Autologus adipose tissue grafts to inhibit hemodialysis access stenosis

描述（由申请人提供）：通常通过创建动静脉（AV）通路来实现慢性血液透析（HD）的高血流速率。虽然自体动静脉瘘一旦发挥功能，并发症较少，但高达60%的动静脉瘘从未发展成为功能性通路。AV移植物在早期更可靠，但在移植物-血管病变处的增生和第一年高达50%的失败之后受到困扰。如果狭窄的发生率可以降低，AV移植物将是慢性HD的更好选择。令人遗憾的是，目前还没有确定的预防AV移植物狭窄的临床治疗方法;因此，迫切需要有效的治疗方法。脂肪细胞释放许多肽，包括脂联素（ADPN），其具有有益的血管效应，如降低细胞粘附分子和炎性细胞因子的表达。例如，与野生型小鼠相比，ADPN敲除小鼠血管损伤后增生显著增加，而皮下脂肪组织（AT）靠近血管的放置已被证明对血管损伤具有保护作用。因此，很可能可以利用AT来抑制AV移植物中的狭窄。抗糖尿病药物格列酮还对导致血管狭窄的关键过程具有抑制作用，包括炎症和血管平滑肌细胞（SMC）增殖。特别相关的是，格列酮还增加AT的ADPN表达。格列酮是亲脂性的，并且积极地分配到AT中，因此可以认为AT是药物的内源性储库。因此，该策略将利用AT的血管保护特性及其作为格列酮储库的潜力。此外，还将利用格列酮的血管保护作用及其促进ADPN释放的能力。自体皮下移植AT修复软组织缺损是整形外科常用的方法。因此，本文的策略是将自体载格列酮皮下AT移植到AV移植物中，作为格列酮局部递送的储库和格列酮增强ADPN产生的内源性工厂。有两个具体目标。目的1优化猪AT与格列酮的体外混合制剂，为动物实验提供实验依据。将比较由与不同浓度的格列酮混合的培养AT产生的条件培养基抑制SMC增殖的能力。目的2将载格列酮的自体AT皮下移植到猪移植物周围血管周围。AV移植物中的管腔面积和血液流速将用作通过磁共振成像确定的有效性结局。伤口愈合也将被评估为安全性结局。这项工作提出了一种非常新颖和简单的药物和内源性激素递送方法，由于其局部性质和使用天然组织，该方法应该具有非常有限的毒性。该技术还可以改善瘘的可用性，并广泛适用于其他血管病变。 公共卫生相关性：血液透析血管通路是通过外科手术创建的部位，通常位于手臂上，用于在肾衰竭患者的血液透析过程中清除和置换血液。 不幸的是，这些通路由于通路部位中的细胞过度生长而以高比率失败，从而导致更多的手术、显著增加的感染风险以及患者死亡风险的增加。 这项工作使用患者自身脂肪组织与药物混合的移植物，将药物和有益蛋白质释放到通路部位，这将抑制细胞过度生长，并有望改善这些通路的功能寿命。

DESCRIPTION (provided by applicant): Access to high blood flow rate for chronic hemodialysis (HD) is usually achieved by the creation of an arteriovenous (AV) access. While native AV fistulas have fewer complications once they become functional, up to 60% never develop into a functioning access. The AV grafts are more reliable early but are plagued later with hyperplasia at the graft-vessel anastomoses and up to 50% fail in the first year. If the incidence of stenosis can be decreased, the AV graft would be a better option for chronic HD. Regrettably, there are no established clinical treatments for the prevention of AV graft stenosis; therefore, effective therapies are urgently needed. Adipocytes release many peptides, including adiponectin (ADPN) which has beneficial vascular effects, such as decreasing the expression of cellular adhesion molecules and inflammatory cytokines. For example, hyperplasia increased markedly following vascular injury in ADPN knock-out mice versus wild-type mice, while the placement of subcutaneous adipose tissue (AT) near blood vessels has been shown to have protective effects against vascular injury. Thus, it is likely AT can be exploited to inhibit stenosis in AV grafts. The anti-diabetic glitazone drugs also have inhibitory effects on key processes that contribute to vascular stenosis, including inflammation and vascular smooth muscle cell (SMC) proliferation. Of particular relevance, glitazones also increase the expression of ADPN by AT. The glitazones are lipophilic and avidly partition into AT, which can therefore be considered an endogenous depot for the drug. Thus, this strategy will exploit the vasculo-protective properties of AT and its potential to serve as a depot for glitazones. Also, the vasculo- protective effects of glitazones, and their ability to promote the release of ADPN will be utilized. Autologous grafting of subcutaneous AT to repair soft-tissue defects is commonly used in plastic surgery. Hence, herein the strategy is to transplant autologous glitazone-loaded subcutaneous AT to the AV graft, as both a depot for local delivery of glitazones and as an endogenous factory for the glitazone-enhanced production of ADPN. There are two Specific Aims. Aim 1 will optimize the mixture of porcine AT and glitazone in vitro in preparation for its use in animal studies. The conditioned media produced from cultured AT mixed with different concentrations of glitazone will be compared for their ability to inhibit SMC proliferation. Aim 2 will transplant autologous glitazone-loaded subcutaneous AT to the perivascular space around the anastomoses of AV graft in a porcine model. The lumen area and blood flow rate in the AV graft will be used as efficacy outcomes as determined by magnetic resonance imaging. Wound healing will also be assessed as a safety outcome. This work proposes a very novel and simple means of drug and endogenous hormone delivery that should have very limited toxicity due to its localized nature and the use of native tissue. This technique may also improve fistula usability and has broad applicability to other vascular pathologies. PUBLIC HEALTH RELEVANCE: Hemodialysis vascular accesses are surgically created sites, typically in the arms that are used to remove and replace blood during hemodialysis for patients with kidney failure. Unfortunately these accesses fail at a high rate due to cell overgrowth in the access site resulting in more surgeries, significantly increased risks of infection, and increased risk of death for patients. This work uses the transplant of the patient's own fat tissue mixed with a drug to target the release of drug and beneficial proteins to the access site that will inhibit cell overgrowth and hopefully improve the functioning lifespan of these accesses.