CA2263933C - Resorbable, macro-porous, non-collapsing and flexible membrane barrier for skeletal repair and regeneration - Google Patents

Abstract

A resorbable, flexible implant in the form of a continuous macro-porous shee t (42) is disclosed. The implant (42) is adapted to protect biological tissue defects especially bone defects (49) in the mammalian skeletal system, from the interposition of adjacent soft tissues (57) during in vivo repair. The membrane (42) has pores (46) with diameters from 20 microns to 3000 microns. This porosity is such that vasculature (61) and connective tissue cells derived from the adjacent soft tissues (57) including the periosteum (64) can proliferate through the membrane (42) into the bone defect (49). The thickness of the sheet (42) is such that the sheet (42) has both sufficient flexibility to allow the sheet (42) to be shaped to conform to the configuration of a skeletal region (55) to be repaired and sufficient tensile strength to allow the sheet (42) to be so shaped without damage to the sheet (42). The sheet (42) provides enough inherent mechanical strength to withstand pressure from adjacent musculature and does not collapse.

Description

?10152025CA 02263933 l999-02- 18W0 98/07384 PCT/US97/13695RESORBABLE, MACRO-POROUS, NON-COLLAPSING AND FLEXIBLEMEMBRANE BARRIER FOR SKELETAL REPAIR AND REGENERATIONBackground of the InventionField of the InventionThe present invention relates generally to implantsfor use in repairing various portions of the mammalianskeletal system and, more particularly, to implants foruse in clinical procedures such as bone fracture repair,regeneration of bone loss, augmentation of deficientbone, and related procedures.Description of Related ArtVarious types of defects in the mammalian skeletalsystem can be treated by various surgical procedures.Defects in the mammalian skeletal system may includebone fracture, loss of bone occurring from traumatic,surgical, or infectious sources, and bone deficienciesstemming from conditions such as atrophy and congenitalanomalies.One procedure that is common in the prior art fortreating bone defects involves the placement ofadditional bone into the bone defect area. Thisprocedure, which is commonly referred to as bonegrafting, is the second most frequently performedsurgical grafting procedure, with skin grafting the mostcommon surgical grafting procedure. Current bonegrafting procedures include the use of vascularized ornon—vascularized autografts and allografts.A bone autograft is a portion of bone taken fromanother area of the skeletal system of the patient. A?101520253035WO 98/07384CA 02263933 l999-02- 18PCT/US97/136952bone allograft, in contrast, involves a human donorsource other than the recipient patient. Allogenic bonegraft typically comprises bone harvested from cadavers,which is subsequently treated and stored in a bone bankand ultimately used as a bone graft implant. Allogenicbone graft is known to have osteoconductive andosteoinductive capabilities, although the osteoinductiveproperties are limited because of the necessary tissuesterilizing and cleaning procedures associated withharvesting these bone grafts. The term osteoconductionrefers to a class of biomaterials which provide a three-dimensional porous framework to conduct the ingrowth ofnew living bone into this structure. The termosteoinduction refers to a class of materials havingcapabilities of recruiting mesenchymal stem cells of thepatient and promoting their differentiation intoosteoblasts, which are bone forming cells. Anosteoinductive material will typically form bone ifimplanted into an area where bone would not normallygrow. For example, the placement of bone morphogenicproteins into the muscle of a patient will result inectopic (outside of bone) bone formation.Both bone autografting procedures and boneallografting procedures are associated with shortcomingsin the healing of bone defects within the mammalianskeletal system. Bone autografting procedures aretypically associated with limitation of donor sites,bone quantity, and donor site morbidity (especially ifmultiple donor sites are required). Bone allograftingprocedures, to begin with, only have limitedosteoinductive capabilities. In addition to the verylimited osteoinduction properties of allogenic bonegrafts, compared to autograft samples, allografts areimmunogenic to a certain degree, bear the risk ofdisease transmission (e.g. HIV and Hepatitis), and,?101520253035WO 98/07384CA 02263933 l999-02- 18PC T/U S97/ 136953depending on the size of the allograft, require a longtime for ingrowth and partial substitution with newbone. This long substitution process often requires atime duration of greater than one year beforesatisfactory clinical results are obtained.Additionally, pressure from the adjacent musculature maydislocate bone graft material. Bone grafts may re-fracture after fixator removal if bone ingrowth andsubstitution is inadequate.As a substitute to actual bone grafts, whichinclude autografts and allografts, various bone graftsubstitutes have been used by the prior art for treatingbone defects in the mammalian skeletal system.Porous ceramic bone graft substitutes, forinstance, such as coralline hydroxyapatites, operatesimilarly to bone grafts by providing a three-dimensional structural framework. This frameworkconducts the regenerating bone of the patient into theporous matrix of the three—dimensional structuralframework. This process of conducting the regeneratingbone into the porous matrix is commonly referred to asosteoconduction, as opposed to osteoinduction discussedabove. Permanent, non—resorbable, inorganic, ceramicimplants have shortcomings such as inherent brittlenessand large framework volume fractions. The frameworkvolume fraction of a typical bone graft substitutecomprises approximately 40 percent of the volume wherenew bone could otherwise grow. This 40 percent volumeoccupied by a bone graft substitute, consequently,cannot be occupied by the regenerating bone of thepatient.A process referred to as guided tissue regenerationis widely used by periodontists to regenerate bone andperiodontal ligaments (ligaments between the tooth rootand the bone) around dental implants, for example. This?101520253035WO 98/07384CA 02263933 l999-02- 18PCT/U S97/ 136954surgical procedure uses cell-occlusive (cells cannotpass through) but fluid—permeable membranes, which areotherwise known as semipermeable membranes, in order tocover and segregate a bone defect from the surroundingsoft tissues. U.S. Patent No. 3,962,153 discloses sucha cell-occlusive, fluid-permeable membrane. Use ofthese cell-occlusive, fluid permeable membranes, hasbeen predominantly developed and used by periodontistsover the last decade, who worked in the mouth aroundteeth. The human body has many tissue types whichoriginate from three primary germ layers of the embryo:the ectoderm, the mesoderm and the entoderm. From theectoderm are derived the skin and its attached tissues,such as nails, hair and glands of the skin, the nervoussystem, external sense organs and the epithelial liningof the mouth and anus. From the mesoderm are derivedthe connective tissues, bone, cartilage, muscle, bloodand blood vessels. From the entoderm are derived, amongothers, the digestive tract, bladder and urethra. The"precursor" cells of these layers are limited to onlybecoming cells of their respective tissue type. Bone,muscle, connective tissue, blood vessels and cartilageare of mesenchymal origin which means from the meshworkof embryonic connective tissue in the mesoderm, and areformed from versatile mesenchymal stem cells, whereasthe lining of the mouth is of ectodermal origin and isformed of epithelial cells derived from the ectoderm.Ectodermal cells do not have the potential to becomebone forming cells and, conversely, mesenchymal cells donot have the potential to form epithelium.Epithelial cells are present in the mouth, but arenot present in many other areas of the mammalianskeletal system, such as areas near long bones of themammalian skeleton. The development of cell—occlusive,fluid permeable membranes was developed in the context. ,-..,..A..,,i_..........,......?1015202530WO 98/07384CA 02263933 l999-02- 18PCT/U S97/ 136955of periodontal and oral applications, for the purpose ofexcluding the introduction of epithelial cells into thebone defect area of the patient because they areEpithelial cellsproliferate faster than bone cells and, therefore, thebelieved to hinder bone formation.exclusion of these epithelial cells from the bone defectarea has been considered to be essential for optimalbone and ligament regeneration in these periodontal andoral applications. Although cell-occlusive, fluidpermeable membranes have been predominantly used inperiodontal and oral applications, these cell—occlusivemembranes have recently also been applied for tissuesegregation in other defect sites in the mammalianskeletal system, such as long bone defects.These cell-occlusive membranes of the prior arthave a shortcoming of blocking blood vessels andmesenchymal cells from entering into the bone defectarea. Thus, the advantage of precluding epithelialcells from the bone defect area in the oral cavity isachieved at the expense of also precluding entry ofblood vessels and surrounding mesenchymal cells into thebone defect area, as well. In periodontal and oralapplications, the advantage of precluding epithelialcells is believed to be worth the shortcoming of alsoprecluding blood vessels and surrounding mesenchymalcells from the bone defect area. In other areas of themammalian skeletal system, however, where epithelialcells are not present, these cell-occlusive, fluid-permeable membranes preclude the introduction of bloodvessels and surrounding mesenchymal cells for noapparent reason. Thus, a need has existed in the priorart for a cell—permeable membrane barrier to protectnon—periodontal bone defects from gross soft tissueprolapse and to thereby facilitate bone regeneration.?101520253035WO 98107384CA 02263933 l999-02- 18PCT/U S97/ 136956Turning to Figure 1, a typical cell-occlusive,fluid permeable membrane 10 is illustrated surrounding afirst section of the long bone 12 and a second sectionof long bone 14. The bone defect area 20 is bounded bythe two ends 16, 18 of the first section of long bone 12and the second section of long bone 14, respectively,and by the cell-occlusive, fluid-permeable membrane 10.Although this bone defect area 20 can receive blood fromthe bone vessels 23, blood and cells from thesurrounding blood vessels 25 and tissues 27 is precludedfrom entering the bone defect area 20. The periosteum31 and the surrounding tissues 27 are just external tothe cell- occlusive, fluid-permeable membrane 10 and areguided in the directions of the arrows A1 and A2.In addition to being cell-occlusive, the cell-occlusive, fluid permeable membrane 10 suffers from alack of rigidity, as evidenced by the hour-glassconfiguration of the cell-occlusive, fluid-permeablemembrane 10 in Figure 1. A typical thickness of thecell-occlusive, fluid~permeable membrane 10 comprisesless than 5 microns. Since periodontal defects aretypically small, and since oral soft tissues typicallydo not apply much pressure, the cell-occlusive, fluid-permeable membrane 10 of the prior art has maintainedits very thin and flexible configuration. Unfortunately,this very thin and flexible configuration, which issomewhat suitable for periodontal and oral applications,is not suitable for maintaining and protecting asufficiently large bone defect area 20 in non-periodontal and non-oral applications. Since musclesare much larger and more powerful in orthopedicapplications, for example, the cell-occlusive, fluid-permeable membrane 10 cannot provide sufficientprotection against the prolapse of soft tissues into thebone defect area 20. When the surrounding tissues?WO 98/07384101520'253035CA 02263933 l999-02- 18PC1VUS97?36957prolapse into the bone defect area 20, these interposedtissues present a physical barrier for the regeneratingbone. The regenerating bone will not be able to pushthe interposed soft tissues out of the bone defect area,and subsequently, further regeneration of the bone inthese areas occupied by the prolapsed soft tissues isprevented. A "non-union" (or pseudoarthrosis whichmeans pseudo—joint) may result, comprising fibrous scartissue instead of bone. Additionally, the prior artcell-occlusive, fluid—permeable membrane 10 is non-resorbable, and cannot be absorbed by the patient'sbody. in order to avoid the risk ofbacterial infection, the cell-occlusive,Consequently,fluid—permeablemembrane 10 must be removed during a subsequentoperation, which may introduce further complications andrisks to the patient. Thus, in addition to being cell-occlusive, prior membranes suffer from lack of inherentstrength and non—resorbability.A few other devices have been developed in theprior art for treating bone defects, but these devicescomprise either fixation devices or prosthetic devices.A fixation device, comprising a titanium screen mesh, isPatent No. 5,346,492.screen mesh forms a fixation device, which is designeddisclosed in U.S. This titaniumto be non-resorbable. The fixation device comprises ametallic plate structure which provides the necessarystrength, at the cost of being non-resorbable. To date,any known resorbable material would not be capable ofproviding