CN107686546A

CN107686546A - A kind of novel degradable polyurethane biomaterial and its preparation method and application

Info

Publication number: CN107686546A
Application number: CN201710462495.3A
Authority: CN
Inventors: 许开天
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-06-19
Filing date: 2017-06-19
Publication date: 2018-02-13
Also published as: CN108409938A

Abstract

Application the present invention relates to a kind of novel degradable polyurethane biomaterial extremely preparation method and in degradable implantation and non-implanted medical device.The new material is the alternating block polyurethane high molecule material obtained based on biodegradable polyester diol and Hydrophilicrto polyether dihydric alcohol, is obtained by the selectively coupled reaction between aliphatic polyester binary alcohol and diisocyanate terminated Hydrophilicrto polyether or between aliphatic poly esterdiol and diisocyanate terminated aliphatic polyester block.Product of the present invention has the polymer chain of controllable and predictable chemical constitution and rule, and there is the patterning structure of surface microfacies, many medical treatment and non-medical instrument field are can be widely applied to, wherein all showing excellent performance in the application such as periphery nerve rehabilitating tube, meniscal repairs, anti-adhesion membrane, meninx, eyelid rebuilding support, wound dressing, the compound porous recovery support of bone, other soft tissues and regeneration of sclerous tissues.

Description

A kind of novel degradable polyurethane biomaterial and its preparation method and application

Technical field

The present invention relates to biomedical polymeric material field, particularly a kind of novel degradable polyurethane biomaterial and Its preparation method and application.

Background technology

Biodegradable block polyurethane is a kind of widely used biomaterial, has had several moneys to plant accordingly at present Enter medicine equipment and obtain European CE and U.S. FDA approval to be applied to human body.Due to its excellent blood compatibility, excellent Machinery and processing characteristics, it is widely used in the application necks such as organizational project, regenerative medicine, control medicine delivery, wound healing Domain.However, almost all of traditional block polyurethane is all using diisocyanate as coupling agent, by dihydric alcohol or/and more The terminal hydroxyl of first alcohol synthesizes with the coupling reaction of isocyanates, though the material with improved property is this method provide, but Actually it lacks the permutation and combination of block selectivity and rule, and can only turn into block copolymer by assembly and connection in a random basis (i.e. traditional random block polyurethane macromolecule, abbreviation：RanPU, as shown in Figure 1), and this kind of random structure will cause material Property is difficult to regulate and control.

The content of the invention

For overcome the deficiencies in the prior art, the invention provides a kind of novel degradable polyurethane biomaterial and its system Preparation Method, the material have good blood compatibility, histocompatbility, have excellent surface nature, mechanical mechanics property, Moulding processability and biodegradability, pH caused by its catabolite are changed very little, and are advantageous to the raising of biocompatibility.

The technical solution adopted for the present invention to solve the technical problems is：

Present invention firstly provides a kind of novel degradable polyurethane biomaterial, including some formed by first polymer First block, some the second blocks formed by second polymer, the first block and the second block are alternately arranged, and adjacent first Between block and the second block by carbamate key connection formed alternating block polyurethane (AltPU), as it is described it is new can Degradable polyurethane biomaterial；

Wherein, the first polymer is the polyester of dihydric alcohol end-blocking, and the second polymer is diisocyanate terminated Aliphatic polyether or aliphatic polyester polymers, the second polymer can also be substituted by aliphatic dihydroxy alcohol, such as second Glycol, 1,4- butanediols etc..

Preferably, the polyester of the dihydric alcohol end-blocking combines the copolymerization to be formed for aliphatic polyester or different aliphatic polyesters Thing.

Preferably, the diisocyanate is aliphatic diisocyanate, specially hexamethylene diisocyanate, fourth two Isocyanates, lysine diisocyanate, ethyl ester of lysine diisocyanate, IPDI, 4,4'- methylene One kind in double (cyclohexyl) diisocyanate, the conjunction for the diisocyanate terminated segment in synthesis of selective coupling reaction Into.

The present invention also provides a kind of preparation method of above-mentioned novel degradable polyurethane biomaterial, with the described first polymerization Thing and second polymer are reaction raw materials, are reacted 8~72 hours at 30~100 DEG C, obtain the alternating block polyurethane.

Preferably, above-mentioned reaction is carried out in reaction raw materials body or organic solvent, can also be added with reaction system Machine tin catalyst.

Preferably, hydroxyl is identical with the mol ratio of isocyanate groups in the reaction raw materials.

Above-mentioned novel degradable polyurethane biomaterial is used to be implanted into and the preparation of non-implanted medical device.

Preferably, it is porous to be used for CO2 laser weld socket pipe, meniscal repairs for the novel degradable polyurethane biomaterial Plate, Antiadhesive film, meninx, eyelid reconstruction support, wound repair film and dressing or the preparation of bone complex repairation support.

The positive effect of the present invention：This is to invent this kind of to there is segment to be alternately arranged the complete of new structure and give birth to for the first time Thing degraded block polyurethane material.Novel degradable polyurethane biomaterial of the present invention is alternating block polyurethane (AltPU) a kind of new block polyurethane biomaterial is developed as, it includes being alternately arranged (as shown in Figure 1) for block. These block polyurethanes have the physics microstructure of controllable chemical constitution and rule.With good controllable chemical constitution And the surface microstructure of rule, compared with RanPU, AltPU has higher crystallinity, and higher surface energy is more regular With stable picture on surface.Its alternating structure adds microphase-separated, so as to allow some fragments such as to be moved than more hydrophilic fragment Move on material surface, so as to possess higher surface energy；Higher crystallinity enhances mechanical strength, and alternating structure causes to have Well-regulated surface.The roughness on surface is further studied by AFM (AFM), record has identical chemical composition AltPU and RanPU height image, it is found that 101.8nm Ra (mean roughness) is presented in alternate AltPU material surfaces With 762.9nm Rmax (maximal roughness), it is significantly larger than the RanPU material tables that Ra is 47.6nm and Rmax is 387.9nm Face, the patterning structure on these surfaces are advantageous to the adhesion and growth of cell.Alternating block polyurethane (AltPU) of the present invention Biomaterial not only props up in CO2 laser weld socket pipe, orthopaedics reparation, eyelid rebuilding support, wound dressing and compound porous repair of bone Good application effect is embodied on frame, in the application of other medicine equipments, including skin reconstruction and reparation, Antiadhesive film, blood Tubing patch film, meninx, ligament and tendon reparation etc. also embodies excellent repairing performance.

