聚左旋乳酸(poly-L-lactic acid, PLLA)可在生物體內引發異物反應刺激自體膠原新生，最具代表性的產品為Sculptra，但若注射至皮膚中的深度不正確或是過於聚集皆容易產生丘疹、結節等不良事件發生。本研究將PLLA微球包覆進玻尿酸微針(PLLA MP-MN)，利用微針將PLLA均勻分散在真皮層中以避免注射深度不一或過於集中，同時微針穿刺可在皮膚表面形成機械性損傷並藉由傷口修復過程快速刺激膠原蛋白沈積。使用不含PLLA之玻尿酸微針(HA MN)最佳化微針穿刺頻率及施打片數，於大鼠實驗中確認以四天穿刺一次共施打4片微針，不僅不會對皮膚造成傷害並能在真皮淺層誘導最明顯的膠原蛋白新生。大鼠之中長期有效性及安全性實驗中，將PLLA MP-MN和HA MN與皮內注射(ID) PBS、PLLA MP和Sculptra進行比較，在實驗第8週可發現PLLA MP-MN及HA MN在真皮淺層微針穿刺區域皆可觀察到明顯膠原纖維新生，而在PLLA組之微球周圍可觀察到異物反應引起之膠原沈積，值得注意的是在Sculptra ID中發現由於PLLA過於聚集，導致發炎情形相對嚴重，於大鼠皮膚表面觀察到結節，進而造成肉芽腫之不良症狀。第8週時HA MN及PLLA MP-MN相較PBS ID誘導第三型膠原再生非常明顯(p < 0.01)，亦觀察到皮膚彈性明顯增加(p < 0.01)，而在第20週HA MN機械刺激膠原新生效果不顯著，新生之第三型膠原逐漸轉為成熟的第一型膠原，反觀PLLA ID、Sculptra ID和PLLA MP-MN則因PLLA逐漸刺激膠原新生在第三型膠原有顯著增加之情形(p < 0.01)，且相較於PBS ID及HA MN在皮膚彈性上有明顯提升(p < 0.01)。本研究之PLLA MP-MN可有效避免因注射PLLA不均勻所引起的不良症狀，還可在治療初期藉由微針機械刺激及中後期PLLA引發的異物反應，使膠原新生及皮膚彈性達到長期有效之提升與改善，有潛力成為新一代抗老化之微侵入式療法。

Poly-L-lactic acid (PLLA) can induce foreign body reaction and stimulate collagen regeneration in the body. In this study, we encapsulate PLLA into hyaluronic acid microneedles (PLLA MP-MN), using microneedles to evenly disperse PLLA in the dermis to avoid incorrect injection depths or over-concentration that can lead to adverse events such as papules and nodules. Additionally, microneedle punctures create mechanical injuries on the skin surface, stimulating collagen deposition through the wound healing process. In the long-term efficacy and safety experiments, PLLA MP-MN and HA MN could induce collagen regeneration in the superficial dermal microneedle puncture areas through mechanical stimulation and significantly induced type-III collagen regeneration compared to PBS ID at week 8. However, we observed severe inflammation due to excessive PLLA aggregation led to nodule formation on the skin surface, causing adverse symptoms such as granulomas in the Sculptra ID group. At week 20, type-III collagen induced by microneedle mechanical stimulation gradually matured into type-I collagen. Conversely, PLLA ID, Sculptra ID, and PLLA MP-MN, which still stimulated collagen production through PLLA, showed significant increases in type-III collagen and improved skin elasticity compared to PBS ID and HA MN. Therefore, we demonstrate that PLLA MP-MN can effectively avoid adverse symptoms caused by uneven injections and achieves long-term efficacy in collagen production and skin elasticity.

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