This scoping review was conducted in accordance with the PRISMA-ScR guidelines [19] and the methodological framework proposed by Arksey and O’Malley [20] as enhanced by Levac et al. [21]. The review protocol was registered prospectively on the Open Science Framework (OSF registration ID: https://osf.io/e8mqc).

The following research questions guided this review: (1) What are the different applications of atelocollagen that have been investigated in spine surgery? (2) What preclinical evidence exists for atelocollagen use in spinal tissue regeneration? (3) What clinical evidence exists for the safety and efficacy of atelocollagen in spine surgery patients? (4) What formulations, delivery methods, and dosages have been investigated? (5) What are the current knowledge gaps and future research needs?

The Population-Concept-Context framework was used to define eligibility. The population included both preclinical models (in vitro cell cultures and animal models) and clinical populations (patients with spinal disorders or undergoing spine surgery). The concept was the use of atelocollagen, in any form, for any spine-related application. The context encompassed all settings including laboratory, preclinical, and clinical environments without restriction on geographic location or publication date.

Inclusion criteria were: (1) original research investigating atelocollagen (explicitly named) in any spine-related application, (2) study types including in vitro, animal, and clinical studies of any design, (3) published in peer-reviewed journals, and (4) available as full text or with sufficient abstract data. Exclusion criteria were: (1) studies using generic collagen without specifying atelocollagen, (2) review articles, editorials, conference abstracts, and letters, (3) studies focused exclusively on nonspinal orthopedic applications, and (4) duplicate publications.

A systematic search was conducted across 5 electronic databases from inception through February 2026: PubMed/MEDLINE, Scopus, Web of Science (SCIE and ESCI), Embase, and the Cochrane Library. Google Scholar was searched supplementarily (first 200 results). Reference lists of included studies and relevant review articles were hand-searched for additional eligible records.

The search strategy combined 2 concept blocks using Boolean operators. Block 1 (atelocollagen) included: “atelocollagen” OR “atelo-collagen” OR “pepsin-solubilized collagen” OR “pepsin-treated collagen” OR “telopeptide-poor collagen” OR “telopeptide-free collagen.” Block 2 (spine) included: “spine” OR “spinal” OR “intervertebral disc” OR “nucleus pulposus” OR “annulus fibrosus” OR “spinal fusion” OR “spinal cord” OR “lumbar” OR “cervical” OR “thoracic” OR “vertebral” OR “paraspinal” OR “multifidus” OR “disc degeneration” OR “spondylodesis” OR “interbody fusion.” The final search combined Block 1 AND Block 2 with no filters applied.

All retrieved records were imported into reference management software and deduplicated. Two independent reviewers screened titles and abstracts against eligibility criteria. A calibration exercise using the first 50 records was conducted to ensure interrater reliability (target Cohen kappa > 0.80). Full texts of potentially eligible studies were retrieved and independently assessed. Disagreements at any stage were resolved through discussion with a third reviewer. A PRISMA-ScR flow diagram was generated to document the selection process (Figure 1).

A standardized data charting form was developed and pilot-tested on the first 5 included studies. The following variables were extracted: study details (first author, year, country, journal, study design, funding), study type (in vitro, animal, clinical), population characteristics, atelocollagen specifications (type, form, concentration, commercial product, delivery method, combination agents), spine application domain, comparator details, outcomes measured, key findings with statistical significance, and reported limitations.

Quality assessment was performed using the following tools: Cochrane Risk of Bias 2.0 for randomized controlled trials, Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized clinical studies, JBI Critical Appraisal Checklist for case series, Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) Risk of Bias Tool for animal studies, and a modified OHAT (Office of Health Assessment and Translation) tool for in vitro studies. Two reviewers independently assessed each study, with discrepancies resolved by consensus.

Given the anticipated heterogeneity in study designs, populations, interventions, and outcomes, a narrative synthesis approach was adopted. Results were organized thematically by application domain: (A) IVD regeneration, (B) spinal fusion scaffolds, (C) paraspinal muscle preservation, and (D) SCI repair.

The database search yielded 247 records (PubMed: 45, Scopus: 62, Web of Science: 48, Embase: 55, Cochrane Library: 12, Google Scholar: 25). After removal of 98 duplicates, 149 unique records were screened by title and abstract, of which 52 proceeded to full-text review. After full-text assessment, 35 studies were excluded for the following reasons: not specifically atelocollagen (n=14), not a spine application (n=8), review articles or editorials (n=7), conference abstracts without full text (n=4), and duplicate cohort data (n=2). Ultimately, 17 studies met all inclusion criteria and were included in the final synthesis (Figure 1). The included studies were published between 2003 and 2024. Studies originated predominantly from Japan (n=8) and South Korea (n=5), with additional contributions from Ireland (n=1), Poland (n=1), the United States (n=1), and Spain (n=1). Study designs included in vitro investigations (n=5), animal studies (n=6), mixed in vitro and animal studies (n=4), and clinical studies (n=2). Table 1 presents the summary characteristics of key included studies.