The block alternating structure of alternating block polyurethane of the present invention imparts the much special properties of this material and work( Energy.Such as traditional PLLA, PLGA and/or based on PCL implantation instrument during degraded, significant change can occur for pH value (increase acidity), so as to cause the inflammation in local organization, the regeneration function of tissue is influenceed, and can be to the performance of medicine equipment Have a negative impact.And implantation instrument is only shown during degraded made of the alternating block polyurethane (AltPU) of the present invention Very small pH value change, the change of its pH value are significantly smaller than raw material such as PCL and corresponding random block polyurethane material Expect Ran-PU pH value change.Because polyurethane has carbamate chemical structure, it produces acid simultaneously in degradation process Property carboxyl and alkaline amido, this is different from aliphatic polyester such as PGA and PLA only produces acidic carboxypolymer during degraded, causes fat The pH of adoption ester implant regional area is significantly reduced, and PLLA, PLGA, and is compared based on implant made of PCL material, The property of AltPU implants of the present invention pH value minor variations caused during degraded helps to reduce caused by implant Inflammatory reaction risk, improve the reparative regeneration function of histoorgan.

Brief description of the drawings

Fig. 1：The high molecular schematic arrangement of traditional random block polyurethane；

Fig. 2：The schematic arrangement of alternating block polyurethane of the present invention；

Fig. 3 a：CO2 laser weld micrurgy schematic diagram；

Fig. 3 b：The CO2 laser weld socket pipe being implanted into rat body；

Fig. 3 c：The SEM of the socket pipe prepared by alternating block polyurethane (Alt-PU) schemes；

Fig. 4：Sciatic nerve function index (SFI) value during different materials group CO2 laser weld；

Fig. 5 a：The postoperative 4 weeks rats footprint figure of Alt-PU groups；

Fig. 5 b：The postoperative 8 weeks rats footprint figure of Alt-PU groups；

Fig. 5 c：The postoperative 14 weeks rats footprint figure of Alt-PU groups；

Fig. 6：Different phase electro physiology injury side peak swing and healthy side contrast situation；

Fig. 7 a：The postoperative 1h observations figure of Alt-PU group rats；

Fig. 7 b：The postoperative 24h observations figure of Alt-PU group rats；

Fig. 7 c：Postoperative two weeks observation figures of Alt-PU group rats；

Fig. 7 d：The postoperative surrounding observation figure of Alt-PU group rats；

Fig. 8 a：Gauze group different periods skin ultrastructure compares figure；

Fig. 8 b：Ran-PU group different periods skin ultrastructure compares figures；

Fig. 8 c：Alt-PU group different periods skin ultrastructure compares figures；

Fig. 9：Contraction of wounds rate of each group in the different wound repair times；

Figure 10 a：The histopathological analysis figure of normal skin wound repair；

Figure 10 b：The histopathological analysis figure of Alt-PU group skin ultrastructures；

Figure 10 c：The histopathological analysis figure of gauze group skin ultrastructure；

Figure 11 a：Alt-PU porous foam bone repairing support SEM photographs without hydroxyapatite；

Figure 11 b：Alt-PU porous foam bone repairing support SEM photographs containing 90% percentage by weight hydroxyapatite；

Figure 11 c：Alt-PU porous foam bone repairing support SEM photographs containing 70% percentage by weight hydroxyapatite；

Figure 11 d：Alt-PU porous foam bone repairing support SEM photographs containing 50% percentage by weight hydroxyapatite；

Figure 11 e：Alt-PU porous foam bone repairing support SEM photographs containing 30% percentage by weight hydroxyapatite；

Figure 11 f：Polymetylmethacrylate rack surface SEM photograph without hydroxyapatite；

Figure 12 a：Structure half storey head injury figure on the right side of Rat calvarial；

Figure 12 b：Experimental group stenter to implant defect figure after 18 days；

Figure 12 c：The control group head injury area image of postoperative 40 days；

Figure 12 d：Experimental group implantation support head injury healing image after 80 days.

Embodiment

Below to a preferred embodiment of the present invention will be described in detail, but embodiment the present invention is not done it is any type of Limit.Reagent and device used in embodiment, all it is using this area common reagent and device unless otherwise specified.

Embodiment 1

Synthesize alternating block polyurethane (Alt-PU) and the poly- ammonia of random block based on aliphatic polyester and Hydrophilicrto polyether Ester (Ran-PU)：

In the organic solvent (chloroform) that aliphatic polyester binary alcohol is initially dissolved in three-neck flask, then it will utilize Hydrophilicrto polyether-diisocyanate that end capping reaction is prepared, by with dihydric alcohol 1：1 molar equivalent is slowly dropped into flask In, after reacting 8-72h at 30-100 DEG C, obtain alternating block polyurethane Alt-PU.Above-mentioned reaction also can be directly former in reaction Carried out in material body, one thousandth can also be used to the organotin catalysts of ten a ten thousandths (weight ratio), such as 2- ethyl hexyls Sour tin, butyl tin dilaurate etc., hydroxyl and isocyanate groups should have equal mol ratio in reflection system.

