CurrentBlue Cross Blue Shield - IowaPolicy N/A

Platelet‑Rich Plasma (PRP) and Autologous Protein Solution (APS) for Orthopedic Applications

This policy governs the use and coverage stance of platelet-rich plasma and autologous protein solution (e.g., nSTRIDE) for orthopedic musculoskeletal conditions and as adjuncts to orthopedic surgery for Blue Cross Blue Shield - Iowa members.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyPlatelet‑Rich Plasma (PRP) and Autologous Protein Solution (APS) for Orthopedic Applications

Policy CodePolicy N/A

Change TypeAnnual review — no material changes

Effective DateAugust 2007

Next Review DateN/A

Key ActionDo not authorize PRP or APS for orthopedic indications because these therapies are considered investigational and not medically necessary.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Investigationalcoverage stance

Jun 2025most recent review

Aug 2007policy origin

7related policies

Lowevidence quality

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Coverage Criteria and Evidence Summary

Investigational / Not Medically Necessary (PRP and APS)

PRP and APS are considered investigational; use is not supported as medically necessary for the following specific primary and adjunctive indications.

Investigational PRP primary uses: PRP injections as primary treatment for tendinopathy (eg, Achilles tendinopathy, lateral epicondylitis), non-tendon soft tissue injuries (eg, plantar fasciitis), osteochondral lesions, osteoarthritis (hip, knee, shoulder), rotator cuff injuries, temporomandibular disorders, muscle injuries, acute joint injuries, carpal tunnel syndrome, soft tissue trauma

List is illustrative and not limited to examples provided in policy

Investigational PRP adjunctive surgical uses: PRP used adjunctively with orthopedic surgeries including ACL reconstruction, Achilles tendon repair, fractures (including hip fracture), hip arthroscopy, long bone non-union, musculoskeletal soft tissue injury repairs, patellar tendon repair, rotator cuff repair, spinal fusion, subacromial decompression, total or partial knee arthroplasty

List is illustrative and not limited to examples provided in policy

Investigational APS uses: Autologous protein solution (APS, e.g., nSTRIDE) is investigational for all orthopedic indications including knee and hip osteoarthritis

Evidence insufficient to determine improvement in net health outcome

Summary findings

Evidence and conclusions regarding PRP for tendinopathy based on systematic reviews and RCTs:

Overall evidence: Systematic reviews of RCTs show mixed results with generally low-quality evidence and significant heterogeneity; most trials do not demonstrate consistent superiority of PRP over controls for pain or function across tendinopathy subtypes

See Masiello 2022, Dai 2023, Muthu 2021, Johal 2019

Preparation variability: Multiple PRP preparation systems and protocols (single/double/triple spin, leukocyte-rich vs leukocyte-poor, activation methods) lead to inconsistent products across studies

Device and preparation variability increases heterogeneity of clinical evidence

Clinical trial signals: Some subgroup analyses and individual trials suggest short- to medium-term benefit for selected conditions (eg, carpal tunnel, leukocyte-rich PRP for lateral epicondylitis) but these findings are limited by imprecision, risk of bias, and inconsistent durability

Interpret subgroup and selective positive findings with caution

Coverage considerations by indication

Evidence-based coverage considerations for PRP as a primary treatment:

Tendinopathy: Recent systematic reviews and RCTs generally fail to show consistent, clinically important benefits of PRP for tendinopathy; therefore routine coverage as a primary treatment is not supported by current evidence

See systematic reviews and recent larger RCTs

Non-tendon soft tissue injury (eg, plantar fasciitis): Small RCTs report inconsistent results; some show short-term improvements versus corticosteroid but long-term efficacy (eg, 2 years) is unestablished; larger, blinded RCTs with adequate duration are needed2 years follow-up recommended

Insufficient long-term evidence for routine coverage

Osteochondral lesions: Evidence is limited to a single quasi-randomized study with methodological limitations; adequately powered, blinded RCTs are required to support coverage28 weeks minimum follow-up reported in existing study

Evidence synthesis and required study characteristics

Evidence and efficacy considerations

Osteochondral lesions evidence: Only a single quasi-randomized study (Mei-Dan 2012) reported improvement in AOFAS and global function versus hyaluronic acid at 28 weeks but had small size, lack of blinding, and baseline imbalances; confirmatory blinded RCTs are needed28 weeks follow-up noted in study

