (Pan et al., 2019).

3.3 Amputation

Amputation is the ultimate clinical treatment for patients with CLTI (Norgren et al., 2007). It includes minor and major amputation. Minor amputation barely affects the patient’s motor function, whereas major amputation is usually performed above the ankle joint, reducing the independent motor ability after surgery (Nazri et al., 2019). It will seriously affect the quality of life of patients, so clinicians should intervene in the early stages of LEAD to reduce the occurrence of amputation.

3.4 Lifestyle management

As we known, lifestyle changes are an efficient way in treating abnormal glucose tolerance. However, most patients are not very compliant and have difficulty adhering to good lifestyle habits. We recommend all pre-diabetics and diabetics to initiate lifestyle management which will reduce the incidence of diabetic complications. Firstly, smoking ranks first in all risk factors for PAD. Stopping smoking can slow the procession of limb ischemia and reduce amputation, even mortality in patients (Armstrong et al., 2014). Secondly, the LEAD patient need physical exercise along with glycemic control, this benefit weight loss, lowering blood pressure and improving insulin sensitivity (Abrignani, 2018; Lee et al., 2018). It also helps patients alleviate ischemic symptoms and decrease the incidence of cardiovascular disease (CVD) (Lane et al., 2017).

Diet is an important way to both prevention and treatment of diseases, including DM (Martin-Pelaez et al., 2020). Studies have demonstrated that the Geriatric Nutrition Risk Index (GNRI) and Controlled Nutritional Status (CONUT) scores are predictors of prognosis for patients with LEAD. Therefore, improving malnutrition is a new therapeutic target in elder population (Yokoyama et al., 2018; Jhang et al., 2020).

4 Therapeutic angiogenesis

Although conventional treatments of diabetic LEAD are commonly used in the clinical stage, the methods mentioned above still have certain limitations, such as the inability to allow revascularization of the ischemic limb itself (Xing et al., 2021a). Moreover, the overall prognosis is less than ideal, and the mortality after amputation remains high. To fill these gaps, researchers have explored “therapeutic angiogenesis” since the 1990s. It mainly includes protein therapies, gene and nucleic acid-based therapies, drug and drug-like compounds therapies and stem cell-based therapies (Veith et al., 2019). Therapeutic angiogenesis strategies are extensively studied in animal experiments, and the safety of growth factor and stem cell-based biologic therapies has also been confirmed in randomized clinical trials.

4.1 The conception of therapeutic angiogenesis

Therapeutic angiogenesis was firstly proposed in an experiment in which vascular endothelial growth factor (VEGF) was injected into the ischemic hind limb of rabbits to demonstrate revascularization (Takeshita et al., 1994). Therapeutic angiogenesis can be divided into three types (Figure 2) (Xing et al., 2021a): 1) Angiogenesis: a new capillary network is sprouted based on the inherent blood vessels. This process includes the activation of VEGF, hypoxia-inducible factor-1α (HIF-1α) and erythropoietin (EPO). These cytokines act on endothelial cells and promote angiogenesis; 2) Arteriogenesis: including collateral vessel formation and artery maturation (Chalothorn et al., 2007). When the microenvironment changes, the expression of tumor necrosis factor (TNF) and fibroblast growth factor (FGF) increases, which further induces arteriogenesis (de Muinck and Simons, 2004); 3) Vasculogenesis: new blood vessels form in situ. Firstly, endothelial progenitor cells (EPCs) gather with each other, then fuse with the surrounding cells, gradually form the vascular lumen structure, and finally become the mature blood vessel (Kamei et al., 2006; Xing et al., 2020). With more in-depth studies of therapeutic angiogenesis, researchers found that this novel treatment strategy can help the body form endogenous revascularization and restore blood perfusion in ischemic tissue. Therefore, therapeutic angiogenesis is expected to become a new scheme to treat limb ischemia in patients with diabetic LEAD.

FIGURE 2

4.2 Growth factor therapy

At present, many studies have been conducted on growth factors such as FGF, VEGF, HGF, PDGF, and EGF to induce angiogenesis. Interestingly, in the experimental animal stage, exogenous growth factors showed an excellent function of stimulating ischemic collateral circulation; however, the effect was slightly inadequate in clinical trials. Makarevich et al. (2012) demonstrated that intramuscular injection of a mixture of plasmids that contain VEGF 165 and HGF could restore the blood flow in ischemic skeletal muscle. Upon this, they developed a novel bicistronic plasmid expressing both VEGF165 and HGF. The results showed that HGF/VEGF165 plasmid could induce angiogenesis in human umbilical vein endothelial cells (HUVECs) and improve blood perfusion in a hind limb ischemia mouse model (Figures 3A,B) (Slobodkina et al., 2020). Regarding the effectiveness of growth factor therapy in clinical trials, its therapeutic effect on patients with LEAD is less significant. Gu et al. studied the efficiency of HGF plasmid NL003 for the treatment of limb ischemia. They found those 6 months after intramuscular injection of NL003, patients experienced relief of ischemic symptoms and had a higher rate of ulcer healing. However, no statistical differences were found in transcutaneous oxygen pressure (TcPO₂), ankle-brachial index (ABI), or toe-brachial index (TBI) in both control and experimental groups (Figures 3C,D) (Gu et al., 2019). It shows that the clinical value of growth factors in LEAD patients still needs a large number of in-depth studies to verify their effectiveness.

FIGURE 3

4.3 Stem cell therapy

Stem cell therapy can be used for patients who cannot undergo open surgery or EVT. Many types of stem cells are already being explored, like EPCs, bone marrow mononuclear cells (BMMNCs), peripheral blood mononuclear cells (PBMNCs) and mesenchymal stem cells (MSCs), etc. At present, numerous researches have proved the effectiveness, such as improving blood perfusion, relieving rest pain and increasing ABI and TcPO₂ (Jonsson et al., 2012; Moazzami et al., 2014; Rigato et al., 2017). In addition to conducting studies about stem cell transplants, researchers have also combined growth factors with stem cells to explore their effects on angiogenesis. Park et al. (2019) used VEGF and enhanced green fluorescent protein (EGFP) to transfect MSCs, and then transplanted the MSCs into the ischemic hind limbs to observe their effect of revascularization. They found that this MSCs-based transplantation therapy could not only enhance the expression of VEGF, but also improve blood perfusion and induce angiogenesis (Figure 4).

FIGURE 4

Similar to growth factor therapy, the results of stem cell therapy in clinical trials are not as favorable as in animal experiments, and the results vary from one researcher to another. Ai et al. (2016) and Rigato et al. (2017) found that cell-based transplantation may reduce amputation and increase the survival rate of non-amputation. Xie et al. (2018) and Gao et al. (2019) found that although the total amputation rate decreased after stem cell therapy, it did not improve the preservation of major limbs. In addition, a large-scale randomized controlled trial showed that the total amputation rate, mortality and non-amputation survival rate in the treatment group might not be significantly improved after stem cell transplantation (Peeters Weem et al., 2015; Liew et al., 2016; Pan et al., 2018). It remains unclear whether stem cell therapy can actually benefit patients with diabetic LEAD, we sincerely hope that its efficacy can be verified and therefore we summarize some of the current studies on stem cell therapy in Table 1.

Based on current research reports, stem cell-based therapies may have better efficacy than other therapeutic angiogenesis strategies (Ho et al., 2022), as cell therapy has been shown to induce therapeutic angiogenesis in both animal models and human experiments (Van Raemdonck et al., 2015; Novakova et al., 2016). Compared to other stem cells, induced pluripotent stem cells (iPSC) and their derivative cells may have enhanced therapeutic potential. It reported that human iPSC-derived smooth muscle cells (hiPSC-SMC) can mediate angiogenesis, thereby improving hind limb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel therapeutic angiogenesis strategy for the treatment of LEAD (Gao et al., 2021; Park et al., 2021).

The therapeutic angiogenesis strategy was carried out as early as 1990s and it is currently under great investigation. Although promising preclinical studies in animal models, cell-based therapies in LEAD patients still show limitations. It has been demonstrated that ion channels differ between humans and animal models and that the disease state in humans cannot be fully replicated in animal models (Tanner and Beeton, 2018) . Most previous investigations used autologous cells, which damaged by chronic hyperglycemia, and have a low survival rate in the ischemic environment (Qadura et al., 2018). However, we can initially screen some effective drugs through animal studies, and then verify their safety and effectiveness through clinical trials. In the future, multicenter, larger-scale clinical trials are needed to verify the effectiveness of therapeutic angiogenesis in clinical LEAD patients.

