Development of Scar-Inhibiting Compliant Tissue Adhesive

描述(由申请人提供)：据估计，美国有2200万妇女接受了子宫切除术；2004年，有61.7万人接受了这样的手术。手术中意外的膀胱撕裂是子宫切除术最常见的并发症(发生率高达8.3%)。这些膀胱损伤大多在手术中通过缝合修复，术后用导尿管引流膀胱。然而，这些膀胱损伤会导致疤痕组织的形成。缝合线的使用和疤痕组织的形成尤其不可取，因为这两种方法都会损害膀胱的适当扩张来储存尿液。此外，在康复期间使用导尿管和收集袋会严重降低患者的生活质量。为了解决这些严重的健康问题，拟议的工作将设计一种组织粘合剂，这种粘合剂将消除缝合的需要，并将疤痕形成降至最低。拟议研究的主要目标是设计一种临床适用的组织粘合剂，该粘合剂易于使用(快速固化，双组分溶液，保质期长)，符合膀胱壁的拉伸(高度顺应性)，并可通过控制释放抑制瘢痕形成的生物活性分子来降解。研究人员将结合他们在聚合物合成、受控药物/基因输送和生物力学方面的专业知识，开发和评估一种可生物降解的组织粘合剂，用于修复目前正在开发的高强度顺应性水凝胶系统，用于修复膀胱组织损伤。本研究的具体目的是1)优化膀胱组织粘合剂的体外力学性能，2)优化组织粘合剂的体外抗瘢痕功能，3)评价所选的抑制瘢痕组织粘合剂的体内效果。实现这些特定目标所涉及的任务包括：a)通过调整化学成分、浓度、相对分子质量和反应条件来调整水凝胶的拉伸性能、固化时间和组织粘附性，b)评估降解率、释放动力学和核酸疗法的有效性，以对抗培养细胞中与瘢痕形成相关的基因的表达，以及c)通过在大鼠膀胱损伤模型中评估宿主反应来评估新设计的水凝胶系统的安全性和有效性。这些初步的体内数据将被用于进一步修改设计，并将成为将这项研究推进到更大动物的功能性膀胱损伤模型的基础。 公共卫生相关性：在美国，三分之一的女性预计在60岁之前接受子宫切除术，与这一手术相关的最常见的并发症(发生率高达8.3%)是手术中意外划破膀胱。这项拟议研究的主要目标是设计一种新型的、可生物降解的组织胶，用于就地治疗外科膀胱损伤。这种新型胶水不仅在康复过程中不再需要缝合、导尿管和收集袋，而且在愈合过程中还可以释放治疗药物来阻止膀胱上多余的疤痕组织，因此，将有助于提高许多女性的生活质量。

DESCRIPTION (provided by applicant): An estimated 22 million women in the United States have undergone hysterectomy; in 2004, 617,000 of these procedures were performed. Accidental laceration of the bladder during surgery is the most common (incidence of up to 8.3%) complication of hysterectomy. Most of these bladder injuries are repaired by suturing during the surgery, and the bladder is drained with a catheter postoperatively. However, these bladder injuries can result in scar tissue formation. The use of sutures and the formation of scar tissue are especially undesirable because either can compromise the proper distension of the bladder to store urine. In addition, the use of catheters and collecting bags during recovery can severely diminish patients' quality of life. To address these serious health issues, the proposed work will engineer a tissue adhesive that will eliminate the need for suture and will minimize scar formation. The main goal of the proposed research is to design a clinically applicable tissue adhesive that is easy to use (rapid curing, two-component solutions with long shelf life), conforms with stretching of the bladder wall (highly compliant), and degrades with controlled release of bioactive molecules that inhibit scar formation. The investigators will combine their expertise in polymer synthesis, controlled drug/gene delivery, and biomechanics to develop and assess a biodegradable tissue adhesive for repair of bladder tissue injuries using a high-strength, compliant hydrogel system currently in development. Specific aims of the proposed research are 1) To optimize mechanical properties of the bladder tissue adhesives ex vivo, 2) to optimize the scar-inhibiting function of the tissue adhesive ex vivo, and 3) to evaluate the efficacy of the selected scar-inhibiting tissue adhesive in vivo. Tasks involved in achieving these specific aims include, a) tuning the hydrogel tensile properties, cure time, and tissue adhesiveness by adjusting the chemical composition, concentration, molecular weights, and reaction conditions, b) evaluating degradation rate, release kinetics, and efficacy of nucleic acid therapeutics for antagonizing the expression of genes pertinent to scar formation in cultured cells, and c) evaluating the safety and efficacy of the newly designed hydrogel system by evaluating the host response in a rat bladder injury model. These initial in vivo data will be used for further modification of the design and will be the basis for advancing this research to a functional bladder injury model in larger animals. PUBLIC HEALTH RELEVANCE: In the United States, 1/3 of women can expect to have hysterectomy by age 60 and the most common (incidence of up to 8.3%) complication associated with this procedure is accidental nicking of the bladder during surgery. The main goal of the proposed research is to engineer a novel, biodegradable tissue glue for on-the-spot treatment of surgical bladder injuries. The new glue will not only eliminate the need for stitches, catheters, and collecting bags during recovery, but also release therapeutics to block unwanted scar tissues on the bladder during healing, and thus, will help increase the quality of life of many women.