43

43
Ìèíè-îáçîðû
Ñèíòåòè÷åñêèå áèîìàòåðèàëû íà îñíîâå ïîëèìåðîâ
îðãàíè÷åñêèõ êèñëîò â òêàíåâîé èíæåíåðèè
À.Â. Âîëêîâ
 ïîñëåäíåå âðåìÿ âñå áîëüøèìè òåìïàìè èäåò ðàçâèòèå áèîòåõíîëîãèé, â òîì ÷èñëå è ìåäèöèíñêîé áèîòåõíîëîãèè. Èçó÷åíèå ìåõàíèçìîâ ðåãåíåðàöèè òêàíåé è îðãàíîâ,
ïîèñê íîâûõ òåõíîëîãèé, êîòîðûå ìîãëè áû âîññòàíîâèòü
óòðà÷åííóþ ôóíêöèþ êàêîãî ëèáî îðãàíà èëè ñèñòåìû, ïðèâåëè ê ïîÿâëåíèþ íîâûõ îòðàñëåé, âîçíèêøèõ íà ñòûêå
áèîòåõíîëîãèè è ìåäèöèíû – òêàíåâîé èíæåíåðèè, ðåãåíåðàòèâíîé ìåäèöèíû è îðãàíîãåíåçà. Ýòè íàóêè èçó÷àþò
ñîçäàíèå îðãàíîâ è òêàíåé de novo. Â èõ îñíîâå ëåæèò
ïðèíöèï òðàíñïëàíòàöèè êëåòîê íà ìàòðèöàõ-íîñèòåëÿõ.
Ìàòðèöà-íîñèòåëü èëè ìàòðèêñ – ïðåäñòàâëÿåò ñîáîé ñèíòåòè÷åñêèé èëè áèîëîãè÷åñêèé êîìïëåêñ äëÿ îáåñïå÷åíèÿ
ìåõàíè÷åñêîé ïðî÷íîñòè êîíñòðóêöèè ñ çàäàííûìè ñâîéñòâàìè, òðåõìåðíîãî îðèåíòèðîâàíèÿ íàíåñåííîé íà íåãî
êëåòî÷íîé êóëüòóðû. Îñíîâíûìè êðèòåðèÿìè áèîëîãè÷åñêè
ñîâìåñòèìîé ìàòðèöû äëÿ ñîçäàíèÿ òêàíåèíæåíåðíîé êîíñòðóêöèè äîëæíû áûòü: îòñóòñòâèå öèòîòîêñè÷íîñòè, ïîääåðæàíèå àäãåçèè, ôèêñàöèè, ïðîëèôåðàöèè è äèôôåðåíöèðîâêè, ïîìåùåííûõ íà åå ïîâåðõíîñòü êëåòîê, îòñóòñòâèå
ýôôåêòà ïîääåðæàíèÿ âîñïàëåíèÿ, â òîì ÷èñëå èììóííîãî,
äîñòàòî÷íàÿ ìåõàíè÷åñêàÿ ïðî÷íîñòü â ñîîòâåòñòâèè ñ íàçíà÷åíèåì, áèîðåçîðáèðóåìîñòü îáû÷íûìè ìåòàáîëè÷åñêèìè ïóòÿìè, íàïðèìåð, ôåðìåíòàòèâíûì èëè ãèäðîëèçîì
[1, 4-10, 15-18, 20, 22, 25-27].
Îäíèìè èç ïåðâûõ ìàòåðèàëîâ äëÿ òêàíåâîé èíæåíåðèè ñòàëè áèîäåãðàäèðóåìûå ñèíòåòè÷åñêèå áèîìàòåðèàëû íà îñíîâå ïîëèìåðîâ îðãàíè÷åñêèõ êèñëîò. Áëàãîäàðÿ
ñâîèì õèìè÷åñêèì è ôèçè÷åñêèì ñâîéñòâàì îíè ïîçâîëÿþò ïîëó÷àòü èç íèõ øèðîêèé ñïåêòð êîíñòðóêöèé, òàêèõ, êàê
ñåòêè, ïîðèñòûå ìàòðèöû, ïëåíêè è íåòêàíûå ìàòåðèàëû.
Ñåò÷àòûå êîíñòðóêöèè â îñíîâíîì èñïîëüçóþòñÿ êàê àðìèðóþùèé ìàòåðèàë â êîìáèíèðîâàííûõ ãðàôòàõ, òàê êàê
áîëüøèå â äèàìåòðå íèòè íå ïîçâîëÿþò êóëüòèâèðîâàòü íà
íèõ íåîáõîäèìîå êîëè÷åñòâî êëåòîê. Îíè ìîãóò ðàçìåùàòüñÿ
ñ áîëüøåé èëè ìåíüøåé ïëîòíîñòüþ òîëüêî â óçëàõ ðåøåòêè,
÷òî íåäîñòàòî÷íî äëÿ ïðåñëåäóåìûõ èññëåäîâàòåëåì öåëåé.
