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Osseointegration for AmputeesCurrent Implants, Techniques, and Future Directions

Jason Shih Hoellwarth, MD

Kevin Tetsworth, MD, FRACS

S. Robert Rozbruch, MD

M. Brianne Handal, MS

Adam Coughlan, MBBS

Munjed Al Muderis, MBChB

Investigation performed at MacquarieUniversity Hospital, Sydney, NewSouth Wales, Australia

COPYRIGHT © 2020 THE AUTHORS.PUBLISHED BY THE JOURNALOFBONE AND JOINT SURGERY,INCORPORATED. ALL RIGHTSRESERVED.

Abstract» Osseointegrated prostheses provide a rehabilitation option foramputees offering greater mobility, better satisfaction, and higher usethan traditional socket prostheses.

» There are several different osseointegrated implant designs, surgicaltechniques, and rehabilitation protocols with their own strengths andlimitations.

» The 2 most prominent risks, infection and periprosthetic fracture, do notseem unacceptably frequent or insurmountable. Proximal amputations orsituations leading to reduced mobility are exceptionally infrequent.

» Osseointegrated implants can be attached to advanced sensory andmotor prostheses.

In2005, there were approximately1.6 million amputees in the UnitedStates, a prevalence of almost 1 in200 people, and that number is

expected to double by 20501. The globalamputee census is difficult to establish2, butestimates have suggested that worldwidethere is a lower-extremity amputationperformed every 30 seconds for a patientwith diabetes3. The current accepted stan-dard for rehabilitation and mobility fol-lowing amputation is a socket-mountedprosthesis. Unfortunately, problems arecommon. Up to three-quarters of patientsundergoing a lower-extremity amputationexperience skin ulcers or intolerable pers-piration4, require frequent refitting5, orhave prosthesis-fit issues due to residuumsize fluctuation6; approximately 7%sustaina fracture in the residual limb7; and the

majority have reported that they lackconfidence with mobility8.

Osseointegration surgery of theappendicular skeleton for reconstructionin amputees is defined as a procedure inwhich a metal implant is directly anchoredto the residual bone, which is then attachedto a prosthetic limb using a transcutaneousconnector through a small opening in theskin. This technique has gradually gainedgreater acceptance in the almost 30 yearssince the first osseointegration surgicalprocedure was performed in Sweden onMay 15, 1990. On that date, a patient whohad undergone bilateral traumatic trans-femoral amputations a decade earlier hadthe first-stage titanium implant anchoredto 1 of the femora9. This implant technol-ogy was based on the work of Per-IngvarBranemark,who first discovered that rabbit

Disclosure: The authors indicated that no external funding was received for any aspect of this work.

On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version

of the article, one or more of the authors checked “yes” to indicate that the author had a relevant

financial relationship in the biomedical arena outside the submitted work (including with the

manufacturers of some of implants discussed in this article) and “yes” to indicate that the author had

a patent and/or copyright, planned, pending, or issued, broadly relevant to this work (including for

some of the implants discussed in this article) (http://links.lww.com/JBJSREV/A561).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non

Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share

the work provided it is properly cited. The work cannot be changed in any way or used commercially

without permission from the journal.

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bone became strongly bound and inex-tricably linked with titanium implants,leading to him coining the term os-seointegration and using titanium forhuman dental implants as early as196510. Dental implant technology hasshown successful outcomes with screwfixation devices because of the small sizeof the bone, the high vascularity of the

jaw, substantial support by the sur-rounding teeth minimizing torsionalforces that can lead to early loosening,and the dental implants experiencingmostly axial compression forces11. Jointreplacement has shown success withpress-fit implants that provide a highsurface area of integration and substan-tial porosity and rely on maximum

contactwith inherent geometric featuresof the implant to provide rotationalstability12. The principles of osseointe-gration for amputees are more compa-rable with the principles of arthroplastythan those of dentistry13. For clarity, theremainder of this article will use the term“osseointegration” to refer specifically todirect metal-to-bone anchorage in the

TABLE I Comparison of Osseointegration Implant Systems

OPRA ILP OPL Compress POP ITAP

Material Titanium Cobalt-chromium-molybdenum

Titanium Titanium Titanium Titanium

Retention Threaded Press-fit Press-fit Cross-pin Press-fit Press-fit

Anatomic suitability Long bones, digits Long bones Long bones, pelvis Humerus, femur Femur Humerus, femur