By the use of aliphatic polyester binary alcohol and Hydrophilicrto polyether as reacting body, tin-containing catalyst is added, at the same it is different with two For cyanate as coupling agent, the amount of the diisocyanate of addition is equal to the amount of the material of-OH groups in reaction solution, will react Mixture stirs 8-72h at 30-100 DEG C under nitrogen protection, then collects product and dries under vacuum to constant weight, Obtain the random block polyurethane Ran-PU.

The following examples will be with CO2 laser weld socket pipe, eyelid rebuilding support, wound dressing and the compound porous reparation of bone Support is representative, illustrate the alternating block polyurethane (AltPU) of preparation on applied to implanted medical device with it is other conventional Degradable biomaterial compares possessed superiority.

Embodiment 2

By the alternating block polyurethane (Alt-PU) prepared in embodiment 1 and random block polyurethane (Ran-PU) biological material Preparation of the material applied to CO2 laser weld socket pipe：Porous CO2 laser weld socket pipe is prepared by using dip-coating and salt leaching method, used Then the stainless steel wire that external diameter is 1.5mm air-dries the polymer coating on the mould of gained 2 days, vacuum drying as mould 2 days, then salt is leached in deionized water, freeze-drying and the demoulding obtain CO2 laser weld socket pipe.

CO2 laser weld socket pipe, also referred to as nerve rehabilitating tube or CO2 laser weld sheath；It may also be referred to as CO2 laser weld cladding Piece and neuroprotection open tube.CO2 laser weld socket pipe prepared by the alternating block polyurethane (Alt-PU) has porosity For the microporous pipeline structure, micropore laminated structure and pore openings pipeline that 10-99% and aperture are 100nm to 500 μm (micron) Structure.

The CO2 laser weld socket pipe can also include bioactive substance, such as reactive protein RGD, nerve growth The factor (NGF), nerve growth medicine, schwann cell and other neural benefit materials.

Peripheral nerve defect is very common clinical wound, and frequently result in patient sensation and motor function forever Long property is disabled, and 900,000 new cases are there are about every year in China.Nerve autograft is the conventional treatment means of neurotrosis, so And this method has the size between many shortcomings, including defect nerve and Nerve Graft to mismatch；For extracting the god of donor Through second operation to be undergone；Donor graft is insufficient；Donor site is also easy to produce neuroma etc..In order to overcome these problems, Biodegradable CO2 laser weld socket pipe repairs alternative means as effective, for promoting neurotrosis to regenerate and providing god Path through growth.

The CO2 laser weld socket pipe having been commercialized at present is generally by the type i collagen and synthesized degradable biology material of biological source Expect that this two classes material is made, for example, polycaprolactone (PCL), poly- (lactide-co-caprolactone) (PCLLA), PLLA (PLLA), poly- (D, L- lactic acid-ethanol copolymer) (PLGA) and polyvinyl alcohol (PVA).However, by these biomaterial systems Following FAQs be present in the CO2 laser weld socket pipe made：

1) too fast degraded, this causes early stage to collapse (a few weeks), or too slow degraded (>8 months, even>1 year), it is adjoint Incomplete or segment degradation；

2) biocompatibility of material is limited, it is impossible to promotes the growth of nerve cell；

3) inflammation caused by acid degradation products；

4) the flexibility deficiency of neural socket pipe, causes neural residul end during regeneration to be torn from neural socket pipe chamber；

5) cause tube chamber to block and prevent the kink resistance of nerve regneration poor；

6) easily cause fibrosis and extensive inflammation reaction of nerve regneration etc. is presented；

7) rejection etc. is immunized caused by biogenic material.

Due to AltPU material structures and the particularity of function, manufactured nerve trachea effectively overcomes the shortcoming of the above, makes Obtain restoration effect and be not only better than nerve autograft, nerve socket better than made of the above degradable polymer The repairing effect of pipe.

The CO2 laser weld socket pipe that will be prepared in the present embodiment, CO2 laser weld experiment is carried out in SD rat animal models, To neural socket pipe and nerve autograft made of Alt-PU and Ran-PU (embodiment 1), PCL, set made of silicone tube Adapter carries out the system research of CO2 laser weld and compared, and nerve is evaluated using 80 adult SD rats that weight is 300-350g Repairing effect.Wherein, Fig. 3 a are CO2 laser weld micrurgy schematic diagram；Fig. 3 b are the CO2 laser weld socket in implantation rat body Pipe；Fig. 3 c are that the SEM of the socket pipe prepared by alternating block polyurethane (Alt-PU) schemes.

Animal is divided into 5 groups, every group 15.Dimension scale that neural socket pipe makes is similar to autologous nerve, and (internal diameter is about 1.3mm；Wall thickness about 0.4mm), neurotrosis mould is used as by sciatic nerve 12mm defects caused by the surgery excision of nerve fiber Type, the repairing effect for neural socket pipe are evaluated.Animal is anaesthetized with the yellow Jackets of 50mg/kg body weight, the ischium on right side Nerve exposure, from the horizontal nerve segment for removing 12mm of big midleg.15mm conduits or the nerve of removal are inserted in near-end in itself Between distal stump, sutured in each junction with No. 8-0 absorbable PLGA suture.After implantation, No. 5-0 seam is used Zygonema sutures muscle incision, and with 2-0 silk suture skins.Every rat receives an implant, and at identical interval Time removes.It is postoperative, by every animal feeding in a cage, ad lib and drinking-water.Concentrate to animal carry out autotomy and The inspection of contracture sign.In each time interval, sciatic nerve function index, electro physiology and histomorphometry are carried out, To assess the efficiency of CO2 laser weld.All zooperies are according to ISO10993-2：1992 animal welfares require to carry out.