Íåòêàíûå ìàòåðèàëû ïðåäñòàâëÿþò ñîáîé ìàòåðèàë, ñõîäíûé ïî ñòðóêòóðå ñ âàòîé, òîíêèå íèòè, ïåðåïëåòåííûå ìåæäó
ñîáîé, îáåñïå÷èâàþò äîñòàòî÷íóþ ïðî÷íîñòü è ôèêñàöèþ
êëåòîê â 3D ïðîñòðàíñòâå. Ïîðèñòûå ìàòåðèàëû ïîëó÷àþò
ñìåøèâàíèåì ïîëèìåðîâ ñ òàê íàçûâàåìûìè ïîðîãåíàìè –
âåùåñòâàìè, êîòîðûå âûìûâàþòñÿ èíûìè, ÷åì ïîëèìåð,
ðàñòâîðèòåëÿìè, íàïðèìåð, NaCl è âîäà. PGA, ðàñòâîðåííûé â ñâîåì ðàñòâîðèòåëå (õëîðîôîðì), ñîåäèíÿåòñÿ ñ
íóæíûìè ïî ðàçìåðó êðèñòàëëàìè ñîëè. Ïîñëå òîãî, êàê óëåòó÷èâàåòñÿ õëîðîôîðì è çàòâåðäåâàåò ïîëèìåð, åãî îïóñêàþò â ðàñòâîðèòåëü äëÿ ïîðîãåíà (âîäó). Âîäà ðàñòâîðÿåò
ñîëü è â ìåñòàõ ïðèñóòñòâèÿ êðèñòàëëîâ îáðàçóþòñÿ ïîðû.
Ïîðèñòûå ìàòåðèàëû ïîäõîäÿò äëÿ ïîëó÷åíèÿ ýêâèâàëåíòîâ òàêèõ òêàíåé, êàê êîñòíàÿ è õðÿùåâàÿ. Ïëåíêè èç ïîëèìåðîâ îðãàíè÷åñêèõ êèñëîò ïîçâîëÿþò ïîëó÷èòü ëèøü 2D
êîíñòðóêöèè, êîòîðûå ìîãóò áûòü èñïîëüçîâàíû è äëÿ ñîçäàíèÿ ýêâèâàëåíòîâ ýïèòåëèàëüíûõ òêàíåé è êàê àðìèðóþùèé ýëåìåíò.
Áèîäåãðàäèðóåìûå ïîëèýñòåðû – ñåìåéñòâî áèîäåãðàäèðóåìûõ ìàòåðèàëîâ, ñîñòîÿùèõ èç öåïè ïîâòîðÿþùèõñÿ
îñòàòêîâ êîðîòêîöåïî÷å÷íûõ îðãàíè÷åñêèõ êèñëîò, òàêèõ, êàê
ìîëî÷íàÿ è ãëèêîëåëèåâàÿ.  ñîñòàâ ïîëèìåðà ìîæåò âõî-
äèòü êàê îäèí òèï êèñëîòíîãî îñòàòêà - PGA, PLA, òàê è èõ
ñî÷åòàíèå â ðàçëè÷íûõ ïðîïîðöèÿõ, íàïðèìåð PGLA 30/70.
 ìåäèöèíñêîé ïðàêòèêå ýòè ïîëèìåðû íàøëè øèðîêîå
ïðèìåíåíèå â âèäå øîâíîãî ìàòåðèàëà, àðìèðóþùèõ êîíñòðóêöèé, ñåòîê äëÿ ãåðìèíîïëàñòèêè. Ïåðâûì êîììåð÷åñêèì
ïðîäóêòîì áûë øîâíûé ìàòåðèàë ïîä íàçâàíèåì Dexon TM è
Vicryl (American Cyanamid Co.).
