CN108409938A

CN108409938A - A kind of novel degradable polyurethane biomaterial and its preparation method and application

Info

Publication number: CN108409938A
Application number: CN201810111018.7A
Authority: CN
Inventors: 许开天
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-06-19
Filing date: 2018-02-07
Publication date: 2018-08-17
Also published as: CN107686546A

Abstract

A kind of novel degradable polyurethane biomaterial extremely preparation method and the application in preparing 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 applications such as periphery nerve rehabilitating tube, meniscal repairs, anti-adhesion membrane, meninx, eyelid rebuilding holder, wound dressing, the compound porous recovery support of bone, other soft tissues and the 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, especially a kind of novel degradable polyurethane biomaterial and 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 medical instrument and obtains the approval of European CE and U.S. FDA applied to human body.Due to its excellent blood compatibility, excellent Machinery and processing performance are widely used in the application necks such as organizational project, regenerative medicine, control drug delivery, wound healing Domain.However, almost all of tradition block polyurethane is all using diisocyanate as coupling agent, by dihydric alcohol or/and more The terminal hydroxyl of first alcohol is synthesized with the coupling reaction of isocyanates, though this method provides the materials with improved property, but Actually it lacks the permutation and combination of block selectivity and rule, and can only become 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 lead to material Property is difficult to.

Invention content

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

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

Present invention firstly provides a kind of novel degradable polyurethane biomaterial, including several formed by first polymer First block, several the second blocks formed by second polymer, the first block and the second block are alternately arranged, and adjacent first Be keyed to form alternating block polyurethane (AltPU) by carbamate between block and the second block, as it is described it is novel can Degradable polyurethane biomaterial；

Wherein, the first polymer is the polyester of dihydric alcohol sealing end, 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 sealing end is that aliphatic polyester or different aliphatic polyesters combine the copolymerization to be formed Object.

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

The present invention also provides a kind of preparation methods of above-mentioned novel degradable polyurethane biomaterial, polymerize with described first Object 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 carries out in reaction raw materials ontology or organic solvent, can also be added in reaction system Machine tin catalyst.

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

Above-mentioned novel degradable polyurethane biomaterial can be used for preparing implantation and non-implanted medical device.

Above-mentioned novel degradable polyurethane biomaterial can be applied to but be not limited to prepare following degradable medical apparatus：

Soft tissue regeneration reparation, as Peripheral nerve repair socket pipe, Peripheral nerve repair coating film, Peripheral nerve repair are protected Bluff piece；

Artificial skin regenerates；

Biodegradable coating, as the degradable drug-carried coat of intravascular stent, foot fungus infection treat drug-carried coat；

Adherence preventing material, such as operation antiblocking film, cranium brain film；

Cartilage complex repairation holder, such as meniscal repairs porous plate, eyelid reconstruction holder；

Wound repair film and dressing, such as liquid adhesive bandage, negative pressure drainage dressing, hemostatic yarn, ear nose hemostasis cotton；

Bone complex repairation holder, such as the compound porous recovery support of skull；

Special medical absorbable suture, such as elastic force operation suture thread；

It is other can et al. Ke medical instrument and medical and beauty treatment product, as hernia repair sticking patch, soft tissue lift belt (line).

The positive effect of the present invention：This is to invent this kind of to there is segment to be alternately arranged new structural can give birth to completely for the first time Object degradation block polyurethane material.Novel degradable polyurethane biomaterial, that is, alternating block polyurethane of the present invention (AltPU) it is developed as a new class of block polyurethane biomaterial comprising block is alternately arranged (as shown in Figure 1). 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, higher surface energy more regular With stable picture on surface.Its alternating structure increases microphase-separated, to allow some segments such as to be moved than more hydrophilic segment It moves on material surface, to have 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 atomic force microscope (AFM), record has identical chemical composition AltPU and RanPU height image, it is found that the Ra (mean roughness) of 101.8nm is presented in alternate AltPU material surfaces With the Rmax (maximal roughness) of 762.9nm, it is significantly larger than the RanPU material tables that Ra is 47.6nm and Rmax is 387.9nm The patterning structure in face, these surfaces is conducive to the adherency and growth of cell.Alternating block polyurethane (AltPU) of the present invention Biomaterial is not only propped up in CO2 laser weld socket pipe, orthopaedics reparation, eyelid rebuilding holder, wound dressing and the compound porous reparation of bone Good application effect is embodied on frame, in the application of other medical instruments, including skin reconstruction and reparation, Antiadhesive film, blood Tubing patch film, meninx, ligament and tendon repair etc. also embody excellent repairing performance.