5 Application of biomaterials in the treatment of diabetic LEAD

Researchers have verified the effectiveness of therapeutic angiogenesis in the experimental animal stage, but when it turns to clinical trials, this therapeutic strategy remains to be further explored. At present, most studies transport growth factors, stem cells or other bioactive molecules to ischemic tissue in order to restore blood perfusion. However, how to maintain the activity of these substances and how to improve the accuracy of delivery still requires more in-depth research. Due to the excellent biocompatibility, biodegradability and non-toxicity, biomaterials can be used as a carrier of various bioactive molecules to treat LEAD. As reported, the vascular scaffold has been used in patients with PAD, and no amputations or deaths have been observed over a 2-years clinical trial (Lammer et al., 2016). Therefore, biomaterials are of great clinical importance in the treatment of LEAD.

5.1 Biomaterials overview

Biomaterials are one of the significant components of tissue engineering, acting as an extracellular matrix (ECM) and promoting cell migration, tube formation, tissue maturation and wound healing (Zhang et al., 2013; Lee et al., 2014). There are numerous ways to classify biomaterials; for example, according to the origins, biomaterials can be classified as natural or synthetic materials (Troy et al., 2021). Researchers use these biomaterials to prepare tissue engineering materials with different structural forms and diverse functions, such as hydrogels, microneedles, nanoparticles and scaffolds, etc. (Figure 5). Taking hydrogel as an example, on the one hand, it has good biological properties and mechanical properties; on the other hand, the preparation is more straightforward compared with other biomaterials. Therefore, in biomaterial-based therapeutic angiogenesis strategies, hydrogels have become promising candidates (Buwalda et al., 2017). Here, we will mainly focus on some of the explorations that have been completed in the field of hydrogels and list some studies in the treatment of LEAD based on other biomaterials.

FIGURE 5

5.2 Hydrogel overview

Hydrogel is a kind of hydrophilic polymer material, which is extensively used in the medical stage because of its excellent water absorption, biocompatibility, and ion transferability (Xing et al., 2021a). Due to the conventional treatments of LEAD and therapeutic angiogenesis strategies having certain limitations and side effects, researchers have made an in-depth exploration of therapeutic angiogenesis based on hydrogels. They have designed various studies to treat LEAD by encapsulating various angiogenic factors or stem cells in hydrogels and then transporting them to ischemic tissues effectively. According to the different sources of materials for preparing hydrogel, it can be divided into natural hydrogel and synthetic hydrogel.

5.2.1 Natural hydrogel

The natural materials for preparing hydrogels include chitosan (CS), gelatin, fibrin, alginate, collagen, hyaluronic acid (HA), silk fibroin (SF), etc. (Figure 6). Chitosan has been broadly used in biomedical fields for its biocompatibility, degradability and antibacterial (Jayakumar et al., 2010; Kalantari et al., 2019). Recently, Wang et al. (2020b) synthesized a temperature-responsive chitosan hydrogel encapsulated with ferulic acid (FA). The hydrogel is capable of the stable release of FA, which has the effects of both antioxidant and pro-angiogenic. They validated the efficacy of the FA-chitosan hydrogel in a hind limb ischemia mouse model and demonstrated its remarkable ability to promote blood perfusion and angiogenesis (Figure 7A). Gelatin has good temperature responsiveness; when the temperature is below 40°C, it forms into a transparent gel solution (Chu and Wang, 2012). Lee et al. (2020) prepared a microchannel network hydrogel with gelatin solution and poly (N-isopropyl acrylamide) (PNIPAM) fibers. The in vivo results proved that this hydrogel could increase blood perfusion (Figure 7B). Fibrin has a large number of binding sites to growth factors, which allows angiogenesis (Loureiro et al., 2019). Recently, Pei et al. (2020) prepared a fibrin hydrogel encapsulating cardiac stem cells (CSCs) and transfected HIF-1α into CSCs. The in vivo results of animal experiments showed that the hydrogel has a solid ability to promote angiogenesis and restore the blood perfusion of ischemic limbs (Figure 7C). Alginate is a kind of natural anionic polymer, which is widely used in the preparation of hydrogel due to its easy gelation. Ruvinov et al. (2010) prepared an alginate hydrogel encapsulated with HGF, which released HGF in a rapid and controlled manner. Then, they established a mouse model to verify the effect of the HGF-hydrogel. The in vivo results proved that the HGF-hydrogel could improve blood perfusion by improving angiogenesis through its pro-angiogenesis effect (Figure 7D). Since many research used natural hydrogels for LEAD, we summarized some of studies in Table 2.

FIGURE 6

FIGURE 7

5.2.2 Synthetic hydrogel

The synthetic materials for preparing hydrogels include polyethylene glycol (PEG), poly (Lactic-co-glycolic Acid) (PLGA), self-assembling peptide (SAP), tetronic-tyramine (Tet-TA), etc. (Figure 8). Polyethylene glycol (PEG) hydrogel has good biocompatibility, which is widely used in biomedical fields (Lin and Anseth, 2009). Mulyasasmita et al. (2014) prepared a protein-PEG hybrid hydrogel, which could co-deliver human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) and VEGF. The in vivo results of a PAD mouse model revealed that the protein-PEG hydrogel could lower inflammation and decrease ischemia-reperfusion injury (Figure 9A). Poly (Latic-co-glycolic Acid) (PLGA) is also widely used in the preparation of biomaterials, and some researchers have made it into micron or nanoparticles and 3D scaffolds (Bharadwaz and Jayasuriya, 2020). In a recent study, Hong et al. (2020) prepared a PLGA-Cys-mPEG porous hydrogel and realized the “gel-solution” transition with glutathione (GSH). The hydrogel can not only support the formation of adipose-derived stem cells (ASCs) spheroids, but also treat hind limb ischemia by minimally invasive injection. The in vivo results indicated that the hydrogel had an apparent therapeutic effect in limb ischemia, which could enhance paracrine secretion of ASCs, promote angiogenesis of ischemic limbs (Figure 9B).

FIGURE 8

FIGURE 9

The development of self-assembling peptide (SAP) is inspired by the phenomenon of molecular self-assembly in vivo, such as protein winding, folding and the construction of DNA double helix (Palmer and Stupp, 2008). Huang et al. (2019a) synthesized a novel small molecular hydrogel by disulfide bond reduction, named Nap-GFFYK-Thiol hydrogel. The results showed that the hydrogel could not only improve the activity of human placental mesenchymal stem cells (hP-MSCs), but also promote blood flower recovery (Figure 9C). Since many research used synthetic hydrogels for LEAD, we summarized some of the studies in Table 3.

5.2.3 Hydrogel loaded with growth factors or stem cells

With the boosting studies of biomaterials, more and more research is focusing on the combination of biomaterials with growth factors and stem cells. Among all these materials, hydrogel is frequently used due to its 3D porous structure and efficient water content. Thus, hydrogels are chosen as carriers for growth factors and stem cells to treat LEAD. In a recent study, Xing et al. (2021b) transfected VEGF and TFEB plasmids into extracellular vesicles (EVs) derived from endothelial cells. Then prepared a hydrogel loaded with VEGF/TFEB-engineered EVs. Their work demonstrated that the EV-loaded hydrogel could improve angiogenesis (Figure 10A). Huang et al. (2019b) designed a functionalized SAP hydrogel with RADA16-GGQQLK (QLK) and RADA16-GGLRKKLGKA (LRK) sequences. The LRK sequence is a cofactor that could help growth factors to encapsulate in this SAP hydrogel. The results revealed that the VEGF/HGF-loaded SAP hydrogel could promote tube formation in vitro and angiogenesis in vivo (Figures 10B,C). Stem cells therapy has been proved to treat limb ischemia, but it is still limited by problems such as inaccurate cell release and poor cell survival (Tang et al., 2017). Due to a lack of blood perfusion, the temperature of ischemic limb is often lower than normal tissues (Fernandez et al., 2018). Inspired by this, Wang et al. (2019) created a temperature-responsive hydrogel, which based on Methylcellulose (MC), encapsulated with human placental mesenchymal stem cells (PMSCs). The results showed that MC-based hydrogel can effectively release PMSCs into ischemic area, and then improve blood perfusion, enhance revascularization. The above experiments confirm that hydrogels as carriers have a good synergistic effect with growth factors or stem cells in promoting angiogenesis. Therefore, it is reasonable to believe that this type of research deserves to be further explored to facilitate the treatment of LEAD in the clinical field.

