Continuing Education Activity

Regenerative medicine is an evolving field that applies biological science principles to promote tissue repair and functional restoration through organ, cell, or tissue-based therapies. While some interventions, such as viscosupplementation for knee osteoarthritis, have received FDA clearance for specific indications, many biologic therapies—including platelet-rich plasma (PRP), prolotherapy, and cell-based treatments—remain investigational or are used off-label. This course reviews the major therapeutic avenues of regenerative therapy in pain, including viscosupplementation, prolotherapy, PRP, and mesenchymal stromal cell–based therapies, each differing in mechanism, regulatory status, indications, and evidence base, as well as the clinical applications of these modalities, which are increasingly used to manage musculoskeletal conditions such as osteoarthritis, tendinopathies, ligament injuries, and select spine disorders.

This activity explores regenerative medicine pain therapies, emphasizing indications, mechanisms of action, preparation techniques, contraindications, safety considerations, and current clinical evidence. Participants will also gain an understanding of patient selection, counseling regarding risks and benefits, understanding regulatory and ethical considerations, and integrating regenerative pain therapies into interprofessional, patient-centered musculoskeletal care. This activity for healthcare professionals is designed to enhance the learner's competence in the application of regenerative therapy in pain, recommended delivery techniques, safety considerations, and implementing an appropriate interprofessional approach when treating patients with musculoskeletal conditions. 

Objectives:

• Identify the indications for regenerative pain medicine therapies.
• Apply recommended techniques of regenerative pain medicine therapies.
• Assess the most common therapy-specific complications associated with regenerative pain medicine.
• Apply interprofessional team strategies to improve care coordination and outcomes in patients receiving regenerative pain medicine treatment.

Introduction

Regenerative medicine has been in existence for many decades; several products and devices used within regenerative medicine have received United States Food and Drug Administration (FDA) clearance or approval for specific indications (eg, viscosupplementation for knee osteoarthritis), whereas most biologic therapies, eg, platelet-rich plasma (PRP) and cell-based treatments, remain investigational or off-label. Regenerative medicine is a field that applies biological principles to promote regeneration by delivering or replacing organs, cells, or tissues to restore diseased or damaged tissues and whole organs.[1] Viscosupplementation, PRP, stem cells, and prolotherapy are 4 main avenues of therapy in regenerative medicine.

Viscosupplementation

Injection of hyaluronic acid into the intra-articular space restores the viscosity and elasticity of synovial fluid affected by osteoarthritis.[2][3] Hyaluronic acid plays a critical role in shock absorption, joint lubrication, and maintenance of synovial fluid viscoelasticity. Although viscosupplementation does not directly regenerate articular cartilage, clinical practice often categorizes this therapy as a regenerative or biologic treatment because of its capacity to favorably modify the joint microenvironment.

Prolotherapy

Prolotherapy involves the injection of an irritant solution, most commonly hypertonic dextrose, to trigger a controlled inflammatory response that promotes fibroblast activation, collagen deposition, and strengthening of connective tissues.[4][5] This approach differs from other regenerative medicine techniques because the injectate lacks a biological component. Hypertonic dextrose serves as the primary agent used in prolotherapy and stimulates the body’s inflammatory cascade to initiate tissue repair processes.[6][5]

Platelet-Rich Plasma

Platelet-rich plasma releases bioactive proteins that stimulate the body’s ability to heal due to its regenerative, analgesic, and anti-inflammatory properties.

Mesenchymal Stromal Cells

According to the International Society for Cellular Therapy, the criteria for cells to be considered mesenchymal stromal cells include:

• Plastic adherence when maintained under standard culture
• Must express CD105, CD73, and CD90, and lack expression of hematopoietic and endothelial markers including CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR [7]
• Ability to differentiate into osteoblasts, chondroblasts, and adipocytes in vitro [8]

Indications

Viscosupplementation

Viscosupplementation holds FDA approval or clearance for the treatment of knee osteoarthritis.[9][10] Clinical use often follows failure of conservative therapies, including physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and joint aspiration. Older adult patients commonly benefit from this intervention. Younger patients with mild to moderate knee osteoarthritis who exhibit persistent clinical symptoms and wish to defer invasive surgical intervention also represent appropriate candidates.

