Limb amputation is a life-altering event, affecting mobility, quality of life, and participation in daily activities. The leading cause of lower-limb amputation in developed countries is atherosclerosis, often with concomitant diabetes1, whereas in developing countries, traumatic etiology related to industrial, traffic, and wartime injury predominates1,2. In the United States Army, the reported amputation rate related to military conflicts ranged from 7.4% to 19%3,4 of all major extremity injuries sustained, which has potentially shifted the prevalence of amputations to younger individuals, including a higher prevalence of multiple limb amputations5.
Prosthetic limbs have evolved, with substantial technological advancements in the past 2 decades, but there are still limitations to their use. The conventional method of attaching a prosthetic limb to the body is through a custom-designed socket6. The socket must fit securely to the residual limb to maximize comfort, to transmit the forces of the skeleton to the ground through the interposing soft tissues, and to allow the movement of the residual limb to control the artificial limb. The quality of the interface between the residual limb and the socket is one of the most critical aspects for the success of any prosthesis, complicated by the fact that the residual limb is a dynamic organ (i.e., it tends to atrophy over time, or may swell with heat or weight gain), which can lead to irritation and loss of socket fit1. Discomfort and problems related to the fit of the socket are common and have been shown to negatively impact the quality of life and mobility of the user7-10. The most commonly faced issues with socket prostheses reported in a survey of 97 individuals with transfemoral amputation included heat or sweating in the prosthetic socket (72%), sores or skin irritation from the socket (62%), inability to walk in woods and open fields (61%), inability to walk quickly (59%), and pain in the residual limb (51%)9. Other studies have shown that between one-fourth of 78 participants interviewed8 and one-third of 935 participants interviewed10 expressed dissatisfaction with their prosthesis; they reported problems with wounds, skin irritation, and pain and considered themselves to have a poor or extremely poor quality of life10.
These problems led to the development of new techniques of attaching prosthetic components directly to the skeleton of the residual limb, thereby bypassing the need for a socket interface. Osseointegration refers to the direct structural and functional connection between living bone and the surface of an artificial metal implant11, providing stable fixation between remodeled biological tissues and a titanium implant without initiating rejection mechanisms12. In the 1950s, Per-Ingvar Brånemark used a titanium implant chamber to study blood flow in rabbit bone and noted that the chambers could not be removed at the end of the experiment13. Following this remarkable discovery that bone can integrate with titanium components, he coined the term osseointegration.
Direct skeletal fixation by osseointegration is currently used in total joint replacements, dental implants, the edentulous mandible, craniofacial deficiencies, maxillofacial reconstruction, orbital prostheses, bone-anchored hearing aids, and, since the 1990s, percutaneous implants for attachment of prosthetic limbs. The use of osseointegrated prosthetic implants for limb amputation is now being performed in several centers in the world, and recently, in the United States, clinical trials are under way with a U.S. Food and Drug Administration Humanitarian Use Device designation14. Various osseointegration approaches have emerged and have evolved over the past several years. This goal of this article was to present a comparative descriptive review of the use, safety, and reported outcomes of lower-limb osseointegrated prosthetic implants.
Materials and Methods
A computer-based literature search was performed to identify studies focusing on osseointegrated lower-limb prostheses. Our search utilized the following databases from their inception to April 7, 2017: PubMed, Embase, Scopus, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials. The search terms used (truncation indicated with an asterisk) were: (osseointegrat* OR bone-anchored OR bone anchored) AND (prosthe*) AND (leg OR lower limb* OR lower extremit* OR transfem* OR transtib*). The following MeSH keywords were also used if they were required by the database: Osseointegration, Prostheses and Implants, Artificial Limbs, Leg, Femur, and Tibia.
Inclusion criteria were articles pertaining to physical, functional, and health-related quality-of-life outcomes, implant survival rate, infections, and complications. Primary exclusion criteria were articles pertaining to animal models; loading or stress evaluation; biomechanical, radiographic, microbiological, or histological evaluation; the upper limb; and myoelectric implants. Secondary exclusion criteria were study protocols, single-case studies, systematic reviews, conference abstracts, and articles in languages other than English.
