新的生物降解支架材料治療半月板損傷的組織長(zhǎng)入情況

1、The American Journal of Sports online version of this article can be found at:DOI: 10.1177/03635465113980402011 39: 774 originally published online March 7, 2011Am J Sports Med René Verdonk, Peter Verdonk, Wouter Huysse, Ramses Forsyth and Eva-Lisa HeinrichsPartial Meniscal LesionsTissue Ingrow

2、th After Implantation of a Novel, Biodegradable Polyurethane Scaffold for Treatment ofPublished by: On behalf of:American Orthopaedic Society for Sports Medicine can be found at:The American Journal of Sports Medicine Additional services and information for Email Alerts: Subscriptions: nectioCorr ap

3、pended to the original article in this reprint.have been correction A correction has been published for this article. The contents of the Reprints: Permissions:Tissue Ingrowth After Implantationof a Novel,Biodegradable Polyurethane Scaffold for Treatment of PartialMeniscal LesionsRene´Verdonk,*

4、y MD,PhD,Peter Verdonk,y MD,PhD,Wouter Huysse,z MD,Ramses Forsyth,§MD,PhD,and Eva-Lisa Heinrichs,|MDInvestigation performed at Ghent University Hospital,Ghent,BelgiumBackground:A novel,biodegradable,aliphatic polyurethane scaffold was designed to fulfill an unmet clinical need in the treat-ment

5、 of patients with irreparable partial meniscal lesions.Hypothesis:Treatment of irreparable partial meniscal lesions with an acellular polyurethane scaffold supports new tissue ingrowth.Study Design:Case series;Level of evidence,4.Methods:Fifty-two patients(with34medial and18lateral lesionswere recru

6、ited into a prospective,single-arm,multicenter, proof-of-principle study and treated with the polyurethane scaffold.The scaffold was implanted after partial meniscectomy using standard surgeon-preferred techniques for suturing.Tissue ingrowth was assessed at3months by dynamic contrast-enhanced magne

7、tic resonance imaging(DCE-MRIand at12months by gross examination during second-look arthroscopy,in the course of which a biopsy sample from the inner free edge of the scaffold meniscus was taken for qualitative histologic analysis. Results:Tissue ingrowth at3months was demonstrated on DCE-MRI in35of

8、43(81.4%patients.All but one12-month second-look(43of4497.7%showed integration of the scaffold with the native meniscus and all biopsy specimens(44showed fully vital material,with no signs of cell death or necrosis.Three distinct layers were observed based on morphologic structure,vessel structure p

9、resence or absence,and extracellular matrix composition.Conclusion:The DCE-MRI demonstrated successful early tissue ingrowth into the scaffold.The biopsy findings demonstrated the biocompatibility of the scaffold and ingrowth of tissue with particular histologic characteristics suggestive of meniscu

10、s-like tissue.In conclusion,these data show for the first time consistent regeneration of tissue when using an acellular polyurethane scaffold to treat irreparable partial meniscus tissue lesions.Keywords:Actifit;meniscus;biodegradable scaffold;meniscectomy;polyurethane scaffold;partial meniscectomy

11、Treatment of meniscal lesions is the most common surgical intervention performed by orthopaedic surgeons today,with over1million surgical interventions involving the meniscus performed annually in the United States and approximately400000in Europe.28These semilunar, fibrocartilaginous structures pre

12、serve a pain-free func-tional knee and play an important role in the biomechani-cal functions of the knee,including load bearing,load and force distribution between the femoral condyles and tibial plateau,joint stabilization,lubrication,and propriocep-tion.10,16Furthermore,it is now accepted that lo

13、ss of all or part of the meniscus leads to long-term degenerative changes attributable to higher peak stresses on the articu-lar cartilage in the meniscectomized compartment as a result of the decreased contact area.18When an injury occurs in the nonvascularized white zone of the meniscus,no reparat

14、ive natural tissue response takes place.Classic tissue repair can occur in the outer 10.0%to25.0%of the meniscus(a vascularized region also referred to as the red zone,11,22resulting in cellular fibrovascular scar tissue1that eventually matures to*Address correspondence to Rene´Verdonk,MD,PhD,D