Bone-implant interface Laser-etched Czech hedgehog 1.5 mm Plasma-sprayed up to 0.5 mm Porous-coated, axialcompression

Porous-coated Hydroxyapatite

Skin-implant interface Polished Polished Polished Polished Polished Hydroxyapatite

Surgical stages 2 2 1 1 2 1

Months from implantationto full weight

3 to 18 2 to 3 2 to 3 Unspecified Unspecified Unspecified

Fig. 1

TheOPRA. The cannulated titaniumalloy implant is secured to the skeletonbyusinga threading tool to cut spiral groove threads in the intramedullarycortex of the residual bone and then screwing in the implant. The external threading of the OPRA is laser-etched to promote osseous ongrowth. Thetypical OPRA consists of a threaded bone implant that is coupled to a transcutaneous abutment and an abutment screw to interface with theappropriate external prosthesis for the patient. Immediate retention is achieved by screw thread interdigitationwith bone. Fig. 1-A Schematic of theOPRA. (Reproduced, with modification, from: Cecilia Berlin, PhD, Chalmers University of Technology, Gothenburg, Sweden. Adapted version of anillustration by Cecilia Berlin, originally published in Tillander et al., 2017, p. 3102. Illustration licensed under Creative Commons BY 4.0. http://creativecommons.org/licenses/by/4.0/) Fig. 1-B Radiographic depiction during stage-1 implantation. (Reproduced, with permission, from: StenlundP, TrobosM,LasumaaJ, BranemarkR, ThomsenP,PalmquistA. Effectof loadonthebonearoundbone-anchoredamputationprostheses. JOrthopRes.2017May;35[5]:1113-22. Epub 2016 Jul 4. © 2016Orthopaedic Research Society. Published byWiley Periodicals, Inc.) Fig. 1-C Radiographic depictionafter placement of the transcutaneous abutment. (Reproduced, with permission, from: Stenlund P, Trobos M, Lasumaa J, Branemark R, Thomsen P,Palmquist A. Effect of loadon thebonearoundbone-anchoredamputationprostheses. JOrthopRes. 2017May;35[5]:1113-22. Epub2016 Jul 4.©2016Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

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appendicular skeleton as a means toreconstruct amputated limbs or digits.

Osseointegration surgery using tita-nium implants directly attached to bonewas successful from the start. The initialefforts to cement transcutaneous implantsinto bone, byDr. VertMooney and othersurgeons at Rancho Los Amigos NationalRehabilitation Center in Los Angeles in1977, resulted in uniform loosening andinfection, requiring early removal14, as didother earlier experiments15. The Brane-mark technique is instead able to achieveintimate bone-titanium contact, and pre-

liminary results were so encouraging thatclinical trials soon expanded to patientswho underwent upper-extremity ampu-tation16. This demanding procedurerequiresmeticulous attention todetail andskillfully merges hard-tissue and materialsscience principles from both dental andorthopaedic surgery, together with soft-tissue handling techniques more familiarto plastic surgeons. Perhaps due in part tothis, only approximately400patientshavebeen treated using this technique17.

Inspired by these preliminary out-comes, and with the goal of vastly increas-

ing clinician adoption and patient accessto this transformative prosthetic solution,Munjed Al Muderis began osseointegra-tion with a different implant design,improved operative techniques, and accel-erated rehabilitation strategies in 2009.Their goal was to make this technologymore readily applicable for use by a widercommunity of surgeons, adhering to prin-ciples familiar to arthroplasty and recon-struction surgeons18. With the recentapproval by the U.S. Food and DrugAdministration(FDA) forosseointegrationto be used in situations of humanitarian

