CN106333965B - A kind of preparation and treatment method for treating osteoarthritis - Google Patents
A kind of preparation and treatment method for treating osteoarthritis Download PDFInfo
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Abstract
本发明涉及一种治疗骨性关节炎的制剂，该制剂采用人羊膜间充质干细胞和0.01～2mg/mL分子量为20～2200KD的透明质酸溶液混匀，细胞密度为1×106～1×109个/mL，该制剂可治疗骨性关节炎和软骨损伤，也可在该制剂中加入药学上可接受的载体。治疗方法为采用局部注射hAMSCs细胞制剂0.01～1mL到骨性关节炎哺乳动物模型的关节腔内，每3～5周进行局部注射等量的hAMSCs细胞制剂，连续2～5次。该细胞制剂可显著抑制病灶炎症、促进糖胺聚糖和II型胶原蛋白的表达、修复受损软骨组织，疗效显著。
The invention relates to a preparation for treating osteoarthritis. The preparation adopts human amniotic membrane mesenchymal stem cells and 0.01-2 mg/mL hyaluronic acid solution with a molecular weight of 20-2200 KD to mix uniformly, and the cell density is 1×10 6 -1 ×10 9 /mL, the preparation can treat osteoarthritis and cartilage damage, and a pharmaceutically acceptable carrier can also be added to the preparation. The treatment method is to locally inject 0.01-1 mL of hAMSCs cell preparation into the joint cavity of a mammalian model of osteoarthritis, and locally inject the same amount of hAMSCs cell preparation every 3 to 5 weeks for 2 to 5 consecutive times. The cell preparation can significantly inhibit the inflammation of the lesions, promote the expression of glycosaminoglycan and type II collagen, repair damaged cartilage tissue, and has a remarkable curative effect.
Description
Technical field
The invention belongs to regenerative medicine and osteopathy field, in particular to a kind of preparation for treating Osteoarthritis and treatment
Method.
Background technique
Osteoarthritis (osteoarthritis, OA) is a kind of common with articular cartilage retrogression pathological changes, secondary bone
The chronic disease that matter hyperplasia is characterized.OA disease incidence is high, and especially mid-aged population, 50 years old or more crowd's disease incidence are more than 50%, and
The disability rate of OA is up to 53%, occupies all diseases first places, and the extent of injury is more than cardiovascular and cerebrovascular disease.At present China patient there are about
1.5 hundred million, WHO speculate that global patient in 2025 will be more than 800,000,000, it has also become seriously affect the important diseases of human health, and will
Annual October 12 is set to world joint buring sun.
The treatment of OA mainly includes physical therapy, drug therapy and operative treatment according to state of an illness weight.These routines
Therapeutic modality, general curative effect is unsatisfactory, or even there are the series of problems such as side effect and complication at a specified future date.In recent years, being directed to
Serious OA patient, the technical applications such as the transplanting of self or homogenous cartilage tissue block, Autologous Chondrocyte transplanting, there is certain treatment
Effect.But the limited life span of cartilage cell, allogeneic immunogenicity, causes joint fibrosis at limited donor source
The problems such as complication.Therefore, with regard to the treatment of OA, the good plan of radical cure and the key issues of osteopathy field concern be there is no at present.