Existing study limited; higher-quality trials required

Knee/hip osteoarthritis evidence: Multiple RCTs and systematic reviews report heterogenous PRP protocols; pooled analyses often favor PRP over placebo or HA for pain/function but results are limited by high heterogeneity, risk of bias, and uncertain clinical significance at 12 months12 months follow-up considered minimal for OA trials

Longer-term durability uncertain; additional rigorous RCTs needed

Evidence-based coverage considerations

Evidence synthesis and RCT findings relevant to coverage decisions for PRP in knee/hip OA and as adjunct in ACL reconstruction:

Knee/OA pooled findings: Systematic reviews/meta-analyses commonly find PRP more effective than placebo or hyaluronic acid in pooled analyses for knee OA, but heterogeneity, publication bias, and variable protocols limit confidence in clinical significance

Consider trial quality and heterogeneity when interpreting pooled results

Subsequent RCT findings: RCTs with ≥12-month follow-up published after reviews show some statistically significant 12-month improvements with PRP versus comparators but are limited by selection bias risk, blinding issues, and inconsistent long-term benefits; benefits not demonstrated at 5 years12 months minimum; longer-term durability not established

Evidence insufficient for definitive coverage decisions

ACL reconstruction evidence: Systematic reviews and multiple RCTs show no consistent clinically relevant benefit of adjunctive PRP on function or activity outcomes at 12 months and beyond; individual studies report mixed short-term signals

Coverage evidence summaries by indication

Summaries of evidence by indication

ACL reconstruction: Systematic reviews and RCTs generally show no sustained clinically meaningful benefit of adjunctive PRP on IKDC, Lysholm, or activity scores at 12 months and beyond; some short-term improvements at 6 months have been reported but are not durable; retrospective data suggest possible increased postoperative motion loss in some series

Adjunctive PRP for ACL reconstruction not consistently beneficial

Hip fracture: A single open-label RCT (Griffen 2013) found no significant reduction in revision surgery at 12 months when PRP was applied during fixation; most secondary outcomes showed no difference12 months follow-up reported

Evidence does not support routine adjunctive PRP for hip fracture

Long bone nonunion: Three RCTs evaluated PRP for long-bone nonunion with mixed results; one showed increased union in a modified analysis but not in intention-to-treat, Calori et al found lower union rates and slower healing versus rhBMP-7, and another trial found no difference versus no treatment

Evidence synthesis — PRP plus orthopedic surgery

Evidence summary for PRP plus orthopedic surgery:

Long-bone nonunion RCT evidence: Three RCTs of PRP for long-bone nonunion reported mixed or negative findings: modified analyses suggested benefit in one trial but intention-to-treat analyses did not; PRP performed worse than rhBMP-7 in Calori et al (120 patients) with lower union rates and slower healing

Randomized evidence does not support reliable benefit for nonunion

Rotator cuff repair evidence: Systematic reviews and RCTs show inconsistent benefits of adjunctive PRP for rotator cuff repair; some reviews report reduced pain at 12 months but no consistent improvements in function or retear rates through the 3.5-year follow-up considered necessary3.5 years follow-up desired

Long-term clinically meaningful benefit not established

Safety signal: Adverse events reporting is limited; one review reported complications in 5.6% of PRP participants in a single RCT (infection, hematoma, skin reaction)

Evidence-based coverage considerations

Coverage considerations reflecting evidence summarized for PRP adjunctive use:

Rotator cuff repair - general evidence summary: Systematic reviews find small reductions in pain at 12 months but inconsistent or no clinically meaningful improvements in function or retear rates; heterogeneity and risk of bias limit confidence

Subgroup long-term retear reduction limited and not consistently reproduced

Rotator cuff repair - long-term subgroup: A subgroup meta-analysis of RCTs with ≥24 months follow-up showed reduced retear rate (RR ~0.40) but this is limited to that subgroup and does not establish consistent benefit across outcomesRCTs ≥24 months

Considered limited evidence

Spinal fusion evidence: One small unblinded RCT (N=62) reported improved fusion rates but no VAS pain benefit; methodological limitations (unblinded, no placebo) limit conclusions and do not support broad coverage

Evidence insufficient for coverage of adjunctive PRP in spinal fusion

Evidence summaries by indication

Coverage assessment should consider the following evidence summaries for each indication:

Spinal fusion: Evidence includes a single small unblinded RCT and observational studies; improved fusion rates were reported in one small trial but no symptomatic benefit was shown

Clinical benefit on pain/function not demonstrated

Subacromial decompression surgery: A small double-blind RCT (N=40) reported reduced early postoperative pain, decreased analgesic use, and improved early ROM but no improvement in instability; larger RCTs required to confirm benefits

Insufficient evidence for routine coverage

Total knee arthroplasty (TKA): Systematic reviews/meta-analyses report some improvement in intraoperative blood-loss parameters but generally no significant differences in ROM, function, or long-term pain; transient VAS improvements at early timepoints are inconsistent

Not sufficient to support routine adjunctive PRP use in TKA

Coverage considerations based on available evidence

Evidence summary and implied criteria based on trial populations and outcomes

Typical trial-aligned patient selection: Trials often enrolled patients with unilateral knee OA Kellgren-Lawrence grade 2-3, age 21-80, BMI <40 kg/m2, and prior nonoperative management including physiotherapy or analgesia

Patient selection should align with trial inclusion when claiming evidence-based benefit

Expected documentation and outcomes: Document baseline and follow-up patient-reported outcomes (WOMAC, KOOS, VAS), and adverse event monitoring up to at least 12 months (and longer where indicated); imaging (MRI/radiographs) may be used for structural endpoints12 months minimum for OA outcomes; 28 weeks for osteochondral lesions; 3.5 years for rotator cuff repair

Follow-up durations derived from trials and evidence synthesis

Efficacy expectation for APS: Randomized evidence does not demonstrate consistent superiority of APS over saline for primary outcomes at 12 months; some trials favored saline on pain measures

Coverage considerations and limitations

Coverage considerations based on available evidence and society guidance:

General evidence requirement: Coverage should be supported by high-quality RCT evidence demonstrating clinically meaningful benefit over placebo or standard treatments; current evidence is mixed, heterogeneous, and limited in size and follow-up

High-quality, adequately powered, blinded RCTs with appropriate follow-up required

Indications without published evidence: Use for indications without published clinical trials (eg, APS for hip OA) should be considered investigational until supportive RCT evidence is available

Professional society guidance and absence of trials support investigational stance

Advanced OA (KL4): APS is unlikely to improve symptoms in severe (KL4) knee OA based on retrospective data showing lower KOOS outcomes and higher dropout rates; coverage as disease-modifying therapy for advanced OA is not supported

AAHS/AAOS guidance does not recommend biologics for advanced hip/knee OA

The policy considers both platelet‑rich plasma (PRP) injections and autologous protein solution (APS, e.g., nSTRIDE) to be investigational for all orthopedic indications. This investigational designation applies to PRP as a primary injection therapy for conditions such as tendinopathies (eg, Achilles, lateral epicondylitis), non‑tendon soft tissue injuries (eg, plantar fasciitis), osteochondral lesions, and osteoarthritis (hip, knee, shoulder), as well as to PRP or APS when used adjunctively with orthopedic surgeries (eg, ACL reconstruction, rotator cuff repair, spinal fusion, fracture fixation, long bone nonunion). Because available evidence is insufficient to determine net health outcomes, these uses are not supported as medically necessary.

This review does not address the use of fibrin sealants. Several PRP preparation systems have 510(k) clearance for producing platelet‑rich preparations intended to be mixed with bone graft materials, but use of PRP as an office injection is off‑label. Device and preparation variability across systems can produce inconsistent platelet and protein concentrations, increasing heterogeneity in clinical studies and limiting generalizability of results.

For non‑tendon soft tissue injuries (for example, plantar fasciitis), there are no large double‑blind randomized controlled trials with at least 2 years of follow‑up that demonstrate durable efficacy. The evidence base for these indications is limited to smaller trials and observational reports, and long‑term efficacy beyond the short‑ to medium‑term remains unproven.

To maintain the integrity of the evidence synthesis, studies with duplicative or overlapping populations were excluded from pooled analyses. This approach reduces bias from double‑counting participants and preserves the validity of trial‑level conclusions.

Long‑term follow‑up data are limited. Although some RCTs report improvements at 12 months, benefits were not maintained at 5 years in the available long‑term data. Evidence is also insufficient to conclude superiority of PRP or APS versus non‑hyaluronic acid comparators due to high heterogeneity, variable risk of bias, and uncertain clinical significance of reported effects.

