Description
This evidence review addresses orthopedic implants that are constructed by additive manufacturing, commonly known as 3-dimensional (3D) printing. Three situations are considered: 3D printing of standard-sized implants, 3D printing of patient-matched implants for individuals who have typical bone and joint anatomy, and custom 3D printed implants for patients who have bone or joint deformity.

For individuals who have typical bone and joint anatomy and are undergoing standard orthopedic procedures who receive a standard-sized 3D printed implant, the evidence includes a randomized controlled trial and systematic review. Relevant outcomes include symptoms, functional outcomes, and quality of life. Three-dimensional printed implants are often manufactured with titanium and allow greater porosity than can be achieved with traditional manufacturing techniques. Greater porosity is believed to facilitate bony in-growth and theoretically improve the stability of the implant. However, the effect of these devices on the adjacent bone, particularly subsidence and resorption, is unknown. Studies are needed that compare these newer devices with the established alternatives. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have typical bone and joint anatomy and are undergoing standard orthopedic procedures who receive a patient-matched 3D printed implant, the evidence includes no comparative studies. Relevant outcomes include symptoms, functional outcomes, and quality of life. Studies are needed to determine whether patient-matched implants improve outcomes compared with conventional implants. It is noted that other methods for the customization of orthopedic procedures, specifically patient-specific cutting guides and sex-specific implants, have failed to demonstrate improvements in health outcomes. Demonstration of improvement in key outcome measures is needed to justify the greater resource utilization (e.g., time, imaging) of patient-matched 3D printed devices. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have bone or joint deformity requiring a custom orthopedic implant who receive a custom 3D printed implant, the evidence includes case series. Relevant outcomes include symptoms, functional outcomes, and quality of life. The largest case series with the longest follow-up is from outside of the United States. The most commonly reported indications are for revision total hip arthroplasty with severe acetabular defects, reconstruction following orthopedic tumor resection, and spinal abnormalities. These cases would require a custom process for design and manufacturing, even with traditional manufacturing methods. Therefore, the design and manufacturing of a single implant with 3D printing is an advantage of this technology. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background  
Three-dimensional (3D) printed implants are made by a process of additive manufacturing. Additive manufacturing uses a computer-aided process with a 3D printer to build devices 1 layer at a time. The most commonly used technologies in medical devices are powder bed fusion, stereolithography, fused filament fabrication, and liquid-based extrusion.¹ Stereolithography systems use a vat of liquid that is cured by light. Fused filament fabrication melts a solid filament at the point of deposition, after which it solidifies, while liquid-based extrusion systems eject a liquid which then solidifies. Orthopedic implants are frequently made with cobalt-chromium or titanium powder bed fusion, which uses an energy source such as laser or electron beam to melt or sinter a layer of metal powder onto the layer below.

Additive manufacturing contrasts with the traditional methods of manufacturing, which include forging (shaped by hammering or bending), casting (formed by molten metal poured into a mold), and machining (removes material to create the desired geometry). Traditional manufacturing methods are frequently used with cobalt-chromium alloys for orthopedic implants. Titanium is also used for implants, including the femoral stems and acetabular cups used for total hip arthroplasty. The manufacturing of titanium and titanium alloys with traditional production methods is more difficult. Production of complex shapes is also limited with forging, casting, or machining.

Advantages of additive manufacturing include the ability to manufacture complex structures that traditional manufacturing processes cannot, and to create devices individually matched to the patient’s anatomy. Additive manufacturing also allows rough or porous surface textures that promote bone in-growth, and some have proposed that fully porous implants may reduce bone resorption around the implant. Three-dimensional printed models of a joint or spine can also be constructed to plan and practice complex surgeries. In addition to increased design flexibility and potential improvements in function, additive manufacturing wastes less raw materials and may reduce processing costs.

Additive manufacturing may, however, introduce variability into the manufacturing process. A number of factors affect the production of patient-matched orthopedic implants. One factor is whether the device is based on a standard template or custom-designed. Another is if the design could be affected by image quality, rigidity of anatomic structures, or clarity of anatomic landmarks. Some patient-matched devices are based on a standard-sized template with specific features modified within a defined design or performance envelope. Patient-matched devices that follow the patient anatomy more precisely are more vulnerable to design errors.

Manufacturing processes that occur after printing can also affect device performance and material properties. Postprocessing may include removal of manufacturing residues, heat treatments, and final machining and polishing when needed and where surfaces are accessible. For devices made with additive manufacturing, the U.S. Food and Drug Administration (FDA) recommends process validation, revalidation if there are any changes to the device or process, and mechanical device testing in a manner similar to testing of devices made with a traditional manufacturing method. Three-dimensional printing of orthopedic implants at a central facility permits the manufacturer to regulate quality, biocompatibility of materials, and sterility.

REGULATORY STATUS
The FDA (2017) published guidance for industry and technical considerations for 3D printed medical devices.¹ The recommendations in this guidance are intended to supplement any device-specific recommendations and represent the FDA's initial thinking and recommendations. The guidance does not apply to 3D printing at the point-of-care.

The FDA expects "that AM [additive manufacturing] devices will follow the same regulatory requirements and submission expectations as the classification and/or regulation to which a non-AM device of the same type is subject." The required information, characterization, and testing will depend on a variety of factors, such as whether it is an implant or instrument, and whether it is available in standard sizes or is patient-matched.

