ical experience with orthobiologic therapies (eg, platelet-rich plasma, bone marrow aspirate concentrate, microfragmented adipose tissue). This represents an important educational gap for those training in sports medicine fellowships. To address this gap, an educational toolkit was envisioned...
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UNIT 1. INTRODUCTION TO ORTHOBIOLOGICS
Module 1. Basic Principles of Regenerative Medicine
- Definition
- a. What is regenerative medicine
- b. Components in orthobiologics: hematologic, cellular
- Basic science (see Module 8)
- a. Regenerative capacity of human musculoskeletal tissues
- b. Wound healing phases: (1) inflammatory, (2) proliferative, (3) remodeling
- c. Limitations in the healing process and abnormal response to injury
- Types of orthobiologic therapies in regenerative medicine
- a. Hematologic: PRP, autologous conditioned plasma (ACP), platelet-poor plasma (PPP)
- b. Cellular: bone marrow aspirate concentration (BMAC), microfragmented adipose tissue (MFAT)
- Types of nonbiologic therapies in regenerative medicine
- a. Injectable: hyper- and hypo-osmolar dextrose
- b. Other: Extracorporeal shockwave (focused shockwave, radial pressure wave), laser
- Tissue pathology
- a. Bone: acute fracture, fracture nonunion, avascular necrosis
- b. Cartilage: osteoarthritis, chondral defect(s)/chondromalacia, torn meniscus/labrum
- c. Tendon: tendonitis, tendinopathy, partial thickness tears
- d. Muscle: strain, partial tears
- e. Ligament: sprain, partial thickness tear, capsule injury
- f. Other: plantar fasciopathy, surgical augmentation
- Indications
- a. Pathology refractory to typical conservative management
- b. Pathology for which surgery may not be indicated or timely
- c. Treatment supported by high-level evidence suggesting better long-term outcomes
- d. Patient is a poor surgical candidate
- e. Faster return to sport/accelerated rehabilitation timeline
- f. Patient preference
Module 2. Key Concepts on the Responsible Use of Orthobiologics
- How to counsel patients
- a. What it is: definition of orthobiologic therapies and regenerative medicine (see Module 1)
- b. What it is not: totipotent/pluripotent embryonic “stem cells” and/or complete tissue regeneration
- c. Awareness of common unethical practices: grossly overpriced, nonevidence-based therapies, misleading advertisement, etc.
- Limitations in understanding
- a. Mechanism of action
- b. Number or series of injections
- c. Timing of injections (eg, stage of injury/disease)
- d. Optimal dose range for each indication
- e. Medication use or abstinence pre- and postprocedure
- Other treatment options
- a. Do nothing/wait-and-see approach
- b. Oral pharmacologic therapies
- c. Corticosteroid injection(s)
- d. Physical therapy or individualized exercise prescription
- e. Surgical intervention
- Patient selection
- a. Absolute versus relative contraindications: systemic infection, local infection
- b. Comorbid conditions: cancer, bleeding diathesis, anemia, thrombocytopenia, pregnancy, uncontrolled autoimmune condition
- c. Concurrent medications: anticoagulants, antiplatelets, anti-inflammatories, statins
- d. Considerations in personalized treatment plan: severity of condition (eg, grade 4 osteoarthritis), patient and provider expectations
- Informed consent and patient discussion
- a. Risks and benefits
- b. Preprocedure preparation
- c. Postprocedure recovery
- d. Current research involvement of the provider and/or conflicts of interest
- e. Quality control
- f. Oncologic implications
- g. Associated cost
- Expected outcomes: dependent on unbiased synopsis of the available literature
- Billing concerns: lack of insurance coverage because of heterogeneity in preparation and heterogeneity in the literature
UNIT 2. ORTHOBIOLOGIC THERAPIES
Module 3. Hemoderivative Therapy: Platelet-Rich Plasma
- Overview: definition and history
- Basic science: components and proposed mechanisms of action
- Classification schemes for reporting and documentation
- a. Basic: leukocyte rich/poor and platelet count or concentration
- b. PAW: (1) platelet count [absolute number], (2) activation method, (3) white blood cells/leukocytes present or absent
- c. PLRA: (1) platelets per microliter, (2) leukocytes present or absent, (3) neutrophil percentage, (4) red blood cells/erythrocytes present or absent, (5) activating platelet agent use or nonuse
- d. DEPA: (1) dose of platelets [in billions], (2) efficiency of production [in percentage], (2) purity of concentrate [erythrocyte contamination], (4) activating platelet agent