Fig. 2

Endo-Exo prosthesis (Figs. 2-A and 2-B) and ILP (Fig. 2-C). All iterations of this implant are made of cobalt-chromium-molybdenum, with an intra-medullarynail-type stemfeaturingonlaid1.5-mmCzechhedgehogs (a3-dimensional plus sign, featured inFig. 2-A) topromotebone ingrowth.Allmodelsachieve immediate implant retention via the press-fit implantation, analogous to hip arthroplasty, and the external prosthetic limb is mounted via amulticomponent dual cone and screw system. Fig. 2-A The original version of this device featured a distal collar that was porous-coated to promote skinadhesion and a lateral stabilizing bracket to fit over the external bone surface to enhance torsional stability. Early failures were attributed to this bracketand the rough collar, which promptedmodifications. (Adapted, by permission, from Springer Nature: Springer Nature, Sports Engineering. Direct skeletalattachment prosthesis for the amputee athlete: the unknown potential. Al Muderis M, Aschoff HH, Bosley B, Raz G, Gerdesmeyer L, Burkett B. SportsEngineering. 2016 Sep;19[3]:141-5. Copyright 2016. The zoom-in box of ILP texture in Fig. 2-A is adapted, by permission, from Springer Nature: SpringerNature, Der Orthopade. Juhnke DL, Aschoff HH. Endo-Exo-Prothesen nach Gliedmaßenamputation. Der Orthopade. 2015 Jun; 44[6]:419-25. Epub 2015May 14. Copyright 2015.) Fig. 2-B A revised version retained the bracket but polished the collar. (Adapted with permission from: Kennon RE. Atranscutaneous intramedullary attachment forAKAprostheses. ReconstructiveRev. 2013Mar;3[1]:49-51. LicensedunderCreativeCommonsBY4.0. http://creativecommons.org/licenses/by/4.0/) Fig. 2-C The next version, renamed ILP, removed the bracket and coated the collar with titanium niobiumoxynitride ceramic to prevent skin adherence. Note that osseointegration is only designed to occur at the textured surface approximately 1.5 cmproximalto theabutment, noton the smooth surfacebetween theabutment and the textured surface. 1, proximal cap screw; 2, ILPbodywithmainportion textured,distal flare untextured, abutment highly polished with titanium niobium oxynitride ceramic surface; 3, dual cone abutment adapter; 4, safety screw; 5,taper sleeve; 6, distal bushing; 7, permanent locking propeller screw; and 8, temporary cover screw. (Adapted by permission from Springer Nature:Springer Nature, Operative Orthopadie und Traumatologie. Aschoff HH, Clausen A, Tsoumpris K, Hoffmeister T. Implantation der Endo-Exo-Femurprothese zur Verbesserung der Mobilitat amputierter Patienten. Oper Orthop Traumatol. 2011 Dec;23[5]:462-72. German.)

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exemption19, and with the current FDAclinical trial spearheaded by the U.S.DepartmentofDefense (ClinicalTrials.govNCT03720171), global interest in os-seointegration for amputees is expected toincrease dramatically in the coming years.

The purposes of this article were tointroduce and describe the current os-seointegration implant designs, to identifykey variations of surgical and rehabilitationconcepts, to briefly summarize the salientbenefitsofandresidualconcernswithregardto osseointegration, and to forecast whereosseointegrationmay be headed in the near

future. In this article,wewill focus attentionon lower-extremity (transfemoral andtranstibial) osseointegration, as it representsthe overwhelming majority of current andimmediate future surgical procedures in theUnited States1 and around the world20-23.

Currently Active OsseointegrationImplant SystemsThe currently active osseointegrationimplant systems are shown in Table Iand are discussed individually below.

The Osseointegrated Prosthesesfor the Rehabilitation of Amputees

(OPRA) (Integrum) has evolved fromthe first osseointegration surgical pro-cedure in 1990 under the direction ofRickard Branemark24. The OPRA hasprincipally been implanted into patientswith transfemoral amputations, withsmaller numbers of transhumeral,transradial, finger or thumb, and trans-tibial amputations. The OPRA isdetailed in Figure 1.

The Integral Leg Prosthesis (ILP)(Orthodynamics) evolved from theEndo-Exo implant (ESKA OrthopaedicHandels), which was introduced by