The self-renewing of stem cell and the potential for being divided into multiple functions cell or even histoorgan under given conditions,
Hope is brought for the treatment of injuries of tissues and organs and some difficult and complicated cases.Stem cell mainly includes embryonic stem cell, Cheng Tigan
It cell and induces multi-potent stem cell, is based on ethnics Problem and Operative risk, it is dry with mesenchymal stem cell, fat mesenchymal
The adult stem cells such as cell become the main seed cell resource of cellular replacement therapy.These mescenchymal stem cells all have
The cell of self-renewing and Multidirectional Differentiation ability can be divided into the Various Tissues such as bone, cartilage, fat, have diving for treatment OA
Power.Recently a large amount of studies have shown that human amnion mesenchymal stem cell (human amniotic mesenchymal stem
Cells, hAMSCs) than adult stem cells such as mesenchymal stem cell, fat mesenchymal stem cells there is stronger amplification energy
Power, differentiation capability, and be in low immunogenicity, no tumorigenesis risk and ethics limitation, and can secretory immune inhibiting factor and anti-
The advantages such as the scorching factor, it is considered to be ideal seed cell (the Xiao Jianhui people amnion stem cell: regeneration of cellular replacement therapy
Ideal seed cell resource Zunyi Medical College's journal 2015,38:439~449 of medicine).We grind the early period in laboratory
Study carefully prompt, under certain condition, the good chondroblast differentiation capability of hAMSCs presentation (Song Xiujun, Chen Daixiong, Fang Ning,
Equal human amnion mesenchymal stem cell has a potential China Tissue Engineering Study for being divided into cartilage and osteoblast, and 2007,
11:10056~10060), it is the ideal seed cell of transplantation treatment OA.However, so far there is not yet being controlled using hAMSCs transplanting
Treat the report of OA.
Hyaluronic acid is a kind of by D-Glucose aldehydic acid, N- acetylaminohydroxyphenylarsonic acid D-Glucose, with -1,3 glycosidic bond and-Isosorbide-5-Nitrae sugar
Glycosidic bond joins the non-protein class straight chain polymer acid mucopolysaccharide to be formed.It is also extracellular matrix principal structural component.And cell
Epimatrix determines the shape of cell, influences vigor, migration, the Proliferation, Differentiation of cell, and participates in signal transmitting, and hyaluronic acid is at it
In play key player, and in body performance multi-biological function normally and under pathological state.Moreover, there is study group's discovery
Hyaluronic acid can be obviously promoted young rat cranium progenitor cell proliferation and induce differentiation into the ability of osteocyte, it is also considered to be structure
Build the important element of cartilage tissue engineered rack material.For example, hyaluronic acid is added in chitosan stent material, it can be obvious
Promote seed cell adhesive capacity and cartilage matrix generates；Hyaluronic acid is as in collagen as tissue engineering scaffold, extremely significant promotion SOX-
9, II collagen type and cartilage matrix generate.
Summary of the invention
For the deficiency of existing Osteoarthritis treatment method, the purpose of the present invention is to provide a kind of safe and efficient
HAMSCs combines the arthritic preparation of hyaluronic acid transplantation treatment of bone and treatment method.
A kind of preparation for treating Osteoarthritis, said preparation the preparation method comprises the following steps: by health full term Cesarean esction fresh human placenta
Passivity mechanical stripping amnion is removed after remaining bloodstain and surface mucus with 1% dual anti-D-Hank ' s liquid repeated flushing amnion is contained,
Amnion is cut into 1~3 cm2Size is sub-packed in 50 mL centrifuge tubes, and addition about 2 times of volumes of amnion tissue contain 0.02%
0.05% tryptic digestive juice of EDTA-2Na, in 35~37 DEG C of constant water bath box, 150~185 rpm rotation digestion is about
30 min discard the digestive juice containing amniotic epithelial cells, rejoin fresh contain after the filtering of 300 mesh stainless steel filtering nets
0.05% tryptic digestive juice of 0.02% EDTA-2Na is repeated to digest once, be filtered again through 300 mesh stainless steel filtering nets
Afterwards, digestive juice is discarded；Remaining amnion tissue cleans one with containing 1% dual anti-D-Hank ' s liquid after above-mentioned trypsin digestion
It is secondary, remaining tryptic digestive juice is removed, the 0.5 mg/mL II Collagenase Type containing 0.05 mg/mL DNase I is added and disappears
Change liquid, in 35~37 DEG C of constant water bath box, 150~185 rpm rotation 1~2 h of digestion, until remaining amnion tissue fragment
Be digested to completely it is cotton-shaped, through 300 mesh stainless (steel) wires filter, collect cell filtrate；1500rpm, 4 DEG C of 10 min of centrifugation abandon supernatant,
Cell precipitation is hAMSCs；Cell is resuspended with the low sugar DMEM containing 10% fetal calf serum, kind in T25 Tissue Culture Flask, 35~
37 DEG C, contain 1~10% CO2And 85~100% saturation of the air humidity constant temperature incubations, it is passed on to cell fusion degree up to 80% or more
Culture；Human amnion mesenchymal stem cell and 0.01~2mg/mL hyaluronic acid solution are mixed, cell density 1 × 106~1 ×
109A/mL is to get the cell preparation for treating Osteoarthritis.
