Skip to main content
NCBI home page
Clinical Orthopaedics and Related Research logoLink to Clinical Orthopaedics and Related Research
. 2013 Nov 21;472(10):2957–2965. doi: 10.1007/s11999-013-3381-0

Progression of Bone Ingrowth and Attachment Strength for Stability of Percutaneous Osseointegrated Prostheses

Sujee Jeyapalina 1,2, J Peter Beck 1,2, Roy D Bloebaum 1,2,3, Kent N Bachus 1,2,3,4,✉
PMCID: PMC4160472  PMID: 24258685

Abstract

Background

Percutaneous osseointegrated prosthetic (POP) devices have been used clinically in Europe for decades. Unfortunately, their introduction into the United States has been delayed, in part due to the lack of data documenting the progression of osseointegration and mechanical stability.

Questions/purposes

We determined the progression of bone ingrowth into porous-coated POP devices and established the interrelationship with mechanical stability.

Methods

After amputation, 64 skeletally mature sheep received a custom porous-coated POP device and were then randomized into five time groups, with subsequent measurement of percentage of bone ingrowth into the available pore spaces (n = 32) and the mechanical pullout force (n = 32).

Results

Postimplantation, there was an accelerated progression of bone ingrowth (~48% from 0 to 3 months) producing a mean pullout force of 5066 ± 1543 N. Subsequently, there was a slower but continued progression of bone ingrowth (~23% from 3 to 12 months) culminating with a mean pullout force of 13,485 ± 1855 N at 12 months postimplantation. There was a high linear correlation (R = 0.94) between the bone ingrowth and mechanical pullout stability.

Conclusions

This weightbearing model shows an accelerated progression of bone ingrowth into the porous coating; the amount of ingrowth observed at 3 months after surgery within the porous-coated POP devices was sufficient to generate mechanical stability.

Clinical Relevance

The data document progression of bone ingrowth into porous-coated POP devices and establish a strong interrelationship between ingrowth and pullout strength. Further human data are needed to validate these findings.

Introduction

Socket suspension of exoprostheses is the current standard for amputee care but is far from ideal for many patients. This approach commonly fails in patients with multiple limb loss or short residual limbs [51, 52]. Even patients considered successful users of socket suspension frequently experience pain from continued soft tissue compromise resulting from changing or poor socket fit [18, 21, 22, 29, 45, 46]. Particularly in the military population, blast-related heterotopic ossification (refers as bone formation at an abnormal anatomic sites) within the soft tissues of the residual limb can make successful socket fitting difficult or impossible [34, 50, 51]. Because these limitations significantly impair the quality of life for a large percentage of amputees, percutaneous osseointegrated prosthetic (POP) suspension devices are currently being investigated.

As early as the 1940s, clinician-scientists tried to circumvent the problems of socket suspension with attempts at percutaneous skeletal exoprosthetic docking, and an intramedullary, stainless steel attachment device was cemented in the residual stump bone of lower-extremity amputees [25, 48]. In this small group of patients, early soft tissue infections resulted in device removal before the bony stability of the endoprosthesis could be determined [48]. In the 1970s, Mooney et al. [47] again used bone cement to attach a stainless steel endoprostheses with a carbon collar into three above-elbow amputees. All of the implants failed due to infection and were removed after 6 months. Once again, infection prevented assessment of the stability of the device in the bone. In the late 1960s, Per-Ingvar Brånemark [11] reported that living bone formed a bond with devices fabricated from titanium. Termed osseointegration, this phenomenon allows bony attachment to implanted devices without the use of bone cement to create a bond between device and bone. Implants designed to achieve osseointegration (attachment) with the living bone have been widely used in hip and knee arthroplasty for decades. This attachment technology is now being utilized for POP devices for amputees [11–13, 30].

Since the 1990s, three groups throughout Europe have tried a variety of POP devices for patients with limb loss [1, 11–13, 30, 33, 42]. Early results suggest that POP devices can improve the quality of life for patients by increasing the time of exoprosthesis use per day [26, 33], facilitating faster doffing and donning of the exoprosthesis [31, 33], improving gait [26], and providing proprioceptive sensation to the residual limb known as osseoperception [32]. The primary limitation to the widespread use of POP devices has been the potential for periprosthetic infections [57, 58]. However, recent advances using porous subdermal barriers to limit infections have greatly reduced this problem [38, 41]. The relative ability of these human POP device surfaces to become osseointegrated remains poorly understood, and for obvious reasons, the rate at which they do so is impossible to document in the human implant situation. These uncertainties lead to questions, including when does the device actually become mechanically stable in the bone and when can postoperative weightbearing safely begin?

The purpose of this study was to determine the progression of bone ingrowth into porous-coated POP devices and to establish the interrelationship with mechanical stability in a translational animal model. Using an axially weightbearing large-animal model, we specifically sought to (1) measure the progression of bone ingrowth into the porous coating of the POP device, (2) evaluate the progression of mechanical stability (ie, resistance pullout) over a 1-year period of bone ingrowth, and (3) determine the relationship between the amount of ingrowth and mechanical stability.