- e. MARSPILL: (1) machine or handmade preparation method, (2) activated or inactivated platelets, (3) red blood cell/erythrocyte presence or absence, (4) spin count [1 or 2], (5) platelet concentration times baseline, (6) imaging guidance [with or without], (7) leukocyte rich or poor, and (8) light activation [with or without]
- Optimization
- a. Relative and absolute contraindications
- b. Patient comorbidities
- c. Stage or severity of condition
- d. Preprocedural concerns: hydration, medication use, or abstinence
- e. Timing of procedure
- Injectate preparation
- a. Processing kits
- b. Venipuncture and blood volume
- c. Use of platelet activators
- d. Component separation and extraction
- Procedural considerations
- a. Risk and safety
- i. Standard injection risks: local site pain, infection, ecchymosis, iatrogenic nerve injury
- ii. Unique patient risks/challenges: bleeding diathesis, allergic response to component(s)
- iii. Failure to provide relief
- b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
- c. Use of anesthetics
- d. Injection frequency
- e. Immediate postprocedural care: pain management, rest, modified weight bearing, follow-up (see Module 9)
- Documentation and billing
- Clinical applications
- a. Hyaline cartilage/fibrocartilage
- i. Upper extremity osteoarthritis: shoulder, elbow, wrist, hand
- ii. Lower extremity osteoarthritis: hip, knee, ankle, foot
- iii. Spine: osteoarthritis of the facet/zygapophyseal joint, intradiscal pathology, osteoarthritis of the sacroiliac joint
- b. Tendon
- i. Upper extremity tendinopathy: rotator cuff, common extensor at the lateral epicondyle of the humerus, common flexor/pronator mass at the medial epicondyle of the humerus
- ii. Lower extremity tendinopathy: gluteus, patella, hamstring, Achilles
- c. Muscle
- i. Lower extremity: quadriceps, hamstring, gastrocnemius, soleus
- d. Ligament
- i. Upper extremity: ulnar collateral ligament of the elbow
- ii. Lower extremity: anterior cruciate ligament of the knee, medial collateral ligament of the knee, anterior talofibular ligament of the ankle
- e. Other: plantar fasciopathy
- Practical hands-on instruction
- a. Patient selection
- b. Venipuncture technique
- c. PRP/PPP/ACP kit use
- d. Case-based simulation
- e. Management of side effects and complications
- f. Return-to-play considerations (for which minimal evidence is available)
Module 4. Cellular Therapy: Bone Marrow Aspirate Concentrate
- Overview: definition and history
- Basic science
- a. Marrow components (eg, cell types, “red” vs “yellow” marrow)
- b. Relationship with multipotent adult mesenchymal stem cells
- c. Proposed mechanisms of action (in vitro vs in vivo)
- Classification schemes for reporting and documentation
- a. Site of injection
- b. Harvest technique: aspiration site(s), type of needle/syringe/anticoagulant, number of insertions, total volume harvested
- c. Cell count: leukocytes, hematopoietic, and mesenchymal stem cells
- d. Cytokine dosage: growth factors and interleukins
- e. Colony forming unit count (ie, indirect quantification of mesenchymal stem cells)
- f. Phenotype of hematopoietic and mesenchymal stem cells (requires flow cytometry)
- g. Cell differentiation evaluation (requires induction of chondrocytes, adipocytes, and osteocytes)
- h. Functional assays: wound healing, lymphocyte proliferation, population doubling time
- Optimization
- a. Relative and absolute contraindications
- b. Patient comorbidities: age, weight, body mass index, hematocrit, bone density, positioning difficulties
- c. Stage or severity of condition
- d. Preprocedural concerns: medication, dietary, or supplement use/avoidance (eg, corticosteroids, statins, nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelets, curcumin, alcohol)
- e. Timing of procedure
- Injectate preparation
- a. Harvest site(s)
- b. Aspiration tools and technique
- c. Volume required for application
- d. Manipulation/processing: commercial kits, anticoagulant type, centrifugation
- e. Component separation and extraction
- Procedural considerations
- a. Risk and safety
- i. Standard injection risks: local site pain, clot formation, iatrogenic nerve damage, hemorrhage, ecchymosis, infection
- ii. Unique patient risks/challenges: bone density, body habitus, bleeding diathesis
- iii. Failure to provide relief
- b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
- c. Use of anesthetics: careful selection to avoid cellular toxicity, maximize patient comfort
- d. Injection frequency
- e. Immediate postprocedural care: wound bandage, pain management, rest, modified weight bearing, follow-up (see Module 9)
- Documentation and billing
- Clinical applications
- a. Bone: avascular necrosis, subchondral bone pathology
- b. Hyaline cartilage/fibrocartilage: meniscus tears in the knee, knee osteoarthritis, other osteoarthritis