The hAMSCs for treatment was 2~5 generations.
The molecular weight of the hyaluronic acid is 20~2200KD.
Using the method for above-mentioned preparation for treating Osteoarthritis are as follows: using locally injecting hAMSCs cell preparation 0.01~
In 1mL to the articular cavity of Osteoarthritis mammalian animal model, the hAMSCs suspension of locally injecting equivalent is carried out within every 3~5 weeks, even
It is 2~5 times continuous.
HAMSCs joint hyaluronic acid for treating Osteoarthritis, be also included within wherein be added it is pharmaceutically acceptable
Carrier.
The present invention is based on the superperformances of hAMSCs and hyaluronic acid, establish hAMSCs joint hyaluronic acid transplanting for the first time
The preparation of Osteoarthritis is treated, and has significant curative effect, disease pain can be mitigated for many patients.
Detailed description of the invention
Fig. 1 is the gross examination of skeletal muscle (A) of normal SD rat animal articular cartilage and Osteoarthritis SD rat model, tissue disease
Reason variation (B), Magnetic resonance imaging (C), glycosaminoglycan distribution (D) and II collagen type expression (E) (× 200)；
Fig. 2 is the morphological feature (× 200) before and after human amnion mesenchymal stem cell label superparamagnetic iron oxide；
Fig. 3 is the curative effect of human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model,
(A) gross examination of skeletal muscle (× 200) after joint capsule, (B) Magnetic resonance imaging are cut；
Fig. 4 is the pathology after human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model
Organize HE dyeing morphological feature (× 200)；
Fig. 5 is cartilage group after human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model
The glycosaminoglycan distribution detection (× 200) knitted；
Fig. 6 is cartilage group after human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model
The expression analysis (× 200) for the II collagen type knitted；
Fig. 7 is cartilage after human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model
1 expression conditions of Col2 α
Fig. 8 is blood plasma after human amnion mesenchymal stem cell and hyaluronic acid combination treatment Osteoarthritis SD rat model
And in synovia inflammatory factor (A), anti-inflammatory factors and osteoprotegerin (B) expression.
Specific embodiment
The present invention is described further by following examples and attached drawing, and embodiments of the present invention are not limited thereto.
Embodiment 1: human amnion mesenchymal stem cell combine hyaluronic acid treatment Osteoarthritis preparation preparation method and
Using
1, human amnion mesenchymal stem cell is separately cultured
Health full term Cesarean esction fresh human placenta passivity mechanical stripping amnion, with containing 1% dual anti-D-Hank ' s liquid (final concentration
For penicillin: 100 IU/mL, streptomysin: 100 IU/mL, before use Fresh) repeated flushing amnion, remove residual bloodstain
After surface mucus.Amnion is cut into 1~3 cm2Size is sub-packed in 50 mL centrifuge tubes, and about 2 times of volumes of amnion tissue are added
0.05% tryptic digestive juice containing 0.02% EDTA-2Na, in 35~37 DEG C of constant water bath box, 150~185 rpm
Rotation digestion about 30 min, through 300 mesh stainless steel filtering nets filtering after, discard the digestive juice containing amniotic epithelial cells, again plus
Enter fresh 0.05% tryptic digestive juice containing 0.02% EDTA-2Na, repeats to digest once, it is stainless through 300 mesh again
After steel strainer filtering, digestive juice is discarded.Remaining amnion tissue, which is used, after above-mentioned trypsin digestion contains 1% dual anti-D-
The cleaning of Hank ' s liquid is primary, removes remaining tryptic digestive juice, and 0.5 mg/ for containing 0.05 mg/mL DNase I is added
ML II Collagenase Type digestive juice, in 35~37 DEG C of constant water bath box, 150~185 rpm rotation 1~2 h of digestion, until surplus
Remaining amnion tissue fragment be digested to completely it is cotton-shaped, through 300 mesh stainless (steel) wires filter, collect cell filtrate (i.e. digestive juice),
1500 rpm, 4 DEG C of 10 min of centrifugation abandon supernatant, and cell precipitation is hAMSCs.With the low sugar DMEM weight containing 10% fetal calf serum
Outstanding cell is planted in T25 Tissue Culture Flask, at 35~37 DEG C, contains 1~10% CO2And 85~100% the saturation of the air humidity constant temperature training
It supports, carries out secondary culture up to 80% or more to cell fusion degree, it is alternative in experiment to collect the 2nd~5.
