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ARTICLE in TISSUE ENGINEERING PART B REVIEWS · DECEMBER 2010
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Mineralization of Hydrogels for Bone Regeneration
Katerina Gkioni,M.Sc.,1Sander C.G.Leeuwenburgh,Ph.D.,1Timothy E.L.Douglas,Ph.D.,1
Antonios G.Mikos,Ph.D.,2and John A.Jansen,D.D.S.,Ph.D.1
Hydrogels are an important class of highly hydrated polymers that are widely investigated for potential use in soft tissue engineering.Generally,however,hydrogels lack the ability to mineralize,preventing the formation of chemical bonds with hard tissues such as bone.A recent trend in tissue engineering involves the development of hydrogels that possess the capacity to mineralize.The strategy that has attracted most interest has been the incorporation of inorganic phases such as calcium phosphate ceramics and bioglasses into hydrogel matrices.These inorganic particles act as nucleation sites that enable further mineralization,thus improving the me-chanical properties of the composite material.A second route to create nucleation sites for calci?cation of hydrogels involves the use of features from the physiological mineralization process.Examples of these bio-mimetic mineralization strategies include (1)soaking of hydrogels in solutions that are saturated with respect to calcium phosphate,(2)incorporation of enzymes that catalyze deposition of bone mineral,and (3)incorporation of synthetic analogues to matrix vesicles that are the initial sites of biomineralization.Functionalization of the polymeric hydrogel backbone with negatively charged groups is a third mechanism to promote mineralization in otherwise inert hydrogels.This review summarizes the main strategies that have been developed in the past decade to calcify hydrogel matrices and render these hydrogels suitable for applications in bone regeneration.Introduction
Bone substitution materials
B one is a composite material comprised of a collage-
nous ?brous matrix that is enriched with platelet-shaped
nanocrystals of carbonated apatite (average dimensions:
50nm long,25nm wide,and 3nm thick).This complex na-
nostructure makes bone a unique tissue with exceptional
mechanical and biological properties.1,2
Despite several decades of research on synthetic bone
substitutes,the use of autografts is still the gold standard in
clinical practice.Autografting requires a surgery in which
parts of healthy bone from the patient are harvested from,
for instance,the iliac crest and subsequently transferred to
the site of application.Alternative options include the use of
bone harvested from another donor (allografts)or from an-
imals (xenografts).3,4Even though these surgical treatments
have resulted into good clinical outcome,they are accom-
panied by strong drawbacks such as infections,pain,and
morbidity at the donor site,high costs,and the necessity of
additional surgery.5,6To eliminate these severe problems,
there is a pressing need for novel synthetic materials that can
substitute bone suf?ciently.
Several materials,such as metals 7,ceramics,and poly-
mers 8,have been used for bone replacement.In the era of
regenerative medicine,the poor degradability of metallic and ceramic scaffolds has become the major disadvantage that inhibits complete regeneration of bone tissue.Polymers,on the other hand,are known for the ease by which degradation can be tailored by controlling the chemical composition of the monomer units during synthesis.Until recently,the majority of polymeric bone substitutes were premade con-structs that were implanted surgically via invasive surgery.Clinically,there is a growing need for materials that can be inserted using minimally invasive methods such as a simple injection.9Ideally,such a material should be of viscosity low enough to be injected and harden after injection,thereby enabling incorporation of drugs,cells,and growth factors in the viscous solution before administration.10Hydrogels are a speci?c,highly hydrated class of polymers that ful?ll all of the abovementioned requirements.Hydrogels Hydrogels are hydrophilic crosslinked polymers that are formed by the reaction of one or more monomers,by associ-ation of hydrogen bonds or van der Waals interactions be-tween the chains.11,12The crosslinking can be achieved either physically or chemically.While in chemical crosslinking co-valent bonds must be formed,physical crosslinking happens when physical interaction between the chains occurs.131
Department of Biomaterials,Radboud University Nijmegen Medical Center,Nijmegen,The Netherlands.2Department of Bioengineering,Rice University,Houston,Texas.
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DOI:10.1089/ten.teb.2010.0462
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Hydrogels can be classi?ed according to their origin(natural or synthetic),14method of preparation(homopolymer,co-polymer,multipolymer,and interpenetrating hydrogels),io-nic charges(neutral,anionic,cationic,and ampholytic hydrogels),and physical structure(amorphous,semicrystal-line,and hydrogen bonded structures).11
When hydrogels are in contact with water,they swell and form an insoluble three-dimensional network.Other than injectability,hydrogels display many properties15that make them desirable candidates for tissue engineering applica-tions.One of the most important advantages is their aqueous environment,which protects cells and sensitive drugs that can be incorporated in the network for controlled delivery at the site of injury.The aqueous environment allows trans-portation of substances,such as nutrients and by-products from cell metabolism,in and out of the hydrogels.16Hy-drogels can also be derivatized with functional groups that mediate processes such as cell attachment and subsequent spreading.17Until recently,hydrogels have been mainly considered for soft tissue regeneration.In the last few years, however,the interest to test the feasibility of using the ben-e?cial properties of hydrogels for hard tissue regeneration has increased.Still,for applications in hard tissue engineer-ing,hydrogels are associated with a number of disadvan-tages such as their poor mineralization upon implantation.18 Further,the inherent mechanical weakness of hydrogels is a limiting factor that restricts their use to non-load-bearing applications15,19,even though reinforcement can be achieved by the addition of other phases.6,18,20,21Finally,many hy-drogels are dif?cult to sterilize due to their high water con-tent and the polymer reactivity under UV light.22
It is not in the scope of this study to review a list of all the hydrogels—natural or synthetic—used in the?eld of tissue engineering,since there are many excellent reviews that thoroughly elaborate on this subject.19,23–28This article will focus on the strategies developed during the past decade to induce mineralization in inert,nonmineralizing hydrogels in vitro(immersion in simulated body?uids[SBF])or in vivo for use in bone regeneration.Three major strategies used for calci?cation of hydrogels will be reviewed,including(1)the addition of inorganic particles aiming at mineralization and improvement of the mechanical properties of hydrogels,(2) the creation of nucleation sites by biomimetic methods,such as soaking treatments and the use of enzymes and vesicles that play an important role in physiological biomineraliza-tion,and(3)the derivatization of the polymeric hydrogel backbone with anionic functional groups.In addition,some indirect methods of mineralization such as growth factors and cell incorporation or addition of demineralized bone matrix will be brie?y discussed.
Mineralization by Adding Inorganic Phases
The capacity of a speci?c class of bone-substituting ma-terials to induce calci?cation is often referred to as bioac-tivity,which implies that these materials possess the capacity to promote nucleation and subsequent proliferation of cal-cium phosphate crystals.Generally,most polymeric materi-als do not possess this capacity,but the addition of a ceramic phase can still render the resulting composites bioactive by providing nucleation sites for the promotion of hydroxyap-atite(HA)precipitation.The concept of combining a hydro-gel with an inorganic phase is inspired by the composite nature of bone itself.One of the many advantages of adding an inorganic phase is that the dispersed mineral will provide nucleation sites for HA formation as well as cell adhesion sites that enable integration with surrounding bone tis-sue.29,30Further,degradation of the temporary hydrogel implant will allow for replacement by new bone formation, thus increasing mechanically stability.
Degradation times and mechanical properties of organic–inorganic composite materials can be controlled to a large extent by the addition of inorganic phases.20,21,31Moreover, the handling characteristics of such composite materials can be greatly improved,since brittle ceramic particles can be delivered in moldable or even injectable formulations using the elasticity of the hydrogels.5Finally32,the addition of carbonated apatites in polymers can have a neutralizing ef-fect on the acidic pH caused by the degradation by-products, thus minimizing excessive in?ammation around the im-plantation site.