In predetermined time period (postoperative 2,4,8,10 and 14 weeks), nerve regneration is evaluated by walking orbit analysis.In Fig. 4 Middle more different groups sciatic nerve function index (SFI) value, implantation 14 weeks after in Alt-PU groups observe SFI values be- 24%, recover SFI value -28% higher than autograft group, be much better than -35%SFI the values of Ran-PU groups, and PCL groups, silica gel The SFI values of pipe group.4,8,14 weeks after surgery implantation Alt-PU nerve socket pipes are respectively illustrated in Fig. 5 a, Fig. 5 b and Fig. 5 c Animal footprint.As can be seen that at 2 and 8 weeks, footprint image is quite narrow and abnormal, and now motor function is not completely extensive It is multiple.Marked at the 14th week, footprint image recovers normal, shows that neuromotor function significantly recovers.

Different phase electro physiology injury side peak swing and offside (healthy side) contrast situation are as shown in Figure 6, it can be seen that AltPU groups just already exceed autotransplantation group on the 4th week.

After implantation 4,8 and 14 weeks, Alt-PU, Ran-PU, autograft, PCL supports, silicone tube C MAP current potential Signal contrasts (result is as shown in Figure 4).Action potential in Alt-PU, Ran-PU, autotransplantation group and PCL support groups is 4 Zhou Houneng is clearly illustrated, shows that the functional rehabilitation of injured nerve is quick.Current potential becomes stronger after 9 and 14 weeks, shows that nerve is repaiied Recover lost eyesight aobvious.But surprisingly Alt-PU groups show the signal more stronger than autotransplantation group.This shows new alternating block Autotransplantation of the CO2 laser weld socket pipe of polyurethane (Alt-PU) with being considered as " goldstandard " in restoration effect is suitable, It is even better.

Embodiment 3

Alternating block polyurethane (Alt-PU) biomaterial prepared in embodiment 1 is applied to the preparation of eyelid support, Manufacture method is liquid-solid phase separation and freeze-drying：It is put into beaker, is added organic molten with a certain amount of Alt-PU materials Agent, until Alt-PU is completely dissolved into clear solution.Solution is poured into stainless steel mould, liquid level thickness is poured into control, will contain The mould for having solution is placed in 1-10h in -20-0 DEG C of frozen water mixing insulating box, 1-24h in -10-4 DEG C is placed in after taking-up, afterwards Move in freeze drier and freeze, be freeze-dried 1-24h afterwards, taking-up stainless steel mould, which is put into ambient temperature vacuum drying machine, to be dried 1-48h, the demoulding take out shaped support, support then are cut into 1cm²Support, obtain 0.7mm × 1cm²Eyelid is implanted into support.This eye Eyelid implantation support have porosity be 10-99% and aperture be 100nm to 500 μm (micron) porous membrane structure.

The processing method of commercialization ADM eyelid supports：ADM is put into lyophilized overnight on freeze drier, from freezing Taken out on drying machine, support is then cut into 1cm²。

Important appendicle of the eyelid as eye, only possesses the work(of its protection eyeball of complete form and function competence exertion Energy.With the continuous improvement of social industrialization degree, the various wounds of eye, especially soda acid chemical injury, thermal burn and machinery The caused eyelid wound of wound increasingly increases.The defect of eyelid skin, muscle, tarsus, papebral conjunctiva is often resulted in after defect of eyelid, no Only influence attractive in appearance, and exposed property ulcer of the cornea is usually caused due to the exposure of eyeball, and then cause the opacity of the cornea, or even wear Blind in hole.The damage of eyelid usually requires different materials as tissue substituent to fill up or reinforce the part of damage.Therefore, There are Various Tissues to be developed the reparation for carrying out eye wounds, including autologous tissue, allosome tissue and artificial organ etc..Its In, the autologous material such as limited source such as Ear cartilage, hard palate mucous membrane, elasticity and toughness are difficult to meet the requirements, and topography is closed System is complicated, and operation time-histories length is, it is necessary to second of operative incision；Allohisto compatibility such as allogeneic sclera, Homologous dura etc. are transplanted Thing is antigenic different from body tissue, serious immune rejection can be nearly all faced after implantation, while local inflammation is anti- Ying Qiang, material are easily degraded and absorbed.So far, can be very good to be widely used in clinic without a kind of tarsus substitute.

Preferable eyelid substitute should comply with following condition：

1) it is convenient to obtain and preserve.

2) it is easy to be operated in art, only need to simply trim and both can reach operation requirement.

3) price is relatively cheap, and most of patient can afford.

4) there is the hardness similar to physiological tissue, thickness and elasticity.

5) host tissue can be facilitated to grow into, and is merged over time with host, it is difficult to differentiated.

6) immunological rejection caused by is slight, inflammatory reaction is small.

7) it is few to be implanted into infectious-related complication.

8) the effect above can continue for quite a long time, or even all the life.

Meanwhile needed with reference to the specific function of eye, tarsus substitute should also have the surface of relative smooth, twinkle During will not wear cornea under it, it is basic after implantation to meet face symmetrically and protect the effect of eyeball.

Tarsus is replaced with allogeneic acellular dermal (ADM), all sees that correlative study reports that its effect is more both at home and abroad Ideal, it is that the relatively broad eyelid of current clinical practice substitutes graft.In recent years, the appearance with organizational project and modern times The fast development of ophthalmology medical science, the constantly improve of medical science theory, we are with the alternating block polyurethane (AltPU) of the present invention for base Material, the porous support with ultra microstructure is prepared by liquid-solid phase partition method and substitutes the dynamic of tarsus progress eyelid reconstruction in situ Thing is tested, and using the strong ADM of clinical practice dominance as control, the foundation of feasibility is obtained from histology and cytology evaluation, Prove that alternating block polyurethane tarsus timbering material can be used as preferable eyelid substitute to be applied to clinic.