The FDA has noted that although patient-matched devices are sometimes referred to as customized devices, they are not custom devices meeting custom device exemption requirements under the U.S. Federal Food, Drug, and Cosmetic Act unless they comply with all of the criteria of section 520(b). The FDA published guidance for industry and on the custom device exemption act in 2014.² Custom devices are those created or modified to comply with the order of an individual physician or dentist, do not exceed 5 units per year, and are reported by the manufacturer to the FDA for devices manufactured and distributed under section 520(b) of the Food, Drug, and Cosmetic Act.

Under Section 520(b) of the Food, Drug, and Cosmetic Act, custom devices are exempt from premarket approval (PMA) requirements and conformance to mandatory performance standards.

"A device not covered by an existing marketing approval would require either a PMA or a valid exemption from the requirements to obtain PMA approval in order to be introduced into interstate commerce. Examples of potential valid exemptions or alternatives from the PMA requirement include: (1) establishing the substantial equivalence of the new device to a valid predicate device, (2) approval of an Investigational Device Exemption (IDE) or (3) meeting all custom device exemption requirements."

"Custom Devices are not exempt from any other requirements, including, but not limited to, the Quality System Regulation, including Design Controls (21 CFR Part 820); Medical Device Reporting (21 CFR Part 803); Labeling(21 CFR Part 801); Corrections and Removals (21 CFR Part 806); and Registration and Listing (21 CFR Part807)."

A custom device may not be marketed to the general public.

The FDA has also noted that most patient-matched devices will fall within the existing regulatory pathway for that device type. In addition to standard labeling, specific labeling information is recommended for AM devices that are patient-matched. The FDA has stated that "modifications to a 510(k)-cleared device that maintain its original intended use and could be clinically studied do not appropriately qualify as a custom device."

A large number of titanium spinal interbody implants with increased roughness and porosity than traditional designs have received marketing clearance by the FDA through the 510(k) process. They have a biomechanical stiffness similar to polyetheretherketone cages and less than solid titanium. Some examples of 3D interbody implants include:

• Cascadia™ Cervical and Cascadia ™AN Lordotic Oblique Interbody Systems (K2M)
• CONDUIT (DePuy Synthes)
• EIT (Emerging Implant Technologies)
• Fortilink IBF system (RTI Surgical)
• Foundation 3D (CoreLink)
• IB3D (Medicrea)
• Modulus XLIF (NuVasive)
• NanoHive interbodies (HD Lifesciences)
• Spira-C (Camber)
• Tirbolox (Captiva Spine)
• Tritanium (Stryker)
• IB3D (Medicrea)

A porous 3D printed titanium implant for minimally invasive sacroiliac joint fusion has received 510(k) clearance.

• iFuse 3D (SI Bone).

Patient matched knee implants include:

• ConforMIS iTotal® Cruciate Retaining Knee Replacement System (ConforMIS)　
• ConforMIS iTotal® Posterior Stabilized Knee Replacement System (ConforMIS)
• ConforMIS iUni® Unicondylar Knee Replacement System (ConforMIS)
• ConforMIS iTotal Hip system (ConforMIS).

Related Policies 
701144  Personalized Cutting Guides 

Policy  
Three-dimensional (3D) printed orthopedic implants that have a design that is approved or cleared by the Food and Drug Administration (FDA) and produced in standard sizes for patients with typical bone and joint anatomy are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Patient-matched 3D printed implants that are based on non-standard shapes and sizes for patients with typical bone and joint anatomy and do not qualify as custom devices according to FDA custom device exemption requirements are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Custom 3D printed implants for patients with bone or joint deformity may be considered MEDICALLY NECESSARY when the devices are produced at a central manufacturing facility and meet FDA custom device exemption requirements.

Three-dimensional printed orthopedic implants produced outside of FDA-regulated manufacturing facilities are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.  

Policy Guidelines 
This policy does not address custom mandible or maxillofacial implants.

CODING
There are no specific codes for 3-dimensional printed orthopedic implants. It is possible that providers may use the following code:

L8699 Prosthetic implant, not otherwise specified.

Benefit Application  
BLUECARD/NATIONAL ACCOUNT  ISSUES
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Standard-Sized 3-Dimensional printed Orthopedic Implants
Clinical Context and Therapy Purpose
One proposed benefit of standard sized 3D printed orthopedic implants in patients who have typical bone and joint anatomy is to allow rough or porous surface textures that promote bone in-growth. Increased porosity may also increase the flexibility of metal implants, potentially leading to less bone resorption and subsidence.

The question addressed in this evidence review is: Do standard sized 3D printed orthopedic implants improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with typical bone and joint anatomy.

Interventions
The therapy being considered is standard sized 3D-printed implants.

Comparators
The comparator is orthopedic implants made by traditional manufacturing methods.

Outcomes
The general outcomes of interest are a reduction in pain, typically measured by a visual analog scale (VAS), and improvement in function and quality of life measured by joint-specific questionnaires. The minimally clinically significant difference on the Oswestry Disability Index (ODI) is 15 points.

A beneficial outcome would be a reduction in pain and improvement in function and quality of life.

A harmful outcome would be an adverse event requiring revision surgery.

Pain and function may be measured after 3 to 6 months for short-term outcomes and after at least 2 years to evaluate the effect of the implant on the bone (e.g., ingrowth or subsidence).

