Hybrid Inorganic-Organic Hydrogel Scaffolds for Osteochondral Regeneration

描述(申请人提供)：我们的长期研究目标是使用新型无机-有机混合支架来制造工程化的骨软骨界面，这种支架的化学和物理性质的梯度使其能够独特地诱导相关的人骨髓间充质干细胞(MSCs)逐渐从骨样基质向纤维软骨样基质转化。在骨科重建中，如前十字韧带(Acl)的重建，软组织移植往往由于整合不良而失败。 相关的骨是由于未能复制出天然的“软”骨软骨界面--从纤维软骨样基质逐渐过渡到骨样基质造成的。一种重建骨软骨界面的再生策略可能受益于最近的报道，这些报道表明固有支架属性在决定相关细胞行为方面具有强大的性质。在设计促进骨软骨再生的支架时，存在两个主要挑战：(1)关于支架特性的有限知识，这些特性能以最佳方式诱导MSCs再生骨或纤维软骨；(2)开发具有逐渐转变特性的支架，这本质上促进了MSC行为的逐渐转变。鉴于之前的文献证明了无机疏水材料的骨诱导特性，我们假设无机-有机杂化支架可以被特定地设计成具有梯度化学和物理性质的支架，从而诱导MSC从骨向纤维软骨的逐渐转变。建议的“梯度支架”是基于无机、疏水性甲基丙烯酸酯星形聚二甲基硅氧烷(PDMSstar-MA)和有机亲水性聚乙二醇二丙烯酸酯(PEG-DA)的组合。PI首次报道了将PDMS共大分子引入到聚乙二醇胺支架中，这些研究表明，PDMS共大分子不仅拓宽了可实现的支架性能，还调节了细胞的行为，包括MSCs的行为。将使用不同极性的制造溶剂来定制PDMS的分布和孔隙率。利用现有的梯度制造技术，支架将被制备成梯度，以允许快速筛选诱导的MSC行为。根据这些结果，将构建一种无机-有机梯度支架，以在体外再生骨软骨界面。目前R03的具体范围是建立我们的假设的可行性，这些梯度支架的 化学成分(如无机含量、化学官能度和亲水性)和物理性质(如形态、孔隙率和模数)将充分诱导所需的MSC分化。该小组由拟议工作的所有关键领域的专家组成。梅丽莎·格伦兰教授(PI)将领导构建支架的工作。Mariah Hahn教授(PI)将领导这些支架的组织工程学研究。意见将由整形外科重建专家沃尔特·洛博士(顾问)提供。

DESCRIPTION (provided by applicant): Our long-term research goal is to produce an engineered osteochondral interface using new hybrid inorganic-organic scaffolds whose gradient in chemical and physical properties make them uniquely capable of inducing a gradual transition from bone- to fibrocartilage-like matrix production by associated human bone marrow-derived mesenchymal stem cells (MSCs). In orthopedic reconstruction, such as that of the anterior cruciate ligament (ACL), soft tissue grafts are often unsuccessful due to poor integration with the associated bone resulting from a failure to reproduce the native-like "soft" osteochondral interface - a gradual transition from fibrocartilage-like matrix to a bone-like matri. A regenerative strategy to re-establish the osteochondral interface could benefit from recent reports indicating the potent nature of intrinsic scaffold properties in dictating associated cell behavior. In designing scaffolds which promote osteochondral regeneration, two primary challenges exist: (1) the limited knowledge regarding scaffold properties which "optimally" induce regeneration of bone or fibrocartilage by MSCs and (2) the development of scaffolds with a gradual transition in properties which intrinsically promotes the desired gradual transition in MSC behavior. Given previous literature demonstrating the osteoinductive nature of inorganic, hydrophobic materials, we hypothesized that inorganic-organic hybrid scaffolds could be specifically engineered with gradient chemical and physical properties which would induce a gradual transition in MSC differentiation from bone to fibrocartilage. The proposed "gradient scaffolds" are based on a combination of inorganic, hydrophobic methacrylated star polydimethylsiloxane (PDMSstar-MA) and organic, hydrophilic poly(ethylene glycol) diacrylate (PEG-DA). The PIs were the first to report the introduction of a PDMS co-macromer into PEG-DA scaffolds and these studies demonstrated that the PDMS co-macromer not only broadens achievable scaffold properties but also modulates cell behavior, including that of MSCs. Fabrication solvents of varying polarities will be used tailor PDMS distribution and porosity. Using existing gradient- making technologies, scaffolds will be prepared as gradients to permit rapid screening of induced MSC behavior. From these results, a inorganic-organic gradient scaffold will be fabricated to regenerate the osteochondral interface in vitro. The specific scope of the present R03 is establishing the feasibility of our hypothesis that these gradient scaffolds' chemical (e.g. inorganic content, chemical functionality, and hydrophilicity) and physical properties (e.g. morphology, porosity, and modulus) will sufficiently induce desired MSC differentiation. The team is comprised of experts in all key areas of the proposed work. Prof. Melissa Grunlan (PI) will lead efforts to fabricate scaffolds. Prof. Mariah Hahn (PI), will lead tissue engineering studies with these scaffolds. Input will be provided by an orthopedic reconstruction specialist, Dr. Walter Lowe (consultant).