PGA - òâåðäûé, òåðìîïëàñòè÷íûé ìàòåðèàë, òåìïåðàòóðà
ïëàâëåíèÿ 225 ãðàäóñîâ. Áëàãîäàðÿ âûñîêîé êðèñòàëëè÷íîñòè (40-50%) îí íå ðàñòâîðèì â áîëüøèíñòâå îðãàíè÷åñêèõ
ðàñòâîðèòåëåé. Áèîäåãðàäàöèÿ ïîëèìåðà ïðîèñõîäèò ïóòåì
ãèäðîëèçà äî óãëåêèñëîãî ãàçà è âîäû (ðèñ. 1), ñ íåêîòîðûì
ïîâûøåíèåì pH îêðóæàþùèõ òêàíåé [11], à òàêæå âûâîäèòñÿ
â âèäå ìîíîìåðà. Ìåõàíè÷åñêàÿ ïðî÷íîñòü ñîõðàíÿåòñÿ ìàêñèìóì äî 21 – 29 äíÿ, ñ ïîòåðåé ìàññû äî 40% ê ýòîìó ïåðèîäó. Ìàòåðèàë íå îáëàäàåò öèòîòîêñè÷åñêèìè ñâîéñòâàìè,
ïîääåðæèâàåò àäãåçèþ è ïðîëèôåðàöèþ êëåòîê, à òàêæå â íåêîòîðîé ñòåïåíè îáëàäàåò îñòåîèíäóêòèâíûìè ñâîéñòâàìè. Èç
ýòîãî ìàòåðèàëà ìîãóò áûòü èçãîòîâëåíû ìàòðèöû ðàçëè÷íîé
ñòðóêòóðíîé îðãàíèçàöèè (ðèñ. 2, 3).
Ðèñ. 1. Ñõåìà ãèäðîëèçà PGLA. Ïðîäóêòû ãèäðîëèçà
íå òîêñè÷íû è ó÷àñòâóþò â öèêëå Êðåáñà ñ îáðàçîâàíèåì
óãëåêèñëîãî ãàçà è âîäû
Ñåìåéñòâî PLA – âêëþ÷àåò ïîëèìåðû èç îñòàòêîâ ìîëî÷íîé êèñëîòû, ïðåäñòàâëåíî öåëîé ïëåÿäîé ïðîäóêòîâ,
îòëè÷àþùèõñÿ ñâîèìè ñâîéñòâàìè, áëàãîäàðÿ èçîôîðìàì
è êîëè÷åñòâó ìîëåêóë â ïîëèìåðå (òàáë. 1). Ïî ñâîèì õèìè÷åñêèì, ôèçè÷åñêèì è áèîëîãè÷åñêèì ñâîéñòâàì ýòîò ïîëèìåð áëèçîê ê PGA, îäíàêî óñòóïàåò åìó â ïðî÷íîñòè è ñêîðîñòè
ãèäðîëèçíîé ðåçîðáöèè, êîòîðàÿ ó íåãî íèæå.
Ðèñ. 2. Âîëîêíèñòàÿ
(íåòêàíàÿ) ìàòðèöà
èç PGA. Ñêàíèðóþùàÿ
ýëåêòðîííàÿ
ìèêðîñêîïèÿ (ÑÝÌ)
Ðèñ. 3. Ãóá÷àòàÿ
ìàòðèöà èç PLA. ÑÝÌ
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 2, 2005
44
Ìèíè-îáçîðû
Íàèëó÷øèìè æå ïîêàçàòåëÿìè îáëàäàþò ñîïîëèìåðû PGA
è PLA (PDLA) – PGLA (PGDLA).  çàâèñèìîñòè îò ïðîöåíòíîãî
ñîîòíîøåíèÿ ìîëî÷íîé è êëèêîëåâîé êèñëîò ìîæíî ìåíÿòü
ñâîéñòâà ïðîäóêòà, íàïðèìåð, ïëàñòè÷íîñòü, ïðî÷íîñòü, ñðîê
áèîäåãðàäàöèè è äð.  òå÷åíèå äëèòåëüíîãî âðåìåíè ïðîèçâîäèëîñü òåñòèðîâàíèå ýòèõ ïîëèìåðîâ ñ ðàçëè÷íûìè òèïàìè
êëåòîê. Áûëî óñòàíîâëåíî, ÷òî äàííûå ìàòåðèàëû ìîãóò ñëóæèòü ìàòðèöåé äëÿ ñîçäàíèÿ òêàíåèíæåíåðíûõ êîíñòðóêöèé
ìûøå÷íîé, õðÿùåâîé, êîñòíîé è ýïèòåëèàëüíîé òêàíåé. Îñîáîå
ìåñòî ïîëèìåðû íà îñíîâå ìîëî÷íîé è êëèêîëåâîé êèñëîò
çàíÿëè â ðåêîíñòðóêòèâíîé õèðóðãèè è ðåãåíåðàòèâíîé ìåäèöèíå. Îíè èñïîëüçóþòñÿ äëÿ âîññòàíîâëåíèÿ äåôåêòîâ êîñòíîé è õðÿùåâîé òêàíè â êëèíè÷åñêîé ïðàêòèêå [1, 6-10, 15,
19, 25-27] è áûëè îäîáðåíû FDA (Àãåíòñòâîì ïî êîíòðîëþ
çà ëåêàðñòâàìè è ïðîäóêòàìè ïèòàíèÿ ÑØÀ) êàê áåçîïàñíûå
ìàòåðèàëû äëÿ òêàíåâîé èíæåíåðèè [28].