The eyelid prepared in the present embodiment implantation support is subjected to eyelid repairing test in SD rat animal models.Animal Operation consent, Alt-PU eyelids implantation support is rinsed through sterile saline, be sealed after ultraviolet ventilation irradiation 24h in sterile Saved backup in centrifuge tube.

The foundation of animal model：SD rats 30, male, body weight 300-350g, are randomly divided into 2 groups, every group 15：① Alt-PU groups；2. ADM groups.Using 1.0% (w/v) yellow Jackets, intraperitoneal injection of anesthesia (40mg/kg), effective rear preserved skin is used Shaving machine shaves off eye circumference hair, then the whole preserved skin region of routine disinfection, afterwards at the eyebrow of mouse inject 1% lidocaine and The mixing of 0.75% Bupivacaine (contains 1:100000 adrenaline) subcutaneous infiltration anesthesia.Parallel eyes-affinity is used flat at away from margo palpebrae 2mm Tweezer is risen, and two arc incision lines of skin are drawn with black gel ink pen, is marked at the 5mm of canthus both sides at operation opening, then Do the skin incision of upper eyelid by mark line, separate two otch hypodermis and orbicular muscle of eye to tarsus, after finding out tarsus, with aobvious Micro- clipper for surgical use wipes out 1mm²Size tarsus tissue, obtain eyelid tarsal defect model.By ready Alt-PU eyelids support and The corresponding tarsal defect position of ADM eyelid stenter to implant, then with the degradable absorbable suture lines of 8-0 by implant and the tarsus broken ends of fractured bone The corresponding pin of interrupted suture 2, it is interrupted apposition suture skin of upper eyelid with 6-0 absorbable sutures and hypodermis, about 2 pins, art finishes, hinder Mouth Pressure bandage.Postoperative SD rats are put into mouse cage, after waiting its anesthesia to wake up, give sub-cage rearing, it is postoperative The wound location of observation rat whether there is redness, infects, festers daily；Wound pairing situation, whether there is and split and plant piece and come off, cruelly Dew；Conjunctival surface whether there is damaged and corneal damage；Margo palpebrae whether there is deformation；Whether there is that fornix narrows, eyeball adhesion, eyelid movement are abnormal or Situations such as dysraphism.

The clinical follow result of Alt-PU groups is as shown in Fig. 7 a-7d：A) postoperative one hour, skin incision was degradable with 7-0 Suture suture is absorbed (shown in Fig. 7 a)；B) a small scab is formed within postoperative 24 hours, there is a little slight redness in upper eyelid, does not have Have and observe that obvious rejection and gangrenous phenomenon occur (shown in Fig. 7 b)；C) hair at postoperative two weeks eyelid surgeries starts to give birth to It is long, without it is congested, ooze out and be observed that (shown in Fig. 7 c) with inflammatory reaction phenomenon；D) postoperative 4 weeks art branch holes portion return to Preoperative the same, arrow points to operative site (shown in Fig. 7 d).Postoperative 1h, the consciousness of rat all recover normal；Postoperative 24h is shown in mouse Upper eyelid gently swells, and margo palpebrae suture is in place, and wound pairing is good, and local desiccation is without oozing out, a small amount of scab.Eyelid knot is had no after each group implantation Film is worn out and corneal epithelial wound, and margo palpebrae organizes nothing without incisura, no hypophasis, otch without oozing out and infecting after implantation Exposure.It is that 1W, the hair of its art side wound of postoperative 2W start to repair completely after surgery that its scab, which is completely fallen off,.Postoperative 2W and 8W art branch hole portion does not have obvious difference, and during eyelid reparation, their daily life system is normal, and art branch hole portion also acts normally Eye opening eye closing activity, with normal side eye activity.Occur without significantly rejection, gangrene or inflammatory reaction, it was demonstrated that Its postoperative eyelid wound recovers rapid, it can be seen that, biomaterial of the invention has fine mechanical flexibility, biodegradable Property and eyelid soft tissue compatibility, can repair very well tarsus damage.

Embodiment 4

Alternating block polyurethane (Alt-PU) biomaterial prepared in embodiment 1 is applied to the system of wound dressing foam Standby, preparation method is：Weigh alternating block polyurethane (Alt-PU) biomaterial prepared in 2g embodiments 1 and be dissolved in In 40mL water, the solution that concentration is 50mg/mL is made into, is sufficiently stirred and is poured into after it is completely dissolved in 90mm culture dish.Again Precooling 1-24h in -20 DEG C of refrigerator is transferred them to, then transfers them to rapidly in -80 DEG C of low temperature refrigerator and freezes 1- 24h.Quickly be transferred in freeze drier, be freeze-dried after taking-up, taken out after 24h, spongy Alt-PU wounds repair Multiple foam dressing.This wound repair dressing has that porosity is 10-99% and aperture is the porous of 100nm to 500 μm (micron) Foaming structure.

Ran-PU wound repairs are prepared using the random block polyurethane (Ran-PU) and the above method prepared in embodiment 1 Foam dressing.

Wound repair is always the focus of current medical domain research, at present, the polyurethane material as wound dressing Rarely found report is studied, because polyurethane high molecule has waterproof and breathable, moisturizing and the function of preventing bacterium from penetrating into, with degradable PLA and biocompatibility it is good PEG synthesis polyurethane there are good potentiality as the research of wound dressing.The present invention PLA, PEG group biodegradable polyurethane material are applied to wound repair first, by the full thickness skin for building SD rats Model, control is used as using hospital gauze.Animal test results show:The repairing effect of biomaterial group of the present invention is substantially better than doctor With gauze, there are application and commercial value well as a kind of new wound dressing materials.

The Alt-PU wound repairs foam dressing prepared in the present embodiment is carried out into wound in SD rat animal models to repair Retrial is tested.