The block alternating structure of alternating block polyurethane of the present invention imparts this material many special properties and work( Energy.Such as traditional PLLA, PLGA and/or based on the implantation instrument of PCL during degradation, significant change can occur for pH value (increasing acidity), so as to cause the inflammation in local organization, influences the regeneration function of tissue, and can be to the performance of medical instrument Have an adverse effect.And the implantation instrument made of the alternating block polyurethane (AltPU) of the present invention is only shown during degradation Very small pH value variation, pH value variation are significantly smaller than raw material such as PCL and corresponding random block polyurethane material Expect the pH value variation of Ran-PU.Since polyurethane has carbamate chemical structure, acid is generated simultaneously in degradation process Property carboxyl and alkaline amido, this is different from aliphatic polyester such as PGA and PLA only generates acidic carboxypolymer during degradation, leads to fat The pH of adoption ester implantation material regional area is significantly reduced, and is compared with PLLA, PLGA, and implantation material made of the material based on PCL, The property of AltPU implantation materials of the present invention pH value minor change caused during degradation contributes to caused by reducing implantation material Inflammatory reaction risk improves the reparative regeneration function of histoorgan.

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：By the SEM figures of socket pipe prepared by alternating block polyurethane (Alt-PU)；

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 comparative situation；

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

Fig. 7 b：The postoperative observation chart for 24 hours of Alt-PU group rats；

Fig. 7 c：The postoperative two weeks observation charts of Alt-PU group rats；

Fig. 7 d：The postoperative surrounding observation chart 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% weight percent hydroxyapatite；

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

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

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

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

Figure 12 a：Half storey head injury figure is built on the right side of Rat calvarial；

Figure 12 b：Defect figure after experimental group stenter to implant 18 days；

Figure 12 c：Postoperative 40 days control group head injury area images；

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

Specific implementation mode

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 It limits.Reagent used in embodiment and device are all unless otherwise specified using this field common reagent and device.

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 is pressed and 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 It is carried out in material ontology, 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 molar ratio in reflection system.

It uses aliphatic polyester binary alcohol and Hydrophilicrto polyether as reacting body, tin-containing catalyst is added, while different with two For cyanate as coupling agent, the amount of the diisocyanate of addition is equal to the amount of the substance of-OH groups in reaction solution, will react Mixture stirs 8-72h at 30-100 DEG C under nitrogen protection, then collects product and is dried 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 holder, wound dressing and the compound porous reparation of bone Holder is representative, illustrate the alternating block polyurethane (AltPU) of preparation on applied to implanted medical device with it is other common Degradable biomaterial compares possessed superiority.

Embodiment 2

By the alternating block polyurethane (Alt-PU) prepared in embodiment 1 and the biological material of random block polyurethane (Ran-PU) 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, uses the stainless steel wire that outer diameter is 1.5mm As mold, then the polymer coating on the mold of gained is air-dried 2 days, vacuum drying 2 days, then in deionized water Salt is leached, freeze-drying and 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 10-99% and microporous pipeline structure, micropore laminated structure and pore openings pipeline that aperture is 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 drug, schwann cell and other neural benefit materials.