The potential of atelocollagen-based scaffolds as bone graft substitutes for spinal fusion has been explored in preclinical studies. Ryan et al. [28] fabricated a novel composite scaffold using self-assembling atelocollagen combined with nano-hydroxyapatite and chondroitin sulfate, cross-linked by microbial transglutaminase. The scaffold exhibited appropriate mechanical stiffness, suitable pore size for MSC adhesion and growth, low cytotoxicity, and a slow degradation profile conducive to sustained bone formation. Gene expression analysis demonstrated significant upregulation of osteogenic markers including BMP-2, osteocalcin, RUNX2, and TGF-β1 in human MSCs seeded on the scaffold. The same group also demonstrated the effect of different hydroxyapatite incorporation methods on structural and biological properties of porous atelocollagen scaffolds for bone repair [28].

Additionally, atelocollagen sponge scaffolds have been investigated as carriers for recombinant human BMP-2 delivery in spinal fusion models. These scaffolds, produced through freeze-drying and crosslinking of self-assembled atelocollagen fibrils, demonstrated enhanced osteogenic differentiation and improved bone formation in vitro compared to unloaded controls [29]. This approach addresses a recognized clinical need, as the collagen sponge carrier used in commercially available BMP-2 delivery systems has been associated with complications at supraphysiologic doses [30].

The most clinically advanced application of atelocollagen in spine surgery involves intramuscular injection for the prevention or treatment of paraspinal muscle atrophy, with 2 clinical studies identified (Table 1).

Park et al. [14] conducted a pilot study of 118 patients who underwent single-level posterior lumbar interbody fusion (PLIF). In the study group (n=60), 3 mL of gel-type 3% atelocollagen solution was injected into the multifidus muscle during wound closure. The primary outcomes demonstrated that the reduction in postoperative paraspinal muscle density and cross-sectional area (CSA) on computed tomography was significantly lower in the atelocollagen group compared to the control group (n=58). Furthermore, serum levels of creatine phosphokinase and C-reactive protein were significantly lower postoperatively in the atelocollagen group. Visual analogue scale scores for back pain were numerically lower in the study group but did not reach statistical significance. No major procedure-related complications were observed.

Kim and Gil [13] reported a larger retrospective study of 608 consecutive patients with chronic low back pain treated with lumbar epidural steroid injection with or without additional paraspinal intramuscular atelocollagen injection. The atelocollagen group (n=268) received injections into the psoas, erector spinae, and multifidus muscles under fluoroscopic guidance, using a mixture of 1-mL atelocollagen (CollaShield, DALIM TISSEN Corp., Korea) with 9 mL of 0.3% mepivacaine. At 3 months follow-up, both the Numerical Rating Scale and Oswestry Disability Index were significantly more improved in the atelocollagen group compared to the epidural steroid injection-only group (p<0.05). The treatment success rate was also significantly higher in the atelocollagen group. No serious adverse events related to the atelocollagen injection were reported.

The application of atelocollagen in SCI repair represents a nascent but promising area with 4 studies identified. Fortuna et al. [31] investigated 3D collagen scaffolds derived from pepsin-solubilized atelocollagen for culturing olfactory ensheathing cells (OECs) intended for transplantation into the damaged spinal cord. These scaffolds provided structural support for cell engraftment while permitting neurite extension through their porous architecture, with OECs maintaining viability and phenotype throughout culture.

Onuma-Ukegawa et al. [18] demonstrated that bone marrow stromal cells combined with honeycomb collagen sponges, originally developed for IVD tissue engineering using the ACHMS platform, facilitated neurite elongation in vitro and supported neural restoration in hemisected rat spinal cord models. At 8 weeks postoperatively, animals receiving the scaffold-cell composite showed improved locomotor scores and enhanced axonal growth through the lesion site compared to controls.

Additional preclinical studies have demonstrated that atelocollagen-based 3D scaffolds support neural progenitor cell survival and differentiation when transplanted into the SCI milieu. The favorable biocompatibility and tunable degradation rate of atelocollagen make it a suitable candidate for neural tissue engineering, where prolonged scaffold presence is necessary to guide axonal regeneration across the injury gap.