- c. Tendon: rotator cuff tendinopathy, partial thickness tear
- Practical hands-on instruction
- a. Patient selection
- b. Harvest technique and processing
- c. Case-based simulation
- d. Management of side effects and complications
- e. Return-to-play considerations (for which minimal evidence is available)
Module 5. Cellular Therapy: Adipose Tissue Derivatives
- Overview: definition and history
- Basic science: components and proposed mechanisms of action
- a. Roles and cellular contents of adipose tissue [incl. mesenchymal stem cells (MSCs), supportive cells, extracellular matrix fragments, bioactive secretomes]
- b. Mechanisms of action: immunomodulation, angiogenesis, paracrine signaling, mechanical cushioning, extracellular matrix remodeling, in vivo versus in vitro differences
- c. Adipose tissue derivatives
- i. MFAT
- ii. Stromal vascular fraction (SVF) (more than minimal manipulation, use requires biologic license application from Food and Drug Administration [FDA])
- iii. Nanofat: autologous fat particles < 0.1 mm diameter
- iv. Whole fat graft/transfer
- Classification schemes for reporting/documentation
- a. Harvest site and aspiration method
- b. Washing, mechanical fragmentation/emulsification, filtration
- c. Centrifugation
- d. Enzymatic treatment (more than minimal manipulation, use requires biologic license application from FDA)
- e. Culture expansion (more than minimal manipulation, use requires biologic license application from FDA)
- Optimization
- a. Relative and absolute contraindications
- b. Patient comorbidities (incl. body mass index, history of abdominal surgery)
- c. Stage or severity of condition
- d. Preprocedural concerns: hydration, medication use or abstinence, preprocedural exercise
- e. Timing of procedure
- Injectate preparation
- a. Harvest site(s)
- b. Processing kits
- c. Active product
- Procedural considerations
- a. Risks and safety
- i. Standard injection risks: local site pain, infection, ecchymosis
- ii. Unique patient risks/challenges: bleeding diathesis, allergic response to component, cosmetic defect at site of aspiration, fat embolism
- iii. Failure to provide relief
- b. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
- c. Injection frequency
- d. Immediate postprocedural care: wound bandage, abdominal brace, pain management, rest, modified weight bearing, follow-up (see Module 9)
- Documentation and billing
- Clinical applications
- a. Joint/Hyaline cartilage: chondral defect, osteoarthritis of the shoulder, hip, knee
- b. Tendon: rotator cuff tendinopathy, partial thickness tear
- Practical hands-on instruction
- a. Patient selection
- b. Harvest technique
- c. Case-based simulation
- d. Management of side effects and complications
- e. Return-to-play considerations (for minimal evidence is available)
Module 6. Nonbiologic Therapies in Regenerative Medicine
- Prolotherapy
- a. Basic science and history
- i. Usage of various agents and needling techniques: dextrose (d-isomer of glucose), glycerin, sodium morrhuate, phenol
- ii. Rationale for injecting ligaments, fascia, enthesis, periosteum
- iii. Transition to hyperosmolar dextrose
- iv. Proposed mechanism of action: dextrose concentration 5% to 10% versus 15% to 25%
- b. Procedural considerations
- i. Needle selection
- ii. Patient positioning
- iii. Injectate preparation
- iv. Imaging guidance: anatomic/palpation, ultrasound, fluoroscopy
- v. Series versus single injection
- vi. Comprehensive regional treatment
- c. Role of concomitant needling/tenotomy
- i. Soft tissue microtrauma stimulates healing tissues
- ii. Needle contacting bone/periosteum
- d. Indications for treatment
- i. Osteoarthritis: mild, moderate, severe
- ii. Tendinopathy: mild, moderate, severe
- iii. Chronic postsurgical pain
- iv. Chronic back, neck pain
- v. Hypermobility/joint laxity
- vi. In-season athlete
- e. Practical considerations
- i. Relative and absolute contraindications to prolotherapy
- ii. Rehabilitation considerations
- iii. Return-to-play considerations (in season, off season)
- iv. Adverse effects
- v. Billing and coding
- Hypo-osmolar (5%) dextrose in water: nerve hydrodissection, other applications
- Extracorporeal shockwave therapy: radial pressure wave, focused shockwave
- Emerging nonbiologic therapies (included for awareness only): Botulinum toxin type A, low-level laser light therapy/photobiomodulation, low-intensity pulsed ultrasound therapy, low-dose radiation therapy
UNIT 3. PRACTICE AND APPLICATION
Module 7. Technical and Procedural Considerations
- Device and equipment selection
- a. Ultrasound: transducer types and selection, settings and image manipulation to optimize target image, needle localization, key images to save for the medical record