Ïîëèêàïðîëàêòîí (PCL) – åùå
îäèí ïðåäñòàâèòåëü ñåìåéñòâà ïîëèýñòåðîâ (ðèñ. 4). Ïîëóïðîçðà÷íûé ïîëèìåð ñ òåìïåðàòóðîé ïëàâëåíèÿ ìåíåå 60 ãðàäóñîâ (ñì. òàáë. 1). Ñðîê
áèîäåãðàäàöèè ñîñòàâëÿåò îêîëî 3
Ðèñ. 4.
Ôîðìóëà PCL
ëåò. Ýòè ñâîéñòâà ïîçâîëÿþò ïîëó÷àòü
äîñòàòî÷íî ïëàñòè÷íûå êîíñòðóêöèè, îáåñïå÷èâàþùèå äëèòåëüíóþ ìåõàíè÷åñêóþ ïðî÷íîñòü è ïîääåðæêó. Êðîìå òîãî,
ïîëèìåð îáëàäàåò îò÷åòëèâûìè îñòåîèíäóêòèâíûìè ñâîéñòâàìè, è íà íåì áåñïðåïÿòñòâåííî àäãåçèðóþòñÿ ìàëîäèôôåðåíöèðîâàííûå ìåçåíõèìàëüíûå êëåòêè (ðèñ. 5).
Êîììåð÷åñêèé ïðåïàðàò, ïðèìåíÿåìûé â çäðàâîîõðàíåíèè,
MONOCRYL, Ethicon Inc. – øîâíûé ìàòåðèàë äëÿ õèðóðãèè.
Ðèñ. 5.
Ôèáðîáëàñòîïîäîáíûå
êëåòêè, àäãåçèðîâàâøèå
â óñëîâèÿõ êóëüòóðû
ê ãðàíóëàì êàïðîëàêòîíà (À)
è ê ïîðèñòîìó
êàïðîëàêòîíó (Â). ÑÝÌ
Òàáëèöà 1. Ñâîéñòâà áèîäåãðàäèðóåìûõ ïîëèìåðîâ
Ïîëèìåð
Òåìïåðàòóðíûå è ìåõàíè÷åñêèå
ñâîéñòâà
t ïëàâëåíèÿ
(°C)
ëèçàöèè
(°C)
ïðî÷íîñòü
Âðåìÿ
äåãðàäàöèè
(ìåñÿöû)
t êðèñòàë-
Ïðîäóêòû
äåãðàäàöèè
Ïðèìå÷àíèÿ
Poly(glycolic acid), PGA
225—230
35—40
7,0 GPa
6—2
Glycolic acid, CO2,
H2O
Poly(l-lactic acid), PLLA
173—178
60—65
2,7 GPa
>24
l-lactic acid, CO2,
H2O
Poly(d,l-lactic acid), PLDA
Àìîðôíûé
55—60
1,9 GPa
12—16
d,l-lactic acid, CO2,
H2O
Poly(d,l-lactic-co-glycolic
acid)(85/15), PDLGA85/15
Àìîðôíûé
50—55
2,0 GPa
5—6
d,l-lactic acid b
glycolic acid, CO2,
H2O
Poly(d,l-lactic-co-glycolic
acid)(85/15), PDLGA85/15
Àìîðôíûé
50—55
2,0 GPa
4—5
d,l-lactic acid è
glycolic acid, CO2,
H2O
Poly(d,l-lactic-co-glycolic
acid)(85/15), PDLGA85/15
Àìîðôíûé
45—50
2,0 GPa
3—4
d,l-lactic acid è
glycolic acid, CO2,
H2O
Poly(d,l-lactic-co-glycolic
acid)(85/15), PDLGA85/15
Àìîðôíûé
45—50
2,0 GPa
I—2
d,l-lactic acid è
glycolic acid, CO2,
H2O
Poly(capro- lactone), PCL
58—63
60—65
0,4 GPa
>24
Caproic acid, CO2,
H2O
Òêàíåñîâìåñòèìûé
ïîëèìåð ñ íèçêîé
öèòîòîêñè÷íîñòüþ
Poly(propylene fumarate)
—
—
Fumaric acid,
propylene glycol
è poly(acrylic acidco-fumaric acid)
Âûçûâàåò
óìåðåííûå
ìåñòíûå
âîñïàëèòåëüíûå
ðåàêöèè, ðåàêöèþ
íà èíîðîäíîå
òåëî, ôèáðîç
Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 2, 2005
2—30 MPa  çàâèñèìîñòè îò
ôîðìóëû,
ìîæåò
äîñòèãàòü
íåñêîëüêî
ìåñÿöåâ
Áîëüøîå
êîëè÷åñòâî
èññëåäîâàíèé
ïîêàçàëè, ÷òî
äàííûå
ïðåïàðàòû íå
èìåþò
âûðàæåííîé
öèòîòîêñè÷íîñòè,
õîòÿ è ñíèæàþò ðÍ
ñðåäû âî âðåìÿ
ãèäðîëèçà.