Materials and Methods

POP Device Design

An intramedullary endoprosthetic device (Thortex Inc, Portland, OR, USA) was developed to fit the medullary canal of the fused metacarpal III/IV bone of sheep (Fig. 1A) and has been described in our previous publications [41, 55]. Regions 3 and 4 (Fig. 1B) of the device had a porous titanium coating, a proprietary pure titanium coating (P2; DJO Global, Vista, CA, USA) (Fig. 2).

Fig. 1A–B.

Fig. 1A–B

Open in a new tab

(A) An engineering drawing shows the design features of a POP construct to fit the fused III/IV metacarpal medullary canal of a skeletally matured sheep. Three sizes of this design were manufactured. (B) This particular tapered POP implant design was developed to promote an ideal anatomic fit and fill within the medullary canal to allow immediate weightbearing. 1 = tapered smooth region; 2 = fluted region; 3 = porous-coated region of the endoprosthesis; 4 = subdermal barrier; 5 = Morse taper to connect to the exoprosthesis.

Fig. 2A–C.

Fig. 2A–C

Open in a new tab

(A) A representative secondary SEM micrograph of the P2 coating shows interconnecting open pores. (B) A BSE micrograph of the same area as (A) depicts the occasional smaller pores, which connect with the larger pores. (C) A representative BSE micrograph shows a cross-sectional area of the P2 coating, which was embedded in polymethylmethacrylate and processed for SEM imaging. This image shows the open pore structure of this coating. Scale bar = 100 μm for (A) and (B) and 250 μm for (C).

Surgery

Sixty-four female and male mixed-breed sheep (2–5 years of age), with a mean body mass of 88 ± 12 kg, were used in this study from a cohort of 86 animals. Sheep were randomly separated into five experimental groups according to time of euthanasia: Time 0 (n = 11), 3 months (n = 14), 6 months (n = 14), 9 months (n = 14), and 12 months (n = 11). Randomization of the animals was not stratified by sex. Following institutionally approved animal use protocols of the US Department of Defense, Salt Lake City Veterans Affairs, and Innovative Medical Device Solution Discovery Research (Logan, UT, USA), the POP device (both endo- and exoprosthetic components) was implanted into the right amputated forelimb of each animal under sterile conditions [41].

This study was part of a larger study, where 86 sheep were used to test various aspects of the POP device’s performance [38, 40, 41, 55].

Postoperative Animal Care

After skin closure, the operative site was protected with a dressing and the animals were kept indoors in temperature-controlled pens for the first 14 days. For the remainder of the study, animals were housed outside in a covered paddock with hay flooring. Full weightbearing was allowed as tolerated immediately after the surgery. Limb function was frequently evaluated by either trained animal care technicians or a veterinary surgeon, which was based on subjective observations of lameness and clinical signs of infection [15]. As an objective measure, monthly gait measurement was also taken from a subset of these sheep and reported elsewhere [55]. The skin neighboring the percutaneous portion of the device was then cleaned weekly and sprayed with PureWorks® antiseptic spray (benzethonium chloride; Pure Works, LLC, Farmington, UT, USA).

End Point Criteria

Sheep were euthanized when infected at a Grade 3 on the modified Checketts scale [15] or at predetermined time periods of 0, 3, 6, 9, and 12 months. Euthanasia was performed in accordance with the American Veterinary Medical Association guidelines. At necropsy, each group of animals was randomly subgrouped for histologic (n = 32) and pullout strength (n = 32) evaluations. The POP devices with surrounding tissues were harvested en bloc.

Histologic Evaluations

All histologic specimens were fixed using 10% formalin buffer for 7 days, followed by dehydration in successive concentrations of ethanol. The specimens were then infiltrated and embedded in polymethylmethacrylate, sectioned, and ground and polished to an optical finish, as described in our previous publications [38, 40, 41].

The host bone tissues were separated into three regions (porous coated, fluted, and smooth) corresponding to the surface morphologies of the intramedullary device (Fig. 1B) and the porous-coated region (n = 3) was used for the ingrowth analysis presented in this study. Polished sections were carbon coated for 25 seconds and evaluated for the percentage of bone present within the pores. Each section was examined in a scanning electron microscope (SEM) (JSM 6100; JEOL Inc, Peabody, MA, USA) by using the backscattered electron (BSE) detector (JEOL-64090BEIW; JOEL Inc) at ×20 and ×100 magnifications. The amount of bone present within the porous coating was calculated by using gray-scale threshold values, with values of 0 to 5 representing the pores (black), 6 to 245 representing the bone tissue (gray), and 246 to 255 representing device material (white) (IQ Materials System, Version 2; Media Cybernetics, Bethesda, MD, USA) [54]. The percentage of bone within the porous-coated region was represented as the area occupied by bone as a fraction of available pore spaces. Polished 50- to 70-μm-thick sections of bone-implant interfaces were stained with a solution of Sanderson’s Rapid Bone Stain™ (Dorn and Hart Microedge, Villa Park, IL, USA) with acid fuchsin, counterstain (Surgipath Medical Industries, Inc., Richmond, IL, USA).