Clinical utility extends to patients with Kellgren–Lawrence stages 1 to 3. Patients with stage 4 osteoarthritis who seek to delay total knee replacement may receive viscosupplementation for short-term symptomatic relief, although the predictability of benefit declines with advanced disease. This therapy also serves as an alternative or adjunctive option for patients with multiple comorbidities and polypharmacy to reduce exposure to antiarthritic medications. Consideration applies to patients unable to use nonsteroidal anti-inflammatory drugs because of gastrointestinal disease, renal disease, or unstable hypertension.

Prolotherapy

Indications for prolotherapy include osteoarthritis, degenerative syndromes, myofascial pain syndrome, spine and pelvic pain, refractory tendinopathies, and plantar fasciitis.[4][5][6] Preclinical studies demonstrate that hypertonic dextrose promotes direct intracellular expression of growth factors within tenocytes and fibroblasts.[11]

The therapeutic goal of prolotherapy is to stimulate endogenous healing within the joint to improve the tensile strength of stabilizing structures. Hypertonic dextrose induces cellular dehydration at the injection site, producing localized tissue trauma that recruits granulocytes and macrophages to facilitate repair. Studies involving human fibroblasts and chondrocytes show that elevated extracellular dextrose concentrations enhance cellular proliferation and production of essential growth factors for tissue repair. These mediators upregulate type 1 and type 3 collagen expression in tenocytes, supporting the growth and repair of tendons, ligaments, and cartilage.[6][11]

Plasma-Rich Plasma

PRP has been investigated and used for the treatment of osteoarthritis, ligament injuries, meniscal injuries, muscle injuries, tendinopathy, and spine disorders. Numerous preparation methods exist, resulting in variability that precludes a universal classification system. Current practice primarily categorizes PRP into 2 types: leukocyte-rich and leukocyte-poor. Leukocyte-rich formulations contain neutrophil concentrations above baseline and are associated with proinflammatory effects.[12] Although select data suggest potential benefit of leukocyte-rich preparations for certain tendinopathies, neutrophil-rich formulations may exacerbate inflammation in other conditions, contributing to heterogeneous clinical outcomes. Leukocyte-poor PRP demonstrates greater effectiveness for osteoarthritis.[13][14]

Scientific interest in PRP reflects its regenerative, analgesic, antimicrobial, and anti-inflammatory properties.[15] Platelets represent anucleate cytoplasmic fragments derived from megakaryocytes. Early wound healing phases involve platelet activation, adhesion, and aggregation. Subsequent degranulation of platelet alpha granules releases multiple growth factors and cytokines. PRP contains high concentrations of mediators involved in cell proliferation, tissue remodeling, enhanced mitogenesis, extracellular matrix synthesis, mesenchymal differentiation, and inflammation suppression, all of which contribute to wound healing.[16] Delivery of supraphysiologic concentrations of these bioactive molecules to injured tissue supports repair, remodeling, and regeneration.[17]

Mesenchymal Stromal Cells

Clinical indications for mesenchymal stromal cells vary depending on the source of harvest. Potential sources include bone marrow, adipose tissue, umbilical cord, muscle, peripheral blood, and amniotic fluid.[18] Bone marrow–derived mesenchymal stromal cells have undergone investigation for the treatment of osteonecrosis of the femoral head and shoulder osteoarthritis, with additional applications in rotator cuff and patellar tendinopathy. Adipose-derived mesenchymal stromal cells support treatment of lateral epicondylitis and Achilles tendinopathy. Amniotic-derived mesenchymal stromal cell–based products have undergone investigation for plantar fasciitis, although supporting clinical evidence remains limited.

Common Regenerative and Biologic Therapies in Musculoskeletal Pain

Multiple regenerative and orthobiologic therapies have been developed to modulate healing, repair, or inflammation in musculoskeletal tissues (see Table. Overview of Common Regenerative and Biologic Therapies in Musculoskeletal Pain)

Table

Table. Overview of Common Regenerative and Biologic Therapies in Musculoskeletal Pain.