the equivalent rigidity and function of thetitanium mesh screen. The metallic plate structure ofthe fixation device comprises a number of perforationsdesigned specifically for accommodating screws forfixation. These screw perforations have diameters(between 4.8 millimeters and 17.5 millimeters), which donot prevent gross prolapse of soft tissues into the bone?1015202530WO 98/07384CA 02263933 l999-02- 18PCT/US97l136958defect area. Such gross prolapse of soft tissuesoccupies space which would otherwise be filled with newbone. The physical barrier presented by the prolapsingsoft tissues greatly impairs new bone formation withinthe bone defect area. The fixation device is securedonto the bone of the patient with the screws and isdesigned to be permanently left inside the patient. Anyproliferation of blood vessels through these screw holeswould be destroyed by any subsequent removal of thefixation device. On the other hand, if the fixationdevice is left in permanently, which is a disclosedembodiment, the bone of the patient will be permanentlystress shielded. In other words, the mended bone, afterinitial healing will subsequently start to resorb, sincethis new bone is not exposed to functional (mechanical)stress. The fixation device, if left in the patient,will shield the bone defect-area from functional stressand thus prevent an optimal amount of new boneformation.A prosthetic device, which comprises holes punchedinto a planar material for facilitating suturing of theprosthetic device, is disclosed in U.S. Patent No.5,222,987. This prosthetic device, however, is onlydisclosed in the context of fabricating artificial bonestructure. In other words, this prosthetic device isnot used in any process associated with boneregeneration. The prosthetic device comprises a fabric-like composite onto which a polymer or resin is added,before the resulting product is molded into the shape ofa bone. A polymerizable initiator is subsequently addedto harden and bond the materials together. Small holesor ports may be added to accommodate sutures forattaching the prosthetic device to the body. Theprosthetic device is specifically designed as a?10152025‘3035WO 98/07384CA 02263933 l999-02- 18PC1VUS97?36959replacement for the rib cage of a mammalian skeletalsystem, and does not facilitate bone regeneration.other porous devices, in addition to the above-mentioned fixation and prosthetic devices, have beenimplemented by the prior art. One such device, which isdisclosed in U.S. Patent Nos. 5,306,304, 5,464,439, and4,932,973, disclose an allogenic bone graft membranehaving pores therein. The allogenic bone graft membraneis disclosed in these patents as providing a filler forbone defects. The matrix-like properties of theallogenic bone graft provide osteoconduction, and themorphogenic proteins within the allogenic bone graftprovide osteoinductive properties. As mentioned before,an allogenic bone graft is typically harvested from ahuman cadaver and subsequently processed forimplantation. The allogenic bone graft is intended tobecome integrated with the new bone of a patient andpartially remodeled over time into a composite of bothcadaver bone and new regenerated natural bone, whilepermanently remaining within the bone defect area of thepatient. The pores in the allogenic bone graft membraneof these patents are designed to maximize the exposedsurface area in order to enhance its osteoinductivecontribution, as bone morphogenic proteins are releasedfrom the surface of the allogenic bone graft. Thisallogenic bone graft matrix will never be completelyresorbed. This is obviously disadvantageous, becauseits structure reduces the space for new boneregeneration.Another device, which comprises apertures or poresfor facilitating tissue growth therein, is disclosed inU.S. Patent No. 5,326,356. This patent is directed toan apparatus for generating artificial skin grafts.Bio—compatible membranes comprising natural, synthetic,or semi-synthetic origin are used as a support for the?1015202530WO 98/07384CA 02263933 l999-02- 18PCT/US97/1369510in vitro (outside of a living organism) growth ofepithelial skin cells. These epithelial skin cells aregrown into the pores of the membrane outside of the bodyof the patient. The resulting artificial skin graft isobviously not intended for use on the mammalian skeletalsystem. This artificial skin graft, in any event, wouldbe far too thin and flexible for use on the mammalianskeletal system, and further would not have adequatefixation strength. Moreover, the epithelial cells whichcomprise the artificial skin graft are not present inthe non-periodontal and non-oral applications, such aslong bones, where a cell-permeable membrane is needed inthe prior art for facilitating bone regeneration.Summary of the InventionThe present invention recognizes that a cell-occlusive, fluid permeable membrane is not suitable forbone regeneration in non-periodontal and non-oralapplications. In addition to lacking rigidity andresorbability, the present invention recognizes thatthese prior art cell-occlusive, fluid—permeablemembranes hinder bone regeneration by blocking theingress of blood vessels and cells into the bone defectarea. The protective bone regeneration membrane of thepresent invention has a much smaller net surface area,compared to prior art cell-occlusive, fluid permeablemembranes, resulting from the introduction of cell-permeable apertures into the membrane of the presentinvention. In addition to having a smaller net surfacearea, the protective bone regeneration membrane of thepresent invention is substantially stronger and morerigid than prior art cell-occlusive, fluid permeablemembranes.?101520253035WO 98/07384CA 02263933 l999-02- 18PCTIUS97/136951 1According to one aspect of the present invention,an implant for protecting biological tissue defects froma prolapse of adjacent soft tissues during in vivorepair of the biological tissue defects includes asubstantially planar sheet of non-metallic basematerial. The implant further includes a plurality ofapertures disposed in the substantially planar sheet ofnon-metallic base material. The apertures are adaptedfor allowing a proliferation of vasculature andconnective tissue cells, derived from the adjacent softtissues, into the biological tissue defect, whilepreventing any gross prolapse of the adjacent softtissues into the biological tissue defect. Theconnective tissue cells include mesenchymal cells, andthe implant may be impregnated with at least onesubstance for cellular control. This substance forcellular control may include at least one of achemotactic substance for influencing cell-migration, aninhibitory substance for influencing cell—migration, amitogenic growth factor for influencing cellproliferation, a growth factor for influencing celldifferentiation, and factors which promoteneoangiogenesis (formation of new blood vessels). Thebiological tissue defect preferably comprises a bonedefect and, more preferably, comprises a non-periodontal, non-oral bone defect.The implant may be used in combination with afixation device for stabilizing the bone defect. Thematerial of the implant is flexible enough to conform toa curvature of a bone and strong enough to reduce macro-motion of the bone defect and limit transmission ofsurrounding motion into the interior space when thefixation device is attached to the bone defect. Theimplant is adapted for protecting the bone defect from aprolapse of adjacent soft tissues into the bone defect?101520253035WO 98/07384CA 02263933 l999-02- 18PCT/U S97/ 136951 2during repair of the bone defect and, further, isadapted for preventing stress shielded resorption ofbone after the repair of the bone defect. The bone,which is prevented from being resorbed, may includeeither an autograft, an allograft, and/or newregenerated bone within the bone defect.According to another aspect of the presentinvention, the implant is resorbable. The resorption ofthe implant, according to the present invention, canprevent stress shielding of the bone defect, to therebyprevent resorption of new bone which would occur if thebone defect were stress shielded by either the fixationdevice or the implant, or both. The fixation device maybe resorbable or non-resorbable. When the fixationdevice is resorbable, the fixation device loses itsmechanical strength within 24 months and, morepreferably, within 4 to 12 months. This loss ofmechanical strength of the fixation device can preventresorption of new bone near the bone defect which wouldoccur if the bone defect were stress shielded by eitherthe fixation device, the implant, or both. If thefixation device is non-resorbable, according to thepresent invention, the resorption of the implant canreduce stress shielding of the bone defect area tothereby minimize resorption of new bone near the bonedefect. As another option, the implant may be non-resorbable, but flexible enough to prevent stressshielding of the bone defect after the resorbablefixation device has lost its mechanical strength.Each of the apertures within the implant has adiameter in a range between 20 microns and 3000 microns,and, preferably, has a diameter of approximately 1500microns. The implant has a thickness in a range between100 microns and 2000 microns, but may also be configuredas thin as 10 microns. This implant comprises at least?101520253035WO 98/07384CA 02263933 l999-02- 18PCT/U S97! 136951 3one of a biodegradable synthetic material and abiodegradable natural material, that is also a non-osteogenic, non-metallic substance having a stiffnesssufficient to prevent gross soft tissue prolapse into anarea of the bone defect where new bone ideally wouldgrow.According to one aspect of the present invention, aplanar membrane is provided for preventing soft tissuefrom prolapsing into a protected area of a bone defect.The planar membrane is adapted for being placed outsideof the bone defect area, as opposed to being placedwithin the bone defect area where new bone would ideallygrow, to thereby facilitate entirely new bone growthonly within the protected area. The planar membraneincludes a plurality of apertures disposed therein. Eachof the plurality of apertures is adapted for allowing aproliferation of vasculature and connective tissue cellsinto the protected area, while preventing a prolapse ofadjacent soft tissues into the protected area. Theplanar membrane is adapted for resorption into the bodyof a patient, within a period of approximately 24 monthsfrom an initial implantation of the planar membrane intothe body of the patient.According to another aspect of the presentinvention, a resorbable membrane is provided forfacilitating protected bone regeneration. Theresorbable membrane is adapted for being wrapped aroundthe bone defect area, to thereby cover and surround theentire bone defect area and to overlap adjacent areas ofbone near the bone defect area. The resorbable membranehas a strength sufficient to prevent prolapse ofadjacent soft tissues into the bone defect area and tothereby facilitate bone regeneration independently,without any aid from a fixation device, when theresorbable membrane is secured around the bone defect?1015202530CA 02263933 2004-01-1614area and secured to the adjacent areas of bone near thebone defect area. The resorbable membrane forms a tubesurrounding the entire bone defect area and overlappingthe adjacent areas of bone near the bone defect area,when the resorbable membrane is secured both around thebone defect area and to the adjacent areas of bone nearthe bone defect area. The resorbable membrane can befrictionally secured around the bone defect area, or canbe secured around the bone defect area using at leastone of clamps, staples, screws, sutures, and tacks. Thefixation device can include at least one of a plate, ascrew, an intramedullary rod, and an external fixationdevice.According to yet another aspect of the presentinvention, a method of protecting a biological tissuedefect area from soft tissue interposition is provided.The method includes a step of placing a resorbablemembrane outside of a boundary of the biological tissuedefect, where the resorbable membrane comprises aplurality of apertures adapted for allowing aproliferation of vasculature and connective tissue cellstherethrough, while preventing the prolapse of adjacentsoft tissues into the biological tissue defect. Thebiological tissue defect area can include a bone defectarea, and the step of placing a resorbable membraneoutside of the boundary of the bone defect area caninclude a step of wrapping the resorbable membranearound two ends of a long bone to thereby surround avoid between the two ends of the long bone. A rigidfixation device can subsequently be secured between thetwo ends of the long bone.?101520253035CA 02263933 2004-01-1614aIn a further aspect of the present invention, there isprovided a protective bone regeneration membrane for protecting ahard tissue defect from a prolapse of adjacent soft tissues duringin vivo repair of the hard tissue defect, the protective membranehaving a pre—implant configuration, which is defined as aconfiguration of the protective membrane immediately before theprotective membrane is implanted over the hard tissue defect andplaced into Contact with any adjacent soft tissue, the protectivemembrane comprising: a substantially planar sheet of resorbablepolymer base material having a first side, a