Axial Pullout Strength

All mechanical testing specimens were wrapped in saline-soaked gauze, refrigerated, and transported to the Orthopaedic Research Laboratory, University of Utah. To grip the POP device for axial pullout testing, a 0.5-inch-diameter hole was drilled through the subdermal barrier just proximal to the Morse taper of the POP device. Within the cortical bone proximal to the device tip, drywall screws were placed perpendicular to the shaft, and it was then submerged in melted Cerrobend™ low-melt potting material (Scottsdale Tool, Phoenix, AZ, USA) in a custom-made aluminum cylinder with a 5-inch (12.7-cm) diameter and 4-inch (10.2-cm) height. The Cerrobend™ potting compound was then cooled until it became solid. Each specimen was clamped (ensuring axial alignment) in place and a stainless steel rod was placed through the 0.5-inch (1.3-cm) diameter hole drilled through the POP device and connected to the actuator of a hydraulic material testing system (Model 8500; Instron Corp, Canton, MA, USA) (Fig. 3). The device was loaded uniaxially using displacement control at a constant rate (100 mm/minute) until ultimate failure of the bone-device interface occurred.

Fig. 3A–B.

Fig. 3A–B

Open in a new tab

(A) A photograph shows the axial pullout strength measurement test setup. (B) A close-up view shows the bone-prosthesis submerged in potting material in an aluminum cylinder.

Statistical Analysis

Data are presented as mean ± SD. All statistical analyses were conducted using SPSS® software (Version 11.5; SPSS Inc, Chicago, IL, USA). For ingrowth and axial pullout strength, the 3-month data were compared to Time 0 and 6-month data, 6-month data were compared to 3-month and 9-month data, and 9-month data were compared to 6-month and 12-month data using independent-sample t-tests. The four p values were adjusted for multiple comparisons using the Hochberg’s procedure [2]. All tests were two-tailed and conducted at a 5% significance level.

Results

There was a relatively accelerated bone ingrowth between 0 and 3 months (Figs. 4, 5), followed by a relatively gradual bone ingrowth period. At Time 0, the mean percentage of bone tissue within the porous coating was 5.5% ± 1.3%, which was attributed to bone chips impacted into the coating at the time of insertion. By 3 months, ingrowth data showed a ~10-fold increase (~48% ± 15% of the area occupied by bone as a fraction of the total available pore spaces), which was further increased to ~11-fold (~53% ± 14%) by 6 months, ~12-fold (~64% ± 10%) by 9 months, and ~14-fold (~71% ± 8%) by 12 months when compared to Time 0 values. The most accelerated ingrowth phase was between 0 and 3 months, and ingrowth continued, albeit more slowly, over the rest of the 12-month study period (Fig. 5).

Fig. 4A–H.

Fig. 4A–H

Open in a new tab

A representative set of BSE micrographs shows the bone ingrowth into the porous-coated region of the Time 0 and 3-, 6-, and 12-month groups (A–D: original magnification, ×20; E–H: original magnification, ×100). These images show the progressive bone ingrowth into the pores with increasing implant in situ periods. White = porous coating; gray = bone; black = marrow cellular components.

Fig. 5.

Fig. 5

Open in a new tab

Boxplots show five-number summaries (ie, minimum, first quartile, median, third quartile, and maximum) of the percentage of bone tissue found inside the pores as a function of implant in situ time. The data indicate an initial accelerated bone ingrowth phase within the porous-coated region between 0 and 3 months (p = 0.002), which was followed by moderately progressive bone ingrowth and a remodeling period of up to 12 months. n = 7 animals/group for all groups except for the Time 0 group (n = 5 animals).

In terms of mechanical attachment strength, we observed that it improved rapidly over the first 3 months and that more gradual changes were followed over the next 9 months of the study (Fig. 6). The pullout force data showed that the attachment improved with increasing device in situ time, from a mean of 988 ± 847 N measured at Time 0 to 5066 ± 1543 N at 3 months, to 9636 ± 1303 N at 6 months, to 10,347 ± 2417 N at 9 months, and to 13,485 ± 1626 N by 12 months (Fig. 6). The axial pullout force data followed a pattern similar to that of the ingrowth data (Fig. 5). When compared to Time 0 data, an initial fivefold increase in pullout force data within 3 months was further increased to approximately 14-fold progressively by the end of 1 year postsurgery (Fig. 6). However, it must be noted that there was a 50% increase in bone ingrowth between 3 and 12 months but a 166% increase in attachment strength at the same time points.

Fig. 6.

Fig. 6

Open in a new tab

Boxplots show the five-number summary (ie, minimum, first quartile, median, third quartile, and maximum) and the outliers (open circles) of pullout force as a function of implant in situ time. The data suggest that an initial accelerated increase of strength leveled off by 9 to 12 months. n = 7 animals/group for all groups except for the Time 0 group (n = 6 animals) and the 12-month group (n = 5). The outlier noted in the Time 0 group may be attributed to the tight fit and fill of the implant within the intramedullary canal. If the implant was tightly impacted with multiple points of contact with the endosteal bone, the frictional forces might have contributed to the observed high pullout strength data.