Fig. 3

OPL. Three models exist, labeled A, B, and C. The OPL is a forged titanium alloy, stem-shaped implant whose surfaces have a plasma-sprayedcoating, up to 0.5 mm thick, to promote bone ingrowth and rapid integration. The external portions of the collars are treated with titaniumniobiumoxynitride ceramic to promote smooth soft-tissue gliding, limiting theprobability of symptomatic soft-tissue adhesion and tethering.Proximal fluted fins provide initial rotational stability, akin to a Wagner-style hip arthroplasty stem. Fig. 3-A OPL types A, B, and C withmatching dual cone abutment adapters. Type A has a flat abutment with a relatively long smooth collar and a proximal tail that is tapered toaccept an extension nail or an arthroplasty attachment, when indicated. Type B has a conical abutment that embeds into the distal bonewith asmaller, smooth extraosseous collar; these also possess the tapered tail adapter, identical to Type A. Type C features the same abutment andcollar style as Type B but the body is shorter, and instead of a tapered tail adapter, there is a 135° hole bored near the proximal tail to accept afemoral neck screw, which can prophylactically be used to prevent femoral neck fractures. This type is most suitable for short femoral residua.All models use a similar dual cone connection mechanism to the external prosthetic limb. All models’ dual cone adapter features titaniumniobium oxynitride ceramic at the portion exposed to the skin to prevent skin adhesion. Fig. 3-B Exploded view of a Type-A implant, with thecomponents arranged at approximately the proximal-distal levels inwhich theywould be once assembled and implanted in a patientwho hadundergone a femoral amputation. 1, proximal cap screw; 2, OPL body; 3, safety screw; 4, dual cone abutment adapter; 5, permanent lockingpropeller screw; 6, proximal connector; and 7, prosthetic connector. Fig. 3-C Radiograph of OPL Type A in a patient who had undergone afemoral amputation.

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Hans Grundei in Germany. The Endo-Exo and ILP are detailed in Figure 2.

The Osseointegrated ProstheticLimb (OPL) (Permedica Manufactur-ing) evolved from the experience withthe ILP. AlMuderis began designing theOPL in 2010, and it became commer-cially available in 201425. For all 3 types,

immediate implant retention is achievedthrough press-fit interdigitation25. TheOPL is detailed in Figure 3.

A percutaneous osseointegratedprosthesis (POP) (DJO Global) is stillcurrently in the development phase26

and is detailed in Figure 4.The Compress Device (Zimmer

Biomet) was originally designed as asolution for large-gap limb salvage forpatients with bone tumors, for which it isstill used, and has since been modified tobecome a transcutaneous implant system.This device features a porous-coated tita-nium abutment with a narrowminimallycontacting intramedullary shaft, anchor-ing the implant to bone by transversecross-pins. Spring forces inherent in thisdesign, both static and dynamic, promotebone remodelingcontinuously evenwhenpatients are not weight-bearing27,28. TheCompress Device is detailed in Figure 5.

The Intraosseous TranscutaneousAmputation Prosthesis (ITAP) (StrykerOrthopaedics) is a device that recentlycompleted its clinical trial (ClinicalTrials.gov NCT02491424) but will not bereleased. Itsmain goal was to replicate theskin-implant interface that is seen withanimal antlers, a biologic example of ahard tissueprotruding through skinwhileresisting infection. Although animal trialswere promising29, human trials led toproblems with the hydroxyapatite inter-face breaking down, leading to implantfailure and infection. The ITAP isdetailed in Figure 6.

Major Surgical andRehabilitation PrinciplesThe OPRA is the oldest extant osseointe-gration implant, and has been developedover 3 decades with continuous clinicaluse and research development. Of all os-seointegration techniques, the OPRA hasthe longest patient follow-up data avail-able30. The OPRA technique9 is charac-terized by 2 surgical events per bone,spaced6months apart.Thegoalof the firstprocedure is to implant the threadedintramedullary bone anchor. In brief, thisis achievedbygently reaming thecanal andthen tapping the thread for the implant tolater be screwed into position at least

20mmdeep, beyond the distal bone edge,as a buffer against potential bone resorp-tion. After inserting the implant, the inci-sion is then fully closed. If inadequatebonegraft is harvested during the reaming,iliac crest bone can be auto-transplantedto plug the distal end below the fixture.Either the extremity remains non-weight-bearing, or patients may continue towalk in a traditional socket, to avoidbone loading during the initial osseointe-gration. Following an interval of 6monthsto allow the implant to integrate with thehost bone, the second surgical event isundertaken. This features the attachmentof an abutment to the implanted fixture,the externalization of the abutmentthrough the skin, and additional soft-tissue procedures to create a stoma at theskin-implant interface. The points ofemphasis with this protocol includeeliminating hair follicles surroundingthe implant to reduce this potentialsource of infection and tightly securingsoft tissue to limitmovement, which cancause inflammation and provoke infec-tion. Muscle endings should be suturedto the periosteum within 10 mm of thedistal bone end, and the subcutaneousfat should be excised to promote skinadhesion directly to bone. The patient isthen limited to non-weight-bearing,range-of-motion exercises for 10 to 12days to promote soft-tissue healing.The routine postoperative protocol isdetailed31 but may be summarized asnon-weight-bearing for approximately1 month following the second stage,with progressive weight-bearing limitedto a few hours daily featuring a shorttraining prosthesis attachment andincreasing the amount of weight loadedthrough the prosthesis and the hours ofweight-bearing each day through theinitial 3months.Bymonth4, patients areencouraged to increase prosthetic weartime and to thengraduate to independentwalkingwithout crutches and fullweight-bearing, possibly without a time limita-tion, by month 6. For patients withsuboptimal bone quality, the recom-mended time to each milestone may bedoubled. Approximately 400 OPRAhave been implanted so far17.