There are many bioactive inorganic materials that can be used to render hydrogels mineralizable.These ceramic ma-terials are able to create a?rm bond with bone at the site of implantation by forming an intermediate layer of HA on their surface.33
The most commonly used inorganic phases are calcium phosphates and bioglasses.Many calcium phosphate ce-ramics can be found in literature with the most representa-tive being b-tricalcium phosphate(b-TCP),amorphous calcium phosphate,and HA.This group of ceramics shows strong resemblance to the mineral phase of bone and it is found in many normal or pathological calci?ed sites in the human body.34Thorough reviews of all relevant calcium phosphates that are present in the human body can be found elsewhere.35–37Bioactive glasses are amorphous solids con-taining<60wt%SiO2that are bioactive due to their high reactivity in aqueous media.Modern preparation techniques such as the sol–gel process have yielded a wide range of mesoporous,highly bioactive,and bioresorbable materials for the production of bone implants.38It has been shown39,40 that the formation of HA on the surface of these materials is due to the formation of–OH groups when the glass contacts body?uids.41,42
Composites based on natural hydrogels
Advantages of natural hydrogels include their biocom-patibility,biodegradability,and commercial availability. Composites of natural hydrogels and bioactive phases have been shown to accelerate osteogenesis and sometimes pos-sess osteoconductive properties that were even superior to monolithic HA implants.43There are many natural poly-mers23used for tissue engineering most commonly collagen and its denatured derivative gelatin44,?brin,as well as chitin and its deacetylated derivative chitosan.
Collagen(mostly collagen type I)is the main polymer phase of bone,45and it is highly biocompatible,degrades enzymatically,and can be processed easily into different forms such as sponges,46?bers,47tubes,and sheets.48,49An example of a collagen hydrogel that was combined with an inorganic calcium phosphate phase was reported by Zou et al.49The collagen?bers were crosslinked by using glu-taraldehyde.Ceramic b-TCP particles were homogeneously
578GKIONI ET AL.
dispersed inside the collagen matrix,but also a?rm bond between the ceramic particles and the hydrogel was formed. In addition,the scaffolds showed bone tissue regeneration after12weeks of implantation in animals.For more spe-ci?c information on the use of collagen as matrix phase, the reader is referred to a thorough review about collagen-HA composites for hard tissue engineering by Wahl and Czermuszka.50
Fibrin glue51,52is a synthetic analogue of the blood coagu-lation process that creates a?brin clot upon mixing of the two components?brinogen and thrombin and it can be used as tissue adhesive in many surgical applications due to its fa-vorable biological behavior.Le Nihouannen et al.53combined these bene?cial properties of?brin glue in terms of clinical handling and biocompatibility with the bioactive characteris-tics of an additional ceramic phase to develop a composite material for bone regeneration.Micro-and macroporous biphasic calcium phosphate granules(HA and b-TCP in a weight ratio of60/40,respectively)were mixed with a?brin glue matrix inducing mineralization within the?brin network. Tan et al.54prepared an injectable biomaterial consisting of calcium alginate and nano-HA.The injectability and the setting time of the material could be easily tuned by altering the absolute and relative concentrations of the components. Alginate has the unique capacity to gel in the presence of dissolved calcium ions,which is a very mild method to create crosslinks into an organic matrix.The particles of HA had a diameter of50m m and the?nal concentration of HA in the gel was kept at3%g/mL.CaSO4was used to crosslink the alginate gel.It was concluded that that the?nal com-posite material is a good candidate for bone repair and bone tissue engineering.Alginates for bone reconstruction re-inforced with HA55and octacalcium phosphate56have also been shown to be bioactive.
Addition of SiO2,which is the main component of bio-glasses,inside polymeric matrices also aims to trigger the calci?cation of polymer matrix.Madhumathi et al.57pre-pared a scaffold by dispersing silica nanoparticles inside a chitin hydrogel.The scaffold showed HA formation only after7days of immersion in SBF.Similar particles were also introduced inside chitosan hydrogels58and signi?cant min-eralization of the matrix was observed after immersion in SBF as well as implantation in rat calvaria for3weeks.Si-milarly,addition of sol-gel prepared SiO2-CaO-P2O5bioglass nanoparticles inside a chitosan-based hydrogel also induced bone-like apatite after immersion in SBF.59
Composites based on synthetic hydrogels
Even though naturally derived hydrogels have desirable biological properties,they often exhibit degradation pro?les that are too fast for hard tissue regeneration.60Moreover, chemical characteristics of natural hydrogels such as the molecular weight usually display a wide distribution due to their natural origin,which limits the reproducibility and functionality of the materials.On the contrary,synthetic hydrogels can be prepared with tailored and highly repro-ducible chemical characteristics,thereby allowing for careful degradation properties.61The combination of the different monomer units results in hydrogels with controlled charac-teristics in terms of degradation rate,swelling ratios,and mechanical properties.62
Polymeric chains can be?nely tuned based on the clinical requirements of the various applications in hard tissue engi-neering.As a result,a wide range of crosslinking techniques can be used to form the hydrogels such as photo-polymerization or radical polymerization in the presence of small crosslinking agents.10,17,61The most common synthetic hydrogels that are studied for bone tissue engineering pur-poses include hydrogels based either on polyethylene glycol (PEG)62,63,poly(2-hydroxyethyl methacrylate)(pHEMA),or poly(N-isopropylacrylamide).64,65
A recent example of the use of PEG-based hydrogels as matrix for the addition of inorganic HA nanoparticles was described by Sarvestani et al.,66,67who exploited the calcium-binding capacity of a6-glutamic acid sequence(as found in the terminal sequences of osteonectin)to increase the inter-action strength between inorganic HA nanoparticles and (L-lactide-co-ethylene oxide-co-fumarate).The other end of the peptide was functionalized with an acrylate group that enabled the establishment of covalent bonds between the peptide and the organic polymer.In this way,the functio-nalized peptide acted as a linker between inorganic and organic composite components.
Patel et al.68developed cyclic acetal hydrogels reinforced with nanoparticles of HA for craniofacial tissue engineering application.Incorporation of HA nanoparticles into cyclic acetal hydrogels resulted into enhanced differentiation of bone marrow stromal cells by promotion of endogenous osteogenic signal expression.
Composites based on pHEMA with high mineral content of about37%–50%were prepared by Song et al.69The group used pHEMA polymer that was crosslinked in the presence of HA crystals using viscous ethylene glycol as solvent to facilitate the easy dispersion and prevent sedimentation of the HA particles.Even though the material had a mineral content similar to that of human bone,it possessed elasto-meric properties that allowed for press-?tting the composites into bone defects.After implantation in rats,the material supported osteoblastic differentiation and promoted bone mineralization.The combination of the excellent mechanical properties along with the bene?cial biological response, con?rm the promising concept of using pHEMA in combi-nation with HA crystals.Similarly,pHEMA has been reinforced with inorganic particles such as such as TiO2na-noparticles,70nanocarbonate-substituted apatite,71and SiO2 nanoparticles.72
Biomimetic Mineralization
Hydrogels can also be mineralized by means of biomi-metic methods that take their inspiration from the biomi-neralization process by which native apatite nanocrystals are formed in vivo.Several features from this biomineralization process have been studied for their potential to be used in hydrogel mineralization,including(alternate)soaking treat-ments in?uids that are saturated with respect to apatite deposition,enzyme-directed mineralization,and the incor-poration of synthetic analogs of matrix vesicles as initial sites of biomineralization.
Soaking in solutions containing Ca2tand PO43à
Du et al.73used collagen matrices presoaked in PO43àthat were subsequently immersed in Ca2tsolutions.By
MINERALIZATION OF HYDROGELS579
controlling the parameters of their method,different crystal polymorphs could be created,whereas the materials were shown to be able to promote mineralization upon implan-tation in rats.Furuichi et al.74prepared a calcium phosphate-polyacrylic acid composite hydrogel by crosslinking a polyacrylic acid polymer in the presence of(NH4)HPO4so-lution and then immersing it in a calcium containing solu-tion.The diffusion of Ca2tinto the polyacrylic acid hydrogel that contained phosphate ions induced calci?cation of the hydrogel matrix resulting in a hierarchically organized composite architecture that resembled bone.