- b. Compare/contrast commercially available devices for platelet-rich plasma, bone marrow aspirate concentrate, microfragmented adipose tissue
- c. Supplies
- i. Sterile versus nonsterile supplies
- ii. Needle gauge and syringe size selection
- iii. Activating agent(s)
- iv. Anticoagulant use
- v. Local anesthetic(s)
- vi. Biohazard waste receptacle(s)
- vii. Storage considerations
- d. Procedural concerns
- i. Infection prevention
- ii. Proper handling of blood products and biologic tissues (eg, labeling specimens, storage)
- iii. Patient positioning and comfort
- iv. Setting up the sterile field (incl. draping, skin preparation, arrangement of supplies at the bedside)
- v. Expectations and limitations of a clinical assistant
- vi. Disposal of biohazardous waste
- vii. Role of the trainee during procedures
- Practical hands-on instruction
- a. Introduction to the ultrasound cart and related supplies
- b. Review of institutional procedure room policies and protocols
- c. Demonstration of basic scanning techniques: image optimization, transducer movements, patient positioning and draping, physician ergonomics
- d. Demonstration of sterile field setup and maintenance
- e. Interaction with clinical assistant
- f. Simulated patient interaction for an orthobiologics consultation
Module 8. Science of Injury: Beyond the Basics
- General response to injury in a normal state
- a. Effective stages of the inflammatory response and regenerative capacity of human musculoskeletal tissues
- i. Wound healing phases
- 1. Inflammatory: hours to days
- 2. Proliferative: days to weeks
- 3. Remodeling: months to years
- ii. Important cells and chemicals involved in healing
- 1. Cells: monocytes, macrophages, mesenchymal stem cells, fibroblasts, tenocytes, osteoblasts, myoblasts, muscle satellite cells
- 2. Cytokines: growth factors, interleukins
- 3. Enzymes/precursors: metalloproteases, antiproteases, plasminogen
- b. Important physiologic constituents of specific tissues and general healing timeline: tendon, ligament, muscle, bone, hyaline cartilage, fibrocartilage (eg, meniscus, labrum)
- Impaired healing response
- a. Pathophysiology
- i. Tendinopathy: general features of acute inflammation versus chronic degradation, specific watershed zones (eg, Achilles tendon midsubstance)
- ii. Muscle: role of cytokines such as TGF-B1 and myostatin
- iii. Bone: factors influencing osteoblast and osteoclast activity
- b. Risk factors for impaired healing
- i. Intrinsic
- 1. Nonmodifiable: age, sex, genetic musculoskeletal disorder
- 2. Comorbid conditions: body mass, autoimmune disease, hypercholesterolemia, osteoporosis, anemia, thrombocytopenia, uncontrolled hyperglycemia, end-stage renal disease, cirrhosis, impaired nutrition status
- ii. Extrinsic
- 1. Medications: NSAIDs, chronic immunosuppressant use, corticosteroids, statins, antibiotics, hormone supplementation
- 2. Abnormal loading: repetition to fatigue, ill-fitting equipment, rapid training progression, high force movements, inadequate rest/recovery
- 3. Specific injuries/pathology
- a. Tendon: acute tendon rupture, acute inflammation (eg, tendonitis, tenosynovitis), degenerative tendinopathy, enthesopathy (incl. diseases that predispose to this condition)
- b. Ligament: grading of acute ligament sprains, chronic ligamentous laxity (post-traumatic and/or hereditary), capsule derangement (eg, rupture, laxity)
- c. Muscle: grading of acute muscle strains/rupture, chronic muscle injury, myositis ossificans
- d. Bone: bone stress injury (Fredericson classification), fractures (acute/traumatic, subchondral insufficiency, pathologic, chronic/nonunion, osteoporotic), avascular necrosis
- e. Joint/hyaline cartilage: osteoarthritis, inflammatory/autoimmune arthritis, septic arthritis, osteochondral lesion
- f. Fibrocartilage: knee menisci, triangular fibrocartilage complex of the wrist, glenoid labrum, acetabular labrum, temporomandibular joint, acromioclavicular joint
- g. Nerve: injury (neurapraxia, axonotmesis, neurotmesis), inflammatory and noninflammatory neuritis, neuropathy, entrapment/compressive mononeuropathy
Module 9. Rehabilitation and Return-To-Sport Considerations After Orthobiologics Treatment
- Acute inflammatory phase
- a. Duration: hours to days
- b. Characterized by formation of hematoma, recruitment of inflammatory cells, and edema produced from vasoactive mediators
- c. Use of analgesics
- i. NSAIDs: evidence for holding because of inhibition of growth factor release and impaired platelet aggregation, variation on duration of abstinence pre- and postprocedure, literature lacks definitive guidance
- ii. Acetaminophen