Data on clinical outcomes, walking ability, quality of life, infections, and other complications were systematically extracted and were tabulated to illustrate the published evidence on efficacy and safety of lower-limb osseointegrated prostheses. Although the protocol for this review generally followed the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines15, meta-analysis was deemed infeasible because of heterogeneity in the surgical technique, implant design, study design, methodology, follow-up times, and reported outcomes. Included studies were individually assessed with regard to the Level of Evidence as per the Centre for Evidence-Based Medicine16.
Fourteen articles were included in this review (Fig. 1): with regard to Level of Evidence, 5 were Therapeutic Level II, 5 were Therapeutic Level III, and 4 were Therapeutic Level IV. All studies were evaluated as having a risk of bias inherent to nonrandomized prospective and retrospective cohort studies, with lack of blinding of participants or study personnel, and patient selection criteria including individuals currently having difficulties (and therefore more likely to show improvement).
Published patient selection criteria were relatively consistent across studies and are summarized in Table I. A tabulated descriptive summary of study characteristics is provided in Table II, reported clinical outcomes are provided in Table III, and complications are presented in Table IV. Comparison across groups was challenging as not all centers reported the same outcomes; however, literature consistently reported improved functional mobility, physical performance, and physical health, as well as several domains of health-related quality of life after osseointegration. The most frequently used outcome measure was the Questionnaire for Persons with a Transfemoral Amputation (Q-TFA), designed and validated for evaluating prosthetic use, mobility, problems, and global health of patients using lower-limb prostheses17, with demonstrated criterion validity relative to the Short Form-36 Health Survey (SF-36).
TABLE I -
Summary of Patient Selection Criteria and Contraindications in the Published Literature
|Patient selection criteria
| Problems with conventional socket prostheses18-20,23,25,28-30
| Discomfort, pain, poor suspension, or an inability to use conventional socket prostheses at all19,20,23,25
| Recurrent skin infections and ulceration, a short stump, soft-tissue scarring, volume fluctuation of the stump, extensive areas of skin grafting, socket retention problems due to excessive perspiration30
| Expected to have problems with conventional prosthesis20
| Have reached full skeletal maturity18-20,22,24,25,30
| Normal skeletal anatomy18,20
| Age criteria: <70 years18-20,30, >18 years25,29, or >20 years20
| Be suitable for surgical procedure on the basis of medical history and physical examination18,20,30
| Agree to comply with the treatment program and follow-up20,25,30
| Severe peripheral vascular disease18-20,22,24,25,28,29
| Current chemotherapy treatment18,19,22,24,25,28,29, corticosteroid use19, or immunosuppressant drugs19,20,24,28,29
| Limb exposure to radiation24,25,28,29
| Mental illness or disabling psychiatric disorder22,25,28,29
| Smoking24,25,28,29, encouraged to quit or decrease
| Osteoporosis30, atrophic bone conditions24
| Body weight in excess of 100 kg18,30
| Infection22, not further specified
| Skin disease involving the amputated limb20
| Noncompliant during preoperative screening and evaluation28,29
| Satisfied with conventional socket technology24
The most common complication was superficial skin infection at the stoma site18-29, typically managed by local wound care and a course of oral antibiotics. Deep infections20 and/or removal of the implant due to infection20,22,24,30 were reported less commonly. With subsequent iterations of design and rehabilitation protocols, a reduction in the rates of complications was observed. In the earliest iteration of the Osseointegrated Prosthesis for the Rehabilitation of Amputees (OPRA), the infection rate was 66%20 in a study with 51 subjects. In the most recent prospective cohort of 86 subjects using the Osseointegration Group of Australia Accelerated Protocol (OGAAP), the infection rate was 34%25. This is consistent with the iterative comparison showing fewer infections with the most recent Integral Leg Prosthesis (ILP) design24. Encouragingly, the rate of severe infection (deep bone infection or infection of the implant) was nil in the most recent series24,25,29. The safety study on the Australian protocol also identified specific patient risk factors for complications, namely, increased odds ratios for women, with a sixfold higher risk of severe infection; those with a body mass index of >25 kg/m2, with a threefold higher risk of mild infection; and smokers, with a sevenfold higher risk of recurrent infection25. Other noninfectious complications (Table IV) included fractures of the femur24,25,28, implant loosening19,20, mechanical complications with the abutment20,30, revision surgical procedures22,25,28, soft-tissue refashioning25,28,29, and implant breakage25,28. Reports on phantom or other limb pain were inconsistently reported. Limited information on prosthetic components was provided19; however, most protocols mentioned the importance of a safety device to prevent excessive torque from being transmitted to the implant19,29,30.