15、epartment of Orthopaedics and Traumatology,Ghent University Hospital,De Pintelaan 185,B-9000Ghent,Belgium(e-mail:rene.verdonkugent.be.y Department of Orthopaedics and Traumatology,Ghent University Hospital,Ghent,Belgium.z Department of Radiology,Ghent University Hospital,Ghent, Belgium.§N.Goorm

16、aghtigh Institute of Pathology,Ghent University Hospital, Ghent,Belgium.|Orteq Limited,London,United Kingdom.One or more authors has declared the following potential conflict of interest or source of funding:Dr Heinrichs is an employee of Orteq Ltd;the other4authors or their departments received fun

17、ding/sponsorshipfor this study from Orteq Ltd.The American Journal of Sports Medicine,Vol.39,No.4DOI:10.1177/0363546511398040Ó2011The Author(s774fibrocartilage,although the joint structure may remain compromised in the following months or years.16 Although repair of meniscal lesions is the pref

18、erred treatment,this is not always possible,particularly for lesions in the avascular portion of the meniscus.For such irreparable lesions,partial meniscectomy is the current standard of care.This involves removing the unstable frag-ments of the torn meniscus and contouring the remaining frayed meni

19、scal edges while preserving as much of the meniscal structure as possible.Favorable results have been reported in the short term after partial meniscec-tomy;however,the risk of osteoarthritis and irreversible damage occurring in the long term remains.8,9Meniscal regeneration appears to require the p

20、hysical presence of a scaffold to encourage successful migration and coloniza-tion with precursor cells and vessels,eventually leading to the formation of organized meniscal tissue.15,18,20,21 Meniscal tears are frequently associated with anterior cruciate ligament(ACLdisruption.In such cases,it has

21、 been suggested that long-term results of ACL reconstruction are predicted by the concomitant meniscal lesion and its treatment.Therefore,tears in the avascular zone present a particular problem and techniques involving scaffolds and advancing repair to the avascular zone have been called for.10 Unt

22、il recently,there has only been1meniscus scaffold that has been shown to replace lost or damaged meniscus tissue in human clinical studies.The type I,bovine collagen meniscus scaffold(Menaflex,formerly called CMI,ReGen Biologics,Franklin Lakes,New Jerseyis implanted arthro-scopically after partial m

23、eniscectomy and aims to reduce pain,restore lost knee function,and potentially prevent or minimize progressive joint disease.18,22Recently published data from a prospective,randomized controlled clinical trial show the safety and efficacy of the collagen scaffold in sub-jects with.50.0%loss of menis

24、cal tissue at baseline;how-ever,the collagen implant failed to show benefits for patients with an acute injury.17Although the study data highlight the potential of meniscal scaffolds in the treat-ment of irreparable,partial meniscal tissue lesions,a num-ber of limitations related to the collagen men

25、iscal scaffold have been raised.Specifically,as the product is of animal origin,there is a risk of disease transmission and immuno-logic responses,with1report of a possible allergic reaction that manifested as a severe synovitis and eosinophilia.14In addition,the integrity of the collagen-based scaf

26、fold changes under wet conditions,thus potentially increasing the risk of scaffold damage during implantation and making it difficult to suture.5Degradation rate is of importance in meniscus tissue formation as shown in dog studies where degradation rates comparable with that of the collagen scaffol

27、d seemed to be too rapid to ensure sufficient time to allow for a satis-factory rate of new meniscus tissue formation.3,6,7There-fore,the approximately20-year degradation time for the collagen scaffold may be too short.A novel biodegradable,synthetic,acellular scaffold com-posed of aliphatic polyure

28、thane(Actifit,Orteq Ltd,Lon-don,United Kingdomwas designed to fill an unmet clinical need in the treatment of patients with irreparable partial meniscal tissue lesions.The treatment objective of the scaffold is to provide pain relief and restore lost menis-cus functionality.The scaffold comes in2con

29、figurations,1for the medial meniscus and1for the lateral.Design criteria were bio-compatibility,strength,flexibility and ease of handling (insertion and suturing using standard arthroscopic tech-niques,high and interconnected porosity supporting tis-sue ingrowth,and,finally,degradation over a suitab

