JP2004507283A - Hydrogel biosensor and health alarm system based on biosensor (HYDROGELBIOSENSORANDBIOENSENSOR-BASEDHEALTHALARMSYSTEM) - Google Patents

Abstract

The biosensor (10) has a hydrogel in a rigid and preferably biocompatible enclosure (20). The hydrogel (30) includes an immobilized analyte binding molecule (ABM) and an immobilized analyte. The immobilized analyte competitively binds the free analyte and changes the number of cross-links in the hydrogel (30). Thus, in a limited space, the hydrogel swelling tendency (and thus the osmotic pressure) is changed in proportion to the free analyte concentration. By measuring the pressure change of the hydrogel with the pressure transducer (4), the biosensor (10) accurately measures the concentration of free analyte molecules without the problems of oxygen limitation and interference of conventional biosensors. can do. A telemeter (60) driven by a battery (64) is operably coupled to the pressure transducer (40) and has a receiver (66) having an alarm system operably mounted on the computer (62). ) To send a wireless data signal. In addition, the alarm system utilizes such sensors to automatically signal that the analyte level is outside a predetermined parameter range and to automatically inject medication for harmful analyte levels.

Description

【００２７】
ヒドロゲルの用意−荷電ペンダントグルプ、固定化アナライト、及びＡＢＭｓ
ｐＨ敏感な帯電ペンダント基を持つゲル等の高分子メトリックスとヒドロゲルを準備する一般的な方法は文献で記術されている。例えば、Ｂｒｏｎｄｓｔｅｄ Ｈ 高分子電解質のゲル：特性、準備、及び適用：Ｈａｒｌａｎｄ ＲＳ、Ｐｒｕｄ Ｈｏｍｍｅ Ｐ Ｋ、ｅｄｓ ＡＣＳ： ２８５， １９９２； Ｇｈａｎｄｅｈａｒｉ Ｈ ｅｔ ａｌ １９９６ Ｊ． Ｍａｃｒｏｍｏｌ． Ｃｈｅｍ． Ｐｈｙｓ． １９７：９６５； ａｎｄ Ｉｓｈｉｈａｒａ Ｋ ｅｔ ａｌ １９８４ Ｐｏｌｙｍ． Ｊ． １６：６２５ 等を参照。 これら特許の内容を本明細書の一部を構成するものとして援用する。ｐＨ敏感なヒドロゲル製造の一部の関連内容は懸案の特許出願でまた記述されている（ＰＣＴ／ＵＳ００／２３１９４，出版２００１年 ３月８日、米国特許出願 第 ０９／３０８、３９２と第０９／８２４、５５２）。これら特許の内容を本明細書の一部を構成するものとして援用する。
【００２８】
ヒドロゲルは、多様な官能基を含んでいるか、又は含むように変更されることができる。当業者によってこれらの官能基グループは、ヒドロゲルの骨格へＡＢＭ及びアナライトを結合するために使用されることができる。これらの官能基は次のとおりであるが、これらに限られない。Ｃａｒｂｏｘｙｌ， ｈｙｄｒｏｘｙｌ， ａｌｋｙｌ， ｋｙｄｒｏｘｙｌａｌｋｙｌ， ｏｘｙａｌｋｙｌ， ｏｘｙｈｙｄｒｏｘｙａｌｋｙｌ， ｓａｃｃｈａｒｉｄｅ， ｃａｒｂｏｘｙｌ， ｃａｒｂｏｘａｍｉｄｅａｌｋｙｌ， ａｒｏｍａｔｉｃ ａｍｉｎｏ， ｐｈｅｎｏｌｉｃｈｙｄｒｏｘｙｌ， ｐｏｌｙｅｔｈｙｌｅｎｅ ｇｌｙｃｏｌ等である。結合反応は下記のとおりであるが、これらに限られない。Ｄｉａｚｏｎｉｕｍ ｃｏｕｐｌｉｎｇ， ｉｓｏｔｈｉｏｃｙａｎｏ ｃｏｕｐｌｉｎｇ， ｈｙｄｒａｚｉｄｅ ｃｏｕｐｌｉｎｇ， ａｍｉｄｅ ｆｏｒｍａｔｉｏｎ， ｄｉｓｕｌｆｉｄｅ ｃｏｕｐｌｉｎｇ， ｄｉｍｅｔｈｙｌａｃｅｔｙｌ ｃｏｕｐｌｉｎｇ， ｍａｌｅｉｃ ａｎｈｙｄｒｉｄｅ ｃｏｕｐｌｉｎｇ， ｔｈｉｏｌａｃｔｏｎｅ ｃｏｕｐｌｉｎｇ， ａｎｄ ｄｉｃｈｌｏｔｒａｚｉｎｅ ｃｏｕｐｌｉｎｇ。これら二つの官能基の間の結合反応は上手に証明されていって、当業者によく知られている。例えば、ヒドロゲル中のｃａｒｂｏｘｙｌグループは、１―ｅｔｈｙｌ−３−（３−ｄｉｍｅｔｈｙｌａｍｉｎｏｐｒｏｐｈｙｌ）ｃａｒｂｏｄｉｉｍｉｄｅ ｈｙｄｒｏｃｈｌｏｒｉｄｅ（ＥＤＣ）及びｄｉｃｙｃｌｏｈｅｘｙｌｃａｒｂｏｄｉｉｍｄｅのような結合媒体を使用してぺプチド（ｐｅｐｔｉｄｅ）のアミノグループへ共有結合ができる。ＥＤＣは、ｃａｒｂｏｘｙｌ酸グループとアミノグループと反応する。この過程は、ＡｎａｌＬｅｔｔ．１５、１４７−１６０ １９８２，Ｊ．Ｂｉｏｃｈｅｍ ９２、１４１３−１４２４ １９８２に現れている。
【００２９】
ＡＢＭとアナライト中のぺプチド鎖の第一アミノグループは下記の結合媒体及び・又は架橋媒体を利用し、官能基（例えば、ちオール（ｔｈｉｏｌ）、ヒドロシル（ｈｙｄｒｏｘｙｌ）、アシル塩化物（ａｃｙｌ ｃｈｌｏｒｉｄｅ）、硫酸塩、ｓｕｌｆｏｎｙｌ の塩化物（ｃｈｌｏｒｉｄｅ）、燐酸塩、燐酸塩塩化物（ｐｈｏｓｐｈａｔｅ ｃｈｌｏｒｉｄｅ）、及びイミド（ｉｍｉｄｅ）のような）を含んでいるヒドロゲルへ結合させられる。結合媒体及び・又は架橋媒体は、ｂｅｎｚｙｌ ｃａｒｂａｍａｔｅ， ｃａｒｂｏｎａｔｅ， Ｎ−ｓｕｃｃｉｎｉｍｉｄｙｌ ３−（２−ｐｙｒｉｄｙｌｄｔｈｉｏ） ｐｒｏｐｉｏｎａｔｅ（ＳＰＤＰ）， ｓｕｌｆｏ−ＬＣ−ＳＰＤＰ， ｓｕｃｉｎｉｍｄｙｌ ４−（Ｎ−ｍａｌｅｉｍｉｄｏｍｅｔｈｙｌ） ｃｙｃｌｏｈｅｘａｎｅ−１−ｃａｒｂｘｙｌａｔｅ（ＳＭＣＣ）， ｓｕｌｆｏ−ＳＭＣＣ， ｍ−ｍａｌｅｉｍｉｄｏｅｎｚｏｙｌ−Ｎ−ｈｙｄｒｏｘｙｓｕｃｉｎｍｉｄｅ ｅｓｔｅｒ（ＭＢＳ）， ｓｕｌｆｏ−ＭＢＳ， Ｎ−ｓｕｃｉｎｉｍｄｙｌ（４−ｉｏｄｏａｃｅｔｈｙｌ） ａｍｉｎｏｂｅｎｚｏａｔｅ（ＳＩＡＢ）， ｓｕｌｆｏ−ＳＩＡＢ， ｓｕｃｃｉｎｉｍｉｄｙｌ ４−（ｐｍａｌｅｉｍｉｄｏｈｅｎｙｌ） ｂｕｔｙｒａｔｅ（ＳＭＰＢ）， ｓｕｌｆｏ−ＳＭＰＢ， ｄｉｔｈｉｏｂｉｓ （ｓｕｃｃｉｎｉｍｉｄｙｌｐｒｏｐｉｏｎａｔｅ）， ３， ３’−ｄｉｔｈｉｏｂｉｓ（ｓｕｃｃｉｎｉｍｉｄｙｌｐｒｏｐｉｏｎａｔｅ）， ｄｉｓｕｃｃｉｎｉｍｉｄｙｌ ｓｕｂｅｒａｔｅ， ｂｉｓ（ｓｕｌｆｏｓｕｃｉｎｉｍｉｄｙｌ） ｓｕｂｅｒａｔｅ， ｄｉｓｕｃｃｉｎｉｍｉｄｙｌ ｔａｒｔａｒａｔｅ （ＤＳＴ）， ｓｕｌｆｏ−ＤＳＴ， ｂｉｓ［２−（ｓｕｃｃｉｎｉｍｉｄｏｏｘｙｃａｒｂｏｎｙｌｏｘｙ）ｅｔｈｙｌ］ｓｕｌｆｏｎｅ（ＢＳＯＣＯＥＳ）， ｓｕｌｆｏ−ＢＳＯＣＯＥＳ， ｅｔｈｙｌｅｎｅ ｇｌｙｃｏｌｂｉｓ（ｄｉｓｕｃｃｉｎｉｉｄｙｌｓｕｃｃｉｎａｔｅ（ＥＧＳ）， ｓｕｌｆｏ−ＥＧＳ等である。 チオール（ｔｈｉｏｌ）、ヒドロシル（ｈｙｄｒｏｘｙｌ）、アシル塩化物（ａｃｙｌ ｃｈｌｏｒｉｄｅ）、硫酸塩、ｓｕｌｆｏｎｙｌ の塩化物（ｃｈｌｏｒｉｄｅ）、燐酸塩、燐酸塩塩化物（ｐｈｏｓｐｈａｔｅ ｃｈｌｏｒｉｄｅ）、及びイミド（ｉｍｉｄｅ）のような複数の官能基が有する他のアナライトとＡＢＭも上記の結合媒体と架橋媒体を使ってヒドロゲルと結合することができる。
【００３０】
ヒドロゲルの骨格からの荷電部分ペンダントは、ＡＢＭ相手から固定化アナライトが置き換えることに応じてヒドロゲルの膨潤現象の基になる原動力である。従って、特定の荷電部分が含まれていると、電荷が陽か陰かとは関係なく、純電荷が存すべきである。
【００３１】
ヒドロゲルを作る好ましい方法としては、アミン（ａｍｉｎｅ）とヒドロッシル（ｈｙｄｒｏｘｙｌ）基等の官能基を含むアナライトとＡＢＭには、アルリルアルコール（ａｌｌｙｌ ａｌｃｏｈｏｌ）とエーテル化（ｅｔｈｅｒｉｆｉｃａｔｉｏｎ）反応及び塩化メタクリロイル（ｍｅｔｈａｃｒｙｌｏｙｌ ｃｈｌｏｒｉｄｅ）との救核反応によって、ビニル基が結合されているものが好ましい。アクリルアミド（ａｃｒｙｌａｍｉｄｅ）及びヒドロキシエチルメタクルレート（ｈｙｄｒｏｘｙｌｅｔｈｙｌ ｍｅｔｈａａｃｒｙｌａｔｅ）（ＨＥＭＡ）等の単量体と並びに架橋剤を用いたアナライト及びＡＢＭの共重合反応は、遊離基反応によって進行することが好ましい。重合鎖は化学的に固定化されたアナライト及びＡＢＭをペンダント基として有することが好ましい。このようにして得られたヒドロゲルは多孔性であることが好ましい。多孔性の制御は、バブリングや共重合反応物への粉末塩の過剰添加等、数種の方法によって行うことが好ましい。 遊離アナライトをヒドロゲルに導入した場合、競合してヒドロゲル中の固定化ＡＢＭに結合することにより、ヒドロゲルが膨潤することが好ましい。ヒドロゲルの膨潤比は、溶液中の遊離アナライト濃度に比例することが好ましい。遊離アナライト濃度の変化によるヒドロゲルの膨潤及び膨潤低下（ｄｅ−ｓｗｅｌｌｉｎｇ）を圧力トランスデューサを用いて圧力として測定できるように、ＡＢＭやモノマーや架橋剤とアナライトとの反応比が最適化されることが好ましい。
【００３２】
膨潤傾向／浸透圧の変化の範囲、そして遊離アナライト濃度の有用な敏感度は、ヒドロゲル中の固定化アナライトとＡＢＭ分子の量／比、及びペンダント帯電部分の超過電荷（純陽性又は陰性電荷）の量／配電に左右されることは明白である。これら三つの重要な構成要素は、ある程度特定アナライトの特性にも依存する。どの状況にしても測定方法の原理、発明の装置、及びヒドロゲルの一般的な化学合成法を熟知していると、ターゲットアナライトの三つの構成要素の最適レベルを容易に測定することができる。
【００３３】
グルコースバイオセンサー
バイオセンサー発明の具体的な例は、関連出願ＰＣＴ／ＵＳ００／２３１９４（２００１年３月８日 発刊）に述べられているグルコースバイオセンサーである。この内容を本明細書の一部を構成するものとして援用する。グルコースバイオセンサーにおいて、アナライト結合パートナーはコンカナバリンＡである。
【００３４】
測定手段−圧力トランスデューサ
本バイオセンサはヒドロゲールの圧力を測定する手段４０を含む。この要素は必須である。遊離アナライト濃度の変化に直接依存するバイオセンサ１０は、外部からの重要な干渉源を回避できる。間接的なパラメータを電極により測定するパラメータのではなく、遊離アナライトそのものが制御パラメータであって測定できる。
【００３５】
図６及び図７にし示すように、測定手段としては圧力トランスデューサ４０が好ましい。圧力トランスデューサは本技術分野において知られており、当業者はバイオセンサ１０の特定の必要性に応じて最適化されたトランスデューサを構成できる。トランスデューサとしては、ハリソン（Ｈａｒｒｉｓｏｎ ＤＲ．， Ｄｉｍｅｆｆ Ｊ ． Ｒｅｖ． Ｓｃｉ． Ｉｎｓｔｒｕｍ． ４４：１４６８−１４７２（１９７３））及びハリソン（Ｈａｒｒｉｓｏｎ）らの“Ｄｉｏｄｅ−Ｑｕａｄ Ｂｒｉｄｇｅ Ｃｉｒｃｕｉｔ Ｍｅａｎｓ”米国特許第３，８６９，６７６号に発表されるものを挙げることができ、それらの発表をここに援用する。
【００３６】
図７に示すように、バイオセンサ１０は更に、小さなしんちゅう管７２を受容する較正穴７０、はんだ銅線（ｓｏｌｄｅｒ ｓｔｒａｎｄｅｄ ｃｏｐｐｅｒ ｗｉｒｅ）７４、ブレードシールド（ｂｒａｉｄｅｄ ｓｈｉｅｌｄ）７６、絶縁体７８及び同軸ケーブル８０を含むことができる。
【００３７】
最も好適な態様において、測定手段４０は、上述したフレキシブルダイアフラム２８に関連付けられる容量性圧力トランスデューサ４０である。好ましいトランスデューサ４０は、絶縁体４８により隔離された第一電極４４及び第二電極４６を含む。好ましい態様においては、第一電極４４及び第二電極４６は、絶縁体４８と共に同軸上一列に並べられた筒である。弾性ダイアフラム２８は第一導電体４４上に溶接され、トランスデューサ４０のコンデンサ部の電極の一つとして機能する。第一電極４４はダイアフラム２８と接続し、ダイアフラム２８と第二電極４６とは空間５０により分離される。
【００３８】
ダイアフラム２８はヒドロゲル３０と機能的に接触しており、ダイアフラム２８がヒドロゲル３０の圧力変化に応答して変形することにより第二電極４６とダイアフラム２８との間の空間５０の容積を変化させる。よって、キャパシタンスの値が変化する。キャパシタンスの変化は、好ましくはダイオード・ クアッド ・ブリッジ回路５２を用いて、遠隔的に検出される。これらの圧力トランスデューサ４０は、流れるポリマー液の１パスカル程度の小さな圧力変化を効果的に測定するのができる。