Contraindications

Contraindications vary depending on the regenerative medicine method employed. General contraindications include active infection, either systemic or at the injection site, and coagulopathy.[19] Therapy-specific contraindications include hypersensitivity to hyaluronan products, particularly avian protein allergy, as some formulations are derived from rooster combs.[20][21] Cell-based therapies should be avoided in patients with active malignancy, particularly hematologic cancers, or in immunocompromised states.[22] 

Absolute contraindications of PRP administrations are severe thrombocytopenia, platelet dysfunction syndromes, and hemodynamic instability. Relative contraindications include active malignancy, severe anemia, NSAID use within 48 hours of the procedure, corticosteroid intra-articular injection of the knee within 1 month, or systemic steroid use within 2 weeks.[23] Absolute contraindications for prolotherapy include active infection, uncontrolled systemic inflammatory or autoimmune disease, known allergy to the injectate, or ongoing immunosuppressive therapy.[5]

Technique or Treatment

Viscosupplementation

Hyaluronic acid injection can be done in the office and is usually a quick procedure, typically performed under local anesthesia. Hyaluronic acid (injected volumes typically range from 2 to 6 mL, depending on the specific product formulation) should be injected directly into the joint capsule to be effective. Patients are advised to avoid excessive weight-bearing in the first 48 hours after the injections. Physical therapy is recommended afterward to improve functioning and range of motion.

Prolotherapy

The most commonly used agent for prolotherapy is dextrose; concentrations greater than 10% are considered inflammatory, while those lower than 10% are considered noninflammatory.[6] Dextrose solutions are FDA-approved for intravenous use but are used off-label for prolotherapy injections.

Plasma-rich platelets

PRP is obtained from autologous blood using single- or double-spin centrifugation, depending on the preparation system. The first step separates whole blood into platelet and cell fractions. In double-spin preparation methods, the second centrifugation step concentrates platelets by separating them from platelet-poor plasma. The platelet concentration in PRP typically ranges from approximately 2 to 5 times baseline whole-blood levels, depending on the preparation method. It is usually activated by calcium chloride, bovine thrombin, or autologous thrombin.

Mesenchymal stem cells

Typically, 30 to 60 mL of bone marrow aspirate is collected and processed to yield approximately 3 to 10 mL of bone marrow aspirate concentrate, depending on the processing system used. MSCs are multipotent and can be harvested from several tissues, eg, bone marrow, adipocytes, and amniotic tissue. The iliac crest is the most common site for bone marrow aspiration, typically performed under local anesthesia with or without sedation due to procedural discomfort.[22]

Complications

Regenerative therapy is generally well tolerated. The most common adverse effects are injection-site swelling, pain or soreness, and stiffness.[24][25] Therapy-specific complications include hemarthrosis, septic arthritis, and rare hypersensitivity reactions, depending on the specific therapy and injection technique. However, these more severe adverse effects are extremely rare. Cell-based therapies are generally well tolerated in published studies, although high-quality safety and efficacy data remain limited. Other reported adverse effects include low-grade fevers.[26][27] 

Complications of PRP injections are extremely rare. The risk of allergic or immune reaction is extremely low, given the autologous nature of PRP. The most common adverse effects include transient pain, swelling, or soreness at the injection site. Historically, bovine thrombin has been used as an activator in some commercially available PRP kits; however, it carries a potential risk of coagulopathy. When bovine thrombin is used as an activator, a risk of antibody formation against bovine factor V and bovine thrombin is noted. When the factor V level decreases below 30%, the risk of hemorrhage increases in patients; for this reason, autologous thrombin or recombinant human thrombin is available as an activator.[28][29] Rare adverse effects of prolotherapy reported include sleep disturbance, radicular pain, irregular menstruation, and lumbar puncture headache. Other even rarer effects reported include meningitis, adhesive arachnoiditis, and encephalomyelitis.[30][31]

Clinical Significance

Multiple systematic reviews and meta-analyses suggest that intra-articular knee hyaluronic acid injections are generally safe, decrease pain, and may provide modest pain relief and functional improvement in some patients.[32][33][34][35] A Cochrane database review of 76 trials concluded that hyaluronic acid injections are generally safe, with small to moderate and variable clinical benefits for knee osteoarthritis.[36] This review showed improved pain and functional status for up to 26 weeks. Prolotherapy offers a cost-effective and conservative approach to the treatment of chronic pain. Prolotherapy demonstrates moderate evidence for efficacy in reducing pain and improving function in chronic musculoskeletal conditions, particularly tendinopathies and osteoarthritis, especially in patients refractory to standard conservative treatments.[37][21] Further studies are needed to determine a standard protocol for prolotherapy injections.