Peripheral nerve defect is very common clinical wound, and frequently result in patient feeling and motor function forever Long property is disabled, and in China, there are about 900,000 new cases every year.Nerve autograft is the common treatment means of neurotrosis, so And there are many sizes between disadvantage, including defect nerve and Nerve Graft to mismatch for this method；God for extracting donor Through second operation to be undergone；Donor graft is insufficient；Donor site is also easy to produce neuroma etc..In order to overcome the problems, such as these, 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 usually by the type i collagen of biological source and synthesized degradable biology material Expect that this two classes material is made, such as polycaprolactone (PCL), poly- (lactide-co-caprolactone) (PCLLA), poly (L-lactic acid) (PLLA), poly- (D, L- lactic acid-ethanol copolymer) (PLGA) and polyvinyl alcohol (PVA).However, by these biomaterial systems There are following FAQs for the CO2 laser weld socket pipe made：

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

2) biocompatibility of material is limited, cannot promote the growth of nerve cell；

3) inflammation caused by acid degradation products；

4) flexibility of neural socket pipe is insufficient, and neural residul end during regeneration is caused to be torn from neural socket pipe chamber；

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

6) the extensive inflammation reaction etc. for easily causing fibrosis and nerve regneration being presented；

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

Due to the particularity of AltPU material structures and function, manufactured nerve trachea effectively overcomes above shortcoming, makes It obtains restoration effect and is not only better than nerve autograft, better than nerve socket 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 carries out CO2 laser weld experiment in SD rat animal models, To neural socket pipe and nerve autograft made of Alt-PU and Ran-PU (embodiment 1), PCL, the manufactured set of silicone tube It takes over the system research for carrying out CO2 laser weld and compares, nerve is evaluated for 80 adult SD rats of 300-350g using weight Repairing effect.Wherein, Fig. 3 a are CO2 laser weld micrurgy schematic diagram；Fig. 3 b are the CO2 laser weld socket being implanted into 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), the sciatic nerve 12mm defects generated by the operation excision of nerve fiber are used as neurotrosis mould Type, the repairing effect evaluation for neural socket pipe.The yellow Jackets of animal 50mg/kg weight are anaesthetized, the ischium on right side Nerve exposure, the nerve segment of 12mm is removed from big midleg level.15mm conduits or the nerve of removal are inserted in proximal end in itself Between distal stump, sutured with No. 8-0 absorbable PLGA suture in each junction.After implantation, stitched using No. 5-0 Zygonema sutures muscle incision, and 2-0 silk suture skins are used in combination.Every rat receives an implantation material, 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 of sciatic nerve function index (SFI) value, implantation observe in Alt-PU groups after 14 weeks SFI values be- 24%, restore SFI value -28% higher than autograft group, is much better than -35%SFI the values and PCL groups of Ran-PU 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 motor function is not completely extensive at this time It is multiple.It was marked at the 14th week, footprint image restores normal, shows that neuromotor function significantly restores.

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

Implantation 4,8 and 14 weeks after, Alt-PU, Ran-PU, autograft, PCL holders, silicone tube C MAP current potential Signal compares (the results are shown in Figure 4).Action potential in Alt-PU, Ran-PU, autotransplantation group and PCL holder 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.However surprisingly Alt-PU groups show signal more stronger than autotransplantation group.This shows novel alternating block The CO2 laser weld socket pipe of polyurethane (Alt-PU) is suitable with the autotransplantation for being considered " goldstandard " in restoration effect, It is even better.

Embodiment 3

Alternating block polyurethane (Alt-PU) biomaterial prepared in embodiment 1 is applied to the preparation of eyelid holder, Manufacturing method is liquid-solid phase separation and freeze-drying：

Be put into beaker with a certain amount of Alt-PU materials, be added organic solvent, until Alt-PU be completely dissolved into it is transparent Solution.Solution is poured into stainless steel mould, liquid level thickness is poured into control, and the mold containing solution is placed in -20-0 DEG C of ice 1-10h in water mixing insulating box, taking-up are placed on 1-24h in -10-4 DEG C, move in freeze drier be lyophilized later, Zhi Houleng Dry 1-24h is lyophilized, takes out stainless steel mould and is put into ambient temperature vacuum drying machine dry 1-48h, shaped support is taken out in demoulding, then Holder is cut into 1cm²Holder obtains 0.7mm × 1cm²Eyelid is implanted into holder.It is 10- that this eyelid, which is implanted into holder to have porosity, 99% and aperture be 100nm to 500 μm (micron) porous membrane structure.