【００３９】
トランスデューサの他の例はタカキ（Ｔａｋａｋｉ）に付与された米国特許第５，７１１，２９１号とファウラー（Ｆｏｗｌｅｒ）に付与された米国特許第５，７２５，９１８号に記載されており、これらの米国特許の記載を本明細書の一部を構成するものとしてここに引用するトランスデューサのより詳細な理論は以下の文献に見出される。これらの文献の記載を本明細書の一部を構成するものとしてここに引用する：
Ｂａｅｋ ＳＧ， Ｐｈ．Ｄ． Ｔｈｅｓｉｓ， Ｕｎｉｖｅｒｓｉｔｙ ｏｆ Ｕｔａｈ，（１９９１）， Ｍａｇｄａ ＪＪ， Ｂａｅｋ ＳＧ， Ｌａｒｓｏｎ ＲＧ， ＤｅＶｒｉｅｓ ＫＬ， Ｍａｃｒｏｍｏｌｅｃｕｌｅｓ ２４： ４４６０−４４６８，（１９９１）， Ｍａｇｄａ ＪＪ， Ｌｏｕ Ｊ， Ｂａｅｋ ＳＧ， Ｐｏｌｙｍｅｒ ３２： ２０００−２００９，（１９９１）， Ｌｅｅ ＣＳ， Ｔｒｉｐｐ Ｂ， Ｍａｇｄａ ＪＪ， Ｒｈｅｏｌｏｇｉｃａ Ａｃｔａ ３１： ３０６−３０８，（１９９２）， Ｌｅｅ ＣＳ， Ｍａｇｄａ ＪＪ， ＤｅＶｒｉｅｓ ＫＬ， Ｍａｙｓ ＪＷ， Ｍａｃｒｏｍｏｌｏｅｃｕｌｅｓ ２５： ４７４４−４７５０，（１９９２）， Ｍａｇｄａ ＪＪ， Ｂａｅｋ ＳＧ． Ｐｏｌｙｍｅｒ ３５： １１８７−１１９４ ，（１９９４）， Ｆｒｙｅｒ Ｔ． Ｂｉｏｔｅｌｅｍｅｔｒｙ ｉｉｉ， Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ， Ｎｅｗ Ｙｏｒｋ， ｐｐ．２７９−２８２，（１９７６）， Ｔａｎｄｅｓｋｅ， Ｊ．， Ｃｈａｐｔｅｒ ５ ｉｎ Ｐｒｅｓｓｕｒｅ Ｓｅｎｓｏｒｓ Ｓｅｌｅｃｔｉｏｎ ａｎｄ Ａｐｐｌｉｃａｔｉｏｎ（圧力センサの選択と応用の第５章）， Ｍａｒｃｅｌ Ｄｅｋｋｅｒ， Ｎｅｗ Ｙｏｒｋ， １９９１， Ｕｐｄｉｋｅ ＳＪ， Ｓｈｕｌｔｓ ＭＣ， Ｒｈｏｄｅｓ ＲＫ， Ｇｉｌｌｉｇａｎ ＢＪ， Ｌｅｕｂｏｗ ＪＯ， ｖｏｎ Ｈｅｉｍｂｕｒｇ Ｄ． ＡＳＡＩＯＪ． ４０：１５７−１６３，（１９９４），及びＦｏｕｌｄｓ ＮＣ， Ｆｒｅｗ ＪＥ， Ｇｒｅｅｎ ＭＪ． Ｂｉｏｓｅｎｓｏｒｓ Ａ Ｐｒａｃｔｉｃａｌ Ａｐｐｒｏａｃｈ（Ｃａｓｓ ＡＥＧ． Ｅｄｓ．） ＩＲＬ Ｐｒｅｓｓ Ｏｘｆｏｒｄ Ｕｎｉｖｅｒｓｉｔｙ， ｐｐ．１１６−１２１（１９９０）
【００４０】
好ましい圧力トランスデューサ４０について説明したが、当業者であれば他の測定手段４０を考案できるであろう。また、他の代替的態様としては、圧電トランスデューサやセンサ、及びピエゾ抵抗圧力センサを挙げることができる。他の圧力測定手段又は容積増加測定手段も用いることができる。これらの代替手段は、本明細書に記載する発明と等価であると考えられる。
【００４１】
報告手段：デレメータ
最後に、バイオセンサ１０は、測定したアナライト分子の濃度を報告する手段６０を含む。この要素は、バイオセンサ１０の特定の用度及びユーザのニーズに依存して大きく変化する。図４に示す最も単純な形態では、トランンスデューサ４０は、一般にはパーソナルコンピュータであるコンピュータ手段に電気的に接続されているだけである。コンピュータはトランスデューサ４０からのデータを較正曲線と比較し、報告手段を介して出力する有用なデータを発生する。一実施態様では、アナライト分子の濃度があるレベルを超えた場合、コンピュータがアラーム音を発生する。他の実施態様では、コンピュータは、コンピュータモニタ等の報告出力部に対してデータを出力する。更に、他の実施態様では、コンピュータはフィードパックループを制御して、アナライト分子の濃度の変化に応答してプロセスを変化させる。
【００４２】
図３に示す好ましい実施態様では、本発明バイオセンサ１０である。この場合、報告手段６０は、コンピュータに作動的に受信機にデータ信号を送信する電池駆動式テレメータ６０であることが好ましい。このコンピュータもデータ信号を較正曲線と比較し、報告手段を介して濃度を報告する。報告手段は、アナライトレベルが過剰に高くなったり、低くなったりした場合に患者に警告する可聴アラームであることが好ましい。
【００４３】
バイオセンサを使用する方法
本発明は更に、溶液中のアナライト濃度の測定にバイオセンサ１０を使用する方法も含む。本発明による方法は以下のステップから成る。最初に、上述の様なバイオセンサ１０を提供する。好ましくは化学的結合により、ＡＢＭを化学的又は物理的にヒドロゲル３０に固定化する。バイセンサ１０は、緩衝液に浸した後、コントロール溶液内に入れることが好ましい。得られたデータを較正曲線と比較してバイオセンサ１０を較正する。バイオセンサ１０を取り出した後、他の緩衝液内で注ぎ、その後、バイオセンサ１０を溶液中にいれる。高分子ヒドロゲル３０中でアナライト分子を拡散させ、ＡＢＭとの結合に関し、遊離アナライトと固定化アナライトを競合させる。ＡＢＭに対する、遊離アナライトと固定化アナライトとの間の競合的結合によりヒドロゲルの架橋が減少し、ヒドロゲル３０が膨潤して、図５に示す様にダイヤフラムに圧力がかかる。この膨潤を測定手段４０によって測定する。この測定手段４０は圧力トランスデューサ４０であることが好ましい。圧力トランスデューサ４０は、ヒドロゲル３０内の遊離アナライトの濃度に比例するヒドロゲル３０の圧力を測定するために使用される。この測定値に関するトランスデューサ４０からのデータは報告手段６０に送られる。埋め込み可能なバイオセンサ１０では、データをコンピュータに送信するために電池駆動式のタレメータ６０が使用される。このデータは、コンピュータモニタ、可聴アラーム、又はフィードバックシステムを介してユーザに報告される。使用期間を通して、血液のサンプルを取り、アナライトの測定値をバイオセンサ１０から報告された値と比較することによってシステムを再較正できる。コンピュータによって作動される較正手段は誤差を補正するように調整することができる。
【００４４】
以上、少なくとも一つの好適な実施態様を参照して本発明を述べたが、本発明はそのような実施態様に限定されるものでないことは当業者には明白であろう。本発明の範囲は添付の特許請求の範囲のみによって解釈すべきものである。
【００４５】
作動原理
センサの出力を常に監視し、予め設定した値（即ち、閾値）と比較する。もしセンサ出力が予め設定した範囲外である場合には、アラーム信号を発生する。このアラーム信号を用いて、自動ダイアル等の所定のアラームプロトコルを実行して、検出された状態に対応する事前に記録したメッセージを送ることができる。
【００４６】
図９は、血糖値が低血糖のレベル低下した時に、糖尿病患者にアラームを与えると共に、自動ダイヤルを使用して管理者に信号を与え、また事前に記録したメッセージを送るための実動モデルのブロック図を示す。
【００４７】
図９−１５に示す自動アラーム装置の主要な要素は、電池１００、センサ（バイオセンサ１０又は生理的状態を監視するその他のセンサ）、信号調整回路１０４、比較器回路１０８、送信機１１２ａ、受信機１１２ｂ、ダイアルアクチュエータ１１６、及び制御回路である。
【００４８】
電源１００は、電力を必要とする装置の全ての要素に対して電気エネルギーを供給することが好ましい。装置の携帯性を考慮し、電源として乾電池を使用するのが好ましい。しかし、全ての要素の電力要求（電圧及び容量）に対してのセルの適合性から、使用できる電池の形式が決まる。現在分かっている範囲では、大容量の９Ｖの電池が最適であると考えられる。開発途上で２個のバッテリーを使用した双極型電源としたが、これにより回路設計が非常に簡単になった。電池電圧低下表示器は必須の部品である。
【００４９】
信号調節回路１０４ガ必要が否かはセンサからの信号の質による。センサ信号が多くの環境雑音を含んでいる場合、装置を信頼性をもって作動させるためには信号調整回路１０４（図１１）が必要である。典型的には、高入力インピーダンス差動増幅器如何なる種類のセンサに対しても使用できる。“インスツルメンテーション増幅器”と呼ばれるプリパッテージされた回路が市販されている。しかし、プロトタイプノの装置では、クワッド ・オペアンプ ＩＣ（例えば、ナショナルセミコンダクター社製のＬＭ３８４）が４個の増幅器を提供することから非常に役に立つであろう。差動増幅器は同相モード雑音を除去する上で優れている。差動増幅器のゲインは、良好な線形範囲の信号を提供するように調整できる。差動増幅器の後にローパスフィルタを設けることにより高周波ノイズを更に低減できる。ＲＣ時定数は０．１〜１秒が適切である。例えば、１００キロオームと１０ミリファラッドを用いることによって１秒のＲＣ時定数を得ることができる。
【００５０】
図９−１５に示す比較機は常時、監視信号（ここでは、信号調整回路の出力からの信号）を予め設定した値と比較する。この基本値はポテンショメータを使用して調整する。監視信号が基本値を超えると、比較器の出力の状態が‘０’から‘１’、即ち‘オフ’から‘オン’に変化する。この状態変化を後続のデジタル回路を作動させるために、使用する。最も単純な回路は、電気機械式スイッチを‘オン’位置に駆動するものであり、これにより送信機回路が電源に接続される。なお、ＬＭ３１１型比較器がここでの目的に最も適合する。
【００５１】
比較器回路１０８には追加の制御回路１３０（図１２）を設けなければならない。この追加の制御回路は、誤操作又は装置の異常によりアラームが送出された場合に、装置の作動を停止し、装置をリセットする。更に、如何なる場合においても装置のユーザの裁量でダイヤリングを作動できるように追加のスイッチが設けられていなければならない。これらの全ての機能は、デシタルＤフリップフロッフィＩＣ（Ｃ７４７４）を用いて達成できる。
【００５２】
もし必要であれば、アラームを送信するだけでなく、センサ１０が正常に作動しているか否かを判定するために比較器回路１０８を使用することもできる。センサ出力が警報レベルを含む予想動作範囲を超えた場合には、比較器１０８はセンサ１０の異常を表示する。
【００５３】
装置を装着した人から離れた場所にある電話１１４を作動させるために送信機１１２ａと受信機１１２ｂが必要になる。（図１３） 典型的なＦＭ法により電話１１４を無線で作動させることができる。典型的には、送信機は、搬送波発生器１４０、信号発生器１４４、信号を搬送波に混合する変調器１４８、パワープースタ１５２、及び放射器１５６から成る。搬送波周波数は数十メガヘルツから数百メガヘルツの範囲である。信号は、他の電子装置からの環境雑音による誤ダイヤルを防止するために、受信機がピックアップする独特な信号でなければならない。受信機１１２ｂは送信機１１２ａと逆に動作する。送信機１１２ａと受信機１１２ｂは最終的にはカスタム設計としなければならないが、子供用のリモコン玩具に使用される送信機を最小限変更したものを使用することもできる。（本明細書の開示に基づき当業者であれば、電子メール等、其の他の遠隔通信形態も利用可能であることが理解できるであろう）。
【００５４】
遠隔アラーム信号のダイヤリングは当業者の間で良く知られている種種の方法で行うことができる。そのようなシステムの概略図を図１４に示す。遠隔電話インターラクションに馴染みのある者であれば、図に示す構成や其の他の構成を実施する多くの方法に馴染みがあるであろう。
【００５５】
現状の留守番電話システムを使用したり、ダイヤリングやメッセージングのための現状の留守番機能（ａｎｓｗｅｒｉｎｇ ｆｕｎｃｔｉｏｎ）を利用するためにはある程度の改造が必要となる。全体として、全てが、電話機内に設けられているのが好ましい。受信機からのアラーム信号によってスイッチオンすることが必要になるだけである。
【００５６】
上記に加え、アラームシステムは、糖尿病患者の低血糖症を治療するためのシステムとしても機能する。図１５に、図９に示したものと類似のアラームシステムの概略図を示す。しかし、このシステムは、アラームに応答して、患者の血流中にアナライト、その外の糖、又は薬剤を供給するインジェクション機構１５０を含む。当業者であれば、インジェクション機構１５０は所定の投与量で供給を行ってもよく、或は、センサ１０によって検知した生理的状態に応じて投与量を変化させてもよいことが分かるであろう。インジェクション機構１５０はシステムの配線によって接続されていてもよく、或は、送信機１１２ａによって制御するようにしてもよい。
【００５７】
インジェクション機構１５０に加え、システムにグローバルポジショニングシステム１６０を設け、これを電話１１４又はアラームシステムの他の箇所に接続してもよい。このグローバルポジショニングシステム１６０により、治療が必要となった場合に対象となる個人の居場所を迅速に見つけ出すことか可能になる。そのようなシステムは、糖尿病ではあるが、サイクリング、狩猟、釣りなどの活動に加わる人について特に有利である。
【００５８】
代替的実施態様−図１６−２３
図１６に示す自動アラームが最も好ましいシステムであるが、システムの有用な図１７−２３に示されている。図１６で見られるように、主要素は、センサー（生理学的状態をモニタリンするためのバイオセンサー１０又は他のセンサー）、電池２００、信号調整ユニット、ＧＰＳ受信機 ２６０、ＭＣＵ回路ユニット２７０及びデータ送信機２１４である。
【００５９】