- iii. Opioid-derived analgesics (eg, tramadol): short course, not required for all patients
- d. Cryotherapy (ice): may be avoided because of theoretical reduction of blood flow and platelet activity
- e. Immobilization, weight-bearing modifications, and/or protected use of the limb (incl. durable medical equipment)
- i. Joint: no consensus in the literature because of heterogeneity of studies, wide variation in practice
- ii. Soft tissue: (see “Joint” above) a period of immobilization is recommended, followed by early loading for mechanotransduction to augment healing (ideal parameters unknown)
- Repair/proliferative phase
- a. Duration: days to weeks
- b. Characterized by fibroblast proliferation at the site of injury, synthesis of collagen and extracellular matrix
- c. Joint interventions: begin range of motion as soon as tolerated, progress aerobic activities as pain/swelling allow
- i. Days 7 to 21: controlled stimulation to healing cartilage, correct biomechanical deficits leading to abnormal joint forces, restore/correct strength deficits, proprioceptive/balance activities
- ii. Days 21+: individualized loading program based on procedure target site and specifics of sport/activity, begin sport-specific training
- d. Soft tissue interventions: begin range of motion as tolerated, maintain pain <3/10, timeline of starting sport-specific training depends on sport, procedure target site, athlete, timing of season
- i. Weeks 2 to 4: Isometric, isotonic exercise
- ii. Weeks 4 to 6: Concentric exercise, followed by eccentric exercise
- iii. Weeks 6+: Eccentric exercise with heavy slow resistance
- iv. Weeks 8+: Closed kinetic chain plyometrics and sport-specific training
Module 10. Orthobiologics as Orthopedic Surgical Adjuncts
- Fundamental characteristics of osseous healing: (1) osteoconduction, (2) osteoinduction, (3) osteogenesis
- Additional orthobiologic compounds used in orthopedic surgery
- a. Demineralized bone matrix
- b. Bone morphogenic protein-2
- c. Recombinant human platelet-derived growth factor-BB
- Indications for potential use
- a. Fracture nonunion/osseous atrophic nonunion: platelet-rich plasma, bone morphogenic protein-2
- b. Joint fusion/arthrodesis: bone marrow aspirate concentrate, recombinant human platelet-derived growth factor-BB, bone morphogenetic protein-2
- c. Avascular necrosis: bone marrow aspirate concentrate
- d. Tendon repair/debridement: bone marrow aspirate concentrate, platelet-rich plasma
- e. Meniscus repair: platelet-rich plasma
- f. Ligament repair/reconstruction: bone marrow aspirate concentrate in ACL reconstruction
UNIT 4. UNDERSTANDING THE LANDSCAPE
Module 11. Research
- Critical appraisal of orthobiologics literature
- a. Scientific rigor: levels of evidence, quality of data collected, alpha level (α), power (β), minimal clinically important difference (MCID), number needed to treat (NNT), short- versus long-term outcomes among published studies
- b. Challenges to conducting high-quality randomized controlled trials (RCTs): time, feasibility, cost/funding (eg, funding from industry might carry stipulations that bias findings)
- c. Compare/contrast meta-analyses and systematic reviews
- d. Statistical methods and graphs used to compare treatments/therapies: analysis of variance, post hoc tests, forest plot
- e. Risk of bias and attraction of “novelty” therapies
- Levels of evidence
- 1. Level 1: RCTs, meta-analysis of homogeneous RCTs
- 2. Level 2: prospective cohort studies, meta-analysis of level 2 studies
- 3. Level 3: retrospective cohort studies, case control studies; many treatments in orthopedics and sports medicine
- 4. Level 4: case series
- 5. Level 5: expert opinion, case report/personal observations
- Role of basic science in orthobiologics research
- a. Topics: mechanisms for cellular signaling, platelet/pericyte/MSC biology, role in healing
- b. Cell and tissue behavior: in vivo versus in vitro
- c. Progression: laboratory studies to animal studies to human studies
- d. Limitations: advancements in clinical research require advancements in basic science research
- Common challenges in orthobiologics research
- a. Heterogeneous or uncharacterized formulations limit comparison, conclusions, and applicability (see “Classification Schemes” in Modules 3, 4, 5)
- b. Nocebo and placebo effects
- c. Control group validity: potential treatment effects of saline injection, masked roles of the patient and/or physician
- d. Variations on injection technique/procedure
- i. Use/nonuse of local anesthetic and types
- ii. Imaging guidance: palpation/anatomic/landmark, ultrasound, fluoroscopy
- iii. Concomitant tenotomy/needling
- e. Periprocedural protocols vary or are not described in the literature