The processing method of ADM eyelid holders is commercialized：ADM is put into lyophilized overnight on freeze drier, from freezing It is taken out on drying machine, holder is then cut into 1cm²。

Important appendicle of the eyelid as eye only has 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 is increased.The defect of eyelid skin, muscle, tarsus, papebral conjunctiva is often resulted in after defect of eyelid, no Beauty is only influenced, and exposed property ulcer of the cornea is usually caused, and then cause the opacity of the cornea, or even wear due to the exposure of eyeball It blinds in hole.The damage of eyelid usually requires the part that damage was filled up as tissue substituent or reinforced to different materials.Therefore, There are many tissues by the reparation, including autologous tissue, allosome tissue and artificial organ etc. of exploitation progress eye wounds.Its In, the limited sources such as autologous material 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 is long, needs second of operative incision；The transplanting such as allohisto compatibility such as allogeneic sclera, Homologous dura Object is different from the antigenicity of 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, it can be very good to be widely used in clinic without a kind of tarsus substitute.

Ideal eyelid substitute should comply with the following conditions：

1) facilitate acquisition and preservation.

2) it operates and is easy 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 hardness similar with 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) implantation infectious-related complication is few.

8) said effect can continue for quite a long time, or even lifelong.

Meanwhile being needed in conjunction with the specific function of eye, tarsus substitute should also twinkled with the surface of relative smooth The cornea under it will not be worn in the process, it is basic after implantation to meet facial symmetrical and protection eyeball effect.

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

The eyelid prepared in the present embodiment implantation holder is subjected to eyelid repairing test in SD rat animal models.Animal Operation consent rinses Alt-PU eyelids implantation holder through sterile saline, and ultraviolet ventilation irradiation is sealed afterwards in sterile for 24 hours It is saved backup in centrifuge tube.

The foundation of animal model：SD rats 30, male, 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 entire preserved skin region of routine disinfection, later 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 rises, and two arc incision lines of skin are drawn with black gel ink pen, is marked at operation opening at the 5mm of canthus both sides, then Do the skin incision of upper eyelid by mark line, detach two notch subcutaneous tissue and orbicular muscle of eye to tarsus, after finding out tarsus, with aobvious Micro- clipper for surgical use wipes out 1mm²Size tarsus tissue obtains eyelid tarsal defect model.By ready Alt-PU eyelids holder and Then the corresponding tarsal defect position of ADM eyelid stenter to implant uses the degradable absorbable suture lines of 8-0 by implantation material and the tarsus broken ends of fractured bone 2 needle of corresponding interrupted suture is interrupted apposition suture skin of upper eyelid and subcutaneous tissue, about 2 needles with 6-0 absorbable sutures, and art finishes, wound Mouth Pressure bandage.Postoperative SD rats are put into mouse cage, after waiting for its anesthesia to wake up, give sub-cage rearing, it is postoperative Daily the wound location of observation rat whether there is or not it is red and swollen, infect, fester；Wound pairing situation, whether there is or not split and plant piece to fall off, cruelly Dew；Whether there is or not damaged and corneal damages for conjunctival surface；Whether there is or not deformations for margo palpebrae；Whether there is or not fornixs to narrow, 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 Absorb suture suture (shown in Fig. 7 a)；B) it is formed there are one small scab within postoperative 24 hours, there is a little slight redness in upper eyelid, does not have Observe that (shown in Fig. 7 b) occurs for apparent rejection and gangrenous phenomenon；C) hair at postoperative two weeks eyelid surgeries starts to give birth to It is long, it is observed that (shown in Fig. 7 c) without congested, exudation and inflammatory reaction phenomenon；D) postoperative 4 weeks art branch holes portion be restored to Preoperative the same, arrow is directed toward operative site (shown in Fig. 7 d).The consciousness of postoperative 1h, rat all restore normal；Postoperative sees mouse for 24 hours Upper eyelid gently swells, and margo palpebrae suture is in place, and wound pairing is good, and local desiccation is without exudation, 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 exudation and infection without incisura, no hypophasis, notch after implantation Exposure.It is that 1W, the hair of its art side wound postoperative 2W start to repair completely after surgery that its scab, which is completely fallen off,.Postoperative 2W and During the art branch hole portion of 8W does not have apparent difference, eyelid to repair, their daily life system is normal, and art branch hole portion also acts normally Eye opening eye closing activity, with the activity of normal side eye.Occur without significantly rejection, gangrene or inflammatory reaction, it was demonstrated that Its postoperative eyelid wound restores 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：

