振動（TDD）について

振動（血流促進）について

毛細血管に於ける血流促進について

血行不良状態になっている毛細血管の血流を改善するには、
微細で深達力のある振動が不可欠です。
トレルでは、プローブの物性に合わせた、
微細な流体ダイナミクス振動を発生させる事により、
毛細血管の血流改善が可能です。

TDD＜Transdermal drug delivery：
経皮ドラッグデリバリー（経皮による薬液送達）＞について

一般論

物を振動（シェ―キング）させると、浸透や溶解のスピードが速くなるのは一般的によく知られています。

実際、大学の研究室で組織染色する際もシェ―キングを行っています。

また、TDDの促進技術として、超音波も良く使われていますが、細胞を傷つける可能性が高い為、Refresh Technology では、振動を採用しています。

※ 超音波 ≒ 20KHz～１GHz の音波（圧力波）

肌内部の構造写真

TDDについて

TDD（経皮ドラッグデリバリー）を考える上でまず知っておくべき事は、皮膚（角質層）はバリアであり、親水性、及び高分子の液体は基本的には通しません。

従って、上清液等を肌に浸透させる事を考える場合には、その上清液が親油性なのか、低分子な状態なのかを考える必要があります。

バリア（角質層）の浸透経路について

肌の最初のバリアは、角質層再外部の皮脂です。皮脂を通過して角質層の内部へ入り、その下の顆粒層へ到達する、角質層内部いある経路は以下の通りです。

• 経細胞経路（細胞実質透過経路）
• 細胞間ルート（細胞間隙経路）
• 濾胞経路（毛穴等）・・・吸収率（透過率）が最も高い
• エクリン線経路（汗腺の1つ：アポクリン線）

角質層に於ける浸透経路図 1

肌内部の構造図

角質層に於ける浸透経路図 2

TDD機器（抜粋：市販製品＆開発中含む

TDDに於いて用いられる方法について

	Passive	Active（外部の物理的トリガーを適用）
		非熱ベース					熱ベース		非・熱双方
方法名	パッチ（粘着性経皮デリバリーシステム）	粘着テープ　or 接着剤（ストリッピングン）	圧力駆動型ジェット	イオン導入（IP：イオンフォレイシス）	エレクトロポレーション	マイクロニードル	超音波（ソノフォレイシス）	熱支援マイクロポレーション（レーザー）	etc,
作用機序	受動的経皮薬物送達	角質細胞と細胞外脂質の両方が除去され、薬剤が通過する必要がある経路の長さが短縮	100～200m/sにて薬液を吹付け角質層に穴を開けます	電気浸透と呼ばれる：肌に電流を流し、溶質分子に電荷をかける：電荷の反発力に基づく：薬物分子に直接作用させる	脂質二重膜の習慣的な構造摂動：角質層に一時的な水性細孔を形成する：肌に作用して浸透力を高める	薬剤が塗布されたミクロサイズの小さな針を肌に挿入	マイクロバブルの生成によるキャビテーション効果と熱効果により、角質層に微視的欠陥を作成する	レーザーにより角質層に微細孔を作成する	ナノ材料を使用した光熱増強（プラズモン共鳴）、高周波（100KHz以上）、光応答型マイクロニードル、浸透促進剤、マイクロエマルジョン、ベシクル、ナノ粒子・電子線照射、化学的エレクトロポレーション、化学的超音波、イオン導入×超音波、エレクトロポレーション×イオン導入エレクトロポレーション、非キャビテーション超音波、熱切除、マイクロダーマブレージョン（研磨）
使用範囲	ニコチンパッチ等は広く普及	最も古い物理的方法	臨床医学にて導入	いくつかの薬物に於いて成功（送達速度は電流量に比例）	加速的に使用が広がった（μsの高電圧パルスの印加）	低分子・高分子治療	局所麻酔の前処理等広く活用されている	高分子治療
薬剤の範囲	低分子、親油性（ナノ粒子を除く）	低分子、高分子	人成長ホルモン、ソマトロピン等に使用	低分子	親油性、サイズが異なる分子	低分子、高分子	低分子、＋マイクロニードル併用	低分子、高分子
欠点	一部の薬剤のみの適応。肌荒れの可能性がある	制御と再現性の欠如。痛みや炎症の誘発	痛みを伴い、アザが残る事もある	定量送達の欠如、たんぱく質の損傷、一定の値を超えると痛みを伴う	皮膚の透過性が一瞬で元に戻る（使用しにくい）	生体的合成、皮膚の損傷	身体に対するダメージを発生させる可能性がる	火傷