By alternately incubating a cellulose hydrogel in calcium and phosphate solutions,Hutchens et al.75was able to prepare biomimetic composites.The mineral phase of these compos-ites was characterized as calcium-de?cient HA.X-ray dif-fraction also revealed that the crystallites formed were elongated along the c-axis and had a length of*50nm,which is similar to the apatite crystals found in natural bone.The same mechanism was utilized to induce HA mineralization in a chitosan hydrogel by Madhumathi et al.,76who used chit-osan hydrogel membranes that were alternately soaked in solutions of CaCl2and Na2HPO4.HA deposits were homo-geneously dispersed throughout the matrix after?ve cycles. Similarly,Hong et al.77used a cellulose hydrogel that was?rst treated with a CaCl2solution and then immersed in SBF. Uniform and dense biomimetic mineralization was observed after immersion for14days in the SBF solution.
Using a urea-containing solution,Kim et al.managed to precipitate calcium phosphate crystals on top and inside a PEG-based hydrogel.78The PEG-fumarate polymer was crosslinked with ethylene glycol methacrylate phosphate, which acted as a source of phosphorous for the formation of apatitic crystalline platelets with a ratio of Ca/P equal to1.60. Vesicles loaded with Ca2tand PO43à
Another aspect of bone biomineralization that has been exploited to calcify hydrogel matrices relates to the vesicular nature of physiological calci?cation.Initial mineralization occurs in the so-called matrix vesicles,which are cellularly derived structures of40–200nm in diameter that are sepa-rated from other structures in the extracellular matrix by a limiting phospholipid membrane enclosing a central aque-ous core.After their formation in speci?c regions of the outer membrane of osteoblasts,these vesicles migrate toward the calci?cation front of growing bones.Here,the vesicles secrete apatitic crystals that subsequently calcify periodically ar-ranged,calcium-binding hole zones with speci?c amino acid composition in collagen?bers of the extracellular matrix.79,80 Liu et al.81created liquid vesicles that entered the hydrogel matrix using a current-mediated ion diffusion method that resulted in mineralization at the interior of a pHEMA hy-drogel.The dense hydrogel acted as binding site for the Ca ions and promoted mineralization of nanoapatite.The min-eral that was formed inside the entire volume of the hydrogel exhibited a structure very similar to the inorganic component of bone.A similar strategy to promote mineralization ac-cording to vesicular mineralization was developed by Ped-erson et al.82and Westhaus and Messersmith.83In the latter studies the vesicles were designed to melt at body temper-ature to release the Ca2tand PO43àions necessary for mineralization of the surrounding hydrogel matrix.Enzymatic mineralization
Alkaline phosphatase(ALP)84is an enzyme that plays an important role in the remodeling of bone and more speci?-cally in the resorption of bone and the mineralization of carbonated apatite.The enzyme acts as a catalyst for the hydrolysis of the organic phosphoesters,thereby increasing the local concentration of inorganic phosphate groups that results into enzyme-directed deposition of carbonated apa-tites.85,86Moreover,ALP decreases the concentration of py-rophosphates that act as inhibitors of apatite crystal growth. Recently,several groups have tried to immobilize this en-zyme onto implant surfaces or into hydrogels to induce local mineralization of implant surfaces and scaffolds.87
ALP has been immobilized88onto a?brin gel by activating the–COOH groups from?brin glue using1-ethyl-3-(di-methylaminopropyl)carbodiimide hydrochloride.Subse-quently,these scaffolds were incubated in ALP solutions resulting in covalent bonding between the enzyme and the ?brin https://www.doczj.com/doc/5918686995.html,ing a mouse calvarial defect model,it was demonstrated that the?brin scaffold with the immobilized ALP enhanced new bone formation.
Similarly89,ALP has been immobilized onto a pHEMA hydrogel using a copolymerization technique.The enzyme retained its activity after copolymerization,and after im-mersion in SBF containing organophosphates for17days, mineral deposition was observed.
Spoerke et al.90report the synthesis of a novel gel com-posed of amphiphilic nano?bers functionally enriched with phosphorylated and acidic groups.The hydrogels were formed in the presence of cell culture media supplemented with calcium chloride and immersed in calci?cation media containing b-glycerolphosphate and ALP among others. After8days of immersion the mineralization was visibly apparent throughout the hydrogel.
Chemical Modi?cation of Hydrogels
A different approach to induce mineralization in hydrogels involves the introduction of negatively charged functional groups onto the backbone or side chains of hydrogel poly-mers.This mechanism resembles the biomineralization pro-cess in bone tissue,where noncollagenous,calcium-binding proteins are essential as modulators of nucleation and growth of apatitic biomineral nanocrystals.Generally,these proteins are acidic and phosphorylated and accumulate in mineraliz-ing bone matrix91.Important mineral-inducing proteins such as osteonectin and bone sialoprotein(BSP)are enriched in anionic glutamate(Glu).92,93These acidic sequences are re-sponsible for the attraction of Ca2tand subsequent creation of a local supersaturation that is necessary for CaP precipitation, which make them quintessential for biomineralization of hard tissues.Similarly,alternating sequences of anionic carboxyl-ate,phosphate,or hydroxyl groups along the backbone of synthetic or natural polymers can endow the resulting hy-drogels in swollen state with apatite-nucleating properties. Therefore,the implementation of acidic sequences into hy-drogels opens up new perspectives for the development of hydrogels with mineral-attracting capacity.The following section will address the functionalization of hydrogels with negatively charged groups(PO43à,COOH,and OH)that are either present as isolated functional groups or as part of peptide sequences.
580GKIONI ET AL.
PO43à,-COOH,and-OH groups
Addition of negatively charged groups such as phosphate, carboxylate,and hydroxyl groups is commonly performed by copolymerization of the hydrogel-forming polymer with monomers containing one or more of these groups. Stancu et al.94developed copolymers of diethyl amino ethyl methacrylate and methacryloyloxyethyl phosphate (MOEP),as well as copolymers of MOEP with1-vinyl-2-pyrrolidinone and compared the calci?cation ability of both types of copolymer.Samples with different phosphate con-tent were prepared and immersed in SBF for15days.The results revealed that globular mineralization occurred on the surface of the MOEP-diethyl amino ethyl methacrylate hy-drogels.The absence of mineral deposition onto the MOEP-1-vinyl-2-pyrrolidinone copolymers was attributed to the fact that each calcium ion was double bonded by two phosphate groups from adjacent MOEP units formed during copolymerization.
Nuttelman et al.95coupled ethylene glycol methacrylate phosphate groups to PEG-diacrylate hydrogels.The polymers were immersed in human mesenchymal stem cell culture media that were supplemented with b-glycerophosphate, which resulted in mineral formation on their surface.The precipitated mineral was found to resemble biological apa-tites not only in composition,but also in molecular structure. Wang et al.96also modi?ed a PEG hydrogel by copolymeri-zation with a phosphoester.Upon immersion in osteogenic media for3weeks,extensive mineralization was observed throughout the three-dimensional network of the copolymer. The introduction of carboxymethyl groups on the pHEMA backbone was described by Filmon et al.97,98The prepared carboxylated scaffolds were immersed in SBF supplemented with antibiotics for15days.The results showed that min-eralization was induced only by the functionalized pHEMA-carboxymethyl hydrogel,whereas the unfunctionalized pHEMA hydrogels did not display any mineral formation. Crosslinked pHEMA has also been modi?ed by exposing carboxylate groups on the surface of the hydrogel using urea to hydrolyze the2-hydroxyethyl esters of the polymer by Song et al.,99who also prepared libraries of pHEMA-based hydrogels100copolymerized with negatively charged monomers in a separate study.Both types of carboxylate-functionalized hydrogels were reported to induce mineralization after im-mersion in SBF.