Increased ingrowth as demonstrated histologically was associated with increased mechanical stability of the POP device. We observed a positive, linear relationship between the amount of bone ingrowth into the porous-coated POP device and the resulting mechanical attachment (Fig. 7). Plotting the mechanical pullout data as a function of the bone ingrowth data, we found a positive correlation (y = 166.74x; R = 0.94) between axial pullout strength and bone ingrowth.

Fig. 7.

Fig. 7

Open in a new tab

A scattergram shows mechanical pullout force as a function of percentage of bone ingrowth.

Discussion

Although socket suspension of exoprostheses is the current standard of care, it is not successful for all amputees. POP devices are one alternative to socket systems and are under clinical investigation in Europe. Osseointegration has been used as a method of attaching these POP devices to the residual stump bone [1, 30, 42], and different designs of POPs are currently used in these clinical trials. Because the required experimental techniques cannot be tested in humans, the progression of osseointegration and POP device stability has not been adequately studied and this has led to differences in clinical rehabilitation protocols for postoperative weightbearing. While few animal studies evaluated the relationship between osseointegration and mechanical stability of these devices [14, 19, 20], to our knowledge, no studies have compared the attachment of bone to pullout strength. Moreover, data from small-animal studies, as previously tested, are difficult to translate to humans because of the rate of cortical bone remodeling of rats [16], which has been shown to be eight times faster than that in humans [17, 44]. We therefore used a sheep model to determine the rate of bone ingrowth into porous-coated POP devices and the rate of mechanical resistance to pullout with POP devices and established the relationship between the amount of bone ingrowth and mechanical pullout strength.

There are limitations to this study. Although the pore sizes and porosity chosen in this study fall within the literature’s recommended values [7], additional studies, using the same animal model, could validate other porous-coating types or surfaces for human POP applications. In this weightbearing sheep model, nearly 48% of the pore space on the endoprostheses was filled with bone with a resulting pullout force of more than 5000 N within the first 3 months postimplantation. Human retrieval studies often show more than 10% pore fill at the same time period [3]. Currently, it is not known precisely how much bone ingrowth is adequate for clinical fixation of human POP devices, but it is noteworthy that, in this sheep model, bone kept growing into pores over the study period of 12 months. Testing the validity of the reported one-stage surgical protocol compared to the current two-stage surgery clinical practice in a translational model could have been beneficial, but obtaining an institutional approval to carry out such studies had proven impossible. Also, the gait distribution differs between bipedal humans and quadrupedal sheep, which limit the direct translation of the data to humans. Although the bone-healing response in sheep was similar to that of humans with secondary osteonal remodeling, initially a human amputee bone would likely be more osteopenic at implantation than sheep bone. The bone quality differences could contribute to the mechanical stability differences in human studies. Although rotational stability has significance for devices in the cylindrical human femoral canal, the sheep metacarpal canal is asymmetrical, nearly oval in cross section. Due to this geometrical restriction of the device, only pullout testing was performed, since the torsional testing would only have shattered the bone.

Other studies have demonstrated that the bone ingrowth into the porous coating can be an effective means of bone-device fixation [4–6, 24, 43, 49, 56]. Similar to previously reported mineral apposition rate results [40], the ingrowth data further validated that there were two distinct phases of bone remodeling: (1) a rapid bone ingrowth phase between 0 and 3 months and (2) a gradual bone ingrowth phase between 3 and 12 months. This ingrowth trend was also similar to data published for human bone tissue [35] and for sheep bone [38, 59]. Although these studies did not analyze their data in the same manner as we did, their data (Fig. 5 [35] and Fig. 7 [59]) clearly displayed the statistical differences between Time 0 and the 3-month time points. Moreover, similarities between this study and the previous human bone ingrowth data further supported the translational relevance of the sheep model used in this investigation [35, 59].

The observed phases of bone ingrowth may be explained by the fundamental principles of bone healing and remodeling. The bone repair process was expected to be accelerated for a period of time after the surgical insult, possibly due to the stimuli for healing or increased bone turnover due to a described regional acceleratory phenomenon [27]. The initially accelerated bone ingrowth phase has therefore been attributed to the regional acceleratory phenomenon, the injury response to the surgical trauma and implant insertion. This appears to be in line with the observations of other researchers, who also have attributed the early increase in bone apposition or ingrowth to the regional acceleratory phenomenon [36, 37, 60]. During the 3-month accelerated bone ingrowth phase, newly formed bone filled approximately 48% of total available pore space of the P2 structure, increasing the stability of the device. This phase was then followed by a slower gradual bone ingrowth phase, possibly due to the mechanical and bone adaptation responses stimulated by the direct weightbearing forces transmitted from the implant to the endosteal wall. As a result, an additional 20% (as a percentage of total available pore spaces) of bone tissue was deposited between the 3- and 12-month periods.