ご参考資料：参照した論文

Year	Author	Tittle	Abstract
2018	Sabine Szunerits* and imageRabah Boukherroub	Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery	Transdermal delivery systems have become a successful alternative for a continuous drug delivery on demand. The clinical potential of light-based transdermal activation using lasers, photodiodes and in combination with light-to-heat converting materials is large. Considering the progress made in the transdermal field, the future of transdermal drug delivery depends largely on the implementation of novel approaches to overcome constraints of passive diffusion without compromising skin integrity.
2012	Amit Alexander , Shubhangi Dwivedi , Ajazuddin, Tapan K. Giri , Swarnlata Saraf Shailendra Saraf, Dulal Krishna Tripathi	Approaches for breaking the barriers of drug permeation through transdermal drug delivery	Transdermal drug delivery system (TDDS) utilizes the skin as executable route for drug administration but the foremost barrier against drug permeability is the stratum corneum and therefore, it limits therapeutic bioavailability of the bioactive. This review focuses on the recent advancements in the TDDS which include iontophoresis, sonophoresis, electroporation, microneedles, magnetophoresis, photomechanical waves and electron beam irradiation. These advancements are exhaustively discussed with techniques involved with their beneficial claims for different categories of bioactive. However, a lot of research has been carried out in TDDS, still the system has many pros and cons such as inconsistent drug release, prevention of burst release formulation and problems related to toxicity. In addition to that, to exploit the TDDS more efficiently scientists have worked on some combinational approaches for manufacturing TDDS viz., chemical–iontophoresis, chemical–electroporation, chemical–ultrasound, iontophoresis–ultrasound, electroporation–iontophoresis electroporation–ultrasound and pressure waves–chemicals and reported the synergistic effect of the same for safe, effective and practical use of TDDS. The present article covers all the above-mentioned aspects in detail and hence the article will assuredly serve as an enlightening tool for the visionaries working in the concerned area.
2014	Mark R. Prausnitz*, Samir Mitragotri and Robert Langer	CURRENT STATUS AND FUTURE POTENTIAL OF TRANSDERMAL DRUG DELIVERY	The development of transdermal delivery systems involves balancing increased transdermal transport with patient safety/comfort and cost. Because intact skin is not sufficiently permeable to the large majority of drugs, enhancement methods are needed. Despite extensive research during the past few decades, hemical enhancers have achieved only limited success in increasing transdermal transport of small molecules and have only a relatively poor ability to increase macromolecular transport under conditions likely to be clinically acceptable. Methods involving ultrasound and electric fields, including iontophoresis and electroporation, have more extensively increased transdermal delivery for small drugs and macromolecules. The ability of these technologies to deliver drugs effectively is partially counterbalanced by their reliance on electronically controlled devices that require an energy source, which constrains applications and cost. Methods that pierce micron-scale holes in skin, such as microneedles, thermal poration and jet injection, can dramatically increase transdermal delivery of small drugs, macromolecules and even particles, butmore work is needed to establish safety/skin damage and cost effectiveness. Each of these technologies is likely to suit the needs of different applications and, in some cases, combinations of enhancers might be the most effective strategy (TABLE 2).
2008	Mark R Prausnitz1 & Robert Langer2	Transdermal drug delivery	Overall, transdermal drug delivery offers compelling opportunities to address the low bioavailability of many oral drugs, the pain and inconvenience of injections, and the limited controlled-release options of both. Building off the successes of first-generation transdermal patches, second-generation chemical enhancers and iontophoresis are expanding delivery capabilities for small molecules, whereas third-generation physical enhancers (including ultrasound, thermal ablation and microneedles) could enable transdermal delivery of macromolecules and vaccines. These scientific and technological advances that enable targeted disruption of stratum corneum while protecting deeper tissues have brought the field to a new level of capabilities that position transdermal drug delivery for an increasingly widespread impact on medicine.
2015	Mei-Chin Chen, Ming-Hung Ling, Kuan-Wen Wang, Zhi-Wei Lin, Bo-Hung Lai, Dong-Hwang Chen	Near-infrared light-responsive composite microneedles for on-demand transdermal drug delivery	This study presents near-infrared (NIR) light-responsive polymer-nanostructure composite microneedles used for on-demand transdermal drug delivery. Silica-coated lanthanum hexaboride (LaB6@SiO2) nanostructures were incorporated into polycaprolactone microneedles, serving as an NIR absorber. When the microneedles were irradiated with NIR light, light-to-heat transduction mediated by the LaB6@SiO2 nanostructures caused the microneedle melting at 50 °C. This increased the mobility of the polymer chains, enabling drug release from the matrix. Drug release from the microneedles was evaluated for four laser on/off cycles. In each cycle, the samples were irradiated until the temperature reached 50 °C for 3 min (laser on); the laser was then turned off for 30 min (laser off). The results showed that light-induced phase transition in the polymer triggered drug release from the melted microneedles. A stepwise drug-release behavior was observed after multiple cycles of NIR light exposure. No notable drug leakage was found in the off state. This NIR-light-triggerable device exhibits excellent reproducibility, low off-state leakage, and noninvasive triggerability and, thus, represents an advance in transdermal delivery technology.
2004	Weiyong Li, David Nadig, Henrik T. Rasmussen, Kudan Patel, Tridarsh Shah	Sample preparation optimization for assay of active pharmaceutical ingredients in a transdermal drug delivery system using experimental designs	A simple but very effective sample preparation method is discussed for a matrix or drug-in-adhesive type of transdermal drug delivery system (TDS). The method is a one-step extraction using a methanol/water solvent system. Because of the unique design and physical property of the delivery system, special considerations were taken in selection of sample solvent, sample container and extraction enhancement device. The main focus of the article is on method optimization using experimental designs. A Plackett–Burman design was used to screen multiple method factors including extraction solvent strength, extraction solvent volume, shaking speed of a reciprocating shaker, and shaking time. Later, two of the factors were studied in more details using a 4 × 5 general factorial design. From the experimental results, the so-called main effects plots and interaction plots were generated using a statistical software. The plots are helpful in choosing the method conditions.