The policy text does not list additional explicit exclusions beyond the investigational designation; coverage decisions are guided by the absence of sufficient high‑quality evidence for benefit.

Within the provided excerpt there are no additional explicit exclusions specified for PRP or APS use; instead, the document emphasizes the need for higher‑quality RCT evidence to support routine coverage across indications.

Because PRP preparations and administration techniques vary substantially across studies, and because systematic reviews and many RCTs show mixed or inconsistent results, PRP remains experimental/unproven when a consistent, clinically meaningful improvement across functional outcomes is expected.

Available randomized trials and meta‑analyses for tendinopathy are heterogeneous and of generally low quality; due to variability in PRP preparation, patient characteristics, and study methods, the evidence does not reliably demonstrate consistent functional benefit across tendinopathy outcomes.

Systematic reviews and recent RCTs fail to show consistent, clinically important benefit of PRP across the range of outcomes assessed (pain and function). Overall, the literature does not establish a reliable, reproducible advantage of PRP or APS for most orthopedic indications.

Case series and observational data suggest APS (nSTRIDE) is unlikely to improve symptoms in severe knee osteoarthritis (Kellgren‑Lawrence grade 4); these reports show lower efficacy metrics, higher dropout rates, and greater rates of subsequent arthroplasty for KL4 compared with milder disease.

There are no published clinical studies of APS for hip osteoarthritis in the peer‑reviewed literature, and systematic reviews of hip OA interventions do not support use of biologic orthobiologics for advanced disease. Professional society statements also do not recommend biologic therapies for advanced hip or knee arthritis.

Because the evidence is insufficient to demonstrate net health benefit, the policy states that PRP injections and APS injections are investigational and not medically necessary for the orthopedic indications and surgical adjuncts enumerated in the document.

For tendinopathy indications, pooled analyses from multiple systematic reviews and meta‑analyses generally do not show consistent superiority of PRP versus controls; heterogeneity in trial methods and outcomes contributes to uncertainty about any true treatment effect.

Given the body of recent RCTs and systematic reviews, routine primary use of PRP for tendinopathy is not supported by robust evidence and therefore is not recommended as a standard treatment option.

When analyses are restricted to higher‑quality randomized trials, some meta‑analyses fail to demonstrate significant differences between PRP and comparators. High heterogeneity, risk of bias, and inconsistent follow‑up durations are recurring limitations noted across reviews.

Systematic reviews of PRP for hip osteoarthritis generally find no clear advantage of PRP over hyaluronic acid, corticosteroids, or placebo; pooled analyses report mixed and non‑robust results with small trial sizes and methodological limitations.

For adjunctive uses such as ACL reconstruction and hip fracture fixation, systematic reviews and RCTs have not demonstrated consistent, clinically meaningful benefit of adjunctive PRP on functional outcomes or need for revision surgery at typical follow‑up intervals.

Evidence for adjunctive PRP through mid‑ and long‑term follow‑up is inconsistent; some outcomes assessed up to approximately 3.5 years do not show durable efficacy, and subgroup findings (for example, reduced retear rates in some long‑duration rotator cuff trials) are limited and not consistently reproduced.

Routine adjunctive use of PRP for procedures such as rotator cuff repair or spinal fusion is not supported by consistent evidence of clinically meaningful improvements in pain, function, retear or fusion rates across trials and meta‑analyses.

Across surgical adjunct indications, adjunctive PRP has generally failed to show consistent, clinically significant improvements in key outcomes. Small trial sizes, methodological weaknesses, and heterogeneity in PRP protocols limit confidence in reported positive findings.

APS (nSTRIDE) for knee osteoarthritis should be considered not medically necessary when intended to provide durable benefit beyond that demonstrated in randomized trials; a recent double‑blind RCT (Ross et al. 2024) showed no significant difference versus saline at 12 months and some pain measures favored saline.

Procedure and Billing Codes

Codes table referencedmixed

No codes listed

See Codes tablemixed

No codes listed

Covered CPT CodesCPT

0232T

Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed.

Covered CPT CodesCPT

0481T

Injection(s) autologous white blood cell concentrate (autologous protein solution), any site, including image guidance, harvesting and preparation when performed.