Fig. 4

Photograph of a POP. Manufactured from atitanium alloy, its shape is tubular and solidand retains features in common with a hiparthroplasty stem with a plasma-sprayedcoating. Osseointegration occurs over a fewcentimeters near the abutment; the remain-der of the proximal aspect of the implant isfor alignment only. The goal of this limitedintegration, analogous to uncemented totalhip implants that integrate mainly at theproximal femoral metaphyseal flare, is toavoid stress-shielding. The abutment issmooth niobium oxide, with the goal of in-hibiting skin adhesion to the implant.Attachment to the external implant featuresa dual cone adapter, and immediate implantretention is achieved through press-fitimplantation. (Reproduced, with modifica-tion, from: Allyn G, Bloebaum RD, EppersonRT, Nielsen MB, Dodd KA, Williams DL. Abilityof awash regimen to removebiofilm fromtheexposed surface of materials used in os-seointegrated implants. J Orthop Res. 2019Jan;37[1]:248-57. Epub 2018 Nov 19. Thisarticle is a U.S. Governmentwork and is in thepublic domain in the USA.)

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The ILP was developed by HansGrundei for2-stage implantation.The firststage is implant placement via sequentialbroaching (without reaming) and insertionof the implant using a press-fit techniqueand a temporary plug inserted into thedistal end of the implant. The wound isfully closed, and, 4 to 6 weeks later, a cir-cular corer is used to open the skin over theabutment to create a stoma. The implantplug is then removed, and a dual coneadapter is inserted percutaneously. Therehabilitation protocol involves activityprogression as tolerated, and permanentprosthetic limbs usually are attachedwithin the first few weeks thereafter32.

The OPL was designed for single-stage implantation by Al Muderis,the first implant available specificallywith this intent, and there have alreadybeen.800 implantations of the OPLworldwide33. For patients with prohib-itively short residual bone (less thanapproximately 8 cm), lengthening of theresiduum using an externally poweredintramedullary magnetic telescopicnail can be performed34-36. Following aperiod of bone consolidation after at-taining the desired length, routine os-seointegration ensues.Using a guillotineor other incision as is best suited toaddress any existing skin compromise,

first the distal bone end is prepared. Thismay include heterotopic ossificationremoval or resection and face reaming toa uniform surface using a calcar reamer.Flat reaming fits OPL type A implantsand conical reaming fitsOPL type B andC implants. The developing surgeonrecommends tight purse-string cerclageclosure of themuscular envelope aroundthe bone-implant interface; there is nosuturing to bone. Canal preparationis then performed using sequential flex-ible reamers, followed by sequentialimplant-specific broaches. Press-fit