The introduction of hydroxyl-containing silanol(Si-OH) groups on thermosensitive poly(N-isopropylacrylamide)–PEG dimethacrylate copolymer is described by Ho et al.101 These silanol groups were introduced to the main polymer backbone by reacting with trimethacryloxypropyltrimetho-xysilane(MPS).It was reported102that MPS could be added at various concentrations,thereby improving the mechanical properties of the?nal hydrogel without altering its lower critical solution temperature.Similar to carboxylate and phosphate groups,Si-OH groups present in MPS provided sites that bound calcium and induced subsequent mineral deposition upon soaking in SBF.
Peptide-mediated mineralization—acidic peptides
Acidic peptide sequences can be conjugated on a hydro-gel,but there are also formulations of hydrogels composed of polymerized polypeptides.The mineralization capacity of a hydrogel made from crosslinked polyglutamic acid was studied by Sugino et al.103The hydrogel samples studied were injectable and bioresorbable,and after crosslinking they were treated with different concentrations of CaCl2solutions for24h at body temperature.Upon soaking in SBF for7 days,HA was formed on the surface of the treated hydrogels irrespective of the CaCl2concentration of the solution used for the pretreatment.
The HA nucleation potency of BSP-collagen hydrogels was tested and compared with agarose-BSP gels by Baht et al.104To assess the mineralization potency,the hydrogel scaffolds were perfused with buffers containing either Ca(NO3)2or Na2HPO4 with a steady?ow state.The results showed that collagen favors the BSP nucleation potency by nearly a factor of10 when compared to agarose gels.The synergistic interaction between collagen and BSP appeared to improve the mineral-ization capacity of these natural hydrogels.
Chirila et al.105immobilized three different arti?cial protein sequences onto pHEMA hydrogels.These sequences(two of them can be found in nacrein and the third is present in dentin matrix acidic phosphoprotein)were tested in vitro and their ability to nucleate calcium phosphate was assessed in solu-tions.Disks prepared from the peptide conjugated polymers were immersed in Ca2tand PO43àcontaining media for a total period of6weeks.The peptide sequences were shown to have no or an enhancing effect on calcium mineralization. Gungormus et al.106developed a peptide-based hydrogel that mediated the formation of HA.The27residue peptide MDG1self-assembles into a hydrogel by changing its form when alternating the ionic strength of the solution.By entrapping ALP in the hydrogel and immersing it in a b-glycerophosphate solution,mineralization of the hydrogel was achieved.
Indirect Mineralization
Even though it is not the scope of this review to address drug or cell delivery systems,it should be emphasized that hydrogels are often used to deliver osteoinductive growth factors such as bone morphogenetic proteins,demineralized bone matrix,107–114and/or cells,115–125and in many of these cases extensive mineralization is observed as a secondary consequence.According to this mechanism,growth factors trigger cell signaling pathways that stimulate stem cells in the direct vicinity of the hydrogel to differentiate into the osteogenic lineage and produce biomineral.In the case of cell delivery,cells that have been differentiated into the osteo-genic lineage are encapsulated directly into hydrogels before implantation that subsequently calcify the carrier hydrogel. Introduction of the Arginine–Glysine–Aspartate amino acid sequence(RGD or Arg-Gly-Asp)is commonly used to provide attachment and differentiation sites for cells inside the hydrogels resulting in indirect mineralization.126–128 For further information on mineralization induced by growth factors release and/or cell encapsulation,the reader is referred to reviews by Salinas and Anseth,123Hunt and Grover,129and Schmidt et al.130