電池２００は動力を要するすべての装置の要素に電気エネルギーを提供する。装置の可搬性を考慮して、電池は供給力のため好まれた選択である。但し、電池のすべての要素の電力需要事情との適合性（電圧と容量）は使用タイプによる。電池を供給するために、＋３．３ボルト（＋３．３Ｖ）の再充電可能な電池を使う。この充電システムは全体動力源として使用される。
【００６０】
充電器は８５Ｖから２６５Ｖまでの交流入力電圧を＋５Ｖの一定した直流電圧に変えるためにＳＭＰＳ（スイッチモード電源）２００ａが使用される。ＳＭＰＳからの出力直流電圧の使用によって、充電回路２００ｂは、充電の容量及び残った電池のレベルに従って再充電電池を受電する。充電方式として、リチウムイオン、Ｎｉ−ｃａ及びＮｉ−Ｈ等が再充電可能電池２００ｃのために使用される。バッテリー電力低下ライト及び充満状態を示す標識は大切な部分である。
【００６１】
再充電可能電池は＋３．３まで充電できてＬＣＤ、送信機及びミクロコントローラーユニット（ＭＣＵ）を除く全体回路に供給される。ＬＣＤと送信機を作動させるために＋５Ｖの付加電圧が必要であり、この電圧は電池から従来の直流−直流変流器（ＤＣ−ＤＣ Ｃｏｎｖｅｒｔｅｒ）２００ｄの使用によって得られる。
【００６２】
信号調整単位２０４のための必要性はセンサーからの信号の質に左右される。センサー信号が大量の環境の騒音及び又は低電圧と共に伝連する場合信頼できる方法の装置を作動させる信号調整回路装置２０４（図１１）が必要である。信号調整ユニット２０４は、騒音減少そしてセンサーからの入力信号拡大のために設計されている。
いわゆる、‘機器使用アンプ’と呼ばれる多段階拡大回路は商業的に利用できる。但し、標準装置として、チョッパＯＰアンペアＩＣ（例えば、ＭＡＸ４２０又はＭＡＸ４２１）及び又はクォードＯＰアシペアＩＣ（例えばＮａｔｉｏｎａｌ ＳｅｍｉｃｏｎｄｕｃｔｏｒｓからのＩＭ３８４）が多数アンプを提供することで騒音のない低電圧信号の拡大によく役立つ。差動増幅器は、通常モード騒音を取除くことで優秀である。差動拡大後の低域フィルタは更に高周波騒音を減らす。０．１から１秒の一定ＲＣ時間が適切である。例えば、１００ｋｏｈｍと１０ｍ Ｆを使用して、 一定ＲＣ時間１秒が得られることができる。
【００６３】
チョパー安定 アンペアＩＣ（ｃｈｏｐｐｅｒ−ｓｔａｂｉｌｉｚｅｄ ａｍｐ ＩＣ）（信号調整回路２０４のＡ１，Ａ２，Ａ３，Ａ４，Ａ５，Ａ６）は、 信号調整回路の標準装置に使用する。オプアンペア（Ｏｐ−ａｍｐｓ）は精密な入力特徴を持っている単一チョパーオプアンペアである。典型的に、増幅回路の図２０４ａのＡ１とＡ２のような緩衝回路として高入力インピーダンス 差動増幅器は、 増幅回路の図２０４ａのＶＲ１（可変的な抵抗器）のような利用できる抵抗器と共にゼロ交差（ｚｅｒｏ ｃｒｏｓｓｉｎｇ）を調節するためにどの種類のセンサーのためにも利用できる。Ａ１と Ａ２は、線形拡大をするために４００ヘルツのチョッピング（ｃｈｏｐｐｉｎｇ）周波数の機能を持つＣ３、Ｃ４、Ｃ５、Ｃ６のような蓄電器と共に電圧調整機能を持つことが好ましい。Ｃ１のマイラ蓄電器は信号の騒音減少のためであり、Ｖ_ｏｕｔがゼロクロシングになるようにＶ１は調節される。コンデンサーＣ７は高周波の利得を減らし、騒音を減らす。
【００６４】
第一増幅回路（Ａ３）２０４ａは、騒音減少のための低減フィルタとアンプでできている。低減フィルタは拡大の前に騒音のレベルを減らす。チョッパ安定の実行増幅器として図２０４ａのＡ３は、ろ過されたセンサー信号を増幅する。低電圧信号のために、実行増幅器Ａ３は１μＶｔｙｐの低入力相殺電圧を、 そして０．０２μＶ／Ｃｔｙｐの低ドリフトオフセット（ｌｏｗ ｄｒｉｆｔ ｏｆｆｓｅｔ）を備えている。増幅回路の規則は、Ｒ１＝Ｒ３，Ｒ６／Ｒ７＝Ｒ４／Ｒ５，Ｇａｉｎ＝（１＋２Ｒ１／Ｒ_ｘ）＊Ｒ６／Ｒ４、及びＲ_ｘ＝（ＶＲ１＊Ｒ２）／（ＶＲ１＋Ｒ２）である。
【００６５】
第２増幅回路２０４ｂは、第２低減フィルタ（Ｒ１２とＣ１３）、緩衝回路（Ａ５）、及び装置騒音の広帯域を減らすために使用されるアンプ（Ａ４）から成っている。抵抗器Ｒ９とＲ１０は利得の信頼性（＝１＋Ｒ１０／Ｒ９）をきめるため、＋／−１％の低温係数の許容が好まれる。Ｄ１とＤ２は回路へ高圧入力されるのを防止するためのダイオードである。
【００６６】
信号の状態回路２０４ｃの最後の部分は、オフセットの補償（ＶＲ２とＶＲ３）機能と第３増幅（図２０４ｃのＡ６）を提供する。ループ反応を極めて弱まるためにコンデンサーＣ１７はむしろ選ばれる。信号が外れ、騒音レベルが入力電圧Ｖ_ｃｃより大きいとき、入力電圧Ｖ_ｃｃはダイオードＤ４の前進方向でとばされる。信号がはずれ、騒音レベルが電圧よりひいたとき、入力電圧Ｖ_ｃｃはダイオードＤ５の逆方向でとばされる。
【００６７】
制御装置の機能は入力センサ信号を所定の基準信号と比較すること、アラーム状態をきめること、センサー信号の新しい数値を貯えること、貯えられた数値を取り出すこと、緊急連絡のためのデータ電送機と連結すること、注入装置を活動化させること、アラームブザーを始めること、患者からの主な入力資料に答えること等をする。
【００６８】
自動アラームシステムの第一次制御装置として、８ビット ミクロプロセサーは自動警報システムのあらゆる情報交換のためにむしろ使用される。アーセンブラー及び又はＣ コンピュータ言語で、交換のコード化が好ましい。これは、ミクロ プロセサで利用できるように編集される。アラーム状態、ＧＰＳ装置コード、センサーからの信号などは、Ｆｌａｓｈ ｍｅｍｏｒｙ、ＳＲＡＭ、ＤＲＡＭ、又はＥＥＰＲＯＭのような記憶セミコンタクターに貯えられる。ＥＥＰＲＯＭ １７２ａの８Ｋバイトがその目的に好ましく選ばれる。
【００６９】
ミクロ プロセサの第一次機能は実施間モイニタリンと自動アラム通知システムを確立するためである。低電力消費の８ビット ミクロ プロセサ実施間モニタリンと自動アラム システムの制御ができる。ＴＯＳＨＩＢＡ ２７０ａのＴＭＰ８７ＣＨ４８はこの目的で選ばれる。
【００７０】
患者はリセット、信号の数値表示、位置コード表示及び手動でも作動できる。制御装置は各機能を達成するために使用者が押すキーによって電圧量の注入力を確認し、解釈する。２行２０文字の表示容量を持ってＬＣＤのＴＮタイプ又はＲＯＨＭ２７３ａのＲＣＭ２０７２Ｒが好ましいのである。警報が間違って送信されるとか、装置機能不全によって送られるとき、余分の制御機能は装置の非活動化及び装置の修正２７０ｂをする。
【００７１】
緊急事態時、制御装置は注入装置の作動を始める出力位相信号２７５ａを発進する装置があり、アラーム ブーザー２７１ａを活動化させる。ミクロ プロセサが「０」と「１」の機能で「高い」から「低い」、「低い」から「高い」のようなアナログ出力回路を付けるとき、注入装置は活動化させる。
【００７２】
制御装置のモニタリン機能によって非常時に患者の情報はデータ伝送機へ絶えず移るのが好ましい。患者の情報は、患者の身分証明コード、アラーム状態、ＸＹＺのＧＰＳ位置及びセンサーからの現在の生理学的な数値を含んでいる。
【００７３】
バイオセンサー、自動化されたアラーム通告システム（ＧＰＳ）及び非常時の処置システム（自動 Ｉｎｊｅｃｔｉｏｎ システム）の組み合わせが健康管理を健康管理を増進する為に重要な利点を提供することを技術の専門家は認める。患者が生理学的損傷を受ける条件について警告されることに限らず、既定の閾値を超えた状態になると、保健管理者に患者の位置についての最新情報を知らせる。
【００７４】
送信機２１４ａは通信装置２１４を作動させるために必要である。データ送信機２１４ａの候補装置は携帯用無線通信装置を含む電話のような通信装置２１４である。該装置は、自動アラームシステムとのデータ交換のため、外部データポト（ｅｘｔｅｒｎａｌ ｄａｔａ ｐｏｒｔ）が設置されていって自動的にアラーム状態とデータを遠隔地の所定的装置に知らせる。ケーブルと接続子は、データ送信機と自動アラームシステムを連結する。無線データ通信装置によってケーブルとコネクターを選ぶ。Ｂｌｕｅｔｏｏｔｈのような無線接続プロトコル（ｐｒｏｔｏｃｏｌ）は装置の間のデータ転送を達成させる。
【００７５】
自動アラームシステムからのアラーム状態、位置の情報、及び他の必須情報等は遠隔地装置によって音声伝言又はテキスト伝言の形で送信できる。
【００７６】
無線通信装置は、現在通用されているＣＤＭＡ，ＴＤＭＡ，ＧＳＭ等を支える無線個人電話が好ましい。遠隔インターネットサービスＴ付きＰＤＡ（Ｐｅｒｓｏｎａｌ Ｄｉｇｉｔａｌ Ａｓｓｉｓｔａｎｃｅ）は、他の好ましい無線携帯用通信装置である。
【００７７】
典型的に送信機は２１４ａは搬送波発電機、信号発電機、信号を搬送波に混ぜる変調器、及びラジエタで構成されている。搬送波は数千から数百ＭＨＺの範囲である。受信機で受信された信号は他の電子機器の環境的騒音で誤伝されるのを防止するために唯一デないとならない。ＡＭ又はＦＭ無線通信は自動のアラーム システムに適切であるが、適切な通信プロトコル（Ｐｒｏｔｏｃａｌ）を用いて送信機（２１４ａ）からのデータを受けるようにＡＭ又はＦＭ受信機も合わせるようにする。
【００７８】
自動アラーム装置持ちＧＰＳ装置の主機能はアラーム受信者に位置データを提供することである。患者が自分の位置を把握していない時、意識不明の時、又は自分の位置を伝えるのができない場合、ＮＭＥＡ プロトコル（Ｐｒｏｔｏｃａｌ）を支えるＧＰＳ受信機２６０ａは自動アラーム システムにむしろ使う。受信機はＢｉｎａｒｙ形式のＸＹＺ座標を従来のＲＳ２３２ｃシリアル通信によってコードが統制システムに伝連される。ＧＰＳ受信機は通常待期モードになって、患者が危険の状態になると健康管理人に患者の位置を自動的に通知するように作動する。
【００７９】
図２１、２２、２３は標準装置として自動アラーム システムの三つの主要要素のプロク図である。図２１はスイッチ形式動力供給（ＳＭＰＳ）と充電器を示し、図２２は信号調整回路、図２３は全体コントロール装置を示す。自由電圧入力ＳＭＰＳ回路と充電プロクのプロックを示す。
【００８０】
図２１で貯えたように、交流の騒音は交流電波（ＡＣ８５Ｖから２６５Ｖまでの）が全て波に変えるブリッジ回路２９１の前の交流入力ピールタ２９０でろ過される。直流電同時騒音がろ過されると同時にＲＣピルータ２９２は全ての波動をＤＣ転換する。それにも関わらず、転換ＤＣスパーック騒音がなって、Ｓｎｕｂｂｅｒ回路２９３を使って除去する。
【００８１】
転換ＤＣ電圧レベールは調整回路２９４で４．５Ｖから５Ｖまで調整されるが、これは流電バッテリ電圧容量より通常少し高くなる。直流電圧レベルの調整の間に発生する騒音を減少するため、ＬＣフィルター２９６によってろ過さる転換直流電源電圧が好ましい。バッテリ充電回路２９５は充電電流及び該電圧を制御するが、再充電バッテリに充電される容量に依る。
【００８２】
信号調整機のブロック図面が図２２に示されている。センサーの信号レベルは非常に低く、環境からの騒音の影響を受けやすい。低信号レベルは、増幅の前、図２８０の低パースフィルター１（ＬＰＦ１）のＲＣフィルターによってろ過されることが好ましい。そうではないと、信号と共に騒音も増幅され、信号は騒音と識別できない。
【００８３】
ろ過された信号は増幅利得比が約１００になるように増幅されることが好ましい。低信号レベルに対し、より高い増幅利得比は信号が悪くなる可能性であり、騒音から信号の復元ができない。図２８５の増幅器２の第２の増幅で 制御ユニットにあるＡ／Ｄ転換機に十分なダイナミックレインジ（ｄｙｎａｍｉｃ ｒａｎｇｅ）を与えるために 約１００の増幅利得が使われる。図２８６のＬＰＦ３は騒音減少のために用いられる。
【００８４】
前記増幅器の総増幅利得比が、１００を１０倍し、１０００になるはずだが、実際には、総利得比１０００は達成できない。その理由は、ｏｐ−ａｍｐｓ、抵抗器、コンデンサー等、各装置のそれぞれの固有誤差に起因する。この増幅利得の相違を補正するため、図２８７に示す増幅器の調整回路の可変抵抗器のよって調整されることが好ましい。総増幅利得比は、センサーからの初期入力信号によって調整される。希望としては、電圧のサージによる損傷を防止するため、サージフィルター２８８を含む。
【００８５】
ブロック図２３に示したように、ミクロプロせサー制御ユニット（ＭＣＵ）２７０は、ＧＰＳ受信機２６０の全部の装置、無線通信装置２１４、信号調整器２０４、ブーザと録音音声２７１、記憶装置２７２、標識装置２７３、キー２７４、自動注入装置２７５、及びリセット２７６等を制御する。これは、水晶２７７によって決められる指定速度で作動する。ＭＣＵ２７０で、自動アラームシステムの作動に必要なデータの貯蔵と取り戻し用の記憶装置を利用することができる。使用者はリセットスイッチ２７６を使ってＭＣＵ２７０を始める。リセット２７６は、システムを消し、再びつけるように、全体システムと共にＭＣＵ２７０を初めの状態に返す。ＭＣＵ自動アラームシステムの情報をＬＣＤ（Ｌｉｑｕｉｄ Ｃｌｅａｒ Ｄｉｓｐｌａｙ）２７３に示すことができるものが好ましい。使用者は、電圧レベルで感知できる既定キー入力２７６によってＭＣＵ２７０を自由に使える。
【００８６】
ＧＰＳ衛生２６１からの位置コードを持つ信号は、ＧＰＳの公称周波数域の２０ＭＨｚバンドウィッド（ｂａｎｄｗｉｄｔｈ）と中心周波数１５７５．４２ＭＨｚのＢＰＦ（Ｂａｎｄ Ｐａｔｈ Ｆｉｌｔｅｒ）２６０ａによって直接にろ過されることが好ましい。衛生２６１からの信号はコード化された信号で受信されるのでＧＰＳ制御器モジュール（Ｃｏｎｔｒｏｌｌｅｒ Ｍｏｄｕｌｅ）２６０ａで解読しなければならない。Ｘ／Ｙ／Ｚ位置に関する該座標のデータはＲＳ２３２Ｃシリアル（ｓｅｒｉａｌ）通信によってＭＣＵ２７０に移される。