The mechanical axial pullout measurements were used in this study to assess the relationship between skeletal attachment by bone ingrowth and the mechanical attachment strength of the POP devices. Although it is well established that bone will infiltrate different pore sizes (20–1000 μm) of an inert porous device system [8, 23, 56], pore sizes of greater than 150 μm have been reported to be required for osteon formation [39]. As seen in this study, the osteons were observed not only in the larger pores of the P2 coating (257 ± 86 μm) but also within the periprosthetic tissue (Fig. 8), indicating further adaptation of bone. This type of “corticalization” of the cancellous bone tissue could have contributed to the increasing pullout strength with increasing device in situ times. This appears to be a reasonable assumption since the tensile strength of cancellous bone has been shown to be less than that of cortical bone tissues (cancellous bone: 10.4 to 14.8 GPa; cortical bone: 17.3 to 26.6 GPa [28, 53]). Moreover, although an initial increase in pullout strength was observed, the data began to reach a strength plateau region between 6 and 12 months (Fig. 6). This result (Fig. 8) further supports the observation that the range of pore size used in the POP system could facilitate the formation of cortical-type bone tissue within the pores, thereby providing a stronger interconnection between the bone and the POP device interface. These data also suggest that the P2 coating used in this study could support direct cortical bone ingrowth into the pores. This observation may be of importance, since most human amputees will have little or no cancellous bone tissue in their residual limbs.

Fig. 8A–C.

Fig. 8A–C

Open in a new tab

A representative bone-implant cross section stained with Sanderson’s accelerated BoneStain™ and counterstained with acid fuchsin shows the cancellous bone ingrowth and adaptation into the porous coating at 12 months postsurgery. (A) A low-magnification photomicrograph (original magnification, ×2; scale bar = 1 mm) shows a cancellous bone structure. Medium-magnification photomicrographs (original magnification, ×20; scale bar = 100 μm) of (B) pores and (C) periprosthetic tissue identify the presence of osteons. White arrows identify the secondary osteons. Pink = bone tissue; blue = cells; black = implant or porous coating.

Our results support that immediate weightbearing did not adversely affect fixation or bone ingrowth, thereby providing provisional support for early weightbearing when porous-coated POP devices are properly fitted. These data are supported by other early weightbearing studies [14, 19, 20]. The weightbearing or mechanical stimuli of loading the device could also have played a crucial role in the rate of bone ingrowth and bone attachment strength. However, the data need to be validated in human trials.

Although the single-stage surgery was successful in our animal study, for human trials, a two-stage surgery, which has been practiced as the current clinical standard, remains the recommended approach, to allow bone and soft tissue healing before loading the POP devices. Based on our results and the principles of skeletal physiology and remodeling, one could also consider exploring limited weightbearing during the first 3 months followed by a gradually increasing weightbearing protocol during the rest of the rehabilitation period. The main result of this study provides support in an animal model for the rehabilitation protocol practiced by the German clinical group, which allows the patients to bear weight as tolerated immediately after the second surgery of the two-stage surgery protocol [1]. Design differences in the threaded device may account for the 6-month delay before the initial weightbearing protocol practiced by the Swedish clinical group led by Dr. Brånemark [12].

Acknowledgments

The authors thank Marc Richelsoph BS for his contribution to the device design, Thortex Inc and DJO Global for providing the P2 porous coating for the endoprostheses, Innovative Medical Device Solution Discovery Research for their support in animal surgeries and daycare, and the laboratory technical team of Trevor Shelton MS, R. Tyler Epperson, and Brooke Kawaguchi BS for their invaluable assistance in processing and collecting data.

Footnotes

The institution of one or more of the authors (SJ, JPB, RDB, KNB) has received, during the study period, funding from the US Department of Defense, PRMRP funding source (Grant PR054520). The US Army Medical Research Acquisition Activity (Fort Detrick, MD, USA) is the awarding and administering acquisition office. The content of this research does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.

One or more of the authors has received, during the study period, funding from the Office of Rehabilitation R&D Service, George E. Wahlen Department of Veterans Affairs Medical Center (Salt Lake City, UT, USA) (JPB, RDB, KNB); The Albert and Margaret Hofmann Chair, Department of Orthopaedics (RDB), University of Utah School of Medicine (Salt Lake City, UT, USA) (RDB); and Department of Orthopaedics, University of Utah School of Medicine (Salt Lake City, UT, USA) (SJ, JPB, RDB, KNB).

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his or her institution approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at Bone and Joint Research Laboratory, George E. Wahlen Department of Veterans Affairs Medical Center (Salt Lake City, UT, USA) and Orthopaedic Research Laboratory, University of Utah Orthopaedic Center (Salt Lake City, UT, USA).

Contributor Information

Roy D. Bloebaum, Email: roy.bloebaum@hsc.utah.edu.

Kent N. Bachus, Email: Kent.Bachus@hsc.utah.edu.