The discussion is presented in historical order according to implant type to illustrate the development and evolution of the technology.
Osseointegrated Prosthesis for the Rehabilitation of Amputees
Carrying on the work of Per-Ingvar Brånemark, a group in Sweden at the University of Gothenburg led by Rickard Brånemark was the first to use percutaneous osseointegrated implants for lower-limb amputation in the 1990s. Their implant and protocol are known as OPRA (Integrum), involving a 2-stage surgical procedure. In the first stage, a threaded titanium implant is inserted into the medullary canal of the femur, and the soft tissue is closed around the end of the limb. The second stage of the surgical procedure follows 6 months later, which includes the attachment of a titanium extension, known as an abutment, to the osseointegrated fixture. The soft tissues and skin are closed around the abutment, to which the prosthetic components can then be directly connected. Varying lengths of residual femur can be implanted, with the most recently reported series classifying the length of the residual limb as long in 4 patients (10%), medium in 27 patients (69%), and short in 8 patients (21%)31. A rehabilitation protocol following the second surgical procedure32 was developed in the late 1990s. The rehabilitation protocol involves gradual loading of the bone-implant interface over a period of 6 months to stimulate and facilitate the process of osseointegration. There is an initial training period using a short training prosthesis (4 to 6 weeks following the surgical procedure) and involving axial weight-bearing and gentle weight shifting, avoiding any rotation. This is followed by gradually increased prosthetic use using crutches (16 to 24 weeks following the surgical procedure) to prepare the user for eventual unrestricted prosthetic use.
To our knowledge, the first peer-reviewed, descriptive, retrospective report on osseointegrated implants for transfemoral amputees was published in 200330 by a group in the United Kingdom. They reported that, at the time of publication, 11 patients had undergone both stages of the surgical procedure and a comprehensive rehabilitation process. Of those patients, 9 were able to use their osseointegrated prostheses every day, and 2 required removal of the implant due to infection.
The Brånemark team’s first prospective report on the outcome for individuals treated with OPRA implants was published in 200818. Using 2 self-reporting questionnaires, SF-36 and the Q-TFA, the investigators reported that, at the 2-year follow-up, 17 of 18 patients were using the osseointegrated prostheses. Significant improvement was reported in physical functioning, bodily pain, prosthetic use, prosthetic mobility, overall health, and all components of the SF-36. The patients demonstrated a general improvement in health-related quality of life compared with their preoperative quality of life.
In 2009, Hagberg and Brånemark presented the results of 100 patients treated with osseointegrated transfemoral prostheses between 1990 and 200819. It was reported that the majority of treatment failures occurred in patients before a strict rehabilitation protocol was established in 1999. By 2009, 68 of 100 patients were still using their prostheses; superficial infections treated with oral antibiotics were the most common complication, but 11 patients had permanent removal of the implant. The implementation of graded rehabilitation was found to be most effective for improved results.
In a prospective study20 of 51 patients treated with the OPRA protocol between 1999 and 2007, 92% (47 patients) were using the osseointegrated transfemoral prosthesis at the 2-year follow-up; 89% used it daily compared with 57% who had used the socket prosthesis prior to the surgical procedure. Improvement in physical function, prosthetic use, mobility, and overall situation was reported. Superficial infection was reported to be the most frequent complication, occurring 41 times in 28 patients. Four patients experienced deep infections, and 1 of them required removal of the implant due to loosening. Four patients experienced falls and 5 fractures; however, there was no fracture involving the implant.
The authors reported on physical health-related quality of life and walking energy cost in a subset of 39 unilateral transfemoral amputees who received the OPRA prostheses and reported significant improvements in prosthetic use, mobility, walking habits, and overall amputation situation31 at the 2-year follow-up. Twenty-six patients reported increased prosthetic use, and walking energy cost was also significantly reduced (p < 0.0001).