second side, athickness measured between the first side and the second side thatis less than 1000 microns, and a porosity that is less than about60 percent; and a plurality of apertures disposed in thesubstantially planar sheet of resorbable polymer base material tosubstantially optimize healing of the hard tissue defect when theprotective membrane is implanted over the hard tissue defect,wherein apertures of the plurality of apertures of the protectivemembrane when the protective membrane is in the pre—implantconfiguration have minimum diameters which are greater than 1000microns and less than 3000 microns and which define isolated, non-intersecting, fluid—flow paths from the first side to the secondside; wherein the protective membrane comprises a configuration andstrength sufficient to prevent gross prolapse of adjacent softtissues into the hard tissue defect, when the protective membraneis implanted over the hard tissue defect and placed into contactwith any adjacent soft tissue; wherein the plurality of aperturesof the substantially planar sheet of resorbable polymer basematerial, immediately after implanting of the substantially planarsheet of resorbable polymer base material over the hard tissuedefect, have diameters sufficient in size and distribution to allowand optimize a proliferation of vasculature and connective tissuecells,derived from adjacent soft tissues, to permeate through theapertures and substantially into the hard tissue defect; andwherein the protective membrane is adapted to be resorbed into amammalian body,and not remodeled, within a period?101520253035CA 02263933 2004-01-1614bof approximately 2 to 24 months from an initial implantationof the protective membrane into the mammalian body.A further aspect of the present invention is a resorbablepolymer planar protective membrane for protecting a bone defectarea from a soft tissue prolapse into the bone defect area, theresorbable polymer planar protective membrane having two opposingsides, a thickness between the two sides that is less than orequal to 1000 microns, a porosity that is less than about60 percent, and being adapted to be placed in a pre—implantconfiguration outside of the bone defect area, as opposed to beingplaced within the bone defect area where new bone would ideallygrow, to thereby allow entirely new bone growth within the area,the resorbable polymer planar protective membrane in the pre-implant configuration comprising a plurality of apertures disposedtherein to substantially optimize healing of the bone defect areawhen the resorbable polymer planar protective membrane isimplanted over the bone defect area, wherein apertures of theplurality of apertures form non—intersecting fluid flow paths,which fluidly connect the two opposing sides, which have minimumdiameters greater than 1000 microns and less than 3000 microns,which are arranged on the resorbable polymer planar protectivemembrane in staggered rows, and which are adapted to allow andoptimize a proliferation of vasculature and connective tissuecells from adjacent soft tissues into the bone defect area, whilepreventing a gross prolapse of adjacent soft tissues into the bonedefect area, the resorbable polymer planar protective membranebeing adapted to be resorbed into a mammalian body, and notremodeled.A further aspect of the present invention is a resorbablepolymer protective membrane having two opposing planar sides, athickness between the two sides that is greater than 500 micronsand less than or equal to about 1000 microns, a porosity that isgreater than about 20 percent and less than about 60 percent, andbeing for facilitating protected bone regeneration within a bonedefect area, the resorbable polymer protective membrane in a pre-?101520253035CA 02263933 2004-01-1614cimplant configuration comprising a plurality of non—intersectingfluid flow paths disposed in the resorbable polymer protectivemembrane to substantially optimize healing of the bone defect areawhen the resorbable polymer protective membrane is implanted overthe bone defect area, wherein non—intersecting fluid flow paths ofthe plurality of non—intersecting fluid flow paths fluidly connectthe two opposing sides and have diameters greater than1000 microns and less than 3000 microns, the resorbable polymerprotective membrane being adapted to be resorbed into a mammalianbody, and not remodeled.A further aspect of the present invention is a use of aresorbable polymer protective membrane for facilitating protectedbone regeneration, wherein: the resorbable polymer protectivemembrane has a thickness, a porosity less than about 60 percent,and a plurality of non—intersecting apertures penetratingcompletely through the thickness of the resorbable polymerprotective membrane and distributed on the resorbable polymerprotective membrane to substantially maximize healing of a bonedefect area when the resorbable polymer protective membrane iswrapped around the bone defect area, wherein apertures of the non-intersecting apertures have 500 micron to 3000 micron minimumdiameters, the resorbable polymer protective membrane having astrength sufficient to prevent gross prolapse of adjacent softtissues into the bone defect area and to allow and optimizeprotected bone regeneration when the resorbable polymer protectivemembrane is secured around the bone defect area and secured to theadjacent areas of bone near the bone defect area, the resorbablepolymer protective membrane being adapted to be resorbed into amammalian body, and not remodeled.A further aspect of the present invention is a use of aresorbable polymer protective base material for protecting a bonedefect area from soft tissue interposition, wherein the materialcomprises: a substantially planar sheet comprising a thickness, aporosity less than about 60 percent, and a plurality of non-intersecting apertures disposed in the substantially planar sheet?101520253035CA 02263933 2004-01-16l4dof resorbable polymer protective base material, apertures of theplurality of non—intersecting apertures penetrating through thethickness of the substantially planar sheet of resorbable polymerprotective base material and having minimum diameters ranging fromapproximately 500 microns to approximately 3000 microns, aperturesof the plurality of non—intersecting apertures further beingdistributed on the substantially planar sheet of resorbable polymerprotective base material to substantially optimize healing of abone defect area when the substantially planar sheet of resorbablepolymer protective base material is placed around a boundary of thebone defect area and being adapted to allow and optimize aproliferation of vasculature and connective tissue cells, derivedfrom adjacent soft tissues, into the boundary of the bone defectarea, while preventing a gross prolapse of adjacent soft tissuesinto the boundary of the bone defect area, the substantially planarsheet of resorbable polymer protective base material being adaptedto be resorbed into a mammalian body, and not remodeled.A further aspect of the present invention is a protectivebone regeneration membrane for protecting a hard tissue defect froma prolapse of adjacent soft tissues during in vivo repair of thehard tissue defect, the protective membrane having a pre-implantconfiguration, which is defined as a configuration of theprotective membrane immediately before the protective membrane isimplanted over the hard tissue defect and placed into contact withany adjacent soft tissue, the protective membrane comprising: asubstantially planar sheet of resorbable polymer base materialhaving a first side, a second side, a thickness measured betweenthe first side and the second side that is less than or equal to1000 microns, and a porosity that is less than about 60 percent;and a plurality of apertures disposed in the substantially planarsheet of resorbable polymer base material to substantially optimizehealing of the hard tissue defect when the protective membrane isimplanted over the hard tissue defect, wherein apertures of theplurality of apertures of the protective membrane when theprotective membrane is in the pre-implant configuration have?101520253035CA 02263933 2004-01-1614ediameters greater than 1000 microns and less than 3000 microns,define fluid-flow paths extending along individual path axes fromthe first side to the second side, and have cross—sectional areasthat are substantially constant along the path axes, whereinapertures of the plurality of apertures of the protective membranewhen the protective membrane is in the pre-implant configurationare adapted to allow and optimize a proliferation of vasculatureand connective tissue cells, derived from the adjacent softtissues, to permeate through the apertures and into the hard tissuedefect, while preventing gross prolapse of the adjacent softtissues into the hard tissue defect, the protective membrane beingadapted to be resorbed into a mammalian body, and not remodeled.A further aspect of the present invention is the protectivebone regeneration membrane for protecting a hard tissue defect froma prolapse of adjacent soft tissues during in vivo repair of thehard tissue defect, the protective membrane having a pre-implantconfiguration, which is defined as a configuration of theprotective membrane immediately before the protective membrane isimplanted over the hard tissue defect and placed into contact withany adjacent soft tissue, the protective membrane comprising: asubstantially planar sheet of resorbable polymer base materialhaving a first side, a second side, a thickness measured betweenthe first side and the second side that is greater than about500 microns and less than 1000 microns, and a porosity that is lessthan about 60 percent; and a plurality of apertures disposed in thesubstantially planar sheet of resorbable polymer base material tosubstantially optimize healing of the hard tissue defect when theprotective membrane is implanted over the hard tissue defect,wherein apertures of the plurality of apertures of the protectivemembrane when the protective membrane is in the pre-implantconfiguration are surrounded by and defined by aperture wallswithin the substantially planar sheet of resorbable polymer basematerial and wherein apertures of the plurality of apertures definefluid flow paths from the first side to the second side; whereinaperture walls of the protective membrane when the protective?101520253035CA 02263933 2004-01-1614fmembrane is in the pre—implant configuration extend substantiallyand continuously from the first side to the second side, to therebydefine corresponding apertures which extend substantially andcontinuously from the first side to the second side; whereinapertures of the plurality of apertures of the protective membranewhen the protective membrane is in the pre—implant configurationhave minimum diameters greater than 1000 microns and less than3000 microns, wherein apertures of the plurality of apertures ofthe protective membrane when the protective membrane is in the pre-implant configuration are adapted to allow and optimize aproliferation of vasculature and connective tissue cells, derivedfrom the adjacent soft tissues, to permeate through the aperturesand into the hard tissue defect, while preventing gross prolapse ofthe adjacent soft tissues into the hard tissue defect; and whereinthe protective membrane is adapted to be resorbed into a mammalianbody, and not remodeled.A further aspect of the present invention is a protectivebone regeneration membrane for protecting a hard tissue defect froma prolapse of adjacent soft tissues during in vivo repair of thehard tissue defect, the protective membrane having a pre—implantconfiguration, which is defined as a configuration of theprotective membrane immediately before the protective membrane isimplanted over the hard tissue defect and placed into Contact withany adjacent soft tissue, the protective membrane comprising: asubstantially planar sheet of resorbable polymer base materialhaving a first side, a second side, a thickness measured betweenthe first side and the second side that is greater than 500 micronsand less than 1000 microns, and a porosity that is less than about60 percent; and a plurality of tunnels disposed in thesubstantially planar sheet of resorbable polymer base material tosubstantially optimize healing of the hard tissue defect when theprotective membrane is implanted over the hard tissue defect,wherein tunnels of the plurality of tunnels of the protectivemembrane when the protective membrane is in the pre—implantconfiguration have minimum diameters greater than 1000 microns and?10152025CA 02263933 2004-01-1614gless than 3000 microns and extend substantially continuously fromthe first side to the second side, wherein tunnels of the pluralityof tunnels of the protective membrane when the protective membraneis in the pre—implant configuration are adapted to allow andoptimize a proliferation of vasculature and connective tissuecells,derived from the adjacent soft tissues, to permeate throughthe tunnels and into the hard tissue defect, while preventing grossprolapse of the adjacent soft tissues into the hard tissue defect,the protective membrane being adapted to be resorbed into amammalian body, and not remodeled.In further aspects of the invention, each of the resorbablebase material, protective bone regeneration membrane, andresorbable protective membrane