Challenges in vascular tissue engineering for diabetic patients

Abstract

Hyperglycemia and dyslipidemia coexist in diabetes and result in inflammation, degeneration, and impaired tissue remodeling, processes which are not conducive to the desired integration of tissue engineered products into the surrounding tissues. There are several challenges for vascular tissue engineering such as non-thrombogenicity, adequate burst pressure and compliance, suturability, appropriate remodeling responses, and vasoactivity, but, under diabetic conditions, an additional challenge needs to be considered: the aggressive oxidative environment generated by the high glucose and lipid concentrations that lead to the formation of advanced glycation end products (AGEs) in the vascular wall. Extracellular matrix-based scaffolds have adequate physical properties and are biocompatible, however, these scaffolds are altered in diabetes by the formation AGEs and impaired collagen degradation, consequently increasing vascular wall stiffness. In addition, vascular cells detect and respond to altered stimuli from the matrix by pathological remodeling of the vascular wall. Due to the immunomodulatory effects of mesenchymal stem cells (MSCs), they are frequently used in tissue engineering in order to protect the scaffolds from inflammation. MSCs together with antioxidant treatments of the scaffolds are expected to protect the vascular grafts from diabetes-induced alterations. In conclusion, as one of the most daunting environments that could damage the ECM and its interaction with cells is progressively built in diabetes, we recommend that cells and scaffolds used in vascular tissue engineering for diabetic patients are tested in diabetic animal models, in order to obtain valuable results regarding their resistance to diabetic adversities.

1. Introduction

Diabetes, one of the major risk factors for cardiovascular diseases, is increasing to epidemic proportion worldwide[1], currently affecting 8% of the world’s population and more than 29 million people in the United States alone[2]. Hyperglycemia, resulting from deficiency in insulin secretion (Type 1 Diabetes) or insulin resistance (Type 2 Diabetes), coexists with dyslipidemia, oxidative stress, and inflammation, significantly increasing the risk of cardiovascular diseases[3, 4]. One of the major complications of diabetes is associated with accelerated atherosclerosis and vascular wall stiffening, the hallmark of diabetes[5]. Despite extensive research and progress in the treatment of cardiovascular diseases, there are still numerous amputations and vascular related deaths associated with diabetes. AHA states that about 500,000 coronary artery bypass graft procedures are performed every year in the US. Additionally, about 12 million patients in the US have a form of peripheral arterial disease and the American Diabetes Association estimates that 20-50% of them are diabetic [6, 7].

Over the last several years, diabetic patients have not shared the same decline in arterial disease-related mortality as non-diabetic patients[8]. Patients with diabetes still have a high incidence of restenosis after receiving drug-eluting stents[9], and coronary artery bypass grafting occlusions are more common among diabetics versus non-diabetics at 1-year angiography[10]. The autologous arteries and veins are the “gold standard” for coronary artery bypass grafting, but 1/3 of patients (about 140,000 each year) do not have vessels suitable for grafting. Vascular synthetic grafts with medium and large diameters function well, but small-diameter grafts fail rapidly (50% patency rate by two years) and cryopreserved cadaveric veins have only 30% patency rates after 12 months[11-13]. Therefore, there is a major need for vascular grafts with long-term stability and patency for diabetic patients.

Progress has been made in tissue engineering that holds great promise to treat vascular diseases[14, 15]. A typical approach in tissue engineering is based on a biodegradable and biocompatible scaffold (based on natural or synthetic polymers, including promising elastomeric polymers[16, 17]) with mechanical properties similar to the target tissue, seeded with autologous stem cells, chemically and mechanically stimulated in a vascular bioreactor, followed by implantation, that leads to remodeling and maturation into fully functional vascular grafts[18, 19] (Fig. 1).

Fig. 1.

Challenges of vascular tissue engineering include non-thrombogenicity, adequate burst pressure and compliance, suturability, appropriate remodeling responses, and vasoactivity[20]. For diabetic patients though, the vascular tissue engineering products would face an additional challenge: an aggressive oxidative environment generated by the increased concentration of glucose and lipids and their altered metabolism. Indeed, hyperglycemia and dyslipidemia that coexist in diabetes would result in inflammation, degeneration, and impaired tissue remodeling, processes that are not conducive to the desired integration of tissue engineered constructs into the surrounding tissues.