implantation is then performed until the

collar solidly abuts the distal part of the

Fig. 5

Compress Device. The distinguishing feature of this device compared with the others is that the cross-pin design allows a screw-and-nut apparatus totransmit force fromaBelleville spring-stylewasher systemdirectly to the endof the residual bone, resulting in a compressive force, forwhich theproductis named. The abutment is polished at the skin interface, and connection to a prosthetic limb is achieved with a customized attachment. Immediateimplant retention is achieved via the unique spring and cross-pin mechanism. The main difference between the tumor endoprosthesis currentlycommercially available and the transcutaneous osseointegrated implant configuration under trial is the addition of a transcutaneous taper sleeve(intellectual property not available to be shown in photography). Fig. 5-A Exploded schematic of the device, with the components arranged atapproximately the proximal-distal levels inwhich theywould be once assembled and implanted in a patientwho had undergone a femoral amputation.1, transverse retention pins; 2, anchor plug; 3, spindle with hydroxyapatite coating at bone interface; 4, Compress nut; 5, temporary compression capbefore nut placement; and 6, centering sleeve to position the anchor plug in the center of themedullary canal. (Reprintedwith permission from ZimmerBiomet.) Fig. 5-B Illustrated cross-sectional schematic of the device showing approximate in situ component positions. 1, transverse retention pins; 2,bone; 3, anchor plug; 4, centering sleeve; 5, spindle; 6, Belleville washers; 7, taper; and 8, Compress nut. (Adapted by permission from Springer Nature:Springer Nature, International Orthopaedics. Compressive osseointegration promotes viable bone at the endoprosthetic interface: retrieval study ofCompress® implants. KramerMJ, TannerBJ, Horvai AE,O’Donnell RJ. IntOrthop. 2008Oct;32[5]:567-71. Copyright 2008.)Fig. 5-CRadiographofCompressDevice in a patient with a femoral amputation. Arrow 1 identifies the transcutaneous taper sleeve. (Adapted, by permission, from Springer Nature:Springer Nature, Der Unfallchirurg. The Compress® transcutaneous implant for rehabilitation following limb amputation. McGough RL, Goodman MA,Randall RL, Forsberg JA, Potter BK, Lindsey B. Der Unfallchirurg. 2017 Apr;120[4]:300-5. Copyright 2017.)

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femur. Further modification of the cir-cumferential myodesis is performed,tightening themuscle so that it is directlyapposed to both implant and bone. Thesubcutaneous tissue is then defatted, andthe skin is secured to adjacent musclebefore tightly closing the amputationincision. Finally, the circular coringdevice is used to create a stoma and topercutaneously insert the dual coneand endoprosthetic connection adapter.Since the development of the single-stageprotocol in 2014, almost all patients have

had a single-stage surgical procedureinstead of a 2-stage surgical procedure37,followed by a standardized rehabilitationprotocol38. Rehabilitation occurs in 3distinct and progressive phases. The firstday after the surgical procedure, thepatients stand and axially load the oper-atively treated leg through a manualbathroom scale, increasing progressivelyby 5 kg each day until they achieve 50 kgor 50% of their body weight, whichshould occur by week 2. A lightweighttraining leg is then attached, and corestrengthening and balance exercises areperformed, as well as supervised ambu-lation. The final stage of rehabilitationconsists of attachment of the final pros-thetic limb, and weight-bearing as toler-ated with crutches is recommended. Thisprocess usually completes by 6 weeksafter osseointegration. Unrestrictedbody-weight loading and ambulation areencouraged, but patients are cautionedthat regaining adequate proprioceptionusually takes close to a year or evenmore,so they must be mindful of their balanceto limit the potential for inadvertent falls.

The POP and the CompressDevice are newer systems and surgicaltechnique or rehabilitation guidelineshave not yet been published to estab-lish the preferences of their develop-ment groups. The ITAP has beendiscontinued and will not be furtherdetailed.

Clinical Aspects ofOsseointegration: Indications,Expected Outcomes, and ConcernsNo formal consensus indications existfor osseointegration. Early contraindica-tions included peripheral vascular disease,diabetes, age of.70 years, ongoing che-motherapy, immunosuppressive medica-tions, skeletal immaturity, irradiatedlimbs, pregnancy, and situations of ques-tionable patient compliance or psychiatricstability31,38,39. On the basis of positiveearly experience, some surgeons haveexpanded indications or disproven sup-posed contraindications to osseointegra-tion, improving the mobility of patientswith peripheral vascular disease40, thosewho underwent total hip arthroplasty41

or total knee arthroplasty42, and elderlypatients who underwent amputationdecades ago43. Although both majordesigns have been implanted into patientswho have undergone transhumeral andtransradial amputations, only theOPLhasdemonstrated a high success rate withpatients who have undergone transtibialamputation, perhaps due to its 3-dimensional printed customization toindividual patient anatomy. The screwdesign of the OPRA system has shown aparticular utility in small implants suchas thumb amputations30 and penileepitheses44. As basic science under-standing and clinical experience im-prove, it is likely that the indicationswill broaden and the contraindicationswill narrow.