Study Selection Criteria

• To assess efficacy outcomes, we sought comparative controlled prospective trials, with a preference for RCTs.
• In the absence of such trials, we sought comparative observational studies, with a preference for prospective studies.
• To assess long-term outcomes and adverse effects, we sought single-arm studies that capture longer periods of follow-up and/or larger populations.
• Within each category of study design, we preferred larger sample size studies and longer duration studies.

Review of Evidence
Interbody Devices for Spinal Fusion
There is limited data on the performance of orthopedic implants produced by additive manufacturing. Porosity can be increased with 3D printing, and basic research has suggested an increase in osteointegration with more porous surfaces. Although a number of spinal interbody spacers are currently manufactured with 3D printing, it is not clear at this time whether the titanium implants lead to improved health outcomes compared with standard polyetheretherketone (PEEK)cages. Some evidence suggests an increase in subsidence (sinking or settling into the adjacent bone) with solid titanium compared with PEEK cages,^3,4 but a 2019 study of porous 3D-printed titanium interbody cages packed with bone graft showed solid fusion in 99% of patents with bridging bone, absence of lucency, no cage subsidence, no endplate cystic changes, and no loosening of implants.⁵ Another series identified a subsidence rate of 3.4% of 59 porous titanium interbody cages, which was lower than what is typically found with PEEK cages.⁶

Total Hip Arthroplasty
The effect of 3D-printed titanium on bone resorption is unclear. The literature on femoral stems for hip arthroplasty indicate that osteolysis and long-term failure might increase with titanium compared with cobalt-chromium stems, which some authors have suggested is due to the increased flexibility of titanium compared with cobalt-chromium.⁷ Other investigators suggest that fully porous 3D printed titanium femoral stems may reduce bone resorption and loosening from stress-shielding.⁸ in addition to the choice of metal, the process of additive manufacturing may also result in more flexibility of the orthopedic implant than traditional manufacturing. 3D-printing of the acetabular component allows greater porosity, which in turn may lead to greater osteointegration and reduce aseptic loosening.⁹ Given the conflicting reports, additional study is needed.

Total Knee Arthroplasty
3D-printing of titanium implants allows a porous design to allow bone in-growth and may reduce the need for cement interfaces, which may be more prone to aseptic loosening. Cohen et al. (2018) reported 3-year results from a prospective study of total knee arthroplasty with 3D-printed tibial and patellar components; outcomes were compared to matched historical controls who received cemented prostheses.¹⁰ There was no significant difference between the groups in the flexion range of motion through 2 year follow-up. Functional outcomes were obtained only for the prospective study of the uncemented prostheses. No implants showed signs of migration or change in position at an average of 37 months postoperatively.

Sacroiliac Joint Fusion
Patel et al. (2019) reported preliminary 6-month outcomes from the first 28 patients in the Study of Bone Growth in the Sacroiliac Joint after Minimally Invasive Surgery with Titanium Implants (SALLY).¹¹ The study is powered for a non-inferiority comparison to prior studies using the conventionally manufactured implant, with a sample size of 50 and a non-inferiority margin of 10 points on the ODI. Data showed non-inferiority to results from the machined implant (see Evidence review 6.01.23) on VAS, ODI, and EuroQOL-5D. Two-year follow-up in the complete sample of patients is needed to establish non-inferiority. A randomized comparison would be needed to determine any benefits of the 3D-printed implant, such as a reduction in revision, compared to machined implants. As of June 30, 2018, there had been 11,070 cases with the machined implant and 3,140 cases with the 3D-printed implant.¹² Post-market surveillance showed a 1-year cumulative probability of revision of 1.5% for machined and 1% for 3D-printed implants (p = 0.041).Out of all surgical revisions, insufficient fixation was the cause of revision for 51/252 (20.2%) machined implant revisions compared to 1/26(3.8%) 3D-printed implant revisions. The other 25 revisions of the 3D-printed implant (96.8%) were due to malpositioning. Interpretation is limited by the non-concurrent controls.

Section Summary: Standard-Sized 3D-Printed Orthopedic Implants
There is limited data on the performance of orthopedic implants produced by additive manufacturing. 3D-printed implants are often manufactured with titanium and permit greater porosity than traditional manufacturing techniques. The literature on solid titanium implants has suggested greater subsidence compared with PEEK interbody spacers for spinal fusion and greater bone resorption compared with cobalt-chromium femoral stems in total hip arthroplasty. Other evidence suggests that porous titanium implants produced by 3D-printing may improve osteointegration and reduce a septic loosening. Due to these conflicting findings, clinical trials are needed to evaluate how 3D-printed implants perform over the long term compared with conventionally manufactured devices.

Patient-Matched 3D-printed Orthopedic Implants
Clinical Context and Therapy Purpose
One proposed benefit of patient-matched 3D-printed orthopedic implants in patients who have typical bone and joint anatomy is to provide a more natural fit and improved function.

The question addressed in this evidence review is: Do patient-matched 3D-printed orthopedic implants improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with normal bone and joint anatomy.

Interventions
The therapy being considered is standard sized 3D-printed implants.

Comparators
The comparator is orthopedic implants made by traditional manufacturing methods.

Outcomes
The general outcomes of interest are a reduction in pain, typically measured by a VAS, and improvement in function and quality of life measured by joint-specific questionnaires. The minimally clinically significant difference on the ODI is 15 points. 

A beneficial outcome would be a reduction in pain and improvement in function and quality of life. 