2, the preparation of Osteoarthritis model
SPF grades of SD rats, age of mouse 13~14 weeks, weight: 6% chloraldurate (0.5mL/ was injected intraperitoneally in 220 ± 24g
100g weight) anesthesia.Electric shaver rejects the coat at right hind knee joint, 75% ethanol for disinfection to knee joint routine disinfection,
100 μ L of intraarticular injection (passing through ligamentum patellae) 20g/L sodium iodoacetate.Normal group gives same amount of normal saline, after modeling 2 weeks,
Normal group takes 2~3 with model group at random, carries out nuclear magnetic resonance (MRI) and checks knee joint position, and in knee joint femoral and shin
About 1 cm cuts joint capsule to bone up and down, carries out gross examination of skeletal muscle；HE, toluidine blue and immuning tissue are carried out to articular cartilage tissue
Learn dyeing；Rat model shows as that the swelling of joint injection position, inflammation, hydrops articuli, HE staining cell be disorganized, damp line mould
Paste, one or more generations (Figure 1A-E) whether the light dye of toluidine blue or mistake dye, II expression of collagen etc. in indexs.
3, superparamagnetic iron oxide (SPIO) marks hAMSCs
For convenience of therapeutic effect is checked, hAMSCs is marked using SPIO.I.e. collection is envisaged for before the hAMSCs for the treatment of (carefully
Intracellular growth degrees of fusion 70~80%), tipping culture medium is added D-PBS and cleans 3 times, after exhaustion residual D-PBS, is added without FBS's
The Fe that LG-DMEM culture medium is now prepared3+Concentration is the SPIO solution of 25 μ g/mL, is placed in 37 DEG C, 5% CO2, 85~100% is empty
It is incubated for 18 h in the incubator of gas saturated humidity, is marked, iron particle blue in visible cell (figure after prussian blue staining
2).Then, it digests, wash, collect hAMSCs, the cell suspension (cell density 1 × 10 prepared with D-PBS6~1 × 109A/
ML).
4, animal packet combines hyaluronic acid transplantation treatment with hAMSCs
Animal is divided into Normal group (NG), model group (MG), hyaluronic acid treatment group (HA), hAMSCs treatment group
(hAMSCs), hAMSCs+ hyaluronic acid combination treatment group (CG), every group 12.It is added in the cell suspension that D-PBS is prepared
0.01~2mg/mL hyaluronic acid solution mixes.The molecular weight of hyaluronic acid is 20~2200KD.HAMSCs combines hyaluronic acid
For treating Osteoarthritis, it is also included within and pharmaceutically acceptable carrier is wherein added.
In position of disease, articular cavity carries out locally injecting treatment, and the 3rd~5 week after treating for the first time carries out the 2nd note
Penetrate treatment.