PRP has been utilized and investigated for conditions, eg, osteoarthritis, tendinopathy, ligament and muscle injuries, and certain spine disorders. Multiple randomized controlled trials, systematic reviews, and meta-analyses have supported the use of PRP in the management of chronic tendinopathy. However, variations in PRP preparation methods, postintervention rehabilitation protocols, and anatomic sites translate into differences in study outcomes.[38][39][40] Several studies suggest that leukocyte-poor PRP may improve pain and functional outcomes in patients with knee osteoarthritis. Some studies have shown symptom relief for up to 1 year after PRP injection for knee osteoarthritis. Patients in earlier stages of knee osteoarthritis may benefit more from PRP than HA injections. Current evidence has not consistently demonstrated a significant clinical benefit of PRP in treating hip osteoarthritis.[41][42]

Many studies have examined the efficacy of PRP for the treatment of ligament injuries. Some studies suggest that PRP may have a potential role in anterior cruciate ligament reconstruction outcomes, although evidence remains limited and heterogeneous.[43] Even though PRP has been used in clinical practice as a nonoperative treatment for ligament injuries, a higher level of literature is scarce to prove any benefit or safety profile of PRP for ligament injuries.[44]

Low back pain is very prevalent among adults in the United States and is one of the most common debilitating outpatient complaints.[45] Several randomized controlled trials and meta-analyses suggest that intradiscal PRP injections may result in pain reduction and functional improvement in selected patients with discogenic low back pain compared to baseline and control interventions, with effects sustained for up to 1 year and, in some studies, as long as 5 to 9 years postinjection for discogenic low back pain.[46][47] Recent in vitro studies have shown that PRP stimulates proliferation and matrix synthesis in the annulus fibrosus and nucleus pulposus.[48][49] PRP also exhibits anti-inflammatory effects on nucleus pulposus cells.[50][51][52] 

Despite promising in vitro results, few high-quality clinical studies have evaluated the role of PRP in treating low back pain.[53][54] Multiple small-scale studies suggest that PRP appears to be safe and beneficial in treating selected cases of discogenic and facet joint-related back pain. Still, more high-quality studies are needed to prove the efficacy of PRP for spine disorders.[55][56][57] A review of studies on the use of bone marrow concentrate for treating musculoskeletal disorders of the knee found level II evidence for its use in treating knee osteoarthritis.[58]

Enhancing Healthcare Team Outcomes

Regenerative medicine encompasses a group of biologic and minimally invasive therapies designed to support tissue repair and symptom management in musculoskeletal conditions. Common approaches include viscosupplementation, prolotherapy, platelet-rich plasma, and mesenchymal stromal cell–based therapies. Viscosupplementation holds FDA approval for knee osteoarthritis and modifies the joint microenvironment to improve lubrication and shock absorption. Prolotherapy, platelet-rich plasma, and cell-based therapies remain investigational or off-label for many indications but show potential benefits in osteoarthritis, tendinopathies, ligament injuries, and select spine disorders. Clinical outcomes vary due to heterogeneous protocols, patient selection, and evolving evidence, underscoring the need for an informed, evidence-based approach.

Physicians, general practitioners, and advanced practitioners require skills in patient selection, informed consent, procedural technique, and interpretation of emerging evidence. Nurses support patient education, periprocedural care, and monitoring for adverse effects, while pharmacists contribute by reviewing medications, identifying contraindications, and minimizing drug interactions. Effective interprofessional communication ensures shared understanding of treatment goals, risks, and follow-up plans. Coordinated care among health professionals promotes patient safety, optimizes outcomes, and supports consistent, patient-centered integration of regenerative therapies into clinical practice.

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Disclosure: Neil Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Das declares no relevant financial relationships with ineligible companies.

Disclosure: Tabish Aijaz declares no relevant financial relationships with ineligible companies.