A harmful outcome would be an increase in pain or adverse event requiring revision surgery. 

Pain and function may be measured after 3 to 6 months for short-term outcomes and after at least 2 years to evaluate the effect of the implant on the bone (e.g., subsidence or revision).

Study Selection Criteria 

• To assess efficacy outcomes, we sought comparative controlled prospective trials, with a preference for RCTs.
• In the absence of such trials, we sought comparative observational studies, with a preference for prospective studies.
• To assess long-term outcomes and adverse effects, we sought single-arm studies that capture longer periods of follow-up and/or larger populations.
• Within each category of study design, we preferred larger sample size studies and longer duration studies. 

Review of Evidence
No published RCTs have been identified on patient-matched knee implants. Results from an RCT (NCT02494544) comparing the ConforMIS iTotal CR Knee Replacement System with off-the-shelf implants are expected in 2029 see Ongoing and Unpublished Clinical Trials section).

It is notable that a number of RCTs have been performed with implants produced using traditional manufacturing and designed specifically for women. These studies with sex-specific implants have not shown improvements in clinicaloutcomes.¹³ Similarly, trials on patient-specific cutting guides have not shown improved clinical outcomes compared with standard cutting guides (see evidence review 701144).

Section Summary: Patient-Matched 3D-Printed Orthopedic Implants
Patient-matched implants refer to the production of orthopedic implants that are modified based on 3D images to matchanatomy that is considered within a typical range. No studies have been identified to evaluate whether matching orthopedic implants to individual patient anatomy improves the net health outcome. It is noted that other methods for the customization of orthopedic procedures, specifically patient-specific cutting guides and sex-specific implants, have failed to demonstrate improvements in health outcomes. Demonstration of improvement in key outcome measures is needed tojustify the greater resource utilization (e.g., time, imaging) of patient-matched 3D-printed devices.

Custom 3D-Printed Orthopedic Implants
Clinical Context and Therapy Purpose
One proposed benefit of custom 3D-printed orthopedic implants is to allow a custom fit in patients who have atypical bone and joint anatomy due to congenital factors, trauma, or revision surgery.

The question addressed in this evidence review is: Do custom 3D-printed orthopedic implants improve the net health outcome in patients with atypical bone and joint anatomy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with atypical bone and joint anatomy. Conditions that may result in a typical anatomy include congenital factors, trauma, tumor resection, and need for revision of acetabular implants.

Interventions
The therapy being considered is custom 3D-printed implants. Custom implants are defined by the U.S. Food and Drug Administration (FDA) as devices created or modified to comply with the order of an individual physician or dentist, do not exceed 5 units per year, and are reported by the manufacturer to the FDA.

Comparators
The comparator is custom orthopedic implants made by traditional manufacturing methods.

Outcomes
The general outcomes of interest are a reduction in pain, typically measured by a VAS for pain, and improvement in function and quality of life measured by joint-specific questionnaires such as the Harris Hip Score; International Society of Limb Salvage; Musculoskeletal Tumor Society Score; and ODI. Implant survival (the need for revision) may also be a relevant outcome measure for orthopedic implants.

A beneficial outcome would be a reduction in pain and improvement in function and quality of life.

A harmful outcome would be an increase in pain or adverse event requiring revision surgery.

Pain and function may be measured after 3 to 6 months for short-term outcomes and after at least 2 years to evaluate the effect of the implant on the bone (e.g., ingrowth or subsidence).

Study Selection Criteria
Because of the population, which is by definition rare, RCTs are unlikely. Therefore, we sought comparative observational comparative studies and single-arm studies. Within each category of study design, we preferred larger sample size studies and longer duration.

Review of Evidence
Examples of custom implants are summarized in Table 1 and include implants for revision arthroplasty with severely compromised acetabulum, reconstruction following bone resection in orthopedic oncology, and complex spinal pathology. A number of cases address severe acetabular defects with revision total hip arthroplasty that cannot be reconstructed using commercially available cages. In the report by Citak et al. (2017), patients had undergone as many as 8 prior revision hip arthroplasties.^14, The custom 3D printed implants are typically designed with flanges to attach the acetabular cup to the pelvis. Postoperative evaluations have shown 30- to 40-point improvements in the Harris Hip Score and up to 91% implant survival at 72 months.¹⁵

Another commonly reported indication for custom implants is pelvic or long bone reconstruction after tumor resection. Case series include up to 35 patients with a follow-up of approximately 2 years. Postoperative scores have ranged from 19 out of 30 on the Musculoskeletal Tumor Society Score (MSTS) for a tibial bone block to 25.8 on the International Society of Limb Salvage score for custom plate fixation or total joint (see Table 2). Liang et al. (2017) have reported outcomes with the MSTS following pelvic tumor resection and reconstruction.¹⁶ The custom devices were designed with a hook, crest, and either flange or braids to attach the device to the adjacent bone. Mean MSTS scores at 20.5 months were 22.7 for an iliac prosthesis, 19.8 for a hemipelvic prosthesis, and 17.7 for a screw-rod connected prosthesis.

Three-dimensional printed spinal implants have also been used to treat complex spinal pathology. Burnard et al. (2020) conducted a systematic review of 3D printing for spinal surgery procedures with a literature review through July 2019.¹⁷ They found 19 case reports and case series with a total of 64 patients who received custom spinal implants; the first publication they identified with 3D printing for spinal implants was in 2016. Various outcome measures were used and all reported improvements compared to baseline. There was minimal subsidence or device migration.