Conclusions
Traditionally,hydrogels have been considered for soft tissue regeneration only,but recently successful attempts have been made to render hydrogels suitable for hard tissue
MINERALIZATION OF HYDROGELS581
regeneration.The highly hydrated nature of hydrogels offers signi?cant advantages over conventional ceramics and non-swelling polymers in terms of biocompatibility,biodegra-dation,drug delivery,and injectability that have not been exploited so far.Since bone is a highly mineralized tissue,the lack of mineralization ability of inert hydrogels can be gen-erally considered as the major stumbling block toward ap-plication of hydrogels for bone-substituting purposes.This review provides an overview of recent strategies that have been explored to calcify hydrogels,including the addition of bioactive inorganic phases,biomimetic mineralization path-ways that adopt principles from biomineralization,and the functionalization of hydrogels with negatively charged functional groups.
Acknowledgments
The authors gratefully acknowledge the support of the Smart Mix Program of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education,Culture and Science.
Disclosure Statement
No competing?nancial interests exist.
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Address correspondence to:
John A.Jansen,D.D.S.,Ph.D.
Department of Biomaterials
Radboud University Nijmegen Medical Center
P.O.BOX9101
6500HB Nijmegen
The Netherlands
E-mail:j.jansen@dent.umcn.nl
Received:August5,2010
Accepted:August23,2010
Online Publication Date:September29,2010
MINERALIZATION OF HYDROGELS585
ＣｈｉｎｅｓｅＪｏｕｒｎａｌｏｆＰｒａｃｔｉｃａｌＳｔｏｍａｔｏｌｏｇｙＪａｎ．２０１０Ｖ０１．３Ｎｏ．１综述 颌骨缺损后下颌骨重建方法及新材料研究进展 王宁综述，黎明审校 文章编号：１６７４—１５９５（２０１０）０１—００５４—０４中图分类号：Ｒ７８文献标志码：Ａ 题要：下颌骨作为面下１／３的骨性支架，对维持面型、保持咀嚼功能具有重要作用。颌骨囊性病变及颌骨肿瘤是造成颌骨缺损的主要原因，临床治疗须进行下颌骨重建，方法包括骨移植、牵引成骨技术、骨组织工程技术。本文就下颌骨重建的方法及新材料的研究进展予以综述。 关键词：下颌骨缺损；下颌骨重建 Ｍａｎｄｉｂｕｌａｒｒｅｃｏｎｓｔｒｕｃｔｉｏｎｍｅｔｈｏｄｓｆｏｒｍａｎｄｉｂｕｌａｒｄｅｆｅｃｔａｎｄｒｅｓｅａｒｃｈｉｎｔｏｎｅｗｍａｔｅｒｉａｌｓ．ＷＡＮＧＮｉ哌．ｕＭｉｎｇ．ＤｅｐａｒｔｍｅｎｔｏｆＯｒａｌａｎｄＭａｘｉｌｌｏｆａｃｉａｌＳｕｒｇｅｒｙ，ｔｈｅＡＪｆｉｌｉａｔｅｄＳｔｏｍａｔｏｌｏｇｙＨｏｓｐｉｔａｌｏｆＫｕｎｍｉｎｇＭｅｄｉｃａｌＣｏｌｌｅｇｅ，Ｋｕｎｍｉｎｇ６５００３１．Ｃｈｉｎａ Ｓｕｍｍａｒｙ：Ａｓｔｈｅｂｏｎｙｆｒａｍｅｏｆａ１／３ｓｕｒｆａｃｅ．ｍａｎｄｉｂｌｅｈａｓａｎｉｍｐｏｒｔａｎｔｒｏｌｅｉｎｔｈｅｍａｉｎｔｅｎａｎｃｅｏｆｆａｃｅｆｉｇｕｒｅａｎｄｍａｓｔｉｃａｔｏｒｙｆｕｎｃｔｉｏｎ．Ｔｈｅｍａｉｎｒｅａｓｏｎｓｏｆｉａｗｄｅｆｅｃｔｓａｒｅｃｙｓｔｉｃ１ｅｓｉｏｎｓａｎｄｔｈｅｔｕｍｏｒ．Ｔｈｅｃｌｉｎｉｃａｌｔｒｅａｔｍｅｎｔｉｎｃｌｕｄｅｓｂｏｎｅｇｒａｔｉｓ，ｄｉｓｔｒａｃｔｉｏｎｏｓｔｅｏｇｅｎｅｓｉｓａｎｄｂｏｎｅｔｉｓｓｕｅｅｎｇｉｎｅｅｒｉｎｇ．Ｉｎｔｈｉｓｐａｐｅｒ，ｍａｎｄｉｂｖｌａｒｒｅｃｏｎｓｔｒｕｃｔｉｏｎｍｅｔｈｏｄｓａｎｄｎｅｗｍａｔｅｒｉａｌｓｒｅｓｅａｒｃｈｗｉｌｌｂｅｒｅｖｉｅｗｅｄ． Ｋｅｙｗｏｒｄｓ：ｍａｎｄｉｂｕｌａｒｄｅｆｅｃｔ；ｍａｎｄｉｂｕｌａｒｒｅｃｏｎｓｔｒｕｃｔｉｏｎ 下颌骨缺损在颅颌面缺损中较为常见，可由多种疾病引起。如颌而部囊肿及肿瘤、急慢性颌骨骨髓炎、放射性骨坏死、创伤等。目前，临床常用的下颌骨缺损治疗方法包括自体骨移植、同种异体骨移植、牵引成骨技术及最近在围内及闰际均较热门的骨组织工程技术，其中材料学的研究进展及新型植入材料的发展对颌骨缺损的治疗也提供了新思路。 ｌ血管化游离骨移植修复下颌骨缺损 自体血管化骨移植修复下颌骨缺损包括带血管蒂游离腓骨肌皮瓣修复下颌骨缺损、自体髂骨游离移植修复下颌骨缺损、自体肋骨游离移植修复下颌骨缺损。 １．１游离腓骨瓣修复下颌骨缺损自Ｈｉｄａｌｇｏ于１９８９年首次报告利用游离腓骨骨肌瓣修复下颌骨缺损以来，游离腓骨瓣在口腔颌面缺损修复重建中很快得到广泛应用。腓骨用作骨移植的长度可达２５ｃｍ，可用以修复下颌骨任何部位的大型缺损。腓骨是高密度的管状皮质骨，有足够的强度足以承受咀嚼压力。此外，尚有以下主要优点：（１）血管蒂长，通过切取较为远端的腓骨，可以达到延长血管蒂的目的；（２）血管ｒ丁径大，血管化游离移植时非常容易吻 作者单位：昆明医学院附属口腔医院口腔颌面外科。昆明６５００３１ 电子信箱：ｒｅｍｆｘｐ＠ｇｎｍｉｌ．