Integral Leg Prosthesis
The success of the osseointegrated prostheses in Sweden spurred design of implants in Germany in the late 1990s. The German implant design diverted from screw-type fixation to intramedullary press-fit, porous-coated, alloy devices similar to those used in joint arthroplasty. This group, led by Horst Aschoff, termed their implant the Integral Leg Prosthesis (ILP) (ESKA Orthopaedic), although, in the first few design iterations, it was known as the Endo-Exo Femur Prosthesis. The intramedullary implant had a porous patented Spongiosa-Metal II surface (Orthodynamics) for osseointegration implantation without cement, which was directly implanted into the residual femur in a retrograde fashion during the first stage of the surgical procedure. It was reported that 12 to 15 cm of the distal part of the femur was needed for successful ILP implant-stem placement22. The initial design also utilized a bone-stabilizing bracket attachment that was deemed necessary to prevent fatigue failure of the implant. Approximately 6 to 8 weeks later, a stoma was created in the second-stage surgical procedure to expose the distal aspect of the implant and to attach a dual cone adaptor for fixation of the prosthetic components22.
Thirty-seven transfemoral amputees were reported to have undergone treatment with the ILP between 1999 and 200922. Twenty of 37 patients underwent ≥1 revisions, with 4 undergoing removal of the implant (2 of these were subsequently successfully replaced). Fourteen of the 37 patients underwent minor revisions due to problems at the stoma, typically as a result of soft-tissue irritation. It was determined that the porous surface of the transdermal coupler caused hypergranulation tissue, which was uncomfortable for the patient and necessitated soft-tissue debridement procedures. This led to subsequent design iterations of the implant.
The next iteration of the ILP implant in 2009 saw the incorporation of a smoothly polished (nonporous) surface for the coupler to reduce soft-tissue irritation, elimination of the bone-stabilizing bracket attachment, shortening of the bridging connector to adjust to the deep soft-tissue channel, and coating of the connector and bone-capping portion of the osseointegrated implant with a nonabrasive titanium niobium oxynitride ceramic. Between 2009 and 2013, 39 patients were treated with the final iteration of the ILP implant24 and the results of these patients were compared with 30 patients who received the prior implant design. There was a significant reduction in the rate of stoma-associated infections, with a 77% absolute risk reduction (p < 0.001) of any interventions due to soft-tissue problems at the stoma. All patients remained infection-free using a simple defined wound-hygiene protocol (cleaning the site with mild soap and water twice a day). The implant did not have to be removed in any patient with the final design of the ILP. For physical rehabilitation, patients were engaged in partial weight-bearing (crutch walking, initially 5 to 10 kg) and a vertical posture immediately after the second surgical procedure and progressed to full weight-bearing without crutches at 4 to 6 weeks after the second surgical procedure.
In a prospective study, Van de Meent et al.23 assessed walking ability and quality of life of 22 transfemoral amputees with ILP implants, compared with their performance at baseline with socket prostheses. At the 12-month follow-up, overall, participants had significantly improved prosthetic use (p < 0.001) and prosthesis-related quality of life. The Q-TFA global score with the osseointegrated prosthesis was significantly higher at 68% (p < 0.005). Prosthetic use improved by 45%, from 56 hours per week with the socket prosthesis to 101 hours per week with the osseointegrated prosthesis. Participants with the osseointegrated prosthesis walked significantly faster, by 44% (p < 0.005), and, at the preferred walking speed, they used 18% less oxygen (p < 0.005). During the 12-month follow-up period, 8 participants had mild infections of the soft tissue at the stoma site. Overall, the participants in this study experienced substantial improvement in their ability to walk and prosthesis-related quality of life with osseointegrated prostheses.
Al Muderis et al. reported on the safety of press-fit ILP implants25 used in Australia and the Netherlands. In a prospective study, they examined adverse events in all patients with transfemoral amputation who were managed with a press-fit implant between 2009 and 2013 at the 2 centers. Eighty-six patients (some bilateral, for a total of 91 implants) were included in the study and were followed for a median of 34 months. Thirty-one patients (36%) had no complications, 29 developed an infection (most resolving with oral antibiotics), and 26 did not develop an infection but had 1 or more other complications that required intervention. Five infections required surgical debridement with revision of the stoma. Four patients had high-grade soft-tissue infection with abscess formation that needed surgical debridement. No patient experienced deep peri-implant infection or implant failure due to infection. Importantly, this article outlined a standard classification system for infectious complications based on clinical and radiographic findings25.