FIGURE 10

5.3 Other biomaterials

In addition to hydrogels, there are still many other types of biomaterials that have been studied to treat LEAD, such as scaffold (Li et al., 2018; Carrabba et al., 2020; Leclerc et al., 2021; Mu et al., 2021), nanoparticle (NP) (Matsumoto et al., 2020; Park et al., 2020; Liu et al., 2017; Albrecht-Schgoer et al., 2017) and spheroid (Park et al., 2014; Choi et al., 2021; Lee et al., 2021).

5.3.1 Scaffold

Many researchers have begun to focus on scaffold-based tissue engineering strategies to restore blood perfusion in ischemic limbs. Recently, Mu et al. (2021) fabricated an electrospun glucomannan decanoate (GMDE) scaffold to simulate microbial invasion and isolate endogenous galectin-1. The in vivo results found that GMDE scaffold can effectively promote blood perfusion (Figures 11A,B). Li et al. (2018) designed a nanoparticle-anchoring hydrogel scaffold and evaluated the therapeutic effect on ischemic hind limbs of mice. The in vivo results showed the scaffold could significantly promote the restoration of blood perfusion (Figures 11C,D).

FIGURE 11

5.3.2 Nanoparticle

Nanoparticles (NPs) have emerged as a new model of drug delivery system with advantages such as targeting and slow release. Matsumoto et al. (2020) designed a NP-mediated, targeted drug delivery system using PLGA and statin as raw materials. The results revealed that Pitavastatin-NPs could significantly improve the therapeutic effect on limb ischemia (Figures 12A,B). According to many studies, cerium oxide nanoparticles (CNP) have shown therapeutic effects both in vivo (Naganuma and Traversa, 2014) and in vitro (Kwon et al., 2016). Park et al. (2020) confirmed the angiogenesis-promoting properties of CNP in a hind limb ischemia mouse model and further investigated molecular mechanisms by which it exerts its promoting effects. The results showed increased expression of pro-angiogenic markers, vascular maturation and muscle remodeling after intramuscular injection of CNP. Moreover, such an efficient pro-angiogenic effect may be due to the upregulation of the Ref-1/APE1 pathway (Figure 12C).

FIGURE 12

5.3.3 Spheroid

As mentioned above, stem cell therapy in therapeutic angiogenesis is a reliable treatment for LEAD. The therapeutic benefit of single-cell transplantation is not ideal. Still, the efficiency will significantly enhance when cells become spheroids, because the 3D spheroid system could create a more biomimetic microenvironment (Lee et al., 2021). Therefore, cell spheroids that act synergistically with biomaterials have been extensively studied. Choi et al. (2021) cultured human adipose-derived stem cells (hASCs) in an FGF-2 matrix, which in turn developed into an enhanced cells spheroid (FECs-Ad) and were able to secrete a variety of angiogenic growth factors. Their work proved that the injection of FECs-Ad promotes angiogenesis in ischemic hind limbs, which also increases the expression of VEGF (Figures 13A,B).

FIGURE 13

Since there have been many studies using other biomaterials to investigate the treatment of LEAD, so we summarize some of the studies in Table 4.

6 Conclusion and future perspectives

As diabetes continues to increase around the world, complication also arises. In all vascular complications of diabetes, LEAD is an essential cause of death for patients. The end-stage of LEAD is called CLTI, and the study found that the 5-years survival rate of diabetic patients with CLTI is lower than those without limb ischemia. Therefore, they need more effective treatments to repair ischemic limbs, minimize amputation and mortality. Conventional treatments include medication, open surgery, endovascular treatment, amputation and lifestyle management are not always enough. Crucial aspect is the lack of awareness of the disease among both physicians and patients. This means that patients often present to the physician’s attention already with an advanced disease: CLTI. In these cases, currently available treatment options often perform poorly. The therapeutic angiogenesis strategy proposed in recent years aims to promote the spontaneous formation of revascularization and restore the blood perfusion of ischemic limbs through growth factors and stem cell transplantation. However, all of the above treatments have their limitations, urging us to explore novel methods to treat diabetic LEAD. With the continuous development of biomedicine and tissue engineering, many natural or synthetic biomaterials have been used to research of limb ischemia mouse models due to their promising biological properties. At present, many researchers have confirmed the effectiveness of biomaterials to rescue limb ischemia. Unfortunately, most of the studies are still in the experimental animal stage, and the animal models established are not as complicated as many other complications of clinical diabetic patients. Although some clinical trials have already verified the safety of the biomaterials they use, however, the translation of biomaterials into clinical products still needs to face many questions. For example, whether biomaterial-based therapeutic angiogenesis strategies can produce good angiogenesis-promoting effects in real-world patients is still debatable; and how to translate various biomaterials from small-scale application in the laboratory stage to high-volume use in treating patients in the clinic. Therefore, randomized clinical trials are needed to clarify the role of these new technologies in treating patients with diabetic LEAD. In conclusion, we hope that biomaterials will be further developed and gradually applied to clinical treatment from the current animal research stage, thus providing more ways to treat diabetic LEAD.

References

• 1

  Abrignani M. G. (2018). Physical exercise and risk of arterial hypertension and diabetes mellitus. Let's move, it is never too late. Eur. J. Prev. Cardiol.25 (10), 1063–1064. 10.1177/2047487318781116

  • CrossRef
  • Google Scholar

• 2

  Adam D. J. Beard J. D. Cleveland T. Bell J. Bradbury A. W. Forbes J. F. et al (2005). Bypass versus angioplasty in severe ischaemia of the leg (BASIL): Multicentre, randomised controlled trial. Lancet366 (9501), 1925–1934. 10.1016/S0140-6736(05)67704-5

  • CrossRef
  • Google Scholar

• 3

  Adler A. I. Stratton I. M. Neil H. A. Yudkin J. S. Matthews D. R. Cull C. A. et al (2000). Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. Br. Med. J.321 (7258), 412–419. 10.1136/bmj.321.7258.412

  • CrossRef
  • Google Scholar

• 4

  Agudelo C. A. Tachibana Y. Hurtado A. F. Ose T. Iida H. Yamaoka T. (2012). The use of magnetic resonance cell tracking to monitor endothelial progenitor cells in a rat hindlimb ischemic model. Biomaterials33 (8), 2439–2448. 10.1016/j.biomaterials.2011.11.075

  • CrossRef
  • Google Scholar

• 5

  Ai M. Yan C. F. Xia F. C. Zhou S. L. He J. Li C. P. (2016). Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis. Cytotherapy18 (6), 712–724. 10.1016/j.jcyt.2016.02.009

  • CrossRef
  • Google Scholar

• 6

  Albrecht-Schgoer K. Barthelmes J. Schgoer W. Theurl M. Nardin I. Lener D. et al (2017). Nanoparticular delivery system for a secretoneurin derivative induces angiogenesis in a hind limb ischemia model. J. Control. Release250, 1–8. 10.1016/j.jconrel.2017.02.004

  • CrossRef
  • Google Scholar

• 7

  Amann B. Lüdemann C. Ratei R. Schmidt-Lucke J. A. (2009). Autologous bone-marrow stem-cell transplantation for induction of arteriogenesis for limb salvage in critical limb ischaemia. Zentralbl. Chir.134 (4), 298–304. 10.1055/s-0029-1224532

  • CrossRef
  • Google Scholar

• 8

  American Diabetes A. (2003). Peripheral arterial disease in people with diabetes. Diabetes Care26 (12), 3333–3341. 10.2337/diacare.26.12.3333

  • CrossRef
  • Google Scholar

• 9

  Anderson E. M. Silva E. A. Hao Y. Martinick K. D. Vermillion S. A. Stafford A. G. et al (2017). VEGF and IGF delivered from alginate hydrogels promote stable perfusion recovery in ischemic hind limbs of aged mice and young rabbits. J. Vasc. Res.54 (5), 288–298. 10.1159/000479869

  • CrossRef
  • Google Scholar

• 10

  Armstrong E. J. Wu J. Singh G. D. Dawson D. L. Pevec W. C. Amsterdam E. A. et al (2014). Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J. Vasc. Surg.60 (6), 1565–1571. 10.1016/j.jvs.2014.08.064

  • CrossRef
  • Google Scholar

• 11

  Barker N. W. (1939). Occlusive arterial disease of the lower extremities associated with lipemia and xanthoma tuberosum. Ann. Intern. Med.12 (11), 1891–1895.

  • Google Scholar

• 12

  Belch J. J. Mackay I. R. Hill A. Jennings P. McCollum P. (1995). Oxidative stress is present in atherosclerotic peripheral arterial disease and further increased by diabetes mellitus. Int. Angiol.14 (4), 385–388.