No randomized controlled trials were identified among the included studies. The 2 clinical studies [13,14] were assessed using the ROBINS-I tool, with both rated as having moderate risk of bias primarily due to their retrospective design and potential for confounding variables. The absence of blinding and randomization was a notable limitation. Preclinical animal studies assessed using the SYRCLE tool generally showed unclear risk of bias for allocation concealment and blinding of caregivers, though most adequately described their experimental protocols and outcome measurements. In vitro studies were rated as moderate quality overall, with most providing adequate methodological descriptions but limited reporting on replication and blinding of outcome assessors (Table 2).

The strongest preclinical evidence supports the use of atelocollagen as a cell carrier and scaffold for IVD regeneration. The pioneering work by Sakai et al. [16,22] established that atelocollagen gel provides a favorable 3D microenvironment for MSC survival, proliferation, and differentiation within the harsh disc environment. The capacity of atelocollagen to self-assemble into a fibrous meshwork in situ represents a significant practical advantage over other hydrogel carriers, as it enables injectable delivery while providing sustained structural support [32]. Moreover, the enhancement of proteoglycan synthesis observed with atelocollagen-based scaffolds combined with growth factor gene therapy [24] suggests that this biomaterial may serve as an effective platform for multimodal regenerative approaches.

The paraspinal muscle preservation domain represents the most clinically translated application, with 2 studies enrolling a combined 726 patients [13,14]. Both studies demonstrated a favorable safety profile with no serious adverse events, and the larger study by Kim and Gil [13] showed statistically significant improvements in pain and functional outcomes at 3 months. The biological rationale is compelling: paraspinal muscle atrophy is a well-documented consequence of posterior spinal surgery that contributes to chronic postoperative pain and disability [4,33]. By providing a collagenous scaffold that may promote myofiber regeneration and reduce scar tissue formation at the surgical site, atelocollagen injection addresses a recognized unmet clinical need.

The spinal fusion scaffold domain, while supported by promising preclinical data, has not yet advanced to clinical testing. The composite scaffold developed by Ryan et al. [28] combining atelocollagen with nano-hydroxyapatite and glycosaminoglycans represents an innovative biomimetic approach that mimics the composition of native bone tissue. Given the ongoing limitations of current bone graft substitutes and the well-documented complications associated with supraphysiologic BMP-2 dosing [30], atelocollagen-based fusion scaffolds merit further investigation.

A critical comparison with established biologics reveals both the potential and current limitations of atelocollagen. Recombinant human BMP-2, the most widely studied biologic in spinal fusion, has demonstrated robust efficacy in multiple randomized controlled trials (RCTs) and is U.S. Food and Drug Administration-approved for anterior lumbar interbody fusion; however, its clinical use has been tempered by well-documented complications at supraphysiologic doses, including heterotopic ossification, osteolysis, radiculitis, and potential carcinogenicity [30]. Atelocollagen-based scaffolds may offer an alternative delivery platform that permits lower, more physiologic BMP-2 dosing through sustained release from the collagen matrix, though this hypothesis remains untested in clinical trials. PRP, another commonly used biologic, suffers from significant batch-to-batch variability depending on preparation method, centrifugation protocol, and patient-specific factors [34]. In contrast, atelocollagen can be manufactured under standardized industrial conditions with consistent molecular weight, purity, and concentration, offering superior quality control. However, PRP has the practical advantage of autologous point-of-care preparation, whereas atelocollagen requires commercial sourcing. Regarding MSC-based therapies for disc regeneration, atelocollagen addresses a key translational barrier: cell retention. Direct injection of MSCs into the disc space without a carrier results in significant cell leakage, potentially inducing osteophyte formation [35]. Atelocollagen’s capacity for in situ gelation provides a 3D matrix that improves cell retention and viability. From a regulatory perspective, atelocollagen products currently hold regulatory approval in South Korea (CollaShield, DALIM TISSEN Corp.) for soft tissue applications, but no spine-specific regulatory approval exists in any jurisdiction. This contrasts with BMP-2, which has undergone the full regulatory pathway for spinal indications. Cost data are limited; however, atelocollagen injection as performed in the 2 clinical studies [13,14] required only 1–3 mL of commercially available product, suggesting a substantially lower cost profile compared to BMP-2 products or autologous cell-based therapies that require ex vivo expansion.

