SynDaver: sostituire gli animali in chirurgia e nei test di dispositivi medici

Da SynDaver™ Labs:

Validazione dei progetti
Le parti sintetiche del corpo umano SynDaver™ e i tessuti umani sintetici SynTissue™ sono stati originariamente progettati per l’utilizzo nella verifica dei dispositivi medici e nel processo di progettazione e convalida. Tali studi sono a volte chiamati prove simulate di impiego in quanto implicano la valutazione della funzionalità del dispositivo, la sicurezza e l’efficacia in una simulazione dell’ambiente (umano) in cui si attua il suo reale utilizzo. Gli animali vivi sono spesso impiegati in questi test perché sono stati tradizionalmente il miglior modello disponibile per simulare la complessità di anatomia e fisiologia umana. Tuttavia, i prodotti SynDaver™ e SynTissue™ possiedono una serie caratteristica unica che consente loro di essere sostituiti di animali vivi, cadaveri umani, e altri modelli in questi test.

Tessuti Sintetici Umani
I prodotti SynDaver™ Labs possono essere dei sostituti per i modelli tradizionali in tali prove per la natura della loro somiglianza con l’ambiente reale d’utilizzo. Questa somiglianza è caratterizzata da un accostamento di proprietà meccaniche, fisiche e chimiche, la geometria e l’interazione organo-organo. Al livello più semplice, singoli organi sintetici (muscolo retto femorale, piccolo intestino, aorta addominale, ecc) sono costruiti in modo da replicare la geometria (forma, diametro, spessore della parete, ecc) di una particolare porzione dell’anatomia del target. Inoltre, i singoli tessuti analoghi sintetici utilizzati per fabbricare questi componenti sono formulati in modo tale da presentare le proprietà chimiche e fisiche (acqua, fibre e contenuto di sale, forza o modulo a taglio, coefficiente di attrito statico o dinamico, energia superficiale, proprietà dielettriche, capacità termica, porosità, ecc) che imitano le proprietà del tessuto bersaglio. Infine, i componenti del modello sono assemblati in modo tale che l’interazione tra i componenti adiacenti è simile a quella attesa nel tessuto bersaglio. Cioè, la parte del corpo è progettata in modo che le proprietà interfacciali come il coefficiente di attrito dinamico (inter- organo) e gli allegati meccanici imitino quelli esposti nell’anatomia del target.

Per progettare queste parti del corpo sintetiche, l’anatomia da simulare deve essere concettualmente divisa in sezioni discrete che formeranno la base del modello. Per esempio, un modello molto semplice dell’aorta toracica potrebbe essere separato in due parti: la prima composta dell’arteria stessa e la seconda dai tessuti circostanti.

Almeno due (e forse molti di più) tessuti analoghi sarebbero quindi progettati per la fabbricazione di questo modello. In questo caso, sarebbe necessario un tessuto analogo per il componente arteria e l’altro sarebbe usato per costruire il componente del tessuto di sostegno. Naturalmente, in pratica i modelli richiedono più di due componenti del tessuto per simulare accuratamente la risposta dell’anatomia del target, e ciascuno di questi componenti tipicamente utilizzerebbe tre o più analoghi tissutali. Le arterie elastiche SynDaver™, ad esempio, utilizzano analoghi tissutali separati per intima, media e avventizia, e ciascuno di questi strati è composto singolarmente da più materiali.

Tessuti analoghi sintetici
I tessuti sntetici umani SynDaver™ Labs sono progettati per simulare una o più proprietà di uno specifico tessuto bersaglio, e al fine di sviluppare ogni analogici due set di ingressi di progettazione (proprietà modellata e sorgenti dei dati) devono essere definiti. Le proprietà modellate sono determinate dando priorità alla chimica, fisica, meccanica, e ad altre proprietà che l’analogico deve mimare, e in senso stretto queste possono variare a seconda del tipo di dispositivo in fase di test o procedura simulata, dell’anatomia di destinazione, e dell’obiettivo dell’esercizio . Ad esempio, se un obiettivo è determinare il danno intimale causato da un dispositivo di tracciamento attraverso l’arteria femorale, la resistenza all’abrasione sarebbe inclusa nella lista di target per i tessuti analoghi. Inoltre , se si era anche voluta simulare la tendenza del dispositivo di penetrare l’arteria allora anche la resistenza alla penetrazione o la resistenza al taglio del guscio (una proprietà legata alla meccanica) sarebbero incluse nella lista. Qualsiasi numero di proprietà può essere aggiunto a questa lista . Tuttavia, via via che il numero di proprietà modellate cresce diventa progressivamente, diventa più difficile soddisfare simultaneamente tutti i requisiti di progettazione. Infatti, se un particolare tessuto o organo devono imitare più di tre proprietà meccaniche sarà tipicamente necessario impiegare più analoghi per soddisfare i requisiti di progettazione.