  • Google Scholar

• 13

  Benoit E. O'Donnell T. F. Jr. Iafrati M. D. Asher E. Bandyk D. F. Hallett J. W. et al (2011). The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: Implications for clinical trial design. J. Transl. Med.9, 165. 10.1186/1479-5876-9-165

  • CrossRef
  • Google Scholar

• 14

  Bhang S. H. Kim J. H. Yang H. S. La W. G. Lee T. J. Sun A. Y. et al (2009). Combined delivery of heme oxygenase-1 gene and fibroblast growth factor-2 protein for therapeutic angiogenesis. Biomaterials30 (31), 6247–6256. 10.1016/j.biomaterials.2009.07.058

  • CrossRef
  • Google Scholar

• 15

  Bharadwaz A. Jayasuriya A. C. (2020). Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration. Mat. Sci. Eng. C Mat. Biol. Appl.110, 110698. 10.1016/j.msec.2020.110698

  • CrossRef
  • Google Scholar

• 16

  Biscetti F. Nardella E. Rando M. M. Cecchini A. L. Gasbarrini A. Massetti M. et al (2021). Outcomes of lower extremity endovascular revascularization: Potential predictors and prevention strategies. Int. J. Mol. Sci.22 (4), 2002. 10.3390/ijms22042002

  • CrossRef
  • Google Scholar

• 17

  Bonaca M. P. Bauersachs R. M. Anand S. S. Debus E. S. Nehler M. R. Patel M. R. et al (2020). Rivaroxaban in peripheral artery disease after revascularization. N. Engl. J. Med.382 (21), 1994–2004. 10.1056/NEJMoa2000052

  • CrossRef
  • Google Scholar

• 18

  Buwalda S. J. Vermonden T. Hennink W. E. (2017). Hydrogels for therapeutic delivery: Current developments and future directions. Biomacromolecules18 (2), 316–330. 10.1021/acs.biomac.6b01604

  • CrossRef
  • Google Scholar

• 19

  Campbell D. A. Smith R. G. (1950). The arteriographic examination of the lower extremity. Angiology1 (1), 100–105. 10.1177/000331975000100108

  • CrossRef
  • Google Scholar

• 20

  Carrabba M. Jover E. Fagnano M. Thomas A. C. Avolio E. Richardson T. et al (2020). Fabrication of new hybrid scaffolds for in vivo perivascular application to treat limb ischemia. Front. Cardiovasc. Med.7, 598890. 10.3389/fcvm.2020.598890

  • CrossRef
  • Google Scholar

• 21

  Chalothorn D. Clayton J. A. Zhang H. Pomp D. Faber J. E. (2007). Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains. Physiol. Genomics30 (2), 179–191. 10.1152/physiolgenomics.00047.2007

  • CrossRef
  • Google Scholar

• 22

  Chappell J. C. Song J. Burke C. W. Klibanov A. L. Price R. J. (2008). Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis. Small4 (10), 1769–1777. 10.1002/smll.200800806

  • CrossRef
  • Google Scholar

• 23

  Choi J. Choi W. Joo Y. Chung H. Kim D. Oh S. J. et al (2021). FGF2-primed 3D spheroids producing IL-8 promote therapeutic angiogenesis in murine hindlimb ischemia. NPJ Regen. Med.6 (1), 48. 10.1038/s41536-021-00159-7

  • CrossRef
  • Google Scholar

• 24

  Chu H. Wang Y. (2012). Therapeutic angiogenesis: Controlled delivery of angiogenic factors. Ther. Deliv.3 (6), 693–714. 10.4155/tde.12.50

  • CrossRef
  • Google Scholar

• 25

  de Muinck E. D. Simons M. (2004). Re-evaluating therapeutic neovascularization. J. Mol. Cell. Cardiol.36 (1), 25–32. 10.1016/j.yjmcc.2003.10.002

  • CrossRef
  • Google Scholar

• 26

  Delcroix G. J. Schiller P. C. Benoit J. P. Montero-Menei C. N. (2010). Adult cell therapy for brain neuronal damages and the role of tissue engineering. Biomaterials31 (8), 2105–2120. 10.1016/j.biomaterials.2009.11.084

  • CrossRef
  • Google Scholar

• 27

  Dhatariya K. Bain S. C. Buse J. B. Simpson R. Tarnow L. Kaltoft M. S. et al (2018). The impact of liraglutide on diabetes-related foot ulceration and associated complications in patients with type 2 diabetes at high risk for cardiovascular events: Results from the LEADER trial. Diabetes Care41 (10), 2229–2235. 10.2337/dc18-1094

  • CrossRef
  • Google Scholar

• 28

  Farber A. Eberhardt R. T. (2016). The current state of critical limb ischemia: A systematic review. JAMA Surg.151 (11), 1070–1077. 10.1001/jamasurg.2016.2018

  • CrossRef
  • Google Scholar

• 29

  Fernandez S. Parodi J. C. Moscovich F. Pulmari C. (2018). Reversal of lower-extremity intermittent claudication and rest pain by hydration. Ann. Vasc. Surg.49, 1–7. 10.1016/j.avsg.2018.01.074

  • CrossRef
  • Google Scholar

• 30

  Fowkes F. G. Aboyans V. Fowkes F. J. McDermott M. M. Sampson U. K. Criqui M. H. (2017). Peripheral artery disease: Epidemiology and global perspectives. Nat. Rev. Cardiol.14 (3), 156–170. 10.1038/nrcardio.2016.179

  • CrossRef
  • Google Scholar

• 31

  Fowkes F. G. Rudan D. Rudan I. Aboyans V. Denenberg J. O. McDermott M. M. et al (2013). Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis. Lancet382 (9901), 1329–1340. 10.1016/S0140-6736(13)61249-0

  • CrossRef
  • Google Scholar

• 32

  Fujita M. Horio T. Kishimoto S. Nakamura S. Takikawa M. Nakayama T. et al (2013). Effects of platelet-rich plasma-containing fragmin/protamine microparticles in enhancing endothelial and smooth muscle cell growth and inducing collateral vessels in a rabbit model of hindlimb ischemia. J. Biomed. Mat. Res. B Appl. Biomater.101 (1), 36–42. 10.1002/jbm.b.32808

  • CrossRef
  • Google Scholar

• 33

  Gao W. Chen D. Liu G. Ran X. (2019). Autologous stem cell therapy for peripheral arterial disease: A systematic review and meta-analysis of randomized controlled trials. Stem Cell Res. Ther.10 (1), 140. 10.1186/s13287-019-1254-5

  • CrossRef
  • Google Scholar

• 34

  Gao X. Gao M. Gorecka J. Langford J. Liu J. Luo J. et al (2021). Human-induced pluripotent stem-cell-derived smooth muscle cells increase angiogenesis to treat hindlimb ischemia. Cells10 (4), 792. 10.3390/cells10040792

  • CrossRef
  • Google Scholar

• 35

  Gebauer K. Reinecke H. (2018). PCSK9 inhibition for LDL lowering and beyond - implications for patients with peripheral artery disease. Vasa.47 (3), 165–176. 10.1024/0301-1526/a000689

  • CrossRef
  • Google Scholar

• 36

  Gerhard-Herman M. D. Gornik H. L. Barrett C. Barshes N. R. Corriere M. A. Drachman D. E. et al (2017). 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: Executive summary: A report of the American college of cardiology/American heart association task force on clinical practice guidelines. Circulation135 (12), e686–e725. 10.1161/CIR.0000000000000470

  • CrossRef
  • Google Scholar

• 37

  Gu Y. Cui S. Wang Q. Liu C. Jin B. Guo W. et al (2019). A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia. Mol. Ther.27 (12), 2158–2165. 10.1016/j.ymthe.2019.10.017

  • CrossRef
  • Google Scholar

• 38

  Gupta P. K. Chullikana A. Parakh R. Desai S. Das A. Gottipamula S. et al (2013). A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J. Transl. Med.11, 143. 10.1186/1479-5876-11-143

  • CrossRef
  • Google Scholar

• 39

  Heyward J. Mansour O. Olson L. Singh S. Alexander G. C. (2020). Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis. PLoS One15 (6), e0234065. 10.1371/journal.pone.0234065

  • CrossRef
  • Google Scholar

• 40

  Ho J. Yue D. Cheema U. Hsia H. C. Dardik A. (2022). Innovations in stem cell therapy for diabetic wound healing. Adv. Wound Care (New Rochelle)2022. 10.1089/wound.2021.0104