30、le time as new tissue forms and matures.The scaffold is highly porous,with approximately20%of the structure composed of biodegradable aliphatic polyurethane and the remaining80%being the pores.The requirement of vascular ingrowth for meniscal healing to take place has been well established.4,11,13,2

31、2 When implanted into the void created in the meniscal tis-sue after a standard arthroscopic partial meniscectomy and connected to the vascularized portion of the meniscus, the scaffold provides a3-dimensional matrix of intercon-nected pores for vascular ingrowth.The Actifit polymer is a slowly degr

32、ading polymer with polycaprolactone and urethane segments.The degradation starts by hydrolysis of the ester bonds in the polycaprolac-tone segments.This process is expected to take about5 years.23The urethane segments are more stable than the polycaprolactone segments and will eventually be safely p

33、hagocytized by macrophages or giant cells or become inte-grated into the surrounding tissue.27,32Preclinical canine studies with the scaffold have reported,at3months postimplantation,intensive integra-tion with the periphery and complete infiltration of all pores of the implant with vascularized fib

34、rous tissue that had produced an abundant extracellular matrix,showing abundant collagen type I antibody labeling throughout the implant.At6months after implantation,the scaffold was integrated with the peripheral capsule and was com-pletely filled with tissue.24The objectives of the study reported

35、in this article included evaluation of the potential of the polyurethane scaffold to safely support new tissue ingrowth. METHODSStudy Design and Main Inclusion/Exclusion CriteriaA prospective,single-arm multicenter proof-of-principle study was conducted in9centers in Europe.The investiga-tors were c

36、hosen for their expertise and experience in per-forming meniscal surgery.The main inclusion criteria for the study were(1irreparable medial or lateral meniscal tear or partial meniscus loss,with intact rim;(2skeletally mature male or female patients;(3age16to50years;(4 stable knee joint or knee join

37、t stabilization procedure within 12weeks of index procedure;(5International Cartilage Repair Society(ICRSclassification 2;(6patient willing and able to give consent to participate in the clinical study and attend all follow-up visits and procedures;and(7no more than3prior surgeries on the involved m

38、eniscus. EthicsIndependent ethics committee approvals for the study were obtained before patient recruitment.WrittenVol.39,No.4,2011Tissue Ingrowth After Polyurethane Meniscal Scaffold Implantation775informed consent was provided by each patient,and Good Clinical Practice(GCPand the Declaration of H

39、elsinki were strictly adhered to throughout the study.Surgical ProceduresAll patients underwent arthroscopic partial meniscectomy with surgical debridement back to the vascularized zone of the damaged portion of the meniscus.The resulting void was measured for sizing along the peripheral edge using

40、the meniscal ruler guide and ruler supplied with the scaf-fold.The scaffold was cut to fit using a blunt-nosed grasper,placed into the knee joint through the anterome-dial or anterolateral portal,and sutured to the native meniscus.The suturing techniques employed were all-inside,inside-out,or outsid

41、e-in depending on the area to be sutured and the surgeons experience and preference. Postoperative Treatments and RehabilitationPostoperative medications and treatments were provided, if required,according to the standard practice at each investigational center.To ensure protection of the newly form

42、ed fragile tissue and to provide optimum conditions for healing,all patients were required to undergo a conser-vative rehabilitation program similar to that for a meniscal allograft.The rehabilitation protocol was followed for16to 24weeks,with the patient nonweightbearing for the first3 weeks.Partia

43、l weightbearing was permitted from week4 onward,with a gradual increase in loading up to100% load at9weeks after implantation.Progressive weight-bearing was initiated in stages,increasing by10kg per week for patients weighing 60and90kg and by15kg per week for patients weighing 90kg.Full weightbearin

44、g with an unloader brace was allowed from week9onward, and without the use of the unloader brace from week14 onward.Gradual resumption of sports was generally com-menced as of6months at the discretion of the responsible orthopaedic surgeon;however,contact sports were to recommence only after9months.