By building the full thickness skin trauma model of rat, to evaluate the novel degradable polyurethane biomaterial of the present invention Curative effect as wound dressing to wound.18 rats (about 300 g) are divided into three groups by random, and every group six is only used as putting down Row experiment.Intraperitoneal injection of anesthesia agent (10% chloraldurate), dosage 3ml/kg.The hair of area will be tested needed for rat back Number is cleaned with gently being struck off after 70% alcohol disinfecting with clear water.Then with the surgical scissors after sterilization cut at back 10mm × 10mm wound size, and the surface of a wound thoroughly expand and created, the surface of a wound, the surface of a wound are cleaned repeatedly with sterile saline and Iodophor liquid Thoroughly hemostasis.The area of original wound is recorded with the ruler after sterilizing, and photographs to record data.Experimental group is Alt-PU wounds Foam dressing group is repaired, with Ran-PU wound repair foam dressing groups and hospital gauze as a control group.Change once within every two days Dressing, wound size is recorded with ruler, and photograph to record wound situation.After ten days, remaining four days no longer more change dressingses, record 14 days data for repairing the phase.Contraction of wounds rate is calculated using following formula：Contraction of wounds rate (%)=[(Ao-At)/Ao] × 100.Wherein Ao is the area of original wound, and At is the wound area in different reparation periods.

After Skin Wounds, wound recovery situation is observed and recorded by way of taking pictures, as a result such as Fig. 8 a-8c It is shown.It can be found that the skin wound of three groups of rats has a different degrees of contraction, i.e. the skin of edge of wound is to wound center Mobile, the surface of a wound reduces, and this means that wound is constantly healing.The 4th day after wound, the surface of a wound of gauze group and Ran-PU groups all goes out Show inflammatory exudate and clot, and the wound surface of Alt-PU groups does not have the phenomenon of inflammation, redness and empyema.The 8th after wound My god, the incrustation of gauze group wound, contraction of wounds is slow, and Ran-PU groups still have a small amount of hydrops and blood, but contraction of wounds is better than yarn Cloth group, the surface of a wound of Alt-PU groups have the granulation tissue of new life, the result shows the recovery of the skin of Alt-PU groups is most fast, have entered The last repairing phase of skin is entered, so as to which the repairing effect than first two groups will be good.The 14th day after wound, gauze group still has ratio Obvious scar, shrinkage factor now is only that the contraction of wounds rate of 40%, Ran-PU groups can reach 80%, and Alt-PU groups Skin substantially healed completely, and surface is grown with hair, it is difficult to it was observed that the scar of wound.Wherein Fig. 9 is Wound records wound size, and the contraction of wounds rate as obtained by calculating formula, contraction of wounds rate during reparation, with ruler It is bigger, illustrate that the surface of a wound is smaller, it is also better to recover.It can be seen that the shrinkage factor of Alt-PU groups is always above other two in Fig. 9 Control group, this result are also consistent with result above.

It was found from gross examination of skeletal muscle, polyurethane biomaterial of the invention can provide the effect of protection for wound, and have Certain acts on every bacterium, the surface of a wound of a moistening can be formed by absorbing diffusate, there is provided give cambium one good life Long environment.Very close, the Ke Yitong additionally, due to the ammonia ester bond in polyurethane macromolecular and the amido link in people's vivo protein Cross to the specific effect of cell surface and promote the adhesion and growth of cell, accelerate the healing of wound.Along with suitable parent Hydrophobicity, mechanical property and pliability etc. all have an impact to wound reparation, and alternating block polyurethane of the invention can turn into The ideal material of wound repair and skin repair.

The histology pathological analysis of wound repair：In order to further determine that the situation of skin repair, we took at 14 days Lower neoplastic skin tissue, pathological analysis is carried out to tissue by HE dyeing, as a result as shown in Figure 10 a-10c.As above created Hinder described in repair mechanisms, be inflammatory reaction first after skin wound is formed, it is the basis of wound healing.This stage master Have substantial amounts of inflammatory cell, it by phagocytosis, the oxidation effect such as antimicrobial effect and activating complement remove slough and Foreign matter, normal structure is protected, prevents infection.Followed by fibroblastic a large amount of propagation, it is main repair cell, The engineer, builder and keeper of wound repair, it is with extracellular matrix, contraction of wounds, the renewal of collagen and paralysed trace Formation has close relationship.Finally enter back into the regeneration of the organs such as blood vessel and lymph, i.e. regeneration and revascularization.From Contrast and find in figure, substantial amounts of fibroblast (shown in Figure 10 c) occurs in the wound of gauze group, mainly also in the second of reparation Stage.And the wound of Alt-PU groups can see the organs such as the new vessels of many, lymph generation (Figure 10 b under the microscope It is shown), the institutional framework (Figure 10 a shown in) of closer normal skin substantially smaller than gauze group into fibrosis region, this Phenomenon also can promote migration of epithelial cells relevant with PEG in component.From pathological examination, Alt-PU groups are proved again (alternately Polyurethane material group) repairing effect be significantly better than gauze group.

Embodiment 5

It is porous that alternating block polyurethane (Alt-PU) biomaterial prepared in embodiment 5 is applied to skull complex repairation The preparation of support, preparation method are：The Alt-PU alternating block polyurethane biomaterials prepared in appropriate embodiment 1 are weighed, are put Enter in 20ml vials, add DMF to polyurethane and be completely dissolved.Weigh the sodium chloride of certain particle diameter Grain, hydroxyapatite (HA) and tricalcium phosphate (TCP) are added in polyurethane solutions after shaking mixing in proportion, and vibration mixes, will Mixture is coated on slide, and drying at room temperature 48h is complete to DMF volatilization.Slide is placed in ultra-pure water Middle 24h fully dissolves sodium chloride particle, changes liquid once per 8h, slide is placed in into drying at room temperature 48h in vacuum drying chamber, produced Alt-PU skull complex repairation porous supports, this support have that porosity is 10-99% and aperture is 100nm to 500 μm (micro- Rice) porous foam structure.It is easy to the reference of support to contrast simultaneously, we also using polymethyl methacrylate (PMMA) and exist In the case of there is no HA and TCP, porous support is produced as shown in figure 11f.

