This clinical trial is designed to evaluate whether a stepwise injection-based treatment approach can reduce pain and improve function in adults with joint hypermobility, connective tissue laxity, and joint instability.

Joint hypermobility occurs when joints move beyond their normal range, often because of looser connective tissue. For some patients, this can contribute to chronic pain, recurrent instability, reduced function, and disability. This study focuses on adults with hypermobile Ehlers-Danlos syndrome (hEDS), hypermobility spectrum disorder (HSD), or joint instability after injury who have already completed physical therapy without adequate relief.

The main question this study aims to answer is whether the first treatment step, dextrose prolotherapy, can reduce pain by 40% or more two weeks after the second injection.

Participants will receive treatment in a step-by-step sequence, based on their response:

Step 1: Dextrose prolotherapy A dextrose-based injection used to stimulate a healing response in ligament, tendon, or joint-supporting tissue.

Step 2: Platelet-rich plasma (PRP) An injection prepared from the participant's own blood, designed to support tissue repair and recovery.

Step 3: Doxycycline injections A low-dose injectable treatment used in this study to help protect joint-supporting tissue. It is not being used to treat infection.

Alternative option: Hyaluronic acid injections An injection into the joint that may be offered if the earlier treatment steps do not provide enough improvement.

Each treatment step begins with two injections, given approximately two weeks apart. If a participant improves by 40% or more, they may continue with that treatment pathway. If they do not improve enough, they may be offered the next step in the study.

Participants will be followed for up to 12 months, with study visits used to monitor pain, function, treatment response, and safety.

This is a prospective, open-label, single-arm, step-care interventional study evaluating a structured regenerative medicine treatment protocol for adults with symptomatic joint hypermobility or instability who have failed conservative therapy including physical therapy.

All eligible participants begin with dextrose prolotherapy (20% final concentration). Response is assessed at 2 weeks after the second injection using the Global Percentage of Improvement (GPI) scale. Participants who improve by 40% or more continue with that treatment. Those who do not improve enough are offered the next treatment in the sequence.

The step-care sequence is:

Phase 1: Dextrose prolotherapy (20% dextrose with local anesthetic) Phase 2: Autologous platelet-rich plasma (PRP) prolotherapy Phase 3: Investigational injectable doxycycline hyclate prolotherapy (10 mg/mL; 5-25 mg per joint site; maximum 100 mg per session) Alternative pathway: Visco-3 hyaluronic acid viscosupplementation (FDA-approved for knee osteoarthritis; off-label use in other joints disclosed in consent)

Each phase follows the same cycle: 2 injections approximately 2 weeks apart, followed by a decision point at 2 weeks after the second injection. The dextrose phase decision point is the study primary endpoint.

Outcome measures collected include the Brief Pain Inventory (BPI), Global Percentage of Improvement (GPI), and region-appropriate joint-specific functional measures (DASH for upper extremity, KOOS for knee, LEFS for lower extremity, ODI for spine). Long-term follow-up occurs at 3, 6, and 12 months.

Safety is monitored continuously. An Independent Medical Monitor reviews all serious adverse events. The injectable doxycycline use is investigational; an IND exemption determination request has been submitted to the FDA. Enrollment into the doxycycline phase will not begin until the FDA determination is received and IRB approval is in place.

The study is investigator-initiated with no external funding. It is conducted at a single site - Manhattan Pain Medicine, New York, NY.

Inclusion Criteria:

• Adults age 18 years or older, any gender.

• Symptomatic joint hypermobility or instability attributable to one of the following:

  1. hEDS diagnosed using the 2017 International Classification of the Ehlers-Danlos Syndromes diagnostic criteria;
  2. HSD classified using the 2017 framework (generalized, peripheral, localized, or historical HSD) with Beighton scoring; or
  3. post-traumatic joint instability with ligamentous injury documented by examination and/or imaging.