HCPCS CodesHCPCS

P9020

Platelet rich plasma, each unit.

Minimum follow-up — general

Minimum follow-up to demonstrate efficacy (general)2 years

RationaleLonger follow-up is necessary to fully observe outcomes for non-tendon soft tissue injuries; studies described reported variable lengths of follow-up

ImplicationInsufficient follow-up (<2 years) may be considered inadequate evidence to demonstrate efficacy and could support denial

Minimum follow-up durations by indication

Osteochondral lesions - minimum follow-up28 weeks

Provider Actions, Prior Authorization, and Documentation

Note

Prior Approval / Authorization

Prior approval: Not applicable — no prior authorization requirement is specified in the appendix excerpt. Verify member benefits and contract exclusions; benefits may vary by plan.

Prior approval: Not applicable (No PA stated in appendix excerpt).
Benefit verification required: Confirm member benefits and any contract exclusions prior to service.

Denial Risk

Investigational / Coverage Status and Claims Impact

This policy considers platelet-rich plasma (PRP) and autologous protein solution (APS) investigational for orthopedic indications; claims may be denied as not medically necessary where coverage criteria are not met. Coding and billing must be accurate to ensure correct claim adjudication.

Investigational stance: PRP and APS are considered investigational for all orthopedic indications in this policy.
Claims consequence: Services deemed investigational or not medically necessary may be denied.

Background and Rationale

Platelet‑rich plasma (PRP) is an autologous platelet concentrate prepared from centrifuged autologous blood intended to deliver concentrated growth factors (eg, platelet‑derived growth factor, transforming growth factor) to a target tissue via injection or as an activated gel adjunct to surgery. AP S (autologous protein solution) is a blood‑derived orthobiologic prepared to concentrate platelets, white blood cells, plasma and anti‑inflammatory cytokines for intra‑articular injection. Both therapies are proposed to modulate healing and inflammation, but preparations and intended uses differ between products and kits.

Definitions and Key Terms

Platelet-rich plasma (PRP) — definition

PRP — basic definitionAutologous platelet concentrate suspended in plasma prepared from centrifuged autologous blood (platelet-rich plasma) intended to deliver growth factors for injection or as a gel adjunct to surgery

Growth factors includedPlatelet-derived growth factor, transforming growth factors, epidermal growth factor, fibroblast growth factors, insulin-like growth factors

Forms of useInjected into tissues or polymerized into a platelet gel for surgical application

Autologous protein solution (APS, nSTRIDE) — definition

APS (autologous protein solution, e.g., nSTRIDE) — definitionAn autologous blood-derived therapy composed of concentrated white blood cells, platelets, and plasma intended to provide high concentrations of anti-inflammatory cytokines and anabolic growth factors for intra-articular injection

Policy History and References

The policy history documents annual reviews and renewals from 2011 through June 2025. The appendix and coding section list reporting codes (for example, 0232T, 0481T, P9020), but the provided appendix pages do not specify an applicable prior authorization requirement. The policy notes that prior approval is not applicable for this investigational stance.

The appendix pages included in this extract do not state any explicit prior authorization requirements for PRP or APS; the policy lists prior approval as not applicable given the investigational designation.

Although prior authorization is not specified in the appendix, the policy language and evidence considerations indicate that services involving PRP or APS are investigational and therefore may be denied for medical necessity. Providers should verify member benefits and follow any applicable contract‑specific authorization processes.

Policy Summary

PayerBlue Cross Blue Shield - Iowa

PolicyPlatelet‑Rich Plasma (PRP) and Autologous Protein Solution (APS) for Orthopedic Applications

Policy CodePolicy N/A

Change TypeAnnual review — no material changes

Effective DateAugust 2007

Next Review DateN/A

Key ActionDo not authorize PRP or APS for orthopedic indications because these therapies are considered investigational and not medically necessary.