It weighs alternating block polyurethane (Alt-PU) biomaterial prepared in 2g embodiments 1 and is dissolved in 40mL water In, it is made into the solution of a concentration of 50mg/mL, is sufficiently stirred and is poured into the culture dish of 90mm after it is completely dissolved.Again by its turn Precooling 1-24h in -20 DEG C of refrigerator is moved to, then transfers them to rapidly in -80 DEG C of low temperature refrigerator and freezes 1-24h.It takes Quickly be transferred in freeze drier, be freeze-dried after go out, taken out afterwards for 24 hours, spongy Alt-PU wound repairs foam Dressing.This wound repair dressing has the porous foam knot that porosity is 10-99% and aperture is 100nm to 500 μm (micron) 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 hot spot of current medical domain research, currently, the polyurethane material as wound dressing Rarely found report is studied, since polyurethane high molecule has waterproof and breathable, moisturizing and the function of preventing bacterium from penetrating into, with degradable PLA and the polyurethane of the good PEG synthesis of biocompatibility have good potentiality as the research of wound dressing.The present invention PLA, PEG group biodegradable polyurethane material are applied to wound repair for the first time, by the full thickness skin for building SD rats Model, as a contrast with 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 novel wound dressing materials.

The Alt-PU wound repairs foam dressing prepared in the present embodiment is carried out 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 As wound dressing to the curative effect of 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 It gently strikes off after 70% alcohol disinfecting of number, is cleaned with clear water.Then with disinfection after surgical scissors back cut 10mm × The wound size of 10mm, and the surface of a wound is carried out thoroughly to expand wound, 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, as a control group with Ran-PU wound repair foam dressing groups and hospital gauze.It replaces within every two days primary Dressing records wound size with ruler, and photographs to record wound situation.After ten days, remaining four days no longer more change dressings, 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, 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 that inflammation, redness and empyema.The 8th after wound It, 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 newborn granulation tissue, the result shows the recovery of the skin of Alt-PU groups is most fast, into The last repairing phase of skin is entered, thus will be good than preceding two groups of repairing effect.The 14th day after wound, gauze group still has ratio Obvious scar, shrinking percentage at this time, which is only 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 observe the scar of wound.Wherein Fig. 9 is Wound records wound size, and the contraction of wounds rate as obtained by formula calculating, contraction of wounds rate in repair process, with ruler It is bigger, illustrate that the surface of a wound is smaller, it is also better to restore.It can be seen that the shrinking percentage of Alt-PU groups is always above other two in Fig. 9 Control group, this result are also consistent with result above.

From gross examination of skeletal muscle it is found that the polyurethane biomaterial of the present invention can provide the effect of protection for wound, and have Certain acts on every bacterium, can form the surface of a wound of a moistening by absorbing diffusate, be supplied to one good life of cambium Long environment.Very close, the Ke Yitong additionally, due to the ammonia ester bond in polyurethane macromolecular and the amido bond in human body internal protein The adherency and growth for promoting the specific effect of cell surface cell are crossed, the healing of wound is accelerated.Along with suitable parent Hydrophobicity, mechanical property and flexibility etc. all have an impact wound reparation, and alternating block polyurethane of the invention can become The ideal material of wound repair and skin repair.