Based on the current knowledge of pathological modifications induced by diabetes in the vascular wall, this review will focus on the likely modifications generated by the glycoxidative and lipoxidative environment in the major extracellular matrix components and in the cells used in blood vessel tissue engineering. Strategies for maintaining a good patency and durability of the vascular grafts in a diabetic milieu will also be presented.

2. Effect of diabetes on extracellular matrix components

Vascular tissue engineered grafts require resilient porous scaffolds with controlled biodegradability and appropriate mechanical properties from the onset of implantation[21]. Therefore, there is an increased interest in extracellular matrix (ECM) -based scaffolds processed from xenogeneic or allogeneic blood vessels by complete removal of cells [22, 23]. These biological scaffolds have adequate physical properties and are biocompatible, biodegradable with safe byproducts[24, 25]. Plus, the 3D organization of the ECM components distinguishes them from synthetic scaffolds[22]. Particularly, elastin, the vascular wall component that reduces the cell proliferative response to arterial injury[26] and maintains tissue elasticity, is not regenerated experimentally; therefore, it’s an advantage to use decellularized structures that preserve the entire matrix composition. Hyaluronic acid is a component of the ECM, considered a space filling macromolecule for a long time and responsible for tissue hydration. However, recently it has been shown that the hyaluronic acid chains in the glycocalyx are involved in regulating the functions and dysfunctions of vascular cells, linked to atherosclerosis and diabetes[27]. Low molecular weight hyaluronic acid fragments could promote endothelial cell dysfunction and smooth muscle cell migration, in atherosclerosis and restenosis after injury. Hyaluronidases start the fragmentation of hyaluronic acid macromolecules in the extracellular space, continuing the degradative process inside the cells. These enzymes, activated by hyperglycemic conditions, contribute to glycocalyx volume reduction, increased coagulation, endothelial cell dysfunction[28], and smooth muscle cell migration. However, due to the ability of hyaluronic acid to form hydrogel-based scaffolds that favor tissue repair processes, and especially due the pro-angiogenic properties of hyaluronic acid fragments, this ECM component is extensively used in tissue engineering, particularly in diabetic wound healing applications[29]. Indeed, stem cell-containing hyaluronic acid-based spongy hydrogels enhance diabetic wound healing by positively impacting re-epithelialization and by modulating the inflammatory response[30].

It is remarkable that these ECM-based scaffolds promote the transition from classically activated pro inflammatory M1 macrophage phenotype in favor of an alternatively activated pro healing M2 macrophage phenotype; the mechanism is unknown, but it has been suggested that specific peptide sequences present in the structure of matrix components interact and activate particular cells [31]. Indeed, amino acid sequences were identified in the matrix proteins or their degradation products, also referred to as matrikines[32] that might be involved in macrophage polarization; these peptides induce several biological activities, such as chemotaxis, MMP release, and modulation of cell phenotypes, via a 67-kD elastin laminin receptor present on the surface of fibroblasts, smooth muscle cells, and monocytes [33-36].