ｃｏｍ合成功，并且吻合口不易发生血栓；（３）腓骨瓣可以根据需要制备成各种形式的复合组织瓣，其中腓骨可用以修复缺损，肌肉可用以填塞死腔，如有局部皮肤缺损，还可携带采用带血管蒂游离腓骨骨肌瓣同期修复下颌骨缺损带腓骨表面的皮肤形成骨皮瓣修复创面；（４）腓骨瓣制备简便．供区并发症少；（５）腓骨瓣供区远离头颈部，便于同时实施双组手术；（６）腓骨可以根据需要作多处截骨后行ｉ维塑形，恢复牙槽突的形态…。栾修文等幢１对ｌ１例下颌骨节段性缺损的患者同期采用游离腓骨瓣进行重建，其中腓骨肌瓣６例，腓骨肌皮瓣５例。结果显示，ｌｌ例血管化游离腓骨肌（皮）瓣移植全部成功，所有病例供区伤口均一期愈合，供区下肢均无明显功能障碍，患者术后面部外形对称，张口度３．５—４．２ｃｍ。由此得ｌ电结论，游离腓骨肌（皮）瓣是重建下颌骨节段性缺损的理想方法。 １．２游离骼骨瓣修复下颌骨缺损在诸多供骨部位中，骼骨的天然形态类似于自然下颌骨，且骨量充足，含有丰富的骨松质和骨髓，位置表浅，易于切取。术区并发症相对较少。移植后不仅起着骨传导作用，还有骨诱导和骨生成作用。是理想的供骨源。非血管化的自体骼骨移植，手术时间短，取骨手术简单。创伤小，术后外形恢复理想，患者住院时间短。由于近期不能修复义齿，缺乏功能负荷刺激可能导致非血管化的移植骨术后骨萎缩严重。该法比较适合缺损较小、年龄较大的病例，植骨时需注意恢复牙槽骨高度，断端坚同固定。 万方数据
宋涛，主任医师，硕士研究生，西安市红会医院骨显微修复外科主任。现任中华 医学会显微外科学会委员、中华医学会骨科学分会第十一届委员会显微修复学组委员、 中华医学会第四届医疗鉴定专家库成员、中国医师协会显微外科医师分会第一届委员会 常务委员、中国医师协会显微外科医师分会软组织修复（皮瓣）专业委员会第一届委员 会委员、中国医药教育协会骨质疾病专业委员会第一届常务委员、中国医师协会骨科医 师分会中西医结合骨科工作委员会委员、中国医药教育协会骨病老年骨创伤分会委员、 中国中西医结合学会骨伤科专业委员会足踝学工作委员会委员、中国医药生物技术协会骨组织库分会委员、中国修复重建外科专业委员会骨延长专业学组委员、首届中国研究型医院学会骨科创新与转化专业委员会显微骨科学组委员、SICOT中国部显微修复专业委员会委员、亚太修复重建联盟中国部委员、陕西省骨与关节学会微生物与感染分会副会长、陕西省保健协会手外科与显微外科专业委员会副主任委员、陕西省保健协会骨创伤微创修复专业委员会常委、A0创伤中国区委员会陕西分会第一届委员、中国医药教育协会骨科专业委员会西安培训基地第一届常委、西安医学会针法微型外科副主任委员、西安医学会显微外科学分会副主任委员、西安医学会医疗技术鉴定专家库委员、西安医学院教授、《中华显微外科杂志》特邀编委等。对四肢各类创伤、畸形及病变等治疗经验丰富，擅长周围血管、神经损伤，尤其是臂丛神经损伤及周围神经损伤的修复与重建及应用显微外科技术治疗骨感染、骨髓炎。主持参与省、市级课题5项。在国家级杂志发表论文20余篇。发表《足踝部创伤与矫形》专著1部。 田力、宁， 副主任医师，硕士研究生。1991年毕业于第四军医大学。毕业后分配到新疆南疆军区解放军第18医院，先后在广州军区广州总医院、第一军医大学、北京军区 总医院骨科等进修学习，2008年从部队转业到西安市红会医院。擅长四肢骨与软组织损 伤的诊断与治疗，其是开放伤、严重创伤的保肢与重建治疗，各种周围血管神经损伤的 诊治，骨与关节常见疾患、骨髓炎、骨结核的治疗。发表专业论文20余篇。 张文韬，副主任医师，在职博士。现任中国医师协会显微外科医师分会骨修复专业委员会第一届委员、中国健康管理协会健康科普专业委员会第一届委员、陕西省保健 协会手外显微外科专业委员会常务委员等。在核心期刊发表文章10余篇。参与省、市级 科研数项，主持院级科研项目1项。擅长四肢组织缺损的显微修复、皮瓣转移修复皮肤软 组织损伤、四肢骨不连的显微修复、周围血管损伤、周围神经损伤的显微外科修复、手 部损伤治疗及功能重建等。 江仁奇，副主任医师，中华医学会会员，中国医师协会骨科医师分会会员。曾在 台湾花莲、大林慈济医院、北京积水潭医院及第四军医大学西京医院进修学习，主编专 著1部，发表SCI论文2篇，中文核心期刊论文20余篇，多次在COA大会发言。擅长四肢骨 不连、骨缺损、骨感染、四肢组织缺损、周围血管、神经损伤的显微外科修复及重建； 膝、髓人工关节初次置换及翻修术，对复杂关节内及其周围骨折的治疗有丰富的临床经 验。 ■■■刘洋，副主任医师，硕士研究生。连续多年在COA大会、SICOT、亚太显微等大会发言。发表中文及SCI论文10余篇，国家发明专利2项，实用新型专利1项，担任国家及 省市及专业委员以上学术职务7项。2016年《中华显微外科杂志》朱家恺全国显微外科■1青年医师病例英文竞赛（广州）全国三等奖。擅长骨科及显微修复重建外科的常见病和多发病的诊治如开放性骨折、感染、创面修复、复杂骨折等，多次参加骨科的疑难病I“例、危重病例的分析、诊治、讨论和抢救工作。 从飞,在职博士，副主任医师。现为中国显微外科医师协会青年委员、中国医药教育协会骨科分会西安委员会常委、陕西保健协会手显微外科协会委员、骨微创专业委 员、陕西省医师协会骨质疏松委员会委员等。在SCI及中文核心期刊、统计源期刊发表专 业论文20余篇。擅长四肢复杂开放骨折的同期修复重建及保肢治疗、肢体感染及慢性创 面的治疗、创伤后肢体功能障碍的晚期功能重建等。
高分子超分子化学史佳MG1724066 自修复超分子聚合物 摘要：超分子聚合物的完整性是通过形成非共价相互作用来实现的。这些相互作用包括氢键，金属配位，离子相互作用，π-π堆积和主客体相互作用。非共价键具有可逆性、方向性和高灵敏度的特征，使得超分子聚合物可以自发地或在外部刺激下对损伤部位进行多个循环的自修复，而在自修复领域得到了广泛关注。本文主要综述了氢键、π-π堆叠和金属配位型三类自修复超分子聚合物的研究进展。 引言 自修复是生物的重要特征之一，自修复机理来源于生物体具有的自动感知、自动响应和自愈合损伤的特性[1]。将此机理用于聚合物材料中可有效修复材料内部损伤，减少由裂纹引起的安全隐患并有效延长材料的使用寿命。超分子聚合物是以非共价键如氢键、π-π相互作用型、金属配位、拓扑(主-客体)和离子键连接单体单元的聚合物。分子聚合物和分子聚合物通过非共价键连接称为杂化聚合物，通常也被视为超分子聚合物[2]。因此超分子材料的完整性是通过形成非共价相互作用来实现的。这些非共价键的可逆性、方向性和高灵敏度的特征使得超分子在自修复领域有着很大的吸引力。 图1 超分子聚合物的自修复过程[4] 超分子自修复材料依赖于使用非共价键、瞬态键来产生网络，与共价键相反，
这些网络可以从流体状态到固态状态快速而可逆地重构，因此在外界刺激下能够修复受损的位点，并可以完成多个自修复周期[3]。如图1所示，超分子聚合物受到外力损伤后，弱超分子键或簇先断裂，产生的新界面包含许多未结合的超分子键，其在断裂表面处可以保持一段时间，断裂面重合时，这些超分子键会重新排列形成新的可逆网络，从而封闭缝隙并修复受损部位[4]。本文主要综述氢键、π-π堆叠和金属配位型三类自修复超分子聚合物的研究进展。 1 氢键自修复超分子聚合物 利用多种氢键相互作用将单体单元聚合成聚合物结构是生成超分子的主要方法之一。利用其中氢键相互作用的重排来修复微米尺度的裂缝，可以桥接裂缝空隙，实现聚合物的多次自修复[5]。由于脲基-嘧啶酮（UPy）端基可以引入大量遥爪低聚物，并且容易二聚化，导致线性链延伸，易于生产热可逆的超分子聚合物材料，因此广泛应用于氢键自修复超分子聚合物中[6]。研究[7]表明，UPy封端的聚（己内酯）（PCL）作为修饰涂层在铝表面被刮擦后，将其加热到140 ℃，由于其高温依赖性粘度的显著降低，样品在数秒内完全愈合。UPy基水凝胶的自愈作用也被证实（图2）。将含有15 wt％的聚乙二醇/UPy系水凝胶的凝胶切断，通过使两片接触而迅速自愈[8]。 a b c d 图2 UPy基水凝胶的自修复过程(a)心形水凝胶，(b)压缩显示弹性，(c)切割成两部分，(d) 自修复后的心形水凝胶[8] 2008年报道了第一种设计用于自修复的氢键超分子热塑性弹性体[9]。这种物质很容易用两步法从脂肪二酸和三酸的混合物中合成得到，首先将混合物与二亚乙基三胺缩合，然后与尿素反应（图3）。得到的多分散支化低聚物可以通过N-H和C=O之间多组强相互作用氢键单元形成玻璃化转变温度（Tg）为28 ℃的超分子玻璃状网络。为了在环境条件下自我修复，需要用十二烷烃增塑。结果表明，得到的软橡胶（Tg=8 ℃）的断裂伸长率超过500％，并且受损后修复3小