The overwhelming majority ofamputees who change from a traditionalsocket prosthesis to an osseointegratedprosthesis improve dramatically, bothsubjectively and objectively. One studyshowed that when amputees changedfrom a socket prosthesis to an osseointe-grated prosthesis, there were improve-ments on the Questionnaire for Personswith Transfemoral Amputation (from45.27 to 84.86 points), Short Form-36Physical Component Summary (from36.97 to 49.00 points), 6 Minute WalkTest (from 286.25 to 512.72 meters),and the Timed Up and Go test (from13.86 to 9.12 seconds)45. Another groupreported similar trends for those samemetrics and also found that the oxygenrequirement was reduced from 1,330mL/min to 1,093mL/min46. Laboratorygait analysis revealed that cadence, dura-tion of the gait cycle, and support phasesare closer to normal in patients with os-seointegrated prostheses than in patientswith socketed prostheses47,48. Sittingcomfort and position are improved49.Prosthesis use is high, with 82% to 90%of patients reporting daily use50. Thedonning and doffing are quicker andeasier51. Patients have also reported thatosseointegrated prostheses provide amuch more intimate and “part of me”experience than socket prostheses52.

An additional exciting phenomenonthat improves the patient experience with

Fig. 6

ITAP. The implant features a titanium intra-medullary stem and a large expansile flangedcap that is coated with hydroxyapatite. Thegoal of the distal coating was to promote skinadhesion, with the aim of achieving a com-plete seal against bacterial infiltration. Fig. 6-AThe model used in a canine study before thehuman clinical trial. Note the proximal pol-ished surface with hydroxyapatite coating ofthe distal portion. (Reproduced from: Fitzpa-trick N, Smith TJ, Pendegrass CJ, Yeadon R,Ring M, Goodship AE, Blunn GW. IntraosseousTranscutaneous Amputation Prosthesis [ITAP]for limb salvage in 4 dogs. Vet Surg. 2011 Dec;40[8]:909-25. Epub 2011 Nov 4. © Copyright2011 by The American College of VeterinarySurgeons. Reproduced with permission.) Fig.6-BRadiographic viewof ITAP in apatientwitha humeral amputation. (Reprinted from: JHand Surg. 35[7], Kang NV, Pendegrass C,Marks L, Blunn G. Osseocutaneous integrationof an Intraosseous Transcutaneous Amputa-tion Prosthesis implant used for reconstruc-tion of a transhumeral amputee: case report,1130-4, 2010. Copyright 2010,with permissionfrom Elsevier.)

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an osseointegrated prosthesis is that of os-seoperception.Osseoperception is definedas the mechanical stimulation of a bone‐anchored prosthesis that is transduced bymechanoreceptors likely located in themuscles, joints, skin, and other bone-adjacent tissues that travel to the centralnervous system to cause passive awarenessof a patient’s own sensorimotor positionand function53.Osseoperception has beenwell studied in dental implants, in whichmechanical and neurologic mechanismshavebeen identified54.Although relativelyfew studies focus on this aspect of appen-dicular skeletal osseointegration, it is clearthat osseointegrated prostheses facilitateimproved vibration detection in patientscompared with socket prostheses55,56.This improved sensation may, in part, bedue to innervation in the newly integratedbone57. Further studies are needed tofurther characterize the potential clinicalutility and day-to-day impact of this phe-nomenon on the patient quality of life.

One potential risk of osseointegra-tion is periprosthetic fracture, whichmight lead to further impairment ormoreproximal amputation. To date, safetystudies have only briefly touched on thattopic18,58. Although, to our knowledge,no currently available peer-reviewed arti-cle exists specifically addressing fracturesadjacent to osseointegration implants,periprosthetic fractures are managed withdevice removal and potential replacementin cases involving OPRA9 and POP59

implants, whereas fractures adjacent toILP andOPL implants are managed withimplant retention and routine fracturetechniques such as plating60. Infectioncontinues to be the main challenge,although this is less common thanmanybelieve. Even in this early stage ofdevelopment and exploration, infectionrequiring an additional surgical proce-dure occurs in only 5% to 8% ofpatients18,61. This risk appears to bereducing as soft-tissue managementexperience increases, especially with asingle-stage surgical procedure, and therisk of implant removal due to infectionis even less common. Curiously, the riskof osteomyelitis following osseointegra-tion might be influenced by the implant

design62. Currently published infectionrates reflect the outcomes of relativelytightly controlled and highly selectedcohorts of patients. Unfortunately, thevast majority of amputees worldwidehave diabetes3 and would be expected tohave an increased risk of deep infection.