【００８７】
中にＡ／Ｄ転換機のあるＭＣＵ２７０によって信号調整器２０４からのアナログ信号はデジタル信号に転換される。デジタル信号は患者の状態を既定の閾値と比較するために利用される。
【００８８】
アラームブザー２７１を活動させるＭＣＵ２７０の出力信号は、音のレベルを制御するため、電流ドライバ２７１ａを通す。非常時、ＭＣＵ２７１はアラーム音と共に自動インジェクション装置に活動信号を提供する。
【００８９】
アラームがなると同時に、通信装置２１４を使って患者の位置座標及び入力、記録された情報は既定の目的地へ送信される。無線通信装置２１４は自動アラーム情報システムに利用されることが好ましい。
【００９０】
浸透圧の変化が血液中のアナライトの変化を示すヒドロゲルバイオセンサーによって、本発明の健康アラームシステムが主に述べられているが、その代わりに、健康アラームシステムは全く別の状況にバイオセンサーを使用することができる。例えば、バイオセンサーが心臓リズム、血液凝固要素、又は他の健康の要望決定要素等を測定するところとか、血液中のアナライトレベルを測定するために浸透圧を測定すること以外の方法、又は糖尿病とは無関係の血液アナライトを測定する等である。患者とは離れた所の関連者らにアラームを伝達することと、緊急時、関係者らに患者のある位置を示すデータをＧＰＳユニットを含む方法で可能性を提供する。旅行、ハイキング、釣り等を望んでいっても多様な健康状態で苦しむ患者には潜在的な有益である。
【００９１】
自動電活通知システム付きバイオセンサが健康管理を増進する為に重要な利点を提供することを技術の専門家は認める。患者が生理学的な損傷をを受ける条件について警告されることに限らず、既定の境界を超えた状況になると健康管理者に、患者の最新情報を知らせる。例えば、糖尿病患者が低血糖性ショックを起こした場合には、医療関係者（又は患者の親近者）はこれに応じて、適切な医療行為を行う。そのようなシステムは一人住まいの人や動くことが不自由な人にとって特に有利である。患者の位置についての情報がアラームを受信する健康管理者に送信できるので、ＧＰＳ（図１６）付きシステムは、特に旅行者に価値がある。
【００９２】
以上、少なくとも一つも好意な実施態様を参照して本発明を述べたが、本発明はそのような実施態様に限定される物ではないことは当業者には明白であろう。本発明の範囲は添付の特許請求の範囲のみによって解釈すべきものである。
【図面の簡単な説明】
【図１】
競合結合及び膨潤メカニズムの例を示す図である。
【図２】
アナライト結合分子含有コポリマーの例を示す図である。
【図３】
本発明の好ましい実施態様の部分断面測面図とダイヤグラムで、サンプルに少々浸めて患者の皮下に埋め込むことのできるバイオセンサを示す。
【図４】
本発明の別の実施態様の部分断面側面図で、コンピュータに電気的に接続されたバイオセンサを示す。
【図５】
好ましい実施態様の部分断面側面図で、アナライトがヒドロゲルに拡散し、ヒドロゲルを膨潤させ、その結果圧力トランスデューサがテレメータを介してコンピュータへ信号を発信する様子を示す。
【図６】
圧力トランスデューサの断面側面図を示す。
【図７】
ダイオード・クワッド ・ブリッジ（ｄｉｏｄｅ ｑｕａｄ ｂｒｉｄｇｅ）回路を形成する小型ダイオードを有する好ましい回路基板を含む圧力トランスデューサの断面測面図を示す。
【図８】
好ましいダイオード・クワッド・ブリッジ回路の回路図を示す。
【図９】
無線ダイヤル発信と組み合わせた自動アラームシステムのブロック図を示す。
【図１０】
図９の自動アラームシステムの各部用電源の概略図を示す。
【図１１】
図９の自動アラームシステムの信号調整回路の概略図を示す。
【図１２】
図９の自動アラームシステムの比較器及び制御回路の概略図を示す。
【図１３】
図９の自動アラームシステムの送受信機の概略図を示す。
【図１４】
図９の自動アラームシステムのダイヤル機構の概略図を示す。
【図１５】
図９の自動アラームシステムに応答して注入を行うインジェクション装置と組み合わせて使用される自動アラームシステムのブロック図を示す。
【図１６】
好ましい自動健康アラームシステムのブロック図を示す。
【図１７】
図１６のアラームシステムの電源回路の図を示す。
【図１８】
図１６のアラームシステムの信号調整回路を 示す。
【図１９】
図１６のアラームシステムのミクロ制御ユニトの回路を示す。
【図２０】
図１６のアラームシステムのＧＰＳと通信送信機を示す。
【図２１】
図１６のアラームシステムの信号調整機のブロック図を示す。
【図２２】
図１６のアラームシステムのミクロ制御ユニトのブロック図を示す。[0001]
[Background of the Invention]
What to say about government rights
This invention was awarded grant / license number R43DK55958 by the United States National Institutes of Health, and the United States has certain rights in the invention.
[0002]
[Technical field to which the invention belongs]
The present invention relates generally to biosensors utilizing hydrogels for measuring the concentration of free analyte molecules in a liquid, and more particularly, to an analyzer installed and selected in a patient's body. The present invention relates to an implantable biosensor capable of monitoring a selected analyze without interruption. The present invention also provides that a biosensor is coupled to the alarm device so that harmful changes in analyte levels and other undesirable changes in the patient's health that occur in the patient's body fluid can be monitored by the patient or / and the caretaker of the patient. Related to a health alarm system for giving a warning.
[0003]
[Description of related technology]
In the past decade, efforts have been devoted to the development of analyte monitoring biosensors to help prevent complications of diseases such as diabetes. A significant advance would be the development of an implantable analyte sensor that is analyte-specific and has sufficient specific sensitivity to accurately and continuously monitor analyte levels in vivo. Such sensors greatly facilitate the collection of data regarding patient analyte levels and biochemical studies.
[0004]
For the purpose of analyzing analytes such as glucose in clinical settings, a new class of implantable technologies utilizing enzymes such as glucose oxidase (GOD) have been developed based on electrochemical principles. The most advanced analyte biosensors based on electrochemical transducers and potentially implantable are the most developed, such sensors being potentiometric sensors, conductive sensors. And amperometric sensors.
[0005]
Currently, neither potentiometric nor conductometric methods appear to be suitable for analyte monitoring in vivo. The reasons are (a) interference by species other than the analyte in the physiological environment and (b) low sensitivity and logarithmic dependence of the signal on analyte concentration. Since the embedded analyte sensor needs to be recalibrated over time, it is highly desirable that the dependence of the signal on analyte concentration be linear. However, even a non-linear calibration curve can be reasonably handled by using a microprocessor.
[0006]
The most advanced analyte sensors for in vivo monitoring include electrochemical methods, including hydrogels on which enzymes that react with the analyte to produce hydrogen peroxide are immobilized, along with an amperometric method used to sense hydrogen peroxide. It is a sensor. This technique can provide a linear calibration curve. In the amperometry method, hydrogen peroxide (H ₂ O ₂ ), Or an electrode that produces a current proportional to the diffusion flux of oxygen (O 2). ₂ 2) using an electrode that produces a current proportional to the diffusion flux. Increasing the analyte concentration in the surroundings increases the diffusion flux of the analyte into the membrane and increases the rate of reaction within the membrane. The increased reaction rate of the enzyme increases the local concentration of hydrogen peroxide in the membrane and decreases the oxygen concentration. This increases the current detected by the hydrogen peroxide based electrode sensor or decreases the current detected by the oxygen based electrode sensor. The latter approach, based on the detection of oxygen flux, also requires a second oxygen-based electrode sensor mounted on the oxygen-free hydrogel. This second electrode is used as a reference electrode.