For acellular ECM-scaffold preparation, several cell removal methods have been published, that eliminate all epitopes associated with cells, including galactose alpha 1,3 galactose (alpha-gal), expressed on the cell surface of all mammals, except humans and old world primates[37]. In the same time, these methods preserve not only the organization of the major matrix components (collagen, elastin) but also the basement membrane proteins (type IV collagen, laminin), essential for tissue regeneration[24, 38-47]. Therefore, acellular biological scaffolds have been used in regenerative medicine applications, for both preclinical animal studies and clinical purposes [23, 48]. Collagen and elastin-based scaffolds implanted sub-dermally in diabetic rats with very strict glycemic control revealed structural alterations caused by the formation of advanced glycation end products (AGEs)[39]. The non-enzymatic nucleophilic addition reaction between a free amino group and the reducing sugar carbonyl group forms a Schiff base, which rearranges into an Amadori product (the Maillard reaction) that generates irreversible cross links in long lived proteins, such as collagen and elastin, leading to vascular stiffening, the hallmark of diabetes. Glucose and lipid molecules also undergo a series of oxidant-induced fragmentation resulting in the formation of glyoxal and methylglyoxal, short-chain reactive compounds involved in protein oxidation and formation of AGEs[49, 50] (Fig. 2). Free radicals containing oxygen or nitrogen were identified among the key participants in glycoxidation and lipid peroxidation[50-52]. The spontaneous reaction of protein glycation is influenced by several variables such as pH, temperature, degree and duration of hyperglycemia, half-life and concentration of protein, duration of hyperglycemia, concentration of glucose, and permeability of the tissue to free glucose. In addition, by crosslinking the extracellular matrix molecules, AGEs can also trap unwanted plasma proteins in the vessel wall, such as lipoproteins, and accelerate atherosclerosis[53]. Besides crosslinking matrix proteins, the high glucose concentration reduces the matrix metalloproteinase activity, impairing collagen degradation and inducing fibrosis, ectopic calcification, and stiffness of the vascular wall[54]. In diabetic patients, these scaffolds could be modified by the high glucose and lipid concentrations. Therefore, clinically it is too early to speculate on the lifetime of these grafts, since there are no acellular heart valves, patches or sheets approved for implantation in human patients. Humacyte collagen vascular grafts are currently in clinical trials as A-V shunts for hemodialysis in diabetic and non-diabetic patients, but results are not yet available (clinicaltrials.gov). The only product we could find in the literature was the human acellular dermal matrix, which has been shown to be beneficial in treating dermal wounds in diabetic patients with no short term complications [55]. However, human acellular dermal matrix has been quite frequently used off-target; for example, when used for breast reconstruction, the total complication rate was almost 20% [56]. A meta-analysis of human acellular dermal matrix used in abdominal wall reconstruction in diabetic patients showed as high as 27% complications with hernia and bulging [57]. Polymeric vascular grafts implanted in diabetic animals also exhibited increased complications and adverse effects [58]. Regarding calcification, a recent Veterans Affair Cooperative Study performed on a large number of persons with type 2 diabetes showed that subjects with coronary artery or abdominal artery calcification had a dramatically high prevalence of peripheral artery disease and coronary artery disease[59].

Fig. 2.

3. Effect of diabetes on tissue-specific cells

The endothelium, the semi-permeable membrane at the blood-tissue interface, which regulates thrombosis, thrombolysis, and platelet adherence, as well as inflammatory and immune reactions, is injured under insulin-resistance conditions; cells decrease their secretion of nitric oxide and increase the production of endothelin-1 and reactive oxidative species (ROS), leading to endoplasmic reticulum stress and apoptosis[60-62], processes that accelerate the early stage of atherosclerosis[63]. Smooth muscle cells in the media are also affected by diabetes. Hyperglycemia stimulates and sustains the inflammatory “synthetic” phenotype of smooth muscle cells and enhances their migration and proliferation[64, 65] during progression of atherosclerosis. Intimal and medial calcification is also a widespread feature of diabetes, associated with atherosclerosis, and elastin pathology[66-70]. The mechanism of diabetic vascular calcification in vivo is still not fully understood, however chronic inflammation and oxidative stress induced by the activation of the AGE–RAGE axis has been shown to be involved[71]. RAGE activation induces alkaline phosphatase expression, calcium deposition, and Msx2 expression, a crucial transcription factor for osteogenic differentiation in human vascular smooth muscle cells, via Notch/Msx2 induction[72]. Ca^2+‒handling alterations in vascular smooth muscle cells play a key role in the development and progression of vascular complications in diabetes[73]. Biomarkers for this actively regulated and complex process are: Klotho/fibroblast growth factor-23, Runx-2, fetuin-A, matrix Gla protein, BMP-2, osteoprotegerin, osteopontin, osteonectin and osteocalcin[74, 75]. The calcium-sensing receptor, a G-protein coupled receptor, plays a pivotal role in the extracellular calcium homeostasis and is expressed in endothelial and smooth muscle cells[76, 77]. Also, by increasing the stiffness of the matrix, AGEs could induce osteoblastic differentiation in the intima and media[72, 78, 79]. The third type of cells in the vessel wall, the adventitial fibroblasts are known to be actively involved in blood vessel homeostasis[80]. Recently though, it has been shown that the adventitia is more than a passive supportive layer. Activated fibroblasts proliferate and migrate to the media and intima, contributing to medial smooth muscle hypertrophy, neointimal growth[81], plaque thickening and fibrous cap formation[82]. Adventitial fibroblasts play an active role in the arterial response to injury, cytokines, stretch, and matrikines, which stimulate their activation and differentiation into myofibroblasts, the contractile cells involved in wound healing and adventitial remodeling (first described by Gabbiani and Majno in 1971)[83, 84] (Fig. 3). Adhesion molecules, such as P-selectin and VCAM-1 are upregulated within the vasa vasorum contributing to homing and accumulation of additional inflammatory cells, recognizing the adventitia as a primary site of inflammation in the course of vascular disease[85]. As the matrix components are modified under diabetic conditions, the cells detect and respond to altered matrix stimuli by pathological remodeling and increased stiffness of the vascular wall; an example is the smooth muscle cell dedifferentiation and vessel wall thickening triggered by hyaluronan[27]. Undeniably, one of the most daunting environments that could damage the ECM and its interaction with cells is progressively built in diabetes. Pericytes, perivascular cells involved in the structural stabilization of the microvascular wall, regulation of blood flow, angiogenesis, and vascular permeability, are frequently used in tissue engineering[86], not only for their supportive role in the vascular wall, but also for their immunomodulatory and phagocytic properties, as well as their multipotent capability and plasticity similar to mesenchymal stromal cells[87, 88]. However, these cells are also affected by diabetes and the related oxidative stress, leading to disruption of endothelial cell-pericyte interaction and apoptosis[89]. For example, muscular pericytes in diabetic patients have an imbalanced redox state due to the downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant PKC βII-dependent p66^Shc signaling pathway[90].