has a porosity greater than about20 percent and preferably greater than about 25 percent. In furtheraspects, the protective bone regeneration membrane and resorbablepolymer protective membrane may each have a first side comprising asubstantially—smooth side and a second side comprising asubstantially-smooth side. In a further aspect of the presentinvention, the resorbable base material is wrappable around twoends of a long bone for surrounding a large segmental void thatseparates the two ends by at least about 60 mm. In a furtheraspect, the resorbable protective membrane is wrappable around twoends of a long bone for surrounding a large segmental void thatseparates the two ends by at least about 30 mm, and preferably byabout 30 mm to about 60 mm.The present invention, together with additional features andadvantages thereof, may best be understood by reference to thefollowing description taken in connection with the accompanyingillustrative drawings.?1015202530WO 98/07384CA 02263933 l999-02- 18PCT/US97/1369515Brief Description of the DrawingsFigure 1 illustrates a longitudinal cross—sectionof a cell-occlusive membrane secured around a long bonedefect according to the prior art;Figure 2 illustrates a longitudinal cross—sectionof the protective bone regeneration membrane securedaround a long bone defect according to the presentlypreferred embodiment;Figures 3a and 3b illustrate the protective boneregeneration membrane according to the presentlypreferred embodiment:Figure 4 illustrates the protective boneregeneration membrane of the present invention, asapplied to a long bone defect:Figure 5 illustrates the protective boneregeneration membrane of the present invention, appliedto various bone defect areas of a human skull;Figure 6 illustrates the protective boneregeneration membrane of the presently preferredembodiment, used to facilitate bone regeneration of theiliac crest of a patient, after a bone autograft hasbeen harvested from the patient;Figure 7 illustrates the protective boneregeneration membrane of the present invention, asapplied to a mandibular (lower jaw) bone defect of apatient; andFigure 8 illustrates the protective boneregeneration membrane of the present invention, used incombination with a fixation device, as applied to a longbone defect of a patient.?5525-A101520253035CA 02263933 l999-02- 18par/us.§%)1369iIPENUS 05JUN1S16E ! .1 3 E . !. E I] E J E E : sTurning to Figure 2, a protective boneregeneration membrane 42 is illustrated, comprising abase material 44 and apertures 46. The protectivebone regeneration membrane 42 is shown in Figure 2The bone,which is surrounded by the protective bonewrapped around a bone defect area 49.regeneration membrane 42, comprises a first sectionof long bone 51, a second section of long bone 53,and a partially healed intermediate section of longbone 55.42 is rigid enough to prevent prolapse of theThe protective bone regeneration membranesurrounding tissues 57 into the bone defect area 49.Unlike the prior—art apertures 35 of the cell-occlusive, fluid permeable membrane 10 (Figure 1) theapertures 46 of the protective bone regenerationmembrane 42 are large enough to allow for aproliferation of cells (not shown) and blood vessels61 therethrough and into the first section of longbone 51, and the’partially healed bone defect area 49. Since thethe second section of long bone 53,protective bone regeneration membrane 42 of thepresently preferred embodiment is rigid enough towithstand prolapse of the surrounding tissue 57, theregeneration of the partially damaged periosteum 64is guided over the protective bone regenerationmembrane 42 in a direction substantially parallel tothe arrows A3 and A4.The apertures 46 Within the protective boneregeneration membrane 42 are both cell and fluidpermeable, and the base material 44 of the protectivebone regeneration membrane 42 is rigid enough tomaintain the available space between the firstsection of long bone 51 and the second section oflong bone 53 for ideal bone regeneration.Additionally, the base material 44 is resorbable,AMfN3a3S“N'?.-_-‘*1.5525-A101520253035CA 02263933 l999-02- 18PCT/Us 97/1369.IPEA/Us 05 JUN 199:17Thecell—occlusive membrane of the prior art membrane 10according to the presently preferred embodiment.(Figure 1), in contrast, is specifically designed toprevent the proliferation of cells and vesselstherethrough. This membrane 10 is alsoinsufficiently rigid and non—resorbable.Figures 3a and 3b illustrate differentembodiments of a sheet of the protective boneregeneration membrane 42, comprising the basematerial 44 and the apertures 46. As presentlyembodied,42 comprises either a biodegradable syntheticthe protective bone regeneration membranematerial or a biodegradable natural material, orboth.comprise polymers,The biodegradable synthetic material mayand the biodegradablefor example.for example,natural material may comprise collagen,Each of the apertures 46 preferably has a diameterwithin a range of between 20 microns and 3000microns. In the presently preferred embodiment, eachaperture 46 comprises a diameter of approximately1500 microns. A thickness of the base material 44 ispreferably within a range between 100 microns and2000 microns, but may also be configured as thin as10 microns. The pattern of distribution of theapertures 46 may vary according to the bone defectbeing treated. The ranges of aperture 46 sizes, basematerial 44 thickness, and aperture 46 shape anddistribution is preferably implemented by the presentinvention in order to optimize the protective boneregeneration membrane 42 to different environmentalconditions. Examples of the different environmentalconditions encountered in different bone defectsinclude the location of the defect (long bone or flatbone), the type of defect (discontinuity defect,trephine defect), sizecontour defect, window defect,of the defect, the presence or absence of periosteumAMENDED SHST?5525-A101520253035CA 02263933 l999-02- 18PCT/Us 97/ 1369IPEAIUS o5JuN199£1864,tissues covering the bone defect.and the general condition of the adjacent softFigure 4 illustrates the protective boneregeneration membrane 42 applied to a long bone 68 ofa patient. The protective bone regeneration membrane42 is applied to the long bone 68 in combination witha fixation device 70. The fixation device 70 can besecured to the long bone 68 using conventional means,such as screws 72. In alternative embodiments, tacksmay be used in place of or in combination with thescrews 72.and theprotective bone regeneration membrane 42 togetherThe fixation device 70, the screws 72,securely hold the first section 75 of the long bone68 to the second section 77 of long bone 68. A bonedefect area 79 is protected against the prolapse ofadjacent soft tissues, for example, by the protectivebone regeneration membrane 42.In contrast to the titanium screen mesh of theprior art, the inventors believe that the combinationof the protective bone regeneration membrane 42 andthe fixation device 70 may in some instances beadapted for operating together to relieve stressshielding of the long bone 68, to thereby preventsubsequent resorption of new bone. The prior arttitanium screen mesh is designed to remainpermanently attached to the bone, resulting in long-term stress shielding and resorption of newly formedbone within the bone defect area 79. In contrast tothe prior art titanium screen mesh, the protectivebone regeneration membrane 42 of the presentinvention is preferably configured of a resorbable,At about the time that thenew bone within the bone defect area 79 is fullybio-compatible material.regenerated, the protective bone regenerationmembrane 42 of the presently preferred embodimentwill have resorbed sufficiently to no longer shieldAMENDED SHEET. ...............................l,...,.2_. ,. ., I .?5525-Al01520253035CA 02263933 l999-02- 18PCT/US 97/1369}teams 05 JUN 199219stress from the bone defect area 79 to therebyencourage an increase of bone formation. Inaddition, according to the presently preferredand/or the screwsThattheembodiment, the fixation device 70,72,is,are also formed of a resorbable material.the combination of the fixation device 70,screws 72, and the protective bone regenerationmembrane 42 prevent excessive motion between thefirst section 75 and the second section 77 of thelong bone 68.As presently embodied, this period of timesufficient for complete new bone regeneration withinthe bone defect area 79 is between approximately 2 to24 months.the resorption of the protective bone regenerationThus, according to the present invention,membrane 42 to a point where the protective boneregeneration membrane 42 can no longer shieldsignificant mechanical stress on the first section 75and the second section 77 is between approximately 2and 24 months.In an alternative embodiment, the protectivebone regeneration membrane 42 may comprise a non-resorbable material. In this alternative embodimentwhere the protective bone regeneration membrane 42 isnon-resorbable and the fixation device 70 isresorbable, resorption of newly formed bone withinthe bone defect area 79 is still prevented. Moreparticularly, the protective bone regenerationmembrane 42 is configured to be flexible enough toprevent stress shielding between the first section 75and the second section 77, after the fixation device70 has been resorbed to a point where the fixationdevice 70 no longer exerts mechanical strength on thefirst section 75 and the second section 77 of thelong bone 68.As another distinguishing feature, theprotective bone regeneration membrane 42 of the~u=-*°**““. ....«..... ..%Mmm...._w _?5525-A101520253035CA 02263933 l999-02- 18PCT/US 97 I 1369am.-us 0 5 JUN 199820present invention is designed to be used incombination with a fixation device 70, in a preferredembodiment, while the titanium screen mesh of theprior art comprises a fixation device designedpredominantly to be used alone. In one conceivableembodiment of the present invention, the protectivebone regeneration membrane 42 of the presentinvention may be used in combination with the priorart titanium screen mesh, as well as in combinationwith any other conventional fixation device.Generally, internal fixation devices can be dividedinto two classes. Cortical compression platescomprise a first class and intramedullary rodscomprise a second class. Both classes of devices areunable to secure and stabilize shattered bone,because bone fragments are often small and freefloating within the fracture cavity. Furthermore,the periosteum around such fracture sites is usuallydestroyed and cannot serve as a membrane barrieragainst the dislocation of bone fragments. Multiplebone fragments are naturally resorbed unless they canbe rigidly held together and provided with sufficientblood supply. Bone fragment resorption can present asignificant obstacle to efficient healing ofcomminuted fractures. Bone fragment resorption oftennecessitates additional bone grafting procedures. Incontrast to the protective bone regeneration membrane42 of the present invention, both of the abovementioned classifications of fixation devices areunable to achieve this end.The protective bone regeneration membrane 42 ofthe presently preferred embodiment is preferablyresorbed within the body of the patient to a pointwhere substantial mechanical fixation is no longerexerted on the first section 75 and the secondsection 77 of the long bone 68, within a period ofapproximately 1 year. Complete resorption of the.=.';v.a‘~:z.*..'