Bone tissue engineer research experienced from without immunologic function animal to small-sized mammalian, then to large mammal, Most Zhongdao clinical stage, its validity, security be proved more and more, its basic fundamental relative maturity.It is careful planting In terms of born of the same parents, in addition to currently used BMSCs, also occur adipose-derived and Cord Blood-Derived stem cell successively, it Wide material sources, osteogenic ability be similar to even better than BMSCs.In terms of timbering material, except previously wide variety of different Beyond body bone holder material, occurs timbering material that is a large amount of artificial and naturally extracting at present, it is wide that these materials are respectively provided with source General and degradable characteristic, needs of its mechanical strength all close to tissue engineered bone.In terms of constructing technology, work is largely organized The appearance of journey bone bioreactor, the structure for the tissue engineered bone of specific demand provide possibility.Along with bone tissue engineer The continuous maturation of technology and product, extensive clinical practice are possibly realized.

The Tissue Engineering Study of bone is concentrated mainly on two aspects at present：

First, bone tissue induces：Defect is filled using a kind of porous, biodegradable stent.This support has self-bone grafting And osteoconductive potential, the other cells of Gegenbaur's cell and the region can be triggered to grow into and be adsorbed on support.As matrix is accumulated, bone Tissue gradually forms, and again moulding.Because it has the potentiality of healing and remodeling, make the poroid material of non-organic combination with group Knit and grow into the bone tissue to form organic structure.This kind of material mainly has bioceramic and poly- fumaryl propylene (PPF).

Second, cell delivery：Autologous osteoblasts cell in osteoconductive scaffold or the healing tool into osteoblast for Cranial defect There is an important function, Gegenbaur's cell transplanting contributes to bone tissue to grow into be formed with extracellular matrix.Transplanted cells can discharge wide spectrum Growth factor promotes self-bone grafting and osteanagenesis；Poly α-hydroxylation ester is a kind of up-and-coming cell delivery material.It is other to have The material of transfusion cell function has PLA (PLA), polyglycolic acid (PGA) and the bifunctional polymerizable of PLA and polyglycolic acid Thing.

Alternating block polyurethane (AltPU) biomaterial using the present invention is the main material of skull regeneration recovery support Material, it is blended with the hydroxyapatite and tricalcium phosphate of different content, using percolation of saltouing, the three-dimensional for preparing loose structure is answered Timbering material is closed, internal stent has high porosity, is mutually communicated between micropore, disclosure satisfy that cell proliferation apoptosis and tissue fluid Infiltration exchange, is advantageous to the transport of nutriment and metabolite.This support has good blood compatibility and cytocompatibility Property.It is fine that support repairs Rat calvarial damage effect：It has been shown that, prop up from morphometric evaluation this support reparation Rat calvarial damage results Frame can keep more complete three-dimensional porous rack profile in reparation early and middle portion, and internal microcellular structure can be that cell is bred Space is provided with migration, the support of later stage higher HA/TCP contents repair skull can damage quickly, and timbering material is also complete Degraded, is substituted, appearance is no different with normal bone by area of new bone, it was demonstrated that biomaterial of the invention and thus bone made from material is repaiied Multiple support can effectively support the effect of skull regeneration reparation.

The foundation of Rat calvarial damage model：The chloraldurate of adult SD rats (300-350g) 10% presses 0.35ml/100g Body weight intraperitoneal injection of anesthesia, head unhairing, iodine tincture disinfection, calvarium skin 1cm otch, blunt separation periosteum and its surrounding tissue, Half storey 5x5mm skull defecis are manufactured on the right side of skull with cranial drill, it is compound to be implanted into Alt-PU skulls manufactured in the present embodiment respectively Repair porous scaffold (experimental group) and HA/TCP compound cranial bones porous support (control group), and fixed support, seam concurrent disinfection wound Mouthful, injection penicillin (400000IU/ml, 0.2ml/kg) continues 7 days, is implanted into and took skull to carry out after 18 days, 40 days and 80 days Morphological observation and pathological staining observation, the Alt-PU skulls of the different HA contents of ESEM (SEM) the observation display present invention Complex repairation porous support internal structure is as shown in Figure 11 a-11e.

Pathological observation and coloration result show：Postoperative 18 days, the skull defeci region of control group was without significant change；In support In the experimental group of implantation, cell has dissociated into inside skull porous support and starting to breed, cell it is loose be distributed in support Inside, osteocyte and osteoclast substantially show, and have more New born formation.Postoperative 40 days, control group skull defeci region Without significant change；Experimental group internal stent cell showed increased, new bone largely generate, and skull defeci region is in closure trend；Portion Experimental group skull defeci region is divided almost to close completely.Postoperative 80 days, it is new that the defect area of control group grows a thin layer Bone, in skull porous support group, defect is healed completely, and support is all degraded.Skull porous support (the experiment of the present invention Group) repair Rat calvarial damage effect it is fine.Rat calvarial damage results are repaired from morphometric evaluation experiment pack support to show：Branch Frame can keep more complete three-dimensional porous rack profile in reparation early and middle portion, and internal microcellular structure can be that cell is bred Space is provided with migration, skull porous support repair skull can damage quickly, and the timbering material later stage is also completely degraded quickly, Substituted by area of new bone, appearance is no different with normal bone, it was demonstrated that this timbering material can effectively support the effect of skull regeneration reparation.