SourceLink

On This Page

Current evidence insufficient to support routine coverage

Adjunctive use with ACL reconstruction not supported as proven to improve net health outcome

Implication for coverage: Because evidence is inconsistent and heterogeneous, coverage considerations should require documentation of trial-quality patient selection, prior conservative therapy, and clearly described PRP protocol with outcome follow-up

Prior authorization may request study-level justification

Evidence does not demonstrate consistent benefit

Safety data sparse and underreported

Knee osteoarthritis / APS: APS (nSTRIDE) evidence is limited to small RCTs and observational studies; RCTs show inconsistent results with some trials favoring saline and others showing short-term improvements; crossovers and small sample sizes limit conclusions

APS not established as clinically effective for knee OA

APS use reflects uncertainty of clinical benefit

Comparative effectiveness and stepwise care: Given inconsistent RCT evidence and guideline positions, require documented failure or contraindication of guideline-recommended conservative and non-biologic treatments before considering biologic injections; routine coverage of PRP/APS over established therapies is not supported

Consider prior authorization to document rationale and trial-aligned patient selection

Knee/Hip osteoarthritis - minimum follow-up

RationaleLonger follow-up required because existing literature has varying follow-up lengths; recommended thresholds reflect durations needed to observe meaningful outcomes

Required follow-up duration

Required follow-up duration for efficacy assessment (surgical indications)2 years

ScopeApplies to ACL reconstruction, hip fracture, and other surgical adjunct indications where longer-term outcomes and morbid events are of interest

ConsequenceEfficacy assessments generally require at least 2 years of follow-up; insufficient duration may lead to noncoverage

Minimum follow-up — rotator cuff repair

Rotator cuff repair - minimum follow-up3.5 years

RationaleStudies of rotator cuff repair report follow-up ranging up to 3.5 years; this duration is considered necessary to conclusively demonstrate efficacy across outcomes including retear rates

Evidence noteSystematic reviews found inconsistent benefits at 12 months and subgroup meta-analyses for ≥24 months show limited retear rate reductions, but 3.5 years is the horizon considered necessary

Coding guidance: Report services using appropriate CPT, HCPCS, Revenue, and ICD diagnosis codes (see codes block).

Billing Rule

Coding and Billing

Use the codes listed in the policy when reporting services. Include appropriate CPT/HCPCS and supply-level HCPCS when applicable; incorrect coding may affect claims processing.

CPT code 0232T: Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed.
CPT code 0481T: Injection(s) autologous white blood cell concentrate (autologous protein solution), any site, including image guidance, harvesting and preparation when performed.
HCPCS code P9020: Platelet rich plasma, each unit.

Documentation Required

Appendix and Evidence Crosswalks

Appendix tables provide crosswalks and study-mapping used in evidence review. Table A1 and related appendix materials (e.g., Table A3 crosswalk of RCTs in systematic reviews/meta-analyses) are included as supporting documentation. Submit new evidence or technology information to the policy analyst at the address provided.

Appendix: Table A1 — Comparison of RCTs included in SRs and M-As for mixed tendinopathies.
Appendix: Additional tables (e.g., Table A3 crosswalk) map RCT inclusion across systematic reviews and meta-analyses; use for documentation.
Policy analyst contact: Wellmark Blue Cross and Blue Shield Medical Policy Analyst, PO Box 9232, Des Moines, IA 50306-9232.

Documentation Required

Required Documentation and Follow-up

Documentation to support the medical necessity determination should include indication, prior treatments tried, duration of symptoms, expected clinically meaningful benefit, details of the PRP/APS preparation and administration, and follow-up/outcome assessments consistent with the evidence review timeframes.

Required elements: indication, prior conservative therapies and durations, rationale that biologic is expected to alter clinical outcomes.
Intervention details: PRP/APS preparation method, device used, leukocyte content (if known), number and volume of injections, and timing relative to surgery if adjunctive.
Follow-up expectations: Document outcome assessments and follow-up duration aligned with indication (e.g., ≥12 months for knee/hip OA; ≥28 weeks for osteochondral lesions; ≥2 years for non-tendon soft tissue injuries; ≥3.5 years for rotator cuff adjunctive use).