Osseointegrated Prosthetic Limb
The next development in the field occurred in 2011 when Munjed Al Muderis at the Macquarie University in Sydney, New South Wales, Australia, introduced the Osseointegrated Prosthetic Limb (OPL) (Permedica). The design of this implant is similar to the ILP with a highly polished smooth transcutaneous dual cone adaptor coated with titanium oxide to minimize soft-tissue friction, but also includes a distal flare within the intramedullary portion to assist with bone anchorage25 and an option for inserting top cross-screws for short residual limbs. Insertion of the press-fit implant involves 2 surgical stages, approximately 4 to 8 weeks apart. In the first stage, the soft tissues are prepared with refashioning of the stump, excess subcutaneous fat is excised, neuromas are removed, and the bone is prepared to accept the implant (excision of irregular distal bone, reaming of the medullary canal, and use of locally obtained autologous bone graft when needed). The intramedullary component of the prosthesis is then inserted to achieve mechanically stable press-fit fixation. The second stage involves the creation of the skin opening and insertion of the transcutaneous dual-cone adaptor. Externally, the adaptor is fixed to a torque control safety device, which then connects to the prosthetic limb26.
The Australian group developed a well-defined rehabilitation and outcomes tracking protocol, the OGAAP-1. In a prospective study of 50 consecutive unilateral transfemoral amputees followed for a minimum of 1 year post-surgery28, adverse events were tracked and were analyzed. These patients were fitted with either the ILP or the OPL; therefore, this study evaluated both press-fit implants with the same rehabilitation and surgical protocol. It was reported that a cross-screw was inserted through the femoral neck if the residuum was shorter than 16 cm. A total of 23 patients (46%) did not experience any adverse events, 18 patients (36%) had superficial infections that resolved with antibiotics, and 3 patients (6%) underwent surgical debridement. Infections were confined to soft tissue, and no deep bone infection was reported. Refashioning of the soft-tissue residuum was performed on 10 patients because of redundancy, and 4 patients experienced periprosthetic fractures. There was 1 implant fatigue failure and 1 failure of osseointegration related to an undersized implant, both of which were revised successfully.
The patients reported significant improvements (p < 0.001) in their global amputation situation (Q-TFA), physical health-related quality of life (SF-36), and walking mobility. This included 14 patients who were wheelchair-bound preoperatively and were able to walk postoperatively. Patients were mobilizing with crutches or a forearm support frame on the third day and were discharged home 5 to 7 days following the first surgical procedure. After the second surgical procedure, the rehabilitation protocol began with limited weight-bearing on day 3, and patients were discharged from the hospital in 5 to 10 days, followed by outpatient therapy. Patients progressed from the surgical procedure to unaided walking in approximately 4.5 months, contrasting with the 9 to 12 months seen with previous screw-fit implants18,31. Press-fit fixation appeared to provide adequate, immediate stability to allow more rapid rehabilitation, mobilization, and ambulation.
More recently, a single-stage procedure has been introduced by the Osseointegration Group of Australia, using a prospective cohort study, which began in April 201433. Retrospective preoperative and postoperative clinical data on 22 patients receiving the OPL implant in 1 stage with 1-year follow-up29 showed significant improvement in functional walking tests and global scores (p < 0.05), with main complications of superficial infection (15 cases in 12 patients) and soft-tissue refashioning surgical procedures (in 6 of 22 patients) but no implant failures. Nine of 10 patients who were wheelchair-bound were able to perform walking tests at the 1-year follow-up. Further comment will need to be reserved until publication of the prospective 2-year follow-up data.
Khemka et al.26 also reported on the feasibility of combining total knee replacement with an osseointegrated fixation to the residual tibia in a case series of 4 transtibial cases, and on the feasibility of combining total hip replacement with an osseointegrated transfemoral implant in 3 cases27. These procedures utilized custom implants integrated modularly to the joint replacement components. Clinical outcomes were assessed at baseline and after 1 to 3 years of follow-up. All patients showed improved clinical outcomes, including 2 of the transfemoral patients who were wheelchair-bound at baseline becoming community ambulatory. Khemka et al. reported superficial infection in 1 patient in each case series and no other major complications.