-*0 '?5525—A101520253035CA 02263933 l999-02- 18PCT/US 97/1369!npsms os.1um99=21protective bone regeneration membrane 42 maysubsequently occur after a total period of 1% to 2years have elapsed since the initial implantation.In contrast to the allogenic bone grafts of the priorart, the protective bone regeneration membrane 42 ofthe present invention is resorbed into the body ofthe patient. Allogenic bone grafts are onlypartially substituted with new bone over time,typically comprising 1 to 2 years, forming apermanent composite of viable (new) bone and non-viable cadaver bone. Thus, allogenic bone graftscannot achieve a complete regeneration of the entirebone defect with new living bone, as can theprotective bone regeneration membrane 42 of thepresent invention. This benefit is achieved byplacement of the protective bone regenerationmembrane 42 outside of the bone defect area 49,rather than within the bone defect area 49.Additionally,graft of the prior art are substantially occluded bythe holes within the allogenic boneinduced bone formation therein within approximately 2to 3 weeks after the initial implantation. Finally,as a further distinguishing feature between theprotective bone regeneration membrane 42 of thepresent invention and the prior art allogenic bonegraft, the prior art allogenic bone graft is placedwithin the bone defect area itself, since the purposeof the prior art allogenic bone graft 42 is to becomea part of the new bone. In contrast, the protectivebone regeneration membrane 42 of the presentinvention is designed to be placed completely outsideof the bone defect area, in order to maintain amaximal size of the bone defect area 79 forregeneration of new bone by the patient in the area79.Still further, allogenic bone grafts areinferior to the protective bone regeneration membrane42 of the present invention in providing amimic SHU?5525-A101520253035CA 02263933 l999-02- 18PCT/US 97/1363um/us osJuN19!22combination of patient safety in preventing diseasetransmission, optimal prolapse prevention and maximalspace preservation for bone regeneration, andvasculature ingrowth potential. Similarly to theallogenic bone graft of the prior art, the above-mentioned skin graft of the prior art comprisesapertures which are quickly occluded by the ingrowthof epithelial cells therein. These prior artapertures, similarly to the allogenic bone graftholes, are actually filled with the desired tissues,whereas, the apertures of the protective boneregeneration membrane 42 allow ongoing transmigrationof cells and blood vessels for generating the desiredtissue. Additionally, these apertures are formedhaving a diameter of approximately 1 millimeter,whereas the preferred diameter of the apertures ofthe present invention are approximately 1.5Additionally,of the prior art is specifically designed formillimeters. the skin graft membraneproviding an in vitro scaffold and subsequenttransplantable skin graft, whereas the presentinvention preferably operates in vivo.Many of the above—described differences betweenthe protective bone regeneration membrane 42 of thepresent invention and prior art devices help point toa fundamental difference between the presentinvention and prior art devices. The presentinvention is directed to maintaining a space,protected against adjacent soft tissue prolapse, tothereby facilitate spontaneous bone regeneration bythe patient within the protected space. The presentinvention recognizes that spontaneous boneregeneration by the patient can be greatlyaccelerated and enhanced by allowing the infiltrationof surrounding blood vessels and cells.The present inventors recognize that mesenchymalstem cells, which can be found in surroundingAMENDED 5&1’?5525-A101520253035CA 02263933 l999-02- 18PCT/US <57‘/‘13‘é§5IPEA/US 05JUN199323mesodermal tissues, are the precursor cells thateventually form muscle, cartilage, tendons,ligaments, connective tissues, and bone. These cellsare present in these tissues and are involved in theperpetual renewal of each specific tissue, althoughthese cellsAnin their earliest stage of development,are not committed to becoming any given tissue.uncommitted mesenchymal stem cell found in muscle,for example, will not strictly become a muscle cell.If the mesenchymal stem cell is needed to become abone cell, the mesenchymal stem cell may migrate to abone defect and differentiate into a bone formingcell.The mechanism for attracting these cells anddirecting them to become a specific tissue cell isunderstood by the present inventors to be controlledby morphogenic proteins, although other factors maybe involved. In bone, for example, these proteinsare commonly referred to as bone morphogenicproteins. The apertures 46 of the protective boneregeneration membrane 42 harness this mechanism, byallowing bone morphogenic proteins derived fromwithin the bone matrix to attract mesenchymal stemcells from the surrounding connective tissues,Theattracted elements are then directed to differentiatemusculature, periosteum, and vasculature.into bone forming cells, which are essential for newtheapertures 46 of the present invention allow vitalbone formation by the patient. In addition,contributions of blood vessels from surroundingtissues, musculature, and periosteum into theprotected area. Blood vessels invading the bonedefect throughmembrane 42 ofthe protective bone regenerationthe present invention greatly enhancethe generation of new bone, as compared to prior artcell-occlusive membranes that limit the supply ofblood to that coming from within the bone defectitself. The ability for capillaries from surroundingAMEM£D3|W?5525-A101520253035CA 02263933 l999-02- 18PCT/US 97/1369IPEA/US 05JUN19924soft tissues to proliferate through the protectivebone regeneration membrane 42 helps prevent migratingcells from the osseous bed and the periosteum fromoutstripping their proliferating blood supply. Thisproliferation of blood vessels increases thepotential of spontaneous bone regeneration within agiven defect. Furthermore, mesenchymal stem cellsare believed to be perivascular (around bloodvessels) connective tissue cells, which wouldadditionally foster bone regeneration by thetransmembranous sprouting of capillaries, since mostvasculature has associated connective tissues.The base material 44 (Figure 3), according tothe present invention, may be impregnated with avariety of substances for promoting the regenerationof different tissues such as bone and blood vessels.The base material 44 may be impregnated with achemotactic substance for influencing cell-migration,an inhibitory substance for influencing cell-migration, a mitogenic growth factor for influencingcell proliferation and a growth factor for ‘influencing cell differentiation (e.g. insulinelikegrowth factor, transforming growth factor-beta,fibroblast growth factor, platelet—derived growthfactor), and factors which promote neoangiogenesis(formation of new blood vessels).According to the present invention, the basematerial 44 is flexible both at the time ofThis flexibilityallows the protective bone regeneration membrane 42manufacture and after hydration.to be bent and shaped such that, after the area iscompletely healed, the contour of the healed bonematches the contour of the original bone, or matchesthe contour of the original bone as closely aspossible. According to the present invention, thebase material 44 (Figure 3) further provides anadvantageous rigidity, which is higher than otherAMEMED 83'?5525-A101520253035CA 02263933 l999-02- 18PCT/US §%)135é‘:wsvus o 5 JUN 199225currently used membrane materials (Figure 1) tothereby provide sufficient strength against softtissue pressure.The method of the present invention generallycomprises a step of affixing the protective boneregeneration membrane 42 (Figure 3) onto a portion ofThefixation of the protective bone regeneration membranethe mammalian skeletal system in need of repair.42 may be accomplished by any conventional surgicaltechnique, including the use of resorbable pins,screws, and sutures. Alternatively, the protectivebone regeneration membrane 42 of the presentinvention can be implanted into the patient withoutbeing affixed to existing bone, such as, for example,in the case of orbital floor reconstruction (Figure5).Other applications of the protective boneregeneration membrane of the present invention areillustrated in Figures 5-8. Figure 5 illustratesseveral applications of the protective boneregeneration membrane in the cranio-facial region offa human skull. A protective bone regenerationmembrane 80 is applied over the burrholes and thetrephination defect of a human skull 82, after aneurosurgical procedure or trauma. Inside the orbitsof the skull, protective bone regeneration membranes84 are placed over orbital floor fractures to prevententrapment of overlying muscles and nerves therein.Another protective bone regeneration membrane 86 isapplied over a defect area in the maxillary sinus,and still another protective bone regenerationmembrane 88 is applied over a bone defect area in themaxilla (upper jaw). Another protective boneregeneration membrane 90 is applied over anedentulous bone defect area in the mandible (lowerjaw).menace an?5525-A101520253035CA 02263933 l999-02- 18PCT/Us 97/1369IPEAIUS 05 JUN 199:26A protective bone regeneration membrane 80 isillustrated in Figure 6, applied to the pelvis 82 ofa human patient, after a bone autograft has beenharvested therefrom. The protective boneregeneration membrane 80 protects the bone defectarea 84 from soft tissue interposition, whileIfnecessary, the protective bone regeneration membraneallowing the ingrowth of blood vessels and cells.80 can be affixed onto the adjacent bone using pins,screws, sutures, or other conventional means. Figure7 illustrates a protective bone regeneration membrane93 applied around a segmental defect 94 in a humanmandible 95,regeneration membrane 93 can be implanted using anfor example. The protective boneextra-oral (outside of the mouth) surgical approach.According to this approach, the epithelial lining ofmembranethe mouthextra-oralthe mouth is not broken and the protectiveis placed beneath the epithelial lining of(since the bone defect is accessed from anarea such as below the chin). Therefore theTheintended to applyepithelial cells cannot enter the bone defect.present invention, however, is alsoin intra-oral surgical approaches. The defect may beor just missing aof the mandible95 are fixated together by a plate 97 and screws 99,a discontinuity defect, comminuted,part of the bone. The intact partsif necessary, and the protective bone regenerationmembrane 93 protects the bone defect site frominterposition of surrounding soft tissue.Additionally, the protective bone regenerationmembrane 93 holds any free-floating fragments of bonein place and provides additional circumferentialstabilization to the bone defect. Although theprotective bone regeneration membrane 93 is malleableto a certain extent, the protective bone regenerationmembrane 93 is stiff enough to prevent collapsethereof under the weight of adjacent soft tissues.?5525-A101520253035CA 02263933 l999-02- 18P CWEA/t?s7 6 51 J3 $3933The protective bone regeneration membrane 93 can be27easily cut with scissors and shaped by the hand of auser to adapt three—dimensionally to a bone defectarea.Figure 8 illustrates another application of theprotective bone regeneration membrane 105 of thepresent invention, as applied to a bone defect areaof a long bone 101. The protective bone regenerationmembrane 105 is secured to the long bone 101 using afixation member 107 and screws 109, and comprises abelt-like tab 111. The belt—like tab 111 is adaptedfor being fed through a slot 113, which is formedbetween the fixation member 107 and the long bone101. theprotective bone regeneration membrane 105 is securedIn the presently preferred embodiment,to the fixation member 107, and both the protectivebone regeneration membrane 105 and the fixationmember 107 are resorbable, in order to avoid a secondsurgery for removal of the devices. Surgical removalof non-resorbable, non—metallic membranes isin order to avoid riskAnecessary in the prior art,such as bacterial contamination and infection.user can grip the belt-like tab 111 to securelyfasten the protective bone regeneration membrane 105around the long bone 101. This secure fastening ofthe protective membrane 105 around the long bone 101can facilitate the holding of bone fragments in placewithin the bone defect area, in addition to addingstability to the bone fracture.preferred embodiment, the screws 109 are tightenedinto the long bone 101 after the protective boneIn the presentlyregeneration membrane 105 is tightened around thelong bone 101. The embodiment of Figure 8 isespecially advantageous for setting comminutedto therebyTheprotective bone regeneration membrane 105 can befractures, having multiple bone fragments,reduce the risk of bone fragment resorption.?S525—A101520253035CA 02263933 l999-02- 18PCT/US 97/1369IPEAIUS OSJUN 199828tightened around the long bone 101, until a desiredtension is achieved for holding the native fracturefragments in place. The protective bone regenerationmembrane 105 can also be used to prevent thedislocation of bone grafts or bone graft substitutes.Of course, the protective bone regeneration membrane105 may be used without a fixation member 107. If itis necessary to stabilize major bone fragments, theprotective bone regeneration membrane 105 may be usedin conjunction with other rigid fixation devices,either internal or external.The protective bone regeneration membrane 105may be used with or without a belt-like tab 111 toform a tube around a bone defect area of a long bone101. If the tube overlaps both fracture ends of thelong bone 101, the tube may provide sufficientstructural support, resulting from the strength ofthe protective bone regeneration membrane 105 and thestructural characteristics of the tube, to obviatethe need for additional plates, screws, or externalfixation devices. Structurally, a tube locatessupporting elements in the area of highest stresswhen loaded in shear, compression, or in bending.The tube configuration, according to this alternativeembodiment, is superior to intramedullary rods, whichlay at the approximate neutral load axis, oreccentrically placed orthopedic plates, which supportonly one side of the fracture and which may introduceasymmetrical, non-axial loading on the fracture. Inaddition to superior strength in bending, a tubeconfiguration will also have superior resistance tocolumn (compression) loading. If the ends and seamof the protective bone regeneration membrane 105 aresuitably fixated, the configuration will also besuperior in shear strength. Although the presentmaterial, configurations, and methods have beendescribed in the context of treating humans, theseAMENSEC Si-QT ?(3L}552S—ACA 02263933 l999-02- 18PCT/US 97/1369!IPENUS 05JUN199E29materials, configurations, and methods can also beuseful in treating animals.Although an exemplary embodiment of theinvention has been shown and described, many otherchanges, modifications and substitutions, in additionto those set forth in the above paragraphs,made by one having ordinary skill in the art withoutmay benecessarily departing from the spirit and scope ofthis invention.AMENSED SE3