The histology pathological analysis of wound repair：The case where in order to further determine skin repair, we took at 14 days Lower neoplastic skin tissue carries out pathological analysis, as a result as shown in Figure 10 a-10c by HE dyeing to tissue.As front is created Hinder described in repair mechanisms, is inflammatory reaction first after skin wound is formed, it is the basis of wound healing.This stage master Have a large amount of inflammatory cell, it removed by phagocytosis, oxidation antimicrobial effect and the effects that activating complement slough and Foreign matter protects normal structure, prevents infection.Followed by fibroblastic a large amount of proliferation, it is main repair cell, It is the engineer, builder and administrator of wound repair, it and extracellular matrix, contraction of wounds, the update 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 It compares and finds in figure, a large amount 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 under the microscope there are many organs such as new vessels, lymph generate (Figure 10 b It is shown), the institutional framework (Figure 10 a shown in) of closer normal skin obviously smaller than gauze group at fibrosis region, this Phenomenon also can promote migration of epithelial cells related 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 holder, preparation method are：

The Alt-PU alternating block polyurethane biomaterials prepared in appropriate embodiment 1 are weighed, are put into 20ml vials, N,N-dimethylformamide to polyurethane is added to be completely dissolved.Weigh sodium chloride particle, the hydroxyapatite (HA) of certain grain size It is added in polyurethane solutions after shaking mixing in proportion with tricalcium phosphate (TCP), vibrates mixing, mixture is coated on glass slide On, drying at room temperature 48h is complete to n,N-Dimethylformamide volatilization.Glass slide is placed in ultra-pure water fully dissolving chlorination for 24 hours Sodium particle is changed the liquid once per 8h, and glass slide is placed in drying at room temperature 48h in vacuum drying chamber to be repaiied to get Alt-PU skulls are compound Multiple porous support, this holder have the porous foam structure that porosity is 10-99% and aperture is 100nm to 500 μm (micron). It is compared simultaneously convenient for the reference of holder, we also use polymethyl methacrylate (PMMA) no HA and TCP the case where Under, porous support is produced as shown in Figure 11 f.

Bone tissue engineer research experienced from no immune function animal to small-sized mammalian, then arrive large mammal, The stage of most Zhongdao clinic, validity, safety be proved more and more, basic fundamental relative maturity.It is careful planting In terms of born of the same parents, other than currently used BMSCs, also occur adipose-derived and Cord Blood-Derived stem cell successively, it Derive from a wealth of sources, osteogenic ability is similar to even better than BMSCs.In terms of timbering material, in addition to previously widely applied different Other than 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 all have source General and degradable characteristic, needs of the mechanical strength all close to tissue engineered bone.In terms of constructing technology, weaver 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 application 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 porosity, biodegradable stent.This holder has self-bone grafting And osteoconductive potential, the other cells of osteoblast and the region can be caused and grow into and be adsorbed on holder.As matrix is accumulated, bone Tissue gradually forms, and again moulding.Since it has the potentiality of healing and remodeling, make the poroid substance of non-organic combination with group It knits and grows into the bone tissue to form organic structure.This substance mainly has bioceramic and poly- fumaryl propylene (PPF).Second is that Cell delivery：Autologous osteoblasts cell in osteoconductive scaffold or the healing with important work(for bone defect at osteoblast Can, osteoblast transplanting contributes to bone tissue to grow into be formed with extracellular matrix.Transplanted cells can discharge wide spectrum growth factor rush Into self-bone grafting and osteanagenesis；Poly α-hydroxylation ester is a kind of up-and-coming cell delivery substance.It is other that there is transfusion cell work( Can substance have polylactic acid (PLA), polyglycolic acid (PGA) and polylactic acid and polyglycolic acid bifunctional polymerizable object.

Alternating block polyurethane (AltPU) biomaterial using the present invention is the main material of skull regeneration recovery support Material, is blended with the hydroxyapatite of different content and tricalcium phosphate, and using percolation of saltouing, the three-dimensional for preparing porous structure is multiple Timbering material is closed, internal stent has high porosity, is mutually communicated between micropore, disclosure satisfy that cell Proliferation migration and tissue fluid Infiltration exchange, is conducive to the transport of nutriment and metabolite.This holder has good blood compatibility and cytocompatibility Property.It is fine that holder repairs Rat calvarial damage effect：It shows, props up from morphometric evaluation this holder reparation Rat calvarial damage results Frame can be cell Proliferation repairing early and middle portion to keep more complete three-dimensional porous rack shape, internal microcellular structure Space is provided with migration, the holder of later stage higher HA/TCP contents repair skull can damage quickly, and timbering material is also complete Degradation, 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 holder can effectively support the effect of skull regeneration reparation.

