ISO TC150/SC2/WG7 Workgroup on Absorbable Cardiovascular Devices
Tests for local effects after implantationへの要請事項あるいは意見がいくつか記載されていま10993-6すのでその概要を以下に記します。 ○degradationの定義についていくつかコメントがついている。 ○心臓血管系への埋植なので，それらに特有な技術的考慮が必要としている。例えば，埋植部位を明確にするマーカーは，金製のバンドを利用することが良いとしている。また，陰性対照の埋植や偽手術が必要かどうかも考慮して欲しいとしている。 ○Section 5.3    -    Test periods吸収性材料の評価については，吸収時期以上に長期の実験が期待されている。完全な分解，吸収そして正常組織・機能への回復が無い状態でも，それらのデータは埋植後の局所影響を評価するための資料として十分かもしれない。もちろん，少なくとも完全吸収された以降に１つのデータが得られることが望ましいのですが、組織学的に変化の無い状態あるいは定常状態へ移行したと90％以上判断されるのであれば,吸収性材料の生体内分解性の推定として許容されることを考慮すべきです。 ○5.5.3 Implant retrieval and tissue sample collection心臓血管系への埋植なので，埋植物や分解産物が別の部位へ移動する可能性についても言及の必要がある。また，分解産物が別の組織で代謝され，全身性あるいは他の遠位組織で何らかの影響を尾こぼす可能性に言及すべき。 ...
10993-6
Tests for local effects after implantation   の主たる変更点は以下のとおりです。
Annex   Aに追加
In the absence of complete degradation, absorption, and restoration to normal tissue structure and function, the overall data collected may be sufficient to allow characterization of local effects after implantation.    While acquisition of at least one data point after complete device absorption is highly desirable, in vivo degradation profiling of each respective absorbable materials, which can be interpreted as components, to a quiescence or steady state histological resolution can be considered acceptable. Annex  E E.1 Generalを追加した。元々は， Test animals and implant siteに記載されていた内容を移動した。たぶん，下線部分を強調したかったのだと思います。以下原文With typical bone, muscle and subcutaneous implant designs, test and controls materials are typically implanted in the same animal.   However, with materials placed in neural tissues, tissue responses are not localized but may affect a wide region and may even manifest across the brain hemisphere. Investigators observed that medical device implants can induce hydrocephalus in EXAMPLE patients.[43] In experimental animal models of brain injury, microglia can be induced to migrate along the myelinated tracts of the corpus callosum to the contralateral hemisphere (REFERENCE). Therefore, the implant-activated microglia may migrate across the corpus callosum and influence the biological response on the contralateral side. This could serve to exacerbate the response to a negative control implanted site resulting in a shift in the baseline response.    In addition, influence from the contralateral hemisphere injury could exacerbate the injury response at the test article implanted site.  In the first case, one could shift the normal baseline response to a negative control material resulting in a false negative for the test article.   In the second case, the response occurring in the contralateral hemisphere could exacerbate the response to a "test article" leading to a false positive。 Given the small number of animals required for test, the ability to control for such factors and to decrease the variability of the data is critical.    As such, it is useful to have separate test and control treated animals with one implant sample in each brain.   Sex differences have been documented in responses that may be relevant to evaluation of response to implantation devices (see Bibliography [44], [45] and [46]).   To control for potential variability due to sex differences, similar numbers of males and females of each species and strain should be used for the study. E2に以下が追加。E2のneural tissueがbrain tissueに語句変更。理由不明。 An electrode implanted into the brain and dura mater replacement. EXAMPLE (REFFERENCES) Generalの内容が一部変更された。構成が変えられただけで，内容は変わっていないと判断されE4.1ろ。 For implantation studies, a non-degradable control samples with an acceptable minimal local response should be evaluated at one time point provided an acceptable scientific justification which should address the following: the control material (such control is generally indicated as a 'negative' control), implantation duration and a historical control data. In cases where the test article is expected to elicit more than a minimal response, an alternative control using a comparative material with an acceptable response may be selected, a comparative control material known to evoke an acceptable tissue response (e.g., cyanoacrylates, dura sealants). The selection of the control material should be justified and documented. E4.2  Implant  sizeが独立E.4.3 Test animals and implant siteの一部がE.1Generalとして独立したので，その残りの文章で構成。 E.4.4 Each animal should be weighed prior to implantation and periodically thereafter.下線部が追加。 13行ほどが削除され，以下の一行に変更。 An alternative control method for fixation of the animals, may be considered. E.4.5 3行目and transientの後に,記載されていた化学物質名   MPTPとdomoic   acidが削除されている。 E.4.6 2段落目に下記の一文追加。 As damage to neural tissue can result in abnormal behaviour, clinical observations should be included in the evaluation of the effects of brain implants. 3段落目最後から2文章目が変更• ・ or bizarre behavior (.e.g., self-mutilating, walking backwards) shall be recorded for any behavioral or neurological signs.  Particular attention to behavior and neurological signs for which time of first observation and subsequent progression or resolution are recorded. • ・ ・ shall be recorded.    For the behavior and neurological signs time of first observation and subsequent progression or resolution should be recorded.
E.4.7
3段落目のsuch as Hematoxylin and Eosin (H&E), and specialized histological stains that will detect neuronal ↓ such as Hematoxylin and Eosin (H&E) is not sufficient. In addition specialized histological stainsと変更。削除as would occur with reliance on one general histological stain.   はその後に, Also autofluorescence can be an indication for neuronal damage. [REFERENCE via Joe Carraway]が追加。 Tableの下に次の一文が追加。 Not for all species all specific antibodies are available. ↓