Claims (156)

CLAIMS:

1. A protective bone regeneration membrane for protecting a hard tissue defect from a prolapse of adjacent soft tissues during in vivo repair of the hard tissue defect, the protective membrane having a pre-implant configuration, which is defined as a configuration of the protective membrane immediately before the protective membrane is implanted over the hard tissue defect and placed into contact with any adjacent soft tissue, the protective membrane comprising:
a substantially planar sheet of resorbable polymer base material having a first side, a second side, a thickness measured between the first side and the second side that is less than 1000 microns, and a porosity that is less than about 60 percent; and a plurality of apertures disposed in the substantially planar sheet of resorbable polymer base material to substantially optimize healing of the hard tissue defect when the protective membrane is implanted over the hard tissue defect, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters which are greater than 1000 microns and less than 3000 microns and which define isolated, non-intersecting, fluid-flow paths from the first side to the second side;
wherein the protective membrane comprises a configuration and strength sufficient to prevent gross prolapse of adjacent soft tissues into the hard tissue defect, when the protective membrane is implanted over the hard tissue defect and placed into contact with any adjacent soft tissue;
wherein the plurality of apertures of the substantially planar sheet of resorbable polymer base material, immediately after implanting of the substantially planar sheet of resorbable polymer base material over the hard tissue defect, have diameters sufficient in size and distribution to allow and optimize a proliferation of vasculature and connecive tissue cells, derived from adjacent soft tissues, to permeate through the apertures and substantially into the hard tissue defect; and wherein the protective membrane is adapted to be resorbed into a mammalian body, and not remodeled, within a period of approximately 2 to 24 months from an initial implantation of the protective membrane into the mammalian body.

2. The protective bone regeneration membrane as recited in Claim 1, wherein cross-sectional areas of the non-intersecting fluid flow paths are substantially constant along lengths of the non-intersecting fluid-flow paths from the first side to the second side.

3. The protective bone regeneration membrane as recited in Claim 1, wherein the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

4. The protective bone regeneration membrane as recited in Claim 3, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

5. The protective bone regeneration membrane as recited in Claim 1, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material;
cross-sectional areas of the .apertures are substantially constant along lengths of the apertures from the first side to the second side; and the protective bone regeneration membrane has a porosity greater than about 20 percent.

6. The protective bone regeneration membrane as recited in Claim 1, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material in rows of at least three apertures and columns of at least three apertures.

7. The protective bone regeneration membrane as recited in Claim 1, wherein cross-sectional areas of the apertures have circular perimeters.

8. The protective bone regeneration membrane as recited in Claim 1, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

9. The protective bone regeneration membrane as recited in Claim 1, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

10. The protective bone regeneration membrane as recited in Claim 1, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

11. The protective bone regeneration membrane as recited in Claim 1, wherein:
the thickness of the substantially planar sheet of resorbable polymer base material is greater than or equal to about 50C) microns and less than or equal to 1000 microns, and the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

12. The protective bone regeneration membrane as recited in Claim 11, wherein apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in staggered rows.

13. The protective bone regeneration membrane as recited in Claim 11, wherein cross-sectional areas of the non-intersecting fluid flow paths are substantially constant along lengths of the non-intersecting fluid-flow paths from the first side to the second side.

14. The protective bone regeneration membrane as recited in Claim 11, wherein the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

15. The protective bone regeneration membrane as recited in Claim 14, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

16. The protective bone regeneration membrane as recited in Claim 11, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material.

17. The protective bone regeneration membrane as recited in Claim 11, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material in rows wherein apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in staggered rows of at least three apertures and columns of at least three apertures.

18. The protective bone regeneration membrane as recited in Claim 11, wherein cross-sectional areas of the apertures have circular perimeters.

19. The protective bone regeneration membrane as recited in Claim 11, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

20. The protective bone regeneration membrane as recited in Claim 11, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

21. The protective bone regeneration membrane as recited in Claim 11, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

22. The protective bone regeneration membrane as recited in Claim 11, wherein the sheet of resorbable polymer base material comprises a single layer which is substantially solid.

23. The protective bone regeneration membrane as recited in Claim 11, wherein:
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in a matrix having columns of at least three apertures and rows of at least three apertures, and the rows are staggered.

24. The protective bone regeneration membrane as recited in Claim 1, wherein the sheet of resorbable polymer base material is formed of a single layer which is substantially solid.

25. The protective bone regeneration membrane as recited in Claim 1, wherein:
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in a matrix having columns of at least three apertures and rows of at least three apertures, and the rows are staggered.

26. A resorbable polymer planar protective membrane for protecting a bone defect area from a soft tissue prolapse into the bone defect area, the resorbable polymer planar protective membrane having two opposing sides, a thickness between the two sides that is less than or equal to 1000 microns, a porosity that is less than about 60 percent, and being adapted to be placed in a pre-implant configuration outside of the bone defect area, as opposed to being placed within the bone defect area where new bone would ideally grow, to thereby allow entirely new bone growth within the area, the resorbable polymer planar protective membrane in the pre-implant configuration comprising a plurality of apertures disposed therein to substantially optimize healing of the bone defect area when the resorbable polymer planar protective membrane is implanted over the bone defect area, wherein apertures of the plurality of apertures form non-intersecting fluid flow paths, which fluidly connect the two opposing sides, which have minimum diameters greater than 1000 microns and less than 3,600 microns, which are arranged on the resorbable polymer planar protective membrane in staggered rows, and which are adapted to allow and optimize a proliferation of vasculature and connective tissue cells from adjacent soft tissues into the bone defect area, while preventing a gross prolapse of adjacent soft tissues into the bone defect area, the resorbable polymer planar protective membrane being adapted to be resorbed into a mammalian body, and not remodeled.

27. The resorbable polymer planar protective membrane as recited in Claim 26, wherein the resorbable polymer planar protective membrane has a porosity greater than about 20 percent.

28. The resorbable polymer planar protective membrane as recited in Claim 26, wherein the resorbable polymer planar protective membrane has a porosity of about 25 percent.

29. The resorbable polymer planar protective membrane as recited in Claim 26, wherein the apertures are uniformly distributed on the protective membrane.

30. The resorbable polymer planar protective membrane as recited in Claim 26, wherein the apertures are uniformly distributed on the resorbable polymer planar protective membrane in rows of at least three apertures and columns of at least three apertures.

31. The resorbable polymer planar protective membrane as recited in Claim 26, wherein cross-sectional areas of the apertures have circular perimeters.

32. The resorbable polymer planar protective membrane as recited in Claim 26, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

33. The resorbable polymer planar protective membrane as recited in Claim 26, wherein apertures of the plurality of apertures of the resorbable polymer planar protective membrane when the resorbable polymer planar protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

34. The resorbable polymer planar protective membrane as recited in Claim 26, wherein apertures of the plurality of apertures of the resorbable polymer planar protective membrane when the resorbable polymer planar protective membrane is in the pre-implant configuration have minimum diameters of about 1500 microns.

35. The resorbable polymer protective membrane as recited in Claim 26, wherein the resorbable polymer protective membrane is formed of a single layer which is substantially solid.

36. The resorbable polymer protective membrane as recited in Claim 26, wherein:
apertures of the plurality of .apertures are arranged on the resorbable polymer protective membrane in a matrix having columns of at least three apertures and rows of at least three apertures, and the rows are staggered.