La fonte dei dati che costituirà la base di progettazione per i nuovi tessuti analoghi deve essere definita. Innanzitutto, si deve decidere se gli analoghi saranno formulati per imitare le proprietà di tessuti umani o tessuti animali (vivi o morto). Una volta che tale questione è risolta, i dati rilevanti possono essere ricavato dalla letteratura oppure generati direttamente eseguendo le prove appropriate su campioni di tessuto. […] I risultati delle prove meccanico-fisiche sono altamente dipendenti dalle condizioni di prova, e controllando il test dà il controllo di progettazione su tali condizioni. Ancora più importantemente tuttavia, ciò consente agli analoghi tissutali candidati di essere testati e successivamente convalidati esattamente sotto le stesse condizioni del tessuto bersaglio.

Riportiamo in aggiunta l’abstract di un brevetto precedente al completamento di questa tecnologia, che già mostrava le sue potenzialità di sostituire gli animali in questo campo:

[Christopher Sakezles. Models and methods of using same for testing medical devices. US 7993140 B2]

Full Text: http://www.google.com.br/patents/US7993140

Abstract:

Indicati nel presente documento vi sono modelli anatomici sintetici che sono progettati per consentire l’uso di test simulati da parte di aziende di dispositivi medici, progettisti di dispositivi medici, singoli inventori, o altri soggetti interessati al funzionamento dei dispositivi medici. Questi modelli sono gli unici in possesso di un livello di complessità che permette loro di essere sostituti tanto di un animale vivo, che di un cadavere animale, o di un cadavere umano nel testare questi dispositivi. Questi modelli sono inoltre caratterizzati da una somiglianza di geometria, singole proprietà fisiche dei componenti, e le proprietà interfacciali componente-a-componente con il tessuto e l’anatomia del bersaglio appropriato.

Nel testo:

BRIEF SUMMARY OF THE INVENTION

 

The use of a poorly conceived model in development testing will lead to reduced product quality, increased development costs, and greatly lengthened product timelines. Fortunately, these failures may be avoided by employing an intelligent development scheme in conjunction with a high quality model. Accordingly, the subject invention pertains to complex synthetic anatomical models that are designed to enable simulated use testing by medical device companies, medical device designers, individual inventors, or any other entity interested in the performance of medical devices. These models are unique in possessing a level of complexity that allows them to be substituted for either a live animal, an animal cadaver, or a
human cadaver in the testing of these devices. These models are further characterized by a similarity of geometry, individual component physical properties, and component-to-component interfacial properties with the appropriate target tissue and anatomy.

The model embodiments of the subject invention may serve as a highly sophisticated bench top model that is designed to be used by medical device developers both early and late in the development process. These models mimic not only the geometry of the target anatomy, but also the physical properties of the living tissues that contact the device.

One important feature of certain embodiments of the subject invention is the implementation of synthetic analog materials that can simulate the physical properties of living tissues. These analogs are in most cases hydrogel materials that are designed on the basis of physical tests performed on actual target tissues. For example, a particular analog material might be designed to exhibit a tensile strength close to 10 kPa to mimic a target tissue that exhibits a tensile strength of 10 kPa. One or more components made from these analog materials are then assembled into a configuration that mimics both the size and geometry of the target organ. The resulting bench top model may therefore be described as a synthetic organ, and it will respond to certain physical stimulus (the device) in a fashion that is similar in many respects to the actual organ.

Model embodiments of the subject invention may be nearly as simple to use as a bench top fixture, but provide feedback that is superior in many respects to cadaver tests, animal studies, and even human clinical trials. In fact, a prototype device may be tested not just in terms of device performance, but also in terms of effect on the target anatomy. This is possible because the device interfacing portion of the model is removable, allowing a quasi-histological examination of the target anatomy after each use. In addition, because the models are artificial and mass produced, multiple tests may be performed either under identical conditions or by altering only the test parameters (temperature, flow, contact angle, etc) desired. This capability helps to eliminate the statistically confounding effect of model variation that plagues cadaver, animal, and human subject studies, and also enables the use of designed experiments to explore device-tissue interactions and interactions between various design parameters.

Some embodiments of the subject invention have several advantages over typical bench top fixtures. Some fixtures in use today may be designed to mimic the overall size and geometry of a particular target tissue, and the best of these are also designed to work at body temperature in the presence of fluids. However, the use of engineering materials in the construction of these models make them dissimilar to the target anatomy in a profound way. This calls into question the value of any data collected, even when designed experiments are employed in addition, these models may only be used to predict device performance, not the effect of the device on the target tissue.