Table 1. Key Case Series Characteristics of Custom Orthopedic Implants

Study	Country		Participants		Treatment Delivery		Follow-Up, mo
Acetabulum
Mao et al. (2015)15	China		22 patients with revision THA and severe acetabular defects		Customized acetabular cages		82
Li et al. (2016)18	China		24 patients with revision THA and severe acetabular defects		Rapid prototyping with custom acetabular cages		67
Citak et al. (2017)14	Germany		9 patients with an average of 5 THA revisions and severe acetabular defects		Customized acetabular cages		29
Pelvis
Liang et al. (2017)16	China		35 patients with pelvic tumor resection		3D printed modular iliac or hemipelvic prostheses		20.5
Distal femur or proximal tibia
Ding et al. (2013)19	China		12 patients with osteosarcoma in the distal femur or proximal tibia		Plate fixation or full knee reconstruction		26.5 (range, 5 – 74)
Luo et al. (2017)20	China		4 patients with tumors of the proximal tibia		En-block resection with customized tibial bone block		5-8
Spine
Burnard et al. (2020)17	Australia		Systematic review of 19 case reports and case series with a total of 64 patients.		Spinal implants

THA: total hip arthroplasty.

Table 2. Key Case Series Results of Custom Orthopedic Implants 

Study	Treatment	Outcome	Outcome	Outcome
Acetabulum
Mao et al. (2015)15	Revision THA with custom acetabular cages	HHS 39.6 preoperatively to 80.9 at follow-up (p < 0.01)	Implant survival of 91.2% (95% CI, 58.10%to 73.95%)
Li et al. (2016)18	Revision THA with custom acetabular cages	HHS 36 preoperatively to 82 at follow-up (p < 0.001)	75% of patients could walk unaided and 21% used a cane
Citak et al. (2017)14	Revision THA with custom acetabular cages	HHS 22.1 preoperatively to 58.7 at follow-up	89% implant survival
Pelvis
Liang et al. (2017)16	Modular titanium iliac or hemipelvic prostheses	MSTS of 22.7 for iliac prosthesis	MSTS of 19.8 for standard hemipelvic prosthesis	MSTS of 17.7 for screw-rod connected prosthesis
Distal femur or proximal tibia
Ding et al. (2013)19	Custom endoprosthesis	ISLS score of 25.8 (range,18 – 27)
Luo et al. (2017)20	Custom titanium tibial bone block with standard knee prosthesis	MSTS score, 19
Spine
Burnard et al. (2020)17	Spine surgery implants	Various outcome measures showing improvement compared to baseline	Minimal subsidence or device migration

CI: confidence interval; HHS: Harris Hip Score; ISLS: International Society of Limb Salvage; MSTS; Musculoskeletal Tumor Society Score; ODI: Oswestry Disability Index; THA: total hip arthroplasty.

Section Summary: Custom 3D-printed Orthopedic Implants
The most effective use of 3D printing in orthopedics may be for custom implants, defined by the FDA as devices created or modified to comply with the order of an individual physician or dentist, do not exceed 5 units per year, and are reported by the manufacturer to the FDA. Potential benefits of 3D printed custom devices are flexibility in design, reduced cost, and faster production time in comparison with conventionally manufactured custom implants. Consistent with the limited number of implants that are considered custom, the literature consists of case reports and case series. The largest series with the longest follow-up is from China and the largest number of cases is for revision hip arthroplasty in patients with severe acetabular defects. Another reported use is for bone reconstruction following tumor resection. These cases require a custom process for design and manufacturing. The design and manufacturing of a single implant with 3D printing is an advantage of this technology.

Summary of Evidence
For individuals who have typical bone and joint anatomy and are undergoing standard orthopedic procedures who receive a standard-sized 3D printed implant, the evidence includes a randomized controlled trial and systematic review. Relevant outcomes include symptoms, functional outcomes, and quality of life. There is limited data on the performance of orthopedic implants produced by additive manufacturing. 3D-printed implants are often manufactured with titanium and permit greater porosity than traditional manufacturing techniques. The literature on solid titanium implants has suggested greater subsidence compared with polyetheretherketone interbody spacers for spinal fusion and greater bone resorption compared with cobalt-chromium femoral stems in total hip arthroplasty. Other evidence suggests that porous titanium implants produced by 3D-printing may improve osteointegration and reduce aseptic loosening. Due to these conflicting findings, clinical trials are needed to evaluate how 3D-printed implants perform over the long-term compared with conventionally manufactured devices. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have typical bone and joint anatomy and are undergoing standard orthopedic procedures who receive a patient-matched 3D printed implant, the evidence includes no comparative studies. Relevant outcomes include symptoms, functional outcomes, and quality of life. Studies are needed to determine whether patient-matched implants improve outcomes compared with conventional implants. It is noted that other methods for the customization of orthopedic procedures, specifically patient-specific cutting guides and sex-specific implants, have failed to demonstrate improvements in health outcomes. Demonstration of improvement in key outcome measures is needed to justify the greater resource utilization (e.g., time, imaging) of patient-matched 3D printed devices. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a bone or joint deformity requiring a custom orthopedic implant who receive a custom 3D printed implant, the evidence includes case series. Relevant outcomes include symptoms, functional outcomes, and quality of life. The largest case series with the longest follow-up is from outside of the U.S. The most commonly reported indications are for revision total hip arthroplasty with severe acetabular defects, reconstruction following orthopedic tumor resection, and spinal abnormalities. These cases would require a custom process for design and manufacturing, even with traditional manufacturing methods. Therefore, the design and manufacturing of a single implant with 3D printing is an advantage of this technology. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements
American Society for Testing and Material
The American Society for Testing and Material has drafted standards for additive manufacturing.²¹ The specification onTitanium-6 Aluminum-4 Vanadium with Powder Bed Fusion covers additively manufactured titanium-6 aluminum-4 vanadium components using full-melt powder bed fusion such as electron beam melting and laser melting. The Society states that "the components produced by these processes are used typically in applications that require mechanical properties similar to machined forgings and wrought products. Components manufactured to this specification are often, but not necessarily, post-processed via machining, grinding, electrical discharge machining, polishing, and so forth to achieve desired surface finish and critical dimensions." 