The foundation of Rat calvarial damage model：10% chloraldurate of adult SD rats (300-350g) presses 0.35ml/100g Weight intraperitoneal injection of anesthesia, head unhairing, iodine tincture disinfection, calvarium skin 1cm notch, 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 fixing bracket, seam concurrent disinfection wound Mouthful, injection penicillin (400000IU/ml, 0.2ml/kg) continues 7 days, takes skull to carry out in 18 days, 40 days and 80 days after implantation Morphological observation and pathological staining observation, the Alt-PU skulls of the different HA contents of scanning electron microscope (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 holder In the experimental group of implantation, cell has dissociated into inside skull porous support and starting to be proliferated, cell it is loose be distributed in holder Inside, osteocyte and osteoclast obviously 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 Point experimental group skull defeci region has almost been closed 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 heals completely, and holder 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 be cell Proliferation repairing early and middle portion to keep more complete three-dimensional porous rack shape, internal microcellular structure Space is provided with migration, skull porous support repair skull can damage quickly, and the timbering material later stage is also completely degraded quickly, It is 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 obviously observed from Figure 12 a.Alt-PU holders are planted After entering defect 18 days, it can obviously observe holder form, be attached at defect, be 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 apparent healing phenomenon (shown in Figure 12 c).Implantation After Alt-PU holders 80 days, Alt-PU holders have been completely degraded, and (Figure 12 d institutes are repaired in skull defeci region completely Show).

It is other 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, is a kind of copolymer, including one or two kinds of fat Fat race polyester segment, such as PLA, PHA, PHB, PCL, PCLLA, PLGA；Can include a hydrophilic segment, such as poly- second simultaneously Glycol (PEG), polypropylene glycol (PPG), polytetramethylene glycol (PBG), PolyTHF (PTHF) or ethylene glycol, propylene glycol, butanediol Small molecule dihydric alcohol, trimethylolpropane (TMP) polyalcohol, it is amphipathic to obtain, that is, it is provided simultaneously with hydrophily and hydrophobicity Copolymer.

Embodiment 7：A kind of alternating block polyurethane (AltPU) is provided, aliphatic polyester binary alcohol and two isocyanides are passed through Hydrophilicrto polyether the segment such as PEG, PPG, PBG or aliphatic polyether glycol of acid esters sealing end and diisocyanate terminated fat 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, two isocyanide of lysine Acid esters, fourth diisocyanate, isophorone diisocyanate, 4,4'- di-2-ethylhexylphosphine oxides (cyclohexyl) diisocyanate etc., for closing At the diisocyanate terminated segment in selective coupling reaction；Selective coupling reaction is by tin catalyst such as 2- ethyl hexyls Sour tin (II), butyl is dibutyltindilaurate catalyzed or does not use catalyst；Under an inert atmosphere in ontology or organic molten Selective coupling reaction is carried out in agent.

Embodiment 8：A kind of alternating block polyurethane is provided, 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 applications 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, the design of alternating block polyurethane can generate more regular table Face structure；With the polymer phase ratio of random block polyurethane design, alternating block polyurethane designs the polymerization that can generate enhancing Object is separated.

The alternating block polyurethane (AltPU) has improved medicine, machinery and processing performance, while having minimum The degradation property that degradation pH changes and can well control.