To enhance understanding of the experience of living with an osseointegrated prosthesis, Lundberg et al. conducted a qualitative in-depth interview study on patients using bone-anchored prosthetic limbs34. All participants described living with an osseointegrated prosthesis as a revolutionary change in their lives. All of them described drastic functional changes and being able to sit comfortably and not needing to spend as much time managing the prosthesis, which contributed to an improvement in their quality of life. Many participants reported feeling that the osseointegrated prosthesis became an integrated part of their body; it had strengthened the feeling of having a “whole body,” which influenced their way of looking at and experiencing the world. This impact on their sense of self had been so profound that the patients believed that they could be more the people who they were before the amputation. Osseoperception is the term used to describe the ability of patients with osseointegrated fixtures to identify sensory thresholds transmitted through their prostheses35, and it is thought that this phenomenon contributes to enhancing patients’ subjective sense of integrating the osseointegrated prosthesis into their body schema.
In contrast to the substantial evidence on functional and quality-of-life benefits of osseointegration18,20,23,26-29,31,34, there is limited evidence on cost-effectiveness. One study showed that, compared with socket prostheses, users of osseointegrated prostheses made fewer follow-up visits to the hospital or workshop, and the mean total annual cost of new prostheses, services, repairs, and adjustments was 14% lower for osseointegrated prostheses than for socket-suspended prostheses36. Overall, there is insufficient evidence to address the cost-effectiveness of osseointegrated prostheses, and further longitudinal study is required.
In conclusion, osseointegration for limb amputation has become an established treatment option in several areas of the world, with specific patient selection criteria, rehabilitation protocols, and follow-up. Major clinical benefits from osseointegrated prosthesis include improved quality of life18,20,23,26-29,31,34, prosthetic use18,34, body image34, range of movement at the hip37, comfort when sitting38, ease of fitting and removing prostheses18, osseoperception35,39, and walking ability19,23,26-31. Additional considerations beyond the scope of this review are the potential changes in bone mass due to increased loading through the skeletal tissues.
Considerations include the requirement for rehabilitation that can take between 4 months28 and 18 months19, although the most recent approach utilizes a single-stage procedure with rapid rehabilitation and immediate weight-bearing, as per the principles of joint replacement surgical procedures29. The skin area surrounding the abutment requires daily hygiene, with skin irritation and mild infection being the most commonly reported adverse events. There are less common risks of deeper soft-tissue infection, fractures from falls, and loosening of the implant. Users of osseointegrated prosthetic devices are advised to avoid high-impact activities such as running or jumping and the use of public swimming pools to prevent infection30. Lastly, a permanent abutment may be considered less than desirable by some patients for cosmetic reasons32.
Osseointegration appears to have become an established treatment option for a selected group of patients with limb amputation not tolerating traditional socket fittings. There is sufficient evidence to fully inform patients as to the possible risks and complications compared with the benefits. Osseointegration could provide substantial benefits to function and quality of life for appropriate patients who accept the documented risks. As with any new technology, ongoing incremental iteration to optimize outcomes is expected through this clinical evolutionary phase. Adopting a standard classification system for tracking outcomes and complications would greatly assist in ongoing and future evaluation of implant techniques.
1. Marks LJ, Michael JW. Science, medicine, and the future: artificial limbs. BMJ. 2001 Sep 29;323(7315):732-5.
2. Dillingham TR, Pezzin LE, MacKenzie EJ. Incidence, acute care length of stay, and discharge to rehabilitation of traumatic amputee patients: an epidemiologic study. Arch Phys Med Rehabil. 1998 Mar;79(3):279-87.
3. Islinger RB, Kuklo TR, McHale KA. A review of orthopedic injuries in three recent U.S. military conflicts. Mil Med. 2000 Jun;165(6):463-5.
4. Stansbury LG, Lalliss SJ, Branstetter JG, Bagg MR, Holcomb JB. Amputations in U.S. military personnel in the current conflicts in Afghanistan and Iraq. J Orthop Trauma. 2008 Jan;22(1):43-6.