[0007]
However, there are some hurdles that must be overcome for amperometric sensors to be commercialized as useful for in vivo monitoring. Current analyte sensor designs are unlikely to solve difficult problems in the near future. The first hurdle is due to electrochemical interference. Only the analyte (hydrogen peroxide or oxygen) must generate current at the electrode. Therefore, in both oxygen-based and hydrogen peroxide-based analyte sensors, the inner membrane is permeable to the analyte, but probably impermeable to endogenous interferents that have electrochemical effects. Must be used. In clinical studies of hydrogen peroxide based sensors, a decrease in sensitivity was seen during the implantation period. In other words, a phenomenon that could not be explained by blocking the sensor surface with proteins was observed. To explain this decrease in sensitivity, one possibility is the inactivation of enzymes mediated by hydrogen peroxide. In an oxygen-based sensor, a decrease in sensitivity can be avoided by co-immobilizing catalase and enzyme because catalase consumes hydrogen peroxide. Fourth, if there is a shortage of oxygen for the analyte, an upper limit is imposed on the ability of the biosensor to measure the analyte level. This problem is called "oxygen deficiency".
[0008]
In addition to the biosensors described above, hydrogels have been used in devices that have been developed to release insulin directly into the bloodstream of diabetics in response to high analyte values. As one approach, hydrogels are configured to have pendant groups that are charged and chemically immobilized under physiological solution conditions (pH 2 to pH 10). Glucose-specific binding molecules (GBM; for example, concanavalin A) are also immobilized in the gel. The immobilized glucose molecules of the hydrogel bind to the immobilized GBM in a solution in the absence of free glucose, actually creating non-covalent crosslinks. When the hydrogel comes into contact with a solution containing free glucose, the immobilized glucose disengages from the GBM due to competitive binding and reduces the number of crosslinks. Due to the swelling of the charged pendants in the hydrogel, the reduction in cross-linking results in an increase in the swelling of the hydrogel. In effect, swelling of the hydrogel increases the porosity and / or size of the gel subunits of the gel. These insulin delivery hydrogels also contain insulin. Due to the increased pore size, insulin (slightly larger molecules that cannot be easily diffused through a matrix of closely cross-linked gels) diffuses outwardly into the patient's bloodstream. . Reference: A. Obaidat, et al. Y., Characterization of Protein Release through Glucose-Sensitive Hydrogel Membranes, 18 Biomaterials 801-806 (1997); Ito, et al. , An Insulin-releasing System that is Responsible to Glucose, 10 Journal of Controlled Release 195-203 (1989). The above references are expressly incorporated into the text.
[0009]
However, to our knowledge, the swelling / osmotic pressure changes that occur in pH-sensitive competitive binding hydrogels have not heretofore been recognized and developed for the purpose of measuring free analyte concentration. The prior art does not teach the use of analyte-induced swelling of drogels for the measurement of analyte concentration, and in particular does not specifically teach the use of a transducer to measure swelling of hydrogels. Was. The use of pressure transducers provides a measurement tool that avoids problems with electrochemical sensors.
[0010]
Therefore, there is a need to provide a biosensor that is very sensitive to analyte concentration without relatively interference problems when operated in complex media such as human blood. In addition, since the analyte concentration itself is a parameter that is more controllable than the parameter measured by the electrode, a biosensor that directly relies on analyte changes is needed. This system is relatively free of potential sources of interference and is particularly important in the case of implantable biosensors. In addition, there is a need for a hydrogel-based biosensor that does not consume oxygen during the analyte measurement process.
[0011]
Accordingly, a first object of the present invention is to provide a biosensor as described above. It is another object of the present invention to provide a general method for measuring the concentration of an analyte for which a suitable specific binding partner has been found or can be assembled.
[0012]
[Summary of the Invention]
The present invention relates to a hydrogel-based biosensor for measuring osmotic pressure in a hydrogel containing an immobilized pendant charged swelling moiety, an analyte molecule, and an analyte binding partner molecule. To determine the osmotic pressure or swelling tendency of the hydrogel, the gel is contained in a rigid enclosure. The enclosure is a semi-permeable membrane that allows for contact between a test fluid (patient's blood or other solution) and a pressure sensing device and a hydrogel to detect osmotic pressure or swelling tendency in the hydrogel. Is linked to This instrument utilizes a competitive assay in which free analyte molecules diffused into the hydrogel displace fixed immobilized analyte molecules in proportion to free analyte concentration. This substitution reduces the degree of crosslinking between the fixed analyte and the fixed analyte pendant binding partner molecule. Since the hydrogel contains charged swelling moieties, this reduction in cross-linking results in a swelling tendency or osmotic pressure that is detected by pressure sensing devices.
[0013]
Accordingly, the present invention comprises the following components: a) a polymer hydrogel having pendant charged groups in physiological solution conditions, b) an analyte binding immobilized in the hydrogel and capable of binding free analyte. A molecule, c) an analyte molecule immobilized in the hydrogel, d) a pressure sensing device for measuring the osmotic pressure of the hydrogel. The preferred pressure measuring device looks like a) a diaphragm installed so that changes in osmotic pressure in the gel can monitor the pressure on the diaphragm, b) operatively connected to the diaphragm to measure pressure changes. It is assembled with the pressure transducers. The biosensor of the present invention is immobilized in a hydrogel and is designed to measure an analyte having binding affinity with (immobilized) binding partner having sufficient binding characteristics (see Table 1).
[0014]
Measuring analyte concentration requires calibration of the measured pressure change with a solution of known analyte concentration, as is commonly used in measuring methods. Accordingly, the biosensor is operatively connected to a reporting means associated with the pressure sensing means for reporting the data signal, receiving the data signal and comparing it to the calibration curve to reflect the measured concentration of the analyte. Includes a computer system that emits analyte and data signals.
[0015]
Preferably, the reporting means is a battery-operated telemeter that transmits a data signal to a receiver operatively connected to the computer. More preferably, the computer system is mounted on an alarm system. Although a personal computer may be used, a microprocessor is preferable as the computer system.
[0016]
Most preferred is a computer system that includes or is connected to an alarm device that can transmit an alarm signal when the analyte concentration is outside a predetermined acceptable range.
Further, in a most preferred manner, the portable or patient-worn biosensor system comprises a global positioning system (GPS).
[0017]
Accordingly, the invention also includes a health sensor-based health alarm system that alerts the health caregiver of a patient at a remote location to an undesirable condition detected by the biosensor via telephone or wireless transmission means. Most preferred is a system that includes a GPS system and a mobile phone that can also provide monitoring and alarm services to traveling patients. The biosensors of the system of the present invention include any sensor designed to measure a physiological determinant (such as an analyte selected from a patient's body fluid) that is associated with health. The system includes an automatic dosing device that is capable of injecting an appropriate amount of an agent to improve an undesired physiological change in a human in response to an alarm from the sensor.
[0018]
The invention also includes a method for determining the concentration of free analyte in a solution.
The method comprises the following steps:
Provides a hydrogel comprising charged pendant moieties, analyte molecules, covalently immobilized analyte binding molecules, and the like.
* Include the hydrogel in a rigid enclosure with a semi-permeable membrane portion designed to allow free analyte to diffuse into the hydrogel. The contact between the hydrogel and the test liquid is possible through at least one open end covered by the semipermeable membrane.
* To derive an osmolality versus analyte concentration calibration curve, contact the hydrogel continuously with a series of control solutions that know the concentration of free analyte and measure the osmotic pressure of the hydrogel for each control solution. .
* Contact the test solution with the hydrogel and measure the resulting osmotic pressure.
* Compare the calibration curve with the osmotic pressure to determine the concentration of the test solution.
[0019]
The step of measuring osmotic pressure is completed by installing a pressure measuring device in a rigid enclosure, contacting the hydrogel, and installing a pressure sensing device that transmits a data signal indicative of osmotic pressure.
[0020]
(Detailed description of the invention)
Embodiments of the present invention will be described based on examples with reference to the drawings. In the figures, the various elements of the invention will be numbered and will be described so that those skilled in the art can make and use the invention. It is to be understood that the following description is only illustrative of the principles of the present invention, and that the scope of the appended claims is not to be limited thereby.
[0021]
As shown in the figure, the present invention relates to a biosensor 10 for measuring the concentration of an analyte in a solution. Briefly, the biosensor 10 uses a special polymer hydrogel 30 that swells in proportion to the concentration of free analyte. The ABM is immobilized in the hydrogel 30 and the ABM competitively binds the immobilized analyte and the free analyte, thereby altering the osmotic pressure of the hydrogel 30. The biosensor 10 includes a measuring unit 40 that measures the pressure of the hydrogel 30 and a reporting unit 60 that reports the concentration of the analyte based on the measured pressure of the hydrogel 30. In a preferred embodiment, the biosensor 10 includes a rigid, biocompatible enclosure 20 having a semi-permeable membrane 26 covering the closed end 22, a flexible diaphragm 28 between the semi-permeable membrane 26 and the closed end 24, and It consists of a polymer hydrogel 30 enclosed between them. The hydrogel 30 includes moieties that change the osmotic pressure of the hydrogel 30 in proportion to the free analyte in the hydrogel 30.
[0022]
The enclosure 20 is designed to be slightly submerged in the sample and implanted directly into the human body to monitor the level of analyte in the blood. In this embodiment, the biosensor 10 uses the ABM immobilized in the hydrogel 30. As the measuring means 40 for measuring the osmotic pressure of the hydrogel 30, a pressure transducer 40 operatively associated with the flexible tire flam 28 is preferred. The reporting means 60 for reporting the analyte level is preferably a telemeter 60 driven by a battery 64 for transmitting a wireless data signal to a receiver operatively attached to the computer. The biosensor 10 can be easily modified and implemented by those skilled in the art. If the biosensor 10 has minimal invasiveness due to implantation into the human body, it can be electrically connected directly to the computer 62 instead of using the telemeter 60. Although pressure transducer 40 is currently the preferred tool for measuring hydrogel pressure changes, one skilled in the art could devise alternative means of measuring and reporting hydrogel 30 pressure changes. One such means is to use a piezoresistive sensor instead of the pressure transducer 40.
[0023]
Enclosure, semi-permeable membrane, and diaphragm
As best shown in FIG. 3, the structure of the biosensor 10 is provided by an enclosure 20, which is preferably cylindrical with an open end and a closed end. The open end is sealed with a semi-permeable membrane 26. A flexible diaphragm 28 is mounted between the semi-permeable membrane 26 and the closed end. The hydrogel 30 is encapsulated between the semi-permeable membrane 26 and the diaphragm 28 as described below. The enclosure 20 is preferably made of a rigid, non-permeable, biocompatible material, such as stainless steel. The enclosure 20 is also preferably conjugated to heparin, which inhibits blood clotting, and polyethylene glycol (PEG), which reduces the immune response of the human body to the enclosure 20. The enclosure 20 is preferably cylindrical in shape to facilitate implantation, the cylinder having a length of about 5-12 mm and a diameter of about 0.1-3 mm. If the enclosure 20 is not embedded, a rigid impervious material such as fiber, plastic, or metal can be used.
[0024]
The semipermeable membrane 26 allows small analytes to pass, but does not allow blood clots, cells, proteins, and hydrogels 30 to pass. The semi-permeable membrane 26 is preferably made of a material that is sufficiently rigid to withstand the pressure of the hydrogel 30 that is sensitive to swelling analytes. When the biosensor 10 is implanted in a human body, the semi-permeable membrane 26 is preferably made of an inert, non-toxic material. Suitable semi-permeable materials can be selected from, but are not limited to, the following groups of polymeric compounds: The high molecular compounds include cellulose acetate, methyl cellulose, polyvinyl alcohol, and polyurethane. Semi-permeable materials are also preferably combined with heparin and polyethylene glycol (PEG) to reduce the immune response, blood clotting, and cell attachment to surfaces. For examples of such enclosures and semipermeable membranes, see US Pat. No. 5,593,852 to Heller, US Pat. No. 5,431,160 to Wilkins, Hogan. U.S. Patent No. 5,372,133 to Hogen Esch, U.S. Patent No. 4,919,141 to Zier, and U.S. Patent No. No. 4,703,756. The contents of these patents are incorporated herein by reference. Diaphragm 28 is preferably a flexible but electrically conductive material that can be used for transducer 40. Such diaphragms are known in the art. A preferred diaphragm 28 is KOVAR from Hamilton Technology of Lancaster, PA. ^TM Or INVAR36 ^TM Made with alloy sold under the trademark. The thickness of the diaphragm 28 is preferably about 12.5 mirco meters for optimum spot welding and sensitivity. Such a diaphragm is described in a paper by Dr. Baek SG of the University of Utah. Diaphragm 28 is preferably seal welded to enclosure 20 between semipermeable membrane 26 and closed end 24 of enclosure 20. A hydrogel 30 is placed in the enclosure 20 between the semipermeable membrane 26 and the diaphragm 28. The measuring means 40 and the reporting means 60 described below are located in the enclosure 20 between the diaphragm 28 and the closed end 24 of the enclosure 20.
[0025]
Analyte binding molecule
Table 1 contains the analytes and analyte binding partners to which the biosensor of the present invention can be applied. The analyte binding partner molecule should bind the analyte with sufficiently high binding properties and activity. For example, antibodies (ABMs) bind tightly to highly specific antigens (analytes).
[0026]
[Table 1]

[0027]
Preparation of hydrogels-charged pendant groups, immobilized analytes, and ABMs
General methods of preparing hydrogels and polymeric metrics such as gels with pH-sensitive charged pendant groups are described in the literature. See, for example, Gels of Brondsted H polyelectrolytes: properties, preparation and application: Harland RS, Prud Homee PK, eds ACS: 285, 1992; Ghandehari H et al 1996 J. Am. Macromol. Chem. Phys. 197: 965; and Ishihara K et al 1984 Polym. J. 16: 625. The contents of these patents are incorporated herein by reference. Some relevance to the preparation of pH-sensitive hydrogels is also described in pending patent applications (PCT / US00 / 23194, published March 8, 2001, US patent applications 09/308, 392 and 09 /). 824, 552). The contents of these patents are incorporated herein by reference.