- i. Preprocedure variations: NSAID abstinence, exercise versus relative rest, hydration
- ii. Postprocedure variations: NSAID abstinence, limb immobilization versus unrestricted movement, weight-bearing status, rehabilitation protocol
- Research integrity and integration into clinical practice
- a. Consider evidence and conclusions: Are the findings applicable to my patient? Are there fundamental differences between the population studied and my patient(s)?
- b. Assess the risk of bias: control group validity, funding from industry versus independent source(s), author conflicts of interest, standardization of treatment(s), confounding factors properly addressed (eg, adequate sample size and randomization)
- c. Do the results show the treatment to be consistently safe? Consistently effective?
- d. Financial implications of the procedure/method/intervention for the patient and practitioner/organization
- Current trends and principles of orthobiologics research
- a. Utilization of patient-reported outcome measures (PROM)
- b. Comparison of data registries with real-world evidence
- c. Strengths/advantages of biorepositories
- Apply the research: a tiered approach to orthobiologics use
- a. Consider: best available clinical evidence, personal clinical expertise, capabilities, and limitations, patient values, and preferences
- b. Tier I: proven safety with robust evidence of effectiveness (level 1 evidence)
- i.PRP for osteoarthritis of the knee
- ii.PRP for tendinopathies: lateral epicondyle, rotator cuff, gluteal
- c. Tier II: Proven safety with growing evidence of effectiveness (levels 2 and 3 evidence)
- i. BMAC for knee osteoarthritis and femoral head osteonecrosis
- ii. PRP for patellar and Achilles tendinopathy
- iii. MFAT for knee osteoarthritis
- iv. PPP for muscle injury
- v. Patient should be well informed and guided on reasonable expectations
- d. Tier III: Less evidence and regulatory approval still required
- i. Perinatal products
- ii. Products only offered as part of an IRB-approved study
Module 12. Regulation
- US FDA guidelines
- a. Good clinical practice (GCP) concepts: ensure safety, avoid disease transmission, avoid contamination
- b. US Code of Federal Regulations Title 21: Food and Drugs
- i. Part 1270: regarding human tissue for transplantation, revoked in 2022
- ii. Part 1271: defines human cells, tissues, and cellular and tissue-based products (HCT/P); outlines “Current Good Tissue Practice” to minimize disease
- c. FDA's Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological Health: risk-based regulatory approaches
- d. Biologics License Application
- i. Public Health Service Act (PHS Act) section 361
- ii. FDA pathway 351: if the HCT/P is more than minimally processed
- iii. PHS Act 351(k) for biosimilar products
- iv. Investigational New Drug and Regenerative Medicine Advanced Therapy designations: for a HCT/P “intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition” and labeled as a “regenerative medicine therapy”
- e. Preparations system/device regulation: FDA 510(k) pathway versus 510(f)<sup><a data-reference-links="R2">2</a></sup> pathway
- f. Limitations: products that require more than minimal processing (eg, perinatal products, exosomes) are not currently “legal”
- g. FDA INTERACT toolkit: Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs
- Federal Trade Commission (FTC) marketing regulations
- a. Role of the Bureau of Consumer Protection
- b. FTC has specific incentives to intervene
- c. All products sold and procedures performed within the United States are eligible
- Legal challenges and notable court cases
- a. March 2024: “Stem Cell Institute of America” etc. was found liable for defrauding consumers by the US District Court for the Northern District of Georgia
- b. September 2024: US Ninth Circuit Court of Appeals found that California Stem Cell Treatment Center, Inc.'s manufacture and labeling of SVF violated the FDA's Food, Drug, and Cosmetic Act
- Patient counseling on the above
CONCLUSIONS
The use of orthobiologic treatments in clinical sports medicine practice continues to expand. The rapid growth of orthobiologics research and clinical use requires current and future sports physicians and trainees to access high-quality clinical education along with hands-on procedural training. Wherever evidence is emerging or lacking, expert opinion should be used carefully and thoughtfully. The AMSSM Orthobiologics Toolkit offers SM fellowship directors 12 flexible modules for custom curriculum integration so that trainees may gain the scientific insight needed for responsible application of orthobiologic therapies in their medical practices.