References

  • 1.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;92:180–186. doi: 10.2106/JBJS.J.00806. [DOI] [PubMed] [Google Scholar]
  • 2.Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300. [Google Scholar]
  • 3.Bloebaum RD, Bachus KN, Hofmann AA. Progression of human bone ingrowth into porous-coated implants. In: 10th Combined Meeting Orthopaedic Association Meeting 1998. Aukland, New Zealand: Combined Meeting Orthopaedic Associations: 1998:299.
  • 4.Bloebaum RD, Mihalopoulus NL, Jensen JW, Dorr LD. Postmortem analysis of bone growth into porous-coated acetabular components. J Bone Joint Surg Am. 1997;79:1013–1022. doi: 10.2106/00004623-199707000-00007. [DOI] [PubMed] [Google Scholar]
  • 5.Bloebaum RD, Willie BM, Mitchell BS, Hofmann AA. Relationship between bone ingrowth, mineral apposition rate, and osteoblast activity. J Biomed Mater Res A. 2007;81:505–514. doi: 10.1002/jbm.a.31087. [DOI] [PubMed] [Google Scholar]
  • 6.Bobyn JD, Pilliar RM, Binnington AG, Szivek JA. The effect of proximally and fully porous-coated canine hip stem design on bone modeling. J Orthop Res. 1987;5:393–408. doi: 10.1002/jor.1100050312. [DOI] [PubMed] [Google Scholar]
  • 7.Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC. The optimum pore size for the fixation of porous-surfaced metal implants by the ingrowth of bone. Clin Orthop Relat Res. 1980;150:263–270. [PubMed] [Google Scholar]
  • 8.Bobyn JD, Pilliar RM, Cameron HU, Weatherly GC, Kent GM. The effect of porous surface configuration on the strength of fixation of implants by bone ingrowth. Clin Orthop Relat Res. 1980;149:291–298. [PubMed] [Google Scholar]
  • 9.Brånemark PI. Vital microscopy of bone marrow in rabbit. Scand J Clin Lab Invest. 1959;11:1–82. doi: 10.3109/00365515909060400. [DOI] [PubMed] [Google Scholar]
  • 10.Brånemark PI. Osseointegration and its experimental background. J Prosthet Dent. 1983;50:399–410. doi: 10.1016/S0022-3913(83)80101-2. [DOI] [PubMed] [Google Scholar]
  • 11.Brånemark PI, Adell R, Breine U, Hansson BO, Lindström J, Ohlsson A. Intra-osseous anchorage of dental prostheses. I. Experimental studies. Scand J Plast Reconstr Surg. 1969;3:81–100. doi: 10.3109/02844316909036699. [DOI] [PubMed] [Google Scholar]
  • 12.Brånemark PI, Chien S, Gröndahl HG, Robinson K, editors. The Osseointegration Book: From Calvarium to Calcaneus. Quintessenz Verlags-GmbH: Berlin, Germany; 2005. [Google Scholar]
  • 13.Brånemark R, Brånemark PI, Rydevik B, Myers RR. Osseointegration in skeletal reconstruction and rehabilitation: a review. J Rehabil Res Dev. 2001;38:175–181. [PubMed] [Google Scholar]
  • 14.Brånemark R, Skalak R. An in-vivo method for biomechanical characterization of bone-anchored implants. Med Eng Phys. 1998;20:216–219. doi: 10.1016/S1350-4533(98)00023-X. [DOI] [PubMed] [Google Scholar]
  • 15.Checketts RG, MacEachern AG, Otterburn M. Pin track infection and the principles of pin site care. In: De Bastiani G, Apley AG, Goldberg A, editors. Orthofix External Fixation in Trauma and Orthopaedics. London, UK: Springer-Verlag London Ltd; 2000. pp. 97–103. [Google Scholar]
  • 16.Chow M, Liptak A. A method using MMA for embedding large undecalcified specimens with implants. National Society for Histotechnology Hard Times Communique. July 1992:1–2.
  • 17.Compston JE, Vedi S, Kaptoge S, Seeman E. Bone remodeling rate and remodeling balance are not co-regulated in adulthood: implications for the use of activation frequency as an index of remodeling rate. J Bone Miner Res. 2007;22:1031–1036. doi: 10.1359/jbmr.070407. [DOI] [PubMed] [Google Scholar]
  • 18.DesGroseilliers JP, DesJardins JP, Germain JP, Krol AL. Dermatologic problems in amputees. Can Med Assoc J. 1978;118:535–537. [PMC free article] [PubMed] [Google Scholar]
  • 19.De Smet E, Jaecques S, Vandamme K, Vander Sloten J, Naert I. Positive effect of early loading on implant stability in the bi-cortical guinea-pig model. Clin Oral Implants Res. 2005;16:402–407. doi: 10.1111/j.1600-0501.2005.01156.x. [DOI] [PubMed] [Google Scholar]
  • 20.De Smet E, Jaecques SV, Wevers M, Jansen JA, Jacobs R, Sloten JV, Naert IE. Effect of controlled early implant loading on bone healing and bone mass in guinea pigs, as assessed by micro-CT and histology. Eur J Oral Sci. 2006;114:232–242. doi: 10.1111/j.1600-0722.2006.00355.x. [DOI] [PubMed] [Google Scholar]
  • 21.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;80:563–571. doi: 10.1097/00002060-200108000-00003. [DOI] [PubMed] [Google Scholar]