Rat calvarial injury repair：The half storey skull defeci region of mouse is substantially observed from Figure 12 a.Alt-PU supports are planted After entering defect 18 days, support form can be substantially observed, it is attached at defect, is surrounded by one layer of fibr tissue (shown in Figure 12 b).40 days after surgery, the skull defeci region of control group was without obvious healing phenomenon (shown in Figure 12 c).Implantation After Alt-PU supports 80 days, Alt-PU supports have been completely degraded, and (Figure 12 d institutes are repaired in skull defeci region by complete Show).

It is other one exemplary embodiments below, any type of limitation is not done to the present invention.

Embodiment 6：A kind of alternating block polyurethane (AltPU) is provided, it is a kind of copolymer, including one or two kinds of fat Fat race polyester segment, such as PLA, PHA, PHB, PCL, PCLLA, PLGA；A hydrophilic segment, such as poly- second can be included simultaneously Glycol (PEG), polypropylene glycol (PPG), polytetramethylene glycol (PBG), PolyTHF (PTHF) or ethylene glycol, propane diols, butanediol Small molecule dihydric alcohol, trimethylolpropane (TMP) polyalcohol, it is amphipathic so as to obtain, that is, it is provided simultaneously with hydrophily and hydrophobicity Copolymer.

Embodiment 7：A kind of alternating block polyurethane (AltPU) is provided, it passes through aliphatic polyester binary alcohol and two isocyanides Hydrophilicrto polyether the segment such as PEG, PPG, PBG or aliphatic polyether glycol and diisocyanate terminated fat of acid esters end-blocking It is prepared by the selective coupling reaction between fat race polyester diol segment.Aliphatic polyester binary alcohol segment can be PLA, PHA, PHB, PCL, PGA, PCLLA, PLGA.Aliphatic diisocyanate used is hexamethylene diisocyanate, the isocyanide of lysine two Acid esters, fourth diisocyanate, IPDI, 4,4'- di-2-ethylhexylphosphine oxides (cyclohexyl) diisocyanate etc., for closing Into the diisocyanate terminated segment in selective coupling reaction；Selective coupling reaction is by tin catalyst such as 2- ethyl hexyls Sour tin (II), butyl are dibutyltindilaurate catalyzed or without using catalyst；Under an inert atmosphere in body or organic molten Selective coupling reaction is carried out in agent.

Embodiment 8：A kind of alternating block polyurethane is provided, it is the poly- ammonia of alternating block based on aliphatic polyester and polyethers Ester (Alt-PU).

Embodiment 9：The alternating block polyurethane material is in the application of other biomedical sectors, including Bone Defect Repari branch The application such as frame, skin reconstruction and reparation, Antiadhesive film, vascular repair film, meninx, ligament and tendon reparation.

With the polymer phase ratio of random block polyurethane design, alternating block polyurethane is designed to produce more regular table Face structure；With the polymer phase ratio of random block polyurethane design, alternating block polyurethane is designed to produce the polymerization of enhancing Thing is separated.

The alternating block polyurethane (AltPU) has improved medical science, machinery and processing characteristics, while has minimum Degraded pH changes and the degradation property that can well control.

Alternating block polyurethane material described in embodiment 7 is applied to CO2 laser weld socket pipe, and other soft tissues and hard Regeneration, implantable medical device and non-implanted medical device.

Above-described is only the preferred embodiments of the present invention, should be understood that the explanation of above example is simply used In help understand the present invention method and its core concept, the protection domain being not intended to limit the present invention, it is all the present invention Any modification for being made within thought and principle, equivalent substitution etc., should be included in the scope of the protection.

Claims

A kind of 1. novel degradable polyurethane biomaterial, it is characterised in that：Including it is some formed by first polymer first Block, some the second blocks formed by second polymer, the first block and the second block are alternately arranged, the first adjacent block And second pass through carbamate key connection between block and form alternating block polyurethane (AltPU), as described novel degradable Polyurethane biomaterial；

Wherein, the first polymer is the polyester of dihydric alcohol end-blocking, and the second polymer is diisocyanate terminated fat Fat adoption ether or aliphatic polyester polymers, the second polymer can also be substituted by aliphatic dihydroxy alcohol, such as ethylene glycol, 1,4- butanediols etc..
A kind of 2. novel degradable polyurethane biomaterial according to claim 1, it is characterised in that：The dihydric alcohol envelope The polyester at end is that aliphatic polyester or different aliphatic polyesters combine the copolymer to be formed.
A kind of 3. novel degradable polyurethane biomaterial according to claim 1 or 2, it is characterised in that：Described two is different Cyanate is aliphatic diisocyanate, specially hexamethylene diisocyanate, fourth diisocyanate, the isocyanic acid of lysine two In ester, lysine ester diisocyanate, IPDI, 4,4' methylene bis (cyclohexyl) diisocyanate One kind, the synthesis for the diisocyanate terminated segment in synthesis of selective coupling reaction.
4. the preparation method of novel degradable polyurethane biomaterial described in a kind of claim 1, with the first polymer and Second polymer is reaction raw materials, is reacted 8~72 hours at 30~100 DEG C, obtains the alternating block polyurethane.
A kind of 5. preparation method of novel degradable polyurethane biomaterial according to claim 4, it is characterised in that：Institute State reaction to carry out in reaction raw materials body or organic solvent, organotin catalysts can also be added in reaction system.
6. a kind of preparation method of novel degradable polyurethane biomaterial according to claim 4 or 5, its feature exist In：Hydroxyl is identical with the mol ratio of isocyanate groups in the reaction raw materials.
7. novel degradable polyurethane biomaterial described in claim 1 is applied to implantation and the preparation of non-implantable medical device.
8. novel degradable polyurethane biomaterial described in claim 1 is applied to CO2 laser weld socket pipe, meniscal repairs, resisted Adhesion film, meninx, eyelid reconstruction support, wound repair film or dressing or the preparation of bone complex repairation support.