45、End PointsTissue ingrowth was assessed at3months after index sur-gery using dynamic contrast-enhanced magnetic resonance imaging(DCE-MRIand at12months by histologic analy-sis of biopsy specimens taken during second-look arthroscopy.Safety was assessed through evaluation of cartilage grades from MRI

46、scans at1week,3months,and12 months using the ICRS cartilage scoring system.Efficacy (ie,clinical outcomesperceived pain,functionality,and quality of lifewas assessed at3,6,12,and24months after index surgery.The subject of this article is tissue ingrowth assessment and safety with ICRS cartilage grad

47、e data up to12months. Efficacy data and tissue ingrowth up to24months,as well as24-month ICRS cartilage grade data and other safety data will be reported separately.Tissue Ingrowth AssessmentDiagnostic Imaging.A primary objective was to evalu-ate tissue ingrowth at3months after implantation.This was

48、 assessed using DCE-MRI,an established technique for assessing primarily the vascularization,perfusion, and capillary permeability of various tissues.25,29The DCE-MRI technique involves the measurement of contrast agent influx(in this case,gadoliniuminto the examined tissue for3minutes immediately a

49、fter administration. Influx of contrast agent causes an increase in the signal intensity(SI,which is then measured.An increase in SI in the first minute can only be explained by the presence of blood vessels as the contrast agent has not yet entered the interstitial space in that time.For the purpos

50、e of this study,the inner peripheral half of the scaffold meniscus was designated as a specific region of interest and the pos-terior horn was the recommended and utilized position because it provides the best transection at1week.Impor-tantly,the same area was measured at each time point (1week and3

51、months.For DCE-MRI,the following protocol was followed:the dynamic contrast-enhanced sequence(repetition time TR,1100ms;echo timeTE,3ms;inversion timeTI, 560ms;flip angle,12°field of viewFOV,160mm;slice, 6mm;matrix,192396was positioned such that the meniscus,including the reparative matrix,was

52、depicted as a triangle(Figure1and performed after administra-tion of10to20mL of contrast agent(in this case,gado-pentetatedimeglumineMagnevist,Bayer Schering Pharma,Machelen,Belgium,followed by20mL of saline( 3mL/sec.The amount of contrast medium injected was dependent on the patients body weight(0.

53、5 mL/kg.The dynamic sequence was started simulta-neously with the bolus injection and consisted of a series of at least120images obtained with an acquisition time of 1second during administration of the contrast agent. After dynamic imaging,sagittal and coronal T1-weighted images were obtained using

54、 identical imaging parameters as those used for the T1-weighted sequences.All DCE-MRI was analyzed by an independent asses-sor,blinded to all clinical patient detail and data,at the Radiology Department,Ghent University Hospital, Belgium.Histologic Analysis of Biopsy Specimens at12Months. Tissue ing

55、rowth at12months was assessed by analyses of biopsy specimens taken during second-look arthroscopy. The center of the inner free edge of the implanted scaffold was chosen for the biopsies because it is the area furthest away from the vascularized native meniscus rim and hence would be the area likel

56、y to be populated last.Furthermore, it was concluded that a biopsy in this area would be least likely to damage the scaffold meniscus.All biopsy specimens were fixed in4.0%buffered formol for at least24hours.Using the histochemical stains hema-toxylin and eosin(H&E,Masson trichrome,Sirius red, a

57、nd combined periodic acid SchiffAlcian blue(PAS-AB, the biopsy sections were stained to enable visualization of specific tissue structures.In addition,immunohisto-chemical staining was performed on the biopsy sections using cellular and extracellular matrix(ECMmarkers.776Verdonk et al The American J

58、ournal of Sports MedicineMarkers for collagen type I,type II,and aggrecan were used for the ECM;and cartilage marker S100,the vessel markers CD31and CD34,the smooth muscle marker SMA(smooth muscle actin,and the histiocytic marker CD68were used as cellular markers.Analysis was performed centrally at the Department of Bone and Soft Tissue Pathology,Ghent University Hospital, Belgium by2independent assessors blinded to all other patient data,with any discrepancies resolved by consensus. Safety AssessmentAssessment Grade of Articular Cart