Fig. 3.

4. Effect of diabetes on mesenchymal stem cells

In vascular tissue engineering, mesenchymal stem cells (MSCs) are used [11, 91], due to their proliferative and growth potential, angiogenic activity, as well as ability to differentiate into target vascular cells[92, 93]. Autologous stem cells are seeded into scaffolds in order to induce tissue remodeling and maturation[94]. Healthy vascular cells with precise roles in maintaining the vascular wall homeostasis are needed to support the structural and functional integrity of the new blood vessel. Bone marrow mesenchymal stem cells have been used as a source for both endothelial and smooth muscle cells[95, 96], but adipose tissue - derived stem cells (ASCs) have also been identified as a promising stem cell source, due to their availability and ability to differentiate along desired cell lines [97-101]. However, mesenchymal stem cells of different origins could be affected by hyperglycemia that impairs their ability to adequately repair and regenerate the diabetes-injured vascular tissue[102, 103]. Particularly, type 2 diabetes-induced oxidative stress has been shown to impede the multipotency and proangiogenic activity of adipose tissue-derived stem cells isolated from diabetic patients with coronary artery disease[104] and bone marrow-derived stem cells, and reduce their capacity to increase neovascularization and blood flow recovery in a hindlimb ischemia small animal models[105, 106]. Although their regenerative abilities could be compromised by diabetes[107, 108], a great benefit of using MSCs in cell therapy and tissue engineering is conferred by their broad modulatory effect on the immune system[109]. They secrete a large range of anti-inflammatory factors, such as TGF-beta, IL-6, and prostaglandin E2 in response to pro-inflammatory factors, such as IFN-gamma, TNF-alpha, and IL-17A[110]. Consequently, mesenchymal stem cells affect the function of all immune cell types. Stem cells reduce the production of inflammatory cytokines by immune cells IL-6 and TNF-α, and suppress cytotoxic T-cell proliferation, and stimulate the secretion of anti-inflammatory cytokines such as IL-4 and IL-10 [24, 100, 111, 112] . Mesenchymal stem cells secrete indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan from their environment, inhibiting lymphocyte proliferation and suppress the cytotoxic effect of NK cells. Though the mechanisms for inducing therapeutic effect still remain largely unknown, it is likely that MSCs regulate the adaptive and innate immune systems by soluble factors and cell-cell contacts, that suppress T cells and maturation of dendritic cells, reduce B-cell activation and proliferation, NK cell cytotoxicity, and promote generation of regulatory T cells[113]. Mesenchymal cells also regulate macrophage polarization, by reducing the number of classically activated pro inflammatory M1 macrophage phenotype in favor of the alternatively activated pro healing M2 macrophage phenotype[114-116]; therefore the polarization between M1 and M2 macrophages is of great interest for the field of tissue engineering and regenerative medicine[117].