[0028]
Hydrogels may contain or be modified to contain a variety of functional groups. These groups of functional groups can be used by those skilled in the art to bind ABM and analyte to the backbone of the hydrogel. These functional groups are as follows, but are not limited thereto. Carboxyl, hydroxyl, alkyl, kydroxylalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, carboxyl, carboxamidealkyl, aromatic amino, phenolichydroxyl, is a polyethylene glycol and the like. The coupling reaction is as follows, but is not limited thereto. Diazonium coupling, isothiocyano coupling, hydrazide coupling, amide formation, disulphide coupling, dimethyl alcohol coupling, and lactic acid coupling, lactic acid coupling, and lactic acid coupling. The coupling reaction between these two functional groups has been well documented and is well known to those skilled in the art. For example, carboxyl groups in hydrogels can be conjugated to peptide groups using a coupling medium such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and dicyclohexylcarbodiimide. EDC reacts with carboxylate and amino groups. This process is described in AnalLett. 15, 147-160 1982, J. Am. Biochem 92, 1413-1424 1982.
[0029]
The primary amino group of the peptide chain in the ABM and the analyte utilizes the following binding and / or cross-linking media to provide functional groups (eg, thiol, hydroxyl, acyl chloride). ), Sulfates, sulfonyl chlorides, phosphates, phosphate chlorides, and imides (such as imides). The binding medium and / or the cross-linking medium may be benzyl carbamate, carbonate, N-succinimidyl 3- (2-pyridylthio) propionate (SPDP), sulfo-LC-thylexyl-cyl-exyl-icylamic-ylc-exyl-m-d-yl-c-yl-d-exyl-m-exyl-m-d-yl-c-exyl-m-d-yl-m-exyl-m-d-y-m-d-yl-m-exyl-m-d-y-m-d-yl-m-exyl-m-d-y-m-d-y-m-c ), Sulfo-SMCC, m-maleimidoenzoyl-N-hydroxysuccinimide ester (MBS), sulfo-MBS, N-succinimdyl (4-iodoacetibiosioiBiS iobui ozioiBi s io ce i n io b i s io i n io b i s io i n io b i n s io em i io b i n s io i n io em i b i t io s i n t s s) rate (SMPB), sulfo-SMPB, dithiobis (succinimidylpropionate), 3, 3'-dithiobis (succinimidylpropionate), disuccinimidyl suberate, bis (sulfosucinimidyl) suberate, disuccinimidyl tartarate (DST), sulfo-DST, bis [2- (succinimidooxycarbonyloxy) [ethyl] sulfone (BSOCOES), sulfo-BSOCOES, ethylenglycolbis (disucciniidylsuccinate (EGS), sulfo-EGS, etc. Thiol (thiol) Multiple functional groups such as, hydrosyl, acyl chloride, sulphate, sulfonyl chloride, phosphate, phosphate chloride, and imide. Other analytes and ABMs may be bound to the hydrogel using the binding and crosslinking media described above.
[0030]
The charged partial pendant from the hydrogel backbone is the driving force underlying the swelling phenomenon of the hydrogel in response to the displacement of the immobilized analyte from the ABM partner. Thus, when a particular charged moiety is involved, a net charge should exist, regardless of whether the charge is positive or negative.
[0031]
Preferred methods for making the hydrogel include analytes containing functional groups such as amine and hydroxyl groups and ABM include allyl alcohol and etherification reactions and methacryloyl chloride. Those having a vinyl group bonded thereto by a nucleus-saving reaction with chloride are preferred. The copolymerization reaction of an analyte and ABM using a monomer such as acrylamide and hydroxyethyl methacrylate (HEMA), and a crosslinking agent using a crosslinking agent preferably proceeds by a free radical reaction. The polymer chain preferably has a chemically immobilized analyte and ABM as pendant groups. The hydrogel thus obtained is preferably porous. The porosity is preferably controlled by several methods such as bubbling and excessive addition of a powdered salt to the copolymerization reaction product. When free analyte is introduced into the hydrogel, it is preferred that the hydrogel swells by competing and binding to the immobilized ABM in the hydrogel. Preferably, the swelling ratio of the hydrogel is proportional to the free analyte concentration in the solution. The reaction ratio between ABM, monomer or cross-linking agent and the analyte should be optimized so that the swelling and de-swelling of the hydrogel due to changes in free analyte concentration can be measured as pressure using a pressure transducer. Is preferred.
[0032]
Useful sensitivity of the swelling tendency / osmotic pressure range and the free analyte concentration is determined by the amount / ratio of immobilized analyte and ABM molecules in the hydrogel, and the excess charge (pending positive or negative charge) of the pendant charged moiety. It is clear that it depends on the amount / distribution of These three important components also depend to some extent on the properties of the particular analyte. Regardless of the situation, familiarity with the principles of the measurement method, the apparatus of the invention, and the general chemical synthesis of hydrogels, one can easily determine the optimal levels of the three components of the target analyte.
[0033]
Glucose biosensor
A specific example of a biosensor invention is the glucose biosensor described in the related application PCT / US00 / 23194 (published March 8, 2001). This content is incorporated as a part of the present specification. In a glucose biosensor, the analyte binding partner is Concanavalin A.
[0034]
Measuring means-pressure transducer
The biosensor includes means 40 for measuring hydrogel pressure. This element is required. Biosensors 10 that directly depend on changes in free analyte concentration can avoid significant external sources of interference. The free analyte itself is a control parameter and can be measured instead of a parameter for measuring an indirect parameter by an electrode.
[0035]
As shown in FIGS. 6 and 7, the pressure transducer 40 is preferable as the measuring means. Pressure transducers are known in the art, and those skilled in the art can configure transducers that are optimized for the specific needs of biosensor 10. Transducers include Harrison DR., Dimeff J. Rev. Sci. Instrum. 44: 1468-1472 (1973) and Harrison et al., "Diode-Quad Bridge Circuit Means," U.S. Pat. No. 676, the disclosures of which are incorporated herein by reference.
[0036]
As shown in FIG. 7, the biosensor 10 further includes a calibration hole 70 for receiving a small brass tube 72, a soldered copper wire 74, a braided shield 76, an insulator 78, and a coaxial cable. 80.
[0037]
In the most preferred embodiment, the measuring means 40 is a capacitive pressure transducer 40 associated with the flexible diaphragm 28 described above. The preferred transducer 40 includes a first electrode 44 and a second electrode 46 separated by an insulator 48. In a preferred embodiment, the first electrode 44 and the second electrode 46 are cylinders coaxially arranged in a line with the insulator 48. The elastic diaphragm 28 is welded on the first conductor 44 and functions as one of the electrodes of the capacitor part of the transducer 40. The first electrode 44 is connected to the diaphragm 28, and the diaphragm 28 and the second electrode 46 are separated by a space 50.
[0038]
Diaphragm 28 is in functional contact with hydrogel 30 and changes the volume of space 50 between second electrode 46 and diaphragm 28 by deforming diaphragm 28 in response to a change in pressure of hydrogel 30. Therefore, the value of the capacitance changes. The change in capacitance is detected remotely, preferably using a diode quad bridge circuit 52. These pressure transducers 40 can effectively measure a small pressure change of about 1 Pascal of the flowing polymer liquid.
[0039]
Other examples of transducers are described in U.S. Pat. No. 5,711,291 to Takaki and U.S. Pat. No. 5,725,918 to Fowler, which are incorporated herein by reference. More detailed theory of the transducers cited herein as forming a part of this specification as a part of the present specification can be found in the following documents. The descriptions of these documents are cited herein as forming a part of the present specification:
Baek SG, Ph. D. Thesis, University of Utah, (1991), Magda JJ, Baek SG, Larson RG, DeVries KL, Macromolecules 24: 4460-4468, (1991), MagJa, JagGa, Jagoda, Magda, Jagoda, MagdaJa, Gagoda, Magda, Jagoda, Magda, Jagoda, MagdaJa, Jagoda, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJa, MagdaJo 1991), Lee CS, Tripp B, Magda JJ, Rheologica Acta 31: 306-308, (1992), Lee CS, Magda JJ, DeVries KL, Mays JW, Macrosmo, 47-mago, Macross, Macross, 1992. Baek SG. Polymer 35: 1187-1194, (1994), Freer T. et al. Biotemetry iii, Academic Press, New York, pp. 279-282, (1976), Tandeske, J.M. , Chapter 5 in Pressure Sensors Selection and Application (Chapter 5 of Selection and Application of Pressure Sensors), Marcel Dekker, New York, 1991, UpdgeSk, UpdgeSk, ShrugsJR, Rg. ASAIOJ. 40: 157-163, (1994), and Folds NC, Fresh JE, Green MJ. Biosensors A Practical Approach (Cas AEG. Eds.) IRL Press Oxford University, pp. 116-121 (1990)
[0040]
Although a preferred pressure transducer 40 has been described, those skilled in the art will be able to devise other measurement means 40. Still other alternative aspects include piezoelectric transducers and sensors, and piezoresistive pressure sensors. Other pressure measuring means or volume increase measuring means can also be used. These alternatives are considered to be equivalent to the invention described herein.
[0041]
Reporting means: Demeter
Finally, biosensor 10 includes means 60 for reporting the measured concentration of the analyte molecule. This factor will vary greatly depending on the particular utility of the biosensor 10 and the needs of the user. In the simplest form shown in FIG. 4, the transducer 40 is only electrically connected to computer means, typically a personal computer. The computer compares the data from transducer 40 to a calibration curve and generates useful data for output via reporting means. In one embodiment, the computer emits an audible alarm if the concentration of the analyte molecule exceeds a certain level. In another embodiment, the computer outputs the data to a report output, such as a computer monitor. Further, in other embodiments, the computer controls the feedback loop to alter the process in response to a change in the concentration of the analyte molecule.
[0042]
In a preferred embodiment shown in FIG. 3, the present invention is a biosensor 10. In this case, the reporting means 60 is preferably a battery-powered telemeter 60 that operatively transmits data signals to the receiver to the computer. This computer also compares the data signal with the calibration curve and reports the concentration via the reporting means. Preferably, the reporting means is an audible alarm that alerts the patient if the analyte level becomes too high or too low.
[0043]
How to use a biosensor
The present invention further includes a method of using the biosensor 10 for measuring an analyte concentration in a solution. The method according to the invention comprises the following steps. First, a biosensor 10 as described above is provided. The ABM is chemically or physically immobilized on the hydrogel 30, preferably by chemical bonding. After immersing the bisensor 10 in the buffer solution, it is preferable to put it in the control solution. The biosensor 10 is calibrated by comparing the obtained data with a calibration curve. After removing the biosensor 10, it is poured into another buffer, and then the biosensor 10 is put into the solution. The analyte molecules are diffused in the polymeric hydrogel 30 and the free and immobilized analytes compete for binding to the ABM. Competitive binding of the free and immobilized analytes to the ABM reduces cross-linking of the hydrogel, swells the hydrogel 30 and puts pressure on the diaphragm as shown in FIG. This swelling is measured by the measuring means 40. This measuring means 40 is preferably a pressure transducer 40. Pressure transducer 40 is used to measure the pressure of hydrogel 30 that is proportional to the concentration of free analyte in hydrogel 30. Data from the transducer 40 regarding this measurement is sent to the reporting means 60. The implantable biosensor 10 uses a battery-powered tare meter 60 to transmit data to a computer. This data is reported to the user via a computer monitor, an audible alarm, or a feedback system. Throughout the life of the system, the system can be recalibrated by taking a sample of blood and comparing the measured value of the analyte with the value reported by the biosensor 10. Calibration means operated by the computer can be adjusted to correct the error.
[0044]
While the invention has been described with reference to at least one preferred embodiment, it will be apparent to one skilled in the art that the invention is not limited to such an embodiment. The scope of the invention should be construed solely by the appended claims.
[0045]
Working principle
The output of the sensor is constantly monitored and compared with a preset value (that is, a threshold value). If the sensor output is out of the preset range, an alarm signal is generated. The alarm signal can be used to execute a predetermined alarm protocol, such as an automatic dial, to send a pre-recorded message corresponding to the detected condition.
[0046]
FIG. 9 shows a production model for alarming diabetics, signaling an administrator using automatic dialing, and sending pre-recorded messages when blood glucose levels drop to low glucose levels. FIG.
[0047]
The main components of the automatic alarm device shown in FIGS. 9-15 are a battery 100, a sensor (biosensor 10 or other sensor for monitoring a physiological condition), a signal conditioning circuit 104, a comparator circuit 108, a transmitter 112a, a receiver 112a. Machine 112b, a dial actuator 116, and a control circuit.
[0048]
Power supply 100 preferably supplies electrical energy to all elements of the device that require power. In consideration of portability of the device, it is preferable to use a dry battery as a power source. However, the suitability of the cell for the power requirements (voltage and capacity) of all components determines the type of battery that can be used. It is considered that a large-capacity 9 V battery is optimal in the range currently known. In the course of development, a bipolar power supply using two batteries was used, but this greatly simplified the circuit design. The low battery indicator is an essential component.
[0049]
Whether or not the signal conditioning circuit 104 is necessary depends on the quality of the signal from the sensor. If the sensor signal contains a lot of environmental noise, a signal conditioning circuit 104 (FIG. 11) is needed to operate the device reliably. Typically, a high input impedance differential amplifier can be used for any type of sensor. A pre-pattageed circuit called an "instrumentation amplifier" is commercially available. However, in a prototype device, a quad operational amplifier IC (e.g., LM384 from National Semiconductor) would be very useful because it provides four amplifiers. Differential amplifiers are excellent at removing common mode noise. The gain of the differential amplifier can be adjusted to provide a signal with a good linear range. By providing a low-pass filter after the differential amplifier, high-frequency noise can be further reduced. An appropriate RC time constant is 0.1 to 1 second. For example, an RC time constant of 1 second can be obtained by using 100 kOhm and 10 mF.