  • 22.Ehde DM, Czerniecki JM, Smith DG, Campbell KM, Edwards WT, Jensen MP, Robinson LR. Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation. Arch Phys Med Rehabil. 2000;81:1039–1044. doi: 10.1053/apmr.2000.7583. [DOI] [PubMed] [Google Scholar]
  • 23.Engh CA, Bobyn JD. Biological fixation of porous-surface hip prostheses-clinical evaluation of adaptive femoral bone remodeling. Trans Soc Biomater. 1984;7:70. [Google Scholar]
  • 24.Engh CA, Bobyn JD, Glassman AH. Porous-coated hip replacement: the factors governing bone ingrowth, stress shielding, and clinical results. J Bone Joint Surg Br. 1987;69:45–55. doi: 10.1302/0301-620X.69B1.3818732. [DOI] [PubMed] [Google Scholar]
  • 25.Esslinger JO. A basic study in semi-buried implants and osseous attachments for application to amputation prosthetic fitting. Bull Prosthet Res. 1970;10:219–225. [PubMed] [Google Scholar]
  • 26.Frossard L, Hagberg K, Häggström E, Gow DL, Brånemark R, Pearcy M. Functional outcome of transfemoral amputees fitted with an osseointegrated fixation: temporal gait characteristics. J Prosthet Orthot. 2010;22:11–20. doi: 10.1097/JPO.0b013e3181ccc53d. [DOI] [Google Scholar]
  • 27.Frost HM. The regional acceleratory phenomenon: a review. Henry Ford Hosp Med J. 1983;31:3–9. [PubMed] [Google Scholar]
  • 28.Grimal Q, Haupert S, Mitton D, Vastel L, Laugier P. Assessment of cortical bone elasticity and strength: mechanical testing and ultrasound provide complementary data. Med Eng Phys. 2009;31:1140–1147. doi: 10.1016/j.medengphy.2009.07.011. [DOI] [PubMed] [Google Scholar]
  • 29.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;25:186–194. doi: 10.1080/03093640108726601. [DOI] [PubMed] [Google Scholar]
  • 30.Hagberg K, Brånemark R. One hundred patients treated with osseointegrated transfemoral amputation prostheses—rehabilitation perspective. J Rehabil Res Dev. 2009;46:331–344. doi: 10.1682/JRRD.2008.06.0080. [DOI] [PubMed] [Google Scholar]
  • 31.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;32:29–41. doi: 10.1080/03093640701553922. [DOI] [PubMed] [Google Scholar]
  • 32.Hagberg K, Häggström E, Jönsson S, Rydevik B, Brånemark R. Osseoperception and osseointegrated prosthetic limbs. In: Psychoprosthetics. London, UK: Springer; 2008:131–140.
  • 33.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;29:153–163. doi: 10.1080/03093640500238014. [DOI] [PubMed] [Google Scholar]
  • 34.Henrot P, Stines J, Walter F, Martinet N, Paysant J, Blum A. Imaging of the painful lower limb stump. Radiographics. 2000;20 Spec No:S219–S235. [DOI] [PubMed]
  • 35.Hofmann AA, Bloebaum RD, Bachus KN. Progression of human bone ingrowth into porous-coated implants. Acta Orthop Scand. 1997;68:161–166. doi: 10.3109/17453679709004000. [DOI] [PubMed] [Google Scholar]
  • 36.Hofmann AA, Kane KR, Tkach TK, Plaster RL, Camargo MP. Treatment of infected total knee arthroplasty using an articulating spacer. Clin Orthop Relat Res. 1995;321:45–54. [PubMed] [Google Scholar]
  • 37.Hollister SJ, Guldberg RE, Kuelske CL, Caldwell NJ, Richards M, Goldstein SA. Relative effects of wound healing and mechanical stimulus on early bone response to porous-coated implants. J Orthop Res. 1996;14:654–662. doi: 10.1002/jor.1100140422. [DOI] [PubMed] [Google Scholar]
  • 38.Holt BM, Bachus KN, Beck JP, Bloebaum RD, Jeyapalina S. Immediate post-implantation skin immobilization decreases skin regression around percutaneous osseointegrated prosthetic implant systems. J Biomed Mater Res A. 2013;101:2075–2082. doi: 10.1002/jbm.a.34510. [DOI] [PubMed] [Google Scholar]
  • 39.Hulbert SF, Klawitter JJ, Talbert CD, Fitts CT. Research in Dental and Medical Materials. New York, NY: Plenum Press; 1969. [Google Scholar]
  • 40.Jeyapalina S, Beck JP, Bachus KN, Bloebaum RD. Cortical bone response to the presence of load-bearing percutaneous osseointegrated prostheses. Anat Rec (Hoboken). 2012;295:1437–1445. doi: 10.1002/ar.22533. [DOI] [PubMed] [Google Scholar]
  • 41.Jeyapalina S, Beck JP, Bachus KN, Williams DL, Bloebaum RD. Efficacy of a porous-structured titanium subdermal barrier for preventing infection in percutaneous osseointegrated prostheses. J Orthop Res. 2012;30:1304–1311. doi: 10.1002/jor.22081. [DOI] [PubMed] [Google Scholar]