技术市场 一、下颌骨修复重建方法的重要性及方法选择 下颌骨的重要作用在于它对面形、语言、咀嚼、呼吸等的支持，它的缺损会造成患者在生理、心理的影响，直接看到的是导致面部变形和严重的功能障碍。 下颌骨缺损修复重建的手术效果已经比较稳定可靠。近年来，坚强内固定技术发展很快，它首先应用于骨折的治疗，并显示出了独特的优点。有利于骨断段形成直接的骨愈合，对于骨折断端的愈合具有明显的促进作用，有利于缩短术后病人的恢复时间。对于移植骨愈合过程，移植骨的外形重塑及其术后功能效果都具有较明显的促进作用。 下颌骨修复重建的手术相对复杂，手术后存在着各种影响因素，导致术后并发症也相对复杂。因此，要进行恰当的临床处理，可以避免手术后并发症，提高手术成功率。 手术技术及手术设备的发展，使下颌骨缺损可以进行同期修复。下颌骨修复重建方法很多，如自体游离骨移植，骨替代物植入等。这些方法有利有弊，同时影响下颌骨缺损修复重建的效果还有很多其他相关因素。 医生在手术前应与病人进行充分的交流，通过交流了解患者各方面情况，尽量让病人了解哪种手术方式更适应病人治疗。移植骨的外形与下颌骨缺损类型是否匹配也是非常重要的影响因素。临床上经常采用的自体骨中肋骨及胖骨较细长，骼骨则较为宽厚。对于良性肿瘤切除后造成的较大范围的颌骨缺损的修复是非常好的选择。 恶性肿瘤手术后的缺损修复重建不适于选用游离骨移植，因为放疗及化疗能导致手术部位骨愈合受到影响，影响手术方式选择的重要因素还有恶性肿瘤切除后的软组织缺损。最经常采用的手术方法是钛功能重建板复合软组织瓣，并可以在术前或术后配合进行放疗。其他一些替代物由于排异性较大现在已很少采用，近年来许多新方法新材料也被引入了下颌骨缺损修复重建领域，但还没有作为常规方法用于临床选择。 二、在自体骨移植下颌骨重建中坚强内固定技术的应用 自体骨移植是下颌骨肿瘤切除后最经常采用的修复方法。影响骨移植手术成功的因素很多，重要的影响因素之一是移植骨的固定方法。传统的方法是使用钢丝进行固定，该技术移植骨固定不够牢固，影响移植骨的愈合，还会引起感染。随着技术的发展，坚强内固定技术被广泛应用于骨折的治疗，并显示出了独特的优点。 由于下颌骨特殊的解剖形态和功能运动方式，使自体骨移植下颌骨重建难度加大，为了保证在手术后下颌骨具有一定的功能活动度，促进骨愈合就必须保证移植骨的牢固固定及植骨部位与下颌骨之间的配合性。与骨折的愈合方式不同的是，移植骨部位是以一种“爬行替代”的方式愈合，对移植骨的愈合产生重要影响的是移植骨再血管化的时间及其再血管化的程度，移植骨的再血管化跟骨断端与移植骨之间必须牢固固定且必须符合不同部位下颌骨应力负载特点有关，对于骸状突无法保留的下颌骨游离缺损的修复必须在手术中依据健侧下颌升支高度决定患侧下颌升支高度，以保证下颌关节重建的精确性。移植骨的牢固固定对于下颌支及其解状突无法保留的病人非常重要。它可以创造更加有利于移植骨愈合的条件，保证骨接合部位的牢固固定，保证了移植骨愈合过程中的血供，及正常的咬合关系。 坚强内固定夹板类型及其固定部位的选择非常重要。必须依据下颌骨咀嚼时的应力线放置夹板的位置。在靠近牙槽部选用微型夹板，在下颌骨体部下缘采用小型夹板。夹板还必须放置在骨质坚实的部位，移植骨固定不牢导致手术失败。依据下颌骨外形，对于较大范围的下颇骨缺损可以选择较长多孔的固定夹板。 三、分析下颌骨重建术后的并发症 下颌骨术后缺损修复重建的并发症有多种，如果选择发不当的处理时机或者选择了错误的处理方法会降低下颌骨重建的手术效果，导致患者不同程度的痛苦，直至下颇骨重建失败。 并发症依据严重程度分为五级：重度、较重度、中度、较轻度、轻度。 异体骨移植最主要的问题是排斥反应。医生术后要对患者注意观察，要及时提醒病人手术不要马上咀嚼硬物，要注意延迟咀嚼。下颌骨手术后1个月内，手术部位的薪膜及其皮肤组织尚未长好，骨结合部位正处于再血管化阶段，同时手术后病人全身抵抗力较弱。咀嚼功能减弱，经常需采用鼻饲管进食流食，使患者抵抗力更差，极可能造成病人手术部位感染，所以手术后1个月内是患者出现并发症的高危时期，降低术后并发症的发生首先必须要保证手术方法选择得当，而且要贯彻到术前、术中和术后。只有这样才能获得较好的手术效果。作为医生必须要引起足够的重视，以便及时处理不良情况。 四、在下颌骨缺损修复重建中体内预成血管化骨的应用 体内预成血管化骨属于内源性组织工程化骨。将骨形成蛋白复合特定的载体植入体内的特定部位进行培养是目前最常采用的方法，经过一段时间的培养之后生成具有血管网并可携带一知名血管蒂的骨组织。然后将该骨组织取出，通过血管吻合技术修复骨组织缺损。这种方法解决了下颌骨术后低血管化区域骨组织重建的难题。 体内预成血管化移植骨适合重建的特点是可获得较多的新骨，能较大范围修复下颌骨缺损；可以控制体内预成血管化骨的形状，使种植物与周围的肌肉组织中的多能间充质有最大范围的接触；适合坚强内固定螺钉的锚入；预成血管化骨的移植成活率更高，它表现为由外部从方向随机进入新骨，决定了预成血管化骨的血供更好，提高了移植的成活率；另外，可以携带部分肌肉组织用于相应下颌骨区软组织缺损的修复，不会造成供骨区软组织的缺损。 浅论下颌骨缺损修复及重建 范大伟 （伊通满族自治县第一人民医院） 摘要：本文主要分析和探讨有关下颌骨缺损修复重建中修复方法选择、固定方法以及术后并发症的相关问题。为临床提供十分重要的依据。 关键词:下颌骨重建并发症 225 现代营销
颌骨缺损的修复原则和咬合设计 发表时间：2015-04-09T14:25:28.837Z 来源：《医药前沿》2014年第33期供稿作者：刘城刘毅[导读] 左右两块不规则形状的上颌骨和一块马蹄形的下颌骨构成人面部中、下2／3的大部分骨性支架结构。刘城刘毅 （黑龙江省哈尔滨市口腔医院 150010） 【摘要】目的探讨颌骨缺损患者的修复原则及咬合设计。方法回顾性分析我院2013年7月～2014年5月收治的36例颌骨损伤患者，对其临床资料进行分析总结。结果36例颌骨缺损患者经我院的修复设计后，所有患者皆对效果表示满意。结论对于颌骨缺损的修复方法较多，修复颌骨损伤应考虑到外形和功能两个方法。 【关键词】颌骨缺损修复方法 【中图分类号】R782.2 【文献标识码】A 【文章编号】2095-1752（2014）33-0023-02 左右两块不规则形状的上颌骨和一块马蹄形的下颌骨构成人面部中、下2／3的大部分骨性支架结构，位于人面部较突出的部位，参与相应部位的器官功能。因为肿瘤和外伤造成的上颌骨或者下颌骨的缺损，经常造成骨组织缺损畸形，进一步引起相应的功能障碍，在口腔颌面部表现最突出的是咀嚼、吞咽和发声功能受到明显影响，影响了人的社交活动，降低了生活质量，加重了患者的精神负担。所以颌骨缺损的修复和功能重建是临床上经常面临的问题，尤其是较大块的骨组织缺损包括相应部位的软组织缺损的修复重建仍然是一个具有挑战性的临床问题[1]。 1 临床资料 1.1 一般资料 分析我院收治的颌骨损伤患者36例，其中男性患者20例，女性患者16例，年龄在12～44岁之间。 1.2 颌骨缺损的修复原则 1.2.1 早期修复颌骨缺损不仅使口腔生理功能受到一定程度的障碍，面部产生不同程度的畸形，而且给患者带来莫大的痛苦，因此，尽早进行修复治疗是非常必要的。虽然永久性的修复最好在创口愈合后(一般在2～3个月)制作，但是临时性的修复则应越早越好。如在手术后立即戴入腭护板、翼状导板、预成颌骨修复体等，不但可保护手术区创面，免受唾液和食物的污染，减少瘢痕的挛缩，减轻面部畸形的程度，及早恢复部分的生理功能，而且对患者还起到了一定的安慰作用。 1.2.2 尽可能恢复生理功能颌骨缺损的修复应尽可能恢复咀嚼、语言、吞咽、吮吸等生理功能。其中咀嚼功能的重建难度最大也最为重要，修复医师应充分利用自己的知识和各种技术与材料，千方百计地恢复患者的咀嚼功能。