[0050]
The comparator shown in FIGS. 9 to 15 always compares the monitor signal (here, the signal from the output of the signal adjustment circuit) with a preset value. This base value is adjusted using a potentiometer. When the monitoring signal exceeds the basic value, the state of the output of the comparator changes from “0” to “1”, that is, from “off” to “on”. This state change is used to activate subsequent digital circuits. The simplest circuit drives an electromechanical switch to the 'on' position, which connects the transmitter circuit to a power supply. Note that the LM311 type comparator is most suitable for the purpose here.
[0051]
The comparator circuit 108 must be provided with an additional control circuit 130 (FIG. 12). This additional control circuit stops the operation of the device and resets the device if an alarm is issued due to a malfunction or an abnormality of the device. In addition, additional switches must be provided in any case to enable dialing at the discretion of the user of the device. All of these functions can be achieved using a digital D flip-flop IC (C7474).
[0052]
If necessary, in addition to sending an alarm, the comparator circuit 108 can be used to determine whether the sensor 10 is operating properly. If the sensor output exceeds the expected operating range, including the alarm level, comparator 108 indicates a sensor 10 fault.
[0053]
A transmitter 112a and a receiver 112b are required to operate the telephone 114 at a location remote from the person wearing the device. (FIG. 13) The telephone 114 can be operated wirelessly by a typical FM method. Typically, the transmitter comprises a carrier generator 140, a signal generator 144, a modulator 148 for mixing the signal into a carrier, a power booster 152, and a radiator 156. Carrier frequencies range from tens of megahertz to hundreds of megahertz. The signal must be a unique signal picked up by the receiver to prevent false dialing due to environmental noise from other electronic devices. Receiver 112b operates in a reverse manner to transmitter 112a. The transmitter 112a and the receiver 112b must ultimately be custom designed, but a minimally modified transmitter used in remote control toys for children can be used. (Those skilled in the art based on the disclosure herein will understand that other forms of telecommunications, such as e-mail, are also possible).
[0054]
Dialing of the remote alarm signal can be done in various ways well known to those skilled in the art. A schematic diagram of such a system is shown in FIG. Those familiar with remote telephone interaction will be familiar with the many ways to implement the arrangement shown and other arrangements.
[0055]
Some modification is required to use the current answering machine system or to utilize the current answering function for dialing and messaging. As a whole, it is preferred that everything is provided in the telephone. It only needs to be switched on by an alarm signal from the receiver.
[0056]
In addition to the above, the alarm system also functions as a system for treating hypoglycemia in diabetics. FIG. 15 shows a schematic diagram of an alarm system similar to that shown in FIG. However, the system includes an injection mechanism 150 that delivers an analyte, extra sugar, or drug into the patient's bloodstream in response to the alarm. One skilled in the art will appreciate that the injection mechanism 150 may deliver at a predetermined dosage, or may vary the dosage depending on the physiological condition detected by the sensor 10. . The injection mechanism 150 may be connected by system wiring, or may be controlled by the transmitter 112a.
[0057]
In addition to the injection mechanism 150, the system may be provided with a global positioning system 160, which may be connected to the telephone 114 or other parts of the alarm system. This global positioning system 160 allows the location of the target individual to be quickly located when treatment is needed. Such a system is particularly advantageous for those who are diabetic but participate in activities such as cycling, hunting and fishing.
[0058]
Alternative Embodiment-FIGS. 16-23
Although the automatic alarm shown in FIG. 16 is the most preferred system, a useful system is shown in FIGS. 17-23. As seen in FIG. 16, the main elements are a sensor (biosensor 10 or other sensor for monitoring a physiological condition), a battery 200, a signal conditioning unit, a GPS receiver 260, an MCU circuit unit 270 and data transmission. Machine 214.
[0059]
Battery 200 provides electrical energy to all powered device components. In view of the portability of the device, batteries are the preferred choice for availability. However, the compatibility (voltage and capacity) of all elements of the battery with the power demand depends on the type of use. Use a +3.3 volt (+ 3.3V) rechargeable battery to supply the battery. This charging system is used as an overall power source.
[0060]
The charger uses an SMPS (switch mode power supply) 200a to change the AC input voltage from 85V to 265V to a constant DC voltage of + 5V. By using the output DC voltage from the SMPS, the charging circuit 200b receives the recharged battery according to the charge capacity and the remaining battery level. As a charging method, lithium ion, Ni-ca, Ni-H, or the like is used for the rechargeable battery 200c. The low battery light and the charge indicator are important parts.
[0061]
The rechargeable battery can charge up to +3.3 and is supplied to the entire circuit except the LCD, transmitter and microcontroller unit (MCU). An additional voltage of + 5V is required to operate the LCD and the transmitter, which is obtained from the battery by using a conventional DC-DC Converter 200d.
[0062]
The need for the signal conditioning unit 204 depends on the quality of the signal from the sensor. A signal conditioning circuit device 204 (FIG. 11) is needed to operate the device in a reliable manner when the sensor signal is transmitted with a large amount of environmental noise and / or low voltage. The signal conditioning unit 204 is designed for noise reduction and amplification of the input signal from the sensor.
A so-called multi-stage enlargement circuit, called a "device amplifier", is commercially available. However, as standard equipment, chopper OP amp ICs (eg, MAX420 or MAX421) and / or quad OP assistant ICs (eg, IM384 from National Semiconductors) provide a large number of amplifiers, which can be useful for noiseless low voltage signal expansion. . Differential amplifiers are excellent at removing normal mode noise. The low-pass filter after differential amplification further reduces high-frequency noise. A constant RC time of 0.1 to 1 second is appropriate. For example, using 100 kohm and 10 mF, a constant RC time of 1 second can be obtained.
[0063]
The chopper-stabilized amp IC (Chopper-stabilized amp IC) (A1, A2, A3, A4, A5, A6 of the signal adjustment circuit 204) is used as a standard device of the signal adjustment circuit. Op-amps (Op-amps) are single chopper op amps with precise input characteristics. Typically, a high input impedance differential amplifier as a buffer circuit, such as A1 and A2 in FIG. 204a of the amplifier circuit, will have a zero with an available resistor such as VR1 (variable resistor) in FIG. It can be used for any type of sensor to adjust for zero crossing. A1 and A2 preferably have a voltage regulation function with capacitors such as C3, C4, C5, C6 with a chopping frequency of 400 hertz for linear expansion. The Mya capacitor in C1 is for reducing the noise of the signal. _out V1 is adjusted such that is zero crossing. Capacitor C7 reduces high frequency gain and reduces noise.
[0064]
The first amplifier circuit (A3) 204a is made up of a reduction filter and an amplifier for reducing noise. The reduction filter reduces the noise level before magnification. A3 in FIG. 204a as a chopper-stabilized performing amplifier amplifies the filtered sensor signal. For low voltage signals, the execution amplifier A3 has a low input cancellation voltage of 1 μVtyp and a low drift offset of 0.02 μV / Ctyp. The rules of the amplifier circuit are as follows: R1 = R3, R6 / R7 = R4 / R5, Gain = (1 + 2R1 / R _x ) * R6 / R4 and R _x = (VR1 * R2) / (VR1 + R2).
[0065]
The second amplification circuit 204b includes a second reduction filter (R12 and C13), a buffer circuit (A5), and an amplifier (A4) used to reduce a wide band of device noise. Resistors R9 and R10 are preferred to allow a low temperature coefficient of +/- 1% to determine the reliability of the gain (= 1 + R10 / R9). D1 and D2 are diodes for preventing high voltage input to the circuit.
[0066]
The last part of the signal state circuit 204c provides the offset compensation (VR2 and VR3) function and the third amplification (A6 in FIG. 204c). Condenser C17 is rather chosen to greatly reduce the loop response. Signal is off, noise level is input voltage V _cc Greater than the input voltage V _cc Is skipped in the forward direction of the diode D4. When the signal is off and the noise level is lower than the voltage, the input voltage V _cc Is skipped in the reverse direction of the diode D5.
[0067]
The functions of the control device are to compare the input sensor signal with a predetermined reference signal, determine the alarm status, store the new value of the sensor signal, retrieve the stored value, and use the data transmitter for emergency communication. Coupling, activating the injection device, starting an alarm buzzer, answering key input from the patient, etc.
[0068]
As a primary controller of the automatic alarm system, an 8-bit microprocessor is used rather for any information exchange of the automatic alarm system. In the assembler and / or C computer language, coding of the exchange is preferred. It is compiled for use by the microprocessor. Alarm conditions, GPS device codes, signals from sensors, etc., are stored in a storage semi-contactor such as Flash memory, SRAM, DRAM, or EEPROM. 8K bytes of EEPROM 172a are preferably chosen for that purpose.
[0069]
The primary function of the microprocessor is to establish an automatic alarm notification system with Moinitalin during implementation. Enables low power consumption 8-bit microprocessor monitoring and control of automatic alarm systems. TMP87CH48 of TOSHIBA 270a is chosen for this purpose.
[0070]
The patient can also operate by reset, numerical display of signal, position code display and manual. The controller recognizes and interprets the input of the amount of voltage by means of keys pressed by the user to accomplish each function. It is preferable to use an LCD TN type or a ROHM 273a RCM 2072R having a display capacity of 20 characters per line. When an alert is sent incorrectly or is sent due to a device malfunction, the extra control function causes the device to be deactivated and the device to be modified 270b.
[0071]
In an emergency, the controller has a device that launches an output phase signal 275a that initiates operation of the injector and activates the alarm booter 271a. The injector is activated when the microprocessor attaches analog output circuits such as "high" to "low" and "low" to "high" with "0" and "1" functions.
[0072]
Preferably, the patient information is constantly transferred to the data transmitter in an emergency due to the monitoring function of the controller. Patient information includes the patient's identification code, alarm status, XYZ GPS location and current physiological values from the sensors.
[0073]
Technical experts acknowledge that the combination of a biosensor, an automated alarm notification system (GPS) and an emergency treatment system (automatic injection system) provides health care with significant benefits for enhancing health care. . Not only will the patient be alerted about conditions that may cause physiological damage, but also when a threshold is exceeded, the healthcare provider will be informed of the patient's location.
[0074]
The transmitter 214a is necessary for operating the communication device 214. Candidate devices for data transmitter 214a are communication devices 214, such as telephones, including portable wireless communication devices. The device is provided with an external data port for exchanging data with an automatic alarm system, and automatically notifies an alarm status and data to a predetermined device at a remote place. Cables and connectors connect the data transmitter with the automatic alarm system. Choose cables and connectors depending on the wireless data communication device. Wireless connection protocols such as Bluetooth enable data transfer between devices.
[0075]
Alarm status, location information, and other essential information from the automatic alarm system can be transmitted by the remote device in the form of a voice message or a text message.
[0076]
The wireless communication device is preferably a wireless personal telephone supporting CDMA, TDMA, GSM and the like which are currently used. PDA (Personal Digital Assistance) with remote Internet service T is another preferred wireless portable communication device.
[0077]
Typically, the transmitter 214a comprises a carrier generator, a signal generator, a modulator that mixes the signal with the carrier, and a radiator. Carriers range from thousands to hundreds of MHZ. The signal received at the receiver must be unique in order to prevent it from being erroneously transmitted by the environmental noise of other electronic devices. AM or FM radio communication is appropriate for an automatic alarm system, but the AM or FM receiver is also adapted to receive data from the transmitter (214a) using an appropriate communication protocol (Protocal).
[0078]
The primary function of a GPS device with an automatic alarm device is to provide location data to the alarm recipient. The GPS receiver 260a, which supports the NMEA protocol (Protocal), is rather used for automatic alarm systems when the patient is not aware of his position, is unconscious, or cannot communicate his position. In the receiver, the code is transmitted to the control system by the conventional RS232c serial communication of the XYZ coordinates in the Binary format. The GPS receiver is normally in a standby mode and operates to automatically notify the health care provider of the patient's location when the patient is in danger.
[0079]
Figures 21, 22, and 23 are block diagrams of the three main elements of the automatic alarm system as standard equipment. FIG. 21 shows a switch type power supply (SMPS) and a charger, FIG. 22 shows a signal conditioning circuit, and FIG. 23 shows a general control device. Fig. 4 shows a free voltage input SMPS circuit and a block of charging procks.
[0080]
As stored in FIG. 21, the AC noise is filtered by an AC input peeler 290 in front of the bridge circuit 291 which converts all the AC radio waves (from 85 V to 265 V) into waves. At the same time that the DC and DC noise is filtered, the RC pilator 292 converts all waves into DC. Nevertheless, converted DC spark noise will result and be removed using the Snuber circuit 293.
[0081]
The conversion DC voltage level is adjusted from 4.5V to 5V in the adjustment circuit 294, which is usually slightly higher than the flowing battery voltage capacity. A converted DC power supply voltage filtered by LC filter 296 is preferred to reduce noise generated during adjustment of the DC voltage level. Battery charging circuit 295 controls the charging current and the voltage, depending on the capacity charged to the rechargeable battery.
[0082]
A block diagram of the signal conditioner is shown in FIG. The signal level of the sensor is very low and is susceptible to environmental noise. The low signal level is preferably filtered before amplification by the RC filter of the low perspective filter 1 (LPF1) of FIG. Otherwise, noise is amplified along with the signal, and the signal cannot be distinguished from noise.
[0083]
Preferably, the filtered signal is amplified so that the amplification gain ratio is about 100. For low signal levels, a higher amplification gain ratio is likely to make the signal worse and the signal cannot be recovered from noise. In the second amplification of amplifier 2 of FIG. 285, an amplification gain of about 100 is used to provide sufficient dynamic range for the A / D converter in the control unit. LPF3 of FIG. 286 is used for noise reduction.
[0084]
The total gain ratio of the amplifier should be 10 times 100 to 1000, but in practice, the total gain ratio of 1000 cannot be achieved. The reason is due to the inherent errors of each device such as op-amps, resistors, capacitors, and the like. In order to correct this difference in amplification gain, it is preferable that the gain be adjusted by a variable resistor of the adjustment circuit of the amplifier shown in FIG. The total amplification gain ratio is adjusted by the initial input signal from the sensor. If desired, a surge filter 288 is included to prevent damage from voltage surges.