5, hAMSCs combines hyaluronic acid transplantation treatment Osteoarthritis effect assessment
(1) gross examination of skeletal muscle, imageological examination and histopathologic change
8 weeks after treatment, solution splits knee joint position, and gross examination of skeletal muscle is shown, compares with MG group, and HA group repairs effect without obvious
Fruit；HAMSCs group shows certain repairing effect；And CG group damaged cartilage repairing effect is significant (Fig. 3 A)
The prompt of Fig. 3 B Magnetic resonance imaging result, the 8th week after the treatment, model group (MG) articular cartilage tissue was mainly presented
Apparent high RST, shows inflammation occur.And in articular cavity at cartilage damage tissue, HA group and hAMSCs, especially CG group
Signal it is obviously on the weak side, prompt hAMSCs have moved to cartilaginous lesion site.
The prompt of pathological tissue HE coloration result, in impaired articular cartilage tissue, MG group has not observed apparent thin
Born of the same parents' form, damage have reached at subchondral bone；HA group and the discovery of hAMSCs group have a small amount of cartilage cell；CG group cartilaginous tissue, cell
Marshalling, damp line is clear (Fig. 4), prompts it good to repair of cartilage effect.
(2) expression of glycosaminoglycan and II Collagen Type VI
Using toluidine blue detection cartilaginous tissue glycosaminoglycan secrete situation, as a result prompt, MG group lose dye, HA group with
The light dye of hAMSCs group, NG group and the dense dye of GC group show that two groups of glycosaminoglycan expression quantity are more (Fig. 5), prompt GC group to cartilage group
The reparation knitted has good effect.
II collagen type is detected as shown in Fig. 6 ImmunohistochemistryResults Results, and the II collagen type of model group (MG) is negative,
HA group and the expression of hAMSCs group II collagen type are lower, and normal group (NG) and combination group (CG) II collagen type are in Qiang Yang
Property, prompt GC group to have good effect to the reparation of cartilaginous tissue.
(3) expression of 1 gene of cartilage Col2 α
Although the expression quantity slightly higher than MG group of HA group and hAMSCs group Col2 α 1, and the expression quantity of the Col2 α 1 of CG group is bright
It is aobvious to be higher than MG group (Fig. 7), prompt HA and hAMSCs combination that there is good injury repair effect.
(4) expression of inflammatory factor, anti-inflammatory factors and OPG
The prompt of Fig. 8, compared with MG group, proinflammatory factor TNF-α, IL- in HA group, hAMSCs group and CG group blood plasma and synovia
6 and IL-1βExpression water is lowered, and wherein it is the most obvious to lower effect for CG group.On the contrary, compared with MG group, HA group, hAMSCs
OPG and anti-inflammatory factors IL-4, IL-10 expression are raised in group and CG group blood plasma and synovia, wherein CG group up-regulation effect
Fruit is the most obvious.Therefore, the expression of hyaluronic acid, hAMSCs and all adjustable inflammatory factor of the two combination is used alone, subtracts
Subinflammation reaction promotes the secretion of OPG, and antiphlogistic effects are significant after being especially combined.
The purposes of 2. human amnion mesenchymal stem cell of embodiment and hyaluronic acid combination in other aspects
As described in the above results, human amnion mesenchymal stem cell and hyaluronic acid combination can be remarkably reinforced and cartilaginous tissue
The expression of closely related glycosaminoglycan, II collagen type, and be conducive to human amnion mesenchymal stem cell in bone joint
Scorching model diseased region survival is colonized and is divided into new cartilage cell, there is good preventive and therapeutic effect to cartilage damage.And
And human amnion mesenchymal stem cell and hyaluronic acid combination are not also immunized for xenogenesis SD rat bone arthritis treatment
Rejection.
Embodiment 3. mixes human amnion mesenchymal stem cell and 0.01~2mg/mL hyaluronic acid solution, cell density 1
×106~1 × 109A/mL can be used as the cell preparation for the treatment of Osteoarthritis and cartilage damage for injection.It can also be at this
Pharmaceutically acceptable carrier is added in preparation, such as promotees the growth factor of repair of cartilage.
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