在恢复生理功能的基础上，再根据颌面部的具体情况，尽量恢复患者的面部外形。当功能修复与外形恢复之间有矛盾时，应以功能恢复为主。 1.2.3 保护余留组织除必须拔除的残根或过度松动牙，骨尖、骨突的修整，以及瘢痕组织的切除等外，应尽量保留余留组织。上颌骨缺损后，特别是在广泛缺损者，余留的口腔组织本来就已经不多，而这些余留组织又必须用于修复体的固位和支持。因此，在修复过程中，对余留的口腔组织更应倍加爱护，不可轻易损伤。例如，颌骨缺损后。余留牙不但较少，而且还往往受过不同程度的创伤，牙周情况一般较差，但我们还是应该尽量保留。关于上颌骨缺损修复中余留牙的利用与保护，将在另节专门阐述。其他如牙槽嵴、带状瘢痕、鼻前庭及鼻咽腔等都可充分利用，以便减轻每个基牙或每个固位区的负担，以分散牙合力，减少修复体的翘动和摆动，避免引起组织的创伤。邻近缺损区的周围组织，一般均较脆弱，易于出血，不能承受压力和摩擦，修复时必须注意加以适当缓冲，必要时可采用软性材料，以减轻黏膜的负担。 1.2.4 要有足够的固位颌骨缺损的修复体往往大而重，由于支持组织较少。修复体的翘动和摆动也较大。在设计时须经仔细检查，周密考虑，尽量利用现有组织以获得足够的固位。颌骨缺损修复的效果，在很大程度上取决于修复体的固位效果。因此，固位措施在颌骨缺损修复中是关键性步骤之一。 2 咬合设计 颌骨缺损患者通常伴有咬合关系错乱。在外伤及先天性唇腭裂、颌骨裂的患者尤为严重，因此在人工牙排列及咬合设计上都有其特点。 2.1 口内排牙 颌骨缺损患者的人工牙排列应考虑以下三个方面：恢复咬合关系；重建咀嚼功能；恢复患者颜面部外形。赝复体在口外模型上排牙难以达到此目的，因此，多采用口内直接排牙法。颌位关系记录后。在恒基托上直接排前牙，使前牙有适宜的超覆牙合关系，又使唇颊部丰满度适当，面形自然。还要注意对发音的影响，必要时还可排成对刃牙合、反牙合。排后牙可在口内进行，也可在牙合架上进行，但也应考虑咬合、面形和固位三方面问题。 2.2 咬合设计 在颌骨缺损修复中，必须注意尽可能恢复患者的咬合关系，使患者能较好地恢复咀嚼功能，通常采用下述方法重建咬合关系。由于个别牙尖突出牙合平面而造成的早接触，可以磨改牙尖，使所有牙都有牙合接触。对明显的伸长牙，应在牙髓治疗后，行部分截冠术。个别牙完全无咬合关系时，可采用人造冠修复牙合关系，如铸造全冠、树脂冠或烤瓷冠等，还可采用高嵌体。如果数个相邻牙无咬合时，也可做联冠修复。上、下颌牙列间，只有个别牙有牙合接触，多数牙无牙合接触，可采用铸造牙合垫来恢复牙合关系。双重牙列由于外伤引起的颌骨骨折，当错位愈合后，常造成牙弓缩窄，上颌骨或下颌骨后退，使上、下牙列间接触不良或接触面很小。腭裂患者，由于上颌骨发育不良，前牙呈严重反牙合或重度咬合错乱，此种情况，可在天然牙列的唇侧、颊侧或舌侧排，人工牙列，并与修复体相连，称此为双重牙列。双重牙列的设计，应以不妨碍舌运动为原则，并尽量使牙合力能有效地传递到余留基牙上，取得较好的支持作用。如下牙弓缩窄者，后牙的双重牙列最好设计在上颌的腭侧，其支持作用比设计在下颌颊侧者为强；前牙区者，则设计在下颌的唇侧为好。上颌牙弓缩窄时，后牙区者，可设计在上颌的颊侧：前牙区者，可设计在上颌唇侧。 3 结果 36例颌骨缺损患者经我院的修复设计后，所有患者皆对效果表示满意。 4 讨论
组织工程修复肩袖损伤促进腱骨愈合的研究进展 ——医多多 肩关节已成为继腰背、膝关节之后运动系统疼痛的第三大好发部位，特别是在60岁以上的老年人群中，肩袖损伤是引起肩关节疼痛的最主要原因，并且常伴有功能减退及睡眠障碍等。普通人群调查显示，肩袖全层撕裂的患病率为22.1%(147/664)，其中无症状患者约为有症状的两倍，并随年龄的增长而增加。 肩袖损伤的处理是复杂的，对于非手术治疗失败的患者可行手术一期修补。关节镜下肩袖修补术已成为肩袖损伤修复的“金标准”，具有创伤小、并发症少等优点，可以使绝大多数患者肩关节功能恢复以及长期的疼痛缓解。随着对疾病认识的不断加深和外科技术的发展，肩袖修补术在临床中取得令人满意的效果，但术后影像学随访发现解剖结构的生物学修复成功率较低，肩袖再撕裂的发生率文献报道也不尽相同，但仍然较高，尤其是长期的退变性大面积破裂的修复更容易失败，可高达94%。失败的原因是多方面的，可能与患者的年龄及身体状况、撕裂的大小部位及持续性、肌腱的质量、肌肉萎缩及退变、肌腹脂肪浸润、修复的技术和术后康复等因素有关。最主要的原因是很难重建正常的腱骨界面且过程缓慢。 肩袖是包绕在肱骨头维持肱盂关节运动和稳定性的一组肌肉，肩袖损伤常涉及到一个或多个肌腱逐渐退变而导致与肱骨相结合的部位撕裂。正常的腱骨结合结构由四层细胞类型、组织成分、机械性能及功能各不相同的过渡区域构成：致密纤维结缔组织、未钙化的纤维软骨、钙化的纤维软骨和骨组织。尽管进行适当的手术干预以及经历正常的愈合过程，肩袖残端与其肱骨插入点重新愈合的能力却是有限的，无法再生成损伤前正常组织学腱骨结合结构。为了使愈合的肌腱成功的重新整合到骨组织，需要提供一个理想的条件，提高肌腱细胞的活性增强新陈代谢，重建组织的生物力学特性，进而加速腱骨愈合，最终形成正常的腱骨插入点。 因此，寻找有效促进肩袖腱骨愈合的最佳策略成为目前临床及实验室研究的热点，新颖的生物学方法及材料应运而生：生长因子、修补支架以及干细胞的应用等。现就组织工程技术治疗肩袖损伤促进腱骨愈合问题综述如下。 生长因子
生物材料——骨组织工程讨论组织工程（Tissue Engineering）是近年来正在兴起的一门新兴学科，组织工程一词最早是由美国国家科学基金会1987年正式提出和确定的。它是应用生命科学和工程学的原理与技术，在正确认识哺乳动物的正常及病理两种状态下结构与功能关系的基础上。研究、开发用于修复、维护、促进人体各种组织或器官损伤后的功能和形态生物替代物的科学。 组织工程的核心就是建立细胞与生物材料的三维空间复合体，即具有生命力的活体组织，用以对病损组织进行形态、结构和功能的重建并达到永久性替代。共基本原理和方法是将体外培养扩增的正常组织细胞，吸附于一种生物相容性良好并可被机体吸收的生物材料上形成复合物，将细胞-生物材料复合物植入机体组织、器官的病损病分，细胞在生物材料逐渐被机体降解吸收的过程中形成新的在形态和功能方面与相应器官、组织相一致的组织，而达到修复创伤和重建功能的目的。 骨组织构建 构建组织工程骨的方式有几种：①支架材料与成骨细胞；②支架材料与生长因子；③支架材料与成骨细胞加生长因子。 生长因子通过调节细胞增殖、分化过程并改变细胞产物的合成而作用于成骨过程，因此，在骨组织工程中有广泛的应用前景。常用的生长因子有：成纤维细胞生长因子（FGF）、转化生长因子（TGF-ρ）、胰岛素样生长因子（IGF）、血小板衍化生长因子（PDGF）、
骨形态发生蛋白（BMP）等。它们不仅可单独作用，相互之间也存在着密切的关系，可复合使用。目前国外重点研究的项目之一，就是计算机辅助设计并复合生长因子的组织工程生物仿真下颌骨支架。有人采用rhBMP-胶原和珊瑚羟基磷灰石（CHA）复骨诱导性的骨移植、修复大鼠颅骨缺损，证实了复合人工骨具有良好的骨诱导性和骨传导性，可早期与宿主骨结合，并促进宿主骨长大及新骨形成。用rhBMP-胶原和珊瑚复合人工骨修复兔下颌骨缺损，结果显示： 2个月时，复合人工骨修复缺捐赠的交果优于单纯珊瑚3个月时，与自体骨移植的修复交果无明显差异。 目前，用组织工程骨修复骨缺损的研究，已从取材、体外培养、细胞到支架材料复合体形成等都得到了成功。有人用自体骨髓、珊瑚和rhBMP-2复合物修复兔下颌骨缺损，结果表明：术后3个月，单独珊瑚组及空白对照组缺损未完全修复；珊瑚-骨髓组和珊瑚-rhBMP-2组及单独骨髓组已基本修复了缺损；而骨髓、珊瑚和rhBMP-2复合物组在2个月时缺损即可得到修复。我们用骨基质成骨细胞与松质骨基质复合物自体移植修理工复颅骨缺损的动物实验，也取得了满意的治疗效果。 带血管蒂的骨组织工程是将骨细胞种植于预制带管蒂的生物支架材料上，将它作为一种细胞传送装置。我们将一定形状的thBMP-2、胶原、珊瑚复合物植入狗髂骨区预制骨组织瓣，3个月时，复合物已转变成血管化骨组织。