In contrast, some embodiments of the subject invention enable a potentially large number of tests to be completed in an environment that is both geometrically and mechanically similar to the target anatomy. These tests may be performed by an engineering technician on a lab bench, but the tests still produce very high quality data. Also, because this data may be generated early in the development cycle, design errors are discovered sooner, leading to a shorter cycle and a reduced development budget. Further, unlike traditional bench top testing, use of embodiments of the subject invention allows the user to predict how a device will actually function in the human body, and since the effect of the device on the target tissue can be predicted by way of the quasi-histological examination, the risk to the patient may be predicted from the beginning of the process.

Use of embodiments of the subject invention also have several advantages over cadaver studies. Cadaver models provide a fairly accurate representation of size and geometry, but the mechanical properties of the target anatomy are altered by death of the subject and by the required tissue preservation techniques. It is impossible to use these models at normal body temperature or in the presence of fluids, and they cannot be employed to accurately predict the physical effect of the device on the target tissue. An educational institution must almost always be contracted (along with a principal investigator) to perform the study, and since the specimens are difficult to source it is common to run only a single test. Biohazards are an additional risk.

In contrast, use of embodiments of the subject invention enables the generation of animal study quality data (in a much greater quantity) using a simple bench top setup that may be used by an engineering technician. The need to contract with research facilities, employ costly medical practitioners, and also any exposure to biohazards is eliminated. In addition, these models may be used at body temperature in the presence of any real or simulated physiologic fluid, and since the device contacting portions of the model may be removed and replaced, an unlimited number of tests may be performed.

Models according to embodiments of the subject invention have several advantages over live animal models. As previously stated, the quality of data produced in these studies can be very high, particularly if the proper animal model is selected, the device and protocol are well designed, and the correct number (more is always better) of animals is employed. However, a registered facility must be contracted to run the study and care for any animals purchased. A surgeon must be retained to perform the required procedures, generate the study protocol, and to ensure approval from the animal care and use committee of the facility. The services of a veterinarian, anesthesiologist, and surgical aide are also required. Needless to say, these studies are very expensive and grow ever more costly as the number of animals is increased. The cost of discovering a design flaw at this stage is very high, possibly causing modification, termination, or repetition of the study. Biohazards are also a significant risk.

In effect, the inclusion of models according to the subject invention in the development process allows the collection of animal study quality performance data (Table II) at a risk level that is normally associated with bench top studies. In fact, by employing this technology early on in the development process, vital feedback on device performance may be collected before erroneous assumptions can adversely affect the design. This capability not only reduces the probability of costly late stage design changes, but also shortens the project timeline and reduces the overall cost of development. In addition, these models may be used in an ordinary laboratory by engineering personnel. The need to own or contract with research facilities, pay for costly medical practitioners, and absorb risks associated with biohazard exposure are all eliminated. An innocent life (the animal) is also spared.

[…]

The inability to test prototype devices on human subjects is the reason medical device developers resort to animal studies in the first place. Still, animal models suffer from a whole range of unique problems, including the many deviations between human and animal anatomy and physiology, the confounding effects of variation between individual animals, and the unpredictability that arises from using a model that is extraordinarily complex.

Animal models may include live canine, porcine, or bovine specimens, among others. While these animals do offer an in vivo environment, their anatomy and physiology differs significantly from that of a human. The great expense and specialized
facilities required limit their in-house use. Reproducibility may also be an issue as both inter- and intrasubject variability are difficult to control. Additional considerations include contention with the Animal Welfare Act, the significant expense associated with contracting regulated facilities and medical practitioners, and the risks related to handling biohazardous materials.

[…]

The model embodiments of the subject invention create a test environment similar in many ways (mechanical properties, physical properties, temperature, flow rate, viscosity, etc) to that of a living animal. In addition, individual tests may be repeated as many times as desired under identical or (if desired) altered conditions. Also, the tissue-contacting portion of the model may be removed to allow a quasi-histological examination to be performed after each test, an important feature that allows the engineer to predict the tendency of a particular device to inflict injury (or other effect) on the patient.

A study employing the models of the subject invention allows the generation of data that is comparable, and in some ways superior to that of an animal study. Furthermore, since these studies employ a reproducible model, the statistically confounding effect of variation between animals is eliminated. The ability to perform truly reproducible tests allows interactions between the device and the model, as well as interactions between multiple design parameters to be evaluated, a task which is nearly impossible with an animal study. In addition, the expense related to the purchase and housing of animals, contracting registered facilities, and retaining medical practitioners is eliminated. The risks associated with biohazards are also eliminated and a number of innocent animals are spared.