Preparation contextPrepared at point of care using a kit (cell separator, concentrator, anticoagulant); intended for use within 4 hours of blood draw

Proposed mechanismBlocks interleukin-1B and tumor necrosis factor signaling via concentrated IL-1 receptor antagonist and soluble TNF receptors

PRP mechanism / activation details

PRP mechanism and activationExposure to thrombin and calcium chloride degranulates platelets, releasing growth factors; fibrin polymerization forms a platelet gel used as a surgical adjunct

Intended biological effectRelease of growth factors to promote cell proliferation, angiogenesis, and tissue healing

Preparation sourcePrepared from centrifuged autologous blood (platelet concentrate suspended in plasma)

APS characteristics and time-to-use

APS characteristicsContains concentrated WBCs, platelets, and plasma with anti-inflammatory cytokines (eg, IL-1ra) and anabolic growth factors

Time-to-usePrepared APS should be used within 4 hours after blood draw; frozen storage safety/effectiveness not established

Administration notePhysician may remove synovial fluid prior to intra-articular injection; inject into a single anatomical location (do not partition)

LR-PRP — definition

LR-PRP definitionLeukocyte-rich platelet-rich plasma (LR-PRP) — PRP preparation that includes higher leukocyte concentration compared with leukocyte-poor preparations

RelevanceLeukocyte content is a key variable in PRP preparations and may influence outcomes reported in trials

ReportingSystematic reviews and trials often distinguish LR-PRP from leukocyte-poor PRP in analyses

VISA-A outcome definition

VISA-A outcomeVictorian Institute of Sport Assessment-Achilles (VISA-A) score — validated outcome measure for Achilles tendinopathy used in RCTs

Use in trialsUsed as primary/other outcome to assess pain and disability at predefined follow-up times (eg, 6 months)

Interpretation noteRCTs (eg, Kearney 2021) reported no significant difference in VISA-A at 6 months between PRP and sham

PRP preparation methods — summary

PRP preparation methods — summaryPRP is prepared via centrifugation with variable protocols (single, double, or triple spin) leading to differing platelet and leukocyte concentrations across systems

Device variabilityMultiple commercial PRP preparation systems exist; protocols and outputs vary and increase heterogeneity in clinical evidence

Implication for evidenceHeterogeneous preparation methods limit generalizability of trial results and complicate comparisons

Outcome follow-up thresholds

Osteochondral lesion follow-up thresholdMinimum 28 weeks follow-up required to demonstrate efficacy

Knee/Hip osteoarthritis follow-up thresholdMinimum 12 months follow-up required to demonstrate efficacy

Documentation requirementClinical evidence assessments should include duration of follow-up and specified outcome measures at these timepoints

PRP — general definition

PRP — concise definitionAutologous platelet concentrate suspended in plasma prepared from centrifuged autologous blood used for injection or as a surgical adjunct

Key componentsPlatelets and plasma containing growth factors that may be released on activation

Clinical formsInjected formulations or platelet gel applied intraoperatively

PRP as adjunct in ACL reconstruction — definition

PRP as adjunct in ACL reconstruction — definitionIntraoperative or perioperative PRP injections administered alongside ACL reconstruction intended to improve healing or clinical outcomes versus surgery alone

ComparatorOrthopedic surgery alone (ACL reconstruction without PRP)

Outcome focusFunctional recovery, pain, range of motion, and reoperation rates assessed over adequate follow-up

PRP injections plus orthopedic surgery — definition

PRP injections plus orthopedic surgery — definitionAdministration of platelet-rich plasma in conjunction with orthopedic surgical procedures as an adjunctive therapy to potentially improve healing or outcomes

Examples of proceduresACL reconstruction, rotator cuff repair, spinal fusion, fracture fixation, total knee arthroplasty, subacromial decompression

Evidence considerationAssessments compare PRP plus surgery versus surgery alone with long-term follow-up for clinical and radiographic outcomes

PRP product / use summary

PRP product/use summaryAutologous blood-derived platelet concentrate used as injections or applied in surgery to deliver growth factors; preparation and leukocyte content vary by product

Intended benefitsPromote hemostasis, accelerate healing, and deliver growth factors to target tissues

Clinical applicationsUsed for tendinopathies, osteochondral lesions, osteoarthritis, fracture healing, and as adjunct to multiple orthopedic surgeries

rhBMP-7 — definition (comparator)

rhBMP-7 — definitionRecombinant human bone morphogenetic protein-7, a biologic comparator used to promote bone healing in nonunions

Context in trialsCompared with PRP in RCTs for long-bone nonunion (e.g., Calori et al. 2008) where rhBMP-7 showed higher union rates than PRP

RoleEstablished bone healing biologic used as a comparator in nonunion studies

PRP (policy) — summary definition

PRP (policy definition) — summaryAutologous blood-derived concentrate of platelets and growth factors prepared from centrifuged autologous blood, used via injection or as a surgical adjunct