A notable finding of this review is the geographic concentration of research. The overwhelming majority of studies originated from Japanese and South Korean research groups (13 of 17 studies), reflecting both the historical development of atelocollagen technology in East Asia and the availability of commercial products such as CollaShield (DALIM TISSEN Corp.) and Atelocollagen (Koken Co.). This geographic concentration has implications for the generalizability of findings and highlights the need for international collaborative research and multicenter studies to validate these results across diverse populations.

The methodological quality of the included studies represents a significant limitation. No RCTs were identified for any spine application. The 2 clinical studies were retrospective, single-center, and lacked blinding. Preclinical animal studies varied in their use of appropriate controls and blinding procedures. These limitations place the overall certainty of evidence at a low level, underscoring the need for higher-quality prospective studies.

Based on the available evidence, the most immediate clinical application of atelocollagen in spine surgery is intramuscular injection for paraspinal muscle preservation during or after posterior lumbar surgery. The target patient population would include individuals undergoing PLIF, transforaminal lumbar interbody fusion, or posterior lumbar decompression procedures, in whom iatrogenic paraspinal muscle damage is an expected consequence of the surgical approach. Patients at elevated risk for postoperative muscle atrophy—including those with preexisting sarcopenia, advanced age, multilevel procedures, or revision surgery—may derive the greatest benefit. The injection technique described in the included clinical studies is straightforward and requires minimal additional operative time: 1–3 mL of atelocollagen gel is injected directly into the multifidus muscle belly during wound closure [14], or percutaneously into the psoas, erector spinae, and multifidus muscles under fluoroscopic guidance in an outpatient setting [13]. This minimally invasive delivery method integrates readily into existing surgical workflows without requiring specialized equipment or training beyond standard fluoroscopy. For IVD regeneration, atelocollagen-MSC composites would be most applicable to patients with early-stage disc degeneration (Pfirrmann grades II–III) who have failed conservative management but have not yet developed end-stage collapse or instability requiring fusion. The injectable gel formulation allows percutaneous intradiscal delivery, consistent with current trends toward minimally invasive biological interventions for disc disease. However, this application remains entirely preclinical, and clinical translation will require resolution of several challenges including cell sourcing, regulatory approval for combination products, and establishment of standardized patient selection criteria.

A significant challenge in synthesizing the evidence is the considerable heterogeneity in atelocollagen formulations and delivery methods across the included studies. Atelocollagen has been utilized in at least 4 distinct physical forms: injectable gel (used in IVD regeneration and paraspinal muscle injection), freeze-dried sponge (used in spinal fusion scaffolds and SCI repair), honeycomb-shaped scaffold with membrane seal (the ACHMS platform for AF tissue engineering and SCI repair), and composite scaffolds incorporating hydroxyapatite and glycosaminoglycans (for spinal fusion). Concentrations ranged from 1% to 3%, and the collagen type varied between type I (most common) and type II (specifically for NP regeneration). Delivery methods included direct surgical implantation, intradiscal injection, intramuscular injection during wound closure, and percutaneous fluoroscopy-guided injection. This heterogeneity reflects the versatility of atelocollagen as a platform material but complicates cross-study comparisons and precludes definitive conclusions about optimal formulation parameters for any specific application. Standardization of atelocollagen preparation protocols, concentration, volume, and delivery method within each application domain will be essential for future comparative studies and eventual clinical translation (Table 3; Figure 2).

Several challenges must be addressed before atelocollagen can be broadly adopted in spine surgery. First, optimal dosing parameters have not been established for any application. Second, the long-term safety and durability of atelocollagen effects remain unknown, as the longest clinical follow-up reported was 3 months [13]. Third, standardized outcome measures need to be established to enable meaningful comparison across studies and facilitate future meta-analyses.

We propose the following research priorities: (1) multicenter, prospective, double-blinded RCTs evaluating intramuscular atelocollagen injection during lumbar fusion surgery, with primary outcomes of paraspinal muscle CSA on MRI at minimum 12-month follow-up; (2) phase I/II clinical trials of atelocollagen-MSC composite injection for early-stage IVD degeneration; (3) comparative effectiveness studies between atelocollagen-based and conventional collagen-based BMP-2 carriers for spinal fusion; and (4) international multi-site preclinical studies with standardized protocols (Table 4).

This review has several limitations. First, as a scoping review, no meta-analysis was performed. Second, the literature may be subject to publication bias favoring positive results. Third, the inclusion of studies in any language with an English abstract may have resulted in missing relevant non-English publications. Fourth, the heterogeneity of study designs, outcomes, and applications limits the ability to draw definitive conclusions about efficacy for any single application.