The immunomodulatory properties of ASCs have been demonstrated in a variety of experimental models of diseases, including spinal cord injury, neurodegenerative diseases, and graft versus host disease[118, 119]. ASCs also secrete soluble factors that promote tissue regeneration at the injury site via a paracrine mechanism: angiogenic factors (VEGF), anti-apoptotic factors (IGF-1), hematopoietic factors (colony stimulating factors and interleukins), transforming growth factor-β1 and hepatic growth factor. Results from clinical trials have confirmed the safety and efficacy of ASCs in reducing diabetes-related complications. Diabetic patients infused with bone marrow derived stem cells and ASCs had a 40% decrease in insulin requirements with no adverse effects in a 3 months follow-up period[120, 121]. Studies evaluating the therapeutic impact of ASC in patients with diabetic foot showed improved rest pain score, walking time, and evidence of increased vascular collateral networks within 6 months of intramuscular ASC injection[122]. Wound healing was accelerated in diabetic mice with skin ulcers when ASC were delivered [123, 124]. Inflammation is the central mechanism driving vascular complications in diabetes; therefore, its suppression is a key factor for tissue engineered construct survival and integration. ECM-based scaffolds seeded with autologous ASCs and implanted sub dermally in diabetic rats, revealed moderate diabetes-related inflammatory reactions, only 10.2% T-cells and 5% macrophages, compared to non-seeded scaffolds. Also, a 20% increase in the M2 cell number was noticed, in both control and diabetic conditions, resulting in constructive tissue remodeling[125] (Fig. 4). Injected or infiltrated cells stained positive for alpha-smooth muscle actin and vimentin positive cells, which indicated the presence of fibroblasts or myofibroblasts; they also secreted laminin, a basement membrane protein essential for cell adhesion [126], differentiation, and maturation [127, 128]. Due to the immunomodulation properties of MSC, it is expected that stem cell-seeded vascular scaffolds would moderate the diabetes- induced aggressive inflammation and promote constructive remodeling and integration of tissue engineered vascular tissues. However, it is possible that the aggressive inflammatory diabetic environment could decrease the beneficial immunomodulatory and anti-inflammatory effect of MSCs[129].

Fig. 4.

5. Reactive oxygen species and antioxidants in blood vessel tissue engineering

Hyperglycemia and dyslipidemia generate oxidative stress, initiated by mitochondrial overproduction of superoxide, the precursor of other ROS molecules that contribute to the development of diabetic complications in the cardiovascular system[130]. The excessive free fatty acid and glucose supplies exceed the buffering capacity of the cell endogenous antioxidant defense mechanisms. NADPH-oxidases, the only known enzyme family solely dedicated to producing ROS, are expressed and active in the diabetic aorta[131], in endothelial cells, as well as fibroblasts[132]. ROS and chemotactic molecules, in particular CCL2, CX3CL1, and CCL5TLR4, activate TLR4 on monocytes and macrophages, which infiltrate the diabetic injured tissues. TLR4, a pattern recognition receptor essential for initiating inflammatory responses associated with innate immunity, is highly expressed on the classically-activated, pro-inflammatory macrophages (M1 phenotype), whereas it is down regulated on the alternatively-activated, pro-healing macrophages (M2 phenotype)[133]. M1 macrophages also secrete free radicals containing oxygen and nitrogen [134, 135]. However, preconditioning by moderate mitochondrial ROS generation strongly increases in vivo adipose tissue-derived MSC proangiogenic properties in diabetic tissues[136].

Treatments with antioxidants for reducing diabetes-related damage have been investigated experimentally and clinically[137]. Sources of antioxidants include enzymatic and non-enzymatic compounds. Enzymes with antioxidative activity are superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Commonly known non-enzymatic compounds with antioxidant activity include vitamins A, C, and E, glutathione, α-lipoic acid, mixed carotenoids, coenzyme Q10 or ubiquinone, many bioflavonoids, minerals such as copper and zinc, and cofactors such as folic acid, uric acid, albumin and B vitamins. The fat-soluble vitamin E prevents lipid peroxidation in the vascular tissue of diabetic rats by strengthening the antioxidant defense system and reduces the progression of coronary atherosclerosis in diabetic mice[138]. Additionally, vitamin E also decreases the oxidative stress in macrophages[137]. Vitamin C plays an important role in several oxidative/inflammatory processes, including scavenging ROS, preventing initiation of chain reactions, increasing nitric oxide production in endothelial cells and protecting cell membranes against lipid peroxidation. Several publications report on the protection against diabetic complications by plant extracts containing bioflavonoids and polyphenols, such as quercetin, and resveratrol[139]. Plant polyphenols may influence different initial steps of atherosclerosis through inhibition of the endothelial NADPH oxidase and elevation of nitric oxide bioavailability and bioactivity[140]. Quercetin and resveratrol prevent the redox imbalance in endothelial cells in the presence of oxidized low-density lipoproteins[141].