• Objective evidence of instability or clinically relevant hypermobility at one or more target joints, defined as at least one of:

  1. a positive joint-specific instability provocation test on standardized physical examination;
  2. generalized hypermobility (Beighton score ≥ 5/9 for adults) or documented joint-specific hypermobility at the target joint; or
  3. imaging evidence of ligamentous laxity or injury at the target joint (dynamic ultrasound, stress radiograph, or MRI).

• Pain attributable to the target joint for at least 3 months.

• Baseline pain score of 4 or greater on a 0-10 numeric rating scale.

• Failure of conservative treatment, including at least 6 weeks of physical therapy directed at the affected joint(s).

• Not currently using NSAIDs and willing to avoid NSAIDs during the active treatment period, when clinically appropriate.

• Able to provide informed consent and to comply with study procedures and follow-up.

Additional eligibility for the Hyaluronic Acid (HA) alternative pathway - a participant may enter the HA pathway if ALL of the following apply, in addition to the inclusion criteria above:

• Has completed at least one regenerative medicine phase (dextrose, PRP, or doxycycline) and either

  1. was classified as an inadequate responder at the phase decision point (GPI < 40%) and declined further regenerative rotation,
  2. completed all available regenerative phases without adequate response, or
  3. experienced an adverse reaction during a regenerative phase that, in the investigator's judgment, contraindicates further regenerative treatment.

• A minimum waiting period of 4 weeks has elapsed since the last regenerative medicine treatment attempted, to allow resolution of post-injection effects before HA administration.

• The target joint(s) have clinical or imaging features amenable to HA viscosupplementation (e.g., articular/osteoarthritic pain component identifiable on examination or imaging).

• No contraindication to HA (see Exclusion Criteria).

Exclusion Criteria:

• Impaired decision-making capacity that precludes valid informed consent.
• Active local or systemic infection.
• Known allergy or contraindication to study injections, local anesthetics, iodinated contrast (if fluoroscopy is planned), or required procedural materials.
• Known hypersensitivity or intolerance to tetracycline-class antibiotics, including doxycycline (relevant to the doxycycline treatment phase).
• Mast cell activation syndrome (MCAS) or other mast cell disorder that, in the investigator's judgment, elevates the risk of injection-related hypersensitivity or systemic reactions.
• Active autoimmune or systemic inflammatory connective-tissue disease that, in the investigator's judgment, may confound the response to regenerative treatment or increase procedural risk.
• Known hypersensitivity to sodium hyaluronate or to the specific HA product to be used (Visco-3); active skin disease or infection over the planned injection site; venous or lymphatic stasis in the limb of the planned injection.
• Active malignancy or anticancer treatment within the prior 12 months; a prior malignancy in documented remission may be enrolled at the investigator's discretion with documented rationale.
• Uncontrolled diabetes mellitus, defined as HbA1c ≥ 8.5% on the most recent value within the prior 3 months; the investigator may also exclude for other objectively documented diabetes-related procedural or healing risk.
• Prior joint replacement at the target joint.
• Planned surgery during study participation.
• Corticosteroid injection to the target joint(s) within the prior 6 weeks.
• Concurrent enrollment in another interventional study for the same pain condition.
• Active litigation or disability claim related to the target condition (to limit secondary-gain confounding of self-reported outcomes).
• Pregnancy, or unwillingness to undergo pregnancy testing when fluoroscopy is planned (persons of childbearing potential).
• Inability to comply with study procedures or follow-up.

This is a single-site, investigator-initiated feasibility study with no external funding and no data sharing agreement in place. Individual participant data (IPD) will not be shared with other researchers. All participants are assigned unique study ID numbers and their data are maintained under HIPAA-compliant privacy protections at Manhattan Pain Medicine. Aggregate de-identified findings will be reported through peer-reviewed publication. Future sharing of de-identified data may be considered on a case-by-case basis consistent with the IRB-approved consent form and applicable privacy regulations.