37. A resorbable polymer protective membrane having two opposing planar sides, a thickness between. the two sides that is greater than 500 microns and less than or equal to about 1000 microns, a porosity that is greater than about 20 percent and less than about 60 percent, and being for facilitating protected bone regeneration within a bone defect area, the resorbable polymer protective membrane in a pre-implant configuration comprising a plurality of non-intersecting fluid flow paths disposed in the resorbable polymer protective membrane to substantially optimize healing of the bone defect area when the resorbable polymer protective membrane is implanted over the bone defect area, wherein non-intersecting fluid flow paths of the plurality of non-intersecting fluid flow paths fluidly connect the two opposing sides and have diameters greater than 1000 microns and less than 3,000 microns, the resorbable polymer protective membrane being adapted to be resorbed into a mammalian body and not remodeled.

38. The resorbable polymer protective membrane as recited in Claim 37, wherein cross-sectional areas of the non-intersecting fluid flow paths are substantially constant along lengths of the non-intersecting fluid-flow paths between the two opposing sides.

39. The resorbable polymer protective membrane as recited in Claim 37, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

40. The resorbable polymer protective membrane as recited in Claim 37, wherein the resorbable polymer protective membrane has a porosity of about 25 percent.

41. The resorbable polymer protective membrane as recited in Claim 37, wherein the non-intersecting fluid flow paths are uniformly distributed on the resorbable polymer protective membrane.

42. The resorbable polymer protective membrane as recited in Claim 37, wherein the non-intersecting fluid flow paths are uniformly distributed on the resorbable polymer protective membrane in rows of at least three non-intersecting fluid flow paths and columns of at least three non-intersecting fluid flow paths.

43. The resorbable polymer protective membrane as recited in Claim 37, wherein cross-sectional areas of the non-intersecting fluid flow paths have circular perimeters.

44. The resorbable polymer protective membrane as recited in Claim 37, wherein non-intersecting fluid flow paths of the plurality of non-intersecting fluid flow paths of the resorbable polymer protective membrane when the resorbable polymer protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

45. The resorbable polymer protective membrane as recited in Claim 37, wherein the resorbable polymer protective membrane is formed of a single layer which is substantially solid.

46. The resorbable polymer protective membrane as recited in Claim 37, wherein:
non-intersecting fluid flow paths of the plurality of non-intersecting fluid flow paths are arranged on the resorbable polymer protective membrane in a matrix having columns of at least three non-intersecting fluid flow paths and rows of at least three non-intersecting fluid flow paths, and the rows are staggered.

47. A use of a resorbable polymer protective membrane for facilitating protected bone regeneration, wherein:
the resorbable polymer protective membrane has a thickness, a porosity less than about 60 percent, and a plurality of non-intersecting apertures penetrating completely through the thickness of the resorbable polymer protective membrane and distributed on the resorbable polymer protective membrane to substantially maximize healing of a bone defect area when the resorbable polymer protective membrane is wrapped around the bone defect area, wherein apertures of the non-intersecting apertures have 500 micron to 3000 micron minimum diameters, the resorbable polymer protective membrane having a strength sufficient to prevent gross prolapse of adjacent soft tissues into the bone defect area and to allow and optimize protected bone regeneration when the resorbable polymer protective membrane is secured around the bone defect area and secured to the adjacent areas of bone near the bone defect area, the resorbable polymer protective membrane being adapted to be resorbed into a mammalian body, and not remodeled.

48. The use as recited in Claim 47, wherein the membrane is usable on the bone defect area located on a pelvis of a patient, after a bone autograft has been harvested from the pelvis.

49. The use as recited in Claim 47, further comprising a use of a rigid fixation device for securing to the bone defect area.

50. The use as recited in Claim 47, wherein the resorbable polymer protective membrane is wrappable around two ends of a long bone for surrounding a large segmental void between the two ends of the long bone.

51. The use as recited in Claim 50, further comprising a use of a rigid fixation device for securing to the bone defect area.

52. The use as recited in Claim 50, further comprising a use of a rigid fixation device for securing to the bone defect area, the rigid fixation device comprising one of a rigid bone plate, an intramedullary rod, and an external fixation device.

53. The use as recited in Claim 52, wherein the resorbable polymer protective membrane comprises a first side, a second side, and a thickness measured between the first side and the second side that is less than or equal to about 1000 microns.

54. The use as recited in Claim 53, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

55. The use as recited in Claim 53, wherein the resorbable polymer protective membrane has a thickness greater than about 500 microns.

56. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has a first side, a second side, and a thickness measured between the first side and the second side that is less than or equal to about 1000 microns.

57. The use as recited in Claim 56, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

58. The use as recited in Claim 57, wherein the resorbable polymer protective membrane has apertures arranged thereon in staggered rows.

59. The use as recited in Claim 47, wherein the resorbable polymer protective membrane comprises as a first side, a second side, and a thickness measured between the first side and the second side that is less than about 1000 microns.

60. The use as recited in Claim 59, wherein the resorbable polymer protective membrane has a thickness greater than or equal to about 500 microns.

61. The use as recited in Claim 60, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

62. The use as recited in Claim 61, wherein the resorbable polymer protective membrane has apertures arranged on the sheet of resorbable polymer base material in staggered rows.

63. The use as recited in Claim 60, wherein the membrane is wrappable around two ends of a long bone for surrounding a large segmental void between the two ends of the long bone and wherein a fixation device is securable to the bone defect area.

64. The use as recited in Claim 59, wherein the resorbable polymer protective membrane has apertures arranged on the sheet of resorbable polymer base material in staggered rows.

65. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has apertures arranged on the sheet of resorbable polymer base material in staggered rows.

66. The use as recited in Claim 65, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

67. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has apertures with cross-sectional areas that are substantially constant along lengths of the apertures.

68. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has a porosity greater than about 20 percent.

69. The use as recited in Claim 68, wherein the resorbable polymer protective membrane has a porosity of about 25 percent.

70. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has apertures uniformly distributed on the of resorbable polymer protective membrane in rows of at least three apertures and columns of at least three apertures.

71. The use as recited in Claim 47, wherein the resorbable polymer protective membrane has apertures with minimum diameters greater than or equal to about microns.

72. A use of a resorbable polymer protective base material for protecting a bone defect area from soft tissue interposition, wherein the material comprises:
a substantially planar sheet comprising a thickness, a porosity less than about 60 percent, and a plurality of non-intersecting apertures disposed in the substantially planar sheet of resorbable polymer protective base material, apertures of the plurality of non-intersecting apertures penetrating through the thickness of the substantially planar sheet of resorbable polymer protective base material and having minimum diameters ranging from approximately 500 microns to approximately 3000 microns, apertures of the plurality of non-intersecting apertures further being distributed on the substantially planar sheet of resorbable polymer protective base material to substantially optimize healing of a bone defect area when the substantially planar sheet of resorbable polymer protective base material is placed around a boundary of the bone defect area and being adapted to allow and optimize a proliferation of vasculature and connective tissue cells, derived from adjacent soft tissues, into the boundary of the bone defect area, while preventing a gross prolapse of adjacent soft tissues into the boundary of the bone defect area, the substantially planar sheet of resorbable polymer protective base material being adapted to be resorbed into a mammalian body, and not remodeled.

73. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material is placeable around two ends of a long bone for surrounding a large segmental void between the two ends of the long bone.

74. The use as recited in Claim 72, further comprising a use of a rigid fixation device for securing to the boundary of the bone defect area.

75. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material is placeable around the boundary of the bone defect area located on a pelvis of a patient, after a bone autograft has been harvested from the pelvis.

76. The use as recited in Claim 75, further comprising a use of a rigid fixation device for securing to the boundary of the bone defect area.

77. The use as recited in Claim 75, further comprising a use of a rigid fixation device for securing to the boundary of the bone defect area, the rigid fixation device comprising one of a rigid bone plate, an intramedullary rod, and an external fixation device.

78. The use as recited in Claim 77, wherein the substantially planar sheet of resorbable polymer protective base material comprises as a first side, a second side, and a thickness measured between the first side and the second side that is less than or equal to about 1000 microns.

79. The use as recited in Claim 78, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity greater than about 20 percent.

80. The use as recited in Claim 78, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness greater than about microns.

81. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a first side, a second side, and a thickness measured between the first side and the second side that is less than or equal to about 1000 microns.

82. The use as recited in Claim 81, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity greater than about 20 percent.

83. The use as recited in Claim 82, wherein the substantially planar sheet of resorbable polymer protective base material has apertures arranged thereon in staggered rows.

84. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a first side, a second side, and a thickness measured between the first side and the second side that is less than about 1000 microns.

85. The use as recited in Claim 84, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness greater than or equal to about 500 microns.

86. The use as recited in Claim 85, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity greater than about 20 percent.

87. The use as recited in Claim 86, wherein the substantially planar sheet of resorbable polymer protective base material has apertures arranged on the substantially planar sheet of resorbable polymer protective base material in staggered rows.

88. The use as recited in Claim 85, wherein the substantially planar sheet of resorbable polymer protective base material is placeable around the boundary of the bone defect area located on a pelvis of a patient, after a bone autograft has been harvested from the pelvis.

89. The use as recited in Claim 84, wherein the substantially planar sheet of resorbable polymer protective base material has apertures arranged on the substantially planar sheet of resorbable polymer protective base material in staggered rows.

90. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has apertures arranged on the substantially planar sheet of resorbable polymer protective base material in staggered rows.

91. The use as recited in Claim 90, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity greater than about 20 percent.

92. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has apertures with cross-sectional areas that are substantially constant throughout the apertures.

93. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity greater than about 20 percent.

94. The use as recited in Claim 93, wherein the substantially planar sheet of resorbable polymer protective base material has a porosity of about 25 percent.

95. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has apertures uniformly distributed on the substantially planar sheet of resorbable polymer protective base material in rows of at least three apertures and columns of at least three apertures.

96. The use as recited in Claim 73, wherein the membrane is wrappable around two ends of a long bone for surrounding a large segmental void that separates the two ends by at least about 60 mm.

97. The use as recited in Claim 74, wherein the rigid fixation device is a resorbable bone plate.

98. The use as recited in Claim 72, wherein the planar sheet of resorbable polymer protective base material is placeable around a boundary of and over a burr hole.

99. The use as recited in Claim 98, wherein the substantially planar sheet of resorbable polymer protective base material has a first side, a second side, and a thickness measured between the first side and the second side that is less than 1000 microns.

100. The use as recited in Claim 99, wherein the substantially planar sheet of resorbable polymer protective base material has apertures with cross-sectional areas that are substantially constant throughout the apertures and has a porosity greater than about 20 percent.

101. The use as recited in Claim 99, wherein the substantially planar sheet of resorbable polymer protective base material has apertures with cross-sectional areas that are substantially constant throughout the apertures and has aperture diameters less than about 1000 microns.