Penta-galloyl glucose, (PGG) a well-characterized naturally-derived polyphenol based on gallic acid (3,4,5-trihydroxybenzoic acid) units bound to a polyol core[142], has been reported to have many beneficial effects based on its antioxidant, anti-diabetic, and anti-inflammatory properties[142]. The mechanism is not well understood, but it has been suggested that it may be based on the decrease of metal ions’ uptake or the promoting of their excretion through chelating activities.

Scaffold pretreatments with antioxidants could improve the durability of vascular grafts in diabetes. PGG exhibits high affinity for proline-rich proteins, particularly collagen and elastin[143]; experiments on rat aorta[144] showed and increased stability of collagen and elastin and slow down degradation by a factor of about 50[145]. Pre-treatment of scaffolds with PGG demonstrated reduced accumulation of AGEs, T-cell and macrophage infiltration, as well as inhibited calcium deposition in the matrix-based scaffolds implanted subcutaneously in diabetic rats[39], correlated with significantly reduced stiffening. These results demonstrate the promising ability of polyphenols to stabilize matrix- based vascular scaffolds and protect them from diabetes-related damages, thereby increasing their durability (Fig. 5).

Fig. 5.

6. Diabetic animal models

To understand the effects of the pro-oxidant diabetic environment on scaffolds and cells used in blood vessel tissue engineering, as well as to test the efficacy of antioxidants, in vivo diabetic models are critical. Mainly rodents are used to identify novel treatments for diabetes and its cardiovascular complications. For type I diabetes studies, the non-obese diabetic (NOD) mouse displaying spontaneous autoimmunity is the most commonly model, but experimentally induced diabetes models through surgical (pancreatectomy) and chemical methods (use of the β-cell toxic drugs alloxan and streptozotocin) are also highly preferable. Diet-induced models and monogenic obesity in mice and Zucker fatty rats that have a mutated leptin receptor leading to hyperphagia and obesity are used for type 2 diabetes studies[146]. Pigs are primarily chosen to model type 2 diabetes for determining the mechanisms of metabolic abnormalities that follow diabetes modifications. Swine models are relevant for investigation of cardiovascular complications of diabetes since they can develop coronary, aortic, iliac and carotid atherosclerotic lesions relevant to human condition, and they recapitulate the histopathology seen in humans[147]. Primates are preferentially used in translational safety and efficacy studies in gene-and cell-therapies[148], but they also present a major advantage for studies regarding development of atherosclerosis[147].

Conventionally, tissue engineered vascular grafts are routinely tested by implantation in healthy animals, however to better approximate clinical translation, we propose that these grafts should be also implanted in diabetic animals.

7. Conclusion

Diabetes is a major risk factor for vascular diseases. Changes induced at cellular and extracellular matrix level result in dysfunctional remodeling of the vascular wall, including stiffening, fibrosis, and calcification. There is a major need for vascular grafts with long-term potency and tissue engineering holds great potential for the treatment of vascular diseases. Grafts based on scaffolds and autologous stem cells are developed, but typically they are tested in healthy animals for preclinical evaluation, although most components of the graft could be affected by the aggressive diabetic conditions, in a similar manner to the native vascular structures. Anti-oxidant therapies and tissue engineered grafts implanted in the circulatory system of diabetic animals subjected to elevated circulating glucose and free fatty acids, combined with insulin resistance, could provide valuable knowledge for building blood vessels substitutes resistant to diabetic adversities.

Almost 25 million Americans have diabetes, characterized by high levels of blood sugar that binds to tissues and disturbs the function of cardiovascular structures. Therefore, patients with diabetes have a high risk of cardiovascular diseases. Surgery is required to replace diseased arteries with implants, but these fail after 5–10 years because they are made of non-living materials, not resistant to diabetes. New tissue engineering materials are developed, based on the patients’ own stem cells, isolated from fat, and added to extracellular matrix-based scaffolds. Our main concern is that diabetes could damage the tissue-like implants. Thus we review studies related to the effect of diabetes on tissue components and recommend antioxidant treatments to increase the resistance of implants to diabetes.