5. Krueger CA, Wenke JC, Ficke JR. Ten years at war: comprehensive analysis of amputation trends. J Trauma Acute Care Surg. 2012 Dec;73(6)(Suppl 5):S438-44.
6. Kapp S. Suspension systems for prostheses. Clin Orthop Relat Res. 1999 Apr;361:55-62.
7. Legro MW, Reiber G, del Aguila M, Ajax MJ, Boone DA, Larsen JA, Smith DG, Sangeorzan B. Issues of importance reported by persons with lower limb amputations and prostheses. J Rehabil Res Dev. 1999 Jul;36(3):155-63.
8. Dillingham TR, Pezzin LE, MacKenzie EJ, Burgess AR. Use and satisfaction with prosthetic devices among persons with trauma-related amputations: a long-term outcome study. Am J Phys Med Rehabil. 2001 Aug;80(8):563-71.
9. Hagberg K, Brånemark R. Consequences of non-vascular trans-femoral amputation: a survey of quality of life, prosthetic use and problems. Prosthet Orthot Int. 2001 Dec;25(3):186-94.
10. Pezzin LE, Dillingham TR, Mackenzie EJ, Ephraim P, Rossbach P. Use and satisfaction with prosthetic limb devices and related services. Arch Phys Med Rehabil. 2004 May;85(5):723-9.
11. Brånemark PI, Hansson BO, Adell R, Breine U, Lindström J, Hallán O, Ohman A. Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period. Scan J Plast Reconstr Surg Suppl. 1977;16:1-132.
12. Worthington P. History, development, and current status of osseointegration as revealed by experience in craniomaxillofacial surgery. In: Brånemark PI, Rydevik BL, Skalak R, editors. Osseointegration in skeletal reconstruction and joint replacement. Carol Stream, IL: Quintessence; 1997. p 25-44.
13. Brånemark PI. Vital microscopy of bone marrow in rabbit. Scand J Clin Lab Invest. 1959;11(Supp 38):1-82.
14. U.S. Food and Drug Administration. FDA authorizes use of prosthesis for rehabilitation of above-the-knee amputations. 2015 Jul 16. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM455103
. Accessed 2017 May 17.
15. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA; the PRISMA-P Group. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349:g7647.
16. Marx RG, Wilson SM, Swiontkowski MF. Updating the assignment of levels of evidence. J Bone Joint Surg Am. 2015 Jan 7;97(1):1-2.
17. Hagberg K, Brånemark R, Hägg O. Questionnaire for Persons with a Transfemoral Amputation (Q-TFA): initial validity and reliability of a new outcome measure. J Rehabil Res Dev. 2004 Sep;41(5):695-706.
18. Hagberg K, Brånemark R, Gunterberg B, Rydevik B. Osseointegrated trans-femoral amputation prostheses: prospective results of general and condition-specific quality of life in 18 patients at 2-year follow-up. Prosthet Orthot Int. 2008 Mar;32(1):29-41.
19. Hagberg K, Brånemark R. One hundred patients treated with osseointegrated transfemoral amputation prostheses—rehabilitation perspective. J Rehabil Res Dev. 2009;46(3):331-44.
20. Brånemark R, Berlin O, Hagberg K, Bergh P, Gunterberg B, Rydevik B. A novel osseointegrated percutaneous prosthetic system for the treatment of patients with transfemoral amputation: a prospective study of 51 patients. Bone Joint J. 2014 Jan;96-B(1):106-13.
21. Tillander J, Hagberg K, Hagberg L, Brånemark R. Osseointegrated titanium implants for limb prostheses attachments: infectious complications. Clin Orthop Relat Res. 2010 Oct;468(10):2781-8. Epub 2010 May 15.
22. Aschoff HH, Kennon RE, Keggi JM, Rubin LE. Transcutaneous, distal femoral, intramedullary attachment for above-the-knee prostheses: an endo-exo device. J Bone Joint Surg Am. 2010 Dec;92(Suppl 2):180-6.