102. The use as recited in Claim 99, wherein the substantially planar sheet of resorbable polymer protective base material has minimum aperture diameters less than about 1000 microns.

103. The use as recited in Claim 99, wherein the substantially planar sheet of resorbable. polymer protective base material has a porosity greater than about 20 percent.

104. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness less than 1000 microns and a porosity greater than about 20 percent; and wherein the substantially planar sheet of resorbable polymer protective base material is placeable around a boundary of and over a trephination defect.

105. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness less than 1000 microns and a porosity greater than about 20 percent; and wherein the substantially planar sheet of resorbable polymer protective base material is placeable around a boundary of a defect in an orbital floor.<

106. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness less than 1000 microns and a porosity greater than about 20 percent; and wherein the substantially planar sheet of resorbable polymer protective base material is placeable around a boundary of a defect in a maxillary sinus.

107. The use as recited in Claim 72, wherein the substantially planar sheet of resorbable polymer protective base material has a thickness less than 1000 microns and a porosity greater than about 20 percent; and wherein the substantially planar sheet of resorbable polymer protective base material is placeable around a boundary of a defect in a maxilla.

108. The use as recited in Claim 72, where in the substantially planar sheet of resorbable polymer protective base material has a thickness less than 1000 microns and a porosity greater than about 20 percent; and wherein the substantially planar sheet of resorbable polymer protective base material is placeable around a boundary of a endentulous defect in a mandible.

109. The use as recited in Claim 72, further comprising a use of bone grafts within the bone defect area.

110. The method as recited in Claim 72, and further comprising a use of bone graft substitutes within the bone defect area.

111. A protective bone regeneration membrane for protecting a hard tissue defect from a prolapse of adjacent soft tissues during in vivo repair of the hard tissue defect, the protective membrane having a pre-implant configuration, which is defined as a configuration of the protective membrane immediately before the protective membrane is implanted over the hard tissue defect and placed into contact with any adjacent soft tissue, the protective membrane comprising:
a substantially planar sheet of resorbable polymer base material having a first side, a second side, a thickness measured between the first side and the second side that is less than or equal to 1000 microns, and a porosity that is less than about 60 percent;
and a plurality of apertures disposed in the substantially planar sheet of resorbable polymer base material to substantially optimize healing of the hard tissue defect when the protective membrane is implanted over the hard tissue defect, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have diameters greater than 1000 microns and less than 3000 microns, define fluid-flow paths extending along individual path axes from the first side to the second side, and have cross-sectional areas that are substantially constant along the path axes, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration are adapted to allow and optimize a proliferation of vasculature and connective tissues cells, derived from the adjacent soft tissues, to permeate through the apertures and into the hard tissue defect, while preventing gross prolapse of the adjacent soft tissues into the hard tissue defect, the protective membrane being adapted to be resorbed into a mammalian body, and not remodeled.

112. The protective bone regeneration membrane as recited in Claim 111, wherein apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in staggered rows.

113. The protective bone regeneration membrane as recited in Claim 111, wherein the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

114. The protective bone regeneration membrane as recited in Claim 111, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

115. The protective bone regeneration membrane as recited in Claim 111, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material.

116. The protective bone regeneration membrane as recited in Claim 111, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material in rows of at least three apertures and columns of at least three apertures.

117. The protective bone regeneration membrane as recited in Claim 111, wherein the cross-sectional areas of the apertures have circular perimeters.

118. The protective bone regeneration membrane as recited in Claim 111, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

119. The protective bone regeneration membrane as recited in Claim 111, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

120. The protective bom; regeneration membrane as recited in Claim 111, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

121. The protective bone regeneration membrane as recited in Claim 111, wherein the sheet of resorbable polymer base material is formed of a single layer which is substantially solid.

122. The protective bone regeneration membrane as recited in Claim 111, wherein:
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in a matrix having columns of at least three apertures and rows of at least three apertures, and the rows are staggered.

123. The protective bone regeneration membrane as recited in Claim 112, wherein the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

124. The protective bone regeneration membrane as recited in Claim 123, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

125. The protective bone regeneration membrane as recited in Claim 113, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

126. The protective bone regeneration membrane as recited in Claim 113, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material.

127. The protective bone regeneration membrane as recited in Claim 113, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material in rows of at least three apertures and columns of at least three apertures.

128. The protective bone regeneration membrane as recited in Claim 113, wherein the cross-sectional areas of the apertures have circular perimeters.

129. The protective bone regeneration membrane as recited in Claim 113, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

130. The protective bone regeneration membrane as recited in Claim 113, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

131. The protective bone regeneration membrane as recited in Claim 113, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

132. protective bone regeneration membrane for protecting a hard tissue defect from a prolapse of adjacent soft tissues during in vivo repair of the hard tissue defect, the protective membrane having a pre-implant configuration, which is defined as a configuration of the protective membrane immediately before the protective membrane is implanted over the hard tissue defect and placed into contact with any adjacent soft tissue, the protective membrane comprising:
a substantially planar sheet of resorbable polymer base material having a first side, a second side, a thickness measured between the first side and the second side that is greater than about 500 microns and less than 1000 microns, and a porosity that is less than about 60 percent; and a plurality of apertures disposed in the substantially planar sheet of resorbable polymer base material to substantially optimize healing of the hard tissue defect when the protective membrane is implanted over the hard tissue defect, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration are surrounded by and defined by aperture walls within the substantially planar sheet of resorbable polymer base material and wherein apertures of the plurality of apertures define fluid flow paths from the first side to the second side;
wherein aperture walls of the protective membrane when the protective membrane is in the pre-implant configuration extend substantially and continuously from the first side to the second side, to thereby define corresponding apertures which extend substantially and continuously from the first side to the second side;
wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters greater than 1000 microns and less than 3000 microns, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration are adapted to allow and optimize a proliferation of vasculature and connective tissue cells, derived from the adjacent soft tissues, to permeate through the apertures and into the hard tissue defect, while preventing gross prolapse of the adjacent soft tissues into the hard tissue defect; and wherein the protective membrane is adapted to be resorbed into a mammalian body, and not remodeled.

133. The protective bone regeneration membrane as recited in Claim 132, wherein:
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in staggered rows; and cross-sectional areas of the apertures are substantially constant along lengths of the apertures from the :first side to the second side.

134. The protective bone regeneration membrane as recited in Claim 132, wherein the sheet of resorbable polymer base material has a porosity greater than about 20 percent.

135. The protective bone re;generation membrane as recited in Claim 132, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

136. The protective bone regeneration membrane as recited in Claim 132, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material.

137. The protective bone regeneration membrane as recited in Claim 132, wherein the apertures are uniformly distributed on the sheet of resorbable polymer base material in rows of at least three apertures and columns of at least three apertures.

138. The protective bone regeneration membrane as recited in Claim 132, wherein the cross-sectional areas of the apertures have circular perimeters.

139. The protective bone regeneration membrane as recited in Claim 132, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

140. The protective bone regeneration membrane as recited in Claim 132, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

141. The protective bone regeneration membrane as recited in Claim 132, wherein apertures of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

142. The protective bone regeneration membrane as recited in Claim 132, wherein the sheet of resorbable polymer base material is formed of a single layer which is substantially solid.

143. The protective bone regeneration membrane as recited in Claim 132, wherein:
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in a matrix having columns of at least three apertures and rows of at least three apertures, and the rows are staggered.

144. A protective bone regeneration membrane for protecting a hard tissue defect from a prolapse of adjacent soft tissues during in vivo repair of the hard tissue defect, the protective membrane having a pre-implant configuration, which is defined as a configuration of the the protective membrane immediately before the protective membrane is implanted over the hard tissue defect and placed into contact with any adjacent soft tissue, the protective membrane comprising:
a substantially planar sheet of resorbable polymer base material having a first side, a second side, a thickness measured between the first side and the second side that is greater than 500 microns and less than 1000 microns, and a porosity that is less than about 60 percent; and a plurality of tunnels disposed in the substantially planar sheet of resorbable polymer base material to substantially optimize healing of the hard tissue defect when the protective membrane is implanted over the hard tissue defect, wherein tunnels of the plurality of tunnels of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters greater than 1000 microns and less than 3000 microns and extend substantially continuously from the first side to the second side, wherein tunnels of the plurality of tunnels of the protective membrane when the protective membrane is in the pre-implant configuration are adapted to allow and optimize a proliferation of vasculature and connective tissues cells, derived from the adjacent soft tissues, to permeate through the tunnels and into the hard tissue defect, while preventing gross prolapse of the adjacent soft tissues into the hard tissue defect, the protective membrane being adapted to be resorbed into a mammalian body, and not remodeled.

145. The protective bone regeneration membrane as recited in Claim 144, wherein the sheet of resorbable polymer base material has a porosity of about 25 percent.

146. The protective bone regeneration membrane as recited in Claim 144, wherein:
the tunnels are uniformly distributed on the sheet of resorbable polymer base material;
apertures of the plurality of apertures are arranged on the sheet of resorbable polymer base material in staggered rows;
cross-sectional areas of the apertures are substantially constant along lengths of the apertures from the first side to the second side; and the protective bone regeneration membrane has a porosity greater than about 20 percent.

147. The protective bone regeneration membrane as recited in Claim 144, wherein the tunnels are uniformly distributed on the sheet of resorbable polymer base material in rows of at least three tunnels and columns of at least three tunnels.

148. The protective bone regeneration membrane as recited in Claim 144, wherein cross-sectional areas of the tunnels have circular perimeters.

149. The protective bone regeneration membrane as recited in Claim 144, wherein the first side comprises a substantially-smooth side and the second side comprises a substantially-smooth side.

150. The protective bone regeneration membrane as recited in Claim 144, wherein tunnels of the plurality of tunnels of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters less than about 2000 microns.

151. The protective bone regeneration membrane as recited in Claim 144, wherein tunnels of the plurality of apertures of the protective membrane when the protective membrane is in the pre-implant configuration have minimum diameters of about microns.

152. The protective bone regeneration membrane as recited in Claim 144, wherein the sheet of resorbable polymer base material is formed of a single layer which is substantially solid.

153. The protective bone. regeneration membrane as recited in Claim 144, wherein:
tunnels of the plurality of tunnels are arranged on the sheet of resorbable polymer base material in a matrix having columns of at least three tunnels and rows of at least three tunnels, and the rows are staggered.

154. The use as recited in Claim 50, wherein the membrane is wrappable around two ends of a long bone for surrounding a large segmental void that separates the two ends by about 30 mm to about 60 mm.

155. The use as recited in Claim 63, wherein the membrane is wrappable around two ends of a long bone for surrounding a large segmental void that separates the two ends by at least about 30 mm.

156. The use as recited in Claim 49, wherein the rigid fixation device is a resorbable bone plate.