Ïðåèìóùåñòâî –
ïîëíûé ãèäðîëèç
äî óãëåêèñëîãî
ãàçà è âîäû,
îáû÷íûìè
ìåòàáîëè÷åñêèìè
ïóòÿìè
Ìèíè-îáçîðû
Ïîëèïðîïèëåí ôóìàðàò – äîñòàòî÷íî ïðî÷íûé, ïëàñòè÷íûé ïîëèìåð, òàêæå ïðåäíàçíà÷åííûé äëÿ äëèòåëüíîé ïîääåðæêè ìåõàíè÷åñêîé ïðî÷íîñòè êîíñòðóêöèè â òå÷åíèå êàê
ìèíèìóì 200 äíåé. Áèîäåãðàäàöèÿ ïðîèñõîäèò ôåðìåíòàòèâíûì ãèäðîëèçíûì ïóòåì, íî, â îòëè÷èå îò ïðåäûäóùèõ
ìàòåðèàëîâ, íå âëèÿåò íà pH îêðóæàþùèõ òêàíåé ïðè áèîäåãðàäàöèè. Ê ñóùåñòâåííûì íåäîñòàòêàì ìîæíî îòíåñòè
îáðàçîâàíèå ôèáðîçíîé êàïñóëû êàê îòâåò íà èíîðîäíîå
òåëî, ÷òî îêàçûâàåòñÿ íåáëàãîïðèÿòíûì â ðÿäå ñèòóàöèé
[12, 14].
Òàêèì îáðàçîì, â íàñòîÿùåì îáçîðå ïðåäñòàâëåíû
îñíîâíûå ðàçíîâèäíîñòè îðãàíè÷åñêèõ ïîëèìåðíûõ áèîäåãðàäèðóåìûõ ìàòåðèàëîâ äëÿ òêàíåâîé èíæåíåðèè.
Íàèáîëåå ÿðêèìè ïðåäñòàâèòåëÿìè, çàðåêîìåíäîâàâøèìè
ñåáÿ êàê â ýêñïåðèìåíòàëüíûõ, òàê è â êëèíè÷åñêèõ èññëåäîâàíèÿõ, ÿâëÿþòñÿ ïîëèýôèðû ìîëî÷íîé è êëèêîëåâîé
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êèñëîò. Êðîìå òîãî, äàííûå ìàòåðèàëû îäîáðåíû FDA êàê
áåçîïàñíûå ìàòåðèàëû äëÿ òêàíåèíæåíåðíûõ êîíñòðóêöèé.
Îäíàêî èõ íåäîñòàòêè, òàêèå, êàê ïîâûøåíèå pH îêðóæàþùèõ òêàíåé ïðè ãèäðîëèçå, íåäîñòàòî÷íàÿ ìåõàíè÷åñêàÿ
ïðî÷íîñòü, îãðàíè÷èâàþò èñïîëüçîâàíèå è íå ïîçâîëÿþò èõ
ïðèìåíÿòü êàê óíèâåðñàëüíûé ìàòåðèàë äëÿ ìàòðèö è ïîäëîæåê. Íåñìîòðÿ íà íåêîòîðûå ìèíóñû, åùå â òå÷åíèå äëèòåëüíîãî âðåìåíè îíè ñìîãóò ñîñòàâèòü çíà÷èòåëüíóþ êîíêóðåíöèþ äðóãèì ïîëèìåðàì. Ê ñåãîäíÿøíåìó äíþ ìàòðèöû
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Êëåòî÷íàÿ òðàíñïëàíòîëîãèÿ è òêàíåâàÿ èíæåíåðèÿ ¹ 2, 2005