RECOMMENDED READING FOR FELLOWS
Module 1—Basic Principles of Regenerative Medicine
Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of action of mesenchymal stem cells (MSCs): impact of delivery method. Expert Opin Biol Ther. 2022;22(4):449-463.
Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.
Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal stem cell mechanisms of action and clinical effects in osteoarthritis: a narrative review. Genes. 2022;13(6):949.
Murphy M, Moncivais K, Caplan A. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.
Module 2—Key Concepts on Responsible Use of Orthobiologics
Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.
Shapiro SA, Master Z, Arthurs JR, Mautner K. Tiered approach to considering orthobiologics for patients with musculoskeletal conditions. Br J Sports Med. 2023;57(3):179-180.
Module 3—Hemoderivative Therapy: Platelet-Rich Plasma
Belk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC. Platelet-rich plasma versus hyaluronic acid for knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Am J Sports Med. 2021;49(1):249-260.
Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA. Platelet-rich plasma: from basic science to clinical applications. Am J Sports Med. 2009;37(11):2259-2272.
Mishra AK, Skrepnik NV, Edwards SG, Jones GL, Sampson S, Vermillion DA, Ramsey ML, Karli DC, Rettig AC. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med. 2014;42(2):463-71.
Module 4—Cellular Therapies: Bone Marrow Aspirate Concentrate
Dragoo JL, Guzman RA. Evaluation of the consistency and composition of commercially available bone marrow aspirate concentrate systems. Orthop J Sports Med. 2020;8(1):2325967119893634.
Friedlis MF, Centeno CJ. Performing a better bone marrow aspiration. Phys Med Rehabil Clin N Am. 2016;27(4):919-939.
Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen-year follow-up. Int Orthop. 2021;45(2):365-373.
Purita JL, Kolber M, Rodrigues BL, Mosaner T, Santos GS, Caliari-Oliveira C, Huber SC. Bone marrow-derived products: A classification proposal—bone marrow aspirate, bone marrow aspirate concentrate or hybrid? World J Stem Cells. 2020;12(4):241-250.
Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O'Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017;45(1):82-90.
Module 5—Cellular Therapies: Adipose Tissue
Greenwood V, Clausen P, Matuska, AM. Micro-fragmented adipose tissue cellular composition varies by processing device and analytical method. Sci Rep. 2022;12:16107.
Riggle C, McLellan M, Bohlen H, Wang D. Complications of stem cell-based injections for knee osteoarthritis: a systematic review. HSS J. 2024 Aug 16:15563316241271058.
Tremolada C, Colombo V, Ventura C. Adipose tissue and mesenchymal stem cells: state of the art and Lipogems technology development. Curr Stem Cell Rep. 2016; 2, 304-312.
Module 6—Nonbiologics in Regenerative Medicine
Hsu C, Vu K, Borg-Stein J. Prolotherapy: a narrative review of mechanisms, techniques, and protocols, and evidence for common musculoskeletal conditions. Phys Med Rehabil Clin N Am. 2023;34(1):165-180.
Sit RWS, Wu RWK, Rabago D, Reeves KD, Chan DCC, Yip BHK, Chung VCH, Wong SYS. Efficacy of intra-articular hypertonic dextrose (prolotherapy) for knee osteoarthritis: a randomized controlled trial. Ann Fam Med. 2020;18(3):235-242.