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials 

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04062630a	Sacroiliac Joint Stabilization in Long Fusion to the Pelvis: Randomized Controlled Trial	220	May 2022
NCT03649490a	A Prospective Multicenter Study Evaluating the Effect of Implant Material and/or Surface Structure on Progression of Fusion in XLIF® Surgery	300	Aug 2022
NCT04086784	3D-printed Porous Titanium Alloy Cages Versus PEEK Cages: Pedicle Screw Loosening Rate and Fusion Rate in Patients With Osteoporosis (3DCOP)	90	Dec 2022
NCT03647501a	Lumbar Fusion With 3D-Printed Porous Titanium Interbody Cages — A Single-Blinded Randomized Controlled Trial Evaluating Nexxt Matrixx(TM) VersusPEEK Cages	70	Sep 2024
NCT02494544a	A Prospective, Randomized, Multicenter Study to Evaluate the ConforMISiTotal® (CR) Knee Replacement System Versus Off-the-Shelf Replacement	187	Aug 2029

NCT: national clinical trial
^a Denotes company sponsored or co-sponsored trial.

Reference  

1. U.S. Food and Drug Administration. Technical considerations for additive manufactured medical devices: Guidancefor industry and Food and Drug Administration staff. 2017;https://www.fda.gov/files/medical%20devices/published/Technical-Considerations-for-Additive-Manufactured-Medical-Devices---Guidance-for-Industry-and-Food-and-Drug-Administration-Staff.pdf. Accessed August 2, 2019.
2. U.S. Food and Drug Administration. Custom device exemption: Guidance for industry and Food and DrugAdministration Staff. 2014;https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm415799.pdf. Accessed August 2, 2019.
3. Chen Y, Wang X, Lu X, et al. Comparison of titanium and polyetheretherketone (PEEK) cages in the surgicaltreatment of multilevel cervical spondylotic myelopathy: a prospective, randomized, control study with over 7-yearfollow-up. Eur Spine J. Jul 2013; 22(7): 1539-46. PMID 23568254
4. Seaman S, Kerezoudis P, Bydon M, et al. Titanium vs. polyetheretherketone (PEEK) interbody fusion: Meta-analysis and review of the literature. J Clin Neurosci. Oct 2017; 44: 23-29. PMID 28736113
5. Mokawem M, Katzouraki G, Harman CL, et al. Lumbar interbody fusion rates with 3D-printed lamellar titaniumcages using a silicate-substituted calcium phosphate bone graft. J Clin Neurosci. Oct 2019; 68: 134-139. PMID31351704
6. R Krafft P, Osburn B, C Vivas A, et al. Novel Titanium Cages for Minimally Invasive Lateral Lumbar InterbodyFusion: First Assessment of Subsidence. Spine Surg Relat Res. 2020; 4(2): 171-177. PMID 32405565
7. Maurer TB, Ochsner PE, Schwarzer G, et al. Increased loosening of cemented straight stem prostheses madefrom titanium alloys. An analysis and comparison with prostheses made of cobalt-chromium-nickel alloy. IntOrthop. 2001; 25(2): 77-80. PMID 11409456
8. Arabnejad S, Johnston B, Tanzer M, et al. Fully porous 3D printed titanium femoral stem to reduce stress-shieldingfollowing total hip arthroplasty. J Orthop Res. Aug 2017; 35(8): 1774-1783. PMID 27664796　
9. Castagnini F, Bordini B, Stea S, et al. Highly porous titanium cup in cementless total hip arthroplasty: registryresults at eight years. Int Orthop. Aug 2019; 43(8): 1815-1821. PMID 30141142
10. Cohen RG, Sherman NC, James SL. Early Clinical Outcomes of a New Cementless Total Knee ArthroplastyDesign. Orthopedics. Nov 01 2018; 41(6): e765-e771. PMID 30168838
11. Patel V, Kovalsky D, Meyer SC, et al. Minimally invasive lateral transiliac sacroiliac joint fusion using 3D-printedtriangular titanium implants. Med Devices (Auckl). 2019; 12: 203-214. PMID 31239791
12. Cher D, Wroe K, Reckling WC, et al. Postmarket surveillance of 3D-printed implants for sacroiliac joint fusion. MedDevices (Auckl). 2018; 11: 337-343. PMID 30319290
13. Cheng T, Zhu C, Wang J, et al. No clinical benefit of gender-specific total knee arthroplasty. Acta Orthop. Aug2014; 85(4): 415-21. PMID 24954488
14. Citak M, Kochsiek L, Gehrke T, et al. Preliminary results of a 3D-printed acetabular component in the managementof extensive defects. Hip Int. May 2018; 28(3): 266-271. PMID 29218689
15. Mao Y, Xu C, Xu J, et al. The use of customized cages in revision total hip arthroplasty for Paprosky type IIIacetabular bone defects. Int Orthop. Oct 2015; 39(10): 2023-30. PMID 26285669
16. Liang H, Ji T, Zhang Y, et al. Reconstruction with 3D-printed pelvic endoprostheses after resection of a pelvictumour. Bone Joint J. Feb 2017; 99-B(2): 267-275. PMID 28148672
17. Burnard JL, Parr WCH, Choy WJ, et al. 3D-printed spine surgery implants: a systematic review of the efficacy andclinical safety profile of patient-specific and off-the-shelf devices. Eur Spine J. Jun 2020; 29(6): 1248-1260. PMID31797140
18. Li H, Qu X, Mao Y, et al. Custom Acetabular Cages Offer Stable Fixation and Improved Hip Scores for RevisionTHA With Severe Bone Defects. Clin Orthop Relat Res. Mar 2016; 474(3): 731-40. PMID 26467611
19. Ding HW, Yu GW, Tu Q, et al. Computer-aided resection and endoprosthesis design for the management ofmalignant bone tumors around the knee: outcomes of 12 cases. BMC Musculoskelet Disord. Nov 22 2013; 14:331. PMID 24267157
20. Luo W, Huang L, Liu H, et al. Customized Knee Prosthesis in Treatment of Giant Cell Tumors of the Proximal Tibia:Application of 3-Dimensional Printing Technology in Surgical Design. Med Sci Monit. Apr 07 2017; 23: 1691-1700.PMID 28388595
21. American Society for Testing and Material. Additive manufacturing technology standards. n.d.;https://www.astm.org/Standards/additive-manufacturing-technology-standards.html. Accessed August 2, 2019. 