Variability notePreparations vary in spin protocols, leukocyte content, and activation methods across devices and studies

Evidence implicationHeterogeneity in PRP preparations contributes to inconsistent clinical trial results

Outcomes of interest

Outcomes of interestPain (eg, VAS), function (eg, WOMAC, KOOS, IKDC), and structural outcomes (retear/fusion/union rates); adverse events and long-term follow-up are also important

Measurement pointsTrials typically report outcomes at multiple timepoints (eg, 3, 6, 12 months; longer for surgical indications) and require durable effects

Documentation implicationWhen requesting coverage, include baseline and follow-up PROs, imaging, and adverse event monitoring up to required follow-up duration

PRP / APS — generic definition

PRP / APS — generic definitionAutologous blood-derived products concentrating platelets and/or white blood cells and plasma to deliver growth factors and anti-inflammatory cytokines for musculoskeletal indications

AdministrationDelivered as intra-articular injections or applied during surgery; APS prepared with kits for point-of-care use

Evidence limitationClinical effectiveness varies by product, preparation, and indication; evidence is mixed and often low quality

Adjunctive PRP/APS therapy — definition

Adjunctive PRP/APS therapy — definitionUse of PRP or APS in addition to standard orthopedic surgical procedures intended to improve healing or clinical outcomes compared with surgery alone

ExamplesAdjunctive use has been studied in ACL reconstruction, rotator cuff repair, spinal fusion, fracture fixation, and TKA

Evidence considerationAdjunctive uses require comparative trials versus surgery alone with adequate long-term follow-up to demonstrate clinically meaningful benefit

APS — definition (duplicate)

APS — definition (duplicate)Autologous blood-derived orthobiologic prepared from a patient’s peripheral blood concentrating growth factors and anti-inflammatory components; examples include nSTRIDE APS

Clinical trial useEvaluated in RCTs for knee OA with outcomes including WOMAC, KOOS, VAS, and OMERACT-OARSI responder rates

Preparation/use notePrepared with a kit and should be used within 4 hours of blood draw

nSTRIDE APS kit — definition

nSTRIDE APS kit — definitionA commercial kit (nSTRIDE) used to prepare autologous protein solution at point of care, including blood processing devices, cell separator, concentrator, and anticoagulant

Intended usePrepares APS for intra-articular injection for knee OA; prepared APS should be used within 4 hours

Regulatory note510(k) clearances exist for certain PRP-related devices; kit-based APS systems are commercial products evaluated in trials

nSTRIDE / APS — summary

nSTRIDE / APS (duplicate)Autologous protein solution prepared from a patient’s blood using the nSTRIDE kit, containing anti-inflammatory cytokines and growth factors for intra-articular injection

Clinical evidenceEvaluated in small RCTs (Kon et al.) and a recent placebo-controlled multicenter RCT (Ross et al.) with mixed results at 12 months

Evidence gapAdditional RCTs comparing APS to placebo and other injectables are needed to determine net health benefit

OMERACT-OARSI responder — definition

OMERACT-OARSI responder — definitionResponder criteria used in osteoarthritis trials to determine clinical effect; used to calculate responder rates in APS studies

Use in studiesReported as a secondary or composite outcome in APS and OA trials (eg, Kuwasawa case series reported OMERACT-OARSI responder rate at 12 months)

InterpretationResponder rates inform proportion of patients achieving clinically meaningful improvement at specified follow-up

M-A abbreviation

M-A abbreviationM-A = meta-analysis

UsageUsed in appendices and evidence legend to denote pooled analyses of RCTs or studies

ContextPart of the evidence legend alongside RCT and SR abbreviations

RCT abbreviation

RCT abbreviationRCT = randomized controlled trial

UsageApplied throughout the policy to identify randomized evidence

ContextUsed in evidence tables, appendix, and study summaries

SR abbreviation

SR abbreviationSR = systematic review

UsageUsed in the evidence legend and to reference synthesized literature

ContextAppears in appendix crosswalks and evidence summaries

Evidence legend (M-A, RCT, SR)

Evidence legendM-A: meta-analysis; RCT: randomized controlled trials; SR: systematic review

PurposeProvides shorthand used in appendices and tables to map studies to reviews and pooled analyses

LocationPresented in the appendix evidence crosswalks and legend