Zhu M, Rabago D, Chung VC, Reeves KD, Wong SY, Sit RW. Effects of hypertonic dextrose injection (prolotherapy) in lateral elbow tendinosis: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2022;103(11):2209-2218.
Module 7—Technical and Procedural Considerations
None.
Module 8—Science of Injury: Beyond the Basics
Cottrell JA, Turner JC, Arinzeh TL, O'Connor JP. The biology of bone and ligament healing. Foot Ankle Clin. 2016;21(4):739-761.
Hildebrand KA, Gallant-Behm CL, Kydd AS, Hart DA. The basics of soft tissue healing and general factors that influence such healing. Sports Med Arthrosc Rev. 2005;13(3):136-144.
Kaeding C, Best TM. Tendinosis: pathophysiology and nonoperative treatment. Sports Health. 2009;1(4):284-292.
Module 9—Rehabilitation and Return-To-Sport Considerations After Orthobiologics Treatment
Honbo ES, Mattfeld R, Khadavi M, Podesta L. Clinical rationale and rehabilitation guidelines for post biologic therapy. Phys Med Rehabil Clin N Am. 2023;34(1):239-263.
Kruse RC, Rossmiller KD, Fleagle TR. Post-procedure protocols after intraarticular orthobiologic injections—A scoping review. PM R. 2025;17(4):463-468.
McKay J, Frantzen K, Vercruyssen N, Hafsi K, Opitz T, Davis A, Murrell W. Rehabilitation following regenerative medicine treatment for knee osteoarthritis-current concept review. J Clin Orthop Trauma. 2019;10(1):59-66.
Sussman WI, Mautner K, Malanga G. The role of rehabilitation after regenerative and orthobiologic procedures for the treatment of tendinopathy: a systematic review. Regen Med. 2018;13(2):249-263.
Townsend C, Von Rickenbach KJ, Bailowitz Z, Gellhorn AC. Post-procedure protocols following platelet-rich plasma injections for tendinopathy: a systematic review. PM R. 2020;12(9):904-915.
Module 10—Orthobiologics as Orthopedic Surgical Adjuncts
Dancy ME, Marigi EM, Krych AJ, Werner BC, Camp CL. Impact of biologic augmentation on revision surgery rates after meniscus repair: a matched-cohort analysis of 3420 patients. Orthop J Sports Med. 2023;11(8):23259671231186990.
Forsythe B, Chahla J, Korrapati A, Lavoie-Gagne O, Forlenza E, Diaz CC, Chung CB, Bae WC, Bach BR, Cole B, Yanke AB, Vermal NN. Bone marrow aspirate concentrate augmentation may accelerate allograft ligamentization in anterior cruciate ligament reconstruction: a double-blinded randomized controlled trial. Arthroscopy. 2022;38(7):2255-2264. [Published correction appears in Arthroscopy. 2023 Jun;39(6):1595].
Schoch BS, Werner BC, Shapiro SA, Camp CL, Chalmers PN, Cancienne JM. Effect of bone marrow aspirate concentrate and platelet-rich plasma augmentation on the rate of revision rotator cuff repair. Orthop J Sports Med. 2022;10(11):23259671221127004.
Module 11—Research
Finnoff JT, Awan TM, Borg-Stein J, Harmon KG, Herman DC, Malanga GA, Master Z, Mautner KR, Shapiro SA. American Medical Society for Sports Medicine position statement: principles for the responsible use of regenerative medicine in sports medicine. Clin J Sport Med. 2021;31(6):530-541.
Shapiro SA, Master Z, Arthurs JR, Mautner K. Tiered approach to considering orthobiologics for patients with musculoskeletal conditions. Br J Sports Med. 2023;57(3):179-180.
Guyatt GH, Sackett DL, Cook DJ. Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1993 Dec 1;270(21):2598-601.
Murad MH, Montori VM, Ioannidis JP, Jaeschke R, Devereaux PJ, Prasad K, Neumann I, Carrasco-Labra A, Agoritsas T, Hatala R, Meade MO, Wyer P, Cook DJ, Guyatt G. How to read a systematic review and meta-analysis and apply the results to patient care: users' guides to the medical literature. JAMA. 2014 Jul;312(2):171-9.
Module 12—Regulation
Jang K, Berrigan WA, Mautner K. Regulatory considerations of orthobiologic procedures. Phys Med Rehabil Clin N Am. 2023 Feb;34(1):275-283.