The ideal implant likely shouldachieve stable fixation immediately toallow independent ambulation, wouldbe short (perhaps 5 to 10 cm) to allowimplantation intoveryshort residualboneswithout pre-lengthening procedures,would be inexpensive to manufacture,would successfully scale to accommodate avariety of long bones with similar tech-niques, would incorporate neural con-nection technology, would limit the riskof infection, and would provide durablelong-term osseointegration. Of all thosegoals, perhaps the least certain is how toaddress the implant-skin interface. Thetranscutaneous nature of the implant andthe exposure to the external environmentrepresent the most clinically importantand obvious risk. Generally, stable skin isless likely to become inflamed than skinthat is moved or stretched18,63. Detailedresearch with regard to the ideal skin-implant interface is activelybeingpursued,andcreative innovationsmaybenecessary.

The Future of OsseointegrationThe field of osseointegration has existedfor almost 30 years and now appears tobe on the verge of greater acceptance andwidespread implementation. Beyondproviding an excellent mobility solutionfor an expanding spectrum of long boneamputees, some patients with a hip dis-articulation, hemipelvectomy, or flailarm due to brachial plexus avulsion havealready had their mobility or qualityof life improved by relatively simpletechnical improvisations to the estab-lished fundamentals of osseointegration.Amputation and osseointegration mayeven prove to be a favorable alternativewhen compared with limb-salvagemegaprostheses for patients withappendicular skeletal tumors64 or thosewho have debilitating chronic pain inan extremity such as persistent complexregional pain syndrome.

Osseointegration already providesdirect skeletal anchorage for prostheticlimbs designed with both afferent andefferent neural integration, allowingpatients to more intuitively control theforce65,66, approaching the scenes de-picted in science fiction movies only agenerationago. Itmay soonbe reasonableto restore sensation and mobility toamputees, perhaps even those withparalysis, with an intimately connectedendoprosthetic limb67. However, theproblemof infectionmust be aggressivelyresearched: is an antler model actuallyachievable in humans, or would a fin-gernail, gum-tooth, or muscular sphinc-ter interface be a better concept to adopt?

Perhaps the most exciting develop-ing frontier of osseointegrationmaynot bestrictly medical, but instead may reflectchanges in regulation and legislation, withgreater access to care afforded by a poten-tial influx of supply. Upon FDA trialcompletion, American institutions withimmediately available funding mayquickly scale procedures to meet existingdomestic demand. With the resultantincreased implant production, the unitcost per implant should be reduced, andthis would, in turn, permit greater accessworldwide.This is especially important forpatients who live in areas of the worldwhere amputation is often the solution torelatively routine trauma, or where landmines and war injuries remain a devastat-ing cause of limb loss68,69.Given the valueand impact of orthopaedic outreachrecently endorsed by the American Acad-emy of Orthopaedic Surgeons (AAOS)70

and the already-proven success providinghigh-quality single-surgery osseointegra-tion even in hospitals with modestresources such as in postwar environ-ments71, osseointegration seems ready toquickly and dramatically improve the livesof millions of amputees around the world.

Osseointegration for the recon-struction of the amputated limb appearsto now be poised to follow a trajectorysimilar to thatdemonstratedby total jointarthroplasty, which gained universalacceptance and then underwent wide-spread adoption globally over the past 50years. As the concepts and principles

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guiding surgical techniques and implanttechnology become further establishedand more uniform, the surgeons andother clinicians providing care and thepatients benefiting most from this pro-cedure can become even more diverse.

Jason Shih Hoellwarth, MD1,Kevin Tetsworth, MD, FRACS2,S. Robert Rozbruch, MD3,M. Brianne Handal, MS4,Adam Coughlan, MBBS2,Munjed Al Muderis, MBChB1

1Department of Orthopaedic Surgery,Macquarie University Hospital, Sydney,New South Wales, Australia

2Department of Orthopaedics, The RoyalBrisbane Hospital, Brisbane, Victoria,Australia

3Limb Lengthening and ComplexReconstruction Service, Hospital forSpecial Surgery, New York, NY

4Geisinger Commonwealth School ofMedicine, Scranton, Pennsylvania

Email address for J.S. Hoellwarth:drjsoon@gmail.com

ORCID iD for J.S. Hoellwarth:0000-0001-7065-0656ORCID iD for K. Tetsworth:0000-0002-3069-4141ORCID iD for S.R. Rozbruch:0000-0003-1632-4600ORCID iD for M.B. Handal:0000-0003-2928-6797ORCID iD for A. Coughlan:0000-0002-0044-183XORCID iD for M. Al Muderis:0000-0002-2010-7185

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