  • 42.Kang NV, Pendegrass C, Marks L, Blunn G. Osseocutaneous integration of an intraosseous transcutaneous amputation prosthesis implant used for reconstruction of a transhumeral amputee: case report. J Hand Surg Am. 2010;35:1130–1134. doi: 10.1016/j.jhsa.2010.03.037. [DOI] [PubMed] [Google Scholar]
  • 43.Kienapfel H, Sprey C, Wilke A, Griss P. Implant fixation by bone ingrowth. J Arthroplasty. 1999;14:355–368. doi: 10.1016/S0883-5403(99)90063-3. [DOI] [PubMed] [Google Scholar]
  • 44.Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB. Effects of a one-month treatment with PTH(1–34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res. 2007;22:495–502. doi: 10.1359/jbmr.070104. [DOI] [PubMed] [Google Scholar]
  • 45.Mak AF, Zhang M, Boone DA. State-of-the-art research in lower-limb prosthetic biomechanics-socket interface: a review. J Rehabil Res Dev. 2001;38:161–174. [PubMed] [Google Scholar]
  • 46.Marshall HM, Jensen MP, Ehde DM, Campbell KM. Pain site and impairment in individuals with amputation pain. Arch Phys Med Rehabil. 2002;83:1116–1119. doi: 10.1053/apmr.2002.33121. [DOI] [PubMed] [Google Scholar]
  • 47.Mooney V, Schwartz SA, Roth AM, Gorniowsky MJ. Percutaneous implant devices. Ann Biomed Eng. 1977;5:34–46. doi: 10.1007/BF02409337. [DOI] [PubMed] [Google Scholar]
  • 48.Murphy EF. History and philosophy of attachment of prostheses to the musculo-skeletal system and of passage through the skin with inert materials. J Biomed Mater Res Symp. 1973;7:275–295. doi: 10.1002/jbm.820070319. [DOI] [PubMed] [Google Scholar]
  • 49.Pilliar RM, Cameron HU, Macnab I. Porous surface layered prosthetic devices. Biomed Eng J. 1975;10:126–131. [PubMed] [Google Scholar]
  • 50.Potter BK, Burns TC, Lacap AP, Granville RR, Gajewski D. Heterotopic ossification in the residual limbs of traumatic and combat-related amputees. J Am Acad Orthop Surg. 2006;14:S191–S197. doi: 10.5435/00124635-200600001-00042. [DOI] [PubMed] [Google Scholar]
  • 51.Potter BK, Burns TC, Lacap AP, Granville RR, Gajewski DA. Heterotopic ossification following traumatic and combat-related amputations: prevalence, risk factors, and preliminary results of excision. J Bone Joint Surg Am. 2007;89:476–486. doi: 10.2106/JBJS.F.00412. [DOI] [PubMed] [Google Scholar]
  • 52.Potter BK, Forsberg JA, Davis TA, Evans KN, Hawksworth JS, Tadaki D, Brown TS, Crane NJ, Burns TC, O’Brien FP, Elster EA. Heterotopic ossification following combat-related trauma. J Bone Joint Surg Am. 2010;92:74–89. doi: 10.2106/JBJS.J.00776. [DOI] [PubMed] [Google Scholar]
  • 53.Rho JY, Ashman RB, Turner CH. Young’s modulus of trabecular and cortical bone material: ultrasonic and microtensile measurements. J Biomech. 1993;26:111–119. doi: 10.1016/0021-9290(93)90042-D. [DOI] [PubMed] [Google Scholar]
  • 54.Rosenbaum Chou TG, Child JR, Naughtin RJ, Rigdon RR, Schumann C, Bloebaum RD. The relationship between femoral periprosthetic cortical bone geometry and porosity after total hip arthroplasty. J Biomed Mater Res A. 2008;87:107–115. [DOI] [PubMed]
  • 55.Shelton TJ, Beck JP, Bloebaum RD, Bachus KN. Percutaneous osseointegrated prostheses for amputees: limb compensation in a 12-month ovine model. J Biomech. 2011;44:2601–2606. doi: 10.1016/j.jbiomech.2011.08.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Spector M. Bone ingrowth into porous metals. In: Williams DF, editor. Biocompatibility of Orthopedic Implants. Boca Raton, FL: CRC Press; 1982. pp. 89–128. [Google Scholar]
  • 57.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;27:114–120. doi: 10.1080/03093640308726667. [DOI] [PubMed] [Google Scholar]
  • 58.Tillander J, Hagberg K, Hagberg L, Brånemark R. Osseointegrated titanium implants for limb prostheses attachments: Infectious complications. Clin Orthop Relat Res. 2010;468:2781–2788. doi: 10.1007/s11999-010-1370-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Willie BM, Bloebaum RD, Bireley WR, Bachus KN, Hofmann AA. Determining relevance of a weight-bearing ovine model for bone ingrowth assessment. J Biomed Mater Res A. 2004;69:567–576. doi: 10.1002/jbm.a.30038. [DOI] [PubMed] [Google Scholar]
  • 60.Willie BM, Yang X, Kelly NH, Merkow J, Gagne S, Ware R, Wright TM, Bostrom MP. Osseointegration into a novel titanium foam implant in the distal femur of a rabbit. J Biomed Mater Res B Appl Biomater. 2010;92:479–488. doi: 10.1002/jbm.b.31541. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical Orthopaedics and Related Research are provided here courtesy of The Association of Bone and Joint Surgeons

RESOURCES