  • CrossRef
  • Google Scholar

• 41

  Hong Y. Chen J. Fang H. Li G. Yan S. Zhang K. et al (2020). All-in-One hydrogel realizing adipose-derived stem cell spheroid production and in vivo injection via "Gel-Sol" transition for angiogenesis in hind limb ischemia. ACS Appl. Mat. Interfaces12 (10), 11375–11387. 10.1021/acsami.9b23534

  • CrossRef
  • Google Scholar

• 42

  Huang A. Liu D. Qi X. Yue Z. Cao H. Zhang K. et al (2019). Self-assembled GFFYK peptide hydrogel enhances the therapeutic efficacy of mesenchymal stem cells in a mouse hindlimb ischemia model. Acta Biomater.85, 94–105. 10.1016/j.actbio.2018.12.015

  • CrossRef
  • Google Scholar

• 43

  Huang L. C. Wang H. C. Chen L. H. Ho C. Y. Hsieh P. H. Huang M. Y. et al (2019). Bioinspired self-assembling peptide hydrogel with proteoglycan-assisted growth factor delivery for therapeutic angiogenesis. Theranostics9 (23), 7072–7087. 10.7150/thno.35803

  • CrossRef
  • Google Scholar

• 44

  Jayakumar R. Prabaharan M. Nair S. V. Tamura H. (2010). Novel chitin and chitosan nanofibers in biomedical applications. Biotechnol. Adv.28 (1), 142–150. 10.1016/j.biotechadv.2009.11.001

  • CrossRef
  • Google Scholar

• 45

  Jhang J. Y. Tzeng I. S. Chou H. H. Jang S. J. Hsieh C. A. Ko Y. L. et al (2020). Association rule mining and prognostic stratification of 2-year longevity in octogenarians undergoing endovascular therapy for lower extremity arterial disease: Observational cohort study. J. Med. Internet Res.22 (12), e17487. 10.2196/17487

  • CrossRef
  • Google Scholar

• 46

  Jia X. Qi Y. Zheng R. Lin L. Hu C. Zhu Y. et al (2022). Discordance of apolipoprotein B, non-HDL-cholesterol, and LDL-cholesterol predicts risk of increased arterial stiffness and elevated carotid intima-media thickness in middle-aged and elderly Chinese adults. Front. Cardiovasc. Med.9, 906396. 10.3389/fcvm.2022.906396

  • CrossRef
  • Google Scholar

• 47

  Jonason T. Bergstrom R. (1987). Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med. Scand.221 (3), 253–260. 10.1111/j.0954-6820.1987.tb00891.x

  • CrossRef
  • Google Scholar

• 48

  Jonsson T. B. Larzon T. Arfvidsson B. Tidefelt U. Axelsson C. G. Jurstrand M. et al (2012). Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant. Int. Angiol.31 (1), 77–84.

  • Google Scholar

• 49

  Jun I. Ahmad T. Bak S. Lee J. Y. Kim E. M. Lee J. et al (2017). Spatially assembled bilayer cell sheets of stem cells and endothelial cells using thermosensitive hydrogels for therapeutic angiogenesis. Adv. Healthc. Mat.6 (9), 1601340. 10.1002/adhm.201601340

  • CrossRef
  • Google Scholar

• 50

  Kalantari K. Afifi A. M. Jahangirian H. Webster T. J. (2019). Biomedical applications of chitosan electrospun nanofibers as a green polymer - Review. Carbohydr. Polym.207, 588–600. 10.1016/j.carbpol.2018.12.011

  • CrossRef
  • Google Scholar

• 51

  Kamei M. Saunders W. B. Bayless K. J. Dye L. Davis G. E. Weinstein B. M. (2006). Endothelial tubes assemble from intracellular vacuoles in vivo. Nature442 (7101), 453–456. 10.1038/nature04923

  • CrossRef
  • Google Scholar

• 52

  Kim P. H. Yim H. G. Choi Y. J. Kang B. J. Kim J. Kwon S. M. et al (2014). Injectable multifunctional microgel encapsulating outgrowth endothelial cells and growth factors for enhanced neovascularization. J. Control. Release187, 1–13. 10.1016/j.jconrel.2014.05.010

  • CrossRef
  • Google Scholar

• 53

  Kwee B. J. Budina E. Najibi A. J. Mooney D. J. (2018). CD4 T-cells regulate angiogenesis and myogenesis. Biomaterials178, 109–121. 10.1016/j.biomaterials.2018.06.003

  • CrossRef
  • Google Scholar

• 54

  Kwon H. J. Cha M. Y. Kim D. Kim D. K. Soh M. Shin K. et al (2016). Mitochondria-targeting ceria nanoparticles as antioxidants for alzheimer's disease. ACS Nano10 (2), 2860–2870. 10.1021/acsnano.5b08045

  • CrossRef
  • Google Scholar

• 55

  Lammer J. Bosiers M. Deloose K. Schmidt A. Zeller T. Wolf F. et al (2016). Bioresorbable everolimus-eluting vascular scaffold for patients with peripheral artery disease (ESPRIT I): 2-Year clinical and imaging results. JACC. Cardiovasc. Interv.9 (11), 1178–1187. 10.1016/j.jcin.2016.02.051

  • CrossRef
  • Google Scholar

• 56

  Lane R. Harwood A. Watson L. Leng G. C. (2017). Exercise for intermittent claudication. Cochrane Database Syst. Rev.12, CD000990. 10.1002/14651858.CD000990.pub4

  • CrossRef
  • Google Scholar

• 57

  Lara-Hernandez R. Lozano-Vilardell P. Blanes P. Torreguitart-Mirada N. Galmes A. Besalduch J. (2010). Safety and efficacy of therapeutic angiogenesis as a novel treatment in patients with critical limb ischemia. Ann. Vasc. Surg.24 (2), 287–294. 10.1016/j.avsg.2009.10.012

  • CrossRef
  • Google Scholar

• 58

  Lasala G. P. Silva J. A. Minguell J. J. (2012). Therapeutic angiogenesis in patients with severe limb ischemia by transplantation of a combination stem cell product. J. Thorac. Cardiovasc. Surg.144 (2), 377–382. 10.1016/j.jtcvs.2011.08.053

  • CrossRef
  • Google Scholar

• 59

  Layman H. Sacasa M. Murphy A. E. Murphy A. M. Pham S. M. Andreopoulos F. M. (2009). Co-delivery of FGF-2 and G-CSF from gelatin-based hydrogels as angiogenic therapy in a murine critical limb ischemic model. Acta Biomater.5 (1), 230–239. 10.1016/j.actbio.2008.07.024

  • CrossRef
  • Google Scholar

• 60

  Leclerc C. J. Cooper T. T. Bell G. I. Lajoie G. A. Flynn L. E. Hess D. A. (2021). Decellularized adipose tissue scaffolds guide hematopoietic differentiation and stimulate vascular regeneration in a hindlimb ischemia model. Biomaterials274, 120867. 10.1016/j.biomaterials.2021.120867

  • CrossRef
  • Google Scholar

• 61

  Lee E. J. Kasper F. K. Mikos A. G. (2014). Biomaterials for tissue engineering. Ann. Biomed. Eng.42 (2), 323–337. 10.1007/s10439-013-0859-6

  • CrossRef
  • Google Scholar

• 62

  Lee J. B. Kim D. H. Yoon J. K. Park D. B. Kim H. S. Shin Y. M. et al (2020). Microchannel network hydrogel induced ischemic blood perfusion connection. Nat. Commun.11 (1), 615. 10.1038/s41467-020-14480-0

  • CrossRef
  • Google Scholar

• 63

  Lee J. Y. Ryu S. Sung K. C. (2018). Association of baseline level of physical activity and its temporal changes with incident hypertension and diabetes mellitus. Eur. J. Prev. Cardiol.25 (10), 1065–1073. 10.1177/2047487318774419

  • CrossRef
  • Google Scholar

• 64

  Lee N. H. Bayaraa O. Zechu Z. Kim H. S. (2021). Biomaterials-assisted spheroid engineering for regenerative therapy. BMB Rep.54 (7), 356–367. 10.5483/bmbrep.2021.54.7.059

  • CrossRef
  • Google Scholar

• 65

  Lee S. Valmikinathan C. M. Byun J. Kim S. Lee G. Mokarram N. et al (2015). Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes. Biomaterials63, 158–167. 10.1016/j.biomaterials.2015.06.009

  • CrossRef
  • Google Scholar

• 66

  Li R. Liang J. He Y. Qin J. He H. Lee S. et al (2018). Sustained release of immunosuppressant by nanoparticle-anchoring hydrogel scaffold improved the survival of transplanted stem cells and tissue regeneration. Theranostics8 (4), 878–893. 10.7150/thno.22072

