在鼠伤模型中，通过胶原转化驱动的PDGF-BB基因转移增强伤口愈合。,ACS Applied Bio Materials

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在鼠伤模型中，通过胶原转化驱动的PDGF-BB基因转移增强伤口愈合。
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-05-04 , DOI: 10.1021/acsabm.9b01147
Raj Kumar Thapa ₁ , David J Margolis ₂ , Kristi L Kiick ₃ , Millicent O Sullivan ₁

Affiliation

伤口愈合是一个复杂的生物学过程，需要协调的细胞增殖，迁移和细胞外基质产生/重塑，所有这些在慢性伤口中均被抑制/延迟。在这项研究中，开发了一种配方，该配方将基于纤维蛋白的临时样基质与胶原蛋白模拟肽（CMP）/血小板源性生长因子（PDGF）基因修饰的胶原蛋白结合，从而形成了坚固的凝胶，暂时控制PDGF的表达并在伤口床内轻松应用。使用体外共凝胶支架的分析证实了基于基质金属蛋白酶（MMP）活性的持续和时间可控的基因释放，与不表达MMP的细胞相比，产生MMP的成纤维细胞中PDGF的表达高约30％。纤维蛋白与基因修饰的胶原蛋白的整合产生了共凝胶，该共凝胶强烈支持成纤维细胞募集/侵袭以及长期愈合过程的多个方面。在小鼠中进行的伤口创面愈合研究使用CMP修饰的PDGF多聚体负载共凝胶建立了更快的创口闭合，在9天后，创面闭合率提高了多达24％（生长因子剂量降低了约2个数量级）。与无CMP的多聚体共凝胶相比，PDGF的共聚凝胶与9天后伤口闭合率提高了19％。此外，在伤口上进行CMP修饰的PDGF多聚体负载共凝胶应用后，将观察到最小的疤痕形成以及改善的胶原蛋白生成，成纤维细胞活性和胶原蛋白取向。总而言之，共凝胶的综合特性

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Enhanced wound healing via collagen-turnover-driven transfer of PDGF-BB gene in a murine wound model.

Wound healing is a complex biological process that requires coordinated cell proliferation, migration, and extracellular matrix production/remodeling, all of which are inhibited/delayed in chronic wounds. In this study, a formulation was developed that marries a fibrin-based, provisional-like matrix with collagen-mimetic peptide (CMP)/platelet-derived growth factor (PDGF) gene-modified collagens, leading to the formation of robust gels that supported temporally controlled PDGF expression and facile application within the wound bed. Analysis employing in vitro co-gel scaffolds confirmed sustained and temporally controlled gene release based on matrix metalloproteinase (MMP) activity, with an ∼30% higher PDGF expression in MMP-producing fibroblasts as compared with that in non-MMP-expressing cells. The integration of fibrin with the gene-modified collagens resulted in co-gels that strongly supported both fibroblast cell recruitment/invasion and multiple aspects of the longer-term healing process. The excisional wound-healing studies in mice established faster wound closure using CMP-modified PDGF polyplex-loaded co-gels, which exhibited up to 24% more wound closure (achieved with ∼2 orders of magnitude lower growth factor dosing) after 9 days as compared to PDGF-loaded co-gels and 19% more wound closure after 9 days as compared to CMP-free polyplex-loaded co-gels. Moreover, minimal scar formation, as well as improved collagen production, myofibroblast activity, and collagen orientation, will be observed following CMP-modified PDGF polyplex-loaded co-gel application on wounds. Taken together, the combined properties of the co-gels, including their stability and capacity to control both cell recruitment and cell phenotype within the murine wound bed, strongly support the potential of the co-gel scaffolds for the improved treatment of chronic nonhealing wounds.

更新日期：2020-05-04

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