振動が身体に与える影響について

一般論

振動が身体（頸部より下）に与える影響については、血行促進や疲労の改善がよく知られており、マッサージ器はこの最たるものです。

但し、近赤外線のご説明資料に記載させて頂いた二相性の反応（アルント‐シュルツの法則）が、身体に対する振動にも当てはまると考えます。

これは、弱い刺激をすることで神経機能を喚起し、中程度の刺激で神経機能を興奮させ、強い刺激は神経機能を抑制し、最強度の刺激で静止するという法則で、適度の刺激を加えることが生体にとって最も良い刺激であると言われております。

振動に於いても、適度な振動（強度・施術時間・施術間隔等）が肝要と考えます。

最新の論文内容のご報告

1	＜内容＞	生体内微小循環モードにおける皮膚血流への振動の影響
	＜結論＞	直接的な皮膚の振動が皮膚の血流を改善する。（本実験に於いては、5分後に血流増加。15分後に減衰となった。）
2	＜内容＞	健康な人間における皮膚の血流と、その根底にある制御メカニズムに対する低強度の振動の影響の調査。
	＜結論＞	低強度の振動は、筋起源の血管制御メカニズムによって部分的に媒介される皮膚血流の急激な増加をもたらした。
3	＜内容＞	健康な人間における皮膚の血流と、その根底にある制御メカニズムに対する低強度の振動の影響の調査。
	＜結論＞	局所断続振動は、糖尿病患者の足の皮膚血流を効果的に改善する可能性があるが、局所連続振動は同レベルの血管拡張を得ない可能性があります。 糖尿病の被験者は、健康な被験者よりも、印加された振動に対する皮膚血流応答が低い。
4	＜内容＞	全身振動が皮膚血流と一酸化窒素産生に及ぼす影響
	＜結果＞	低周波、低振幅のWBVは、SBFを大幅に増加させた（P = .0115）。全血のNO濃度については、有意差が得られなかった（P = .1813）。
	＜結論＞	糖尿病患者に於いて、全身振動による皮膚血流の増加がみられた。全身振動は、糖尿病の神経血管合併症の潜在的な非薬物療法になりえる可能性があります。
5	＜内容＞	マウスと人間の脳機能に対する全身振動の有益な効果
	＜結果＞	全身振動は運動能力を改善し、マウスの覚醒誘発活動を減少させた。人間の認知テストでは、選択的な改善を得た。 全身振動による刺激（介入）は、脳機能の少なくともいくつかの側面を改善できる安全な刺激（介入）である。

小職の所見：論文の内容んい於ける効果の出た方法を纏めています

頸部以下へのバイブレーションは現状試作機のレベル3でも問題ないですが、以下を推奨いたします。

1. 断続と連続を双方使用する事（お客様の趣向を優先するが、基本は断続とすべきです）
2. 振動刺激（介入）の時間は15分までとする事
3. お客様が爽快感（気持ち良さ）を感じる範囲の強さとする事