[0085]
As shown in the block diagram 23, the micro processor control unit (MCU) 270 includes all the devices of the GPS receiver 260, the wireless communication device 214, the signal conditioner 204, the buzzer and the recorded sound 271, the storage device 272, and the sign. It controls the device 273, keys 274, automatic injection device 275, reset 276, and the like. It operates at a specified speed determined by the crystal 277. The MCU 270 can utilize storage for data storage and retrieval needed to activate the automatic alarm system. The user uses the reset switch 276 to start the MCU 270. Reset 276 returns MCU 270 to its original state with the entire system so that the system can be turned off and on again. It is preferable that the information of the MCU automatic alarm system can be shown on an LCD (Liquid Clear Display) 273. The user is free to use the MCU 270 with a default key input 276 that can be sensed at the voltage level.
[0086]
Preferably, the signal having the position code from the GPS satellite 261 is directly filtered by a BPM (Band Path Filter) 260a having a 20 MHz band width and a center frequency of 1575.42 MHz in the nominal frequency range of GPS. The signal from the satellite 261 is received as a coded signal and must be decrypted by the GPS controller module 260a. The data of the coordinates related to the X / Y / Z position is transferred to the MCU 270 by RS232C serial communication.
[0087]
The analog signal from the signal conditioner 204 is converted to a digital signal by the MCU 270 with an A / D converter therein. The digital signal is used to compare the condition of the patient to a predetermined threshold.
[0088]
The output signal of MCU 270 that activates alarm buzzer 271 passes through current driver 271a to control the sound level. In an emergency, the MCU 271 provides an activity signal to the automatic injection device with an audible alarm.
[0089]
Simultaneously with the alarm, the patient's position coordinates and the input and recorded information are transmitted to a predetermined destination using the communication device 214. The wireless communication device 214 is preferably used for an automatic alarm information system.
[0090]
Although the health alarm system of the present invention is primarily described by a hydrogel biosensor in which changes in osmotic pressure indicate changes in the analyte in the blood, instead, the health alarm system integrates the biosensor into a completely different situation. Can be used. For example, where the biosensor measures cardiac rhythm, blood clotting factors, or other health demand determinants, or any other method than measuring osmotic pressure to measure analyte levels in the blood, or diabetes For example, blood analytes that are unrelated to are measured. It provides the possibility of transmitting alarms to relevant parties remote from the patient and in emergency cases, data indicating the location of the patient to the relevant parties in a manner involving a GPS unit. It is potentially beneficial for patients who want to travel, hike, fish, etc. but suffer from a variety of health conditions.
[0091]
Technical experts acknowledge that biosensors with automatic power activation notification systems offer significant benefits for improving health care. Not only are patients warned about conditions that may cause physiological damage, but they also notify healthcare managers of up-to-date information about situations that go beyond predefined boundaries. For example, if a diabetic suffers a hypoglycemic shock, medical personnel (or a patient's immediate family) will take appropriate medical action accordingly. Such a system is particularly advantageous for single-dwellers and those with mobility difficulties. Systems with GPS (FIG. 16) are particularly valuable to travelers, as information about the location of the patient can be sent to the health care manager receiving the alarm.
[0092]
While the invention has been described with reference to at least one preferred embodiment, it will be apparent to one skilled in the art that the invention is not limited to such an embodiment. The scope of the invention should be construed solely by the appended claims.
[Brief description of the drawings]
FIG.
FIG. 3 shows an example of a competitive binding and swelling mechanism.
FIG. 2
FIG. 3 is a diagram showing an example of an analyte-binding molecule-containing copolymer.
FIG. 3
FIG. 3 is a partial cross-sectional elevation and diagram of a preferred embodiment of the present invention showing a biosensor that can be slightly submerged in a sample and implanted under a patient.
FIG. 4
FIG. 6 is a partial cross-sectional side view of another embodiment of the present invention showing a biosensor electrically connected to a computer.
FIG. 5
FIG. 4 is a partial cross-sectional side view of the preferred embodiment showing the analyte diffusing into the hydrogel and causing the hydrogel to swell, thereby causing the pressure transducer to send a signal to the computer via the telemeter.
FIG. 6
FIG. 4 shows a cross-sectional side view of the pressure transducer.
FIG. 7
1 shows a cross-sectional top view of a pressure transducer including a preferred circuit board with miniature diodes forming a diode quad bridge circuit. FIG.
FIG. 8
1 shows a schematic diagram of a preferred diode quad bridge circuit. FIG.
FIG. 9
FIG. 2 shows a block diagram of an automatic alarm system combined with wireless dialing.
FIG. 10
FIG. 10 is a schematic view of a power supply for each part of the automatic alarm system of FIG. 9.
FIG. 11
10 shows a schematic diagram of a signal conditioning circuit of the automatic alarm system of FIG.
FIG.
FIG. 10 shows a schematic diagram of a comparator and a control circuit of the automatic alarm system of FIG. 9.
FIG. 13
FIG. 10 shows a schematic diagram of a transceiver of the automatic alarm system of FIG. 9.
FIG. 14
FIG. 10 is a schematic diagram of a dial mechanism of the automatic alarm system of FIG. 9.
FIG.
FIG. 10 shows a block diagram of an automatic alarm system used in combination with an injection device that makes an injection in response to the automatic alarm system of FIG. 9.
FIG.
FIG. 2 shows a block diagram of a preferred automatic health alarm system.
FIG.
17 shows a diagram of a power supply circuit of the alarm system of FIG.
FIG.
17 shows a signal adjustment circuit of the alarm system of FIG.
FIG.
17 shows a circuit of the micro control unit of the alarm system of FIG.
FIG.
17 shows a GPS and a communication transmitter of the alarm system of FIG.
FIG. 21
FIG. 17 is a block diagram of a signal conditioner of the alarm system of FIG. 16.
FIG.
17 shows a block diagram of the micro control unit of the alarm system of FIG.

Claims (30)

A biosensor for measuring the concentration of an analyte molecule in a human body, wherein the biosensor comprises:
A polymer hydrogel comprising pendant moieties charged under physiological conditions;
An analyte binding molecule that can be immobilized in the hydrogel and bind to the free analyte;
An analyte molecule immobilized in the hydrogel,
A pressure measuring device for measuring the osmotic pressure of the hydrogel,
A biosensor comprising: 2. The biosensor of claim 1, wherein the hydrogel is contained in a rigid enclosure, wherein the enclosure is tested with a semipermeable membrane that allows free analyte molecules to diffuse from body fluids into the hydrogel. A biosensor having at least one open end capable of contacting the body fluid. The biosensor of claim 1, wherein the enclosure includes a diaphragm, the hydrogel is in contact with the diaphragm, and the diaphragm is operatively associated with a pressure transducer, and includes a pressure measuring device that measures the pressure of the diaphragm. Including biosensors. The biosensor of claim 1, further comprising reporting means operatively connected to a pressure measurement device for reporting a data signal reflecting a change in pressure of the hydrogel. 3. The biosensor of claim 2, wherein the enclosure has an open end sealed with a semi-permeable membrane that allows free analyte molecules to diffuse into the hydrogel. 5. The biosensor according to claim 4, wherein the enclosure is combined with heparin and polyethylene glycol. 5. The biosensor according to claim 4, wherein the enclosure is covered with a semi-permeable membrane and a biodegradable polymer on the membrane. 2. The biosensor according to claim 1, wherein the analyte binding molecules are antibodies, enzymes, membrane receptors, kinases, protein A, poly U, poly A, poly lysine, and riadin dyes, nucleosides, boronic acids, A biosensor selected from the group consisting of chiol, heparin, polysaccharide, Coomassie blue, Azure A, metal-bound peptides, proteins, and chelating media. 2. The biosensor according to claim 1, wherein the immobilized analyte is an antigen, a multifactor of an enzyme, an enzyme substrate, an enzyme inhibitor, IGG, sugar, carbohydrate, nucleic acid, nucleotide, nucleoside, stein, arginine. A biosensor selected from the group consisting of lysine, protamine, heparin, dyes, and metal ions. 2. The biosensor of claim 1, wherein the density of the charged pendant groups is selected to optimize the amount of hydrogel swelling in response to changes in free analyte molecule concentration. 2. The biosensor according to claim 1, wherein the degree of honey of the immobilized analyte molecule and the immobilized analyte binding molecule is selected so as to optimize the amount of swelling according to a change in the concentration of the free analyte molecule. Biosensor. 4. The biosensor according to claim 3, wherein the biosensor is selected from the group consisting of a pressure transducer, a piezoresistive pressure transducer, and a volume transducer. 5. The biosensor according to claim 4, further comprising computer means connected to the reporting means for receiving the data signal, the computer means comparing the data signal to a calibration curve and free analyte in the bodily fluid. A biosensor that calculates the concentration of a and produces a result signal indicating the concentration. 5. The biosensor according to claim 4, wherein said reporting means is a battery-operated telemeter and further comprises receiving means located at a remote location remote from the patient for receiving data signals. 15. The biosensor of claim 14, further comprising the computer means operatively connected to the receiving means, wherein the computer means compares the data signal with a calibration curve to calculate a concentration of the fluid free analyte. A biosensor that produces a result signal indicating the concentration. 15. The biosensor according to claim 14, further comprising computer means for comparing the measured concentration of the analyte with a predetermined safe range, and an alarm signal if the analyte concentration is outside the predetermined safe range. To send the biosensor. A method for measuring the concentration of free analyte in a solution, comprising the following steps:
A charged pendant moiety, an analyte molecule, and an analyte binding molecule covalently solidified are provided.
The open end formed by at least one semi-permeable membrane is a rigid enclosure that is capable of contacting the hydrogel with a test solution and includes a hydrogel.
Allow free analyte to diffuse into the hydrogel.
Knowing the concentration of free analyte, the hydrogel is continuously contacted with a series of calibration solutions.
The osmotic pressure is measured for each calibration solution to generate a calibration curve of osmolality versus analyte concentration.
The hydrogel is brought into contact with the solution to be tested.
Measure the result of the osmotic pressure.
The osmotic pressure results are compared with a calibration curve to determine the analyte concentration to be tested.
A method that includes 18. The method of claim 17, wherein the steps of measuring osmotic pressure comprise placing a pressure measuring device in a rigid enclosure, measuring the osmotic pressure by contact with a hydrogel, and transmitting the data signal. A method that can be completed with. 19. The method of claim 18, wherein the pressure sensing device includes a diaphragm in a rigid enclosure contacted with the hydrogel and a pressure transducer operatively associated to measure the pressure of the diaphragm. A health alarm system for alerting a remote party of a physiologically undesired condition of a patient, comprising: a biosensor for detecting a change in a physiological meter of the patient; a biosensor operatively connected to the biosensor; A system including a remote receiver for transmitting an alarm signal sensed by a sensor and selectively generating an alarm in response to a harmless change, receiving the alarm signal, and notifying a party at a remote location. 21. The alarm system of claim 20, wherein the transmitting device further comprises a dial for dialing a telephone and other portable radios in response to the alarm, and a receiver for receiving signals from the transmitter. 21. The alarm system of claim 20, further comprising a GPS operatively coupled to a signal indicating a patient's location and for transmitting an alarm signal to a remote receiver. 22. The alarm system of claim 21, wherein the infusion responds to an alarm from the biosensor and automatically releases the appropriate drug to the patient to return the patient's blood analyte level to within predetermined desired parameters. A system further comprising the device. 22. The alarm system of claim 21, wherein the system is in an implanted biosensor device that includes a hydrogel whose osmotic pressure changes in response to a selected change in analyte concentration. 26. The alarm system of claim 24, wherein the biogel of the biosensor is capable of automatically releasing a drug in response to a change in a selected analyte concentration. 21. The alarm system according to claim 20, wherein the biosensor is a glucos sensor. 21. The alarm system according to claim 20, wherein the biosensor is a cardiac rhythm sensor. A sensor for measuring the free molecule concentration of an analyte in a solution, wherein the sensor comprises:
An enclosure that is rigid and biocompatible and includes a closed end and an open end covered by a semi-permeable membrane;
A diaphragm disposed between the semi-permeable membrane and the open end of the enclosure,
A polymer hydrogel having a pendant moiety charged at physiological pH,
Here, the change in the osmotic pressure of the hydrogel sealed between the semipermeable membrane and the diaphragm accompanies the pressure applied to the diaphragm by the hydrogel,
An analyte binding molecule immobilized in the hydrogel,
Analyte molecules immobilized in the hydrogel,
A pressure transducer operatively engaged with the diaphragm;
Having a sensor. 29. The sensor of claim 28, further comprising a battery powered telemeter operatively engaged with the transducer. A method for measuring the concentration of free analyte molecules in a body fluid using a biosensor, comprising the following steps:
a) providing the following biosensor:
An enclosure having rigidity and biocompatibility, including a closed end and an open end covered with a semipermeable membrane,
The change in osmotic pressure of the hydrogel sealed between the semipermeable membrane and the closed end is accompanied by a change in pressure applied to the diaphragm by the hydrogel.
A polymer hydrogel having a pendant moiety charged at physiological pH,
The change in osmotic pressure of the polymer hydrogel disposed between the semipermeable membrane and the closed end is accompanied by the pressure applied to the diaphragm by the hydrogel,
An analyte binding molecule immobilized in the hydrogel, an analyte immobilized in the hydrogel, and osmotic pressure measurement means operatively engaged with the diaphragm to measure osmotic pressure and provide a data signal;
b) receiving a data signal and comparing the signal to a predetermined calibration curve of osmotic pressure to provide computer means for a free analyte molecule concentration value;
c) injecting the biosensor into a solution and allowing the free analyte molecules to sufficiently secure and equilibrate in the hydrogel;
d) reading the result of the density value produced by said computer means.

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