  • CrossRef
  • Google Scholar

• 67

  Li R. Pang Z. He H. Lee S. Qin J. Wu J. et al (2017). Drug depot-anchoring hydrogel: A self-assembling scaffold for localized drug release and enhanced stem cell differentiation. J. Control. Release261, 234–245. 10.1016/j.jconrel.2017.07.008

  • CrossRef
  • Google Scholar

• 68

  Liew A. Bhattacharya V. Shaw J. Stansby G. (2016). Cell therapy for critical limb ischemia: A meta-analysis of randomized controlled trials. Angiology67 (5), 444–455. 10.1177/0003319715595172

  • CrossRef
  • Google Scholar

• 69

  Lin C. C. Anseth K. S. (2009). PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm. Res.26 (3), 631–643. 10.1007/s11095-008-9801-2

  • CrossRef
  • Google Scholar

• 70

  Liu G. Fang Z. Yuan M. Li W. Yang Y. Jiang M. et al (2017). Biodegradable carriers for delivery of VEGF plasmid DNA for the treatment of critical limb ischemia. Front. Pharmacol.8, 528. 10.3389/fphar.2017.00528

  • CrossRef
  • Google Scholar

• 71

  Loureiro J. Torres A. L. Neto T. Aguiar P. Barrias C. C. Pinto M. T. et al (2019). Conjugation of the T1 sequence from CCN1 to fibrin hydrogels for therapeutic vascularization. Mat. Sci. Eng. C Mat. Biol. Appl.104, 109847. 10.1016/j.msec.2019.109847

  • CrossRef
  • Google Scholar

• 72

  Makarevich P. Tsokolaeva Z. Shevelev A. Rybalkin I. Shevchenko E. Beloglazova I. et al (2012). Combined transfer of human VEGF165 and HGF genes renders potent angiogenic effect in ischemic skeletal muscle. PLoS One7 (6), e38776. 10.1371/journal.pone.0038776

  • CrossRef
  • Google Scholar

• 73

  Martin-Pelaez S. Fito M. Castaner O. (2020). Mediterranean diet effects on type 2 diabetes prevention, disease progression, and related mechanisms. A review. Nutrients12 (8), 2236. 10.3390/nu12082236

  • CrossRef
  • Google Scholar

• 74

  Masaki I. Yonemitsu Y. Yamashita A. Sata S. Tanii M. Komori K. et al (2002). Angiogenic gene therapy for experimental critical limb ischemia: Acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2. Circ. Res.90 (9), 966–973. 10.1161/01.res.0000019540.41697.60

  • CrossRef
  • Google Scholar

• 75

  Matsui M. Tabata Y. (2012). Enhanced angiogenesis by multiple release of platelet-rich plasma contents and basic fibroblast growth factor from gelatin hydrogels. Acta Biomater.8 (5), 1792–1801. 10.1016/j.actbio.2012.01.016

  • CrossRef
  • Google Scholar

• 76

  Matsumoto T. Yamashita S. Yoshino S. Kurose S. Morisaki K. Nakano K. et al (2020). Therapeutic arteriogenesis/angiogenesis for peripheral arterial disease by nanoparticle-mediated delivery of Pitavastatin into vascular endothelial cells. Ann. Vasc. Dis.13 (1), 4–12. 10.3400/avd.ra.19-00130

  • CrossRef
  • Google Scholar

• 77

  McQueen M. J. Hawken S. Wang X. Ounpuu S. Sniderman A. Probstfield J. et al (2008). Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): A case-control study. Lancet372 (9634), 224–233. 10.1016/S0140-6736(08)61076-4

  • CrossRef
  • Google Scholar

• 78

  Minami T. Kameda A. Terauchi Y. (2021). An evaluation of canagliflozin for the treatment of type 2 diabetes: An update. Expert Opin. Pharmacother.22 (16), 2087–2094. 10.1080/14656566.2021.1939675

  • CrossRef
  • Google Scholar

• 79

  Moazzami K. Moazzami B. Roohi A. Nedjat S. Dolmatova E. (2014). Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst. Rev.12, CD008347. 10.1002/14651858.CD008347.pub2

  • CrossRef
  • Google Scholar

• 80

  Mohammedi K. Woodward M. Hirakawa Y. Zoungas S. Williams B. Lisheng L. et al (2016). Microvascular and macrovascular disease and risk for major peripheral arterial disease in patients with type 2 diabetes. Diabetes Care39 (10), 1796–1803. 10.2337/dc16-0588

  • CrossRef
  • Google Scholar

• 81

  Moon S. H. Kim J. S. Park S. J. Lee H. J. Do J. T. Chung H. M. (2011). A system for treating ischemic disease using human embryonic stem cell-derived endothelial cells without direct incorporation. Biomaterials32 (27), 6445–6455. 10.1016/j.biomaterials.2011.05.026

  • CrossRef
  • Google Scholar

• 82

  Mu R. Zhang Y. Yan L. Liao Z. Yang Y. Su H. et al (2021). A "Bridge-Building" glycan scaffold mimicking microbial invasion for in situ endothelialization. Adv. Mater.33, e2103490. 10.1002/adma.202103490

  • CrossRef
  • Google Scholar

• 83

  Mulyasasmita W. Cai L. Dewi R. E. Jha A. Ullmann S. D. Luong R. H. et al (2014). Avidity-controlled hydrogels for injectable co-delivery of induced pluripotent stem cell-derived endothelial cells and growth factors. J. Control. Release191, 71–81. 10.1016/j.jconrel.2014.05.015

  • CrossRef
  • Google Scholar

• 84

  Naganuma T. Traversa E. (2014). The effect of cerium valence states at cerium oxide nanoparticle surfaces on cell proliferation. Biomaterials35 (15), 4441–4453. 10.1016/j.biomaterials.2014.01.074

  • CrossRef
  • Google Scholar

• 85

  Naide Oscillometry (1939). Diagnosis of arteriosclerosis of the lower extremities. Archives Intern. Med.63 (6), 1158–1162.

  • Google Scholar

• 86

  Nakamura S. Ishihara M. Takikawa M. Kishimoto S. Isoda S. Fujita M. et al (2012). Attenuation of limb loss in an experimentally induced hindlimb ischemic model by fibroblast growth factor-2/fragmin/protamine microparticles as a delivery system. Tissue Eng. Part A18 (21-22), 2239–2247. 10.1089/ten.TEA.2011.0741

  • CrossRef
  • Google Scholar

• 87

  Nativel M. Potier L. Alexandre L. Baillet-Blanco L. Ducasse E. Velho G. et al (2018). Lower extremity arterial disease in patients with diabetes: A contemporary narrative review. Cardiovasc. Diabetol.17 (1), 138–151. 10.1186/s12933-018-0781-1

  • CrossRef
  • Google Scholar

• 88

  Nazri M. Y. Aminudin C. A. Ahmad F. S. Mohd Jazlan M. A. Jamalludin Ab R. Ramli M. (2019). Quality of life of diabetes amputees following major and minor lower limb amputations. Med. J. Malays.74 (1), 25–29.

  • Google Scholar

• 89

  Nillesen S. T. Geutjes P. J. Wismans R. Schalkwijk J. Daamen W. F. van Kuppevelt T. H. (2007). Increased angiogenesis and blood vessel maturation in acellular collagen-heparin scaffolds containing both FGF2 and VEGF. Biomaterials28 (6), 1123–1131. 10.1016/j.biomaterials.2006.10.029

  • CrossRef
  • Google Scholar

• 90

  Norgren L. Hiatt W. R. Dormandy J. A. Nehler M. R. Harris K. A. Fowkes F. G. et al (2007). Inter-society consensus for the management of peripheral arterial disease (TASC II). J. Vasc. Surg.45, S5–S67. 10.1016/j.jvs.2006.12.037

  • CrossRef
  • Google Scholar

• 91

  Novakova V. Sandhu G. S. Dragomir-Daescu D. Klabusay M. (2016). Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia. Vasc. Pharmacol.76, 1–10. 10.1016/j.vph.2015.08.005

  • CrossRef
  • Google Scholar

• 92

  Ozturk A. Kucukardali Y. Tangi F. Erikci A. Uzun G. Bashekim C. et al (2012). Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia. J. Diabetes Complicat.26 (1), 29–33. 10.1016/j.jdiacomp.2011.11.007