Coding Section 

Codes		Number		Description
CPT				No specific codes-see Policy Guidelines
HCPCS
ICD-10-CM		C40.20-C40.22		Malignant neoplasm of long bones lower limb, code range
		C47.20-C47.22	Malignant neoplasm of peripheral nerves of lower limb, including hip, code range
		C49.20 - C49.22	Malignant neoplasm of connective and soft tissue of lower limb, including hip, code range
		D16.20-D16.22	Benign neoplasm of long bones of lower limb, code range
		D21.20-D21.22	Benign neoplasm of connective and soft tissue of lower limb, including hip, code range
		L40.50	Arthropathic psoriasis, unspecified
		M05.051-M05.069	Felty’s Syndrome, hip and knee, code range
		M05.451-M05.469	Rheumatoid myopathy with rheumatoid arthritis, hip and knee, code range
		M05.551-M05.569	Rheumatoid polyneuropathy with rheumatoid arthritis, hip and knee, code range
		M05.751-M05.769	Rheumatoid arthritis with rheumatoid factor without organ or systems involvement, hip and knee, code range
		M05.851-M05.869	Other rheumatoid arthritis with rheumatoid factor, hip and knee, code range
		M06.051-M06.069	Rheumatoid arthritis without rheumatoid factor, hip and knee, code range
		M06.251-M06.269	Rheumatoid bursitis, hip and knee, code range
		M06.351-M06.369	Rheumatoid nodule, hip and knee, code range
		M06.851-M06.869	Other specified rheumatoid arthritis hip and knee, code range
		M07.651-M07.669	Enteropathic arthropathies, hip and knee, code range
		M08.051-M08.069	Unspecified juvenile rheumatoid arthritis, hip and knee, code range
		M08.251-M08.269	Juvenile rheumatoid arthritis with systemic onset, hip and knee, code range
		M08.451-M08.469	Pauciarticular juvenile rheumatoid arthritis, hip and knee, code range
		M08.851-M08.869	Other juvenile arthritis, hip and knee, code range
	M08.951-M08.969			Juvenile arthritis, unspecified, hip and knee, code range
	M12.051-M12.069			Chronic postrheumatic arthropathy [Jaccoud], hip and knee, code range
	M12.451-M12.469			Intermittent hydrarthrosis, hip and knee code range
	M12.551-M12.569			Traumatic arthropathy, hip and knee, code range
	M12.851-M12.869			Other specific arthropathies, not elsewhere classified, hip and knee, code range
	M13.0			Polyarthritis, unspecified
	M16.0-M17.9			Osteoarthritis, hip and knee, code range
	M24.651-M24.669			Ankylosis, hip and knee, code range
	M24.7			Protrusio acetabuli
	M24.851-M24.859			Other specific joint derangements, not elsewhere classified, hip code range
	M25.251-M25.269			Flail joint, hip and knee, code range
	M25.351-M25.369			Other instability, hip and knee, code range
	M25.551-M25.569			Pain; hip and knee, code range
	M43.18			Spondylolisthesis, sacral and sacrococcygeal region
	M43.27-M43.28			Fusion of spine, code range
	M46.1			Sacroiliitis, not elsewhere classified
	M48.08			Spinal stenosis, sacral and sacrococcygeal region
	M51.17			Intervertebral disc disorders with radiculopathy, lumbosacral region
	M53.2X7-M53.2X8			Spinal instabilities, code range
	M53.3			Sacrococcygeal disorders, not elsewhere classified
	M53.88			Other specified dorsopathies, sacral and sacrococcygeal region
	M80.051A, M80.052A, M80.059A			Age-related osteoporosis with current pathological fracture, initial encounter for fracture, femur code range
	M80.051K, M80.052K, M80.059K			Age-related osteoporosis with current pathological fracture, subsequent encounter for fracture with nonunion, femur code range
	M80.051S, M80.052S, M80.059S			Age-related osteoporosis with current pathological fracture, sequela, femur code range
	M80.851A, M80.852A, M80.859A			Other osteoporosis with current pathological fracture, initial encounter for fracture, femur code range
	M80.851G, M80.852G, M80.859G			Other osteoporosis with current pathological fracture, subsequent encounter for fracture with delayed healing, femur code range
	M80.851K, M80.852K, M80.859K			Other osteoporosis with current pathological fracture, subsequent encounter for fracture with nonunion, femur code range
	M80.851S, M80.852S, M80.859S			Other osteoporosis with current pathological fracture, sequela femur code range
	M84.461A, M84.462A			Pathological fracture, initial encounter for fracture, tibia code range