23. Van de Meent H, Hopman MT, Frölke JP. Walking ability and quality of life in subjects with transfemoral amputation: a comparison of osseointegration with socket prostheses. Arch Phys Med Rehabil. 2013 Nov;94(11):2174-8. Epub 2013 Jun 14.
24. Juhnke DL, Beck JP, Jeyapalina S, Aschoff HH. Fifteen years of experience with Integral-Leg-Prosthesis: cohort study of artificial limb attachment system. J Rehabil Res Dev. 2015;52(4):407-20.
25. Al Muderis M, Khemka A, Lord SJ, Van de Meent H, Frölke JPM. Safety of osseointegrated implants for transfemoral amputees: a two-center prospective cohort study. J Bone Joint Surg Am. 2016 Jun 1;98(11):900-9.
26. Khemka A, Frossard L, Lord SJ, Bosley B, Al Muderis M. Osseointegrated total knee replacement connected to a lower limb prosthesis: 4 cases. Acta Orthop. 2015;86(6):740-4. Epub 2015 Aug 27.
27. Khemka A, FarajAllah CI, Lord SJ, Bosley B, Al Muderis M. Osseointegrated total hip replacement connected to a lower limb prosthesis: a proof-of-concept study with three cases. J Orthop Surg. 2016;11(13).
28. Al Muderis M, Tetsworth K, Khemka A, Wilmot S, Bosley B, Lord SJ, Glatt V. The Osseointegration Group of Australia Accelerated Protocol (OGAAP-1) for two-stage osseointegrated reconstruction of amputated limbs. Bone Joint J. 2016 Jul;98-B(7):952-60.
29. Al Muderis M, Lu W, Li JJ. Osseointegrated prosthetic limb for the treatment of lower limb amputations: experience and outcomes. Unfallchirurg. 2017 Apr;120(4):306-11.
30. Sullivan J, Uden M, Robinson KP, Sooriakumaran S. Rehabilitation of the trans-femoral amputee with an osseointegrated prosthesis: the United Kingdom experience. Prosthet Orthot Int. 2003 Aug;27(2):114-20.
31. Hagberg K, Hansson E, Brånemark R. Outcome of percutaneous osseointegrated prostheses for patients with unilateral transfemoral amputation at two-year follow-up. Arch Phys Med Rehabil. 2014 Nov;95(11):2120-7. Epub 2014 Jul 24.
32. St-Jean C, Fish N. Osseointegration: examining the pros and cons. inMotion. 2011;21(5):46-7.
33. Al Muderis M, Lu W, Tetsworth K, Bosley B, Li JJ. Single-stage osseointegrated reconstruction and rehabilitation of lower limb amputees: the Osseointegration Group of Australia Accelerated Protocol-2 (OGAAP-2) for a prospective cohort study. BMJ Open. 2017 Mar 22;7(3):e013508.
34. Lundberg M, Hagberg K, Bullington J. My prosthesis as a part of me: a qualitative analysis of living with an osseointegrated prosthetic limb. Prosthet Orthot Int. 2011 Jun;35(2):207-14.
35. Brånemark R, Brånemark PI, Rydevik B, Myers RR. Osseointegration in skeletal reconstruction and rehabilitation: a review. J Rehabil Res Dev. 2001 Mar-Apr;38(2):175-81.
36. Haggstrom EE, Hansson E, Hagberg K. Comparison of prosthetic costs and service between osseointegrated and conventional suspended transfemoral prostheses. Prosthet Orthot Int. 2013 Apr;37(2):152-60. Epub 2012 Aug 20.
37. Tranberg R, Zügner R, Kärrholm J. Improvements in hip- and pelvic motion for patients with osseointegrated trans-femoral prostheses. Gait Posture. 2011 Feb;33(2):165-8. Epub 2010 Dec 3.
38. Hagberg K, Häggström E, Uden M, Brånemark R. Socket versus bone-anchored trans-femoral prostheses: hip range of motion and sitting comfort. Prosthet Orthot Int. 2005 Aug;29(2):153-63.
39. Hagberg K, Häggström E, Jönsson S, Rydevik B, Brånemark R. Osseoperception and osseointegrated prosthetic limbs. In: Gallagher P, Desmond D, Maclachlan M, editors. Psychoprosthetics. London: Springer; 2008. p 131-40.