ご参考資料：原文の内容抜粋

	Author	Tittle	Abstract
1	Andrew D Jung, MD*; Mackenzie C Morris, MD*; Rosalie Veile, BS*; Lou Ann Friend, RVT*; Sabre Stevens-Topie, RVT§; Daniel D. Cox, et al.	Effect of vibration on skin blood flow in an in vivo microcirculatory model	The effect of vibration on skin microcirculation was studied to investigate the possibility of clinical use of vibration to prevent and treat pressure ulcers. Vibrations at a vibrational intensity of 600, 800, or 1,000 mVpp with a fixed frequency of 47 Hz were applied horizontally to the ear of male hairless mice (n = 6 for each group) under inhalation anesthesia. The control group (n = 6) received no vibrations. Venular blood flow was measured by an intravital videomicroscope at the baseline and at 0, 5, and 15 min after the application of vibrations. A significant increase was observed in the 600 mVpp group 5 and 15 min after vibration in comparison to the control group (P = 0.002 and P = 0.046, respectively). We also detected increased blood flow in the 800 mVpp group (P = 0.028) and the 1,000 mVpp group (P = 0.012) 5 min after vibration; however, these increases attenuated after 15 min. These results indicate that direct skin vibration at a frequency of 47 Hz improves skin blood flow. The present study gives further support to the role of vibration on a short-term increase in skin blood flow.
2	Yi-Ting Tzen1, Eileen M. Weinheimer-Haus2, Thomas F. Corbiere2, Timothy J. Koh2* et al.	Increased skin blood flow during low intensity vibration in human participants: Analysis of control mechanisms using short-time ourier transform	Low intensity vibration produced acute increases in skin blood flow mediated in part by vascular control mechanisms of myogenic origin. Further investigation is warranted to determine whether low intensity vibration induces similar increases in skin blood flow in populations prone to developing chronic non-healing wounds, such as spinal cord injury and diabetes.
3	“Weiyan Ren1†, Fang Pu2,3†, Huiqin Luan1, Yijie Duan2, Honglun Su1, Yubo Fan1,2,3* and Yih-Kuen Jan3,4*, Yijie Duan2, Honglun Su1, Yubo Fan1,2,3* and Yih-Kuen Jan3,4*”	Effects of Local Vibration With Different Intermittent Durations on Skin Blood Flow Responses in Diabetic People	For diabetic subjects, the SBF was significantly increased in both Vibration and Recovery Stage with local intermittent vibrations (LIV1 and LIV2), but not with LCV. However, there was no significant difference in change percentage and change rate of SBF in diabetic subjects across the three tests. For healthy subjects, all vibration interventions significantly increased the SBF in the Vibration Stage and in the first 1.5 min of the Recovery Stage. Also, the change rate of SBF during the Vibration stage in LIV1 test was significantly greater than that in LIV2 test for healthy subjects. Moreover, change percentage of SBF in Vibration stage of LIV1 test and in some periods of Recovery stages of LIV1 and LIV2 tests for diabetic subjects were lower than for healthy subjects; the absolute change rate of SBF in LIV1 test for diabetic subjects was also lower than for healthy subjects.　※ LIV：Local intermittent vibrations 、LCV：Local continuous vibration
4	Paula K. Johnson, MS1, J. Brent Feland, PT, PhD1 A. Wayne Johnson, PT, PhD1, Gary W. Mack, PhD1 and Ulrike H. Mitchell, PT, hD1	Effect of Whole Body Vibration on Skin Blood Flow and Nitric Oxide Production	Results: Low-frequency, low-amplitude WBV significantly increased SBF compared to the sham condition (F2,18 = 5.82, P = .0115). Whole blood NO concentrations did not differ between the WBV and sham conditions immediately or 5 minutes after treatment (F2,18 = 1.88, P = .1813). Conclusions: These findings demonstrate that patients with diabetes respond to WBV with increased SBF compared to the sham condition. The implication is that WBV is a potential nonpharmacological therapy for neurovascular complications of diabetes.
5	Ate S. Boerema1,2 , Marelle Heesterbeek2 , Selma A. Boersma1,2, Regien Schoemaker2, Erik F. J. de Vries1, Marieke J. G. van Heuvelen3 and Eddy A. Van der Zee2	The Relationship of Three-Dimensional Human Skull Motion to Brain Tissue Deformation in Magnetic Resonance Elastography Studies	In summary, PET imaging revealed that glucose uptake was not changed as a consequence of a 5-week WBV intervention. The WBV did, however, improve motor performance and reduced arousal-induced activity in mice. Cognitive tests in humans revealed a selective improvement in the Stroop Color-Word test. Taken together, it is concluded that our WBV intervention is a safe intervention that can improve at least some aspects of brain functioning. A limitation of the cognitive test in the human study, however, might be that we did not control for variables such as dietary supplements, caffeine intake, or sleep quality. Other factors influencing the direct comparison between mice and humans are based on the inherent differences between the species. Mice received WBV while standing on 4 legs, sitting or lying down, or a combination of these, whereas our 2-legged human participant were seated. Also the number of WBV sessions and the duration of the WBV session (respectively, 37 and 10 minutes in mice, and 27 and 4 minutes in humans were not similar. The reason for the lower number of WBV sessions in humans was to ensure high adherence rates and to prevent to ask too much from our participants and supervisors (in case of the older participants). The shorter duration of the WBV session was based on pilot studies in which it was found that WBV sessions longer than 4 minutes were perceived as too long for the older participants as used in this study. Nonetheless, we found positive effects of WBV in both mice and humans.