  • CrossRef
  • Google Scholar

• 93

  Palmer L. C. Stupp S. I. (2008). Molecular self-assembly into one-dimensional nanostructures. Acc. Chem. Res.41 (12), 1674–1684. 10.1021/ar8000926

  • CrossRef
  • Google Scholar

• 94

  Pan T. Liu H. Fang Y. Wei Z. Gu S. Fang G. et al (2019). Predictors of responders to mononuclear stem cell-based therapeutic angiogenesis for no-option critical limb ischemia. Stem Cell Res. Ther.10 (1), 15–27. 10.1186/s13287-018-1117-5

  • CrossRef
  • Google Scholar

• 95

  Pan T. Wei Z. Fang Y. Dong Z. Fu W. (2018). Therapeutic efficacy of CD34(+) cell-involved mononuclear cell therapy for no-option critical limb ischemia: A meta-analysis of randomized controlled clinical trials. Vasc. Med.23 (3), 219–231. 10.1177/1358863X17752556

  • CrossRef
  • Google Scholar

• 96

  Papavassiliou V. G. Walker S. R. Bolia A. Fishwick G. London N. (2003). Techniques for the endovascular management of complications following lower limb percutaneous transluminal angioplasty. Eur. J. Vasc. Endovasc. Surg.25 (2), 125–130. 10.1053/ejvs.2002.1822

  • CrossRef
  • Google Scholar

• 97

  Park H. J. Jin Y. Shin J. Yang K. Lee C. Yang H. S. et al (2016). Catechol-functionalized hyaluronic acid hydrogels enhance angiogenesis and osteogenesis of human adipose-derived stem cells in critical tissue defects. Biomacromolecules17 (6), 1939–1948. 10.1021/acs.biomac.5b01670

  • CrossRef
  • Google Scholar

• 98

  Park H. S. Choi G. H. Kim D. Jung T. W. Jung I. M. Chung J. K. et al (2018). Use of self-assembling peptides to enhance stem cell function for therapeutic angiogenesis. Stem Cells Int.2018, 4162075. 10.1155/2018/4162075

  • CrossRef
  • Google Scholar

• 99

  Park I. S. Chung P. S. Ahn J. C. (2014). Enhanced angiogenic effect of adipose-derived stromal cell spheroid with low-level light therapy in hind limb ischemia mice. Biomaterials35 (34), 9280–9289. 10.1016/j.biomaterials.2014.07.061

  • CrossRef
  • Google Scholar

• 100

  Park I. S. Mahapatra C. Park J. S. Dashnyam K. Kim J. W. Ahn J. C. et al (2020). Revascularization and limb salvage following critical limb ischemia by nanoceria-induced Ref-1/APE1-dependent angiogenesis. Biomaterials242, 11991. 10.1016/j.biomaterials.2020.119919

  • CrossRef
  • Google Scholar

• 101

  Park J. J. Kwon Y. W. Kim J. W. Park G. T. Yoon J. W. Kim Y. S. et al (2021). Coadministration of endothelial and smooth muscle cells derived from human induced pluripotent stem cells as a therapy for critical limb ischemia. Stem Cells Transl. Med.10 (3), 414–426. 10.1002/sctm.20-0132

  • CrossRef
  • Google Scholar

• 102

  Park J. S. Bae S. H. Jung S. Lee M. Choi D. (2019). Enrichment of vascular endothelial growth factor secreting mesenchymal stromal cells enhances therapeutic angiogenesis in a mouse model of hind limb ischemia. Cytotherapy21 (4), 433–443. 10.1016/j.jcyt.2018.12.007

  • CrossRef
  • Google Scholar

• 103

  Peeters Weem S. M. Teraa M. de Borst G. J. Verhaar M. C. Moll F. L. (2015). Bone marrow derived cell therapy in critical limb ischemia: A meta-analysis of randomized placebo controlled trials. Eur. J. Vasc. Endovasc. Surg.50 (6), 775–783. 10.1016/j.ejvs.2015.08.018

  • CrossRef
  • Google Scholar

• 104

  Pei X. Kim H. Lee M. Wang N. Shin J. Lee S. et al (2020). Local delivery of cardiac stem cells overexpressing HIF-1α promotes angiogenesis and muscular tissue repair in a hind limb ischemia model. J. Control. Release322, 610–621. 10.1016/j.jconrel.2020.03.017

  • CrossRef
  • Google Scholar

• 105

  Qadura M. Terenzi D. C. Verma S. Al-Omran M. Hess D. A. (2018). Concise review: Cell therapy for critical limb ischemia: An integrated review of preclinical and clinical studies. Stem Cells36 (2), 161–171. 10.1002/stem.2751

  • CrossRef
  • Google Scholar

• 106

  Rajagopalan S. Mohler E. 3rd Lederman R. J. Saucedo J. Mendelsohn F. O. Olin J. et al (2003). Regional angiogenesis with vascular endothelial growth factor (VEGF) in peripheral arterial disease: Design of the RAVE trial. Am. Heart J.145 (6), 1114–1118. 10.1016/S0002-8703(03)00102-9

  • CrossRef
  • Google Scholar

• 107

  Rigato M. Monami M. Fadini G. P. (2017). Autologous cell therapy for peripheral arterial disease: Systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circ. Res.120 (8), 1326–1340. 10.1161/CIRCRESAHA.116.309045

  • CrossRef
  • Google Scholar

• 108

  Ruvinov E. Leor J. Cohen S. (2010). The effects of controlled HGF delivery from an affinity-binding alginate biomaterial on angiogenesis and blood perfusion in a hindlimb ischemia model. Biomaterials31 (16), 4573–4582. 10.1016/j.biomaterials.2010.02.026

  • CrossRef
  • Google Scholar

• 109

  Sacchi V. Mittermayr R. Hartinger J. Martino M. M. Lorentz K. M. Wolbank S. et al (2014). Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164. Proc. Natl. Acad. Sci. U. S. A.111 (19), 6952–6957. 10.1073/pnas.1404605111

  • CrossRef
  • Google Scholar

• 110

  Schwartz L. B. Moawad J. (1997). Gene therapy for vascular disease. Ann. Vasc. Surg.11 (2), 189–199. 10.1007/s100169900034

  • CrossRef
  • Google Scholar

• 111

  Sethi G. K. Scott S. M. Takaro T. (1980). Effect of intraarterial infusion of PGE1 in patients with severe ischemia of lower extremity. J. Cardiovasc. Surg.21 (2), 185–192.

  • Google Scholar

• 112

  Skora J. Pupka A. Janczak D. Barc P. Dawiskiba T. Korta K. et al (2015). Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia. Arch. Med. Sci.11 (2), 325–331. 10.5114/aoms.2013.39935

  • CrossRef
  • Google Scholar

• 113

  Slobodkina E. Boldyreva M. Karagyaur M. Eremichev R. Alexandrushkina N. Balabanyan V. et al (2020). Therapeutic angiogenesis by a "dynamic duo": Simultaneous expression of HGF and VEGF165 by novel bicistronic plasmid restores blood flow in ischemic skeletal muscle. Pharmaceutics12 (12), 1231. 10.3390/pharmaceutics12121231

  • CrossRef
  • Google Scholar

• 114

  Slovut D. P. Lipsitz E. C. (2012). Surgical technique and peripheral artery disease. Circulation126 (9), 1127–1138. 10.1161/CIRCULATIONAHA.111.059048

  • CrossRef
  • Google Scholar

• 115

  Soyoye D. O. Abiodun O. O. Ikem R. T. Kolawole B. A. Akintomide A. O. (2021). Diabetes and peripheral artery disease: A review. World J. Diabetes12 (6), 827–838. 10.4239/wjd.v12.i6.827

  • CrossRef
  • Google Scholar

• 116

  Sun H. Saeedi P. Karuranga S. Pinkepank M. Ogurtsova K. Duncan B. B. et al (2022). IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract.183, 109119. 10.1016/j.diabres.2021.109119

  • CrossRef
  • Google Scholar

• 117

  Suzuki E. Kashiwagi A. Nishio Y. Egawa K. Shimizu S. Maegawa H. et al (2001). Increased arterial wall stiffness limits flow volume in the lower extremities in type 2 diabetic patients. Diabetes Care24 (12), 2107–2114. 10.2337/diacare.24.12.2107

  • CrossRef
  • Google Scholar

• 118

  Szabo G. V. Kovesd Z. Cserepes J. Daroczy J. Belkin M. Acsady G. (2013). Peripheral blood-derived autologous stem cell therapy for the treatment of patients with late-stage peripheral artery disease-results of the short- and long-term follow-up. Cytotherapy15 (10), 1245–1252. 10.1016/j.jcyt.2013.05.017