	M84.461G, M84.462G			Pathological fracture, subsequent encounter for fracture with delayed healing, tibia code range
	M84.461K, M84.462K			Pathological fracture, subsequent encounter for fracture with delayed non-union, tibia code range
	M84.461S, M84.462S			Pathological fracture, sequela, tibia code range
	M84.561A, M84.562A			Pathological fracture in neoplastic disease, initial encounter for fracture, tibia code range
	M84.561G, M84.562G			Pathological fracture in neoplastic disease, subsequent encounter for fracture with delayed healing, tibia code range
	M84.561K, M84.562K			Pathological fracture in neoplastic disease, subsequent encounter for fracture with delayed non-union, tibia code range
	M84.561S, M84.562S			Pathological fracture in neoplastic disease, sequela, tibia code range
	M84.661A, M84.662A			Pathological fracture in other disease, initial encounter for fracture, tibia code range
	M84.661G, M84.662G			Pathological fracture in other disease, subsequent encounter for fracture with delayed healing, tibia code range
	M84.661K, M84.662K			Pathological fracture in other disease, subsequent encounter for fracture with delayed non-union, tibia code range
	M84.661S, M84.662S			Pathological fracture in other disease, sequela, tibia code range
	M87.051-M87.059			Idiopathic aseptic necrosis, femur code range
	M87.151-M87.159			Osteonecrosis due to drugs, femur code range
	M87.251-M87.256			Osteonecrosis due to previous trauma, femur code range
	M87.351-M87.353			Other secondary osteonecrosis, femur code range
	M87.851-M87.859		Other osteonecrosis, femur code range
	M96.661-M96.679		Fracture following insertion of orthopedic implant, joint prosthesis, or bone plate, femur, tibia and fibula code range
	M97.01XA, M97.02XA		Periprosthetic fracture around internal prosthetic hip joint, initial encounter, code range
	M97.01XD, M97.02XD		Periprosthetic fracture around internal prosthetic hip joint, subsequent encounter, code range
	M97.01XS, M97.02XS		Periprosthetic fracture around internal prosthetic hip joint, sequela code range
	M97.11XA, M97.12XA		Periprosthetic fracture around internal prosthetic knee joint, initial encounter, code range
	M97.11XD, M97.12XD		Periprosthetic fracture around internal prosthetic knee joint, subsequent encounter, code range
	M97.11XS, M97.12XS		Periprosthetic fracture around internal prosthetic knee joint, sequela code range
	Q74.2		Other congenital malformations of lower limb(s), including pelvic girdle
	S33.2XXA-S33.2XXS		Dislocation of sacroiliac and sacrococcygeal joint, code range
	S72.401A, S72.402A, S72.409A		Unspecified fracture of lower end of femur, initial encounter for closed fracture code range
	S72.401G, S72.402G, S72.409G		Unspecified fracture of lower end of femur, subsequent encounter for closed fracture with delayed healing code range
	S72.401K, S72.402K, S72.409K		Unspecified fracture of lower end of femur, subsequent encounter for closed fracture with nonunion code range
	S72.401S, S72.402S, S72.409S		Unspecified fracture of lower end of femur, sequela, code range
	T84.010-T84.013		Broken internal prosthesis, hip and knee code range
	T84.020-T84.023		Dislocation of internal prosthesis, hip and knee code range
	T84.030-T84.033		Mechanical loosening of internal prosthetic joint, hip and knee code range
	T84.050-T84.053		Periprosthetic osteolysis of internal prosthetic joint, hip and knee code range
	T84.060-T84.063		Wear of articular bearing surface of internal prosthetic joint, hip and knee code range
	T84.090-T84.093		Other mechanical complication of internal joint prosthesis, hip and knee code range
	T84.51-T84.54		Infection and inflammatory reaction due to internal prosthesis, hip and knee code range
	Z96.641-Z96.659		Presence of artificial joint, hip and knee code range
ICD-10-PCS
Type of service	Surgical
Place of service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2018 Forward     

06/14/2022	Annual review, no change to policy intent.
06/01/2021	Annual review, no change to policy intent. Updating regulatory status, rationale and references.
06/09/2020	Annual review, no change to policy intent. Updating rationale and references.
06/03/2019	Annual review, no change to policy intent.
06/04/2018	New Policy