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

The medical treatment of this project degradable biomaterial possible application and beauty product (including but is not limited to)：

1. soft tissue regeneration reparation is used for, such as Peripheral nerve repair socket pipe, Peripheral nerve repair coating film, peripheral nerve Restoration and protection piece；Artificial skin regenerates；

2. biodegradable coating, such as the degradable drug-carried coat of intravascular stent, foot fungus infection treats drug-carried coat；

3. adherence preventing material, such as operation antiblocking film, cranium brain film；

4. repair of cartilage holder, such as meniscal repairs porous plate, eyelid reconstruction holder；

5. wound repair film and dressing, such as liquid adhesive bandage, negative pressure drainage dressing, hemostatic yarn, ear nose hemostasis cotton；

6. bone complex repairation holder, such as skull complex repairation holder；

7. special medical absorbable suture, such as elastic force medical absorbable suture；

8. it is other can et al. Ke medical instrument and medical and beauty treatment product, as hernia repair sticking patch, soft tissue lift belt The preparation of (line).

It is above-described to be merely a preferred embodiment of the present invention, it should be understood that the explanation of above example is only used In facilitating the understanding of the method and its core concept of the invention, it is not intended to limit the scope of protection of the present invention, it is all the present invention's Any modification for being made within thought and principle, equivalent replacement etc., should all be included in the protection scope of the present invention.

Claims

1. a kind of novel degradable polyurethane biomaterial, it is characterised in that：Including several first formed by first polymer Block, several the second blocks formed by second polymer, the first block and the second block are alternately arranged, the first adjacent block And second be keyed to form alternating block polyurethane (AltPU) by carbamate between block, the as described novel degradable Polyurethane biomaterial.

2. a kind of novel degradable polyurethane biomaterial according to claim 1, it is characterised in that：First block With the second block random alignment, it is keyed to be formed without returning block by carbamate between adjacent the first block and the second block Polyurethane (RanPU) degradable polyurethane biomaterial.

3. a kind of novel degradable polyurethane biomaterial according to claim 1 or 2, it is characterised in that：Described first Polymer is the polyester of dihydric alcohol sealing end, and the second polymer is diisocyanate terminated aliphatic polyether or aliphatic poly Ester polymer, the second polymer can also be substituted by aliphatic dihydroxy alcohol.

4. a kind of novel degradable polyurethane biomaterial according to claim 3, it is characterised in that：Second polymerization Object aliphatic dihydroxy alcohol is ethylene glycol or 1,4- butanediols.

5. a kind of novel degradable polyurethane biomaterial according to claim 3, 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；The diisocyanate is aliphatic two Isocyanates, specially hexamethylene diisocyanate, fourth diisocyanate, lysine diisocyanate, lysine ester two are different One kind in cyanate, isophorone diisocyanate, 4,4' methylene bis (cyclohexyl) diisocyanate.

6. 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.

7. a kind of preparation method of novel degradable polyurethane biomaterial according to claim 6, it is characterised in that：Institute It states reaction to carry out in reaction raw materials ontology or organic solvent, organotin catalysts can also be added in reaction system.

8. a kind of preparation method of novel degradable polyurethane biomaterial according to claim 6, it is characterised in that：Institute It is identical with the molar ratio of isocyanate groups to state hydroxyl in reaction raw materials.

9. novel degradable polyurethane biomaterial described in claim 1 is preparing degradable implantation and non-implantable medical device Using.

10. according to claims require the 9 novel degradable polyurethane biomaterials prepares it is degradable implantation with it is non- The application of the application of implantable medical device, it is characterised in that：The degradable implantation and non-implantable medical device are included in nerve Reparation socket pipe, meniscal repairs, resist blocking and that film, meninx, eyelid reconstruction holder, wound repair film or/dressing, Or cartilage and bone complex repairation holder, artificial skin, biodegradable coating, adherence preventing material, special absorbable operation stitching Line or it is other can et al. Ke medical instrument and medical and beauty treatment product preparation；

1. soft tissue regeneration reparation is used for, such as Peripheral nerve repair socket pipe, Peripheral nerve repair coating film, Peripheral nerve repair Screening glass；Artificial skin regenerates；

6. bone complex repairation holder, such as skull complex repairation holder；

8. it is other can et al. Ke medical instrument and medical and beauty treatment product, if hernia repair sticking patch, soft tissue lift belt (line) It prepares.