  • CrossRef
  • Google Scholar

• 119

  Takeshita S. Zheng L. P. Brogi E. Kearney M. Pu L. Q. Bunting S. et al (1994). Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J. Clin. Invest.93 (2), 662–670. 10.1172/JCI117018

  • CrossRef
  • Google Scholar

• 120

  Tan R. P. Chan A. H. P. Lennartsson K. Miravet M. M. Lee B. S. L. Rnjak-Kovacina J. et al (2018). Integration of induced pluripotent stem cell-derived endothelial cells with polycaprolactone/gelatin-based electrospun scaffolds for enhanced therapeutic angiogenesis. Stem Cell Res. Ther.9 (1), 70. 10.1186/s13287-018-0824-2

  • CrossRef
  • Google Scholar

• 121

  Tan Y. Shao H. Eton D. Yang Z. Alonso-Diaz L. Zhang H. et al (2007). Stromal cell-derived factor-1 enhances pro-angiogenic effect of granulocyte-colony stimulating factor. Cardiovasc. Res.73 (4), 823–832. 10.1016/j.cardiores.2006.12.015

  • CrossRef
  • Google Scholar

• 122

  Tang J. Cui X. Caranasos T. G. Hensley M. T. Vandergriff A. C. Hartanto Y. et al (2017). Heart repair using nanogel-encapsulated human cardiac stem cells in mice and pigs with myocardial infarction. ACS Nano11 (10), 9738–9749. 10.1021/acsnano.7b01008

  • CrossRef
  • Google Scholar

• 123

  Taniwaki H. Shoji T. Emoto M. Kawagishi T. Ishimura E. Inaba M. et al (2001). Femoral artery wall thickness and stiffness in evaluation of peripheral vascular disease in type 2 diabetes mellitus. Atherosclerosis158 (1), 207–214. 10.1016/s0021-9150(01)00414-2

  • CrossRef
  • Google Scholar

• 124

  Tanner M. R. Beeton C. (2018). Differences in ion channel phenotype and function between humans and animal models. Front. Biosci.23 (1), 43–64. 10.2741/4581

  • CrossRef
  • Google Scholar

• 125

  Teraa M. Conte M. S. Moll F. L. Verhaar M. C. (2016). Critical limb ischemia: Current trends and future directions. J. Am. Heart Assoc.5 (2), e002938. 10.1161/JAHA.115.002938

  • CrossRef
  • Google Scholar

• 126

  Troy E. Tilbury M. A. Power A. M. Wall J. G. (2021). Nature-based biomaterials and their application in biomedicine. Polym. (Basel)13 (19), 3321. 10.3390/polym13193321

  • CrossRef
  • Google Scholar

• 127

  Van Raemdonck K. Van den Steen P. E. Liekens S. Van Damme J. Struyf S. (2015). CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev.26 (3), 311–327. 10.1016/j.cytogfr.2014.11.009

  • CrossRef
  • Google Scholar

• 128

  Veith A. P. Henderson K. Spencer A. Sligar A. D. Baker A. B. (2019). Therapeutic strategies for enhancing angiogenesis in wound healing. Adv. Drug Deliv. Rev.146, 97–125. 10.1016/j.addr.2018.09.010

  • CrossRef
  • Google Scholar

• 129

  Wang C. Y. Hsiao C. Y. Tsai K. L. Cheng Y. H. (2020). Injectable thermosensitive chitosan-based hydrogel containing ferulic acid for treating peripheral arterial disease. J. Tissue Eng. Regen. Med.14 (10), 1438–1448. 10.1002/term.3109

  • CrossRef
  • Google Scholar

• 130

  Wang J. Cui W. Ye J. Ji S. Zhao X. Zhan L. et al (2012). A cellular delivery system fabricated with autologous BMSCs and collagen scaffold enhances angiogenesis and perfusion in ischemic hind limb. J. Biomed. Mat. Res. A100 (6), 1438–1447. 10.1002/jbm.a.34081

  • CrossRef
  • Google Scholar

• 131

  Wang K. Dai X. He J. Yan X. Yang C. Fan X. et al (2020). Endothelial overexpression of metallothionein prevents diabetes-induced impairment in ischemia angiogenesis through preservation of HIF-1α/SDF-1/VEGF signaling in endothelial progenitor cells. Diabetes69 (8), 1779–1792. 10.2337/db19-0829

  • CrossRef
  • Google Scholar

• 132

  Wang R. Yao X. Li T. Li X. Jin M. Ni Y. et al (2019). Reversible thermoresponsive hydrogel fabricated from natural biopolymer for the improvement of critical limb ischemia by controlling release of stem cells. Adv. Healthc. Mat.8 (20), e1900967. 10.1002/adhm.201900967

  • CrossRef
  • Google Scholar

• 133

  Xie B. Luo H. Zhang Y. Wang Q. Zhou C. Xu D. (2018). Autologous stem cell therapy in critical limb ischemia: A meta-analysis of randomized controlled trials. Stem Cells Int.2018, 7528464. 10.1155/2018/7528464

  • CrossRef
  • Google Scholar

• 134

  Xie J. Wang H. Wang Y. Ren F. Yi W. Zhao K. et al (2013). Induction of angiogenesis by controlled delivery of vascular endothelial growth factor using nanoparticles. Cardiovasc. Ther.31 (3), e12–8. 10.1111/j.1755-5922.2012.00317.x

  • CrossRef
  • Google Scholar

• 135

  Xing Z. Zhao C. Liu H. Fan Y. (2020). Endothelial progenitor cell-derived extracellular vesicles: A novel candidate for regenerative medicine and disease treatment. Adv. Healthc. Mat.9 (12), e2000255. 10.1002/adhm.202000255

  • CrossRef
  • Google Scholar

• 136

  Xing Z. Zhao C. Wu S. Yang D. Zhang C. Wei X. et al (2021). Hydrogel loaded with VEGF/TFEB-Engineered extracellular vesicles for rescuing critical limb ischemia by a dual-pathway activation strategy. Adv. Healthc. Mat.11, e2100334. 10.1002/adhm.202100334

  • CrossRef
  • Google Scholar

• 137

  Xing Z. Zhao C. Wu S. Zhang C. Liu H. Fan Y. (2021). Hydrogel-based therapeutic angiogenesis: An alternative treatment strategy for critical limb ischemia. Biomaterials274, 120872. 10.1016/j.biomaterials.2021.120872

  • CrossRef
  • Google Scholar

• 138

  Yang S. L. Zhu L. Y. Han R. Sun L. L. Li J. X. Dou J. T. (2017). Pathophysiology of peripheral arterial disease in diabetes mellitus. J. Diabetes9 (2), 133–140. 10.1111/1753-0407.12474

  • CrossRef
  • Google Scholar

• 139

  Yokoyama M. Watanabe T. Otaki Y. Watanabe K. Toshima T. Sugai T. et al (2018). Impact of objective malnutrition Status on the clinical outcomes in patients with peripheral artery disease following endovascular therapy. Circ. J.82 (3), 847–856. 10.1253/circj.CJ-17-0731

  • CrossRef
  • Google Scholar

• 140

  Zhang Z. D. Xu Y. Q. Chen F. Luo J. F. Liu C. D. (2019). Sustained delivery of vascular endothelial growth factor using a dextran/poly(lactic-co-glycolic acid)-combined microsphere system for therapeutic neovascularization. Heart Vessels34 (1), 167–176. 10.1007/s00380-018-1230-5

  • CrossRef
  • Google Scholar

• 141

  Zhang Z. Gupte M. J. Ma P. X. (2013). Biomaterials and stem cells for tissue engineering. Expert Opin. Biol. Ther.13 (4), 527–540. 10.1517/14712598.2013.756468

  • CrossRef
  • Google Scholar

• 142

  Zhao Y. Liu Z. Pan C. Li Z. Zhou J. Wang J. et al (2011). Preparation of gelatin microspheres encapsulated with bFGF for therapeutic angiogenesis in a canine ischemic hind limb. J. Biomater. Sci. Polym. Ed.22 (4-6), 665–682. 10.1163/092050610X489880

  • CrossRef
  • Google Scholar

• 143

  Zhou J. Zhao Y. Wang J. Zhang S. Liu Z. Zhen M. et al (2012). Therapeutic angiogenesis using basic fibroblast growth factor in combination with a collagen matrix in chronic hindlimb ischemia. ScientificWorldJournal.2012, 652794. 10.1100/2012/652794

  • CrossRef
  • Google Scholar